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Purpose: Evidence-based guidelines for the management of polycystic ovary syndrome (PCOS) recommend clinical laboratories use liquid chromatography-tandem mass spectrometry (LC-MS/MS) for diagnosing biochemical hyperandrogenism. However, automated immunoassays are still mostly used in routine laboratories worldwide. Another hurdle for PCOS phenotyping in the clinical setting is ultrasound assessment of polycystic ovarian morphology. We address the impact of using state-of-the-art (LC-MS/MS) and of an anti-müllerian hormone (AMH) assay on the diagnosis of PCOS in routine practice., Methods: In a cross-sectional study, we included 359 premenopausal women consecutively evaluated because of symptoms of functional androgen excess or hyperandrogenemia, and finally diagnosed with PCOS. Patients were submitted to routine phenotyping based on serum androgen measurements by immunoassays and an ovarian ultrasound when necessary. Samples of all patients were also assayed by LC-MS/MS for hyperandrogenemia and for circulating AMH., Results: The observed agreement between immunoassays and LC-MS/MS in identifying hyperandrogenemia was poor [78.0%; k(95%CI): 0.366 (0.283;0.449)]. The observed agreement between ultrasound and increased AMH was 27.3% [(95%CI): 0.060 (0.005; 0.115)]. Using LC-MS/MS changed PCOS phenotypes in 60(15.8%) patients. Fifty-two (18.3%) individuals with hyperandrogenemia by routine immunoassays no longer presented with androgen excess by LC-MS/MS. Overall diagnostic agreement between routine assessment using immunoassays and ultrasound and that derived from LC-MS/MS and the addition of AMH to US was moderate [weighted κ (linear weights): 0.512 (0.416;0.608)]., Conclusions: Immunoassays used in routine practice are unacceptably inaccurate for phenotyping women with PCOS. Our data cast some doubts upon the interchangeability of serum AMH and ultrasound examination for the diagnosis of PCOS., Competing Interests: Declarations. Conflict of interests: The authors have none to declare. Ethical approval and Informed consent: The authors certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All patients and control subjects provided informed consents allowing us to include their data in a database for research purposes including this study. That research database was approved by the local Ethics Committee from Hospital Universitario Ramón y Cajal (Date of approval: 7-March-2002; Reference number: 12/02). The informed consent was revised and again approved by the same local Institutional Review Board on 2022, March 10., (© 2024. The Author(s).)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions., Introduction: Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication., Methods: A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken., Results: Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few interventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it., Conclusion: These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions.

There is a growing body of evidence that links nutrition to muscle mass, strength and function in older adults, suggesting that it has an important role to play both in the prevention and management of sarcopenia. This review summarises the discussions of a working group [ESCEO working group meeting 8th September 2016] that met to review current evidence and to consider its implications for preventive and treatment strategies. The review points to the importance of 'healthier' dietary patterns that are adequate in quality in older age, to ensure sufficient intakes of protein, vitamin D, antioxidant nutrients and long-chain polyunsaturated fatty acids. In particular, there is substantial evidence to support the roles of dietary protein and physical activity as key anabolic stimuli for muscle protein synthesis. However, much of the evidence is observational and from high-income countries. Further high-quality trials, particularly from more diverse populations, are needed to enable an understanding of dose and duration effects of individual nutrients on function, to elucidate mechanistic links, and to define optimal profiles and patterns of nutrient intake for older adults., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 place of calcium supplementation, with or without concomitant vitamin D supplementation, has been much debated in terms of both efficacy and safety. There have been numerous trials and meta-analyses of supplementation for fracture reduction, and associations with risk of myocardial infarction have been suggested in recent years. In this report, the product of an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF), we review the evidence for the value of calcium supplementation, with or without vitamin D supplementation, for healthy musculoskeletal ageing. We conclude that (1) calcium and vitamin D supplementation leads to a modest reduction in fracture risk, although population-level intervention has not been shown to be an effective public health strategy; (2) supplementation with calcium alone for fracture reduction is not supported by the literature; (3) side effects of calcium supplementation include renal stones and gastrointestinal symptoms; (4) vitamin D supplementation, rather than calcium supplementation, may reduce falls risk; and (5) assertions of increased cardiovascular risk consequent to calcium supplementation are not convincingly supported by current evidence. In conclusion, we recommend, on the basis of the current evidence, that calcium supplementation, with concomitant vitamin D supplementation, is supported for patients at high risk of calcium and vitamin D insufficiency, and in those who are receiving treatment for osteoporosis., Competing Interests: DisclosuresN. Harvey has received consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, Consilient Healthcare and Internis Pharma; C. Cooper has received consultancy, lecture fees and honoraria from AMGEN, GSK, Alliance for Better Bone Health, MSD, Eli Lilly, Pfizer, Novartis, Servier, Medtronic and Roche. V. Coxam has received Institutional funding and honoraria for an oral intervention at a scientific meeting Le Centre National Interprofessionnel de l'Economie Laitière (CNIEL); J.-M. Kaufman has received speaker or consultant fees from Amgen, Eli Lilly, Servier; E. Czerwinski has received research support and lecture fees from Amgen; O. Bruyere has received grant support from IBSA, MSD, Nutraveris, Novartis, Pfizer, Rottapharm, Servier, and Theramex; consulting or lecture fees from Bayer, Genevrier, IBSA, Rottapharm, Servier, SMB and TRB Chemedica. B. Dawson-Hughes has received research funding and consultancy from Pfizer Inc. E. Biver, J. Bauer, J. Branco, M.L. Brandi, A. Cruz-Jentoft, H. Dimai, P. Fardellone, F. Landi, J.Y. Reginster, J.A. Kanis, R. Rizzoli that they have no conflict of interest. ESCEO and IOF disclosures: none in relation to this paper.

