Prevalence of Vertebral Fractures and Non-fracture Deformities in Healthy Adult Men: The Importance of Morphologic Criteria.

Vertebral fractures (VF) are common in older men but data on VF prevalence in young men is limited. The aim of this study was to describe the prevalence of VF and non-fracture vertebral deformities (VD) in healthy young to middle-aged men, and compare the characteristics of men with normal vertebrae, VF and VD. In this cross-sectional study, vertebral fracture assessment by dual-energy X-ray absorptiometry was performed in 650 men, aged 32 to 60 years (mean 46.2), from the population-based SIBLOS-SIBEX cohort. For VF and VD assessment, both the modified algorithm-based qualitative approach (morphologic criteria) to discriminate VF from VD and the semi-quantitative (morphometric) grading system of Genant (GSQ) were used. We found 48 (0.6%) fractured vertebrae, of which 15 were classified grade 1, 29 grade 2 and 4 grade 3 VF. There were 378 (4.7%) VD, of which 296 were scored grade 1, 82 grade 2 and none grade 3 VD. Twenty-six participants (4%) had VF, 15 had one and 11 had 2 or more VF. Two hundred and twenty-eight (35.1%) men had VD. Femoral neck, total hip and lumbar spine areal bone mineral density (aBMD) were lower in men with VF than in those with normal vertebrae or VD. Men with VD, in turn, had aBMD values similar to men with normal vertebrae. Our results suggest that -even in young healthy men-using the GSQ without taking qualitative aspects into account overestimates VF prevalence, confirming the importance of morphologic criteria to correctly diagnose and distinguish VF from VD.

Patient preferences for lifestyle behaviours in osteoporotic fracture prevention: a cross-European discrete choice experiment.

Using a discrete choice experiment, we aimed to assess patients' preferences with regard to adopting lifestyle behaviours to prevent osteoporotic fractures. Overall, the 1042 patients recruited from seven European countries were favourable to some lifestyle behaviours (i.e., engaging in moderate physical activity, taking calcium and vitamin D supplements, reducing their alcohol consumption and ensuring a normal body weight). INTRODUCTION: Alongside medical therapy, healthy lifestyle habits are recommended for preventing osteoporotic fractures. In this study, we aimed to assess patients' preferences with regard to adopting lifestyle changes to prevent osteoporotic fractures. METHODS: A discrete choice experiment was conducted in seven European countries. Patients with or at risk of osteoporosis were asked to indicate to what extent they would be motivated to adhere to 16 lifestyle packages that differed in various levels of 6 attributes. The attributes and levels proposed were physical activity (levels: not included, moderate or high), calcium and vitamin D status (levels: not included, taking supplements, improving nutrition and assuring a minimal exposure to sunlight daily), smoking (levels: not included, quit smoking), alcohol (levels: not included, moderate consumption), weight reduction (levels: not included, ensure a healthy body weight) and fall prevention (levels: not included, receiving general advice or following a 1-day fall prevention program). A conditional logit model was used to estimate a patient's relative preferences for the various attributes across all participants and per country. RESULTS: In total, 1042 patients completed the questionnaire. Overall, patients were favourable to lifestyle behaviours for preventing osteoporotic fractures. However, among the lifestyle behaviours proposed, patients were consensually not prone to engage in a high level of physical activity. In addition, in Ireland, Belgium, the Netherlands and Switzerland, patients were also not inclined to participate in a 1-day fall prevention program and Belgian, Swiss and Dutch patients were not prone to adhere to a well-balanced nutritional program. Nevertheless, we observed globally that patients felt positively about reducing their alcohol consumption, engaging in moderate physical activity, taking calcium and vitamin D supplements and ensuring a normal body weight, all measures aimed at preventing fractures. CONCLUSIONS: In a patient-centred approach, fracture prevention should take these considerations and preferences into account.

Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study.

