1 Ph.D. thesis. OSTEOPOROSIS IN MEN Odense Feb 2011 Morten Frost Endocrine Research Unit, Department of Endocrinology, Odense University Hospital Institute of Clinical Research, Faculty of Health Sciences, University of Southern Denmark 2 TABLE OF CONTENTS 1. ACKNOWLEDGEMENTS .......................................................................................................................................... 3 2. FINANCIAL DISCLOSURES ..................................................................................................................................... 4 3. SUPERVISORS ............................................................................................................................................................. 4 4. LIST OF PAPERS ......................................................................................................................................................... 5 5. ABBREVATIONS......................................................................................................................................................... 6 6. ENGLISH SUMMARY ................................................................................................................................................ 7 7. DANSK RESUMÉ ........................................................................................................................................................ 9 8. INTRODUCTION ..................................................................................................................................................... 11 9. AIMS ............................................................................................................................................................................ 12 10. DEFINITION OF OSTEOPOROSIS IN MEN .................................................................................................... 13 11. EPIDEMIOLOGY OF OSTEOPOROSIS IN MEN ............................................................................................. 14 12. EPIDEMIOLOGY OF FRACTURES IN MEN .................................................................................................... 15 13. PATHOGENESIS ..................................................................................................................................................... 20 14. PREVENTION ......................................................................................................................................................... 39 15. CONSEQUENCES OF FRACTURES ................................................................................................................... 42 16. PHARMACOLOGICAL THERAPHY.................................................................................................................... 43 17. CONCLUSION ......................................................................................................................................................... 48 18. PERSPECTIVES ....................................................................................................................................................... 50 19. APPENDICES ........................................................................................................................................................... 51 20. REFERENCES ......................................................................................................................................................... 58 21 VITAMIN D STATUS AND PTH IN YOUNG MEN: A CROSS-SECTIONAL STUDY ON ASSOCIATIONS WITH BONE MINERAL DENSITY, BODY COMPOSITION AND GLUCOSE METABOLISM .................... 76 22 OSTEOPOROSIS AND VERTEBRAL FRACTURES IN MEN AGED 60-74 YEARS ..................................... 98 23 RISK FACTORS FOR FRACTURE IN ELDERLY MEN. A POPULATION-BASED PROSPECTIVE STUDY........................................................................................................................................................................... 117 24 PATTERN OF USE OF DXA SCANS IN MEN. A CROSS-SECTIONAL, POPULATION-BASED STUDY ........................................................................................................................................................................................ 141 3 1. ACKNOWLEDGEMENT Above all, I would like to express my deepest appreciation to the staff at the osteoporosis clinic. Your company and talents are second to none, and it has been a tremendous pleasure to work together with you all. My fellow students are sincerely thanked for their excellent company and the many enjoyable times at home and abroad. The people who designed and conducted the male cohort studies AGSY and OAS are greatly thanked for their collaboration and willingness to share their data. I would like to express my profound gratitude to my supervisors - Marianne, Bo and Kim. Thankyou for your kind support and the introduction to the intriguing world of endocrine research. It has been an enormous pleasure to learn from your immense knowledge of endocrinology and in particular to discuss politics, food, coffee, German movies and English trains and many, many other things. For that I’m most grateful. Someone once told me that supervision was no different from managing a forest: you drop a few tree seeds and then contemplate the growth-potential of those that germinate. Regrettably, there was no indication of when the trees would be axed or whether the fate of the wood would be cardboard or something slightly more notable. In that framework, my main supervisor - Kim Brixen - also manages woodland, but his generous and constant support allows a variety of trees to grow without any restrictions (or fear of the axe). Your enthusiastic pursuit of challenges rather than dreary reflections on difficulties or incapacities, as well as excellent problem-solving skills and a genuine confidence in other people are impressive and inspiring. Our discussions have been very rewarding and for my part they have promoted reasoning and evidence as well as discouraged narrow-mindedness. I highly respect your knowledge and judgment and I am most grateful for your support as supervisor during my PhD. I look forward to future conversations and collaboration. 4 2. FINANCIAL DISCLOSURES This PhD study received financial support from the Velux Foundation and the University of Southern Denmark. The projects were supported by the Novo Nordisk Foundation, the World Anti-Doping Agency, the Danish Ministry of Culture and Pfizer Denmark. I am investigator in clinical studies sponsored by MSD, Amgen and Novartis Healthcare. Finally, I hold stocks in Novo Nordisk. 3. SUPERVISORS Marianne Andersen, Associated Professor, PhD Department of Endocrinology, Odense University Hospital Bo Abrahamsen, Professor, PhD Department of Internal Medicine F, Gentofte Hospital Kim Brixen, Professor, PhD (main supervisor) Department of Endocrinology, Odense University Hospital Who all have affiliation with: Institute of Clinical Research, Faculty of Health Sciences, University of Southern Denmark 5 4. LIST OF PAPERS Paper 1. Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism Clin Endocrinol (Oxf). 2010 (ONLINE) Paper 2. Cross-sectional, population-based study on the prevalence of osteoporosis and vertebral fractures in elderly Danish men Accepted for publication, OI Paper 3. Risk factors for fracture in elderly men: a population-based prospective study Accepted for publication, OI Paper 4. Pattern of use of DXA scans in men: a cross-sectional, population-based study Manuscript submitted 6 5. ABBREVATIONS ADT: AED: BFAT: BMC: BMD: BMDhip: BMDneck: BMDspine: BMDwb: BMI: BTM: COPD: CVD: DB RCT: DXA: E: ESR1: FEA: GC: GIO: GWAS: HR: HR-pQCT: LBM: PBM: pQCT: RA: RR: SERM: SHBG: SNP: SOST: SSRI: T: TCA: T2DM: TCA: VFA: VFx: WHO: Anti-androgen treatment Anti-epileptic drug Total body fat Bone mineral content Bone mineral density BMD total hip (by DXA) BMD femoral neck (by DXA) BMD lumbar spine (by DXA) BMD whole body (by DXA) Body mass index Bone turnover markers Chronic obstructive pulmonary disease Cardiovascular disease Double-blinded, randomized, placebo-controlled study Dual energy x-ray absorptiometry Oestradiol Oestrogen receptor alpha-gene Finite element analysis Glucocortioid steroid Glucocorticoid induces osteoporosis. Genome wide association study Hazard ratio High resolution peripheral quantitative computed tomography Lean body mass. Peak bone mass peripheral quantitative computed tomography Rheumatoid arthritis Relative risk Selective oestrogen receptor modulator Sexual hormone binding globulin Single nucleotide polymorphism Sclerostin Serotonin reuptake inhibitors Testosterone Tricyclic anti-depressants Type 2 diabetes Tricyclic antidepressants Vertebral fracture assessment Vertebral fracture World Health Organization 7 6. ENGLISH SUMMARY Fractures are a leading cause of morbidity and mortality in the elderly. One of the major reasons for fractures is osteoporosis. It has been estimated that in Denmark, 41% of women and 18% of men aged over 50 years have osteoporosis. While the majority of fractures in men are observed in the young, fractures are also prevalent in the elderly, affecting approximately 20% of men aged over 50 years in their remaining lifetime. This thesis reviews the current knowledge about osteoporosis in men. Moreover, it incorporates four studies performed in three population-based cohorts of young and elderly men that focus on aspects of male osteoporosis. Decreased levels of vitamin D are known to cause rickets in children and osteomalacia later in life as well as increase fracture risk in the elderly. The prevalence of vitamin D deficiency and the impact of vitamin D deficiency on peak bone mass, bone markers and other metabolic functions were evaluated in a cross-sectional study comprising 800 Danish men aged 20-29 years (Paper I). In summer and winter, 6% and 44% young of the participants were vitamin D deficient, respectively. Moreover, low levels of vitamin D were associated with significantly lower bone mass in young men at the age where peak bone mass is attained. Data on the prevalence of osteoporosis are essential for priority setting and development of prevention strategies. In Paper II, the prevalence of osteoporosis was evaluated in a populationbased, cross-sectional study of 600 Danish men aged 60-74 years. On the basis of Danish reference material, the prevalence of osteoporosis was found to be 10%. Additionally, 6% of the men had a vertebral fracture. While osteoporosis and fractures are closely related, only one in four participants with a fracture had in fact osteoporosis. Although prevention of these fractures is of key importance, knowledge about risk factors for fracture in elderly men is limited. In Paper III, predictors of fractures in elderly men were evaluated in a population-based study of 4,975 Danish men aged 60-74 years 8 followed for 5 years. We found a 68% increased risk of fracture in men with a family history of hip fractures and a graded relation between number of falls and risk of fracture, particularly among the elderly and non-obese. Assessment of bone mineral density and fracture risk is central to fracture prevention and treatment of osteoporosis. In Paper IV, the pattern of use of DXA and 10-year absolute fracture risk was assessed in the 4,975 participants included in study III. DXA had been performed in 3% of the study population. In all, 21% and 10% of those reporting previous DXA and no previous DXA, respectively, had a 10-year risk of a major osteoporotic fracture above 20%. Conversely, 32% of the patients previously evaluated by DXA appeared to have no clinical risk factors. A number of other studies have made a significant contribution to knowledge about osteoporosis in men. The pathogenesis of the disease is multifaceted; genetics, lifestyle factors, medication and other diseases and conditions are known to confer an increased risk of osteoporosis and fractures. Osteoporosis in men differs in a number of ways from that observed in women. First, fracture incidence is higher in men aged less than 50 years. In contrast, the risk of a second fracture is similar in men and women. Second, the criterion for the diagnosis of osteoporosis in men remains debatable. Third, fractures are associated with a significantly higher mortality in men. Fourth, osteoporosis is less commonly diagnosed and treated in men than in women. Finally, the number of clinical trials evaluating the effect of osteoporosis-specific treatment on fracture risk in men is very low. Although our knowledge about male osteoporosis is growing, a number of issues still remain unanswered, including the reasons for underdiagnosis, inadequate treatment and increased mortality of men with osteoporosis. Future studies will hopefully provide this information. 9 7. DANSK RESUMÉ Knoglebrud medfører betydelig morbiditet og mortalitet hos ældre mennesker. Knogleskørhed er en vigtig årsag til knoglebrud, og i Danmark anslås det, at 41 % af alle kvinder og 18 % af alle mænd over 50 år har sygdommen. Knoglebrud optræder hos mænd hyppigst i ungdomsårene, men 20 % af alle mænd over 50 år antages at pådrage sig et knoglebrud i deres resterende levetid. I de efterfølgende afsnit gennemgås den aktuelle viden om knogleskørhed hos mænd. Desuden inddrages 4 populationsbaserede undersøgelser, som belyser forskellige aspekter af knogleskørhed hos mænd. Lave niveauer af D-vitamin kan medføre knoglesygdom. Forekomsten af mangel på vitamin D hos yngre danske mænd og effekten af en mangel på det maksimale niveau af knoglemassen belyses i den første artikel, som baserer sig på en undersøgelse blandt 800 danske mænd i alderen 20-29 år. Undersøgelsen viste, at niveauerne af D vitamin var utilstrækkelige hos 6 % om sommeren og 44 % om vinteren. Desuden blev det påvist, at vitamin D niveauer, desto lavere var indholdet af mineral i knoglerne. Viden om prævalensen af en given sygdom er afgørende for både prioritering og planlægning af forebyggende tiltag. I den anden artikel, som baserer sig på en populationsbaseret undersøgelse omfattende 600 danske mænd i alderen 60-74 år, fandtes 10 % at have knogleskørhed, mens 6 % havde sammenfald i ryggen. Denne undersøgelse viste også, det ikke har nogen væsentlig betydning for estimatet af prævalensen, om man vælger et dansk eller amerikansk normalmateriale i forbindelse med beregning af forekomsten af knogleskørhed Den væsentligste kliniske følge af knogleskørhed er knoglebrud. Vores viden om årsagerne til knoglebrud hos mænd er desværre begrænset. I den tredje artikel undersøges faktorer, der knytter sig til en øget risiko for knoglebrud. Undersøgelsen baserede sig på en populationsbaseret gruppe omfattende 4,975 danske mænd i alderen 60-74 år, som blev fulgt i 5 år. Undersøgelsen viste, at 10 risikoen for et knoglebrud var forøget med 68%, hvis der i familien var personer, der havde brækket hoften. Desuden var der er sammenhæng mellem antal fald og risikoen for knoglebrud, særligt hos ældre og normalvægtige. Vurdering af BMD og risikoen for knoglebrud er af stor betydning i forbindelse med forebyggelse af knoglebrud og behandling af osteoporose hos mænd. I den fjerde artikel blev anvendelsen af DXA og 10 års risikoen for knoglebrud vurderet i de 4975 mænd, der deltog i det tredje studie. DXA var udført hos 3 % af deltagerne. I alt 21 % af dem, der havde været undersøgt med DXA, og 10 % af dem, der ikke havde været undersøgt, havde en 10 års risiko for knoglebrud på mindst 20 %. Omvendt havde 32 % af dem, der tidligere havde været undersøgt med DXA, ingen umiddelbare kliniske risiko faktorer for knoglebrud. Flere andre undersøgelser har bidraget med en betydelig mængde information om mandlig osteoporose. Patogenesen er multifacetteret; både genetiske, livsstilsmæssige, farmakologiske og konkurrerende sygdomme kan øge risikoen for osteoporose og knoglebrud. Osteoporose hos mænd adskiller sig på en række punkter fra sygdommen hos kvinder. For det første er forekomsten af knoglebrud højere hos mænd inden 50 års alderen, mens hyppigheden af knoglebrud efter 50-års alderen er højest hos kvinder. I modsætning til dette er risikoen for et efterfølgende knoglebrud ens hos mænd og kvinder. For det andet er de diagnostiske kriterier for osteoporose hos mænd fortsat omdiskuterede. For det tredje, knoglebrud er fulgt af en betydelig højere dødelighed hos mænd. For det fjerde, osteoporose diagnosticeres sjældnere og behandles i mindre grad hos mænd. Endelig er der kun få kliniske studier, der belyser effekten af specifik medicinsk behandling af knogleskørhed hos mænd på forekomsten af knoglebrud. Selvom omfanget af viden om mandlig osteoporose er stigende, er en række spørgsmål uafklarede. Dette gælder fx årsagen til den forøgede dødelighed samt utilstrækkelige diagnosticering og behandling. Fremtidige studier vil forhåbentlig bidrage med denne vigtige information. 11 8. INTRODUCTION Life expectancy has increased significantly in the last centuries, and the populations of the developed countries are aging considerably (1). Fortunately, the processes of aging appear to be changeable, and disability is not necessarily a hallmark of aging (2). In elderly men, osteoporosis and osteoporotic fractures are a significant cause of disability and mortality (3). Hip fractures are more prevalent in the elderly, but the incidence appears to be declining in Danish men (4). Bone health is not a concern specific to the elderly. At all ages, bone tissue is continuously degraded and rebuilt in a process known as bone remodelling. Any factor promoting bone resorption without concomitant bone formation or decreased formation with unchanged resorption reduces bone strength causing an increase in fracture risk. Issues potentially detrimental to bone health should therefore be addressed throughout life if osteoporosis and osteoporotic fractures are to be prevented. Osteoporosis is a disease characterized by low bone mineral density (BMD) and disrupted bone microarchitecture that impairs the properties of bone and subsequently leads to an increase in the risk of fracture (5). The World Health Organization (WHO) has operationally defined osteoporosis in men and women as a BMD of less than or equal to 2.5 standard deviations below the mean of a young reference (6). Based on register data, 41% and 18% of Danish women and men aged more than 50 years are thought to have osteoporosis (7). The lifetime risk of fractures in women above 50 years of age is close to 50% while that of men is around 20% (8); the risk of a second fracture is independent of gender, however (9). In addition, hip fractures in men are associated with twice the mortality of hip fractures in women (10). The worldwide distribution of fractures is uneven as the prevalence of osteoporotic fractures including hip fractures is higher in Northern European and Scandinavian countries (3;11;12). Unfortunately, although treatment options are available, limited awareness on the part of both patients and clinicians has caused osteoporosis to be underdiagnosed and inadequately treated in men (13-16). 12 A number of factors are currently known to increase the risk of osteoporosis and osteoporotic fractures in men. These include both modifiable and permanent risk factors, i.e. glucocorticoids (17), falls (18), smoking (19) and genetics (20). The relative importance of several of these risk factors has been substantiated by meta-analyses including almost 15,000 men (21), and the results are now utilized in the WHO fracture risk algorithm (FRAX©). Contrary to preceding fracture algorithms, FRAX allows for calculation of absolute 10-year major osteoporotic fracture risk in men. Subsequently, the algorithm has been validated in approximately 230,000 persons, although only a few hundred of those were men (21). FRAX may prove useful for identification of high-risk patients, but trials conducted on individuals selected for treatment on the basis of their 10-year fracture risk are not available. Since 39% of all fractures occur in men, knowledge about the causes, prevention and treatment of male osteoporosis should be addressed (3). Current knowledge about osteoporosis and fractures in men is reviewed in the following sections. This includes results from the four studies on male bone health, including prevalence of osteoporosis among older Danish men. 9. AIMS The aims of the present thesis were to 1) Investigate the prevalence of vitamin D deficiency among young Danish men and the impact of this on bone turnover markers (BTM) and BMD 2) Evaluate the prevalence of osteoporosis in elderly Danish men 3) Assess risk factors for fractures in elderly Danish men 4) Determine the pattern of use of bone mineral density assessment in elderly Danish men 5) To provide a review of osteoporosis in men. 13 10. DEFINITION OF OSTEOPOROSIS IN MEN The WHO guidelines for the diagnosis of osteoporosis recommend the use of BMD assessed by e.g. dual energy X-ray absorptiometry (DXA) (6), but osteoporosis is also diagnosed in the event of a fragility fracture irrespective of BMD (22). A fragility fracture reflects progression of underlying abnormalities that cause bone loss and acts as a measure of bone status as well as a strong predictor of fracture. BMD and fracture risks are thus inversely associated in both men and women (23-26). Some studies suggest that fracture risk is similar in women and men at the same level of BMD (23;25;27). However, the US Study on Osteoporotic Fractures in Men (US MrOS) and Study of Osteoporotic Fractures (SOF) reported a larger increase in hip fracture risk for every decrease of one standard deviation of BMD in men compared to women (Age-adjusted RH (95%CI): 3.2 (2.4-4.1) vs. 2.1 (1.8-2.4)) (24). In the same studies, fracture risks were lowest in men, whether or not sex-specific or female reference values were used (24). These differences may be related to increased risk of falls in women or differences in the agerelated deterioration of bone structure between men and women. Nevertheless, application of sexspecific references may be prudent, and they are currently recommended for T-score calculations in men by the International Society for Clinical Densitometry and the US National Osteoporosis Foundation (28;29). The T-score cut-off used for the diagnosis of osteoporosis was primarily selected on the basis of the observation that the number of individuals with a T-score of less than -2.5 was equivalent to the proportion of fractures observed in postmenopausal women (6). Currently, the same criterion is recommended in both sexes. The validity of osteoporosis in men being defined as a T-score of -2.5 has been questioned. In the Rotterdam study, the sensitivity of DXA to identify persons who would experience a non-vertebral fracture was estimated to be 44% and 21% in women and men, respectively (27). While BMD is predictive of fractures in women and men, focus on risk factors and estimation of the absolute risk of fractures may prove even more prudent in men. 14 In summary, osteoporosis is currently defined on the basis of measurement of BMD using a cut-off Tscore of -2.5 or less in both sexes. Some, however, also consider a fragility fracture as a criterion for the diagnosis. Men and women with the same T-score have different fracture risks, whereas the risk of a fracture is at least as high in men as in women at similar absolute levels of BMD. 11. EPIDEMIOLOGY OF OSTEOPOROSIS IN MEN The prevalence of osteoporosis depends on the diagnostic criteria as well as ethnic group, age and sex of the population at interest. Thus, in the National Health and Nutrition Survey (NHANES III), the prevalence of osteoporosis was estimated to be 3% in Hispanic, 5% in black and 7% in white men (30). The prevalence of osteoporosis is not uniform, and in particular the Northern European countries are regarded as high risk countries for osteoporosis (31). In a Dutch study, the prevalence of osteoporosis was 20% and 40% in men aged more than 70 and 80 years, respectively (27) whereas the prevalence of osteoporosis was 22% in a Belgian study conducted among men at a mean age 69 years (32). Estimates are generally not concordant, and even within Scandinavia the reports on the prevalence of osteoporosis disagree. In a Swedish study, 17% of men aged 80-84 years were considered to have osteoporosis (33) whereas 18% of all Danish men aged more than 50 years are thought have osteoporosis on the basis of register-based data and Danish reference BMD (7). Recruitment of study participants and the mean age of the study populations explain at least in part this variation. In a population-based, cross-sectional study comprising 600 men aged 60-74 years using DXA and either Danish or NHANES III reference values for the calculation of T-scores, approximately 10% of the study population was found to have osteoporosis (Paper 2). Although the number of individuals considered osteoporotic by use of either of these reference values was similar, there were significant differences in the prevalence of osteoporosis between each site investigated, e.g. using NHANESIII only 0.5% had osteoporosis at the total hip whereas the Danish reference resulted in a prevalence of 15 4.4%. The distributions of BMD in the total hip, femoral neck and lumbar spine measured in young Danish men aged 20-29 years and these older men are presented in Figure 1. These results show that the prevalence of osteoporosis is highly dependent on the reference values used and the anatomical region that is investigated. The estimate of osteoporosis in Danish men may 1.6 1.4 .8 1 1.2 BMD: Lumbar spine (g/cm2) 1.2 .4 .6 .6 .8 1 BMD: Fermoral neck (g/cm2) 1.2 1 .8 .6 BMD: Hip (g/cm2) 1.4 1.4 1.6 prove relevant to priority setting. 20 40 60 80 20 Age (years) 40 60 80 20 Age (years) Figure 1. The distribution of BMD in the total hip, femoral neck and lumbar spine measured in Danish men aged 20-29 years and 60-74 years. (Paper 2) 12. EPIDEMIOLOGY OF FRACTURES IN MEN Fracture incidence differs significantly with age in both sexes. In children and until the age of approximately 50 years, men are more likely than women to sustain a fracture (34). In a British cohort study comprising 6% of the total population, fracture incidences were higher in boys than girls at all times of childhood with peaks at ages 11 and 14 years in girls and boys, respectively (35). Men aged 1559 years experienced a 2.9 times higher fracture incidence compared to women in a Scottish study on 15,000 fractures (36), whereas the incidence of all fractures including the occurrence of diaphyseal fractures of the femur, tibia and forearm was higher in women after the age of 50 years (34;36). These differences are likely to be caused by several factors related to physical activities, i.e. sports or trauma (37), however, intrinsic factors also influence risk of fracture. In an English study including more than 40 Age ( 16 6,000 children aged 10 years, Clark et al. (38) found the risk of fracture to be inversely associated with volumetric BMD irrespective of fracture mechanism, suggesting that an underlying skeletal fragility contribute to the risk of fracture even in children sustaining traumatic fractures. Prospective studies on the impact of childhood fractures on fracture incidence in adulthood are limited, but at least selfreported childhood fractures have been shown not to increase the risk of fractures in adulthood (39). The world-wide osteoporotic fracture incidence in 2000 was estimated to be 9 million, of which 39% reportedly occurred in men (3). The distribution of fractures was uneven as 42% of vertebral, 30% of hip, 25% of humeral and 20% of forearm fractures were observed in men (3). Compared to women, men have the lowest fracture incidence at all ages after the age of 50 years (3;9;12;27;34;36;40;41), and the lifetime risk of fractures in men older than 50 years has been estimated to be 20% compared to 50% in women (12;41;42). In the Dubbo osteoporosis study (DOES) that has 16 years of follow-up, fracture risks were 1% and 3.2% in men and 3.2% and 5.0% in women aged 6069 and 80+ years, respectively (9). There was, however, no difference in the risk of a second fracture (men/women: 60-69 years: 5.7% versus 6.2%; 80+ years: 9.0% versus 8.9 %). A greater relative risk of incident fracture after a low-trauma fracture was reported in men (HR: men: 3.47 (2.68-4.48); women: 1.95 (22.214.171.124)). Due to lower risk of an initial fracture in men, however, absolute fracture risk was similar in both sexes (9). In the population-based Tromsø study including 28,000 participants (12), the 10-year absolute risk for all non-vertebral fractures was higher in men until the age of 45 years. The absolute risk for nonvertebral and osteoporotic fractures exceeded 10% in men aged 65 and 70 years and in women at ages 45 and 50 years. With lifetime risks of non-vertebral and osteoporotic fractures at the age of 50 years reaching 38% and 25% in men and 67% and 55% in women, respectively, incidence rates reported in the Tromsø study are among the highest published (12). 