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Background Ventilation has emerged as an important strategy to reduce indoor aerosol transmission of coronavirus disease 2019. Indoor air carbon dioxide (CO2) concentrations are a surrogate measure of respiratory pathogen transmission risk. Objectives To determine whether CO2 monitors are necessary and effective to improve ventilation in hospitals. Methods A randomized, placebo (sham)-controlled, crossover, open label trial. Between February and May 2021, we placed CO2 monitors in twelve double-bed patient rooms across two geriatric wards. Staff were instructed to open windows, increase the air exchange rate and reduce room crowding to maintain indoor air CO2 concentrations ≤800 parts per million (ppm). Results CO2 levels increased during morning care and especially in rooms housing couples (rooming-in). The median (interquartile range, IQR) time/day with CO2 concentration > 800 ppm (primary outcome) was 110 min (IQR 47–207) at baseline, 82 min (IQR 12–226.5) during sham periods, 78 min (IQR 20–154) during intervention periods and 140 min (IQR 19.5–612.5) post-intervention. The intervention period only differed significantly from the post-intervention period (P = 0.02), mainly due to an imbalance in rooming-in. Significant but small differences were observed in secondary outcomes of time/day with CO2 concentrations > 1000 ppm and daily peak CO2 concentrations during the intervention vs. baseline and vs. the post-intervention period, but not vs. sham. Staff reported cold discomfort for patients as the main barrier towards increasing ventilation. Discussion Indoor air CO2 concentrations in hospital rooms commonly peaked above recommended levels, especially during morning care and rooming-in. There are many possible barriers towards implementing CO2 monitors to improve ventilation in a real-world hospital setting. A paradigm shift in hospital infection control towards adequate ventilation is warranted. Trial registration ClinicalTrials.gov Identifier: NCT04770597, Graphical abstract Unlabelled Image

Orthogeriatrics is increasingly recommended in the care of hip fracture patients, although evidence for this model is conflicting or at least limited. Furthermore, there is no conclusive evidence on which model [geriatric medicine consultant service (GCS), geriatric medical ward with orthopedic surgeon consultant service (GW), integrated care model (ICM)] is superior. The review summarizes the effect of orthogeriatric care for hip fracture patients on length of stay (LOS), time to surgery (TTS), in-hospital mortality, 1-year mortality, 30-day readmission rate, functional outcome, complication rate, and cost. Two independent reviewers retrieved randomized controlled trials, controlled observational studies, and pre/post analyses. Random-effects meta-analysis was performed. Thirty-seven studies were included, totaling 37.294 patients. Orthogeriatric care significantly reduced LOS [mean difference (MD) - 1.55 days, 95% confidence interval (CI) (- 2.53; - 0.57)], but heterogeneity warrants caution in interpreting this finding. Orthogeriatrics also resulted in a 28% lower risk of in-hospital mortality [95%CI (0.56; 0.92)], a 14% lower risk of 1-year mortality [95%CI (0.76; 0.97)], and a 19% lower risk of delirium [95%CI (0.71; 0.92)]. No significant effect was observed on TTS and 30-day readmission rate. No consistent effect was found on functional outcome. Numerically lower numbers of complications were observed in orthogeriatric care, yet some complications occurred more frequently in GW and ICM. Limited data suggest orthogeriatrics is cost-effective. There is moderate quality evidence that orthogeriatrics reduces LOS, in-hospital mortality, 1-year mortality, and delirium of hip fracture patients and may reduce complications and cost, while the effect on functional outcome is inconsistent. There is currently insufficient evidence to recommend one or the other type of orthogeriatric care model. ispartof: Calcified Tissue International vol:110 issue:2 pages:162-184 ispartof: location:United States status: Published online

Purpose: Frailty is often used in clinical decision-making for patients with COVID-19, yet studies have found variable influence of frailty on outcomes in those admitted to the intensive care unit (ICU). In this individual patient data meta-analysis, we evaluated the characteristics, and outcomes of frail patients admitted to ICU with COVID-19.Methods: We contacted the corresponding authors of sixteen eligible studies published between December 1st 2019 and February 28th 2021 reporting the clinical frailty scale (CFS) in patients with confirmed COVID-19 admitted to ICU. Individual patient data was obtained from 7 studies. We classified patients as non-frail (CFS=1-4) or frail (CFS=5-8). The primary outcome was hospital mortality. We also compared the use of mechanical ventilation (MV) and the proportion of ICU bed-days between frailty categories. Results: Of the 2001 patients admitted to ICU, 388 (19.4%) were frail. Increasing age and sequential organ failure assessment (SOFA) score, CFS ≥4, use of MV, vasopressors, renal replacement therapy and hyperlactatemia were risk factors for death in a multivariable analysis. Hospital mortality was higher in frail patients (65.2% vs. 41.8%; pConclusion: Frail patients with COVID-19 were commonly admitted to ICU and had greater hospital mortality but spent relatively fewer days in ICU when compared with non-frail patients. Frail patients receiving MV were at greater risk of death than non-frail patients. Systematic review registration: Registration protocol in PROSPERO (CRD42020224255).

Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen-inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1-CreERT2-positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N-ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic-pituitary-gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N-ARKO mice. However, 36- and 46-week-old N-ARKO mice displayed an accelerated age-related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L5 vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36-week-old N-ARKO mice. Cortical bone loss in N-ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research. ispartof: JOURNAL OF BONE AND MINERAL RESEARCH vol:34 issue:3 pages:508-519 ispartof: location:United States status: published

There is an error in the Conflict of Interest statement. The correct statement is “ML has received lecture and consultancy fees from Alexion, Amgen, Kyowa Kirin, Menarini, Sandoz, Takeda, UCB and Will-Pharma. JS has received lecture, consultancy fees, and conference support from Kyowa Kirin, Alexion, Eli-Lily, Ferring, Ipsen, Menarini, Novo Nordisk, Pfizer, Sandoz, and Siemens Healthcare. DT has received conference support from Novo Nordisk. NG, JLa, and KH have received consultancy fees from Kyowa Kirin. EB has received conference support from Novo Nordisk and Pfizer. CH has received conference support from Novo Nordisk and Ferring. EC has received consultancy fees from bioMérieux, Diasorin, Fujirebio, IDS, and Menarini. PH is an employee of GlaxoSmithKline but participates in his own capacity. J-FK has received consultancy fees and conference support from Heel Belgium, Sanofi, and TRB Chemedica. KW has received conference support from Alexion, Ferring, Kyowa Kirin and Novo Nordisk. CV has received conference support from Boehringer Ingelheim. GM has received consultancy fees from Alexion, Biomarin, Kyowa Kirin, and Pfizer. EL has received consultancy fees and travel support from Kyowa Kirin, Chiesi, and Recordati. JV has received conference support and consultancy fees from Alexion, Bellco, Ferring, Medtronic, and Kyowa Kirin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. There should be a change to Treatment section. A 0.4 mg/kg bodyweight dose is mentioned, whereas the most recently approved dose is a 0.8 mg/kg bodyweight dose. In the subsection “Burosumab” in the fifth paragraph, the first sentence should read as follows: The EMA-approved dose in children is a 2-weekly s.c. injection starting 0.8 mg/kg bodyweight, increased with 0.4 mg/kg dose increments (max. 2.0 mg/kg, cap at 90 mg dose) to achieve fasting plasma phosphate concentrations in the lownormal range for age. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Introduction Fractures of the pelvis and acetabulum are associated with osteoporosis, and their incidence is rising in older adults. In the last decade an increasing number of these fractures are being operated in older patients in certain regions. The goal of this study was to describe the incidence of pelvic and acetabular fractures in Belgium between 1988 and 2018. Materials & methods This retrospective, nationwide, population-based study was conducted with the help of the national health insurance database from the Belgian National Institute for Health and Disability Insurance (NIHDI-RIZIV-INAMI). Multiple codes for the reimbursement of the diagnosis and treatment of pelvic and acetabular fractures were collated and (since 2006) linked to the patients' age group, sex and region. Results Between 1988 and 2018, 91.317 pelvic and acetabular fractures were diagnosed. The overall incidence increased from 15,8/100.000 persons per year in 1988 to 29,7/100.000 persons per year in 2006 and to 37,6/100.000 persons per year in 2018. These fractures showed a bimodal incidence, with a small peak in children (particularly boys), and an increasing incidence in older adults, particularly in women. Between 2006 and 2018, 5.957 (12,4%) patients underwent surgical treatment for their pelvic fracture. 2.088 patients underwent an osteosynthesis of the acetabulum and 3869 patients underwent an osteosynthesis of the pelvic ring. There were 3622 osteosynthesises (60.8%) in patients younger than 60 years old and 2335 (39,1%) in patients over 60 years old. Conclusion There is an increasing incidence of pelvic and acetabular fractures in Belgium with the majority of these fractures occurring in older people. Younger adults have the highest proportion of surgical treatment, but given the much higher incidence in older adults, there is a considerable amount of operations in older adults too.

Purpose To compare the prognostic value and reproducibility of visual versus AI-assisted analysis of lung involvement on submillisievert low-dose chest CT in COVID-19 patients. Materials and Methods This was a HIPAA-compliant, institutional review board-approved retrospective study. From March 15 to June 1, 2020, 250 RT-PCR confirmed COVID-19 patients were studied with low-dose chest CT at admission. Visual and AI-assisted analysis of lung involvement was performed by using a semi-quantitative CT score and a quantitative percentage of lung involvement. Adverse outcome was defined as intensive care unit (ICU) admission or death. Cox regression analysis, Kaplan-Meier curves, and cross-validated receiver operating characteristic curve with area under the curve (AUROC) analysis was performed to compare model performance. Intraclass correlation coefficients (ICCs) and Bland- Altman analysis was used to assess intra- and interreader reproducibility. Results Adverse outcome occurred in 39 patients (11 deaths, 28 ICU admissions). AUC values from AI-assisted analysis were significantly higher than those from visual analysis for both semi-quantitative CT scores and percentages of lung involvement (all P

X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium., SCOPUS: re.j, info:eu-repo/semantics/published

Male gender is a protective factor against the development of osteoporosis but men face a higher refracture risk, higher mortality risk, and a higher treatment gap. Consequently, men contribute considerably to the disease burden of osteoporosis. This chapter aims to review recent advances in our understanding of the epidemiology of male osteoporosis, the reasons why osteoporosis and fractures are less common in men, how sex steroids (androgens and estrogens) and other factors regulate male bone metabolism and contribute to skeletal sexual dimorphism, as well as the diagnosis and treatment of male osteoporosis. We focus on similarities and differences in men versus women. Our work aims to contribute to the understanding of male osteoporosis as a condition that is much more similar than different from osteoporosis in postmenopausal women.