Increased fracture risk in patients with Ehlers-Danlos syndromes has been reported, but the reasons for it are incompletely understood. We aimed to investigate possible determinants of this increased risk and found that hEDS/HSD patients present with a cortical bone size deficit compared with control subjects, possibly related to lower mechanical loading. INTRODUCTION: The Ehlers-Danlos syndromes (EDS) comprise a group of heritable connective tissue disorders caused by defects in the biosynthesis, secretion, and/or organization of fibrillar collagens which might impair bone strength. Our aim was to compare fracture prevalence, volumetric and areal bone mineral density (BMD), bone geometry, muscle size and the muscle-bone interaction, body composition and longitudinal changes therein between patients with hypermobile EDS (hEDS) or hypermobility spectrum disorder (HSD), and healthy control subjects. METHODS: Cross-sectional data comprised 39 female hEDS/HSD patients (age 41 ± 11 years) and 43 age-matched controls. After 8 years, 27 hEDS/HSD and 17 control subjects were re-evaluated. Tibial trabecular and cortical volumetric BMD, bone mineral content (BMC), cortical bone geometry, and lower leg muscle cross-sectional area (CSA) were measured using pQCT. Body composition, areal BMD, and BMC were determined by DXA. RESULTS: At baseline, patients with hEDS/HSD presented with a smaller cortical bone area, smaller cortical thickness and muscle CSA, and a higher fracture prevalence than control subjects (all p < 0.05). No differences in areal or volumetric BMD were found. Longitudinally, muscle CSA decreased in both groups and muscle density decreased in the hEDS/HSD group (p < 0.001) whereas all bone parameters remained unchanged. CONCLUSION: hEDS/HSD patients have a cortical bone size deficit compared with controls, possibly contributing to their increased fracture risk. They presented with decreased muscle CSA but normal bone/muscle area ratio, suggesting that this bone size deficit is likely secondary to decreased mechanical loading. Further, there were no arguments for accelerated bone loss in hEDS/HSD subjects.

Predicting mortality and incident immobility in older Belgian men by characteristics related to sarcopenia and frailty.

There is an increasing awareness of sarcopenia in older people. We applied machine learning principles to predict mortality and incident immobility in older Belgian men through sarcopenia and frailty characteristics. Mortality could be predicted with good accuracy. Serum 25-hydroxyvitamin D and bone mineral density scores were the most important predictors. INTRODUCTION: Machine learning principles were used to predict 5-year mortality and 3-year incident severe immobility in a population of older men by frailty and sarcopenia characteristics. METHODS: Using prospective data from 1997 on 264 older Belgian men (n = 152 predictors), 29 statistical models were developed and tuned on 75% of data points then validated on the remaining 25%. The model with the highest test area under the curve (AUC) was chosen as the best. From these, ranked predictor importance was extracted. RESULTS: Five-year mortality could be predicted with good accuracy (test AUC of .85 [.73; .97], sensitivity 78%, specificity 89% at a probability cut-off of 22.3%) using a Bayesian generalized linear model. Three-year incident severe immobility could be predicted with fair accuracy (test AUC .74 [.57; .91], sensitivity 67%, specificity 78% at a probability cut-off of 14.2%) using a multivariate adaptive regression splines model. Serum 25-hydroxyvitamin D levels and hip bone mineral density scores were the most important predictors of mortality, while biochemical androgen markers and Short-Form 36 Physical Domain questions were the most important predictors of immobility. Sarcopenia assessed by lean mass estimates was relevant to mortality prediction but not immobility prediction. CONCLUSIONS: Using advanced statistical models and a machine learning approach 5-year mortality can be predicted with good accuracy using a Bayesian generalized linear model and 3-year incident severe immobility with fair accuracy using a multivariate adaptive regression splines model.

Osteoporosis in Frail Patients: A Consensus Paper of the Belgian Bone Club.

In this consensus paper, the Belgian Bone Club aims to provide a state of the art on the epidemiology, diagnosis, and management of osteoporosis in frail individuals, including patients with anorexia nervosa, patients on dialysis, cancer patients, persons with sarcopenia, and the oldest old. All these conditions may indeed induce bone loss that is superimposed on physiological bone loss and often remains under-recognized and under-treated. This is of particular concern because of the major burden of osteoporotic fractures in terms of morbidity, mortality, and economic cost. Therefore, there is an urgent need to appreciate bone loss associated with these conditions, as this may improve diagnosis and management of bone loss and fracture risk in clinical practice.