17 12a. OSTEOPOROTIC FRACTURES Generally, fractures are considered osteoporotic if spontaneous or caused by low-energy trauma. Highenergy traumatic fractures, however, were also associated with both reduced BMD and increased risk of subsequent fractures in the SOF and MrOS studies, and the associations were of the same size as those between low-trauma fractures and BMD (43). More recently, the SOF and the DOES linked certain fracture types with osteoporosis (44-46). In women, the risk of a second fracture was the same irrespective of the classification of the first fracture, and a similar but insignificant trend was observed in men (43). The number of high-trauma fractures was significantly higher in men than women (21% vs. 9%) and these were due to sporting and other leisure activities as well as traffic accidents. Hightrauma fractures in women were mainly due to traffic accidents (43). The consequences of these findings are that osteoporosis should be considered in any case of a fracture, independent of the trauma mechanism, and that this may be of particular relevance in men. In a meta-analysis including approximately 60,000 persons (of whom a quarter were men) from Europe, Australia, Japan, US and Canada followed for a duration of 250,000 person-years, a history of previous fracture significantly increased the risk of a further fracture (RR: 1.86 (1.75-1.98)) without any significant sex-related difference in risk ratios (47). The risk of a succeeding fracture remains higher than in the general population in the first year (48), but studies have generally found accumulation of fractures after 1-5 years (49-52) and even 10-15 years (9;53). Any fracture observed should therefore be considered a sign of increased risk of a second fracture and the future fracture risk should be assessed. 12b. TYPES OF FRACTURES IN ELDERLY MEN Several different types of fractures have been linked to osteoporosis in men. van Staa et al. (42) reported that the most commonly observed fractures in men were those of the femur, vertebrae, forearm, humerus, clavicle, scapula, ribs and pelvis (42). Several other research studies or public 18 databases have provided information on fractures in men, including from Scottish (54) and Icelandic (55) sources. 12c. HIP FRACTURES The age-adjusted women:men hip fracture ratio varies internationally and is reported to vary between 34:1 in whites to 1:1 in South African blacks (56). Generally, the incidence increases later in men than women (34). The highest incidence is found among Scandinavian men and white North America men while the lowest is found among Asians and blacks (31;56-58). In Denmark, the incidence in men and women aged over 50 years is 2.5/1000 and 6.6/1000, respectively (59). 12d. SPINE FRACTURES Only 25-33% of vertebral fractures are diagnosed clinically (60;61), but even sub-clinical fractures are associated with significant morbidity (3) and mortality (62) in both men and women. The prevalence of thoracic vertebral fractures was evaluated in 30,000 men and 27,000 Finnish women and showed increased prevalence in men after 40 years of age and in women after 55 years. The prevalence was higher in men at all ages except after the age of 75 years (63), whereas in the European Vertebral Osteoporosis Study (EVOS) comprising more than 15,000 participants including well over 7,000 men aged 50-79 years, the prevalence of vertebral fractures was only higher in men aged under 65 years. The vertebral fracture incidence was up to three times higher in Scandinavians compared to other Europeans (64). The European Prospective Osteoporosis Study (EPOS), which consists of almost 3,000 men and women aged 50+ years, found an incidence in men of about half that observed in women (5.7/1000 vs. 10.7/1000). In the Framingham study, the prevalence of vertebral fractures was comparable between men and women, but the female vertebral fracture incidence was twice as high as that observed in men (24% vs.10%) (65). 19 The occurrence of vertebral fractures has been evaluated in the almost 6,000 male participants of the MrOS. The incidence rate was 2.2/1000 with higher rates in men aged 80+ years. In all, 13% of the incident vertebral fracture cases were observed in participants with osteoporosis compared to 2% in the study population, and approximately three-quarters of the vertebral fractures were caused by unknown factors or low-energy trauma (18). In the previously mentioned Danish study on men aged 60-74 years, the prevalence of vertebral fractures as identified by use of vertebral fracture assessment was 6.3% (Paper 2). In accordance with the findings of the US MrOS, the prevalence of osteoporosis among these fracture patients was low. These results suggest that DXA is inadequate in identifying those with vertebral fractures and new methods of identifying vertebral fractures, e.g. VFA, are needed. This necessity is underlined by results from the UK general practice database showing that the presence of vertebral fractures was associated with increased mortality in men (42). Similar results have been found in a number of other studies from Europe, Canada and Australia (66-68). Therefore, identification of vertebral fractures is as important in men as in women. 12e. FOREARM FRACTURES Contrary to women, the incidence of forearm fractures does not increase in men until late in life (27;34;36;69;70). In the Rotterdam study (27), forearm fractures increased in women from the age of 55 years whereas an increase was noted in men only after the age of 75 years. As with other fractures, the incidence in forearm fractures differs between countries, with the highest occurrence in Norwegians (70). In men as opposed to women, Colles fractures appear to increase the absolute risk of a subsequent hip fracture more than a vertebral fracture (71), and the importance of non-hip, nonvertebral fractures is further underlined by the association with a doubling of mortality risk in men after any of these fractures (68). 20 12f. HUMERUS, RIB AND PELVIC FRACTURES The incidence of humerus fractures increases modestly with age in men and women (27;34;72), although substantially more in women than in men (36). Recent data from the MrOS have highlighted the importance of evaluation of patients with rib fractures (73). Being the most common incident fracture in participants of the MrOS with an incidence rate of 3.5/1000 patient years, the rib fracture was, like other fragility fractures, predictive of fractures of the hip, spine and forearm independently of co-morbid conditions (73). Data on pelvic fractures in men are limited. Singer et al. (36) found similar incidences in men and women aged 15-49 years with increases in the subsequent years, particularly in women. Low-energy pelvic fractures are associated with increased mortality in both sexes, although the increase was higher in men compared to women in a recent German study of 1,100 patients with pelvic fractures and almost 6,000 controls (74). The pattern of fractures observed in men and women differs. Fractures are common in elderly men as in women, but in men the incidence increases at a later age than in women. Men have a lower incidence of fractures; however, fractures are associated with increased morbidity and mortality in men as well as women. 13. PATHOGENESIS Osteoporosis and osteoporotic fractures are caused by both intrinsic and extrinsic factors. Many of these may impact both men and women, but the relative importance of the factors differs. 13a. GENETICS Several studies on twins and family members have assessed the impact of genetics on aspects of bone biology, including BMD, peak bone mass (PBM), bone loss, bone turnover markers, skeletal size and 21 geometry as well as fractures. Studies suggest that the importance of heritability is largest in the young. Hereditary factors account for 60-80% of the variation in PBM, irrespective of sex (75;76). Sex- and site-specific quantitative trait loci that regulate BMD have been found, but the results were not confirmed in meta-analyses including over 11,000 individuals (77;78). Interestingly, the skeletal size of the father appears to be more strongly associated with skeletal size in female than male offspring, further underlining the importance of genetics and that sex-specific effects may be present (79). Studies on candidate genes have been performed in several cohorts, most of which have included substantially more women than men. Only few sex-specific effects of common variations in genes on bone are known. Variations in the oestrogen receptor alpha-gene (ESR1) gene were associated with vertebral fractures in women (80), whereas a specific variation in the transforming growth factor beta 1 gene appeared to associate with lumbar spine BMD in men only (81). Subsequent meta-analyses on studies evaluating candidate genes have provided more power to detect significant effects. These studies have shown that variations in the low-density lipoprotein-related protein 5 (Lrp5) and 6, key regulators of bone mass (82), the ESR1, which plays a role in bone acquisition/maintenance (80), and the collagen type 1 alpha 1 gene (83) are associated with BMD and fracture risk. Genome wide association studies (GWAS) have provided further information on the effect of common differences in genes on BMD. In the Framingham Study, Kiel et al. (84) showed associations between several common genetic variations and BMD as well as bone geometry and a number of other measures of bone status in 1,141 persons including sex-specific associations. Larger and statistically more powerful multi-national GWAS on BMD and fracture risk were reported from an Icelandic cohort (n=5,861, 13% men) with replication in Icelandic (n=4,165, 26% men), Danish (n=2,269, no men) and Australian cohorts (n=1,461, 39% men) (85) as well as a UK study with replication in three Western European cohorts (n=8,557, 9% men)(20). However, the single nucleotide polymorphisms SNPs found to be associated with BMD and fractures were not in complete concordance. Nine SNPs were associated with BMD in a meta-analysis on five GWAS, whereas four were associated with 22 fracture risk, including Lrp5 and SOST, a gene encoding sclerostin which inhibits bone formation. Neither of the GWAS on fracture reported sex-stratified analyses, and the effectiveness of these variants to predict fractures remains inadequate for clinical purposes. Although several genes have been shown to be associated with BMD and fractures, only 4-5% of the variation in BMD is accounted for by known alleles (86). Possibly, the information provided by these GWAS could be explored if geneenvironment interaction was evaluated. In a Danish study, common variations in the Lrp5 gene were found to be associated with PBM in non-sedentary men only, suggesting that the effect of the genetic variation was modulated by physical activity (87). Despite current uncertainties, the variants discovered in these studies provide knowledge about biochemical pathways that is useful for the understanding of the pathogenesis of osteoporosis and, perhaps new targets for treatment of the disease. 13b. FAMILY HISTORY In the Rancho Bernardo Study (88), a family history of a fracture was significantly related to BMD of the hip in men and the lumbar spine in women. The authors also found an inverse relation between BMD and the number of family members known to have osteoporosis. Consistently, a parental history of fracture was associated with lower BMD at the spine and proximal femur in the US MrOS (89). On the basis of almost 35,000 persons followed for well over 130,000 person-years, however, Kanis et al. (90) showed an association between a parental hip fracture and an increased risk of an osteoporotic and hip fracture in women only (osteoporotic: women vs. men, RR (95%CI): 1.38 (1.16-1.65) vs. 1.01 (0.671.52). Hip: 1.75 (1.17-2.63) vs. 1.73 (0.82-3.63)), although the estimates are approximately of the same size (91). In order to evaluate the extent and causes of fractures in elderly Danish men, including the effect of a family history of osteoporosis or hip fracture on fracture risk, we conducted a questionnaire-based survey on aspects of health, and in particular osteoporosis, among a random sample of over 9,000 men 23 aged 60-74 years (Study of osteoporosis and male aging (SOMA)). Responders were asked not only to submit information about lifestyle factors, comorbidities, medication and disposition for osteoporosis and hip fractures but also to consent to a register-based follow-up of incident fractures. In all, 4,696 returned a completed questionnaire and these individuals were subsequently included in the study. Responders were compared to non-responders as well as the complete Danish age- and sex-matched population. These analyses indicated that those included in the study were healthier, had a higher income and were more likely to be married. During a follow-up time of 5.4 years, 203 men experienced a first fracture, of which 85 were considered osteoporotic. Further analyses showed that a family history of hip fracture was associated with a significantly increased risk of any – but not osteoporotic – fracture (1.68 (1.142.49)). This suggests that heritability or shared environment has an impact on fracture risk in elderly Danish men as well. The risk conferred by a parental family history of a fracture, either osteoporotic or hip fracture, appears to be reduced, if not non-existing, in the oldest old. Parental history of a hip fracture was significantly associated with an increased risk of an osteoporotic fracture and a hip fracture at ages 60-75 years in men and women (Osteoporotic fractures: RR age 60: 1.56 (1.22-1.98); RR age 75: 1.31 (1.07-1.61). Hip fractures: RR age 60: 2.41 (1.03-5.64): RR age 75: 1.75 (1.08-2.82)), whereas in participants aged 80+ years, a parental history of a hip fracture had no effect on the risk of an osteoporotic or hip fracture (92;93). These results suggest that fracture heritability may diminish with increased age, something that is likely to be due to greater influence of environment rather than genetics as age increases. These findings favour the idea that genetics primarily affect PBM and are supported by reports that genetic effects on bone loss are inconsistent (92;93). In accordance with these results, a Swedish twin study on fracture risk found an association between genetics and fracture risk (94). The heritability of a hip fracture was age-related with heritability estimates in persons aged <70 years of 0.68, in persons aged 70-79 years 0.47 and in those older than 24 80 years 0.03. None of these estimates appeared to be sex-specific. The age of the study population was 50+ years and the heritability of fractures in younger persons remains unknown. Genetics is important to bone health, but data suggest that hereditary factors are important for fracture risk in the young and elderly but not the oldest old. Current knowledge about genes that confer disease is limited, but future studies evaluating not only SNPs but also copy number variations, epigenetics and other aspects may provide substantiation. 13c. EARLY LIFE According to the foetal origins hypothesis, birth weight is inversely associated with the risk of unfavourable health effects in later life, including type 2 diabetes and coronary heart disease (95). The biological mechanism that may be operating here remains unknown, although common genes may influence both foetal growth and health in adult life or the foetus may be programmed in response to maternal malnutrition (96). A number of studies have suggested that there is a similar association between intrauterine life and adverse bone outcomes in adulthood. Thus, birth weight appears to be associated with PBM (97;98) and bone mass in adulthood (99). Data from our group, however, suggest that the association between birth weight and PBM is driven by the association between birth weight and muscle mass, and then muscle mass and PBM (Frederiksen L et al. Abstract, ECTS 2006). In a Finnish study including approximately 7,000 individuals persons born in the period 1923-33, low growth in early life was associated with increased risk of hip fracture (100). In addition, the level of vitamin D in early life has been associated with bone mineral content at 9 years of age (101). Javaid et al. (101) suggested that intrauterine lack of vitamin D may affect bone mass by influencing calcium transportation across the placenta, which may impair intrauterine and postnatal bone growth (101). Conversely, a recent study on more than 7,000 children showed no effect of maternal pre-pregnancy body mass index on the child’s bone mineral content, suggesting that other factors may explain the 25 association (102). Further studies are needed for substantiation of the effect of vitamin D on birth weight as well as the relation between birth weight and bone health in later life. 13d. PEAK BONE MASS PBM is the amount of bone tissue present at the end of skeletal maturation (103) and is recognized as a major determinant of bone health in later life (104). The timing of PBM has been debated, and by far the majority of studies investigating this issue have been performed in women. It is generally thought, however, that maximum bone mineral content (BMC) and areal BMD (aBMD) in the femoral neck and lumbar spine are achieved later in men (105). In an 8-year follow-up study on BMD in men aged 17-26 years, Nordström et al. (106) found loss of BMD in the hip from the age of 19 years but stable levels of total body and lumbar spine BMD during the last part of the study period. In a Danish cross-sectional study from our group on approximately 800 men aged 20-29 years, PBM had been attained (107). Although useful as a reference, local data on the level of PBM cannot be employed in other geographical regions (108). Studies relying on aBMD may be by weakened by the technique, since aBMD includes information on bone width and height but not depth. Increases in bone size could be perceived as an increase in aBMD, even though the true density or volumetric BMD (vBMD) may be stable. Using vBMD rather than aBMD, Henry et al. (109) showed that PBM is reached in the radius and femoral neck by late adolescence, whereas vBMD of the spine peaked at 22 years in men and 29 years in women. Compared to girls, the trabecular number and thickness increased later in boys and while cortical thickness and density remained stable in boys from pre- to midpuberty, a small decrease was found in girls eventually causing the finite element models to show reduced bone strength in girls compared to boys (110). Evaluating the distal radius, young men aged 20-29 years were found to have larger bones and endocortical areas as well as trabecular thickness and trabecular bone volume/tissue volume ratio, whereas there was an equal number of trabeculae, trabecular separation and cortical thickness (111). 26 The absolute level of bone mass and bone strength is higher in boys at the time of PBM. By the age of 65 years, PBM may still account for half the variation in BMD (112), and the importance of PBM is emphasized further by a doubling of the fracture risk for every single decline of one standard deviation of BMD (113). Although genetics explain most of the variation in PBM (75;114), several factors known to influence PBM are potentially modifiable by preventive strategies such as physical activity (115), protein and calcium intake (116), and vitamin D supplementation (117). Factors favouring gain of bone mass in early adulthood could, therefore, be of great significance to bone health in later life. 13e. AGE-RELATED CHANGES IN BONE MASS AND MICROARCHITECTURE BMD is a significant determinant of fracture risk in men, and assessment of bone mass after achievement of PBM is used clinically (24;118). Several studies have consistently associated advancing age with lower BMD of at the hip, albeit lower in men compared to women (119-122). The grade of reduction in bone mass differed in various age groups in the MrOS. Although the mean loss of BMD was 1.72% during 4.6 years of study participation, those older than 85 years experienced a 2.5 times higher reduction in the femoral neck BMD compared to those aged 65 (123). The effect of age on spinal BMD has been debated. In the Framingham Study (119), BMD of the spine was reduced substantially less than observed in women, whereas no change was found in NEMO (Network in Europe for Male Osteoporosis), a European study consisting of 1300 men aged 50-86 years (124). A UK study reported increases of spinal BMD (121) in men, whereas lumbar spine BMD in Japanese men increased in the younger decades and diminished in the oldest (125). Other age-related factors probably influence the evaluation of spinal BMD as indicated in the French minos study where significant loss of spinal bone mass was evident only after exclusion of cases of arthritis (122). vBMD of the spine, femoral neck, distal radius and distal tibia decrease from early adulthood in both sexes, but the magnitude is larger in women (126). With age, the trabecular thickness decreases more in men than women, whereas trabecular number lessens and the trabecular separation increases in women 27 (111). In a cross-sectional study of men and women aged 20-99 years, total bone area as well as trabecular number and thickness were higher in men and the age-related reductions were comparable in both sexes, with the exception of distal radius trabecular thickness that appeared to be reduced to a larger extent in men (127). In addition, cortical porosity was more extensive in young men than women, although porosity increased substantially more in women than men (127). Cortical thickness and vBMD in the distal tibia and femoral neck in men and women remain stable until the age of 50 years. Afterwards, substantial decreases – albeit significantly greater at the femoral neck in women – of these two parameters are observed (111;128). Accordingly, femoral neck vBMD was 22% lower in men aged >85 years than in men aged 65-69 years as observed in the MrOS study. The femoral shaft cross-sectional area increased by 9%, and the cortical area was reduced by almost 6% due to substantial periosteal apposition and increase of endocortical area (129). Various tests of biomechanical properties and the novel finite-element analysis (FEA) allow for computer-based estimation of changes in bone strength and have been used to assess sex- and agerelated changes. Distal radial and tibial bones are stronger in men as assessed by FEA, and distal radius carries significantly more load in women than men (130). Women experience the largest reduction in vBMD of the femoral neck, but the loss of femoral bone strength is even greater and significantly higher than that observed in men (131). The ratio of fall load and bone strength in the femoral neck and distal forearm appears to worsen more in women than men. Vertebral strength is higher in men and remains so with age, primarily due to a larger cross-sectional area (132). Cortical porosity is more strongly correlated with age than any other measures of bone architecture obtained by HR-pQCT, and changes in cortical porosity confer considerable impairment of the biomechanical properties (133). Collectively, the studies assessing bone density, architecture and strength by use of DXA, pQCT, HRpQCT and FEA have contributed significant information about the potential reason for the observed differences in fracture incidences. Thus, the age-related reductions in femoral neck, vertebrae and distal radius bone strength could, at least in part, explain the substantially lower fracture risk observed in men 28 since loss of trabeculae seen in women causes larger decreases in bone strength than thinning of trabeculae in FEAs (134). Further studies are needed to examine the usefulness of pQCT, HR-pQCT and FEA for fracture prediction. 13f. SEX STEROIDS Sex steroids are essential for growth and preservation of bone in men and women (135). Total, free and bioavailable sex steroids decrease and sex hormone-binding globulin (SHBG) increases with age in men (136;137). In men, anti-androgen treatment (ADT) has been used to study the effect of testosterone (T) and oestradiol (E) on bone. In young men on ADT, T was found to regulate bone formation while resorption was affected by both T and E. In contrast, in elderly men E influenced bone resorption while both E and T affected bone formation (138;139). In the Rancho Bernardo study (136), higher bioavailable T and E in particular were associated with BMD in men, while Slemenda et al. (140) found E to be positively and T negatively associated with BMD in a 2-year prospective study on men with an average age of 65 years. The European Male Ageing Study (141), comprising 3141 men aged 50-79 years, showed significant association between bone quality assessed by ultrasound and free and total E but not T. In the MINOS study (142), low serum levels of E were associated with increased bone turnover markers and lover BMD, whereas in the Framingham study (143;144), hypogonadism appeared not to influence bone health or hip fracture risk unless matched with low E; E was, however, strongly associated with bone mass and increased hip fracture risk. In the MrOS, T and E deficiency were found in 6.9% and 9.2% of osteoporotic participants, respectively, and rapid bone loss was most often found in men with T deficiency (145). Nevertheless, low E, high SHBG or the combination of low bioavailable T and high SHBG were associated with an increased risk of osteoporotic fractures in the MrOS (146). 29 Contrary to these results, the DOES (147) showed that T and not E was associated with fracture risk and the Tromsö study (148) showed that neither T nor E was linked to fracture risk in men. In elderly men, the threshold for increased bone loss due to E has been estimated to be approximately 114 pmol/l (149). Local thresholds may have to be developed, however, as study populations and methods used for measuring sex steroids are likely to influence the results. Hypogonadism due to ADT causes considerable bone loss at cortical and trabecular sites (150). In a study on 50,000 men surviving at least 5 years after being diagnosed with prostate cancer, 19.4% of those who received ADT and 12.6% of controls experienced a fracture. Risk of fracture at the spine, femoral neck, rib, humerus, forearm and pelvis was increased in the ADT group (151). Corresponding increases in fracture risk were shown in a Danish register-based case-control study of prostate cancer patients (152). Sex steroids are key elements in the pathogenesis of male as in female osteoporosis. The increased fracture risk during ADT underlines the importance of T, but E appears to have the strongest association with BMD as well as fracture risk in population-based studies. 13g. BODY WEIGHT AND WEIGHT LOSS In adults, body weight and body mass index (BMI) have been directly associated with BMD. On the basis of a number of previously published studies, Papaioannou et al. (153) suggested that for every extra 10 kg of body weight, BMD of the hip and spine increased by 3-7%. Conversely, low body weight, BMI and weight loss are predictors of bone loss at the hip and spine of approximately the same magnitude in both sexes (154). The increase in fracture risk conferred by low BMI has been shown to depend on BMD but not age and sex (155). In a Norwegian study, loss of forearm BMD during 7 years of follow-up was significantly higher in slim participants compared to those with normal weight (156), and in the MrOS increasing body weight was associated with higher total hip BMD of 0.1%/year while those undergoing intentional weight reduction faced an annual bone loss of 1.4% (157). Several large 30 studies have confirmed the association between BMI and fracture risk (119;158-160). The relation between BMI and BMD is not linear, nor is it fully explained. Thus, after adjustments for BMD and falls, obesity was associated with an increased risk of fracture in the MrOS, which included 72% overweight or obese participants (159). In a Swedish study covering >30,000 middle-aged men and women, high BMI was associated with increase risk of humerus and ankle fractures and lower risk of forearm fractures (161). In the SOMA study, self-reported weight loss was associated with a higher risk of any fracture after adjustment for age, although weight loss was not significantly associated with fracture risk after adjustments for other risk factors (HR (95%CI): 1.35 (0.88-2.06)). The mechanisms explaining the association are largely unknown. The effect of increased fracture risk may be caused by lower levels of vitamin D in obese individuals as well as reduced physical activity and more falls (162;163). While mechanical stress and the effect of load on bone may mediate a substantial part of the observed association between relative weight and bone mass, a recent study on analyses of femoral strength suggested that lean body mass and not fat-mass accounted for the association (164). BMI appears to influence bone status equally in men and women. Low BMI is an established risk factor for fractures, but due to the increasing prevalence of obesity (2), fracture prevention may have to target both under- and overweight individuals. 