The proximal interphalangeal (PIP) joint is particularly vulnerable to trauma. In comminuted fractures, arthroplasty with a silicone implant is a treatment option that may be controversial in an emergency setting. This joint destruction is usually accompanied by soft tissue injuries (skin and tendon damage, devascularization) making the reconstruction all the more complex. The aim of our work was to evaluate emergency finger silicone implants for complex and comminuted fractures of the PIP joint as well as clinical and radiological complications. In this single-center, retrospective study, 13 patients operated between January 2007 and January 2019 on an emergency basis with a Neuflex® PIP arthroplasty were reviewed. This PIP joint reconstruction was associated with the soft tissue repair at the same time (skin cover, tendons, nerves) in all patients. The average age was 57.7 years with a male predominance (92%). The injuries were caused by a domestic accident in 61% of cases. The average follow-up was 4.7 years. The average total active motion arc was 183.8°. The average QuickDASH score was 24. There was one case of broken implant with no functional consequence. No infection or instability was reported. Silicone implant arthroplasty is a simple, reliable, fast, and durable solution for complex PIP fractures when conservative treatment is impossible. This solution is an alternative to arthrodesis or even finger amputation.

This systematic review and meta-analysis found low-quality evidence that orthogeriatric care is positively associated with diagnosis of osteoporosis, prescription of calcium and vitamin D supplements and bisphosphonates in older hip fracture patients. Evidence on fall and fracture prevention was scarce and inconclusive. Orthogeriatrics may reduce the treatment gap following hip fractures. Hip fracture patients are at imminent risk of additional fractures and falls. Orthogeriatric care might reduce the osteoporosis treatment gap and improve outcomes in these patients. However, the optimal orthogeriatric care model (geriatric liaison service, co-management, or geriatrician-led care) remains unclear. To summarize the association of different orthogeriatric care models for older hip fracture patients, compared to usual orthopaedic care, with fall prevention measures, diagnosis and treatment of osteoporosis and future falls and fractures. Two independent reviewers retrieved randomized controlled trials (RCTs) or controlled observational studies. Random effects meta-analysis was applied (PROSPERO ID: 165914). One RCT and twelve controlled observational studies were included, encompassing 20,078 participants (68% women, median ages between 75 and 85 years). Orthogeriatric care was associated with higher odds of diagnosing osteoporosis (odds ratio [OR] 11.36; 95% confidence interval [CI] 7.26–17.77), initiation of calcium and vitamin D supplements (OR 41.44; 95% CI 7.07–242.91) and discharge on anti-osteoporosis medication (OR 7.06; 95% CI 2.87–17.34). However, there was substantial heterogeneity in these findings. Evidence on fall prevention and subsequent fractures was scarce and inconclusive. Almost all studies were at high risk of bias. Evidence was insufficient to compare different care models directly against each other. Low-quality evidence suggests that orthogeriatric care is associated with higher rates of diagnosing osteoporosis, initiation of calcium and vitamin D supplements and anti-osteoporosis medication. Whether orthogeriatric care prevents subsequent falls and fractures in older hip fracture patients remains unclear.

The skeletal effects of renal transplantation are not completely understood, especially in patients managed with a steroid minimization immunosuppressive protocol and long term. We enrolled 69 adult transplant recipients (39 males; ages 51.1 ± 12.2 years), free of antiresorptive therapy and managed with a steroid minimization immunosuppressive protocol, into a 5-year prospective observational study to evaluate changes in areal bone mineral density (aBMD), mineral metabolism and bone remodelling. Dual energy X-ray absorptiometry, laboratory parameters of mineral metabolism (including parathyroid hormone, sclerostin and fibroblast growth factor 23) and non-renal cleared bone turnover markers (BTMs) (bone-specific alkaline phosphatase, trimeric N-terminal propeptide and tartrate-resistant acid phosphatase 5b) were assessed at baseline and 1 and 5 years post-transplantation. The mean cumulative methylprednisolone exposure at 1 and 5 years amounted to 2.5 ± 0.8 and 5.8 ± 3.3 g, respectively. Overall, bone remodelling activity decreased after transplantation. Post-transplant aBMD changes were minimal and were significant only in the ultradistal radius during the first post-operative year {median -2.2% [interquartile range (IQR) -5.9-1.2] decline, P = 0.01} and in the lumbar spine between Years 1 and 5 [median 1.6% (IQR -3.2-7.0) increase, P = 0.009]. BTMs, as opposed to mineral metabolism parameters and cumulative corticosteroid exposure, associated with aBMD changes, both in the early and late post-transplant period. Most notably, aBMD changes inversely associated with bone remodelling changes. In summary, in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol, BMD changes are limited, highly variable and related to remodelling activity rather than corticosteroid exposure. ispartof: Nephrol Dial Transplant vol:35 issue:4 pages:697-705 ispartof: location:England status: published

ispartof: Joint Bone Spine vol:87 issue:2 pages:171-173 ispartof: location:France status: published