The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club.

The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.

Lower insulin sensitivity is related to lower relative muscle cross-sectional area, lower muscle density and lower handgrip force in young and middle aged non-diabetic men.

OBJECTIVES: This study investigated whether an association between insulin resistance (IR) and muscle parameters is appreciable in young healthy men, independent of obesity. Furthermore, markers of muscle metabolism and hormones/possible determinants, were explored. METHODS: 358 healthy young men were divided into a less and more insulin sensitive (LIS [age=33.2±5.4, BMI=23.4±2.3] and MIS [age=35.5±5.3, BMI=28.1±3.7]) group based on upper and lower quartile of HOMA-IR. Muscle cross-sectional area (CSA), -density, handgrip force, serum testosterone, estradiol, SHBG, Vitamin 25(OH)D, creatinine, IGF-1, IGFBP-3 and leptin levels were compared between these groups, correcting for differences in age, physical activity and fat mass. Correlations between HOMA-IR and these parameters, and between muscle measures and biochemical parameters, were calculated. RESULTS: LIS is related to lower relative muscle CSA, muscle density, muscle/fat CSA ratio, relative handgrip force and level of physical activity. Furthermore, lower levels in SHBG, testosterone, Vitamin 25(OH)D and higher leptin, IGF-1 and IGFBP-3 levels were observed in LIS. Bio available T, FT, TE2, FE2, bioavailable E2, serum and urinary creatinine levels did not differ between groups. CONCLUSION: Differences in muscle performance are already present in healthy men with lower insulin sensitivity and could be possibly modifiable risk factors for the development of type 2 diabetes.

Association between insulin resistance, lean mass and muscle torque/force in proximal versus distal body parts in healthy young men.

OBJECTIVES: The purpose of this study was to investigate whether there is already an association of insulin resistance (IR) with muscle mass and -force/torque in an adult population and whether this relationship is the same in distal and proximal body parts. METHODS: 358 Healthy young men were divided into a more insulin sensitive (MIS) (n=89) and a less insulin sensitive (LIS) group (n=89), respectively using lower and upper quartiles of HOMA-IR index (Homeostasis Model Assessment of IR). Muscle force/torque and lean mass, were compared between the two groups. RESULTS: LIS subjects had higher absolute thigh lean mass, but not higher thigh muscle torque, resulting in a lower torque per kg muscle. In upper arm, lean mass was higher in LIS subjects, but also absolute muscle torque resulted higher. For handgrip force, the LIS and MIS group had similar results, despite a trend towards higher forearm lean mass in LIS subjects. Lean mass % of total lean mass is lower in LIS subjects in more distal body parts. CONCLUSIONS: Already in a young healthy population, IR seems to be associated with lower force/torque per muscle mass and lower lean mass % of total lean mass predominantly in more distal body parts.

Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications.

UNLABELLED: Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection. INTRODUCTION: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound. METHODS: The present document is the result of a national consensus, based on a systematic and critical review of the literature. RESULTS: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed. CONCLUSION: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.

Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.

UNLABELLED: In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term. INTRODUCTION: Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years. METHODS: Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm. RESULTS: The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years. CONCLUSIONS: Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club.

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies.

Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club.

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect.

Validation of the IOF quality of life questionnaire for patients with wrist fracture.

INTRODUCTION: Wrist fracture causes pain and decreased physical, social and emotional function. The International Osteoporosis Foundation has developed a specific questionnaire to assess quality of life in patients with wrist fracture. This questionnaire, including 12 questions, was validated in a multicentre study and compared with an osteoporosis-specific questionnaire (Qualeffo-41) and a generic questionnaire (EQ-5D). METHODS: The study included 105 patients with a recent wrist fracture and 74 sex- and age-matched control subjects. The questionnaire was administered as soon as possible after the fracture, at 6 weeks, 3 months, 6 months and 1 year after the fracture. Test-retest reproducibility, internal consistency and sensitivity to change were assessed. RESULTS AND DISCUSSION: The results showed adequate repeatability and internal consistency of the International Osteoporosis Foundation (IOF) wrist fracture questionnaire. The discriminatory capacity between patients and control subjects was very high, with significant odds ratios for each question and domain. The IOF-wrist fracture questionnaire domain scores showed significant improvement after 3 and 6 months and some improvement from 6 months up to 1 year. The sensitivity to change was much higher for the IOF-wrist fracture total score than for Qualeffo-41 and EQ-5D. CONCLUSION: In conclusion, the IOF-wrist fracture questionnaire appears to be a reliable and responsive quality of life questionnaire.