13h. PHYSICAL ACTIVITY Physical activity is generally considered beneficial to bones. In young men, bone appears to adapt to changes in levels of physical activity (165), and while weight-bearing activities promote bone gain (166), sedentary lifestyle impairs bone status due to detrimental effects on particularly trabecular bone (167). Although the beneficial effects diminish after cessation of physical activity, a net gain of bone mass appears to remain at least in young men and women (168). Elderly men and women may also benefit from physical activity. In a 10-year prospective study, continuing physical activity as opposed to a sedentary lifestyle maintained bone mass in elderly men and women (169). In a Norwegian study, 31 leisure physical activity was associated with significantly higher levels of BMD at both weight and nonweight bearing skeletal sites after an observation time of 22 years irrespective of sex (170). In addition, using the “Up and Go” test, Cauley et al. (89) found a 2-4% higher BMD in those capable of getting up whereas Hannan et al. (119) showed a doubling of the bone loss in patients spending most of the day in bed. Paganini-Hill et al. (171) showed in a study population of >8,000 women and >5,000 men that at least one hour compared to less than half an hour of exercise per day was associated with significantly reduced risk of hip fracture in both sexes. A similar result on hip fracture risk was observed in a Finnish study of 3,000 men followed for 21 years (172). Conversely, while physical activity was associated with a reduced risk of vertebral fracture in the EVOS study covering in excess of 5,000 men and 6,000 women, men belonging to the top quartile of physical activity had the highest risk (173), indicating that exercise may not uniformly improve bone status. There may be multiple causes for the observed association between physical activity and bone status. Being physical active may promote balance causing fewer falls, improve muscle strength or stimulate bone formation directly. Although data on potential fracture prevention is limited in men, physical activity – and especially weight-bearing activity – appears to improve bone status. Nonetheless, future studies evaluating the effect of exercise on fracture risk in men are needed. Current knowledge about the type and amount of exercise, effect size, duration of effect and potential adverse effects is incomplete, and randomized studies evaluating the effect of exercise on fracture risk are needed. 13i. VITAMIN D Vitamin D acts primarily by increasing calcium absorption in the intestine and bone mineralization. Secondary hyperparathyroidism may develop in cases of vitamin D inadequacy, increasing bone turnover and subsequently bone loss and fracture risk (174). In the young, only few studies have evaluated vitamin D status and the relationship between vitamin D status and PBM in men. In a French 32 study, approximately 70% of boys aged 13-16 years had vitamin D levels below 25 nmol/l during winter (175), whereas the prevalence of vitamin D deficiency (defined as 25OHD <20nmol/l) in 220 Finnish men (primarily army recruits) aged between 18.3 and 20.6 years was 40% during winter (176). In the latter, reduced levels of BMD in the lumbar spine and total hip were reported in vitamin Ddeficient participants (176). In a Danish population-based sample of 800 men aged 20-29 years, the prevalence of vitamin D deficiency defined as serum 25-OHD below 50 nmol/l, as suggested in a recent report (177), was 44% during winter and 6% in the summer (Paper II). Participants with a sufficient level of vitamin D had significantly higher levels of BMD at the femoral neck, total hip and spine compared to the remaining study population, suggesting that vitamin D status may be improved in otherwise healthy young men. BMI, visceral fat mass, subcutaneous fat mass and smoking were inversely associated with vitamin D levels, while lean body mass, participation in sports and summer and autumn seasons were positively associated. These findings suggest that lifestyle interventions can improve vitamin D status. Inadequate levels of vitamin D is a risk factor for osteoporotic fractures (174;178), and treatment with vitamin D and calcium reduces fracture risk in studies consisting of both men and women (179;180), although specific data for men are lacking. In elderly men, vitamin D has been positively associated with hip and spine BMD (181), and vitamin D levels below 50 nmol/l have been associated with increased bone loss at the hip (182). Vitamin D insufficiency has been shown to increase the risk of hip fractures (183). In the NHANES III, vitamin D and BMD were associated irrespective of sex, race and age (184), but recent data from the same study showed an effect of vitamin D deficiency on BMD primarily in white men (185). Several factors influence the level of vitamin D. The MrOS (162), along with several other studies, has shown inverse associations between vitamin D and estimates of fat mass, e.g.. waist-hip ratio and total body fat mass measured by DXA (162;186-188). A closer association between vitamin D and visceral 33 fat mass than to subcutaneous fat mass has been found, possibly linking vitamin D to the metabolic syndrome (189). The definition of vitamin D inadequacy has been debated. Vitamin D deficiency was defined as levels of 25-OHD below 50 nmol/l and insufficiency as levels lower than 75 nmol/l (177). Perhaps due to the late consensus on the recommendable levels of vitamin D, currently advocated intake of vitamin D is insufficient for the prevention of vitamin D deficiency (190). In line with that, using vitamin supplements including vitamin D did not result in sufficient vitamin D levels in 1606 men in the MrOS (162). 13j. FALLS Falls are particularly common in the elderly as more than one in three aged more than 65 years experience a fall every year and 5-6% of falls cause fractures (191). In a Swedish 12-year register-based study on injuries including 29,000 fractures, 53% and 80% of fractures in persons aged >50 years and >75 years, respectively, were judged to be caused by low-energy trauma (192). Men experience fewer falls than women but are twice as likely to die from the incident (193). In Iceland, more than 70% of hip and forearm fractures in men were caused by low-energy trauma including falls (55), while in the MrOS 60% of all vertebral fractures were caused by falls (18). While the direct consequences of falls include fractures and head injuries, falls also cause long-lasting disabilities due not only to the fracture but also to the fear of another fall (194). A multidisciplinary approach to the prevention of falls is generally recommended (195), and recent Cochrane reviews have supported the use of multidisciplinary methods among elderly residents of nursing care facilities and hospitals as well as elderly, community-dwelling persons (196;197). Vitamin D may not only improve BMD but also non-bone functions including muscle strength, balance and the risk of falls. Vitamin D deficiency causes myopathy whereas increasing the level of vitamin D improves muscle strength and function as well as balance (191;198). A meta-analysis based 34 of eight randomized controlled trials including 2416 persons (19% men) by Bischoff-Ferrari et al. (199) found that supplementation with more than 700 IU of vitamin D reduced falls by 19%. A subgroup analysis on the effect of vitamin D in men was not reported. Falls were also associated with an increased risk of fractures in the SOMA study. The deleterious effect of falls appeared to be graded, with increasing numbers of falls being followed by higher risk of fracture (HR (95%CI): one fall/year: 1.47 (1.00-2.17), 2-4 falls/year: 2.10 (1.37-3.22), >4 falls/year (2.34 (1.083.07)). In addition, the impact was most pronounced in those with a normal BMI (<25kg/m2) and in the oldest participants (men aged >70 years). No sex-specific intervention studies on fall prevention have been published and specific recommendations for the prevention of falls in men are therefore not available. There are no data indicating a sex-related effect of vitamin D, however. As in women, fall prevention in men relies on multidisciplinary input as well as optimization of vitamin D status and eradication of all other factors imposing a higher risk of falls. 13k. SMOKING AND ALCOHOL Alcohol consumption and tobacco use are higher in men than in women. In a meta-analysis of the consequences of smoking on BMD and fracture risk, smoking reduced BMD and increased fracture risk in women and men, with higher risks for all except hip fractures observed in men (200). Interestingly, only 23% of the effect of smoking on fracture risk was explained by detrimental effects of areal BMD. In Denmark, smoking was associated with increased risk of a hip fracture in both men and women, and 19% of all hip fractures may be attributed to the effect of smoking (19). Conversely, results from the SOMA study indicated no significant association between smoking and fracture risk (HR (95%CI): 1.22 (0.87-1.72)), however, this may be related to the relatively low number of events. Smokers with low weight or more than 20 pack-years of smoking seemed to be particularly exposed to 35 the deleterious effects of smoking with regard to bone (170), and BMD remained low in former smokers participating in the MINOS (201). In a review including risk factors for osteoporosis, alcohol intake exceeding 3-4 units per day was found to increase fracture risk by about 2.0 even though BMD was unvarying (202), implying harmful effects of alcohol on non-bone related factors, i.e. falls. In the EPOS, alcohol had no independent relation with fracture risk (203) and some reviews have considered the evidence of an alcohol effect on bone health in men to be weak (153;202). Kanis et al. (204) found alcohol intake to be associated with the risk of any fracture, osteoporotic fracture and hip fracture independent of BMD and gender, although a trend towards larger effects in men was observed. Danish data including almost 18,000 men and 14,000 women associated consumption of more than 27 units of alcohol per week with an increased risk of hip fracture (28-41 units/week: RR (95%CI): 1.75 (1.06-2.89) and >70 units/week: 5.28 (2.60-10.70)) in men, whereas in women no substantial effect was found after adjustment for confounders (205). Both smoking and excessive consumption of alcohol are thus associated with higher fracture risk in men and women. Not all studies agree with regards to the effect of alcohol, although differences in study design, population and size could account for the divergence. 13l. COMMON DISEASES ASSOCIATED WITH OSTEOPOROSIS AND FRACTURES Type 2 diabetes (T2DM) has been associated with an increased fracture risk despite reports of increased BMD in diabetics (160;206). The reason for this is unknown. Lower bone strength compared to body weight could explain part of the observation (207). Also, falls are more prevalent among T2DM patients, possibly due to reduced peripheral nerve function and decreased renal function, weight loss or worsening of vision as well as intensive treatment with insulin (208). Recently, the number of medications – but not the individual medication – prescribed to persons with diabetes was related to the risk of falls (209). Presently, T2DM is not acknowledged as a risk factor for osteoporotic fractures by the Danish Medicines Agency. The data are consistent and point to the need for greater attention to 36 this patient group, but further studies are required to investigate the mechanism causing the detrimental effect of T2DM on bone status. Since cardiovascular disease (CVD) is more prevalent in men than women, CVD could be important in the explanation of sex differences in BMD and fracture incidence. Few studies have evaluated the impact of CVD on fracture risk. Data from Sweden found incidence of hip fractures of 12.6/1000 in patients with heart failure or stroke and 6.6/1000 in patients with ischemic heart disease compared to 1.2/1000 in the population without any of these diagnoses. Due to increased risk of fracture in cotwins not diagnosed with IHD, Sennerby et al. (210) suggested a genetic relation between CVD and hip fractures. Men belonging to the lowest quartile of BMD in the spine and forearm experienced a twofold increased risk of CVD while those with aortic calcifications independently of medication, comorbidities, falls, BMD, BMI and age had a two-three fold increase in fracture risk during the 7.5 years follow-up of the French MINOS, suggesting that the cardiovascular and skeletal systems could interact in presently unknown ways (211;212). In a Danish register-study, hypertension, stroke and myocardial infarction were associated with a slight increase in fracture risk in the first 3 years after the event (213), whereas Hippisley-Cox and Coupland (160) showed that CVD was associated with an increase in osteoporotic fractures in both men and women independent of smoking, T2DM, BMI and several other potential confounders. Certain lifestyle factors, including smoking, are central to the pathogenesis of CVD and osteoporosis and also contribute to the incidence of other diseases, e.g. pulmonary disorders. Chronic obstructive pulmonary disease (COPD) and asthma have recently been associated with bone loss in both spine and hip as well as an increased fracture risk in the MrOS. The risk of osteoporosis was increased in those treated with inhalation (OR (95%CI): 2.05 (1.27-3.31)) or oral steroids (OR: 2.13 (1.15-3.93)). Vertebral and non-vertebral fracture risk was increased by factors of 2.6 and 1.4 in participants with COPD or asthma, respectively (214). In UK, asthma was found to increase fracture 37 risk to a similar extent in both women and men, independent of the use of steroids (160). The cause of the association is, however, largely unknown. While awareness of COPD as a risk factor for osteoporosis is still evolving, rheumatoid arthritis (RA) is acknowledged as a risk factor for osteoporosis in women. In men, the amount of information is limited. A Norwegian study on 366 persons, including 68 men diagnosed with RA, found deleterious effects of treatment with glucocorticoids and beneficial effects on bone loss in those on anti-resorptive treatment. Bone loss measured by DXA occurred in patients with RA earlier in hands than in the remaining skeleton (215), but fracture rates were not reported. During a median follow-up of almost 50 months, 2.9% of the participating 1,055 male RA patients of a Japanese study experienced either a nonvertebral or a vertebral fracture (216). The expected number of fractures in a matching non-RA population was not reported, making the assessment of risk conferred by RA difficult. Longitudinal studies are needed to evaluate the impact of RA on fracture risk in men. In the SOMA study, neither type 2 diabetes nor CVD was associated with fractures. In addition, RA had no significant impact on the occurrence of fractures, whereas pulmonary disease increased the risk of an osteoporotic fracture (HR: 1.95 (1.05-3.62)). Interestingly, other diseases or symptoms were related to an increased fracture risk. Erectile dysfunction was associated with both any fracture and osteoporotic fracture (HR: 1.39 (1.04-1.84) and 2.04 (1.31-3.18), respectively). In addition, report of urinary frequency was associated with any fracture (HR: 2.05 (1.25-3.36)) but not osteoporotic fracture. These results are surprising but also difficult to explain. Both urinary frequency and erectile dysfunction are most likely not the cause of fracture but rather markers of frailty and underlining disease. Although a substantial number of common comorbidities are known to increase fracture risk in men, information on the mechanism increasing the fracture risk is not available. In theory, illness may deteriorate BMD or the bone structure directly or increase fracture risk indirectly through adverse effects of the concomitant medication, reduced level of physical activity, tendency to falls or increased frailty. 38 13m. MEDICATION Numerous compounds have been related to osteoporotic fractures in men including loop diuretics, selective-serotonin reuptake inhibitors (SSRI) and glucocorticoids (GC) (217). 13m. Glucocorticoids GCs suppress bone formation by increasing osteoblast apoptosis and bone resorption, reducing intestinal calcium absorption and increasing renal calcium excretion, and disturbing vitamin D metabolism, thus increasing the risk of vertebral and hip fractures in men and women (17). Inhaled GCs, however, had no impact on hip (218) or any other fracture (219). Danish registry data on men and women suggested an impact of oral steroids on any fracture risk at levels exceeding 7.5 mg of prednisolone (or equivalent), while no effect of topical applications were found (220). GC appears to affect fracture risk equally in men and women, making GC important as a risk factor irrespective of gender. 13m. SSRI and anti-epileptic drugs SSRIs were associated with decreased BMD and increased risk of osteoporotic fracture in large, prospective studies and in a Danish registry-based study in men (217;221;222). SSRIs are consistently associated with osteoporotic fractures (222), and recent data have suggested a biological mechanism for the deleterious effect of SSRI on bone (223). In addition, SSRIs appear to increase the risk of falling in men and women (221). Future studies should evaluate the effects of antidepressants including SSRI as well as tricyclic antidepressants on bone health as well as falling in men, and whether these effects are independent of the underlying disorder, e.g. depression, anxiety etc. 13m. Anti-epileptics Vestergaard et al. (224) showed that epilepsy doubled the risk of fracture, with higher risks in those treated with phenytoin. Once seizure-related fractures (one third of events) were removed, however, 39 the effect was only borderline significant. In a US study on 81 young men, anti-epileptic drugs (AED) were associated with femoral neck bone loss (225), whereas in the MrOS only non-enzyme-inducing AED were associated with increased bone loss (226). 14. PREVENTION The proportion of persons ultimately fracturing is larger among those with osteoporosis, but the absolute number of fractures is higher in the non-osteoporotic population. Preventive strategies could either focus on a reduction of fractures in persons at high risk or aim at decreasing the risk in the total population. Reducing the prevalence of risk factors in the general population would lower the total risk and lessen the societal burden of fractures, but the change may have a larger impact on high-risk individuals. On the other hand, it could be easier to reduce exposure in high-risk individuals. In order to be effective, however, these exposures would have to be both causal and reversible which may not be the case, e.g. age and genetics. International guidelines for osteoporotic fracture prevention have been developed, but the likely impact of population-based guidance should be evaluated before implementation. The prevention of osteoporosis and osteoporotic fractures starts early, as maximising PBM of the individual appears to reduce the overall fracture risk in later life. Physical activity, smoking and adequate nutrition including vitamin D are all relevant to PBM and have to be addressed if bone health is to be improved. Searching for high-risk patients seems of minor importance in a young population, although fractures in early life can be due to underlying bone-related diseases, e.g. osteogenesis imperfecta, that require special intervention. In adults, both population-based prevention and risk reduction in high-risk individuals appears to be sensible ways of improving bone health. In high-risk patients, reducing exposure or protection against the effects of an exposure would be possible, whereas preventive measures on a public health level may reduce the overall impact of osteoporotic fractures on society. In Denmark, case-finding strategies are 40 recommended rather than population screenings (227). This approach, however, seems to divert resources to low-risk patients and provides little coverage of high-risk man and women. Thus, a substantial number of Danish man and women at low risk of a fracture as assessed by the WHO fracture algorithm FRAX have been evaluated with DXA, indicating a need for optimization of the use of DXA (228) (and Paper IV). No studies on community screening for osteoporosis have yet been published, but the UK Screening of Older Women for Prevention of Fracture Study (11.000 women aged 70-85 years) (http://www.scoopstudy.ac.uk) and the Danish ROSE Study (women aged 65-80 years) (www.interreg4a.dk/wm313724) will provide information on the usefulness of screening in women. The present high-risk preventive strategy comes with some advantages. Assessing the individual’s risk factors allows for information appropriate for that person specifically, and interference with those at minor risk is avoided. In addition, it may be easier for patients and medical staff to deal with the specific term osteoporosis rather than an absolute fracture risk. Greater focus on high-risk patients could make long-term treatment more acceptable as the risks due to the medication would be outweighed by the benefit of the intervention. For clinical decision-making, identification of men at high risk of fracture presently includes measuring BMD, as the diagnosis of osteoporosis is based on a T-score. Though significantly related to the risk of a fracture, the diagnosis osteoporosis could be perceived as a risk factor for fracture. Osteoporosis captures some but not all of the risk of a fracture as is the case for falls, TCAs (229) etc. The proportion of individuals identified as osteoporotic on the basis of a T-score of -2.5 or less and who eventually experience a fracture was 21% in the Rotterdam study (27), clearly making way for new approaches to the management of osteoporosis including development of other surrogate markers for fracture. Future indicators of fracture risk could be the strength of the femoral neck or vertebrae as estimated by QCT/finite element analysis, bone structure as measured by HR-pQCT or algorithms based on anthropometrics and medical history (see below) (131). 41 14a. FRACTURE PREDICTION The WHO fracture risk algorithm, FRAX©, allows for calculation of the 10-year absolute fracture risk in men and women (21). FRAX includes a number of risk factors as well as either BMI or BMD (Table 3). FRAX could prove useful in the selection of individuals eventually fracturing, particularly in men as the sensitivity of DXA to detect those who will experience a fracture is low. The algorithm was validated in approximately 230,000 persons, but only a few hundreds of those were men (21). Neither dose-response relationships nor dynamic interactions between the clinical risk factors were accounted for. In addition, clinical trials on pharmacological treatment of osteoporosis have been performed on the basis of T-scores or factures rather than absolute risk estimates. Though not designed specifically for formal testing of FRAX estimates, recent reports on placebo-controlled, randomized clinical trials of clodronate (230) and bazedoxifene (231) demonstrated the ability of FRAX to identify women at high risk of fracture who would respond to treatment. Similar studies are needed in men. At the moment, clinical trials have provided no evidence supporting the usefulness of FRAX in men. Two other risk algorithms have recently emerged. Compared to FRAX, the Australian Garvan (232) algorithm incorporates fewer risk factors and the UK QFractureScore (160) substantially more risk factors (Table 3). The algorithms were derived from rather diverging study populations, thus the Garvan is based on results on the DOES, while the QFractureScore was constructed on the basis of huge datasets from general practitioners in the UK. While FRAX and the Garvan algorithm gave comparable results in women, the ability of FRAX (US version) to predict fractures in men was shown to be inferior to the Garvan algorithm (232). Compared to FRAX, the QFractureScore appears to provide better discrimination of fracture patients (160). In addition, the QFractureScore is applicable to a larger age range and accommodates several factors not present in FRAX such as type 2 diabetes and falls. This algorithm has been validated in >400,000 men and women in the UK. On the other hand, 42 FRAX is based on international data and additions of more risk factors may not necessarily prove sensible in a clinical setting. Validation of the three algorithms is needed, particularly in men. 15. CONSEQUENCES OF FRACTURES Men are less likely than women to return to their own home after hospital discharge following hip fracture (233). One in four male fracture patients who were previously self-sufficient became dependent on others for help at home, while another 50% of those who were previously independent were admitted to residential homes or institutionalized care (234;235). In addition, men are less likely than women to have returned to their previous independent living one year after hip fracture (233). The mortality associated with hip fractures is higher in men than in women. In a recent Danish study, Kannegaard et al. found a 1-year mortality among hip fracture patients (236). Comparable results have been found in a number of countries (14;68;237;238). The increased mortality after a hip fracture – particularly in men – has been confirmed in a meta-analysis (239). Men face twice the risk of dying on admission due to a hip fracture compared with women (240), and their 1-year mortality remains higher in men after a second hip fracture (53). In contrast, the Canadian Multicentre Osteoporosis Study (CaMOS) found no sex-specific difference in mortality after hip fracture, quite possibly due to a limited number of events (n=85)(67). In men with hip fracture, the number of co-morbid conditions is higher than in women. Nonetheless, the excess mortality remained after adjustment for several comorbidities and medications, suggesting that other factors play a role (236). Unfortunately, there is at present no convincing explanation for the increased mortality following fractures observed in men. 15a. CLINICAL CARE In the CaMOS, 20% of the male study population reported a previous fragility fracture at study inclusion in 1996-7; however, only 2.3% had been diagnosed with osteoporosis. After 5 years of study 43 participation, the fraction of fracture patients diagnosed with osteoporosis increased to approximately 10%, and less than 40% of hip and 10% of the wrist fracture patients received treatment after 5 years (16). Bone densitometry was used four times more often in women compared to men in an Australian study (241), even though the life-time risk of a fracture in women and men over 50 years old is estimated to be 44% and 27%, respectively (242), and 39% of all fractures occur in men (3). Although the use of anti-osteoporotic treatment has increased in Denmark (243), the disease remains underdiagnosed and inadequately treated, particularly in men (7). Using baseline self-report data on diagnosis of osteoporosis, use of osteoporosis medication and previous bone mass assessment in a population-based sample of 4,975 Danish men aged 60-74 years, we found that 2.7% of the men had been assessed by DXA (Paper IV). Bone mass assessment was used more often among those with risk factors or a high FRAX score; however, DXA had been performed in only 10% of men with at least three FRAX risk factors as compared to 36% of elderly Danish women (228). Furthermore, 10% of men not assessed by DXA had a 10-year major osteoporotic fracture risk in excess of 20%. Conversely, 32% of the bone assessments in the same study had been performed in men without clinical risk factors as defined by the FRAX algorithm. These results suggest that the strategy used to prevent fractures in men needs to be re-evaluated, and further studies focusing on the causes of the observed sex-related differences are needed. 