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., Competing Interests: The authors have no conflict of interest.

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.

The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20-30% of patients with non-small-cell lung cancer (NSCLC). Loss of LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a calcium/calmodulin-dependent protein kinase kinase 2 inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors.

Background: Bi-allelic CYP24A1 mutations can cause idiopathic infantile hypercalcemia (IIH), adult-onset nephrocalcinosis, and possibly bone metabolism disturbances. It is currently unclear if heterozygous carriers experience clinical problems or biochemical abnormalities. Our objective is to gain insight in the biochemical profile and health problems in CYP24A1 heterozygotes., Study Design: Cross-sectional evaluation of participants. Data of previously reported carriers are reviewed., Setting and Participants: Outpatient clinic of a tertiary care hospital. Participants were eight family members of an infant with a well-characterized homozygous CYP24A1 mutation c.1186C>T p.(Arg396Trp)., Outcomes: Serum vitamin D metabolites. Symptoms or biochemical signs of hypercalcemia, hypercalciuria or nephrocalcinosis. Bone health in heterozygous as compared to wild type (WT) subjects., Measurements: Genotyping by Sanger sequencing; vitamin D metabolites by liquid chromatography tandem mass spectrometry; renal, calcium and bone markers by biochemical analyses; presence of nephrocalcinosis by renal ultrasound; bone health by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography., Results: Six participants were heterozygous carriers of the mutation. None of the heterozygous subjects had experienced IIH. One had a documented history of nephrolithiasis, two others had complaints compatible with this diagnosis. No major differences between WT and heterozygous subjects were found regarding bone health, serum or urinary calcium or 25OHD/24,25(OH)2D ratio. Literature reports on three out of 33 heterozygous cases suffering from IIH. In all three, the 25OHD/24,25(OH)2D ratio was highly elevated. Nephrocalcinosis was frequently reported in family members of IIH cases., Limitations: Small sample size, lack of a large control group., Conclusions: Our and literature data suggest that most heterozygous CYP24A1 mutation carriers have a normal 25OHD/24,25(OH)2D ratio, are usually asymptomatic and have a normal skeletal status but may possibly be at increased risk of nephrocalcinosis. A review of the available literature suggests that an elevated 25OHD/24,25(OH)2D ratio may be associated with symptoms of IHH, irrespective of carrier status., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes., Introduction: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients., Methods: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis., Results: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity., Conclusions: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Context: Osteoporosis is a major public health concern worldwide. Understanding the roles of diet and physical activity in ensuring adequate bone mass accrual during childhood and adolescence may help identify strategies to reduce the risk of osteoporotic fractures later in life., Objective: The present systematic review was conducted to provide an overview of the current knowledge of the combined effects of physical activity and diet on bone mass accrual in children and adolescents., Data Sources: Data were obtained via searches of the PubMed, EMBASE, SPORTDiscus, and ISI Web of Science databases., Study Selection: Studies published in English and Spanish between 1887 and August 2013 were eligible for inclusion. Two investigators evaluated the studies against the inclusion and exclusion criteria. A total of 14 studies (7 cross-sectional and 7 experimental) were included in the review., Data Extraction: The Pedro score and the Black and Down's checklist were used to evaluate the methodological quality of the experimental and the cross-sectional studies, respectively. Study characteristics were summarized in accordance with the review's PICO criteria., Data Synthesis: Significant exercise-by-calcium interaction was detected at several different bone sites., Conclusions: Although the results of cross-sectional studies were inconsistent, the results of randomized controlled trials showed that exercise has the potential to improve bone health under conditions of adequate calcium intake., (© The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To assess the evolution of body composition and bone metabolism in trans men during the first year of cross-sex hormonal therapy., Methods: In a prospective controlled study, we included 23 trans men (female-to-male trans persons) and 23 age-matched control women. In both groups, we examined grip strength (hand dynamometer), biochemical markers of bone turnover (C-terminal telopeptides of type 1 collagen (CTX) and procollagen 1 aminoterminal propeptide (P1NP)), total body fat and lean mass, and areal bone mineral density (aBMD) by dual-X-ray absorptiometry (DXA) and fat and muscle area at the forearm and calf, bone geometry, and volumetric bone mineral density (vBMD) by peripheral quantitative computed tomography (pQCT), before treatment and after 1 year of treatment with undecanoate (1000 mg i.m./12 weeks)., Results: Before hormonal treatment, trans men had similar bone and body composition compared with control women. Testosterone treatment induced in trans men a gain in muscle mass (+10.4%) and strength and loss of fat mass (-9.7%) (all P<0.001) and increased the levels of P1NP and CTX (both P<0.01). Areal and volumetric bone parameters remained largely unchanged apart from a small increase in trabecular vBMD at the distal radius and in BMD at the total hip in trans men (P=0.036 and P=0.001 respectively). None of these changes were observed in the control group., Conclusions: Short-term testosterone treatment in trans men increased muscle mass and bone turnover. The latter may rather reflect an anabolic effect of testosterone treatment rather than bone loss., (© 2015 European Society of Endocrinology.)