The Belgian Bone Club 2020 guidelines for the management of osteoporosis in postmenopausal women.

PURPOSE: To provide updated evidence-based guidelines for the management of osteoporosis in postmenopausal women in Belgium. METHODS: The Belgian Bone Club (BBC) gathered a guideline developer group. Nine "Population, Intervention, Comparator, Outcome" (PICO) questions covering screening, diagnosis, non-pharmacological and pharmacological treatments, and monitoring were formulated. A systematic search of MEDLINE, the Cochrane Database of Systematic Reviews, and Scopus was performed to find network meta-analyses, meta-analyses, systematic reviews, guidelines, and recommendations from scientific societies published in the last 10 years. Manual searches were also performed. Summaries of evidence were provided, and recommendations were further validated by the BBC board members and other national scientific societies' experts. RESULTS: Of the 3840 references in the search, 333 full texts were assessed for eligibility, and 129 met the inclusion criteria. Osteoporosis screening using clinical risk factors should be considered. Patients with a recent (<2 years) major osteoporotic fracture were considered at very high and imminent risk of future fracture. The combination of bone mineral density measured by dual-energy X-ray absorptiometry and 10-year fracture risk was used to categorize patients as low or high risk. Patient education, the combination of weight-bearing and resistance training, and optimal calcium intake and vitamin D status were recommended. Antiresorptive and anabolic osteoporosis treatment should be considered for patients at high and very high fracture risk, respectively. Follow-up should focus on compliance, and patient-tailored monitoring should be considered. CONCLUSION: BBC guidelines and 25 guideline recommendations bridge the gap between research and clinical practice for the screening, diagnosis, and management of osteoporosis.

How to manage osteoporosis before the age of 50.

This narrative review discusses several aspects of the management of osteoporosis in patients under 50 years of age. Peak bone mass is genetically determined but can also be affected by lifestyle factors. Puberty constitutes a vulnerable period. Idiopathic osteoporosis is a rare, heterogeneous condition in young adults due in part to decreased osteoblast function and deficient bone acquisition. There are no evidence-based treatment recommendations. Drugs use can be proposed to elderly patients at very high risk. Diagnosis and management of osteoporosis in the young can be challenging, in particular in the absence of a manifest secondary cause. Young adults with low bone mineral density (BMD) do not necessarily have osteoporosis and it is important to avoid unnecessary treatment. A determination of BMD is recommended for premenopausal women who have had a fragility fracture or who have secondary causes of osteoporosis: secondary causes of excessive bone loss need to be excluded and treatment should be targeted. Adequate calcium, vitamin D, and a healthy lifestyle should be recommended. In the absence of fractures, conservative management is generally sufficient, but in rare cases, such as chemotherapy-induced osteoporosis, antiresorptive medication can be used. Osteoporosis in young men is most often of secondary origin and hypogonadism is a major cause; testosterone replacement therapy will improve BMD in these patients. Diabetes is characterized by major alterations in bone quality, implying that medical therapy should be started sooner than for other causes of osteoporosis. Primary hyperparathyroidism, hyperthyroidism, Cushing's syndrome and growth hormone deficiency or excess affect cortical bone more often than trabecular bone.

Prevalence of low bone mass in relation to estrogen treatment and body composition in male-to-female transsexual persons.