16. PHARMACOLOGICAL THERAPHY When men and women are diagnosed with osteoporosis, the aim of the treatment is fracture reduction. Randomized, double-blinded, placebo-controlled studies on fracture reduction are needed to provide necessary information on efficacy and adverse effects of the treatment. The European Medicines Agency (EMEA) has licensed drugs for the treatment of male osteoporosis on the basis of fracture reduction in women and significant increase of BMD in men (www.emea.europa.eu) if this increase was 44 comparable with that observed in women. Only a few studies have investigated the treatment of osteoporosis in men. 16a. VITAMIN D Several studies have investigated the impact of vitamin D supplementation on bone health and fracture risk. However, meta-analyses have produced varying results. Bischoff-Ferrari et al. (244) found that 17.5-20 µg vitamin D reduced fracture risk, whereas Boonen et al. (245) reported that vitamin D was effective in reducing fracture risk only if administered with calcium. Recently, the need for a combination of vitamin D and calcium for fracture reduction was supported by an even larger metaanalysis including 65,000 individuals (14% men) (2). Interestingly, in the latter study, there was no indication of an interaction between sex and response to treatment, suggesting that vitamin D plus calcium may be as effective in men as it is in women. 16b. BISPHOSPHONATES Orwoll et al. (246) showed significantly reduced risk of vertebral fractures and increased BMD of the spine, femoral neck and whole body in a double-blinded, placebo-controlled, randomized trial on alendronate treatment of 241 men with mean age of 63 years, of whom one-third were hypogonadal (defined as low total testosterone). Positive effects on BMD were also shown in studies on alendronate (247;248), risedronate (249) and ibandronate (250). Ibandronate also increased BMD of the lumbar spine and femoral neck in heart transplant patients (251), whereas zoledronic acid reduced the incidence of all fractures including vertebral fractures and increased BMD at several sites in a 3-year study with male and female hip fracture patients (252). Contrary to all other treatment options, zoledronic acid also reduced mortality in hip fracture patients (252). Together, these studies demonstrated similar effects of bisphosphonates on bone loss and osteoporosis in men as in women. None of the studies suggested sex-specific adverse effects. 45 16c. PTH Although terminated prematurely due to development of osteosarcomas in rats, a study including 437 elderly men on teriparatide for the treatment of male osteoporosis showed beneficial effects on spinal and femoral neck BMD. In addition, the effect was present irrespective of gonadal status (253). Similar results are available from a smaller study of longer duration that in addition showed a reduced incidence of vertebral fractures in the actively treated group of participants (254). As in women, bisphosphonates are effective in maintaining bone mass after anabolic treatment with teriparatide (255). A combination of teriparatide and bisphosphonates (alendronate) in men appears to reduce the effect of teriparatide (256) and is not recommended. Data on the effect of parathyroid hormone (Preotact) on male osteoporosis are not available, but the function of parathyroid hormone is not supposed to be sex-specific. As is the case for bisphosphonates, there appears not to be any sex-specific adverse effects of PTH – there is, however, no clinical data on 1-84 PTH in men. 16d. TESTOSTERONE AND SERM A few, extremely divergent studies have evaluated the effect of testosterone on BMD whereas data on fracture prevention is absent. Behre et al. (257) found a 20% increase in trabecular bone mass as measured by QCT in the first year of testosterone treatment of 72 hypogonadal men. The results are difficult to extrapolate, however, as various formulations of testosterone were used, no control group was included and there were several different causes of the hypogonadism. Testosterone treatment has been tested for prevention of bone loss in hypogonadal men and beneficial effects of testosterone have been shown on measures of BMD, although findings are not consistent. 46 Snyder et al. (258) found increased BMD of the spine in a study on 100 elderly men. Positive effects on BMD have also been reported in other studies (259;260). Selective oestrogen receptor modulators (SERM) imitate the effects of oestrogens on bone. In a randomized, placebo-controlled trial on the effects of raloxifene on bone turnover markers, treatment was associated with decreased bone resorption (urinary NTX) in 50 elderly men with low oestradiol level (261). Unfortunately, BMD was not evaluated in the study. Confirmatory studies have not been published. SERMs seem to be associated with an increased risk of thromboembolic events in men with prostate cancer, an adverse effect similar to that observed in women (261). 16e. OTHER DRUGS There are no data to suggest sex-specific effects of strontium on bone. Data on strontium ranelate for treatment of male osteoporosis is currently not offered. Although calcitonin has been tested in men, the trials were small, of short duration and lacked data on fractures. Trovas et al. (262) found significant increases in spinal BMD and reduced bone resorption markers during one year of treatment, but no effects were noted in the hip or femoral neck. There appears not to be any sex-specific adverse effects of calcitonin. 16e. Special case: glucocorticoid-induced osteoporosis Several bisphosphonates have proven useful in the treatment or prevention of osteoporosis in men currently on or beginning glucocorticoid-treatment including alendronate (263), risedronate (264), ibandronate (265) and zoledronic acid (266). Zoledronoic acid and teriparatide appear superior to alendronate in maintaining BMD in the lumbar spine (266-268). Most studies on the treatment of glucocorticoid-induced osteoporosis (GIO) include both sexes since there appear not to be any significant sex-difference in GIO. 16e. Special case: prostate cancer 47 Bisphosphonates have proven effective in maintaining or increasing BMD at the beginning of or during anti-androgen treatment (ADT) in a number of trials of various sizes and durations (269-273). More recently, denosumab, a human monoclonal antibody against receptor activator of nuclear factor kappaB ligand, decreased the risk of a vertebral fracture in men undergoing ADT due to non-metastatic prostate cancer and increased BMD in the lumbar spine and total hip in a study including 1,468 men (274). SERMs have been evaluated as a preventive measure in men with prostate cancer receiving ADT. A combination of SERM and ADT that increased oestrogen but maintained a suppressed level of androgens could prove effective in preventing deleterious effects of ADT on bone. In a small study, raloxifene increased BMD in the hip (275), whereas toremifene, a SERM, reduced the risk of vertebral fractures and increased BMD in a 2-year study on 646 prostate cancer patients undergoing ADT (276). 16f. TREATMENT IN GENERAL Bisphosphonates have a documented effect on male osteoporosis including cases due to hypogonadism and bone protection during ADT and GC treatment. The PTH-analogue teriparatide is effective in treating male osteoporosis and GIO and appears more potent in treating GIO than bisphosphonates in men. Lately, denosumab has become an option for treating bone loss in prostate cancer patients receiving ADT. A head-to-head study with bisphosphonates for this particular group of patients has not been published and the choice between these drugs is thus not clear. Calcitonin, SERMs and testosterone have not been shown to reduce fracture risk in men and appear irrelevant to the treatment of male osteoporosis. Nevertheless, testosterone is available for substitution in hypogonadism and could improve bone status directly or via the peripheral conversion to oestradiol by aromatase or by increasing muscle mass. 48 Ongoing studies are investigating the effects of zoledronic acid and denosumab on bone status in men and evaluating the 24-month effect of teriparatide in men and women as assessed by HR-pQCT (www.clinicaltrials.gov). 17. CONCLUSION In a population-based study of otherwise healthy young Danish men, the prevalence of vitamin D insufficiency was found to be high during winter, affecting almost half of the study population. The levels of vitamin D were inversely associated with BMD, suggesting that inadequate vitamin D could be detrimental to peak bone mass. Whether this inadequacy is a marker of future low BMD and increased fracture risk remains to be answered. Low BMD and osteoporosis are predictive of fractures in men as in women. Based on a populationbased sample and Danish reference values, 10% of elderly Danish men aged 60-74 had osteoporosis. Using either Danish or NHANES reference values resulted in the same overall prevalence of osteoporosis, although the estimates differed substantially between the different anatomical regions. Estimating the prevalence of osteoporosis on the basis of a single skeletal site will, therefore, provide very different results. Although osteoporosis is a common disorder of elderly men and women, only very few Danish men at high risk of fractures had been evaluated with DXA. The majority of those who reported a previous DXA were at high risk of a fracture, but almost one-third of the DXAs had been performed in individuals at low risk, suggesting that the pattern of referral for DXA was inappropriate. The use of DXA may also allow for assessment of vertebral fractures. In this study, the prevalence of vertebral fracture was 6% as assessed by VFA. Although one in eight of the participants had either osteoporosis or a vertebral fracture, however, less than one per cent reported osteoporosis-specific treatment. 49 Although male osteoporosis has been investigated to a lesser degree than female osteoporosis, there is a current body of knowledge about the causes of osteoporosis in men, covering both reversible and irreversible factors. Thus, insufficient levels of sex steroids and quite possibly increased levels of sex hormone-binding globulin confer a higher risk of osteoporosis and fractures. Heritability also influences the occurrence of fractures in men and women, and common variations in several genes have been shown to influence fracture risk. Large scale genetic studies have provided limited information on the origin of fractures and there is no indication of sex-specific differences in the effects of genetics. The information retrieved from genetic studies nevertheless explains a minor part of the fracture risk compared to age, BMI, falls, previous fractures along with numerous other factors known to increase the prevalence of osteoporosis and fracture risk in men. In a population-based sample of elderly men followed over five years through the use of registers, it was found that family history of a hip fracture, weight loss, falls, erectile dysfunction and urinary frequency may contribute to information about fracture risk in men. Some of these factors are related to osteoporosis, while others are probably markers of frailty or underlining disease. Recently developed algorithms allow calculation of absolute fracture risk and may emerge as a more prudent method for detecting patients likely to benefit from treatment. However, there is a need for further validation of these algorithms in men. In addition, while there are several treatment options approved for use in men and even more presently under investigation, none of them has been shown to be effective in men on the basis of an estimated absolute fracture risk. Although treatment is available, male osteoporosis remains underdiagnosed and undertreated. DXA is used more commonly in women. Even though men have frequent fractures and several well-known risk factors, they are less likely to start specific anti-osteoporotic treatments. 50 18. PERSPECTIVES There are major unanswered questions. First, are the available algorithms for fracture prediction valid in Danish men? The validity of the Garvan algorithm and the QFractureScore can be investigated using the SOMA study, whereas other studies with longer follow-up time are needed for evaluation of FRAX in Danish men. Second, what are the causes of the increased mortality observed in men following fractures? As with the difference in longevity between men and women, there is no biological explanation for the increased mortality in men with fractures. Increased levels of comorbidity may explain parts of the difference. Evaluating monozygotic twins disconcordant with regard to fracture could potentially contribute information due to their shared milieu and genetics. Third, is screening for osteoporosis in men justified? And is it prudent to treat on the basis of a high fracture risk rather than a T-score? While at least two studies on population screening in women are undergoing, there are no such investigations in men. A large-scale study investigating the feasibility of male population screening is certainly needed as osteoporosis defined on the basis of a T-score appears to be inadequate for men. 51 19. APPENDICES Table 1. Randomized studies on pharmaceutical treatment of osteoporosis in men (vitamin D excluded). Bisphosphonates Alendronate Study Participants n Age Design Diagnosis Duration Endpoint 2 years BMD Conclusion [%men if mixed cohort] Orwoll (246) 241 63 DB RCT (10mg(po)/day) Low T-score(-2) BMDspine:+7.1% and/or previous BMDneck:+2.5 % fracture BMDwb:+2% Vfx (treated: 0.8% vs. PBO: 7.1%, p=0.02) Ringe (247) 134 Randomized, T-score<-2.5 in open-label the lumbar 2 year BMD 6 mo BMD spine Hwang (277) 46 Randomized, (70mg(po)/week) Greenspan (269) open-label 112 (70mg(po)/week) Gonnelli (248) T-score<-2.5 77 BMDneck: +2.7% DB RCT, Non-metastatic partial cross prostate cancer, over trial ADT 57 BMDspine:+5.5% T-score<-2.5 2 year BMD BMDspine:+6.7%. BMDneck:+3.2% 3 year (10mg(po)/day) BMD, BMDspine:+8.8%. QUS BMDneck:+4.2% BUA:+3.8% Saag (263) 477 [30% men] DB RCT (10mg(po)/day vs. Glucocorticoids 48 weeks BMD >=7.5mg BMDspine: +2.9% (10mg) vs. PBO:-0.4% 5mg(po)/day vs. BMDneck:+1.0% vs. PBO) PBO:-1.2% de Nijs (278) 201 [38% men] DB RCT Starting (10mg(po)/day vs glucocorticoids alfacalcidol >=7.5mg 18 mo BMD BMDspine: +2.1% vs, alfa: -1.9% (1mg(po)/day) Risedronate Boonen (249) 284 DB RCT T-scores: <-2.5 2 year BMD, BMDspine:+4.5% 52 (35mg(po)/week) spine or <-2 hip sec. Vfx (male reference) Wallach (264) 518 [%men] DB RCT ?? Vfx: treated 4.9% vs. 7.7%, NS 1 year (2.5mg(po)/day vs. BMD, BMDspine:+1.9% (5mg) sec. VFx vs. PBO:-1.0% 5mg(po)/day vs. VFx: RR: 0.30 PBO) Ibandronat Orwoll (250) (150mg 132 DB RCT (po)/mo) Ringe (265) 104 [47% men] T-scores BMD 1 year BMD BMDspine:+3.5% vs. spine or PBO:0.9% BMDneck <-2, BMDneck:1.2% vs. >30years PBO:-0.2% controlled, 2 year 2 year BMDspine:+11.9% vs. (2mg(iv)/3mo vs. prospective, treatment with alfa:+2.2% 1mg alfacalcidol) open-label, >=7.5mg BMDneck:+4.7% vs. parallel-group corticosteroid alfa:+1.3% study Fahrleitner-Pammer 35 RCT (251) (2mg(iv)/3mo) Cardiac 1 year transplant BMD, VFx: 13% vs. PBO: 53%. VFx BMDspine/hip: no change in treated. BMDspine/hip: -25% and -23% in PBO Pamidronate Smith (271) (60mg 47 (sc)/12 weeks) Randomized, ADT + non- 48 we BMD BMDspine/hip: no open-label metastatic change in treated. prostate BMDspine/hip: -3.3% cancer. and -1.8% in PBO Zoledronic acid Orwoll (279) 302 DB RCT 883 [%men] DB RCT 2 years BMD BMDspine: 1 year BMD BMDspine: (5mg/iv)/year vs. 70mg alendronate(po)/week Reid (266) Treatment: (5mg(iv)/year vs 5mg >3mo Treatment: Zol:+4.1% vs. risedronate(po)/day) glucocorticoid Ris:+2.7% Prevention: <3 Prevention: Zol:+2.6% mo vs. Ris:+2.0% 53 glucocorticoid (both non-inferior and superior) Lyles (252) (5mg 2127 [24% men) 75 DB RCT Hip fracture 3 years Fx, BMD (iv)/year) Fx: 8.6% PBO: 13.9%. HR: 0.65 (95%CI:0.500.84) BMDhip:+5.5% vs. PBO:-0.9% BMDneck:+3.6% vs. PBO:-0.7% Satoh (270) 40 ADT + non- (4mg(iv)/year) 1 year BMD metastatic BMDspine:+5.1% vs. controls: -4.6%. prostate cancer. Smith (272) 106 DB RCT (4mg(iv)/3 mo) ADT + non- 1 year BMD BMDspine:+5.6% 1 year BMD BMDspine:+4.0% vs. metastatic prostate cancer. Michaelson (273) 40 RCT (4mg(iv)/1year) Ongoing ADT, non-metastatic PBO: -3.1%. prostate cancer BMDhip:+0.9% vs. PBO:-1.9%) SERMs Raloxifene Smith (275) 44 70 (60mg(po)/day) RCT, open- Ongoing ADT, BMDspine:+1.0% vs. label non-metastatic PBO: -1.0% (NS). prostate cancer BMDhip:+1.1% vs. PBO:-2.6%) Toremifene Smith (1) 1,284 DB RCT (80mg(po)/day) Ongoing ADT, 2 year Fracture RR 50%. non-metastatic risk, Only epub available as of prostate cancer BMD August 2010 BMD BMDspine:+13.5% PTH analogs Teriparatide (1-34PTH) Kurland (254) (400IU(sc)1-34PTH 23 50 DB RCT z-scores <-2 of t-scores <-2.5 18mo BMDneck:+2.9% 54 in spine or femoral neck (male reference) Orwoll (253) T-scores <-2 Median (20microg (sc), in spine or hip 11 mo (20microg), +9.0% 40microg (sc) or PBO (male (due to (40microg) (sc)) reference) cancer in BMDneck:+1.5% and rats) +2.9% Saag (267) (20microg 437 DB RCT 428 DB RCT Min 3 mo of (sc) vs. 10mg >=5 mg alen(po)/day) glucocorticoid Finkelstein (280) 83 58 RCT BMDspine or 18mo BMD BMDspine:+5.9% BMD, BMDspine: +7.2% vs. sec. VFx alen:3.4% VFx: 0.6% vs. alen: 6.1% 30 mo BMD BMDspine: alen:+11.1%, (40microg vs. BMDneck <-2 alen+teriparatide:+18.0%, 40microg+10mg (male teri:+25.8% alen(po)/day vs.10mg reference) BMDneck: alen:+3.2%, alen(po)/day) Langdahl (268) alen+teri:6.2%, teri: 9.7% 83 [%men] DB RCT (20microg (sc) vs. GIO (T- 18mo BMD score<-2.5) BMDspine: 7.3% vs. 3.7% 10mg alendronate(po)/day) Calcitonin Trovas (262) (200IU 28 52 DB RCT T-score<-2.5 1 year calcitonin (nasal)/day BMD, BMDspine:+7.1% vs. BTM PBO:+2.4% BMD, Vfx: treated: 1.5% vs. sec. Vfx PBO: 3.9%, p=0.006) vs. PBO) Denosumab Smith (274;281) 1,486 DB RCT (denosumab vs. PBO) ADT + non- 3 years metastatic prostate BMDspine:+7.9% cancer. Age BMBhip:+5.7% (>70years), Tscore<-1 or osteoporotic fracture Testosterone Snyder (258) 108 73 DB RCT T<1SD and 3 years BMD BMDspine:+4.2% vs. 55 (6mg(sdermal)/day) BMDspine PBO:+2.5% (few received 125IU <mean from The lower pre-treatment vitamin D) young T the larger increase reference Kenny (259) 77 76 RCT Bioavailable T 1 year BMD, BMDneck:+0.3% vs. (5mg(dermal)/day) at lower limit LBM, PBO:-1.6% (all 400IU vitamin D) for adult BFAT, No effect BTM, increased *34% drop-out normal range BTM LBM and decreased BFAT Svartberg Emmelot-Vonk (282) 223 67 DB RCT T<13.7nM 1 year BMD, 6 mo BMD, (T undecenoate (lower half of body 160/day (po) or population- comp etc PBO) based No effect on bone distribution) Amory (260) (T 70 71 DB RCT T<12.1nmol/L 3 years BMD BMDspine:+10.2%(T), enanthate 200mg +9.3%(T+F) vs. PBO: (im)/2wk+PBO or T +1.3% enanthate 200mg BMDhip:+2.7%(T), (im)/2wk + +2.2%(T+F) vs. PBO:- finasteride 0.2% (5mg(po)/day) or double-dummy) *29% drop-out ADT: anti-androgen treatment. BFAT: total body fat. DB RCT: Double-blinded, randomized, placebocontrolled. GIO: Glucocorticoid-induced osteoporosis. LBM: lean body mass. T: testosterone. VFx: vertebral fracture. 56 Table 2. Recommendations regarding use of DXA. Men Women Notes Danish Bone Society(227) Fragility fracture OR risk factor Fragility fracture OR risk factor National Osteoporosis >50 years AND risk factor AND >50 years AND risk factor AND No need for DXA in women with fragility Guideline Group(283) Frax score within upper and lower Frax score within upper and lower fracture or men and women with a high risk assessment threshold assessment threshold as assessed by the Frax score National Osteoporosis >70 years OR >50 years + risk >65 years OR >50 years + risk Foundation(29) factor OR fracture after age 50 factor OR fracture after age 50 years years International Society of >70 years OR >50 years + risk >65 years OR >50 years + risk Clinical Densitometry (28) factor OR fracture after age 50 factor OR fracture after age 50 years years >65 years AND risk factor >65 years AND risk factor American College of Increased risk i.e. >70 years AND >65 years OR >60 years AND Risk based on risk factors rather than age Physicians(285;286) candidates for treatment increased risk defining those men that could be candidates Canadian Osteoporosis Society (284) for DXA 57 Table 3. Algorithms for absolute fracture predictions. FRAXTM 1 QFractureScoreTM 2 Garvan 3 Age Age Age Sex Sex Sex Fragility fracture in adulthood Fractures since the age of 50 Falls Falls over last 12 months Weight and height / or BMD¤ Weight and height BMD# or weight More than 3 units of alcohol/week Alcohol consumption Smoking status Smoking status Use of glucocorticoids (7.5mg/3mo) Regular use of steroid tablets Tricyclic antidepressants Rheumatoid arthritis Rheumatoid arthritis Secondary osteoporosis§ (incl. liver disease) Chronic liver disease Type 2 diabetes Heart attack, angina, stroke, transient cerebral ischemia Asthma Family history of a hip fracture 1 http://www.sheffield.ac.uk/FRAX/, 2 http://www.clinrisk.co.uk/qfracture/, 3 http://www.garvan.org.au/bone-fracture-risk/ ¤ Femoral neck BMD or T-score(female reference), # T-score or actual BMD irrespective of site, § disease associated with fracture, i.e. liver disease, type I diabetes, osteogenesis imperfecta, hypogonadism, premature menopause, chronic malnutrition, malabsorption and long-term untreated thyrotoxicosis. 58 20. 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Ann Intern Med 148:680-684. 286. Nelson HD, Helfand M, Woolf SH, Allan JD 9/17/2002 Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137:529-541. 76 21 Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism Frost M1, Abrahamsen B2, Nielsen TL1, Hagen C3, Andersen M1, and, Brixen K1 1 Department of Endocrinology, Odense University Hospital, Odense, Denmark 2 Department of Internal Medicine, Copenhagen University Hospital Gentofte, Copenhagen, Denmark 3 . Department of Endocrinology, Bispebjerg Hospital, Copenhagen, Denmark 77 Abstract: Objective: Though vitamin D and bone metabolism are closely related, few studies have addressed the effects of vitamin D status on bone in men at time of peak bone mass. The objectives of this study were to evaluate the prevalence of vitamin D inadequacy in a cross-sectional study on young men and the effects of vitamin D and parathyroid hormone (PTH) on bone mass, bone markers and metabolic function. Design and Participants: The study population consisted of 783 men aged 20-29 yrs. Measurements: Bone mineral density (BMD) of the total hip, femoral neck and lumbar spine were measured. DXA was used to evaluate total body fat mass (BFAT). Visceral and abdominal subcutaneous fat mass (ViFM and ScFM) were assessed by use of magnetic resonance imaging. A radioimmunoassay was used to measure the level of 25-hydroxy vitamin D (25OHD). Results: The prevalence of vitamin deficiency (serum 25OHD<50nM) was 6.3% during summer and 43.6% during winter. Serum 25OHD was associated with BMD at all sites and inversely associated with bone-specific alkaline phosphatase and directly with carboxyterminal telopeptide of type-1-collagen. 25OHD and PTH were inversely associated with BFAT, whereas 25OHD also was inversely associated with body mass index, waist-hip ratio, ViFM and ScFM after adjustment for confounders. The associations were found only to be present in participants with non-sufficient levels of 25OHD. 25OHD and PTH were inversely related to insulin resistance in vitamin insufficient participants only. No associations between PTH or 25OHD and blood pressures were noted. Conclusion: The study showed a high prevalence of 25OHD deficiency in young, Northern European men significantly associated with BMD. PTH and 25OHD were found to be inversely related to markers of insulin resistance. 78 Introduction Vitamin D and parathyroid hormone (PTH) are central to the regulation of calcium and bone metabolism. Studies have shown association between serum levels of vitamin D and bone mass (1) and an inverse relation with the risk of osteoporotic fractures (2), moreover some (3) but not all studies (4) show fracture reduction on treatment with vitamin D and calcium. PTH is secreted in response to reduced calcium levels causing an increase in bone resorption and subsequently normalisation of calcium levels. In case of vitamin D deficiency, secondary hyperparathyroidism resulting in increased bone turnover and increased bone loss and “remodelling space” may subsequently increase fracture risk (2). Peak bone mass (PBM) is a determinant of bone health in later life (5). The importance of PBM is emphasized by a doubling of fracture risk for every decline of one standard deviation of bone mineral density (BMD) (6). Any factor favouring gain of bone mass in early adulthood is, therefore, of great significance in order to improve bone health in late life. Most of the variation in PBM is explained by genetics (7), but several factors known to influence PBM are modifiable including physical activity (8) and levels of vitamin D (10). Studies have linked vitamin D to non-skeletal disorders including type I diabetes and cancers (11) as well as obesity (12), insulin secretion (13), hypertension and metabolic syndrome (14). PTH itself has been related to both hypertension (15) and the metabolic syndrome (16) independently of vitamin D. The aims of the present study were first to investigate the prevalence of vitamin D deficiency and insufficiency in young men at the time of peak bone mass. The definition of vitamin D status used was proposed in a recent report (17); vitamin D deficiency defined as levels of 25OHD below 50 nmol/l and insufficiency as levels lower than 75 nmol/l. Second, to assess the impact of modifiable predictors including lifestyle factors and body composition on vitamin D status. Third, to evaluate the relationship between vitamin D and PBM, bone markers and markers of metabolic syndrome. 79 Subjects and methods Subjects This is a population-based observational study on endocrine status, body composition, and bone metabolism in young men conducted in the Danish city Odense (55.2°N). The participants were recruited from a random selection of 3,000 men aged 20-29 years who all received a questionnaire concerning medical history, medication and lifestyle factors. Seventy-three per cent responded and were invited to participate in the study; in all, 783 Caucasian men consented and underwent medical examinations as well as an interview about issues affecting bone health i.e. physical activity, smoking, alcohol consumption, and vitamin D supplementation. All cases of bone disease (n=1), anabolic steroids (n=19), systemic corticosteroids (n=7), thyroid disorders (n=10), low LH (<0.1; n=6), bilateral small testicles (volume <9ml; n=16), or excessive alcohol intake (>6U/day, n=18) were excluded. Participants with a chronic disease affecting bone and vitamin D levels were non-eligible (celiac disease n=2, alcoholism n=1, inflammatory bowel disease n=2, lactose intolerance n=2, diabetes mellitus n=2, Marfan’s syndrome n=1, epilepsy n=5, congenital cretinism n=1, chronic hepatitis n=1, glomerulonephritis n=1, ankylosing spondylitis n=2). In all, 700 men were included in the study. The study was approved by the Local Ethics Committee (file 20010198) and registered in ClinicalTrials.gov as NTC00150163. Participants consented in writing, and the study was carried out in accordance with the Helsinki II declaration. Bone densitometry Dual energy X-ray absorptiometry (DXA) (H4500, Hologic Inc., Waltham, MA) was used to measure BMD (g/cm2) in the lumbar spine (L2-L4), hip and femoral neck. The coefficients of variation (CV) were 1.5% for both the lumbar spine and total hip measurements. 