Unlabelled: Although trans women before the start of hormonal therapy have a less bone and muscle mass compared with control men, their bone mass and geometry are preserved during the first 2 years of hormonal therapy, despite of substantial muscle loss, illustrating the major role of estrogen in the male skeleton., Purpose: The aim of this study is to examine the evolution of areal and volumetric bone density, geometry, and turnover in trans women undergoing sex steroid changes, during the first 2 years of hormonal therapy., Methods: In a prospective observational study, we examined 49 trans women (male-to-female) before and after 1 and 2 years of cross-sex hormonal therapy (CSH) in comparison with 49 age-matched control men measuring grip strength (hand dynamometer), areal bone mineral density (aBMD), and total body fat and lean mass using dual X-ray absorptiometry (DXA), bone geometry and volumetric bone mineral density, regional fat, and muscle area at the forearm and calf using peripheral quantitative computed tomography. Standardized treatment regimens were used with oral estradiol valerate, 4 mg daily (or transdermal 17-β estradiol 100 μg/24 h for patients >45 years old), both combined with oral cyproterone acetate 50 mg daily., Results: Prior to CSH, trans women had lower aBMD at all measured sites (all p < 0.001), smaller cortical bone size (all p < 0.05), and lower muscle mass and strength and lean body mass (all p < 0.05) compared with control men. During CSH, muscle mass and strength decreased and all measures of fat mass increased (all p < 0.001). The aBMD increased at the femoral neck, radius, lumbar spine, and total body; cortical and trabecular bone remained stable and bone turnover markers decreased (all p < 0.05)., Conclusions: Although trans women, before CSH, have a lower aBMD and cortical bone size compared with control men, their skeletal status is well preserved during CSH treatment, despite of substantial muscle loss.

Background: Little is known about the effects of adrenal steroids on skeletal maturation and bone mass acquisition in healthy prepubertal boys., Objective: To study whether adrenal-derived steroids within the physiological range are associated with skeletal maturation, areal and volumetric bone mineral density (aBMD and vBMD) and bone geometry in healthy prepubertal and early pubertal boys., Methods: 98 healthy prepubertal and early pubertal boys (aged 6-14 y) were studied cross-sectionally. Androstenedione (A) and estrone (E1) were determined by liquid chromatography tandem mass spectrometry and DHEAS was determined by immunoassay. Whole body and lumbar spine aBMD and bone area were determined by dual-energy X-ray absorptiometry. Trabecular (distal site) and cortical (proximal site) vBMD and bone geometry were assessed at the non-dominant forearm and leg using peripheral QCT. Skeletal age was determined by X-ray of the left hand., Results: Adrenal-derived steroids (DHEAS, A and E1) are positively associated with bone age in prepubertal and early pubertal children, independently of age. There are no associations between the adrenal-derived steroids and the studied parameters of bone size (lumbar spine and whole body bone area, trabecular or cortical area at the radius or tibia, periosteal circumference and cortical thickness at the radius or tibia) or BMD (aBMD or vBMD)., Conclusion: In healthy prepubertal and early pubertal boys, serum adrenal-derived steroid levels, are associated with skeletal maturation, independently of age, but not with bone size or (v)BMD. Our data suggest that adrenal derived steroids are not implicated in the accretion of bone mass before puberty in boys., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Despite the proven predictive ability of bone mineral density, Fracture Risk Assessment Tool (FRAX®), bone turnover markers, and fracture for osteoporotic fracture, their use as targets for treatment of osteoporosis is limited., Introduction: Treat-to-target is a strategy applied in several fields of medicine and has recently become an area of interest in the management of osteoporosis. Its role in this setting remains controversial. This article was prepared following a European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group meeting convened under the auspices of the International Osteoporosis Foundation (IOF) to discuss the feasibility of applying such a strategy in osteoporosis in Europe., Methods: Potential targets range from the absence of an incident fracture to fixed levels of bone mineral density (BMD), a desired FRAX® score, a specified level of bone turnover markers or indeed changes in any one or a combination of these parameters., Results: Despite the proven predictive ability of all of these variables for fracture (particularly BMD and FRAX), their use as targets remains limited due to low sensitivity, the influence of confounders and current lack of evidence that targets can be consistently reached., Conclusion: ESCEO considers that it is not currently feasible to apply a treat-to-target strategy in osteoporosis, though it did identify a need to continue to improve the targeting of treatment to those at higher risk (target-to-treat strategy) and a number of issues for the research agenda. These include international consensus on intervention thresholds and definition of treatment failure, further exploration of the relationship between fracture and BMD, and FRAX and treatment efficacy and investigation of the potential of short-term targets to improve adherence.

Background: Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting., Objectives: To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence., Methods: Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatography-tandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays., Results: Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages., Conclusion: Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys.