Bone health is a parameter of interest in the daily follow-up of male-to-female (M --> F) transsexual persons both before and after sex reassignment surgery (SRS) due to an intensely changing hormonal milieu. We have studied body composition, areal, geometric, and volumetric bone parameters, using DXA and peripheral quantitative computed tomography at different sites in 50 M --> F transsexual persons, at least 3 yr after the start of the hormonal treatment and 1 yr after SRS. In this cross-sectional study, hormone levels and markers of bone metabolism were assessed using immunoassays. Prevalence of low bone mass as defined by a Z-score < or = -2.0 according to DXA criteria was 26% at lumbar spine and 2% at the total hip. We found no major differences in hormonal parameters between participants with a Z-score < or = or > -2.0. Markers of bone turnover were comparable between subjects with or without low bone mass, indicating a stable bone turnover at the time of investigation. No significant differences in bone size or density were observed between patients on transdermal vs. oral estrogens. Low bone mass is not uncommon in M --> F transsexual persons. Smaller bone size, and a strikingly lower muscle mass compared with men appear to underlie these findings.

Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club.

OBJECTIVES: To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency. METHODOLOGY: Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women. RESULTS: Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance. DISCUSSION: Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and/or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable. CONCLUSION: Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.

Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism.

CONTEXT: There is a large interindividual variation in serum (free) testosterone (FT) levels in men, underlain in part by genetic components. OBJECTIVE: The objective of the study was to explore the hypothesis that this variability results in part from differences in androgen sensitivity and feedback loop set point and assess the role of the androgen receptor (AR) polyglutamine tract polymorphism encoded by a CAG repeat of variable length in exon 1 of the AR gene. DESIGN/SETTING/PARTICIPANTS: We performed a cross-sectional analysis in two independent populations of healthy men, consisting of 2322 men aged 35-59 yr (Belstress study) and 358 men aged 25-45 yr (Siblos study), respectively. MAIN OUTCOME MEASURES: Serum hormonal levels and the AR gene CAG repeat length were determined. RESULTS: In the Belstress population, serum testosterone and calculated FT showed a positive linear association with LH (P < 0.001). In the 200 men with lowest FT, CAG repeat number was lower than in the 200 men with highest FT (P = 0.004). As studied in a larger subset of the population consisting of 857 men covering the whole FT range, FT increased progressively with CAG repeat length (P = 0.003). These findings of a positive relation of FT with both LH and CAG repeat length were confirmed in the Siblos study population (both P < or = 0.001). Difference in FT between extreme quartiles of CAG repeat was 10 and 14% in the Belstress and Siblos study, respectively. In both study populations, CAG repeat length was also positively associated with serum total testosterone (P < or = 0.004). CONCLUSIONS: The data support the view that between-subject variability in serum FT in healthy men is underlain in part by differences in androgen sensitivity and feedback set point, with a contributory role of AR polymorphism. These findings have potential implications for the interpretation of epidemiological studies, diagnosis of hypogonadism, and pharmacogenetics of androgen treatment in men.

Is the effect of testosterone on body composition modulated by the androgen receptor gene CAG repeat polymorphism in elderly men?

OBJECTIVE: The androgen receptor (AR) gene contains a CAG repeat polymorphism coding for a polyglutamine chain, the length of which is inversely correlated with AR transcriptional activity. We explored whether this polymorphism modulates the activities of testosterone (T) related to body composition in elderly men. DESIGN: We performed cross-sectional analyses using data from a 4-year follow-up study in community-dwelling men aged 75-89 years (n=159). METHODS: Body composition was assessed by dual-energy X-ray absorptiometry and its relation with T and the AR gene CAG repeat length was assessed by multiple linear regression analyses, adjusting for confounding and exploring effect modification. RESULTS: AR gene CAG repeat length was not directly related to body composition, either with or without adjustment for confounding variables like age, weight, total T or sex hormone binding globulin (SHBG) levels. However, exploration of effect modification showed that CAG repeat length modulated the relation between T and body composition (standardized regression coefficients of interaction term: beta=0.12, P<0.01 and beta=-0.09, P<0.05 for fat-free mass and fat mass respectively). These results were confirmed using similar models and data of mean T, SHBG and weight of the 2 years' preceding body composition assessment instead of data of the same year (beta=0.09, P<0.05 and beta=-0.09, P<0.05 respectively). CONCLUSION: These findings suggest that the AR gene CAG polymorphism contributes, albeit modestly, to the between-subject variation of T action on body composition in community-dwelling elderly men.