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Key statements of the Russian clinical guidelines on the diagnosis and treatment of osteoporosis are summarized. They were developed by a task force representing the key Russian professional associations involved in the management of osteoporosis and approved by the Russian Ministry of Health., Purpose: To summarize key statements of the Russian clinical practice guidelines for the diagnosis and treatment of osteoporosis., Methods: The Russian clinical guidelines on the diagnosis and treatment of osteoporosis were developed by a task force representing the key Russian professional associations involved in the management of osteoporosis: These comprised the Russian Association of Endocrinologists, the Russian Association for Osteoporosis, the Association of Rheumatologists of Russia, the Association of Orthopedic surgeons and Traumatologists of Russia, the Russian Association of Gynecologists-Endocrinologists, and the Russian Association of Gerontologists and Geriatrics. The guidelines are based on a systematic literature review and principles of evidence-based medicine and were compiled in accordance with the requirements for clinical recommendations developed by the Ministry of Health of the Russian Federation., Results: Key statements included in the Russian guidelines of osteoporosis approved by the Russian Ministry of Health in 2021 are summarized. The statements are graded based on levels of evidence and supported by short comments. The guidelines are focused on the current approach to screening, diagnosis, differential diagnosis, and treatment of osteoporosis., Conclusion: These guidelines are a practical tool for general practitioners, as well as medical specialists, primarily endocrinologists, rheumatologists, orthopedic surgeons, and other physicians who are involved in the management of patients with osteoporosis., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (-28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Competing Interests: MRL has received consultancy fees from UCB (related to romosozumab), travel support and lecture fees from Amgen, and consultancy fees from Alexion, Kyowa Kirin and Sandoz, unrelated to this work. EG has received consultancy fees from UCB (related to romosozumab) and non-financial support from Amgen unrelated to this work. All other authors have nothing to disclose.

Objective: Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover., Design: Prospective cohort study., Methods: Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied., Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered., Conclusions: In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.

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 yr; (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: Nineteen 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., (Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo-controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non-fracture-related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo-controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. The analysis was stratified by trial, and only included data from the placebo-controlled period of each trial. A time-to-event analysis of first fall and exposure-adjusted subject incidence rates of falls were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5030 received denosumab 60 mg subcutaneously once every 6 months for 12 to 36 months and 5006 received placebo. Kaplan-Meier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio = 0.79; 95% confidence interval 0.66-0.93; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