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., SCOPUS: re.j, info:eu-repo/semantics/published

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 (, SCOPUS: ar.j, info:eu-repo/semantics/published

Vitamin D is a calciotropic hormone with essential roles in postnatal skeletal development as well as mineral homeostasis in the elderly. Severe vitamin D deficiency or genetic defects in vitamin D actions may result in rickets (before epiphyseal growth plate closure) or osteomalacia. Vitamin D is mainly synthesized in the epidermis from cholesterol precursors by ultraviolet B light exposure, followed by conversion to 25-hydroxyvitamin D in liver by CYP2R1 and other cytochrome P450 enzymes. The definition of vitamin D deficiency as well as the role of free vitamin D not bound to vitamin D-binding protein (GC globulin) remains controversial. In the kidney, CYP27B1 converts the 25-hydrovitamin D prohormone to the active metabolite 1,25-dihydroxyvitamin D which acts upon the vitamin D receptor to regulate transcription in target cells. The beneficial skeletal effects of vitamin D are mainly determined by its stimulation of intestinal calcium absorption, prevention of secondary hyperparathyroidism and subsequent increases in bone turnover, as well as reducing the risk of falls in vitamin D-deficient elderly. Remarkably low doses are however needed for these beneficial effects, while very high dose vitamin D supplements may stimulate bone resorption, suppress mineralization, and increase the risk of falls. This chapter will critically discuss basic and clinical aspects of vitamin D related to bone health across the lifespan.

Chronic kidney disease and osteoporosis are major public health problems associated with an aging population. Vitamin K insufficiency is prevalent among patients with end-stage renal disease (ESRD). Preliminary data indicate that poor vitamin K status may compromise bone health and that increased inflammation may be in the causal pathway. We performed an ancillary analysis of data collected in the frame of prospective observational cohort studies exploring various aspects of bone health in de novo renal transplant recipients to investigate the association between vitamin K status, inflammation, bone mineral density, and incident clinical fractures. Parameters of mineral metabolism (including biointact PTH and FGF23, sclerostin, calcidiol, calcitriol) and inflammation (CRP and IL-6), osteoprotegerin, bone turnover markers (P1NP, BsAP, and TRAP5B), and dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were assessed on blood samples collected immediately prior to kidney transplantation in 468 patients. Areal bone mineral density (aBMD) was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry within 14 days posttransplant. Poor vitamin K status, defined by dp-ucMGP >500 nmol/L, was highly prevalent (90%). High dp-ucMGP levels independently associated with elevated inflammatory markers and low aBMD. No associations were observed between vitamin K status and bone turnover markers. During a median follow-up of 5.1 years, 33 patients sustained a fragility fracture. In Cox-proportional hazards analysis, a dp-ucMGP above median associated with incident fractures, independent of classical determinants, including age, gender, history of fracture, and aBMD (HR 2.21; 95% CI, 1.00 to 4.91; p

The selective estrogen receptor modulator tamoxifen exerts estrogen agonistic or antagonistic actions on several tissues, including bone. The off-target effects of tamoxifen are one of the most widely recognized pitfalls of tamoxifen-inducible Cre recombinases (CreERs), potentially confounding the phenotypic findings. Still, the validation of tamoxifen induction schemes that minimize the side effects of the drug has not been addressed. Here, we compared the side effects on the skeleton and other androgen-responsive targets of a shortened tamoxifen regimen (2 doses of 190 mg/kg body weight by oral gavage) to a standard protocol (4 doses) and determined their efficiency in inducing CreER-mediated gene deletion. In addition, both a vehicle- and a 10-dose group, which served as a positive control for tamoxifen side effects, were also included. For this purpose, we generated male mice with a floxed androgen receptor (AR) and a neuron-specifically expressed CreER. Treatment with two doses of tamoxifen was the only regimen that did not diminish androgenic bioactivity, as assessed by both seminal vesicles and levator ani/bulbocavernosus muscle weights and serum testosterone concentrations. Similarly, trabecular and cortical femoral bone structure were dramatically altered by both the standard and high-dose protocols but not by the shortened version. Serum osteocalcin and bone-gene expression analyses confirmed the absence of effects on bone by 2 doses of tamoxifen. This protocol decreased AR mRNA levels efficiently and specifically in the nervous system. Thus, we optimized a protocol for tamoxifen-induced CreER gene deletion in mice without off-target effects on bone and male reproductive organs.