Background: Although both testosterone (T) and estradiol (E2) are considered essential in the regulation of the male skeleton, there are few data concerning the relative contribution of T and E2 on bone mineral density (BMD), bone geometry, and bone maturation in healthy boys., Objective: The objective of the study was to analyze the relationship between T and E2 and BMD, bone geometry, skeletal maturation, and body composition., Methods: This is a cross-sectional study in 199 healthy boys (aged 6-19 y). T and E2 were determined by liquid chromatography tandem mass spectrometry. Whole-body and lumbar areal bone mineral density (aBMD) and bone area, lean mass, and fat mass were determined by dual-energy X-ray absorptiometry. Trabecular (distal site) and cortical (proximal site) volumetric BMD (vBMD) and bone geometry were assessed at the nondominant forearm and leg using peripheral quantitative computed tomography. Skeletal age was determined by an X-ray of the left hand., Results: T was positively associated with lean mass (P < .001), lumbar and whole-body bone area (P < .001), trabecular and cortical area (P < .01), and periosteal circumference (P < .01) at the radius. E2 was positively associated with lumbar and whole-body aBMD (P < .001), trabecular vBMD at the radius and tibia (P < .01), and cortical thickness at the radius (P < .05). E2 was an independent negative predictor of the endosteal circumference (P < .01). Moreover, E2 was positively associated with bone age advancement (P < .001)., Conclusion: Circulating E2 is positively associated with bone maturation and aBMD and vBMD and negatively with endosteal circumference in healthy boys, whereas T is a determinant of lean mass and bone size. These findings underscore the important role of E2 in skeletal development in boys.

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.

Objective: This study aims to investigate the efficacy and safety of oral fixed-dose combination of strontium ranelate 2  g/vitamin D₃ 1000  IU daily vs strontium ranelate 2  g daily for correcting vitamin D insufficiency in osteoporosis., Design: A 6-month international, randomized, double-blind, parallel-group, phase 3 study., Methods: A total of 518 men and postmenopausal women aged ≥50 years with primary osteoporosis (T-score ≤-2.5 s.d.) and serum 25-hydroxyvitamin D (25(OH)D) >22.5 nmol/l were included. Patients were allocated to strontium ranelate 2 g/vitamin D₃ 1000  IU daily (n=413) or strontium ranelate 2 g daily (n=105). The participants received calcium 1 g daily. The primary endpoint was serum 25(OH)D at last post-baseline evaluation during 3 months., Results: Both groups were comparable at baseline. Mean baseline of 25(OH)D was 44.1 ± 14.6 nmol/l. After 3 months, the percentage of patients with 25(OH)D ≥50 nmol/l was higher with strontium ranelate/vitamin D₃ vs strontium ranelate (84 vs 44%, P<0.001; adjusted between-group odds ratio=6.7; 95% CI, 4.2-10.9). The efficacy of the fixed-dose combination on 25(OH)D was maintained at 6 months (86 vs 40%, P<0.001). Mean 25(OH)D was 65.1 and 49.5 nmol/l, respectively, after 3 months and 66.9 and 45.4 nmol/l after 6 months. Physical performance improved in both groups. Falls were 17 and 20% in the strontium ranelate/vitamin D₃ and strontium ranelate groups respectively. Parathyroid hormone levels were inversely correlated with 25(OH)D. No clinically relevant differences in safety were observed., Conclusions: This study confirms the efficacy and safety of fixed-dose combination of strontium ranelate 2 g/vitamin D₃ 1000 IU for correction of vitamin D insufficiency in osteoporotic patients.

Summary: The relationship between baseline Fracture Risk Assessment Tool (FRAX®) and treatment efficacy was evaluated using data from a pivotal phase 3 study. Relative risk of vertebral, nonvertebral, and all clinical fractures decreased with increasing probability of fracture for bazedoxifene (BZA) versus placebo but remained generally constant for raloxifene (RLX)., Introduction: To determine whether the FRAX® predicts osteoporosis treatment efficacy, we evaluated reductions in fracture incidence associated with BZA and RLX according to baseline fracture risk determined by FRAX® using data from a phase 3 osteoporosis treatment study., Methods: Hazard ratios (HRs) for effects of BZA and RLX versus placebo on incidence of vertebral, nonvertebral, and all clinical fractures were calculated using a Cox regression model. Cox regression analyses were performed in subgroups at or above 10-year fracture probability thresholds determined by FRAX®., Results: HRs for the risk of vertebral, nonvertebral, and all clinical fractures versus placebo decreased with increasing 10-year fracture probability for BZA, while those for RLX remained stable. In all 10-year fracture probability subgroups, all BZA doses significantly reduced vertebral fracture risk versus placebo (HR = 0.22-0.66). BZA at 20, 40, and 20/40 mg significantly reduced risk of nonvertebral fractures (HR = 0.45, 0.44, and 0.45, respectively) and all clinical fractures (HR = 0.38, 0.41, and 0.40, respectively) for ≥20.0 % fracture probability. Vertebral fracture risk reductions for RLX 60 mg versus placebo were significant in subgroups at lower fracture probabilities (≥2.5- ≥ 10.0 %), but not higher (≥12.5 %), and in no subgroups for nonvertebral or all clinical fractures., Conclusion: The antifracture efficacy of BZA increased with increasing baseline FRAX® score, but there was no clear relationship between RLX and baseline FRAX®. These findings provide independent confirmation of current literature, suggesting that the relationship between FRAX® and treatment efficacy varies for different agents.