80 Body composition Waist and hip circumference (cm) were measured at the navel and at the greater trochanter, and waist-hip ratio (WHR) was calculated as waist divided by hip circumference. Body mass index (BMI, Kg/m2) was calculated as weight (SECA, Hamburg, Germany) divided by height2 (Harpenden, Holtain Ltd, Crymmych, UK). Lean body mass (LBM) and total body fat (BFAT) were measured by DXA. CV’s of LBM and BFAT were 3% and 3.1%, respectively. Magnetic resonance imaging (MRI) (Siemens, Erlangen, Germany) was used to evaluate visceral and abdominal subcutaneous fat mass (ViFM and ScFM, respectively) in the first 364 consecutive participants. . Abdominal subcutaneous and visceral fat mass was assessed by evaluating 3 slices recorded at the intervertebral space of L4/L5 (CV: subcutaneous: 1.7%. visceral: 7.2%) Lifestyle and blood pressure Smoking status was filed dichotomously as never/previous and current smoker. Intake of alcohol was noted as weekly consumption in units (one unit equalling 12 grams of alcohol). Use of multivitamin supplement was registered as yes or no. Consumption of vitamin D was otherwise not registered, however, in Denmark, food is with the exception of margarine not fortified with vitamin D. Physical activity was recorded as to hours spent per week on sports. Blood pressure was measured twice in a sitting position after 5 minutes of relaxation. Biochemistry All samples were collected between 8 and 10 a.m. after an overnight fast of at least 8 hours. Serum 25OHD was measured using a radioimmunoassay (DiaSorin, Stillwater, MN) (intra-assay CV: 6%). Vitamin D deficiency was defined as levels of 25OHD below 50 nmol/l and insufficiency as levels 81 lower than 75 nmol/l. A immunometric assay (Immunolite 2000, DPC, Los Angeles, CA) was used to measure serum PTH (CV: 5%). Serum TSH was measured with a non-immunoflourometric assay (CV: 2%), and a non-competitive immunoflourometric assay was used to measure serum LH (CV: 5%) (both: Delfia, WALLAC, Turku, Finland). Bone specific alkaline phosphatase (BAP) was measured by use of monoclonal capture (Metra Biosystems Inc., Mountain View, CA) (CV: 4%) while a RIA assay (Orion Diagnostica, Espoo, Finland) was used to evaluate the bone marker type1 collagen C-terminal telopeptide (1CTP) (CV: 4%). Insulin was measured using a non-competitive immunoflourometric assay (Delfia, WALLAC, Turku, Finland) (CV: 3%) and plasma glucose by use of a hexokinase-based method (Roche, Mannheim, Germany) (CV: 5.7%). Homeostasis model assessment of insulin resistance (HOMA (IR)) was calculated using the formula: s-insulin (pmol/l) x plasma glucose divided by 162 (18). Statistics Data are shown as mean ± standard deviation or median [25-75 percentiles] when appropriate. Parameters with non-normal distribution according to distribution plots and the Shapiro-Wilk’s test were log-transformed (The distributions of insulin, HOMA(IR), PTH, BAP, 1CTP, ViFM, ScFM and BFAT but not alcohol were rectified), and statistical calculations were performed on logtransformed values. Locally weighted linear regression (Lowess) was used to depict the relationship between serum 25OHD and measures of bone mass, levels of PTH, bone markers and BFAT graphically. Pearson’s correlation coefficients for correlations between 25OHD as well as PTH (log-transformed) and continuous variables were calculated. ANOVA and chi-square tests were used to compare continuous and categorical outcomes, respectively, between groups defined by vitamin D status. Kruskall-Wallis test was used for evaluation of use of alcohol. 82 Determinants of vitamin D sufficiency were evaluated by use of logistic regression analysis including vitamin D status as a dichotomous dependent variable and age, season, multivitamin supplements, smoking, alcohol, sports and BMI as independent variables. Multiple regression analyses were performed with 25OHD as the dependent variable and first BMI and secondly BFAT and LBM as independent variables. Moreover, multiple regression analyses were applied in the investigation of association between 25OHD as well as PTH and markers of metabolic dysfunction including blood pressure, body composition (waist-hip ratio, LBM, BFAT, ViFM and ScFM), lipids and insulin resistance as dependent variables. The residuals were found to be normally distributed according to normality plot. All statistics were performed with STATA v10 (STATA, TX, USA). P-values less than 5% were considered significant. Results General characteristics Median age of the participants was 25.7 [range: 19.4-30.9] years. The study population had a BMI of 24.7 (3.4) kg/m2). A total of 32.9 % (n=230) were smokers, 13 % (n=89) reported taking multivitamins (containing 200 IU of vitamin D) and 46 % (n=322) were actively participating in sports. Vitamin D status The overall serum 25OHD was 64.9 (27.7) nmol/L, and the prevalence of vitamin D insufficiency and deficiency were 31.4% (n=220) and 32.7% (n=229), respectively. As presented in table 1, the prevalence of vitamin-D deficiency was 43.6 % during winter and 6.3 % in the summer (table 1). 83 Corresponding levels of serum 25OHD in winter and summer were 59.3 (27.1) and 75.0 (19.6) nmol/l, respectively. A larger part of vitamin D sufficient participants were taking multivitamin supplements compared to insufficient or deficient participants (18 % vs. 12 % and 8 %, respectively. p=0.002) and they participated more often in sports (57 % vs. 43 % and 37 %, respectively. p<0.001), whereas fewer were smokers (28 % vs. 32 % and 40 %, p=0.015) (table 2). No significant difference in alcohol consumption was found. Calcium homeostasis Vitamin D insufficient participants had significantly higher serum levels of PTH, whereas the level of ionized calcium was unrelated to vitamin D status (table 2). Serum BAP was increased in vitamin D deficient participants (table 2 and fig 1) while the serum level of 1CTP was higher in vitamin D sufficient and deficient participants. BAP remained inversely associated with 25OHD in nonsufficient participants, whereas 1CTP was non-significantly associated with 25OHD after stratification according to vitamin D status. 25OHD was independently and inversely associated with PTH (β = -0.17, p<0.001) as well as BAP (β = -0.12, p=0.015) in the vitamin D insufficient participants only. While PTH was inversely associated with calcium levels irrespective of vitamin D status, 25OHD was positively associated with the level of calcium in sufficient and inversely associated with calcium in insufficient cases (table 3). Bone mass Participants with a sufficient level of vitamin D had significantly higher levels of BMD at all sites investigated. For the femoral neck, total hip and lumbar spine, BMD was 4.3 % (0.96 (95%CI: 84 0.99-0.17) vs. 0.92 (0.96-1.13) g/cm2, p=0.004), 3.8% (1.09 (0.98-1.18) vs. 1.05 (0.96-1.14) g/cm2, p=0.032) and 1.9% (1.08 (0.99-1.17) vs. 1.06 (0.96-1.13) g/cm2, p=0.024) higher compared to vitamin D deficient participants, respectively. The relations between vitamin D levels and BMD are presented as Lowess plots in figures 1-2. BMD appears to be stable at levels of 25OHD of at least 50nM and upwards. BMD and serum 25-OHD were unrelated in participants with 25-OHD-levels above 75 nM, whereas 25OHD was significantly associated with BMDlumbar (β =0.17), BMD neck (β =0.19), and BMD total hip (β =0.24, all p<0.001) in those with a serum 25OHD below 75nM (Table 3). Body composition BMI, waist/hip ratio, BFAT and visceral as well as subcutaneous FM were significantly different among groups defined by vitamin D status (table 2). All measures of FM were inversely correlated with serum 25OHD in unadjusted (r= -0.10; -0.22) and adjusted analyses (β= -0.11; -0.17). In separate analyses, 25OHD was found to be inversely associated with measures of FM in vitamin D non-sufficient participants only (β= -0.12; -0.18) (table 3). An inverse relationship between 25OHD and BMI was present in participants with a high BMI (fig 3); those with a BMI above 25 Kg/m2 (n=244) had a lower level of 25OHD (61.4 (27.8) vs. 66.7 (27.5) nmol/l, p=0.015). In participants with a BMI exceeding 25 Kg/m2, an increase in BMI of 1 Kg/m2 corresponded to a decrease in 25OHD of 1.7 nM (95%CI: -2.8; -0.6, p=0.002) whereas BMI and 25OHD was unrelated in participants with a BMI below 25 Kg/m2 (coef: 0.7 (95%CI: -0.6; 2.0)). PTH was found to be inversely associated with BFAT (β = -0.11) in vitamin D insufficient persons only. Additionally, 25OHD but not PTH was associated with LBM in adjusted analyses and in vitamin D insufficient participants specifically (table 3). 85 Insulin resistance, lipids and blood pressure The plasma level of insulin was significantly higher in participants with vitamin D deficiency, whereas the level of plasma glucose was similar in all groups. Accordingly, HOMA(IR) was higher in vitamin D deficient participants. Serum levels of triglycerides and HDL but not LDL were significantly different between groups defined by vitamin D status (all p<0.01) (table 2). In unadjusted analyses, PTH and 25OHD inversely associated with insulin, whereas the latter in addition was negatively associated with HOMA(IR), LDL and triglycerides and directly associated with HDL (table 3). After stratification according to vitamin D status, serum 25OHD and PTH were inversely associated with insulin and HOMA(IR) in non-sufficient participants only (table 3). PTH was inversely associated with the level of triglycerides in non-sufficient participants and directly associated with HDL in sufficient participants. Neither unadjusted nor adjusted analyses, suggested any association between PTH or 25OHD and blood pressure (table 3). Stratification according to vitamin D sufficiency had no impact on the coefficients. Predictors of vitamin D sufficiency Using logistic regression, the likelihood of being vitamin D sufficient was higher in those taking multivitamin supplementation (OR: 2.40 (95%CI: 1.45-3.84). p=0.001), study participation in seasons “Summer” and “Autumn”, (OR: 3.67 (95%CI: 2.23-6.03) and OR: 1.96 (95%CI: 1.312.92)) as well as partaking in sports (OR: 1.10 (95%CI: 1.05-1.14)) (all p<0.001). As a continuous variable, serum 25OHD was in multiple regression analysis associated with age (β=0.09; p=0.02), sports (r=0.17: p<0.001), taking multivitamins (β=0.11; p=0.003) as well as 86 seasons “Summer” and “Autumn” (β=0.23 and β=0.19; both p<0.001). Smoking and BMI were inversely associated with lower levels of serum 25OHD (β=-0.09; p=0.020 and β=-0.08; p=0.021). Median 25OHD in persons taking multivitamins was 72.8 (23.1) nmol/l and in non-users 63.7 (28.1) nmol/l (p=0.004). In the multiple regression analyses, taking multivitamins was associated with an increase in 25OHD of 9.1 nmol/L. With BFAT and LBM rather than BMI in the model, BFAT was found to be inversely (β=-0.21; p<0.001) and LBM directly associated with 25OHD (β=0.13; p=0.004) (R2adj =0.13). In separate multiple regression analyses, both visceral FM (β: -0.13; p=0.017) (R2adj =0.13) and subcutaneous FM (β: -0.14; p=0.013) (R2adj =0.13) were inversely associated with 25OHD. Discussion This study showed seasonal variation in 25OHD and a high prevalence of vitamin D deficiency in young northern-European men reaching 43.6 % during winter. Vitamin D insufficiency was, however, also prevalent during summer (41.1 %) and fall (38.3 %). Although the average 25OHD level was higher in summer, the increase was inadequate translating into a lower number of deficient and a higher number of insufficient individuals. These results emphasize the need of improvement of vitamin D status among otherwise healthy young men. Another major finding was a reduced level of BMD at all sites investigated at serum 25OHD levels below 50 nM. In absolute terms, the difference in BMD in the lumbar spine, femoral neck and total hip between vitamin D deficient and sufficient participants was 2-3 % corresponding to 0.15 SD for the lumbar spine and 0.3S D for the femoral neck and total hip. If the difference would remain into late adulthood, this could equal an increase in vertebral fracture risk of 35 % and hip fracture of 80 % (6). 87 Few studies have addressed the effects of vitamin D status on bone in men at time of PBM. During wintertime, 70 % of French boys aged 13-16 yrs were found to be vitamin D deficient (19) and in Finland, a study on 220 primarily army-recruits aged 18.3-20.6 yrs showed a prevalence of vitamin D deficiency of approximately 40 % during winter and reduced levels of BMD in the lumbar spine and total hip were reported in vitamin D deficient participants. Additionally, in 78 Swedish men mean age 22.6 yrs, cholecalciferol was associated with total body and lumbar spine BMD (20). In elderly men, 25OHD has been associated with BMD at the hip and spine (21) and increased risk of hip fractures (22). In women, studies have found both absence of an association between 25OHD and BMD in Icelandic women aged 16-20 (23) and an association between the same parameters in 14-16 yrs old Finnish adolescents (24). The NHANES III data showed an association between serum 25-OHD and BMD irrespective of gender, race and age (25), although recent data showed effect of vitamin D deficiency on BMD in white men primarily (26). Our study population consisted of men aged 20-29 yrs. Although PBM is largely attained by the end of the second decade, bone mineral accrual may continue into the third decade (27) suggesting that our study population would have reached PBM. In a 8-year follow-up study on BMD in men aged 17-26 yrs, Nordström et al. (28) found loss of BMD in the hip from the age of 19 yrs but even levels of total body and lumbar spine BMD during the last part of the study period. Changes in body composition may, however, influence the measurement of PBM as increases in lumbar spine BMD measured by DXA would continue even though increases in bone mass measured by quantitative computed tomography had ceased (29). In the present study, BMD levels appeared to increase until 25OHD reached a level of 70-80 nmol/l. Considerable increases in both PTH and BAP were found at levels of 25OHD below 50 nmol/l suggesting secondary hyperparathyroidism may be prevalent in the study population. Although participants were young, secondary hyperparathyroidism could have deleterious effects on future 88 fracture risk at this age (30). Three of the participants had 25OHD below 15nM. Should these cases indeed have osteomalacia, the overall impact on the results is probably small. Consistent with other studies, we found an inverse association between 25OHD and BMI, WHR as well as BFAT and ViFM. On stratification according to vitamin D status, the associations persisted only in non-sufficient participants even after adjustment for life style factors and seasonal variation. Previous studies (31;32) have shown inverse associations between 25OHD and waist-hip ratio or fat mass as well as a more close association between 25OHD and visceral FM than to subcutaneous fat mass (33). Although the association between visceral FM and 25OHD appeared stronger than that of subcutaneous FM and 25OHD, the correlation coefficients were comparable, and we cannot conclude if the distribution of fat mass is related to vitamin D. In our study, 25OHD was negatively associated with HOMA(IR) and triglycerides independently of BMI and several life style factors, where as no adjusted associations were found with HDL and LDL. Interestingly, the significant findings were made in non-sufficient participants only. The unfavourable relationships between 25OHD and markers of metabolic dysfunction, i.e. HOMA(IR), may be present at 25OHD below certain levels. Some earlier studies have found inverse association between 25OHD and insulin sensitivity or metabolic syndrome (32), whereas others have not (16). Accordingly, Pitas et al. found a positive effect of vitamin D on glucose metabolism in a placebocontrolled 3 yr trial (34). In some (35) but not all (15) epidemiological studies, vitamin D and blood pressure are inversely associated. The effect of vitamin D on blood pressure is not evident, and randomised trials are needed for clarification. Snijder et al. (15) found that high levels PTH was associated with increased systolic and diastolic blood pressure in a large population-based Dutch study. Our data did not suggest any association between vitamin D or PTH and blood pressure; perhaps due to differences in age of the participants. 89 The likelihood of vitamin D sufficiency was increased if multivitamins were used. Even though 25OHD was higher in users, the level remained sub-optimal. Since the brand of the multivitamins was not registered, we cannot account for the use of either D2 or D3 possibly influencing the evaluation of effects of intake of multivitamins Partaking in sports and season “summer” and “autumn” were also associated with increased 25OHD. These variables may include exposure to sunlight and information on lifestyle factors not accounted for in this study, i.e. food intake. Data also showed an inverse association between smoking as well as obesity on 25OHD levels. These predictors of sufficient vitamin D levels could be targeted in interventions for improvement vitamin D status. A strength of our study was random recruitment of the study participants from the back-ground population. Additionally, the study population was homogenous and consisted of Caucasians living in a Northern-European country only. On the other hand, our results may not be applicable to other populations. Another shortcoming was the cross-sectional design that deters us from evaluating the direction of cause and effect. In addition, several tests are performed increasing the risk of type I errors. Nevertheless, we believe data could be used for novel hypotheses. In summery, we found a high prevalence of inadequate levels of vitamin D in a population-based study on young men at time of PBM. We also found higher levels of PTH and BAP as well as lower PBM in participants with inadequate vitamin D status. 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N Engl J Med 1992 Dec 3;327(23):1637-42. (31) Lenders CM, Feldman HA, Von SE, Merewood A, Sweeney C, Wilson DM, et al. Relation of body fat indexes to vitamin D status and deficiency among obese adolescents. Am J Clin Nutr 2009 Sep;90(3):459-67. (32) Lee DM, Rutter MK, O'Neill TW, Boonen S, Vanderschueren D, Bouillon R, et al. Vitamin D, parathyroid hormone and the metabolic syndrome in middle-aged and older European men. Eur J Endocrinol 2009 Dec;161(6):947-54. (33) Cheng S, Massaro JM, Fox CS, Larson MG, Keyes MJ, McCabe EL, et al. Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart Study. Diabetes 2010 Jan;59(1):242-8. (34) Pittas AG, Harris SS, Stark PC, wson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007 Apr;30(4):980-6. (35) Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, et al. Plasma 25hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007 May;49(5):1063-9. 93 Table 1. Seasonal variation in serum 25-vitamin D in 700 young Danish men (cross-sectional study). Data are shown as mean (sd). Spring Summer Autumn Winter March-May June-August Sept.-Nov. Dec.-Feb 91 99 199 311 700 59.3 (27.1) 60.6 (27.9) 75.0 (19.6) 70.4 (29.5) 64.9 (27.7) Deficiency (n) 26.1 % 6.3 % 20.7 % 43.6 % 31.4 % Insufficiency (n) 18.3 % 41.1 % 38.3 % 28.7 % 32.7 % N Serum 25OHD (nmol/L) Chi2 test: p<0.001 Overall 94 Table 2. Vitamin D status and relation with lifestyle factors, body composition, bone mass and bone markers. Data are shown as mean (sd) or median [quartiles]. * not normally distributed. Deficiency Insufficiency Sufficiency (n=220) (n=240) (n=240) 25.3 (2.8) 25.6 (2.8) 25.6 (2.9) NS Multivitamin supplementation (y/n) 8% 12 % 18 % P=0.002 Participation in sports (y/n) 37 % 43 % 57 % P<0.001 Alcohol (units) 9 [5-15] 8 [4-16] 8 [5-15] NS Present use of tobacco (y/n) 40 % 32 % 28 % P=0.015 BMI (Kg/m2) 24.8 (4.1) 24.2 (2.9) 24.0 (3.2) P=0.001 Waist/hip ratio 0.91 (0.07) 0.89 (0.05) 0.88 (0.05) P<0.001 BFAT (Kg) * 15.3 [11.1-20.3] 13.4 [10.5-17.3] 12.9 [10.0-16.0] P<0.001 ViFM (cm2) * 39.1 [28.2-51.6] (n=90) 32.6 [25.5-48.9] (n=133) 31.6 [24.6-41.5] (n=141) P=0.021 ScFM (cm2) * 144.7 [93.3-215.8] (n=90) 136.8 [86.0-174.2] (n=133) 119.2 [74.1-160.4] (n=141) P=0.004 LBM (Kg) 63.5 (7.5) 64.0 (7.3) 63.9 (6.7) NS Glucose (mmol/L) 5.2 (0.4) 5.2 (0.4) 5.2 (0.4) NS Insulin (pmol/L) * 37 [26-53] 33 [23-45] 31 [23-41] P<0.001 HOMA (IR) * 1.2 [0.9-1.8] 1.1 [0.5-1.4] 1.0 [0.7-1.3] P<0.001 Triglycerides (mmol/L) 1.4 (1.2) 1.1 (0.7) 1.1 (0.5) P=0.003 LDL (mmol/L) 2.7 (0.9) 2.6 (0.8) 2.5 (0.7) NS HDL (mmol/L) 1.5 (0.3) 1.6 (0.4) 1.6 (0.4) P=0.006 SBP (mmHG) 124 (13) 122 (12) 123 (12) NS DBP (mmHG) 75 (10) 74 (8) 74 (9) NS PTH (pmol/L) 2.5 [1.8-3.2] 2.2 [1.6-3.1] 2.0 [1.4-2.6] P<0.001 Ionized calcium (mmol/L) 1.24 (0.03) 1.25 (0.03) 1.25 (0.03) NS BAP (U/L) * 26.5 [21.5-33.1] 24.4 [21.1-29.8] 24.5 [21.0-30.0] P=0.003 1CTP (μg/L) * 4.7 [4.0-5.6] 4.5 [3.8-5.5] 5.0 [4.2-5.9] P=0.007 Lumbar spine (g/cm2) 1.06 (0.12) 1.09 (0.13) 1.08 (0.12) 0.024 Femoral neck(g/cm2) 0.93 (0.13) 0.97 (0.14) 0.95 (0.13) 0.004 Total hip (g/cm2) 1.05 (0.14) 1.10 (0.14) 1.09 (0.14) 0.032 Age (years) p-value Lifestyle factors Body composition Insulin resistance, lipids and blood pressure Calcium homeostasis and bone markers Bone mineral density 95 Table 3. PTH and 25OHD: associations with body composition and glucose- and bone metabolism. Analyses on all participants and stratified according to vitamin status. All Participants Sufficient Unadjusted Non-sufficient Multiple regression analyses 25OHD logPTH 25OHD LogPTH 25OHD logPTH 25OHD logPTH r r β (R2adj) β β (R2adj) β β (R2adj) β BMI (kg/m2) # -0.10** <0.01 -0.11** (0.02) -0.05 0.07 (<0.01) <0.01 -0.14** (0.02) -0.08 WHR# -0.22*** 0.02 -0.17***(0.15) -0.07 -0.05 (0.07) 0.05 -0.12** (0.15) -0.13** BFAT (kg)## -0.18*** <0.01 -0.17*** (0.36) -0.08* -0.01 (0.27) -0.05 -0.18*** (0.39) -0.11** ViFM (cm2) ## -0.13* -0.04 -0.14** (0.19) -0.08 -0.04 (0.16) -0.12 -0.17** (0.20) -0.06 ScFM (cm2) ## -0.14** -0.05 -0.13* (0.27) -0.09* 0.02 (0.23) -0.09 -0.15* (0.28) -0.10 LBM (kg) ### 0.03 0.03 0.10** (0.32) 0.06 0.02 (0.28) 0.10 0.14** (0.34) 0.06 Insulin resistance, lipids and blood pressure Glucose (mmol/L) -0.06 0.01 -0.04 (0.03) <0.01 0.04 (<0.01) -0.05 -0.06 (0.04) 0.02 Insulin (pmol/L) -0.15*** -0.09* -0.11** (0.26) -0.12** 0.03 (0.13) -0.06 -0.10* (0.30) -0.14** HOMA (IR) -0.17*** -0.06 -0.11** (0.25) -0.08* 0.03 (0.16) -0.05 -0.11 (0.26)* -0.10* Triglycerides -0.15*** -0.03 -0.11** (0.09) -0.05 -0.03 (0.09) -0.03 -0.06 (0.08) -0.13** LDL (mmol/L) -0.12** -0.06 -0.09* (0.11) -0.09 -0.05 (0.11) -0.09 -0.03 (0.09) -0.08 HDL (mmol/L) 0.10* -0.06 0.02 (0.17) -0.08* -0.02 (0.20) -0.25*** 0.06 (0.17) <0.01 SBP (mmHG) <0.01 -0.06 0.01 (0.06) -0.07 0.08 (0.09) -0.02 -0.06 (0.07) -0.09 DBP (mmHG) -0.03 -0.03 -0.03 (0.06) -0.05 0.02 (0.09) -0.06 -0.06 (0.05) -0.05 Ionized calcium <0.01 -0.27*** -0.08* (0.09) -0.31*** 0.14* (0.11) -0.32*** -0.10 (0.10)* -0.32*** BAP (U/L) -0.10** 0.01 -0.09* (0.13) 0.02 -0.01 (0.16) 0.06 -0.12 (0.11)* 0.01 1CTP (μg/L) 0.10** -0.13*** 0.08* (0.32) -0.07* 0.06 (0.23) -0.06 <0.01 (0.36) -0.08 BMDlumbar (g/cm2) 0.09* 0.03 0.06 (0.12) 0.05 -0.01 (0.09) 0.01 0.18*** (0.15) 0.08 BMDfemoral neck (g/cm2) 0.07 -0.02 0.05 (0.20) 0.02 -0.02 (0.17) -0.02 0.19*** (0.23) 0.04 BMDtotal hip (g/cm2) 0.09* <0.01 0.08* (.20) 0.02 -0.06 (0.15) 0.02 0.24*** (.26) 0.04 (mmol/L) Calcium homeostasis Bone mineral density Adjustments for: age, alcohol, tobacco, sports, use of multivitamin supplements, and season and BMI (# not adjusted for BMI ## model includes LBM, not BMI ### model includes BFAT, not BMI). P-values: *p<0.05 **p <0.01 *** p<0.001 96 0 10 20 2 30 40 BAP (U/L) PTH (ng/ml) 4 50 60 6 Fig.1. Association between 25OHD and PTH as well as BAP. 0 50 100 25OHD (nmol/L) 150 200 0 50 100 25OHD (nmol/L) 150 200 1.4 1.2 1 .8 .8 1 1.2 BMD: lumbar spine (g/cm2) 1.4 1.6 1.6 Fig 2. Association between 25OHD and BMD in the lumbar spine, total hip and femoral neck. 50 100 25OHD (nmol/L) 150 200 0 50 100 25OHD (nmol/L) 150 200 .6 .8 1 1.2 1.4 0 0 50 100 25OHD (nmol/L) 150 200 97 0 50 100 150 200 Fig 3. BMI in relation to 25OHD. 15 20 25 30 BMI (kg/m2) 35 40 98 22 Osteoporosis and Vertebral Fractures in Men aged 60-74 Years M Frost1, Wraae K2, B Abrahamsen3, Hoiberg M1, C Hagen4, M Andersen1, and K Brixen1 1 Department of Endocrinology, Odense University Hospital, Odense, 2 Department of Internal Medicine, Holstebro Hospital, 7500 Holstebro, Denmark, 3Department of Internal Medicine, Gentofte Hospital, Copenhagen, 4 Department of Endocrinology, Bispebjerg Hospital, Copenhagen, Denmark 99 Abstract: Introduction and hypothesis: Limited information on the prevalence of osteoporosis and vertebral fractures in men are available. Moreover, the choice of reference values for dual x-ray absorptiometry (DXA) is debated. We evaluated the prevalence of osteoporosis and vertebral deformities in a population-based sample of men. Methods: Bone mineral density (BMD) was measured and vertebral deformities assessed using dual energy x-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), respectively, in a random sample of 600 Danish men aged 60-74 years. Results: The study population was comparable to the background population with regard to age, body mass index and co-morbidity. Osteoporosis was diagnosed in less than 1% of the participants at inclusion. Using Danish and NHANES III reference data, 10.2% and 11.5% of the study population had osteoporosis, respectively. In all, 6.3% participants had at least one vertebral fracture. BMD was significantly lower in participants with vertebral deformities, but only 24% of these cases had osteoporosis. Conclusion: Osteoporosis and vertebral fractures are prevalent in men aged 60-74 years. Although the majority of deformities were present in individuals without osteoporosis, BMD was lower in patients with vertebral fractures at all sites investigated. Male osteoporosis was markedly underdiagnosed. 100 Introduction: Osteoporosis is a leading cause of fractures in both men and women . Although the incidence of osteoporosis is lower in men than women after the age of 50 years, the lifetime risk of fractures in men older than 50 years has been estimated to 21-24 % . The worldwide distribution of fractures is uneven as the prevalence of osteoporotic fractures is higher in Northern European and in particular Scandinavian countries . Since osteoporotic fractures confer significant disability , decreased quality of life  and mortality , data on the epidemiology of osteoporosis are important for the planning of preventive efforts. Population-based information on the prevalence of osteoporosis in men is, however, limited. Bone mineral density (BMD) and vertebral fractures are predictive of future vertebral as well as non-spine fractures independently of other risk factors in men . The lifetime risk of a clinical vertebral fracture has been estimated to be 8.6% in Swedish men . Because only 25-33% of vertebral fractures are diagnosed clinically  and even sub-clinical vertebral fractures are associated with significant additional fracture risk, morbidity  and mortality , this fracture type is commonly a missed opportunity for treatment. In a large prospective study on vertebral fractures in men, approximately 3/4 vertebral fractures were caused by unknown factors or low-energy traumas, and 87% of the incident vertebral fractures occurred in participants with T-scores >-2.5 . This questions the use of DXA to detect individuals at high risk of prevalent and future vertebral fractures. Vertebral fracture assessment (VFA) is based on lateral images obtained from a bone densitometer, and the method allows for evaluation of prevalent fractures without the radiation dose of conventional radiography . Although fractures observed by use of VFA and specific algorithmbased quantitative methods have been shown to predict future spine fractures in women independently of age and BMI , information on the ability of VFA to detect incident fractures is 101 limited. Nevertheless, low radiation exposure, the possibility of combining DXA and an assessment of vertebral fracture as well as the high sensitivity of VFA to detect moderate and severe fractures  suggest that the method could prove useful as an addition to conventional bone mass assessment by DXA. Different approaches to the identification of fractures on VFA are available. The Genant semiquantitative (SQ) method is currently recommended by the International Society of Clinical Densitometry due to ease with which it can be applied to clinical practice and a substantial number of studies showing that the method is reliable and valid . Other procedures have been developed including an algorithm-based qualitative (ABQ) method that appears to identify the same prevalence of radiographic fractures as the SQ method, whereas the latter identified more fractures on VFA in women . In a US study on more than 700 men aged 65+ years, a moderate agreement between these two methods were found . The aims of the present study were first to evaluate the prevalence of osteoporosis as defined by a T-score of less than or equal to -2.5 at the total hip, femoral neck or lumbar spine in a populationbased sample of elderly men. Secondly, we aimed to determine the prevalence of vertebral fractures using VFA. Thirdly, the impact of applying Danish reference values as opposed to NHANESIII values was evaluated. Subjects and methods: Subjects Participants in the study were recruited from a random sample of the background population issued by the Danish Civil Registration System. First, 4,975 men aged 60-74 years and living in the county of Funen received a questionnaire by mail. A second letter was issued to non-respondents and the resulting response rate was 85 %. Second, an age-stratified random sample of 1,845 respondents was asked to take part in further study procedures, which was accepted by 51%. Telephone 102 interviews were conducted in 47% of these respondents as 5 respondents died and another 56 were prevented from attending the clinic due to current illnesses. In all, 697 of the 803 eligible respondents agreed to take part in a clinical assessment, and inclusion of the study participants was completed once 600 had attended clinical evaluation. The study was approved by the local Ethics Committee and all participants received written and oral information prior to giving written consent. The study was performed in accordance with the Helsinki II declaration and registered in