Patients with chronic kidney disease (CKD) are at increased risk of fractures. The fracture risk steadily increases along with the progression of renal disease to become several-fold higher in end-stage renal disease (ESRD) patients as compared to age and sex-matched controls. Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease. Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD, but do have important inherent limitations. The gold standard for the diagnosis and specific classification of renal osteodystrophy (ROD) remains the (quantitative) histomorphometric analysis of the bone biopsy. By informing on bone turnover and mineralization, a bone biopsy may help guide prevention and treatment of ROD and its consequences. This review aims to present an update on epidemiological and procedural aspects, clinical indications, and histomorphometric analysis of bone biopsies and to define the role of bone biopsy in current CKD-MBD care.

ispartof: GASTROENTEROLOGY vol:156 issue:5 pages:E4-E5 ispartof: location:United States status: Published online

Probabilistic models including clinical risk factors with or without bone mineral density (BMD) have been developed to estimate the 5‐ or 10‐year absolute fracture risk. We investigated the performance of the FRAX and Garvan tools in a well‐characterized population‐based cohort of 3560 postmenopausal, volunteer women, aged 60 to 85 years at baseline, included in the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) cohort, during 5 years of follow‐up. Baseline data were used to calculate the estimated 10‐year risk of hip and major osteoporotic fractures (MOFs) for each participant using FRAX (Belgium). We computed the 5‐year risk according to the Garvan model with BMD. For calibration, the predicted risk of fracture was compared with fracture incidence across a large range of estimated fracture risks. The accuracy of the calculators to predict fractures was assessed using the area under the receiver operating characteristic curves (AUC). The FRAX tool was well calibrated for hip fractures (slope 1.09, p

Bone is a biomechanical tissue shaped by forces from muscles and gravitation. Simultaneous bone and muscle decay and dysfunction (osteosarcopenia or sarco-osteoporosis) is seen in ageing, numerous clinical situations including after stroke or paralysis, in neuromuscular dystrophies, glucocorticoid excess, or in association with vitamin D, growth hormone/insulin like growth factor or sex steroid deficiency, as well as in spaceflight. Physical exercise may be beneficial in these situations, but further work is still needed to translate acceptable and effective biomechanical interventions like vibration therapy from animal models to humans. Novel antiresorptive and anabolic therapies are emerging for osteoporosis as well as drugs for sarcopenia, cancer cachexia or muscle wasting disorders, including antibodies against myostatin or activin receptor type IIA and IIB (e.g. bimagrumab). Ideally, increasing muscle mass would increase muscle strength and restore bone loss from disuse. However, the classical view that muscle is unidirectionally dominant over bone via mechanical loading is overly simplistic. Indeed, recent studies indicate a role for neuronal regulation of not only muscle but also bone metabolism, bone signaling pathways like receptor activator of nuclear factor kappa-B ligand (RANKL) implicated in muscle biology, myokines affecting bone and possible bone-to-muscle communication. Moreover, pharmacological strategies inducing isolated myocyte hypertrophy may not translate into increased muscle power because tendons, connective tissue, neurons and energy metabolism need to adapt as well. We aim here to critically review key musculoskeletal molecular pathways involved in mechanoregulation and their effect on the bone-muscle unit as a whole, as well as preclinical and emerging clinical evidence regarding the effects of sarcopenia therapies on osteoporosis and vice versa. publisher: Elsevier articletitle: Muscle-bone interactions: From experimental models to the clinic? A critical update journaltitle: Molecular and Cellular Endocrinology articlelink: http://dx.doi.org/10.1016/j.mce.2015.10.017 content_type: article copyright: © 2015 Elsevier Ireland Ltd. All rights reserved. ispartof: Molecular and Cellular Endocrinology vol:432 issue:C pages:14-36 ispartof: location:Ireland status: published

Context: During ageing, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free testosterone (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. Objective: To investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. Methods: 3334 community-dwelling men, aged 40-79, were included. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/L) and normal cFT (≥220 pmol/L) with those who had normal TT/low cFT, low TT/normal cFT and low TT/low cFT, were assessed by regression models adjusted for age, centre, BMI and comorbidities. Results: 2641 men had normal TT [18.4±5.5 (mean±SD) nmol/L]/normal cFT (326±74 pmol/L), 277 men had normal TT (14.2±3.7)/low cFT (194±23), 96 men had low TT (9.6±0.7)/normal cFT (247±20) and 320 men had low TT (7.8±2.5)/low cFT (160±55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH, and reported more sexual and physical symptoms, while haemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, while features of androgen deficiency were lacking. Conclusions: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms. Therefore cFT levels should be assessed in men with suspected hypogonadal symptoms. ispartof: Journal of Clinical Endocrinology & Metabolism vol:101 issue:7 pages:2647-2657 ispartof: location:United States status: published

Objectives To determine the association between frailty and short-term mortality in older adults hospitalized for coronavirus disease 2019 (COVID-19). Design Retrospective single-center observational study. Setting and participants: N = 81 patients with COVID-19 confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), at the Geriatrics department of a general hospital in Belgium. Measure ments: Frailty was graded according to the Rockwood Clinical Frailty Scale (CFS). Demographic, biochemical and radiological variables, co-morbidities, symptoms and treatment were extracted from electronic medical records. Results Participants (N = 48 women, 59%) had a median age of 85 years (range 65 – 97 years), median CFS score of 7 (range 2 – 9), and 42 (52%) were long-term care residents. Within six weeks, eighteen patients died. Mortality was significantly but weakly associated with age (Spearman r = 0.241, P = 0.03) and CFS score (r = 0.282, P = 0.011), baseline lactate dehydrogenase (LDH) (r = 0.301, P = 0.009), lymphocyte count (r = -0.262, P = 0.02) and RT-PCR cycle threshold (Ct, r = -0.285, P = 0.015). Mortality was not associated with long-term care residence, dementia, delirium or polypharmacy. In multivariable logistic regression analyses, CFS, LDH and RT-PCR Ct (but not age) remained independently associated with mortality. Both age and frailty had poor specificity to predict survival. A multivariable model combining age, CFS, LDH and viral load significantly predicted survival. Conclusions and implications Although their prognosis is worse, even the oldest and most severely frail patients may benefit from hospitalization for COVID-19, if sufficient resources are available., Outcomes of frail older adults hospitalized for COVID-19, particularly long-term care residents, remain unclear. In this retrospective cohort, frailty predicted mortality independently of age or established biomarkers.