Objective: This study evaluated the short- and long-term cardiovascular- and cancer-related morbidities during cross-sex hormone therapy in a large sample of trans persons., Subjects and Methods: A specialist center cross-sectional study compared 214 trans women (male-to-female transsexual persons) and 138 trans men (female-to-male trans persons) with an age- and gender-matched control population (1-3 matching). The participants were on cross-sex hormone therapy for an average of 7.4 years. We assessed physical health and possible treatment-related adverse events using questionnaires., Results: Five percent of trans women experienced venous thrombosis and/or pulmonary embolism during hormone therapy. Five of these adverse events occurred during the first year of treatment, while another three occurred during sex reassignment surgery. Trans women experienced more myocardial infarctions than the control women (P=0.001), but a similar proportion compared with control men. The prevalence of cerebrovascular disease (CVD) was higher in trans women than in the control men (P=0.03). The rates of myocardial infarction and CVD in trans men were similar to the control male and female subjects. The prevalence of type 2 diabetes was higher in both trans men and women than in their respective controls, whereas the rates of cancer were similar compared with the control men and women., Conclusion: Morbidity rate during cross-sex hormone therapy was relatively low, especially in trans men. We observed a higher prevalence of venous thrombosis, myocardial infarction, CVD, and type 2 diabetes in trans women than in the control population. Morbidity rates in trans men and controls were similar, with the exception of the increased prevalence of type 2 diabetes.

Context: Controversy exists on the effect of obesity on bone development during puberty., Objective: Our objective was to determine differences in volumetric bone mineral density (vBMD) and bone geometry in male obese adolescents (ObAs) in overlap with changes in bone maturation, muscle mass and force development, and circulating sex steroids and IGF-I. We hypothesized that changes in bone parameters are more evident at the weight-bearing site and that changes in serum estradiol are most prominent., Design, Setting, and Participants: We recruited 51 male ObAs (10-19 years) at the entry of a residential weight-loss program and 51 healthy age-matched and 51 bone-age-matched controls., Main Outcome Measures: vBMD and geometric bone parameters, as well as muscle and fat area were studied at the forearm and lower leg by peripheral quantitative computed tomography. Muscle force was studied by jumping mechanography., Results: In addition to an advanced bone maturation, differences in trabecular bone parameters (higher vBMD and larger trabecular area) and cortical bone geometry (larger cortical area and periosteal and endosteal circumference) were observed in ObAs both at the radius and tibia at different pubertal stages. After matching for bone age, all differences at the tibia, but only the difference in trabecular vBMD at the radius, remained significant. Larger muscle area and higher maximal force were found in ObAs compared with controls, as well as higher circulating free estrogen, but similar free testosterone and IGF-I levels., Conclusions: ObAs have larger and stronger bones at both the forearm and lower leg. The observed differences in bone parameters can be explained by a combination of advanced bone maturation, higher estrogen exposure, and greater mechanical loading resulting from a higher muscle mass and strength.

Objective: Cross-sex hormonal therapy and sex reassignment surgery (including gonadectomy) in transsexual persons has an impact on body composition and bone mass and size. However, it is not clear whether baseline differences in bone and body composition between transsexual persons and controls before cross-sex hormonal therapy play a role., Design: A cross-sectional study with 25 male-to-female transsexual persons (transsexual women) before cross-gender sex steroid exposure (median age 30 years) in comparison with 25 age-matched control men and a male reference population of 941 men., Main Outcome Measures: Areal and volumetric bone parameters using respectively dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), body composition (DXA), grip strength (hand dynamometer), Baecke physical activity questionnaire, serum testosterone and 25-OH vitamin D., Results: Transsexual women before cross-sex hormonal therapy presented with less muscle mass (p≤0.001) and strength (p≤0.05) and a higher prevalence of osteoporosis (16%) with a lower aBMD at the hip, femoral neck, total body (all p<0.001) and lumbar spine (p=0.064) compared with control men. A thinner radial cortex (p≤0.01) and lower cortical area at the radius and tibia (both p<0.05) was found in transsexual women vs. control men. Serum testosterone was comparable in all 3 groups, but 25-OH vitamin D was lower in transsexual women (p≤0.001)., Conclusions: Transsexual women before the start of hormonal therapy appear to have lower muscle mass and strength and lower bone mass compared with control men. These baseline differences in bone mass might be related to a less active lifestyle., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Vitamin D insufficiency has deleterious consequences on health outcomes. In elderly or postmenopausal women, it may exacerbate osteoporosis., Scope: There is currently no clear consensus on definitions of vitamin D insufficiency or minimal targets for vitamin D concentrations and proposed targets vary with the population. In view of the potential confusion for practitioners on when to treat and what to achieve, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) convened a meeting to provide recommendations for clinical practice, to ensure the optimal management of elderly and postmenopausal women with regard to vitamin D supplementation., Findings: Vitamin D has both skeletal and extra-skeletal benefits. Patients with serum 25-hydroxyvitamin D (25-(OH)D) levels <50 nmol/L have increased bone turnover, bone loss, and possibly mineralization defects compared with patients with levels >50 nmol/L. Similar relationships have been reported for frailty, nonvertebral and hip fracture, and all-cause mortality, with poorer outcomes at <50 nmol/L., Conclusion: The ESCEO recommends that 50 nmol/L (i.e. 20 ng/mL) should be the minimal serum 25-(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Below this threshold, supplementation is recommended at 800 to 1000 IU/day. Vitamin D supplementation is safe up to 10,000 IU/day (upper limit of safety) resulting in an upper limit of adequacy of 125 nmol/L 25-(OH)D. Daily consumption of calcium- and vitamin-D-fortified food products (e.g. yoghurt or milk) can help improve vitamin D intake. Above the threshold of 50 nmol/L, there is no clear evidence for additional benefits of supplementation. On the other hand, in fragile elderly subjects who are at elevated risk for falls and fracture, the ESCEO recommends a minimal serum 25-(OH)D level of 75 nmol/L (i.e. 30 ng/mL), for the greatest impact on fracture.