ClinicalTrials.gov as NCT00155961. Body composition and bone mineral density Body weight was measured in light clothing (SECA, Germany) to the nearest 0.1 Kg while height was determined to the nearest 0.1 cm (Harpenden, Holtain, UK). BMI was calculated as weight divided by height squared (Kg/m2). Bone mineral density (BMD) of the total hip, femoral neck and lumbar spine were measured by use of dual x-ray absorptiometry (H4500, Hologic Inc., Waltham, MA, USA). T-scores were calculated on the basis of a Danish male reference population (Mean (SD): Spine: 1.073 (0.125)), femoral neck (0.948 (0.138)), total hip (1.078 (0.140))  and a combination of Hologic reference values for the spine (1.084 (0.111)) and NHANES III values for the hip regions (Femoral neck: 0.930 (0.136), total hip 1.040 (0.144)). Irrespective of reference material, osteoporosis was defined as a T-score at total hip, femoral neck or the lumbar spine of equivalent to or less than -2.5. Vertebral fracture assessment The same densitometer was used for vertebral fracture assessment (VFA) on postero-anterior and lateral (dual energy) images of the spine (T4-L4). As described by Rea et al. , the cranial and caudal endplates were marked by 6 points at the anterior, middle and posterior part of the vertebrae. The McCloskey algorithm  was used for the classification of fractures. In brief, a vertebrae 103 fracture was defined by 1) a 3 SD reduction in the ratio of vertebral heights compared to reference values, either the anterior-posterior, middle-posterior or between adjacent posterior ratios or 2) a 3 SD reduction in the posterior height as predicted on the basis of the adjacent vertebrae . The algorithm classified the observed vertebrae as either fractured or not. Kappa values for intra- and inter-observer agreement were 0.9 and 0.8, respectively. Statistical methods Results are presented as mean (SD) or median [25-75% percentiles] according to the observed distribution. The study population was compared to the non-respondents using Pearson’s chi square test or Student’s T-test as appropriate. T-scores were calculated as the difference between the observed value and mean reference value for young adult men divided by the standard deviation in young adult men. Osteoporotic and non-osteoporotic as well as vertebral fracture and non-vertebral fracture participants were compared by the use of chi square test, Student’s t-test or Mann-Whitney’s test, as appropriate. The ability of osteoporosis to detect vertebral fractures was evaluated by calculation of the area under the curve, and kappa statistics was used to evaluate the level of agreement between the VFA interpretations. All computations were performed using STATA v10 (STATA, College Station, TX, USA), and p-values less than 5% were considered significant. This study was supported by the World-Anti Doping Agency, Danish Ministry of Culture and Institute of Clinical Research, University of Southern Denmark. Results 104 The study population and those who were not included in the study were comparable with regard to BMI and self-reported chronic illnesses, though smoking and pulmonary disease were observed less frequently among respondents (24.4 % vs. 33.2%, p<0.001, and 6.1% vs. 9.6%, p=0.019, respectively). Also, a higher proportion of the study population reported that they were living with a partner (87.9% vs. 79.8%, p<0.001), participating in sports (15.6% vs. 8.1%, p<0.001) or had a higher education (advanced studies: 32.1% vs. 22.4%, p<0.001) (Table 1). In all, 2 participants reported a diagnosis of osteoporosis at inclusion. BMD was assessed in 585 participants corresponding to 98% of the study population. Using Danish (hip and spine) or NHANES III (with Hologic normative values used for the spine) reference values resulted in a prevalence of osteoporosis in the study population of 10.2%, and 11.5%, respectively (Table 2). Substantial differences in the prevalence of osteoporosis were found at all sites investigated, thus osteoporosis was substantially more common in the total hip and femoral neck when Danish reference values were used (4.4% vs. 0.5% and 5.8% vs. 4.1%, both p<0.01) whereas the Danish reference values resulted in a lower prevalence of osteoporosis in the lumbar spine (4.6% vs. 8.0%, p<0.01) (Table 2). VFA could be performed lege artis in 94% of the participants while evaluation of the remaining scans was impossible due to severe arthritis and scoliosis in 1.2% and poor quality of the scans in the remaining cases. None of the participants had signs of Scheuermann’s disease or malignancy. Vertebral bodies were less frequently visible in the upper part of the spine. Thus, T6L4 and T8-L4 were visible in 48 % and 95 %, respectively (Table 4). In all, 35 (6.3%) participants had at least one vertebral fracture comprising a total of 42 fractures consisting of 24 (62%) thoracic and 16 (38%) lumbar fractures of which 13 fractures (31% of all fractures) were observed in 6 individuals with at least 2 fractures. The fractures were most prevalent in the thoraco-lumbar junction and mid-thoracic spine (Table 4). 105 Including vertebral fractures as criteria for the diagnosis of osteoporosis increased the prevalence of osteoporose to 14.8% and 15.7% depending on reference values used (Table 2). Two (0.3%) of the study participants had been diagnosed with osteoporosis prior to study inclusion and were treated with bisphosphonate. Participants with osteoporosis as defined by Danish reference values were of similar age as non-osteoporotic (Table 3). In men aged 60-64, 65-69 and 70+ years, the prevalence of osteoporosis was 6.6%, 12.1% and 11.5%, respectively (p=0.06). BMI was lower in men with osteoporosis (24.7 [23.3-27.6] vs. 27.5 [25.1-29.9] kg/m2, <0.001), whereas the intake of alcohol was lower (6 [3-15] vs. 10 [6-19] units, p<0.01) and smoking more prevalent (35.5 % vs. 22.9%, p<0.05) (Table 3). Individuals with vertebral fractures on the basis of VFA had lower BMD at all sites investigated compared to the remaining study population (BMDspine: 0.95 (0.88-1.10) vs. 1.05 (0.941.17) g/cm2, p<0.01), BMDtotal hip: 0.87 (0.83-0.98) vs. 0.96 (0.87-1.04) g/cm2, p<0.001, BMDneck: 0.70 (0.64-0.75) vs. 0.77 (0.69-0.84) g/cm2, p<0.001) (Table 3). In men aged 60-64, 65-69 and 70+ years, the prevalence of vertebral fractures was 2.8%, 9.1% and 5.9%, respectively (NS). The proportion of individuals with a family history of osteoporosis or hip fracture or a sedentary lifestyle was comparable in osteoporotic and non-osteoporotic as well as vertebral and non-vertebral fracture participants (Table 3). In all, data on both VFA and BMD were available in 92% of the participants. Twentyfour percent of those with a vertebral fracture had osteoporosis irrespective of reference values used, whereas 1.5% had manifest osteoporosis defined as both a vertebral fracture and osteoporosis. For patients with two or more vertebral fractures, 33% (2 out of 6) had BMD in the osteoporosis range, which is significantly more than observed in individuals without fractures (p<0.05) (Table 3). 106 The diagnostic utility of BMD measurements for detection of coexisting vertebral fractures was independent of the reference values used (area under the curve: 0.571 and 0.566, respectively). The sensitivity of DXA using Danish and NHANESIII reference values and a T-score of ≤ -2.5 to detect the presence of a concomitant vertebral fracture were the same (24%) whereas the specificity was 91% and 90%, respectively. Positive and negative predictive values (PPV and NPV) were also similar. PPV and NPV for BMD using Danish reference values were 14% and 95% and the corresponding results for NHANESIII were 13% and 95%. Discussion This study provided for the first time observational data on the prevalence of osteoporosis as determined by DXA on a population-based sample of elderly Danish men. On the basis of local reference values , 10% of men aged 60-74 years had osteoporosis. Using NHANES III hip and Hologic lumbar spine reference values provided slightly higher but clinically similar estimates of osteoporosis in the study population. In contrast, there appeared to be substantial differences in the prevalence of osteoporosis if only one region was evaluated, i.e. 4.4% and 0.5% of the participants were osteoporotic if a Danish or NHANES III reference values for total hip were used, respectively (Table 2). The prevalence of osteoporosis in Danish men has previously been estimated to be 17.7% in those aged more than 50 years on the basis of register-based data . Our observations are not in complete accordance with these results. This is probably due to the relatively limited range of age covered in our study compared to the study population of men older than 50 years included in the register-based study as well as the fact that fractures were not included in our study. Including prevalent vertebral fractures in the definition would have increased the overall prevalence of osteoporosis in the present study by almost 50%. In addition, BMD has been shown to decrease and 107 the prevalence of vertebral fractures as depicted on radiographs appears to increase with age in men [7,19], therefore, the age of the participants is likely to have considerable impact on the prevalence of both osteoporosis and vertebral fractures. Our data do not support such age-related differences, but this may be due to the limited number of participants or the relative low prevalence of vertebral fractures. Six percent of our participants had a vertebral fracture on the basis of VFA, and most of the vertebral fractures were observed in the thoracic spine, which is in accordance with previous studies . The prevalence of fractures in our study was lower than the 12 % observed in the 50-79 years old men participating in the European Vertebral Osteoporosis Study (EVOS) , 30% observed in Moroccan men of with a mean age of 64 years  and 32% in seen in US men of a mean age of 69 years . In contrast, the result is higher compared to a Finnish study , showing a prevalence of 2.8% in men aged 75+ years. These differences are likely explained by the method used for the evaluation of fractures, differences in the diagnostic cut-off and in the recruitment of study participants. We cannot account for the mechanism causing the observed fractures, but two US studies reported that the vast majority of vertebral fractures are due to low-energy traumas or of unknown origin whereas only 18-26% of the fractures were caused by high energy trauma [7,23]. The lower levels of BMD observed in study participants with a vertebral fracture indicates that these fractures are associated with bone health and not merely due to high-energy traumas. Even if the latter was the case, high-energy trauma fractures have been associated with increased risk of further fractures , suggesting that the observed fractures confer significant risk of future fractures. The prevalence of vertebral fractures was 10-13% in the US MrOS, which included community dwelling men of significantly higher age than those in our study . Information on incident vertebral fractures is limited. In the US MrOS, the incidence was shown to be 2.2/1,000 person- 108 years. Osteoporosis was significantly more prevalent in those that experienced a vertebral fracture (13% vs. 2%), but the vast majority of fractures occurred in individuals without osteoporosis . Due to the cross-sectional design of our study, we were unable to interpret the sensitivity of osteoporosis as defined by a T-score equal to or less than -2.5 to identify future vertebral fractures. Using DXA for detection of concomitant vertebral fracture in the study population resulted in a sensitivity of only 24%. In the Rotterdam study , the sensitivity of DXA, i.e. osteoporosis as defined on the basis of DXA, to identify persons who would experience an incident non-vertebral fracture was estimated to be 44 % and 21% in women and men, respectively. These results suggest that T-score alone provides an inadequate evaluation of fracture risk. VFA rather than X-ray was used to detect vertebral fractures in the present study. Compared to radiographs, VFA appears to be less reliable in detecting grade 1 fractures in the upper thoracic spine, however, conventional x-ray evaluations are also less precise in this region . We used the McCloskey algorithm for the evaluation of the VFA. This algorithm has been shown to predict incident fractures as identified by radiographs in both men and women [27,28]. This algorithm has also been applied to VFA and results in women showed that the McCloskey algorithm was able to predict incident fractures independent of several factors including BMD . Nevertheless, although fractures are less common in men, we are not aware of any indications suggesting that the method should not be appropriate in men. Our results on VFA may have been influenced by problems of detecting grade I fractures, and it is likely that radiographs would have allowed evaluation of a larger proportion of vertebrae. Although most fractures occur between T7 and L3 , our estimate of the prevalence of vertebral fractures is likely to be conservative. The present study is also weakened by the infrequency of osteoporosis in the study population due to the age of the study population rather than a lack of external validity. The limited frequency of the outcome of interest has probably weakened the interpretation of a 109 potential relation between age and osteoporosis or vertebral fractures. Adding to that, the results may only be valid to Caucasian men aged 60-75 years. Our study has a number of important strengths. First, the use of a population-based sample of men limited the risk of selection bias. Second, acquisition of data by questionnaire in non-participants allowed us to demonstrate that the study population was indeed comparable to the general population of age- and sex-matched men. Our results, therefore, provide a reasonable estimate of osteoporosis in elderly, Danish men. Thirdly, the lower levels of BMD observed in fracture patients supported that these cases at least in part are related to poor bone mass and structure rather than to reminiscences of prior high energy traumas. While VFA may not detect grade I fractures or depict the upper part of the thoracic spine, data support the use of this method in men with risk factors for fractures including a low T-score. The International Society of Clinical Densitometry currently recommends the use of VFA in men with a low T-score and one of several risk factors , nevertheless, our data suggest that VFA should be used in all men evaluated with DXA. In conclusion, in our population-based study on men aged 60-74 years, less than 1% reported osteoporosis at inclusion but in fact a total of 10% had osteoporosis and 6% had at least one vertebral. There was no overall substantial difference between results derived from using Danish and NHANES-III reference values but there were significant differences with regard to the prevalence of osteoporosis in specific regions, i.e. 4.4% had osteoporosis at the total hip using Danish reference values while only 0.5% was osteoporotic on the basis of the NHANES values. Moreover, our data demonstrate that VFA adds important information on bone status not captured by T-scores derived from DXA. 110 Table 1. Comparison of the study population and individuals declining participation in the study. Study population Declined participation Normal weight (BMI 18.5-24.9 kg/m2) 36.4% 34.5% Overweight (BMI 25-29.9 kg/m2) 48.5% 49.7% Obese (BMI >30 kg/m2) 14.9% 15.3% Self reported healthy 47.6% 46.5% Diabetes mellitus 6.5% 7.4% Hypertension 22.1% 21.5% Ischemic heart disease 12.6% 11.5% Pulmonary disease 6.1% 9.6%* Osteoporosis 0.2% 0.6% Thyroid disease 0.5% 0.9% Social and life style factors Smoking 22.4% 33.2%*** Sports (1-3 hours/week) 15.6% 8.1%*** High school or technical studies 26.7% 24.2%** Advanced studies 32.1% 22.4%*** Non-retired 20.9% 19.7% Living with a partner 87.9% 79.8%*** *p<0.05 *** p<0.001 111 Table 2. Prevalence of osteoporosis according to reference values. Measurements (n=585) Danish reference NHANES III Lumbar spine (g/cm ) 1.05 (0.18) 4.6 % 8.0 %* # Femoral neck (g/cm2) 0.77 (0.12) 5.8 % 4.1 %* Total hip (g/cm2) 0.95 (0.13) 4.4 % 0.5 %* 10.2 % 11.5 %* Prevalence of osteoporosis defined as either low T-score, VFx or both 14.8% 15.8%* Prevalence of both osteoporosis and VFx 1.5% 1.5% 2 Prevalence of osteoporosis Prevalence of vertebral fractures: 6.3% # Hologic reference for lumbar spine used. * Prevalence significantly different from that derived from Danish reference values 112 Table 3. Comparison of participants with and without osteoporosis or vertebral fracture (VFx). Danish reference values used for the diagnosis of osteoporosis. Osteoporosis No osteoporosis VFx No VFx >1VFx (n=61) (n=524) (n=35) 69 [65-71} 68 [64-71} 69 [67-71] 68 [64-72] 68 [67-68] 42.6% 38.4% 37.1% 39.6% 0% 24.6 [23.3-27.6]*** 27.5 [25.1-29.9] 27.8 (25.5-30.7) 27.1 (24.7-29.6) 28.3 (26.1-29.8) Lumbar spine (g/cm2) 0.80 [0.73-0.91]*** 1.06 [0.96-1.18] 0.95 [(0.88-1.10]* 1.05 [0.94-1.17] 0.92 [0.83-1.05] Femoral neck (g/cm2) 0.60 [0.57-0.64]*** 077 [0.71-0.84] 0.70 [0.64-0.75]*** 0.77 [0.69-0.84] 0.69 [0.59-0.73]* Total hip (g/cm2) 0.74 [0.72-0.79]*** 0.96 [0.90-1.05] 0.87 [0.83-0.98]*** 0.96 [0.87-1.04] 0.84 [0.75-0.85]** Osteoporosis 4.9% 6.7% 11.4% 6.3% 16.7% Hip fracture 9.8% 9.0% 8.6% 9.2% 0% 36.3% * 22.9% 17.1% 24.1% 16.7% Alcohol (units/week) 6 [3-15]** 10 [6-19] 8 [6-16] 10 [6-19] 12 (8-21) Sedentary lifestyle¤¤¤ 27.9% 24.4% 34.3% 23.7% 33.3% (n=6)¤ Age and BMI Age (years) Proportion aged > 70 years BMI (kg/cm2) Bone mineral density Family history of osteoporosis ¤¤ Life style factors Smoker (yes/no) *p<0.05, **p<0.01, *p<0.001 ¤ Compared to the study population including those with one fracture. ¤¤ First degree relative with either osteoporosis or hip fracture ¤¤¤ Sedentary lifestyle defined as METS belonging to the lowest quartile 113 Table 4. Distribution of observed vertebrae and fractures in 558 men aged 60-74 years. Vertebrae Proportion of visible Number of fractures vertebrae Proportion of vertebrae with fractures Th4 3 0.5 % 0 0 Th5 19 3.4% 0 0 Th6 270 48.4% 2 0.7% Th7 475 85.1% 7 1.5% Th8 531 95.2% 5 1.0% Th9 544 97.5% 2 0.4% Th10 550 98.6% 3 0.5% Th11 551 98.7% 3 0.5% Th12 554 99.3% 4 0.7% L1 556 99.6% 9 1.6% L2 557 99.8% 4 0.7% L3 558 100% 1 0.2% L4 556 100% 2 0.4% 114 Reference List 1 Genant HK, Cooper C, Poor G, Reid I, Ehrlich G, Kanis J, Nordin BE, Barrett-Connor E, Black D, Bonjour JP, wson-Hughes B, Delmas PD, Dequeker J, Ragi ES, Gennari C, Johnell O, Johnston CC, Jr., Lau EM, Liberman UA, Lindsay R, Martin TJ, Masri B, Mautalen CA, Meunier PJ, Khaltaev N, . Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis. Osteoporos Int 1999; 10: 259-64 2 Kanis JA, Johnell O, Oden A, Sembo I, Redlund-Johnell I, Dawson A, De Laet C, Jonsson B. 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Acta Orthop Scand 2001; 72: 273-78 117 23 Risk factors for fracture in elderly men. A population-based prospective study Frost M1,2, Abrahamsen B2,3, Masud T2,4 and Brixen K1,2 1 Dept. of Endocrinology, Odense University Hospital, Odense, Denmark 2 Clinical Research Institute, University of Southern Denmark, Odense, Denmark 3 Dept. of Medicine F, Copenhagen University Hospital Gentofte, Hellerup, Denmark 4 Dept. of Geriatrics, Nottingham City Hospital, Nottingham, UK, and Department of Geriatrics, Odense University Hospital, Odense, Denmark 118 Abstract Introduction and hypothesis: Knowledge about risk factors for fracture in men is limited. The aim of this study was to evaluate factors potentially associated with fracture risk in men. Methods: A questionnaire enquiring about potential risk factors for fractures in men was posted to a random sample of 9,314 men aged 60-74 years. A completed questionnaire was returned by 4,696 (50.4%). Follow-up on incident fractures over 5.4 years was performed using public registries. Results: During the study, 203 individuals experienced a first clinical fracture, of which 85 patients were considered osteoporotic (9 in humerus, 10 vertebral, 32 in the hip and 34 in the forearm). Cox proportional hazard regression models were used to evaluate risk factors for any and osteoporotic fractures. The following variables were found to be associated with increased risk of any fracture in adjusted models family history of a hip fracture (HR; 95%CI: 1.56; 1.05-2.33), falls (2-4/year: 2.10; 1.35-3.27, >4/year: 2.46; 1.12-5.41, both compared to no falls), dizziness (2.36; 1.51-3.71), erectile dysfunction (1.41; 1.06-1.87) and frequent urination (2.06; 1.26-3.39). Similarly, falls (2.36; 1.453.86), dizziness (2.83; 1.52-5.25), erectile dysfunction (2.01; 1.30-3.09) and pulmonary illness (1.90; 1.03-3.53) were associated with increased risk of osteoporotic fractures in adjusted models. Conclusion: These results underline the importance of assessment of dizziness, falls and those with a family history of hip fracture. Frequent urination and erectile dysfunction were independently associated with increased fracture risk. Although the mechanism of association is unknown, these variables are likely to be indicators of frailty or hypogonadism. 119 Introduction Fracture incidence is gender-specific, where fractures in young adults occur most frequently in men and fractures in the elderly occur most frequently in women. The lifetime risk of fracture for women above 50 years of age is approximately 50 % while that of men is around 20 % . Of all the osteoporotic fractures observed globally in the year 2000, 39 % were sustained by men . In addition, the consequences of fractures differ between the genders, as hip fractures have been associated with twice the mortality rate in men as in women [3,4]. The causes of these differences in fracture incidence are presently not obvious. Intrinsic factors, such as bone structure and strength and the abrupt decline in sex hormone levels observed at menopause, as well as extrinsic issues, such as an increased risk of falls among women , may explain some of the higher fracture incidence observed in older women. A number of factors have been shown to increase the risk of a fracture in men. Fracture incidence increases after the age of 50 years and in particular after the age of 75 years [6,7]. Low body mass index (BMI) , smoking , walking disability [10,11], a family history of fracture  and a fracture after the age of 50 years  have also been shown to contribute to fracture risk in men. While it makes biological sense that many risk factors for fracture in women should also apply to men, the number of prospective studies evaluating other potential risk factors for osteoporotic fracture in men is limited. Cohort studies have linked type 2 diabetes (T2DM) , cardiovascular disease  and hypertension  with osteoporotic fractures in men , suggesting that these variables could prove useful in fracture prediction. Register-based studies have identified several medications that were associated with fracture risk in men [16,17]. In addition to insights into the pathophysiology of male osteoporosis, the risk conferred by these variables could be translated into clinically useful predictor variables once confirmed in different populations. Recently, a WHO collaborative centre has developed an assessment tool (FRAX) that predicts an individual’s 10-year 120 fracture risk on the basis of BMI, clinical risk factors and bone mineral density (BMD) in men and women . In addition, the Garvan fracture risk calculator  and the QFractureTM fracture prediction algorithm have become available . Even though several risk factors have been established, osteoporosis remains under-diagnosed and inadequately treated in men [3,20]. The aim of the present study was to evaluate self-reported clinical risk factors for fracture in a population-based cohort study in Danish men aged 60+ years. First, we wanted to evaluate the importance of non-modifiable risk factors, such as age and family history of hip fracture or osteoporosis. Second, we wanted to test a number of at least partly modifiable factors potentially associated with fracture risk including i) life style and obesity, ii) mobility, iii) diabetes and cardiovascular disease, iv) genitourinary illness, v) gastrointestinal illness and vi) certain miscellaneous factors. 121 Subjects and methods Subjects The Study on Male Osteoporosis and Aging (SOMA) is an ongoing 10-year, prospective, population-based study on aspects of aging in men. The study was performed as a single-centre study of Danish men living in the Funen County. Recruitment of participants was based on the Danish Civil Registration System (CRS). In Denmark, every citizen is assigned a unique 10-digit identification number by birth. In the autumn of 2004, a questionnaire was posted to a random sample comprising 9,314 men aged 60-74 years living in Funen County. By returning the questionnaire and providing written consent, the responders accepted collection of data and a register-based follow-up on incident diseases including fractures. Non-responders were sent a reminder letter. In all, 4,939 questionnaires were returned with consent to participate; however, only 4,696 of these were completed, rendering the response rate 50.4 %. The study was approved by the local ethics committee (reference number: 20030230) and the Danish Data Protection Agency, and was listed at clinicaltrials.gov (NCT00463411). Registry data Using the individual’s CRS identification number, information on marital status, education, employment and socioeconomic data as of 2004 were retrieved from the national demographic databases of Statistics Denmark (ref.no. 703026). Data on all hospital contacts since 1977 and visits to outpatient clinics since 1999 were retrieved from the Danish National Hospital Registry (DNHR). Information on morbidity was retrieved from the DNHR, and the Charlson comorbidity index  was calculated on the basis of diagnoses as classified in the International Classification of Disease 10th Revision (ICD-10) registered during the last 3 years prior to inclusion. 122 Local hospital discharge records were used for follow-up for vital status and incident fractures. All first fractures after the completion of the questionnaire were recorded and categorized as either any fracture or osteoporotic, the latter including forearm, humerus, clinical vertebral and hip fractures. In order to evaluate the representativeness of the study cohort, their socioeconomic and morbidity data were compared with the data for all Danish men belonging to the same age group in autumn 2004, totalling 339,885. Questionnaires The questionnaire covered 41 items including self-reported height and weight (continuous) as well as loss of height and weight since the age of 25 years (categorical: yes/no). Further items asked about use of tobacco (categorical: present, past and never smoker) and alcohol (categorical: 0, 1-7, 8-14, 15-21, >21 units or unknown). Physical activity items included any difficulties in walking (categorical: yes/no), use of walking aids (categorical: yes/no), and falls during the last year (categorical: times/last year: 0, 1, 2-4, 5-8, 9-12, >12, unknown). Participants were asked about medical history, current disorders and symptoms from all organ systems (categorical: yes/no; those responding ‘yes’ were asked to write the diagnosis or symptom(s)). Participants were specifically asked about previous testicular disease (categorical: yes/no) and treatment with testosterone (categorical: yes/no). In this study, hypogonadism was defined as bilateral orchiectomy in the absence of prostate cancer or prescription of testosterone. Erectile dysfunction (ED) was evaluated by the question “do you suffer from impotence” (categorical: yes/no). The variables ‘dizziness’ and ‘frequent urination’ were derived from self-reported symptoms. Family history items included hip fracture after the age of 50 years (first-degree family) and familial disposition for osteoporosis (first-degree family). 