Background: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. Methodology: Adults with HPP were identified through medical record review. Inclusion criteria were: 1) age ≥ 16 years; 2) consecutively low ALP levels not explained by secondary causes; 3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. Results: 19 patients met our inclusion criteria (n=2 infantile, n=6 childhood, n=10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n=7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N=7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p=0.013) and significantly higher pyridoxal-5’-phosphate (p=0.0018) and urinary phosphoethanolamine (p=0.0001) concentrations. Conclusions: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts. ispartof: JOURNAL OF CLINICAL DENSITOMETRY vol:23 issue:3 pages:340-348 ispartof: location:United States status: published

Kidney transplant recipients are at increased risk of fractures. This prospective observational study investigated whether areal bone mineral density (aBMD) as assessed by dual-energy x-ray absorptiometry can predict incident fragility fractures in de novo kidney transplant recipients and whether bone turnover markers increase diagnostic accuracy. Parameters of bone mineral metabolism including parathyroid hormone (PTH), fibroblast growth factor 23, sclerostin, calcidiol and calcitriol, and bone turnover markers were assessed in blood samples collected immediately prior to kidney transplantation in 518 adult recipients. aBMD was measured at several skeletal sites within 14 days posttransplant. Thirty patients had a history of a fragility fracture at the time of transplantation, and osteopenia or osteoporosis at the femoral neck was observed in 77%. Bone turnover markers were inversely correlated with aBMD at all skeletal sites. Low aBMD and low PTH were associated with history of fragility fracture at the time of transplantation, independent of age, gender, and comorbidity. During a median post-transplant follow-up of 5.2 years, 38 patients sustained a fragility fracture, corresponding to a fracture incidence of 14.1 per 1000 person-years. Low aBMD at the hip and lumbar spine were associated with incident fractures, independent of classical determinants, including history of fracture. PTH and bone turnover markers at the time of transplantation failed to predict incident fractures. In conclusion, aBMD is low, correlates inversely with bone turnover, and predicts incident fractures in de novo kidney transplant recipients. ispartof: KIDNEY INTERNATIONAL vol:95 issue:6 pages:1461-1470 ispartof: location:United States status: published

An overview of selected papers related to bone published in 2017 is provided. This paper accompanies a lecture at the 2018 Belgian Bone Club annual Clinical Update Symposium held in Brussels on January 20th, discussing the best papers (in the opinion of the author) published in the previous year. A PubMed search using the keyword “bone” and articles published in 2017. Hot topics include screening for osteoporosis, novel anabolic drugs such as romosozumab and abaloparatide for osteoporosis and rare metabolic bone diseases, as well as long-term efficacy of denosumab and possible risk of multiple vertebral fractures following its discontinuation. Other selected articles cover effectiveness of bisphosphonates and changes in mineralization after long-term use, new guidelines for glucocorticoid- and aromatase inhibitor-induced osteoporosis, increasing use of high-dose vitamin D supplements despite lack of evidence for their widespread high-dose use, and cardiovascular safety concerns surrounding the use of calcium supplements. Other topics discussed are effects of diabetes on bone health, reciprocal crosstalk between bone cells and adipose tissue, and resistance exercise training to prevent bone loss and sarcopenia. These papers offer a hopeful outlook for a better treatment and management of patients with osteoporosis and other metabolic bone diseases anno 2018.

Low testosterone (T) in men, especially its free fraction, has been associated with loss of energy. In accordance, orchidectomy (ORX) in rodents results in decreased physical activity. Still, the mechanisms through which T stimulates activity remain mostly obscure. Here, we studied voluntary wheel running behavior in three different mouse models of androgen deficiency: ORX, androgen receptor (AR) knock-out (ARKO) and sex hormone binding globulin (SHBG)-transgenic mice, a novel mouse model of "low free T". Our results clearly show a fast and dramatic action of T stimulating wheel running, which is not explained by its action on muscle, as evidenced by neuromuscular studies and in a muscle-specific conditional ARKO mouse model. The action of T occurs via its free fraction, as shown by the results in SHBG-transgenic mice, and it implies both androgenic and estrogenic pathways. Both gene expression and functional studies indicate that T modulates the in vivo sensitivity to dopamine (DA) agonists. Furthermore, the restoration of wheel running by T is inhibited by treatment with DA antagonists. These findings reveal that the free fraction of T, both via AR and indirectly through aromatization into estrogens, stimulates physical activity behavior in male mice by acting on central DA pathways. ispartof: Scientific Reports vol:8 issue:1 pages:957- ispartof: location:England status: published