Objective: Sclerostin inhibits osteoblast differentiation and bone formation. If aberrant sclerostin action is involved in less efficient bone acquisition in men with idiopathic low bone mass, this might be reflected in higher serum sclerostin levels., Methods: In 116 men with idiopathic osteoporosis (≤65 years old), 40 of their sons and healthy controls, areal bone parameters were measured using dual-energy X-ray absorptiometry, and volumetric and geometric bone parameters were measured using peripheral quantitative computed tomography. Serum analytes were measured using immunoassays and estradiol (E2) levels using liquid chromatography-tandem mass spectrometry., Results: Men with idiopathic low bone mass had lower levels of sclerostin than the controls (0.54±0.17 vs 0.66±0.23 ng/ml; P<0.001). In both groups, sclerostin levels were strongly associated with age; when adjusting for age, no associations with anthropometrics were observed (P>0.14). In multivariate analyses, sclerostin levels displayed a positive association with whole-body bone mineral content (BMC) and areal BMD (aBMD), as well as with trabecular and cortical volumetric bone mineral density (vBMD) at the tibia in the probands. No clear associations were observed in the control group, neither were sclerostin levels associated with BMC at the radius or lumbar spine (all P>0.11). Testosterone, but not E2, was inversely related to sclerostin levels in the probands. No difference in sclerostin levels was found in their sons when compared with their controls., Conclusion: Lower rather than higher serum sclerostin levels in the probands with idiopathic low bone mass suggest that aberrant sclerostin secretion is not involved in the pathogenesis of low bone mass in these subjects.

Summary: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed., Introduction: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors)., Methods: A debate with an expert panel on preselected topics was conducted., Results and Conclusions: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Nowadays, erectile dysfunction (ED) is considered an increasingly important clinical condition in men with heart failure (HF) which may influence the therapeutic approach to these patients. Since there is cogent evidence that ED is a "sentinel marker" of acute cardiovascular events especially in men younger than 65 years or in those affected by type 2 diabetes mellitus, it deserves an early diagnosis and an appropriate treatment. In NYHA III-IV class HF patients, sexual activity could lead to acute cardiovascular events and this should be taken into account when approaching ED patients. Moreover, it is well known that some classes of drugs, normally employed in the treatment of HF patients (e.g.thiazide diuretics, spironolactone and β-blockers), might worsen or even contribute to ED development. On the other hand, growing evidence suggests that PDE 5 inhibitors (vardenafil, tadalafil and sildenafil) seem to better satisfy the needs of NYHA HF I- II class men suffering from ED. In fact, they show few side effects, while improving both cardiopulmonary parameters and quality of life. Therefore, the aim of this review is to sum up the most recent evidence regarding the management of ED in men suffering from HF.

Context: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis., Objective: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year)., Design: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis])., Setting: This international study included 54 centers in 14 countries., Participants: PARTICIPANTS were 261 white men with primary osteoporosis., Intervention: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered., Main Outcome Measures: Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured., Results: Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 μmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated., Conclusions: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Postmenopausal osteoporosis is mainly caused by increased bone remodeling resulting from estrogen deficiency. Indications for treatment are based on low areal bone mineral density (aBMD, T-score  ≤ -2.5), typical fragility fractures (spine or hip), and more recently, an elevated 10-year fracture probability (by FRAX®). In contrast, there is no clear definition of osteoporosis nor intervention thresholds in younger individuals. Low aBMD in a young adult may reflect a physiologically low peak bone mass, such as in lean but otherwise healthy persons, whereas fractures commonly occur with high-impact trauma, i.e., without bone fragility. Furthermore, low aBMD associated with vitamin D deficiency may be highly prevalent in some regions of the world. Nevertheless, true osteoporosis in the young can occur, which we define as a T-score below -2.5 at spine or hip in association with a chronic disease known to affect bone metabolism. In the absence of secondary causes, the presence of fragility fractures, such as in vertebrae, may point towards genetic or idiopathic osteoporosis. In turn, treatment of the underlying condition may improve bone mass as well. In rare cases, a bone-specific treatment may be indicated, although evidence is scarce for a true benefit on fracture risk. The International Osteoporosis Foundation (IOF) convened a working group to review pathophysiology, diagnosis, and management of osteoporosis in the young, excluding children and adolescents, and provide a screening strategy including laboratory exams for a systematic approach of this condition.