123 The questionnaires were scanned electronically. Items covering medical history and present symptoms could be answered in writing. If the computer was unable to interpret a written response and two staff members were unable to interpret the answer, the response was coded blank. Statistics Comparisons with the age-matched Danish male population with respect to register-based data on socioeconomics and morbidity were made using Student’s t-test, Mann-Whitney test (median Charlson index) or chi-square, as appropriate. Data on responders and non-responders were assessed separately. Cox proportional hazard regression models were used to establish the relative hazard and 95% confidence interval for the initial fracture or primary osteoporotic fracture (clinical vertebral, hip, forearm, humerus) using a time line from September 2004 to the first fracture, death or end of study in January 2010. Models including self-reported variables and register-based data were used. All variables used in the models were present in at least 1 % of the participants. The first model included non-modifiable variables including age in 3 strata (60-65, 65-70 and >70 years) and a family history of hip fracture or osteoporosis. All subsequent models incorporated a number of potential risk factors as well as the variables from the first model. In the second model, BMI in 5 strata (<18.5, 18.5-25, 25-30, 30-35 and >35 kg/m2), smoking status (dichotomous: present/previous or never smoker), alcohol intake (none, 1-6, 7-14, 15-21, >21 units/week) and weight loss since the age of 25 years were applied. The third model evaluated mobility by including use of arms for chair stand, walking disabilities, dizziness and falls (0, 1, 2-4 or >4 falls per year). In sub-analysis, the effect of falls on fracture risk was assessed after stratification according to age group or BMI. Type II diabetes (T2DM), hypertension, ischemic heart disease (IHD), stroke, hyperlipideamia, atrial fibrillation, gout and 124 erectile dysfunction (ED) were all included in the fourth model. Enlarged prostate, hypogonadism (including prescription of testosterone or bilateral orchiectomy but not prostate cancer) and frequent urination were fitted in the fifth model. The sixth model included diarrhoea and peptic ulcer, while the last model included rheumatoid arthritis, epilepsy and pulmonary disorders (COPD, asthma and chronic bronchitis). For each factor identified as having a significant association with fracture risk, population attributable risk (PAR) was calculated as prevalence multiplied by the hazard ratio . Calculations were done using STATA version 10 (StataCorp, College Station, TX, US). Significance level was set at p<0.05 using two-sided tests. Results Comparison of responders, non-responders and general population The 4,696 responders were slightly older than non-responders and the background population. The fraction of responders who were married was significantly greater than among non-responders and the background population, and significantly fewer were widowers (Table 1). Personal net income was substantially higher in responders compared to non-responders and the general population (Table 1). In addition, significantly more responders were on pre-retirement pension, whereas fewer were on retirement or disability pension (Table 1). Significantly more responders had a Charlson index of 0 compared to non-responders and the background population (Table 1). The number of individuals with a Charlson index exceeding 6 was higher among non-responders than in the background population (Table 1). Incident fractures 125 During a mean follow-up of 5.4 years (range 0-5.4 years), 203 participants experienced one or more fractures (only the first fracture in each participant was considered). In all, 85 patients suffered osteoporotic fractures (9 in humerus, 10 clinical vertebral, 32 in the hip and 34 in the forearm). Model 1: Non-modifiable factors Age was not significantly associated with risk of either an osteoporotic or any fracture. In univariate analyses, family history of hip fracture or osteoporosis was significantly associated with fracture risk. After adjustments for BMI and the other variables in the model, only family history of hip fracture remained associated with the risk of any fracture (HR=1.56; 95%CI 1.05-2.33) (Table 2). Model II: Life style factors and obesity Based on self-reported body weight and height, mean BMI was 26.8 ± 4.3 kg/m2 (Table 2). Weight loss since the age of 25 years was reported by 8.6 %, while 27.2 % were current smokers and 46.5% were previous smokers (Table 1). Alcohol consumption exceeding 21 units per week was reported by 10.2%. Neither smoking nor alcohol consumption was significantly associated with fracture risk. Those with a loss of weight after the age of 25 years had an increased risk of any and osteoporotic fractures in the complete model including age (HR=1.62; 95%CI 1.05-2.49 and 2.17; 1.18-3.97, respectively), whereas no association was seen with the other variables. Model III: Mobility Eight per cent of the participants reported always using chair arms when standing up from a chair, 13.5 % experienced some level of walking impairment, 4.6 % had dizziness and 19.6 %, 6.6 % and 1.5 % reported at least one, 2-4 or more than 4 falls during the previous year, respectively. When 126 compared to men who did not report a history of a fall, those who reported one fall were significantly more likely to fracture (any: HR=1.56; 95%CI: 1.06-2.31 and osteoporotic: 2.59; 1.564.30, respectively). For any but not osteoporotic fractures, a higher prevalence of self-reported falls was associated with increased hazard ratios (2-4 falls pr year: HR=2.18; 95%CI 1.41-3.37 and >4 falls/year: 2.46; 1.12-5.41) (Table 2). Reporting dizziness was associated with any and osteoporotic fracture (HR=2.34; 95%CI 1.49-3.68 and 2.81; 1.48-5.32, respectively) (Tables 2 and 3). Neither the use of chair arms for standing up or walking difficulty was significantly associated with fracture risk (Tables 2 and 3). In individuals with a BMI below 25 kg/m2, the risk of fracture was higher among those reporting at least 4 falls (HR=6.6; 95%CI 2.6-16.5) compared to those with a single fall (HR=2.5; 95%CI 1.44.6): There was no such effect in men with a BMI exceeding 25 kg/m2 (Table 4). Stratifying according to age group showed increasing risk of fractures among those older than 70 years with multiple falls compared to those with only one fall in the year prior to the survey (HR=4.6; 95%CI 1.4-15.1 vs. 1.7; 0.8-3.7) (Table 4). Model IV. Diabetes and cardiovascular disease Men reporting hypertension had an increased risk of any fracture in the complete model including adjustments for age and BMI compared to those without hypertension (HR=1.41; 95%CI 1.011.97). In the same model, men who reported erectile dysfunction (ED) had an increased risk of both any and osteoporotic fractures compared to those not reporting ED (HR=1.48; 95%CI 1.12-1.96 and 2.18; 1.40-3.39, respectively): Neither of the other variables influenced fracture risk (Table 2). Model V. Genitourinary condtions 127 Men reporting frequent urination were more likely to fracture (any: HR=2.57; 95%CI 1.58-4.18 and osteoporotic: 2.80; 1.35-5.82, respectively). There were no incident fractures among participants reporting hypogonadism. Model VI. GI-tract related symptoms Neither of the variables related to the gastrointestinal tract was associated with fracture risk. Model VII. Miscellaneous variables Men reporting COPD, asthma or chronic bronchitis were more likely to experience an osteoporotic fracture compared to men without pulmonary disease (HR=2.16; 95%CI 1.17-3.98). Neither rheumatoid arthritis nor epilepsy was associated with fracture risk (Table 2). Complete model Any fracture In the model including all variables demonstrated in separate models to be associated with any fracture risk, participants reporting family history of hip fracture had an increased fracture risk (HR=1.68; 95%CI 1.14-2.49). Similarly, men with a history of one fall (HR=1.47; 95%CI 1.002.17), 2-4 falls (2.10; 1.37-3.22) or more than 4 falls (2.34; 1.08-5.07) in the past year or dizziness (2.00; 1.28-3.14) were all more likely to fracture. Equally, both men with ED and those with frequent urination had an increased risk of any fracture (HR=1.39; 95%CI 1.04-1.84 and 2.05; 1.253.36, respectively) (Table 2). Osteoporotic fracture Individuals reporting more than one fall in the previous year and those reporting dizziness had an increased risk of fracture (HR=2.43; 95%CI 1.46-4.03 and 2.72; 1.45-5.10, respectively). Also, men 128 with ED (HR=2.04; 95%CI 1.31-3.18) were significantly more likely to sustain a fracture. Participants with a pulmonary disorder (HR=1.95; 95%CI 1.05-3.62) but not men with weight loss since the age 25 years (HR=1.68; 95%CI 0.93-3.06) had an increased fracture risk. PAR The PAR estimates ranged from 8.2 for more than 4 falls per year to 27.5 for 2-4 falls per year for any fracture, and PAR for at least one fall in the preceding year was 64.4 for osteoporotic fractures (Table 5). PAR estimates for dizziness were 22.6 and 38.4 for any and osteoporotic fractures, respectively. The PAR estimates for frequent urination and pulmonary disease were 18.2 and 27.5 for any and osteoporotic fractures, respectively. Discussion In this prospective population-based study on fractures in elderly Danish men, self-reported erectile dysfunction was found to be associated with an increased risk of fractures. To the best of our knowledge, this is the first report on an association between ED and fracture risk in men. We also found an association between frequent urination and an increased risk of any as well as osteoporotic fractures. The study results further emphasized the importance of falls and dizziness as well as family history of hip fracture and pulmonary disorders for risk of fractures. Whether ED is sentinel to future fractures in men is tentative. BMD and ED were previously not found to be associated with fracture risk in a small cross-sectional study of 75 men aged over 50 years . In our large cohort, we found ED to be associated with fracture risk after adjustment for multiple factors potentially causing the dysfunction. ED probably captures effects not accounted for in our study, including low serum testosterone and vascular insufficiency. Future studies incorporating biochemical tests are needed to evaluate the association so that adjustment can 129 be made for sex hormone levels. Several studies have evaluated the importance of hypogonadism or low levels of sex steroids on fracture risk [24-26]. Although medical history allowed us to evaluate the effects of hypogonadism defined on the basis of prescription of testosterone or bilateral orchiectomy (n=48), fracture risk appeared not to be increased in these cases; the number of participants with these conditions was low, however. Few studies have evaluated the association between self-reported frequent urination and fracture risk in men. In a retrospective study, increased nocturnal micturition and nocturnal urine output were associated with risk of hip fracture  whereas nocturia has been shown to be a risk factor for incident hip fractures . Nocturia could influence fracture risk in men through an increased incidence of falls. Although frequent urination appeared to influence fracture risk independently of falls in our study, we cannot exclude the possibility of an explicit effect of nocturia on fracture risk. Reporting a family history of hip fracture but not osteoporosis was found to be associated with an increased risk of any fractures, which is in line with the meta-analysis by Kanis et al.  showing that a parental history of a fracture was associated with an increased risk of an osteoporotic fracture, whereas in a substantially larger UK study, a family history of osteoporosis and future fractures in men were unrelated . Our results emphasize the significance of falls in the context of fractures and contribute new information on dizziness as a relevant predictor of fractures in men. These findings were unaffected by variables likely to include information on balance and agility, such as walking disabilities. Recently, falls were found to increase the risk of osteoporotic fractures in UK men . It appears that fall prevention is essential to fracture prevention in men as in women. Although dizziness probably predisposes to falls, our results may be confounded by several factors. Physical incapacities causing falls or dizziness could have been captured by 130 adjusting for self-reported walking difficulties or problems with standing from a chair, but none of these variables were related to fracture risk. The association between pulmonary disorder and an increased risk of osteoporotic fracture is in line with previous research. COPD, asthma and use of inhalation and oral steroids were associated with bone loss in both spine and hip as well as an increased risk of vertebral and non-vertebral fractures in a US male cohort study , while others found an increased fracture risk in men with asthma or currently on corticosteroids . In addition, Vestergaard et al.  found a 1.2-1.3 times higher risk of fractures in patients with a chronic pulmonary disorder. Together, these results underline the importance of assessment of pulmonary disorders in fracture prevention in men. From a theoretical point of view and presuming a cause-effect relationship between the risk factor and fracture occurrence, the elimination of several factors found to increase fracture risk could substantially reduce the prevalence of fractures. We did not combine all the PAR results in a single estimate as many of the factors may be related, but falls, dizziness and frequent urination are all potentially modifiable. These results suggest a potential for reducing the burden of fractures in men by addressing a number of prevalent issues, including falls. Advantages of the present study were the random selection of the study population and the possibility to evaluate the representativeness of the study population. Although the study participants were not comparable to the age-matched male background population on all parameters, the differences were small. Our results may have been affected by the study population being more healthy and wealthy, however, and this is important when extrapolating the study results to the general population. None of the participants were lost to follow-up and, due to the public nature of the Danish health system; there was free access to health care for all those with incident fracture. 131 Our study had some limitations. The sensitivity of the approach could be questioned as our data did not identify an effect of age, BMI, smoking and alcohol on fracture risk contrary to other reports [6-9,13,32,33], although we did find an adverse effect of weight loss since adulthood on fracture risk. Only baseline information was available for fracture prediction in this study, and changes in comorbidity are very likely. Recall and information bias are likely to have influenced some of the data, such as the recollection of hip fractures in relatives. Alcohol intake, height and weight are likely to be influenced by report bias and should be interpreted with caution. We used a public register for random selection of our study population; however, selection bias cannot be excluded. In addition, data on fractures were obtained from the public register and thus depend on proper classification and regular update. As spinal X-rays and biochemical tests were not part of the study, we could not identify incident vertebral fractures not coming to clinical attention or adjust for the levels of sex hormones and other biochemical factors. In conclusion, we found erectile dysfunction and self-reported frequent urination to be associated with fracture risk in elderly men. The results of this prospective population-based study underline the importance to fracture prevention of assessment of falls, dizziness and pulmonary disorders as well as weight loss since adulthood. Finally, our data support a positive association between family history of hip fracture and increased fracture risk. Acknowledgements The study received financial support from the Institute of Clinical Research, University of Southern Denmark, the Novo Nordisk Foundation and the Velux Foundation. Conflicts of interest: none 132 Reference List 1 van Staa TP, Dennison EM, Leufkens HG, Cooper C. 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Stat Methods Med Res 2001; 10: 195-216 23 Keles I, Aydin G, Orkun S, Basar MM, Batislam E. Two clinical problems in elderly men: osteoporosis and erectile dysfunction. Arch Androl 2005; 51: 177-84 24 Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, Rockwood AL, Meikle AW, Center JR, Eisman JA, Seibel MJ. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med 2008; 168: 47-54 25 Leblanc ES, Nielson CM, Marshall LM, Lapidus JA, Barrett-Connor E, Ensrud KE, Hoffman AR, Laughlin G, Ohlsson C, Orwoll ES. The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men. J Clin Endocrinol Metab 2009; 94: 3337-46 26 Amin S, Zhang Y, Felson DT, Sawin CT, Hannan MT, Wilson PW, Kiel DP. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med 2006; 119: 426-33 27 Asplund R. Hip fractures, nocturia, and nocturnal polyuria in the elderly. Arch Gerontol Geriatr 2006; 43: 319-26 28 Temml C, Ponholzer A, Gutjahr G, Berger I, Marszalek M, Madersbacher S. Nocturia is an age-independent risk factor for hip-fractures in men. Neurourol Urodyn 2009; 28: 949-52 29 Kanis JA, Johansson H, Oden A, Johnell O, De Laet C, Eisman JA, McCloskey EV, Mellstrom D, Melton LJ, III, Pols HA, Reeve J, Silman AJ, Tenenhouse A. A family history of fracture and fracture risk: a meta-analysis. Bone 2004; 35: 1029-37 30 Dam TT, Harrison S, Fink HA, Ramsdell J, Barrett-Connor E. Bone mineral density and fractures in older men with chronic obstructive pulmonary disease or asthma. Osteoporos Int 2009; 31 Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids. Chest 2007; 132: 1599-607 134 32 Olofsson H, Byberg L, Mohsen R, Melhus H, Lithell H, Michaelsson K. Smoking and the risk of fracture in older men. J Bone Miner Res 2005; 20: 1208-15 33 Kanis JA, Johansson H, Johnell O, Oden A, De Laet C, Eisman JA, Pols H, Tenenhouse A. Alcohol intake as a risk factor for fracture. Osteoporos Int 2005; 16: 737-42 Table 1. The SOMA study population. Comparison with non-responders and the complete Danish population of men aged 60-74 years. n Age (y) Income (£) SOMA 4,939 65 (60-75) 17,544¤¤ Non-SOMA 4,373 66 (60-75) 13,434 Population 339,885 66 (60-75)# 15,479## Civil status Married Widower 80.9%¤¤ 6.3%¤¤ 68.7 % 8.4 % 73.7%## 7.0 %# Socioeconomics Public old age pension Pre-retirement pension Public disability pension 31.2%¤¤ 25.9 %¤¤ 6.7 % ¤¤ 39.2 % 23.2 % 11.1 % 37.1 %## 23.2 %# 8.5 %## Charlson Index 0 1-2 3-4 4-5 6-> 43.0 %¤¤ 11.8 % 0.9 % 0.4 % 36.1 %¤¤ 36.5 % 12.2 % 1.1 % 0.5 % 40.9 % 39.8 %## 10.9 %# 1.0 % 0.5% 39.1%## Values as mean, median (min-max) or per cent SOMA responders vs non-responders: SOMA vs. general population: ¤ p<0.05, ¤¤ p<0.001 # p<0.05, ##: p<0.001 135 Table 2. Predictors of any fracture. Univariate HR (95%CI) Age: 60-65 years Age: 65-69 years Age: 70-74 years Family history of HFx after 50 years Osteoporosis in family Fx/No.reporting variable 80/1825 69/1552 54/54/1116 31/419 28/388 Univariate Fracture Model HR (95%CI) Comprehensive model with significant findings from models 1-7 HR (95%CI) Model 1. Unmodifiable risk factors Model 1 including BMI 1 1.01 (0.73-1.40) 1.11 (0.79-1.57) 1.72 (1.17-2.52)* 1.65 (1.11-2.46)* 1 1.01 (0.73-1.40) 1.12 (0.79-1.58) 1.56 (1.05-2.33) * 1.47 (0.97-2.23) BMI <18.5 kg/m2 BMI 18.5-25.0 kg/m2 BMI 25-30 kg/m2 BMI 30-35 kg/m2 BMI >35 kg/m2 kg/m2 Loss of weight since age 25 Alcohol: none Alcohol: 1-21 units/week Alcohol: >21 units/week Present or past smoker 3/34 69/1491 105/2229 23/600 3/139 26/379 16/375 161/3587 21/457 158/3350 Falls: 0/year Falls: 1/year Falls: 2-4/year Falls: >4/year Dizziness Walking disabilities Arms for chair stand 133/3534 32/506 27/279 7/61 23/191 37/598 24/351 Type II diabetes Hypertension Ischemic heart disease Stroke Erectile dysfunction Hyperlididaemia Atrial fibrillation (chronic and paroxysmal) Gout 13/276 50/839 16/360 2/50 98/1716 27/593 9/142 4/52 Enlarged prostate Nucturia Frequent urination Hypogonadism 9/155 4/42 18/164 0/48 Peptic ulcer 9/216 Model 2. BMI, life style and obesity. Model 2 adjusted for age 1 1 0.55 (0.17-1.75) 0.56 (0.18-1.81) 0.56 (0.18-1.76) 0.63 (0.20-2.02) 0.46 (0.14-1.52) 0.48 (0.14-1.62) 0.26 (0.05-1.28) 0.30 (0.06-1.52) 1.57 (1.04-2.37)* 1.62 (1.05-2.49)* 1 1 1.05 (0.63-1.76) 1.09 (0.65-1.83) 1.09 (0.57-2.10) 1.13 (0.58-2.17) 1.20 (0.86-1.67) 1.22 (0.87-1.72) Model 3. Mobility. Univariate Model 3 adjusted for BMI and age 1 1 1.66 (1.13-2.44) 1.56 (1.06-2.31)* 2.44 (1.60-3.71) 2.18 (1.41-3.37)* 3.02 (1.41-6.45) 2.46 (1.12-5.41)* 2.79 (1.81-4.31)* 2.34 (1.49-3.68)* 1.46 (1.02-2.08)* 1.05 (0.68-1.60) 1.58 (1.03-2.42)* 1.15 (0.70-1.88) Model 4. Diabetes and cardiovascular disease Univariate Model 4 adjusted for BMI and age 1.05 (0.60-1.84) 0.94 (0.53-1.67) 1.41 (1.02-1.93)* 1.41 (1.01-1.97)* 0.90 (0.59-1.65) 1.02 (0.60-1.74) 0.90 (0.22-3.61) 0.83 (0.20-3.34) 1.50 (1.14-1.97)* 1.48 (1.12-1.96)* 1.01 (0.67-1.51) 0.89 (0.58-1.38) 1.40 (0.72-2.73) 1.41 (0.72-2.76) 1.70 (0.63-4.58) 1.62 (0.60-4.37) Model 5. Genitourinary. Univariate Model 5 adjusted for BMI and age 1.31 (0.67-2.55) 1.37 (0.70-2.69) 2.05 (0.76-5.51) 2.25 (0.83-6.07) 2.48 (1.53-4.02)* 2.57 (1.58-4.18)* No fractures Model 6. Gastrointestinal. Univariate Model 6 adjusted for BMI and age 0.93 (0.48-1.82) 0.94 (0.48-1.83) Diarrhoea 4/63 1.40 (0.52-3.77) 1.68 (1.14-2.49)* Univariate Univariate Epilepsy Pulmonary disorder Rheumatoid arthritis 3/67 20/311 4/68 1.01 (0.32-3.17) 1.45 (0.92-2.31) 1.30 (0.48-3.50) 1.40 (0.52-3.77) Model 7. Miscellaneous. Model 7 adjusted for BMI and age 1.00 (0.32-3.14) 1.44 (0.91-2.29) 1.33 (0.49-3.58) 1.35 (0.88-2.06) 1.47 (1.00-2.17)* 2.10 (1.37-3.22)* 2.34 (1.08-5.07)* 2.00 (1.28-3.14)* 1.34 (0.97-1.85) 1.39 (1.04-1.84)* 2.05 (1.25-3.36)* 136 Separate models are presented. The 2° column represents univariate and the 3° individual models (Model 1), adjusted for age (Model 2-7) and BMI (Models 3-7). The 4° column shows a comprehensive model including significant findings from every individual model. * significant findings. 137 Table 3. Predictors of osteoporotic fracture. Fracture Model Comprehensive model: HR (95%CI) significant findings from models 1-7 HR (95%CI) Model 1. Unchangeable variables Univariate Model 1 including BMI Univariate HR (95%CI) Age: 60-65 years Age: 65-69 Age: 70-74 Family history of HFx after 50yr Osteoporosis in family Fx/No.reporting variable 34/1871 26/1595 25/1145 14/436 12/404 BMI <18.5 kg/m2 BMI 18.5-25.0 kg/m2 BMI 25-30 kg/m2 BMI 30-35 kg/m2 BMI >35 kg/m2 kg/m2 Loss of weight since age 25 Alcohol: none Alcohol: 1-21 units/week Alcohol: >21 units/week Present or past smoker 2/35 30/1530 45/2289 7/616 1/141 14/391 5/386 71/3677 7/471 63/3445 Falls: 0/year Falls: 1/year Falls: 2-4/year Falls: >4/year Dizziness Walking disabilities Arms for chair stand 52/3615 22/516 7/298 2/66 12/202 18/617 14/361 Type II diabetes Hypertension Ischemic heart disease Stroke Erectile dysfunction Hyperlididaemia Atrial fibrillation (chronic and paroxysmal) Arthritis urica 6/283 18/871 9/367 2/50 49/1765 13/607 4/147 0/56 Enlarged prostate 6/158 Nucturia Frequent urination Hypogonadism 1/45 8/174 0/48 Peptic ulcer Diarrhoea 2/223 3/64 1 1 0.90 (0.54-1.50) 0.89 (0.54-1.49) 1.21 (0.72-2.03) 1.20 (0.71-2.01) 1.87 (1.06-3.32)* 1.69 (0.93-3.07) 1.70 (0.92-3.12) 1.45 (0.77-2.74) Model 2. Age, life style and obesity. Univariate Model 2 adjusted for age 1 1 0.35 (0.09-1.47) 0.34 (0.08-1.46) 0.35 (0.09-1.45) 0.39 (0.09-1.67) 0.20 (0.04-0.98)* 0.24 (0.05-1.18) 0.13 (0.01-1.40) 0.16 (0.01-1.78) 2.11 (1.19-3.75)* 2.17 (1.18-3.97)* 1 1 1.48 (0.60-3.67) 1.63 (0.65-4.08) 1.16 (0.37-3.65) 1.31 (0.41-4.16) 0.97 (0.60-1.58) 0.93 (0.57-1.52) Model 3. Mobility. Univariate Model 3 adjusted for BMI and age 1 1 2.90 (1.76-4.78) 2.59 (1.56-4.30)* 1.64 (0.75-3.62) 1.28 (0.57-2.89) 2.19 (0.53-8.99) 1.41 (0.33-6.02) 3.54 (1.92-6.52)* 2.81 (1.48-5.32)* 1.75 (1.04-2.95)* 1.15 (0.61-2.18) 2.76 (1.67-4.58)* 1.69 (0.84-3.39) Model 4. Diabetes and cardiovascular disease Univariate Model 4 adjusted for BMI and age 1.16 (0.51-2.67) 1.06 (0.45-2.48) 1.15 (0.68-1.94) 1.14 (0.66-1.96) 1.37 (0.69-2.74) 1.28 (0.61-2.66) 2.20 (0.54-8.93) 1.84 (0.45-7.55) 2.19 (1.43-3.37)* 2.18 (1.40-3.39)* 1.19 (0.66-2.14) 1.00 (0.53-1.90) 1.49 (0.55-4.06) 1.46 (0.53-4.01) No fractures Model 5. Genitourinary. Univariate Model 5 adjusted for BMI and age 2.14 (0.94-4.91) 2.25 (0.97-5.21) 1.19 (0.17-8.57) 1.37 (0.19-9.86) 2.63 (1.27-5.45)* 2.80 (1.35-5.82)* No fractures Model 6. GI-tract related symptoms. Univariate Model 6 adjusted for BMI and age 0.48 (0.12-1.96) 0.49 (0.12-2.00) 2.55 (0.80-8.06) 2.51 (0.79-7.96) Model 7. Miscellaneous. Univariate Model 7 adjusted for BMI and 1.68 (0.93-3.06) 1 2.43 (1.46-4.03)* 1.22 (0.54-2.71) 1.47 (0.35-6.10) 2.72 (1.45-5.10)* 2.04 (1.31-3.18)* 1.72 (0.81-3.64) 138 Epilepsy Pulmonary disorder Rheumatoid arthritis 12/319 3/69 age No fractures 2.19 (1.19-4.03)* 2.16 (1.17-3.98)* 2.39 (0.76-7.57) 2.51 (0.79-7.96) 1.95 (1.05-3.62)* Separate models are presented. The 2° column represents univariate and the 3° individual models (Model 1), adjusted for age (Model 2-7) and BMI (Models 3-7). The 4° column shows a comprehensive model including significant findings from every individual model. * significant findings Table 4. Relation between number of falls and risk of any fracture stratified according to BMI or age. Age 60-65 years 65-69 years 70-75 years BMI: <25kg/m2 >=25kg/m2 One fall/year 2-4 falls/year >=4 falls/year 1.5 (0.8-2.7) 1.9 (1.0-3.6)* 1.7 (0.8-3.6) 2.0 (1.0-4.1)* 2.8 (1.4-5.5)* 2.7 (1.2-6.0)* 2.2 (0.6-9.2) 2.6 (0.6-10.7) 4.6 (1.4-15.1)* 2.5 (1.4-4.6)* 1.3 (0.8-2.2) 2.4 (1.1-5.2)* 2.4 (1.5-4.0)* 6.6 (2.6-16.5)* 1.3 (0.3-5.2) * significant findings Table 5. Population attributable risk. Any fracture Family history of HFx after 50 years Falls: 1/year Falls: 2-4/year Falls: >4/year Dizziness Frequent urination Osteoporotic fracture Falls: 1/year Dizziness Pulmonary disorder Prevalence in fracture cases Prevalence in non-fracture cases PAR 15.3% 16.2% 13.1% 3.5% 11.3% 8.9% 9.3% 11.6% 6.4% 1.4% 4.3% 3.7% 25.7 23.8 27.5 8.2 22.6 18.2 26.5% 14.1% 14.1% 11.5% 4.4% 6.9% 64.4 38.4 27.5 139 Appendix A. Variables used for calculation of the Charlson index. Information obtained from public register. Disease Myocardial infarction Congestive heart failure Peripheral vascular disease Cerebrovascular disease Dementia Chronic pulmonary disease Rheumatologic disease Peptic ulcer disease Mild liver disease Diabetes Diabetes with chronic complications Hemi- or paraplegia Renal disease Malignancy Severe (and moderate) liver disease Metastatic, solid tumours AIDS Codes I21-2, I252 I43, I50, P290, I109, I110, I130, I132, I255, I420, I425, I426, I427, I428, I429 I70, I71, I731, I738, I739, I771, I790, I792, K551, K558, K559, Z959, Z958 G45, G46, I60-69, H340 F00-03, G30, F051, G311 J40-47, J60-67, I278-279, J684, J701, J703 M05-06, M32-34, M315, M351, M353, M360 K25-28 B18, K73, K74, K700-3, K709, K713-15, K717, K760, K762-64, K768-69, Z944 E100-1, E106, E108-11, E116, E118-21, E126, E128-31, E136, E138-41, E146, E148-9 E102- 5, E107, E112-15, E117, E122-25, E127, E132-35, E137, E142-45, E147 G81-82, G041, G114, G801-2, G830-34, G839 N18-19, I120, I131, N032-37, N052, N057, N250, Z490-2, Z940, Z992 C00-26, C30-34, C37-41, C43, C45-61, C63, C65-76, C81-85, C88, C90-97 I850, I859, I864, I982, K704, K711, K721, K729, K765-67 C77-80 B20-22, B24 Appendix B. Items in questionnaire. What is your height without shoes Have you lost height since age 25 years What is your weight Have you lost any weight since the age of 25 years Do you participate in sports activities Do you use fitness centre on a regular basis Do you have any walking difficulties - if yes, do you use walking aids How many hours a day do you stand or walk - none, less than one hour, 1-3 hours, 4 hours or more How often have you experienced a fall in the last 12 months - never, once, 2-4, 5-8, 9-12, more than 12 times Do you use your arms for chair stand - never, rarely, once in a while, often, always Do you live in a home for elderly people Have you ever had a bone mass assessment (bone scan / DXA) Have sustained any fracture after the age of 50 years Have any of your family members fractured a hip after the age of 50 years - if yes, tic who: mother, father, sister, brother Have any of your family members been diagnosed with osteoporosis - if yes, tic: mother, father, sister, brother, son, daughter, other Do you have impotence/erection problems - if yes, when did it start Have you been treated with male sex hormone (testosterone) Have you had any testicular diseases (e.i. severe traumas, cysts, cancer, operations) - if yes, please explain Have you experienced any long term bed rest Do you take any medication, supplements, herbal medicine or vitamins (tablets, sprays, drops etc.) - if yes, state name of drug, strength and dose (if possible) Have you ever been treated for osteoporosis - if yes, state name of drug and start and cessation of treatment Have you ever been treated with corticosteroids (i.e. prednisolone, Cortisol or dexamethasone) - if yes, explain 140 Do you take calcium supplements Do you take vitamin D supplements (i.e. tablets, cod liver oil) Do you drink milk or eat breakfast with milk? - if yes, state average daily use Do you eat fermented milk products - if yes, state average daily use Do you eat cheese - if yes, state average daily use Have any parts of your stomach or bowels been removed