This chapter describes definition, etiology, pathophysiology, diagnosis, treatment and prevention of nutritional rickets and osteomalacia. Rickets and osteomalacia (from Greek osteon and malakia, bone softness) are diseases characterized by hypomineralization of bone matrix. Rickets occurs only in children (before epiphyseal closure) and additionally leads to abnormal growth plate development, stunting, and bone deformities. The causes of osteomalacia and rickets are similar and can be classified according to underlying mechanisms: Vitamin D deficiency or resistance; calcium deficiency independent of vitamin D; hypophosphatemic disorders; and mineralization inhibitors. Patients with rickets and osteomalacia related to vitamin D deficiency typically have very low serum 250-hydroxyvitamin D (25OHD) concentrations, that is below 15 to 30?nmol/L. Vitamin D deficiency rickets responds to small doses of vitamin D. Nutritional osteomalacia may be treated with remarkably low doses of calcium and vitamin D.

Background In men, the long-term consequences of low serum levels of sex steroids, vitamin D metabolites, and insulin-like growth factor 1 (IGF-1) on the evolution of muscle mass, muscle strength, or physical performance are unclear. Moreover, there are no data about the relationship between these hormones and incident sarcopenia defined as low muscle mass and function. The aim of this study was to determine whether the baseline levels of sex hormones, vitamin D metabolites, and IGF-1 predict changes in muscle mass, muscle strength, physical performance, and incident sarcopenia. Methods In 518 men aged 40–79 years, recruited for participation in the European Male Ageing Study, total, free, and bioavailable testosterone (T), oestradiol (E), sex hormone-binding globulin, IGF-1, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone were assessed at baseline. Appendicular lean mass (aLM), gait speed, and grip strength were measured at baseline and after a mean follow-up of 4.3 years. Sarcopenia was defined by the definition of Baumgartner (relative aLM ≤7.26 kg/m2), the International Working Group on Sarcopenia (IWGS), and the European Working Group on Sarcopenia in Older People (EWGSOP). Results aLM significantly decreased from age 50 years, while gait speed and grip strength significantly decreased from age 70 years. The incidence of sarcopenia by the definitions of Baumgartner, IWGS, and EWGSOP was 8.1%, 3.0%, and 1.6%, respectively. After adjustment for age, centre, body mass index, smoking, and number of comorbidities at baseline, baseline levels of T and vitamin D metabolites were not associated with change in aLM, gait speed, and/or grip strength, while a high baseline level of total E2 was associated with a greater decrease in aLM. In men aged ≥70 years, low IGF-1 was associated with a greater decrease in gait speed. Baseline endocrine variables were not independently associated with an increased risk of incident sarcopenia by any definition. Conclusions Low levels of T and 25OHD do not predict loss of muscle mass, gait speed, or grip strength in middle-aged and elderly community-dwelling European men. Low IGF-1 predicts change in gait speed in men aged ≥70 years.

Gastrointestinal bleeding (GI bleed) is a common and potentially life-threatening reason for emergency room and intensive care unit admission. This article reports the case of an 83-year-old man with acute GI bleeding from an unusual cause. The clinical information is presented in a step-by-step and question-answer format for learning purposes. This paper is particularly aimed at an internal medicine readership. ispartof: WikiJournal of Medicine vol:4 issue:1 status: published

The aim of this study was to determine whether bone turnover markers (BTMs) predict changes in areal bone mineral density (aBMD) in middle-aged and elderly European men. Older men with high bone turnover are at a higher risk of accelerated hip bone loss, but the clinical utility of BTMs in individuals is limited. Prospective studies on the value of BTMs to predict changes in aBMD in men are few and conflicting. The aim of this study was to determine whether BTMs predict changes in aBMD in middle-aged and elderly European men. In 487 men aged 40–79 years from the European Male Ageing Study (EMAS), BTMs were assessed at baseline and dual-energy X-ray absorptiometry (DXA) at the lumbar spine (LS), femoral neck (FN) and total hip (TH) was performed at baseline and after a mean follow-up of 4.3 years. The mean aBMD decreased by 0.32 %/year at FN and 0.22 %/year at TH and increased by 0.32 %/year at LS. Higher baseline levels of β C-terminal cross-linked telopeptide (β-CTX) and N-terminal propeptide of type I procollagen (PINP) were significantly associated with higher loss of hip aBMD in the whole cohort and men aged 60–79 years. These associations remained significant after adjustment for age, centre and body mass index (BMI). Men aged 60–79 years with β-CTX in the upper quintile were more likely of being in the upper quintile of annual percentage (%) aBMD loss at FN (OR = 4.27; 95% CI = 2.09–8.73) and TH (OR = 3.73; 95% CI = 1.84–7.57). The positive predictive value (PPV) was 46 % at both hip sites. Older men with high bone turnover have a higher risk of accelerated hip bone loss, but the PPV is low. BTMs are therefore unlikely to be of clinical utility in predicting accelerated hip bone loss in individual subjects.