An operational definition of musculoskeletal decline in older people is needed to allow development of interventions for prevention or treatment, as was developed for the treatment of osteoporosis. Frailty and sarcopenia are linked, but distinct, correlates of musculoskeletal aging that have many causes, including age-related changes in body composition, inflammation, and hormonal imbalance. With the emergence of a number of exciting candidate therapies to retard the loss of muscle mass with aging, the derivation of a consensual definition of sarcopenia and physical frailty becomes an urgent priority. Although several consensual definitions have been proposed, these require clinical validation. An operational definition, which might provide a threshold for treatment/trial inclusion, should incorporate a loss of muscle mass as well as evidence of a decrease in muscle strength and/or physical activity. Evidence is required for a link between improvements in the measures of muscle strength and/or physical activity and clinical outcomes to allow development of interventions to improve clinical outcomes in frail older patients.

Context: Female-to-male transsexual persons (transsexual men) undergo extreme hormonal changes due to ovariectomy and testosterone substitution, allowing studies on sex steroid effects on bone geometry and physiology in the adult., Objective: The objective of the study was to examine the effects of cross-gender sex steroid exposure on volumetric bone parameters in transsexual men., Design: This was a cross-sectional study., Setting: Participants were recruited from the Center for Sexology and Gender Problems at the Ghent University Hospital (Ghent, Belgium)., Participants: Fifty transsexual men after sex reassignment surgery with 50 age-matched control women and an additional 16 transsexual men before testosterone substitution and sex reassignment surgery with 16 control women participated in the study., Main Outcome Measures: The main outcome measures were areal and volumetric bone parameters using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, body composition (dual-energy X-ray absorptiometry), sex steroids, markers of bone turnover and grip strength., Results: Before hormonal treatment, transsexual men had similar body composition and bone geometry as female controls. The transsexual men on long-term testosterone therapy, however, demonstrated a higher lean body mass and muscle mass and a greater grip strength as well as a lower body and subcutaneous fat mass and a larger waist and smaller hip circumference compared with female controls (all P < 0.001). We observed a larger radial cortical bone size (P < 0.001) and lower cortical volumetric bone mineral density at the radius and tibia (P < 0.05) in transsexual men on testosterone therapy., Conclusions: Transsexual men on testosterone substitution therapy present with a different body composition with more muscle mass and strength and less fat mass as well as an altered bone geometry with larger bones compared with female controls.

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.

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.

Unlabelled: Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims., Introduction: Regulation (EC) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims., Methods: Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science (GREES)., Results: The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that well-designed human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength., Conclusion: The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim.

Unlabelled: The competitive price of generic bisphosphonates has had a marked effect on practice guidelines, but an increasing body of evidence suggests that they have more limited effectiveness than generally assumed., Introduction: The purpose of this study is to review the impact of generic bisphosphonates on effectiveness in the treatment of osteoporosis., Methods: This study is a literature review., Results: A substantial body of evidence indicates that many generic formulations of alendronate are more poorly tolerated than the proprietary preparations which results in significantly poorer adherence and thus effectiveness. Poorer effectiveness may result from faster disintegration times of many generics that increase the likelihood of adherence of particulate matter to the oesophageal mucosa. Unfortunately, market authorisation, based on the bioequivalence of generics with a proprietary formulation, does not take into account the potential concerns about safety. The poor adherence of many generic products has implications for guideline development, cost-effectiveness and impact of treatment on the burden of disease., Conclusions: The impact of generic bisphosphonates requires formal testing to re-evaluate their role in the management of osteoporosis.

In healthy middle-aged men, endogenous testosterone does not seem to increase risk for cardiovascular disease (CVD). One explanation might be a differential effect of testosterone, and another, interference with oestradiol with respect to specific cardiovascular functions. To investigate these possibilities, we evaluated in a cross-sectional population of 1223 healthy men, aged 46 (6) years, associations between endogenous testosterone, oestradiol and left ventricular structure and function (echocardiography). Testosterone was inversely associated with ejection fraction (EF) and with more sensitive systolic tissue Doppler imaging indices. Oestradiol was positively associated with EF. These associations were confirmed by linear regression analyses, and consistent for calculated free as well as for total sex steroid concentrations. Standardized regression coefficients were -0.13 for testosterone (P < 0.01) and 0.12 for oestradiol (P < 0.01) for the association with EF, in a model which included height, waist circumference, triglycerides, glucose, systolic blood pressure, drug-treated hypertension, heart rate, haematocrit, current smoking, serum sampling time, age and excessive alcohol use. The study suggests an opposite link, albeit modestly, of testosterone and oestradiol with left ventricle systolic function in healthy middle-aged men. The finding provides a partial explanation for the overall neutral effect on CVD of testosterone in healthy middle-aged men., (© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

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.

Unlabelled: The consensus views on osteoporosis in men are reported., Introduction: A workshop was convened within a meeting on osteoporosis in men to identify areas of consensus amongst the panel (the authors) and the participants of the meeting., Methods: A public debate with an expert panel on preselected topics was conducted., Results and Conclusions: Consensus views were reached on diagnostic criteria and several aspects on the pathophysiology and treatment of osteoporosis in men.