Do you suffer from epilepsy Do you have dementia Do you have any symptoms from / diseases related to - nervous system (i.e. vertigo, paralyses, eye etc). If yes, state symptom or disease - the heart (i.e. chest pain, atrial fibrillation, hypertension, myocardial infarction etc). If yes, state symptom or disease - the lungs (i.e. bronchitis, asthma, dyspnea etc). If yes, state symptom or disease - stomach and bowel (i.e. peptic ulcer, diarrhoea, constipation, blood in stools, inflammatory bowel disease etc). If yes, state symptom or disease - urinary tract (i.e. frequent urination, painful urination etc). If yes, state symptom or disease - metabolic disease (i.e. diabetes, thyroid disease etc). If yes, state symptom or disease -bone and joints (i.e. rheumatoid arthritis, arthrosis etc). If yes, state symptom or disease - any other (i.e. hyperlipideamia, psychiatric disease, skin diseases etc). If yes, state symptom or disease What kind of home do you live in (villa, apartment, semi-detached etc) – and do you own or rent your home What characterises your smoking status: present smoker, previous smoker (year of cessation), never smoker What is your average weekly intake of alcohol (Nil, 1-7 units, 8-14 units, 15-21 units, 22-28 units, >28 units) Do you have any other information 141 24 Pattern of use of DXA scans in men. A cross-sectional, population-based study Frost M1,2, Gudex C1, Rubin KH1,2, Brixen K1,2 and Abrahamsen B2,3 1 Dept. of Endocrinology, Odense University Hospital, Odense, Denmark 2 Clinical Research Institute, University of Southern Denmark, Odense, Denmark 3 Dept. of Medicine F, Copenhagen University Hospital Gentofte, Copenhagen, Denmark 142 Abstract: Purpose: Clinical and socioeconomic factors associated with bone mass assessment (DXA) in men have seldom been evaluated. This study aimed to evaluate factors associated with the use of DXA in men. Methods: Self-report information on prior DXA and osteoporosis risk factors were obtained from the baseline data of a study investigating the health perspectives of men aged 60-75 years. Socioeconomic and comorbidity data were retrieved from national registers. The FRAX algorithm was used to calculate the absolute fracture risk. Regression analysis was used to identify factors significantly associated with previous DXA scan. Results: Of the 4,696 men returning questionnaires (50% response rate), 2.7% had prior DXA but 48% had at least one osteoporosis risk factor. Previous DXA was associated with oral glucocorticoid treatment, secondary osteoporosis, rheumatoid arthritis, fracture after age 50, falls within the previous year, smoking and higher age. Twenty-one per cent of men with prior DXA and 10% of men without prior DXA had greater than 20% risk of a major osteoporotic fracture within the next 10 years. One-third of those with previous DXA had none of the FRAX osteoporosis risk factors. When family history of osteoporosis and falls were included as risk factors, 18% with previous DXA had no clinical risk factors for osteoporosis. Conclusions: DXA was infrequent in this group of elderly men, despite the presence of risk factors for osteoporosis. DXA was also used despite a low fracture risk. There is a need for improved targeting of DXA scans for men at high risk. 143 Introduction The risk of fracture in men over 50 years old is 20-27%, which is lower than the comparable risk in women (50 %) (1;2). However, hip fractures in men are associated with twice the mortality rate of women (3;4). While young men sustain more fractures due to high-energy trauma than women, the majority of fractures in elderly men and women are caused by low-energy trauma. Some of these fractures are preventable as osteoporosis treatment options are available for both sexes (5). Furthermore, treatment with anti-osteoporosis medication has been found to be cost-effective in men aged over 65 years with a self-reported clinical fracture (6). The prevalence of osteoporosis in Danish men aged over 50 years is estimated to be 17.7% (7), but only 1.3 % of men aged over 60 years of age used bisphosphonates (8). Bone mineral density (BMD) is a strong predictor of fractures in men (9;10) and bone densitometry is the standard method for diagnosing osteoporosis in both sexes. However, there appears to be a gender difference with regard to the use of bone densitometry. In 2005 in Australia, bone densitometry was used four times more often in women (11), even though the life-time risk of a fracture in women and men over 50 years old is estimated to be 44% and 27%, respectively (12), and 39 % of all fractures occur in men (13). This suggests that a lack of awareness either among patients, physicians or both has led to osteoporosis being under-diagnosed and insufficiently treated in both men and women (3;1416). Several factors are associated with an increased risk of fractures in men, and development of the 10-year fracture risk algorithm FRAX allows identification of patients at high risk of osteoporotic or hip fractures, with or without assessment by DXA scanning (17). We have limited knowledge about the use of DXA in men, and factors associated with densitometric evaluation in men are not yet clarified (15). Similarly, there is little information available about the risk factors and the 10-year fracture risk in men who have previously undergone DXA scanning. 144 While a number of clinical risk factors are useful for the identification of men who should undergo DXA, other factors including socioeconomic status could influence bone density testing in men. Thus, Neuner et al. (18) found that women living in low income areas were less likely to undergo bone density testing prior to (though not after) fracture, and Demeter et al. (19) showed that use of BMD testing was positively associated with income in women. The aim of the present study was firstly to evaluate the use of densitometry in a population of elderly Danish men and, secondly, to identify factors associated with the use of DXA in men. Subjects and methods Subjects The present study used baseline data from the Study of Osteoporosis and Male Aging (SOMA), which is a population-based, prospective study on health in older Danish men. The SOMA study population was recruited using a random sample of Danish men living in Funen County, identified by the personal unique identification number that all Danish citizens acquire at birth. In the autumn of 2004, an invitation to participate in the SOMA study and a questionnaire covering aspects of men’s health were sent by post to 9,314 men aged 60-74 years. A reminder letter including the questionnaire was sent to non-responders after one month. The local Ethics Committee (reference number: 20030230) and the Danish Data Protection Agency approved the study, and SOMA is listed at clinicaltrials.gov (NCT00463411). Register-based information Information on income and marital status as of October 2004 was retrieved from the public register Statistics Denmark (ref.no. 703026). The Sociodemographic data on the Danish age- and sexmatched population (n=339,885) as of October 2004 were obtained from Statistics Denmark. 145 Questionnaire The self-completed questionnaire comprised 41 items and included questions on diagnosis of osteoporosis, past or present treatment for osteoporosis, family history of osteoporosis or hip fractures, previous bone densitometric evaluation and previous fractures (including the circumstances causing the fracture). Information was also requested on current weight and height and reductions in either of these since the age of 25 years, physical mobility (walking impairment, ability to stand up without the aid of chair arms, frequency of falls) and oral glucocorticoid use. Respondents also provided information on living conditions and lifestyle factors such as use of alcohol and tobacco. Excessive intake of alcohol was defined as consumption of more than 21 units of alcohol per week. Tobacco use was classified binomially as smoker or non-smoker, the latter including ex-smokers. The questionnaire data were read into the computer electronically. Any readable or ambiguous answer was assessed by two medical secretaries. If the answer was still uncertain, the item was left blank. Risk factors and FRAX Absolute fracture risk can be calculated using the algorithm FRAX. Since the Danish version of FRAX is currently under development, the Swedish version was used. Clinical risk factors for fracture were defined as those incorporated in the FRAX scoring system, i.e. age, low body mass index (BMI below 19 kg/m2), previous fracture, family history of hip fracture, present use of tobacco, present use of oral glucocorticoids, rheumatoid arthritis (RA), secondary osteoporosis and excessive use of alcohol (here: more than 3 units of alcohol per day). Secondary osteoporosis was defined by self-report of thyrotoxicosis, hypogonadism (prescribed testosterone or bilateral 146 orchiectomy) or type I diabetes. A computerized call was made to the FRAX website in order to calculate the respondents’ individual 10-year risk of major osteoporotic and hip fractures. Statistics Data are reported as median (quartiles) or percentages of the study population. The participants previously evaluated by DXA were compared to the remaining study population using MannWhitney tests (age, BMI, annual income) or Chi-square tests (all other variables). Multivariate logistic regressions were used to evaluate factors associated with previous bone densitometry. The independent variables in the initial regression analysis were the clinical risk factors from the FRAX algorithm. Falls and family history of osteoporosis were added in a second regression analysis, and income and marital status were added in the third regression analysis. All significant variables were included in a fourth model. Likelihood-ratio tests were used to test model fit. A p-value of less than 0.05 was considered significant and all calculations were performed using STATA v.10 (Stata Corp, College Station, Texas, USA). Results Of the 4,939 questionnaires returned, 4,696 were complete, giving a response rate of 50.4%. A total of 126 (2.7%) men reported previous bone densitometric evaluation and 0.6% reported current treatment for osteoporosis. Compared to non-responders, the study participants were of a similar age (both groups median age 65 [60-75] years) but had significantly higher income (median 190,096 DKK; quartiles 135,175291,059 DKK vs. 162,558 DKK; quartiles 120,006-261,835 DKK; p<0,001), were less likely to be on retirement pension (31.2% vs. 39.2% of non-responders, p<0.01), more often married (80.9% vs. 147 68.7% of non-responders, p<0.01) and had less comorbidity (43% had a Charlson index score of 0 compared to 36.5% of non-responders, p<0.01). Compared to the Danish age- and sex-matched population, the study participants had higher annual income (median 190,096 DKK vs. median 168,806 DKK; quartiles 122,244-275,576 DKK; p<0.001), more often on retirement pension (31.2% vs. 27.1%, p<0.01), more often married (80.9% vs. 73.7%,of the Danish population p<0.01) and had less comorbidity (43% had a Charlson index score of 0 compared to 39.8% of the Danish population, p<0.01). Socioeconomics, physical characteristics and life style As seen in Table 1, study participants with previous DXA were significantly older, more likely to be divorced or live in a rented home and had a lower annual income compared to participants without prior DXA. Participants with previous DXA had lower height and weight than those without prior DXA, and more often reported height or weight loss after the age 25 years. DXA was used similarly among men with a low BMI (Table 1). Participants with previous DXA were more likely to be current smokers. They were also more likely to report at least one fall with in the preceding year, to have walking impairment or to use chair arms for support when standing up (Table 1). Family history and clinical characteristics Participants with previous DXA were more likely to have a family history of osteoporosis, but not hip fracture (Table 2). They were also more likely to report any fracture after the age of 50 years, hip fracture, spine fracture or wrist fracture and to have a diagnosis of osteoporosis (Table 2). 148 Regarding comorbidity, participants with previous DXA were more likely to have rheumatoid arthritis, hypogonadism, thyrotoxicosis, inflammatory bowel disease, and chronic obstructive pulmonary disease but not asthma or chronic bronchitis (Table 2). They were also more likely to be treated with anti-osteoporosis medication or oral glucocorticoids, either currently or in the past (Table 2). FRAX risk factors and scores In the study population as a whole, DXA scanning had been performed in 1.6% of those with no FRAX risk factors and 3.0%, 5.9% and 9.9% of those with 1, 2 or 3+ risk factors, respectively. Of the 126 participants reporting a previous DXA, 31.8% had no clinical risk factors and 39.7% had only one risk factor (Table 3). When family history of osteoporosis and tendency to fall (i.e. more than one fall in past year) where included as risk factors, only 17.5% of the participants with prior DXA scanning had no risk factor, and 23.8% had at least three risk factors (Table 3). Participants with previous DXA had significantly higher median FRAX risk scores for major osteoporotic fractures and hip fractures than participants without DXA and were also more likely to have a greater risk of major fracture within the next 10 years (Table 3). Predictors of previous DXA Multivariate logistic regression analysis showed that oral glucocorticoid treatment (OR 9.05; 95%CI 4.35-18.8), secondary osteoporosis (3.84; 1.79-8.23), rheumatoid arthritis (2.56; 1.07-6.15), fracture after 50 years of age (2.42; 1.55-3.77), falls (2.01; 1.36-2.96), use of tobacco (1.62; 1.112.37) and age (1.05; 1.00-1.10) were associated with prior bone mass assessment. The models explained a minor part of the use of bone mass assessment (R2: 0.07-0.09). Adding falls and a family history of osteoporosis significantly improved the second model (p<0.001) whereas 149 inclusion of the variables used in model 3 did not significantly improve the model. Discussion The study results show that only 2.7% of the men in this study aged 60-75 years reported previous bone mass assessment by DXA scanning, despite a high prevalence of risk factors for osteoporotic fractures. Thus approximately one-third of the participants had never been scanned, despite having greater than 15% risk of a major osteoporotic fracture within the next 10 years. Secondly, approximately one-third of the men who had previously undergone DXA scanning appeared not to have any of the risk factors used in the FRAX algorithm. The low rate of DXA scanning among older men in this study is at odds with an estimated osteoporosis prevalence of 17.7% among Danish men aged over 50 years, and is surprising as both DXA scans and osteoporosis-specific treatments are paid for or reimbursed by the Danish health system. The study population differed slightly from the Danish population in terms of comorbidity, income and marital status. Although these differences may influence the study, in a clinical perspective the results are likely to be generalizable to the Danish age- and-sex matched population as a whole. Only 0.6% of the men in the present study reported previous or current treatment for osteoporosis; this is similar to the findings of register-based studies in which 0.3% and 1.3 % of Danish men aged 50 years and over were receiving osteoporosis-specific treatment in 2004 and 2006, respectively (7;8). These results suggest that there needs to be more widespread treatment of osteoporosis in men. Both patients and the general public in Denmark lack specific knowledge about important risk factors for osteoporosis (21). Previous studies suggest that elderly men have little knowledge about male risk factors for osteoporosis (22) and that men, in contrast to women, do not recognize osteoporosis as a serious disease that they are susceptible to (23). Male patients may be unaware of 150 the importance of DXA or unwilling to have a DXA scan. Equally, limited awareness of the significance of bone scans among both general practitioners and specialists or even reluctance to refer patients for assessment may explain the low use of DXA scanning and inadequate referral rates. Further studies are needed to clarify the separate effects of these factors on the use of DXA. Two separate Australian studies found that 76% of male fracture patients aged 50 years and over remained untreated for osteoporosis despite 27% of these 87 untreated men having prior low trauma fracture (24), and only 25% of the patients who contacted their general practitioner after a fracture were recommended treatment for osteoporosis (25). Collectively, these studies indicate that both patients and medical staff would benefit from an increased awareness and understanding of osteoporosis in men, including the role of risk factors. Targeting patients at risk of fracture is required if the incidence of fractures is to be reduced. However, even among participants in our study who had widely recognized risk factors for osteoporosis (such as oral glucocorticoid use and hip fracture), the use of DXA was very limited. Furthermore, virtually none of the study participants who reported diagnoses that were probably made by internal medicine specialists (such as hypogonadism and rheumatoid arthritis) had been assessed by DXA. In their review of the literature on osteoporosis screening guidelines and patterns of BMD testing, Morris et al. (15) found a weighted average screening rate of 8% for post-fracture patients and 9% for glucocorticoid-treated patients. These rates are comparable to those of the present study for men, and from a previous study among women (26). We found a higher likelihood of bone mass evaluation as the number of clinical risk factors or the FRAX score for major osteoporotic or hip fracture increased. Despite this, DXA had been performed in only 10% of men with at least three FRAX risk factors, and 10% of men not assessed by DXA had a 10-year major osteoporotic fracture risk of at least 20%. In comparison, 36% of Danish women with three or more risk factors reported a previous DXA (26). It is also of concern 151 that 32% of the bone assessments in the present study had been performed in men who had no apparent clinical risk factor as defined by the FRAX algorithm. The results thus suggest an inappropriate pattern of referral of Danish men for DXA. The Swedish FRAX model was used in this study, but it is likely to be similar to a Danish model. It should be noted, however, that the FRAX algorithm has been validated primarily for use among women rather than men. Among women, it was found that substantially fewer (10%) without any risk factors were evaluated by DXA (26), suggesting a gender difference in DXA referral patterns. A previous study found no association between age or co-morbidity and BMD testing (15). In the present study, however, secondary osteoporosis and rheumatoid arthritis were associated with an increased likelihood of a bone assessment. Limitations of the study Information bias may affect our results. Although prior fractures may be recalled with some precision, other factors including falls are likely to be influenced by recall bias. With a response rate of 50% we cannot exclude the possibility that the responders were a biased sample, towards individuals with a particular interest in osteoporosis due to own risk factors or diagnosis of osteoporosis. In addition, reduced renal function, low compliance with osteoporosis medication and other factors that may influence the pattern of referral to DXA were not assessed in this study. Furthermore, the public’s awareness of osteoporosis in men may have improved since the data collection for this study, which may have led to greater use of DXA among individuals with risk factors or previous fracture. Similarly, physicians may have become more aware of the need for DXA referral of patients at high risk of fracture including those with a previous fragility fracture. It has become more common for Australian men to have DXA scanning, and similar changes cannot be excluded in Denmark (11). The availability of DXA scanners also differs between countries with 152 significantly more scanners available in other Nordic countries and fewer in the UK, Spain and the Netherlands in 2003 compared to Denmark (27). The pattern of use of DXA may be different in countries with a higher or lower availability of scanners. Another limitation of our study is the low number of participants with prior DXA scan; this decreases the power to detect predictive factors. Finally, we cannot exclude that some patients were referred for DXA following the finding of reduced bone mineralization on X-rays taken for other indications. Such patients may have no clinical risk factors for osteoporosis. In addition, we do not know whether referral for DXA was initiated by the study participant or a treating physician. The results of the current study rely on participants’ self-report of treatment for osteoporosis and comorbidity and are thus open to bias due to underreporting. Any underreporting would mean that the number of participants likely to benefit from referral to DXA would be even higher. The level of agreement between questionnaire self-report and medical records varies according to the health condition in question; agreement with respect to cardiovascular disease and diabetes appears to be satisfactory whereas there can be a significant discrepancy for diseases of the musculoskeletal system (28;29). In a study involving 120 individuals, more fractures were reported by the patients than were noted in their medical records; however, the participants were a convenience sample and had taken part in a general health screening program (30). Paganini-Hill et al. (31) found a high recall accuracy of hip fractures, where the proportion of falsepositive responses was less than 10%. The recall accuracy of factors such as family history of osteoporosis or hip fractures remains to be clarified. Unexpectedly, we found no effect of socioeconomic status on the likelihood of a prior DXA scan. Participants who had a DXA scan were more likely to be divorced or living in a rented home. Although annual income was lower in those reporting a prior DXA scan, this relationship was not significant after adjustment for age and comorbidity. 153 Few studies have examined the association between socioeconomic status and bone density in men. In elderly Australian men, spine BMD was highest in men with either the highest or lowest socioeconomic status, but there were no differences in BMD at the femoral neck (32). While income appears not to be associated with fracture risk, living with a partner may reduce the risk of fracture (33;34) . Although the men in the study sample had generally higher income and lower comorbidity than their counterparts in the general Danish population, the results are likely to be valid for the Danish population of elderly men. The use of DXA is less likely to have been influenced by socioeconomic status, as DXA scans are provided free of charge in Denmark and osteoporosis treatments are subsidized by the state. Furthermore, the risk of recall bias was reduced through the use of registerbased information on socioeconomics and comorbidity. In conclusion, we found that the use of DXA bone assessment was lower than would be expected in elderly Danish men in comparison to the prevalence of known risk factors. The likelihood of a DXA test was, however, higher in men with several clinical risk factors and a high 10-year fracture risk, and there was only a limited effect from socioeconomic factors. Targeting DXA scans towards individuals at high risk needs to be improved so as to avoid inappropriate resource use. The implementation of a computerized risk algorithm such as FRAX may advance the identification of men most likely to benefit from bone assessment. It appears that current referral rates that rely on awareness and recognition of a number of unquantified, albeit well-described and well-known risk factors are too low. Acknowledgements The study received financial support from the Novo Nordisk Foundation and the Velux Foundation. 154 Table 1. Socioeconomic, body composition and lifestyle characteristics of study population according to DXA scanning status. Data are absolute numbers (percentages) or medians (quartiles). Previous DXA Yes n= 126 No n= 4570 68.2 (63.5-71.2) 66.2 (63.1-69.9)* 158,680 (115,671-249,656) *|* 76.2% 12.7%* 8.7% 5.6% 45.7%*** 20.5% 14.2%*** 191,636 (135,179-292,594) 81.1% 7.2% 6.5% 3.5% 30.8% 26.1% 6.2% 63.5% 23.0%** 1.6% 68.8% 14.0% 1.6% 77 (70-86)*** 175 (170-180)* 25.3 (22.9-28.0)** 2.4% 19.1% *** 50.0% *** 82 (74-90) 176 (172-180) 26.3 (24.3-28.7) 1.0% 8.3% 24.9% 11.1% 42.9% 37.3%* 10.2% 46.6% 26.9% 37.3%*** 33.3%*** 16.7%*** 21.2% 13.0% 7.8% Age (years) Socioeconomics Annual income 1 (DKK) Married Divorced Widower Unmarried Retirement pension Early retirement pension Disability pension Living conditions Owner of home Rented home Care homes Body composition Weight (kg) Height (cm) Body Mass Index (BMI, kg/m) Low BMI (<19kg/m2) Weight loss since aged 25 years Height loss since aged 25 years Life style factors Alcohol > 21 units/week Previous smoker Current smoker Mobility Falls (at least 1/year) Walking impairment Always using arms for chair stand 1 includes pensions. *p<0.05, **p<0.01, ***p<0.001 155 Table 2. Family history and clinical characteristics of study population according to DXA scanning status. Data are percentages. % Family history of hip fracture Family history of osteoporosis Fractures since the age of 50 years Any fracture Hip fracture Spine fracture Wrist fracture Diagnosis of osteoporosis Co-morbidity Chronic bronchitis Asthma Chronic obstructive pulmonary disease Inflammatory bowel disease Thyrotoxicosis Hypogonadism Rheumatoid arthritis Type 1 Diabetes Type 2 Diabetes Treatment with oral glucocorticoids Current treatment Previous treatment Treatment for osteoporosis Current or previous treated *p<0.05, **p<0.01, ***p<0.001 Previous DXA Yes No (n=126) (n=4570) 10.3% 9.6% 15.1%* 8.7% 23.8%*** 5.6%*** 7.9%%*** 4.8% %* 15.9%*** 9.4% 0.9% 1.8% 2.1% 0.2% 3.2% 2.4% 2.4%* 2.4%* 2.4%** 4.8%*** 6.4%*** None 8.7% 4.1% 3.4% 0.6% 0.6% 0.6% 0.9% 1.4 0.2% 6.1 10.3%*** 15.1%*** 0.8% 3.7% 71.4%*** 0.2% 156 Table 3. FRAX risk factors and scores according to DXA scanning status. Data are shown as medians (quartiles) or percentages. Previous DXA FRAX scores Risk of major osteoporotic fracture Risk of hip fracture 10-year risk of major osteoporotic fracture is ≥15% 10-year risk of major osteoporotic fracture is ≥20% 10-year risk of hip fracture is ≥10% 10-year risk of hip fracture is ≥15% Number of FRAX risk factors 0 Falls and family history of osteoporosis included 1 2 3+ Falls and family history of osteoporosis included *p<0.05, **p<0.01, ***p<0.001 Whole study population Yes (n=126) No (n=4696) (n=4696) 14.0 (11-18)*** 4.6 (2.6-7.2)*** 44.4%** 20.6%*** 13.5%** 7.9%*** 12.0 (9.1-16) 3.0 (1.9-5.3) 30.9% 10.3% 6.5% 2.2% 12.0 (9.1-16.0) 4.0 (1.9-5.4) 31.2% 10.6% 6.6% 2.4% 31.8%*** 17.5%*** 39.7% 21.4%*** 7.9%*** 23.8%*** 52.5% 39.9% 36.1% 9.6% 1.8% 6.1% 51.9% 39.3% 36.2% 9.9% 2.0% 6.6% 157 Table 4. Uni- and multivariate logistic regression of the use of DXA in men. R2:0.07 FRAX Age (years) BMI< 19 kg/m2 Family history of hip fracture Fracture after the age of 50 years Current smoker Excessive use of alcohol Current oral glucocorticoid treatment RA Secondary osteoporosis Additional risk factors Family history of osteoporosis Falls within the last year Socioeconomics Income in quartiles Q1 Q2 Q3 Q4 Married Disability pension Early retirement pension 1.05 (1.01-1.10) 2.04 (0.60-6.96) 1.24 (0.71-2.14) 2.72 (1.76-4.21) 1.59 (1.09-2.32) 1.08 (0.60-1.93) 8.90 (4.25-18.7) 2.60 (1.07-6.32) 3.98 (1.86-8.54) Multivariate OR (95%CI) R2:0.09 R2: 0.09 1.05 (1.01-1.10) 1.86 (0.54-6.39) 1.09 (0.62-1.92) 2.34 (1.49-3.65) 1.59 (1.08-2.33) 1.04 (0.58-1.87) 8.83 (4.23-18.4) 2.58 (1.07-6.21) 3.86 (1.79-8.31) 1.05 (1.00-1.11) 1.75 (0.50-6.08) 1.09 (0.62-1.93) 2.26 (1.44-3.54) 1.51 (1.03-2.22) 1.05 (0.58-1.89) 8.67 (4.14-18.1) 2.45 (1.02-5.88) 3.61 (1.67-7.83) 1.64 (0.97-2.78) 1.99 (1.35-2.94) 1.66 (0.98-2.82) 1.93 (1.30-2.86) R2:0.08 1.05 (1.01-1.10) 2.42 (1.55-3.77) 1.62 (1.11-2.37) 9.05 (4.35-18.8) 2.56 (1.07-6.15) 3.84 (1.79-8.23) 2.01 (1.36-2.96) 1 0.94 (0.54-1.63) 0.93 (0.55-1.56) 0.75 (0.42-1.34) 0.92 (0.59-1.43) 1.68 (0.87-3.23) 0.95 (0.55-1.64) The columns represent regression models including 1) clinical risk factors used in FRAX, 2) additional clinical risk factors, 3) additional socioeconomic factors, and 4) significant factors from the preceding models. 158 Reference List (1) van Staa TP, Dennison EM, Leufkens HG, Cooper C. 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