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis. ispartof: Asian Journal of Andrology vol:16 issue:2 pages:213-222 ispartof: location:China status: published

Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ∼10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.-Dubois, V., Laurent, M. R., Sinnesael, M., Cielen, N., Helsen, C., Clinckemalie, L., Spans, L., Gayan-Ramirez, G., Deldicque, L., Hespel, P., Carmeliet, G., Vanderschueren, D., and Claessens, F. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

Biochemical assessments of androgen status (hyper- or hypoandrogenism) are usually based on serum testosterone concentrations. According to the free hormone hypothesis, sex hormone-binding globulin (SHBG) determines free and bioavailable testosterone concentrations. Previous studies have suggested that in vitro androgen bioassay results may also be influenced by SHBG and correlate with free or bioavailable testosterone concentrations. To test this hypothesis, we established a stable HEK293 cell line with high expression of the human androgen receptor (AR) and a luciferase reporter downstream of a classical androgen response element. Importantly, we demonstrate that bioassay results are sensitive to dilution effects which increase apparent bioactivity in an SHBG-dependent manner. We therefore adopted a method using undiluted serum, which reduced cell proliferation but did not significantly affect the luciferase signal, cell viability or cytotoxicity. To correct for serum matrix effects, we applied signal correction based on internal controls with AR agonists or antagonists. Using this method, we provide direct evidence that in vitro androgen bioactivity reflects the inhibitory effects of SHBG, and correlates with free or bioavailable testosterone concentrations in adult hypogonadal men receiving androgen replacement therapy. In men receiving anti-androgens, serum bioactivity decreased tenfold while serum testosterone concentrations decreased only four-fold. Further pilot results in prostate cancer patients showed that androgen synthesis inhibitors result in more complete inhibition of androgen bioactivity than gonadorelin-based androgen deprivation therapy, even in patients whose testosterone concentrations were undetectable by mass spectrometry. We conclude that in vitro androgen reporter bioassays are useful tools to study how androgen bioactivity in serum is determined by androgens, anti-androgens as well as SHBG, provided that dilution and matrix effects are accounted for. publisher: Elsevier articletitle: Effects of sex hormone-binding globulin (SHBG) on androgen bioactivity in vitro journaltitle: Molecular and Cellular Endocrinology articlelink: http://dx.doi.org/10.1016/j.mce.2016.08.041 content_type: article copyright: © 2016 Elsevier Ireland Ltd. All rights reserved. ispartof: Molecular and Cellular Endocrinology vol:437 issue:C pages:280-291 ispartof: location:Ireland status: published

Osteoporosis remains underrecognized and undertreated but more so in men, adding considerably to fracture burden and costs. Fracture-related morbidity and mortality is higher in men, partly due to greater frailty. Improved peak bone mass, geometry and turn-over contribute to lower fracture incidence in men. Bioavailable androgens and oestrogens regulate these aspects of musculoskeletal sexual dimorphism, yet the direct cellular and molecular targets of sex steroids in bone remain incompletely understood. Screening with clinical risk factors and dual energy X-ray absorptiometry are advised in men from age 70 (or 50 with additional risk factors). We now have compelling evidence that osteoporosis drugs are equally effective in men and women, not only to increase bone density but also to prevent osteoporotic fractures. The use of testosterone or selective androgen receptor modulators for osteoporosis, sarcopenia, frailty and falls in men with late-onset hypogonadism requires further investigation.

Approximately 7000 stillbirths occur daily worldwide, and the vast majority of them (98%) Approximately 7000 stillbirths occur daily worldwide, and the vast majority of them (98%) take place in low-income and middle-income countries (LMICs). Despite this enormous burden, progress to reduce the death toll is slow and insufficient. WHO released its Making every baby count guide in 2016, which includes strategies aimed at addressing the challenge of stillbirths. Given the flurry of activity and attention on stillbirths from the Lancet Stillbirth Epidemiology investigator group and WHO, we expect that the wealth of information about stillbirths that is generated will filter down in a timely manner to where it is needed most: the general public.

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a ligand-dependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology.

Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L(5) vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes.

PURPOSE: Children increasingly participate in horseback riding, especially young girls, with more and more accidents during this activity. The severity of the injuries caused by horses seems to be higher than in other sports. METHODS: In a retrospective study, we reviewed 303 accidents of children younger than 15 years of age during the past 13 years. Our study only investigated children who were hospitalized after their accident. RESULTS: Eighty-two percent of the injured children were girls, but there was no difference between girls and boys in terms of severity. In most cases, children were hurt by falling from the horse (87 %). In the other cases, they were kicked or bitten by the animal. The most frequent trauma sustained was fracture (50 %). The upper extremity was injured in 40 % of the traumas followed by the head (32 %). The lower limbs, the abdomen, the spine, or the thorax were injured in less than 10 % of the incidents. The severity of the accidents was studied with the Injury Severity Score and we compared groups of children. Children younger than 11 years old were more severely injured than older children (P=0.0002). CONCLUSION: The youngest horseback riders should be supervised carefully to avoid severe injuries during this activity. Language: fr

to the editor: Cooke et al. provided in their recent review a comprehensive insight into the estrogenic regulation of male physiology ([1][1]). This brings us a good opportunity to revisit our current knowledge on serum estradiol (E2) concentrations in aging men and their potential associations with