Background/objectives: The increase of bone disease in adult cystic fibrosis (CF) patients is partly attributed to inadequate serum concentrations of 25-OH cholecalciferol (25 (OH) D) blamed on fat malabsorption. Based on physiological, clinical and biochemical observations this pathogenesis is debatable. The objective was to ascertain the relative importance of different 25 (OH) D sources., Subjects/methods: Over 4 consecutive years, 474 annual 25 (OH) D serum concentrations from 141 CF patients of all ages were compared with values of healthy peers and weighed against annual ultraviolet B (UVB) exposure., Results: Ranked per month, 25 (OH) D concentrations depicted a curve strikingly parallel to the amount of UVB exposure in the preceding months. A significant difference exists between 25 (OH) D concentrations in the 'Months with high UVB exposure' (May-October) and the 'Months with low UVB exposure' (November-April) but not with healthy controls in the same period., Conclusions: 25 (OH) D concentrations clearly respond to the amount of sunshine in preceding months. They are not clearly influenced by daily oral supplements of 800 IU of cholecalciferol. Sun exposure should be encouraged, and the recommended dosage of oral supplements increased.

Background: Quantitative ultrasound (QUS) is a quick, non-invasive and inexpensive method to measure bone strength. Moreover, the device is portable, which makes it easy to be used in the field. In contrast to other bone measuring techniques, QUS does not use any ionised radiation. However, the validity of QUS in the measurement of bone health and the relationship between QUS output and body composition have not been assessed in very young children., Objective: To investigate the relationship between paediatric calcaneal QUS and both dual-energy X-ray absorptiometry (DXA) and calcaneal DXA with laser (DXL) and body composition parameters., Subjects: A total of 37 Belgian children (10 boys and 27 girls; 4 to 8 years old) underwent a calcaneal QUS as well as a DXA scan. A total of 24 Swedish children (15 boys and 9 girls; 3 to 5 years old) underwent a calcaneal QUS as well as a heel DXL scan. The height and weight of all children were measured., Results: The QUS stiffness index (SI) was significantly negatively correlated with bone mineral density (BMD) of the total body (r=-0.370, P=0.02). No significant correlations were found between the SI and DXL results. In the total sample, the SI showed a significant positive correlation with body mass index (BMI) (r=0.298, P=0.02), even after correction for age, gender and centre. In the Belgian sample, the SI was also significantly positively correlated with total body fat mass content (r=0.416, P=0.01) and body fat percentage (r=0.566, P<0.01) obtained by whole-body DXA., Conclusion: The SI measured by QUS does not correlate significantly with BMD values measured by DXA or DXL in 3- to 8-year-old children. However, there is a significant positive correlation between SI and BMI and body fat %.

Unlabelled: A country-specific FRAX® model was developed from the epidemiology of fracture and death in Belgium. Fracture probabilities were identified that corresponded to currently accepted reimbursement thresholds., Introduction: The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX®) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities., Methods: Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck bone mineral density (BMD). Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium., Results: Fracture probability increased with age, lower BMI, decreasing BMD T-score and all clinical risk factors used alone or combined. The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current reimbursement guidelines ranged from approximately 7.5% at the age of 50 years to 26% at the age of 80 years where a prior fragility fracture was used as an intervention threshold. For women at the threshold of osteoporosis (femoral neck T-score = -2.5 SD), the respective probabilities ranged from 7.4% to 15%. Several combinations of risk-factor profiles were identified that gave similar or higher fracture probabilities than those currently accepted for reimbursement in Belgium., Conclusions: The FRAX® tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX® model supports a shift from the current DXA-based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

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.

Although the role of testosterone in the aetiology of social dominance is often suggested, surprisingly few studies have addressed the relationship between sex steroid hormones and dominance as a personality trait. In this paper, the relationship between testosterone and dominance is studied in a sample of adolescent boys and girls, taking into account the moderating role of gender ideology and same-sex peer group orientation. A direct association between free testosterone (FT) and dominance was found in girls but not in boys. In boys, masculine ideology moderated the relationship between FT and dominance, while in girls the relationship between FT and dominance was moderated by same-sex peer group affiliation.

Unlabelled: Cutaneous adverse reactions are reported for many treatments including antiosteoporotic agents. This position paper includes an algorithm for their recognition. With early recognition and proper management, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration, and systemic corticosteroids, if necessary, the prognosis is good., Introduction: Cutaneous adverse reactions are reported for many therapeutic agents and observed in between 0% and 8% of treated patients depending on the drug. The antiosteoporotic agents are reputed to be safe in terms of cutaneous effects; however, there have been a number of case reports of cutaneous adverse reactions, which merit consideration. This was the subject of a Working Group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, to focus on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. We prepared this position paper following these discussions, and include an algorithm for their recognition., Methods: We reviewed cutaneous adverse reactions observed with antiosteoporotic agents, including information from case reports, regulatory documents, and pharmacovigilance., Results: The cutaneous adverse reactions range from benign reactions including exanthematous or maculopapular eruption (drug rash), photosensitivity, and urticaria to the severe and potentially life-threatening reactions, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Review of available evidence shows that cutaneous adverse reactions occur with all commonly used antiosteoporotic agents. Notably, there are reports of SJS and TEN for bisphosphonates, and of DRESS and TEN for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases)., Conclusion: With early recognition and proper management, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization and rehydration and systemic corticosteroids if necessary, the prognosis is good.