The Fracture Risk Assessment Tool (FRAX®) was developed to predict fracture risk in the general population, but its applicability to patients with chronic kidney disease (CKD) is unknown. Using the Manitoba Bone Mineral Density (BMD) Database, we identified adults not receiving dialysis with available serum creatinine measurements and bone densitometry within 1 year. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Incident major osteoporotic fractures and hip fractures were ascertained from population-based health care databases. The performance of FRAX, derived without and with BMD, was studied in relation to CKD stage. Among 10,099 subjects (mean age 64 ± 13 years, 13.0% male), 2,154 had eGFR 30-60 mL/min/1.73 m2 (CKD stage 3) and 590 had eGFR <30 mL/min/1.73 m2 (CKD stages 4-5). During a 5-year observation period, 772 individuals experienced a major osteoporotic fracture and 226 had a hip fracture. FRAX predicted risk for major osteoporotic fracture and hip fracture in all eGFR strata. For every standard deviation increase in FRAX score derived with BMD, the hazard ratio (HR) for hip fracture was 4.54 (95% confidence interval [CI] 3.57-5.77) in individuals with eGFR ≥ 60 mL/min/1.73m2, 4.52 (95% CI 3.15-6.49) in individuals with eGFR 30-60 mL/min/1.73m2, and 3.10 (95% CI 1.80-5.33) in individuals with eGFR <30 mL/min/1.73m2. The relationship between FRAX and major osteoporotic fracture was stronger in those with CKD compared to those with preserved eGFR. These findings support the use of FRAX to risk stratify patients with non-dialysis CKD for major osteoporotic fractures and hip fractures., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Background: Lumbar spine TBS, a texture index derived from lumbar spine dual-energy x-ray absorptiometry (DXA) images, enhances fracture prediction. No studies to date have studied a broad range of clinical variables to determine which patients might experience the greatest benefit from the use of TBS., Methods: Using the Manitoba BMD Registry, we identified 37,176 subjects with baseline DXA, FRAX®-based fracture probability, lumbar spine TBS, and minimum 5 years of observation. Subgroups considered were based on sex, age, body mass index (BMI), prior fracture, chronic obstructive lung disease (COPD), high alcohol use, rheumatoid arthritis (RA), high glucocorticoid use, osteoporotic femoral neck T-score, number of comorbidities, diabetes, secondary osteoporosis, and prior osteoporosis treatment. Non-traumatic major osteoporotic fractures (MOF, n = 3741) and hip fractures (HF, n = 1008) were identified using population-based health services data. We analyzed baseline TBS using analysis of covariance (ANCOVA). FRAX-adjusted hazard ratios (HR) per SD reduction in TBS were estimated and tested for interactions. Categorical net reclassification improvement (NRI) was estimated using fixed FRAX-based intervention cut-offs., Results: Adjusted baseline TBS was significantly lower (p ≤ 0.001) for women (-4.2%), osteoporotic hip T-score (-4.0%), COPD (-2.8%), diabetes (-2.6%), high alcohol use (-2.3%), prior fracture (-2.2%), glucocorticoid use (-1.5%), RA (-0.9%) and secondary osteoporosis (-0.8%), whereas recent osteoporosis therapy was associated with greater TBS (+1.5%). HRs per SD reduction in TBS for fracture prediction were larger for age < 65 vs 65+ (MOF p-interaction = 0.004, HF p-interaction < 0.001), without vs with prior fracture (MOF p-interaction = 0.003, HF p-interaction = 0.048), without vs with glucocorticoid use (HF p-interaction = 0.029), lower vs higher comorbidity score (HF p-interaction < 0.001), and without vs with osteoporosis treatment (MOF p-interaction = 0.005). NRI for using the TBS adjustment to FRAX in all subjects was 1.2% for MOF (p = 0.002) and 1.7% for HF (p = 0.016). NRI was greater in subjects age < 65 y (MOF:1.7%, HF:5.6%), no prior fracture (HF: 2.4%), non-osteoporotic T-score (HF: 3.0%), and high glucocorticoid use (MOF: 3.9%)., Conclusion: TBS is sensitive to the effects of multiple risk factors for fracture. TBS-adjusted fracture risk assessment resulted in significant improvements for multiple subgroups., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: In adults, growth hormone deficiency (GHD) has been associated with low bone mineral density (BMD), an effect counteracted by growth hormone (GH) replacement. Whether GH is beneficial in adults with age-related bone loss and without hypopituitarism is unclear., Methods: We conducted a systematic literature search using Medline, Embase and the Cochrane Register of Controlled Trials. We extracted and analyzed data according to the bone outcome included [bone mineral content (BMC), BMD, and bone biomarker, fracture risk]. We performed a meta-analysis when possible., Results: We included eight studies. Seven randomized 272 post-menopausal women, 61-69 years, to GH or control, for 6-24 months, and the eighth was an extension trial. Except for one study, all women received concurrent osteoporosis therapies. There was no significant effect of GH, as compared to control, on BMD at the lumbar spine (Weighted mean difference WMD = -0.01 [-0.04, 0.02]), total hip (WMD = 0 [-0.05, 0.06]) or femoral neck (WMD = 0 [-0.03, 0.04]). Similarly, no effect was seen on BMC. GH significantly increased the bone formation marker procollagen type-I carboxy-terminal propeptide (PICP) (WMD = 14.03 [2.68, 25.38]). GH resulted in a trend for increase in osteocalcin and in bone resorption markers. Patients who received GH had a significant decrease in fracture risk as compared to control (RR = 0.63 [0.46, 0.87]). Reported adverse events were not major, mostly related to fluid retention., Conclusion: GH may not improve bone density in women with age-related bone loss but may decrease fracture risk. Larger studies of longer duration are needed to further explore these findings in both genders, and to investigate the effect of GH on bone quality.

Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture., Purpose: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence., Methods: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression., Results: The 24-month analyses included 1479 women (mean age 66.3-72.5 years) from 140 sites; persistence with denosumab was 75.1-86.0%, adherence 62.9-70.1%, and mean MCR 87.4-92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3-6.9% patients., Conclusions: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.

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.

Decreased lumbar spine trabecular bone score (TBS), a dual-energy X-ray absorptiometry (DXA)-derived image texture measurement, is a risk factor for major osteoporotic fracture (MOF) and hip fracture (HF) independent of 10-year fracture probability estimated using FRAX. We determined how often applying the TBS adjustment to fracture probability altered treatment qualification. Using a population-based registry containing all clinical DXA results for Manitoba, Canada, we identified 34,316 women with baseline spine and hip DXA, FRAX-based fracture probability measurements (computed with femoral neck bone mineral density), lumbar spine TBS, and minimum 5 years of observation (mean 8.7 years). Population-based health services data were used to identify incident non-traumatic MOF and HF in 3503 and 945 women, respectively. Baseline MOF and HF probabilities were estimated using FRAX before and after applying the TBS adjustment. Risk recategorization was assessed using net reclassification improvement (NRI) for individual FRAX-based intervention criteria and three national clinical practice guidelines (CPGs) (US National Osteoporosis Foundation, Osteoporosis Canada, and UK National Osteoporosis Guideline Group). Overall, proportions of women reclassified with the TBS adjustment to FRAX were small (less than 5%) with more than 90% of the reclassification occurring close to the intervention threshold. For women close to an intervention cut-off reclassification, rates ranged from 9.0% to 17.9% and were <1% otherwise. There was a small but significant improvement in overall NRI for all individual FRAX-based intervention criteria (range 0.007 to 0.018) and all three national CPGs (range 0.008 to 0.011). NRI was larger in women below age 65 years (up to 0.056 for hip fracture). In summary, a small but significant improvement in MOF and HF risk assessment was found by using lumbar spine TBS to adjust FRAX probability. An improvement in risk reclassification was observed for CPGs from three different countries, with almost all of the benefit found in individuals close to an intervention threshold. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Peripheral quantitative computed tomography scans of the distal and midshaft radius were performed in 514 European men aged 40-79 years at baseline and a median of 4.3 years later. Age-related changes in volumetric bone mineral density (vBMD) and bone geometry were greater in men with higher biochemical markers of bone turnover at baseline., Introduction: This study aimed to determine prospective change in bone density and geometry at the radius in men and examine the influence of bone turnover markers and sex hormones on that change., Methods: Men aged 40-79 years were recruited from population registers in Manchester (UK) and Leuven (Belgium). At baseline, markers of bone formation (P1NP and osteocalcin) and resorption (β-cTX and ICTP) were assessed. Total and bioavailable testosterone and oestradiol were also measured. Peripheral quantitative computed tomography (pQCT) was used to scan the radius at distal and midshaft sites at the baseline assessment and a median of 4.3 years later., Results: Five hundred fourteen men, mean (SD) age of 59.6 (10.5) years, contributed to the data. At the midshaft site, there was a significant decrease in mean cortical vBMD (-0.04 %/year), bone mineral content (BMC) (-0.1 %/year) and cortical thickness (-0.4 %/year), while total and medullary area increased (+0.5 and +2.4 %/year respectively). At the distal radius, total vBMD declined (-0.5 %/year) and radial area increased (+0.6 %/year). Greater plasma concentrations of bone resorption and formation markers were associated with greater decline in BMC and cortical area at the midshaft and total vBMD at the distal site. Increased bone resorption was linked with an increase in total and medullary area and decrease in cortical thickness at the midshaft. Sex hormone levels were unrelated to change in pQCT parameters., Conclusions: Age-related changes in vBMD and bone geometry are greater in men with higher biochemical markers of bone turnover at baseline. Sex hormones have little influence on change in pQCT parameters., Competing Interests: Compliance with ethical standards Ethics approval for the study was obtained in accordance with local institutional requirements in each centre, and each participant gave written informed consent. Funding This work was supported by the Commission of the European Communities Fifth Framework Programme ‘Quality of Life and Management of Living Resources’ (grant number QLK6-CT-2001-00258), Arthritis Research UK (grant number 20380) and the UK National Osteoporosis Society (grant number 120/152). This report includes independent research supported by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The pQCT measurements were funded through a research grant from Central Manchester Universities Hospitals NHS Foundation Trust Endowment Funds. Dr. K.A.W. is supported by the Nutrition and Bone Health Core Program at MRC Human Nutrition Research, funded by the UK Medical Research Council (grant number U10596037). The financial sponsors played no role in the design, execution, analysis and interpretation of data or writing of this study. Conflicts of interest Dr. M.R.L. has received lecture fees from Flanders’ Agricultural Marketing Board (VLAM) and reports consultancy for Novartis and Alexion. Stephen R. Pye, Kate A. Ward, Michael J. Cook, Evelien Gielen, Herman Borghs, Judith E. Adams, Dirk Vanderschueren, Frederick C. W, and Terence W. O’Neill declare that they have no conflicts of interest.

Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution., (Copyright © 2017 the American Physiological Society.)

Aging hypogonadal men are at increased risk of osteoporosis and sarcopenia. Testosterone is a potentially appealing strategy to prevent simultaneous bone and muscle loss. The androgen receptor (AR) mediates antiresorptive effects on trabecular bone via osteoblast-lineage cells, as well as muscle-anabolic actions. Sex steroids also modify the skeletal response to mechanical loading. However, it is unclear whether the effects of androgens on bone remain effective independent of mechanical stimulation or rather require indirect androgen effects via muscle. This study aims to characterize the effects and underlying mechanisms of androgens on disuse osteosarcopenia. Adult male mice received a unilateral botulinum toxin (BTx) injection, and underwent sham surgery or orchidectomy (ORX) without or with testosterone (ORX+T) or dihydrotestosterone (ORX+DHT) replacement. Compared to the contralateral internal control hindlimb, acute trabecular number and bone volume loss was increased by ORX and partially prevented DHT. T was more efficient and increased BV/TV in both hindlimbs over sham values, although it did not reduce the detrimental effect of BTx. Both androgens and BTx regulated trabecular osteoclast surface as well as tartrate-resistant acid phosphatase expression. Androgens also prevented BTx-induced body weight loss but did not significantly influence paralysis or muscle atrophy. BTx and ORX both reduced cortical thickness via endosteal expansion, which was prevented by T but not DHT. In long-term follow-up, the residual trabecular bone volume deficit in sham-BTx hindlimbs was prevented by DHT but T restored it more efficiently to pre-treatment levels. Conditional AR deletion in late osteoblasts and osteocytes or in the satellite cell lineage increased age-related trabecular bone loss in both hindlimbs without influencing the effect of BTx on trabecular osteopenia. We conclude that androgens have antiresorptive effects on trabecular disuse osteopenia which do not require AR actions on bone via muscle or via osteocytes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We examined cross-sectional associations of metabolic syndrome and its components with male bone turnover, density and structure. Greater bone mass in men with metabolic syndrome was related to their greater body mass, whereas hyperglycaemia, hypertriglyceridaemia or impaired insulin sensitivity were associated with lower bone turnover and relative bone mass deficits., Introduction: Metabolic syndrome (MetS) has been associated with lower bone turnover and relative bone mass or strength deficits (i.e. not proportionate to body mass index, BMI), but the relative contributions of MetS components related to insulin sensitivity or obesity to male bone health remain unclear., Methods: We determined cross-sectional associations of MetS, its components and insulin sensitivity (by homeostatic model assessment-insulin sensitivity (HOMA-S)) using linear regression models adjusted for age, centre, smoking, alcohol, and BMI. Bone turnover markers and heel broadband ultrasound attenuation (BUA) were measured in 3129 men aged 40-79. Two centres measured total hip, femoral neck, and lumbar spine areal bone mineral density ( a BMD, n = 527) and performed radius peripheral quantitative computed tomography (pQCT, n = 595)., Results: MetS was present in 975 men (31.2 %). Men with MetS had lower β C-terminal cross-linked telopeptide (β-CTX), N-terminal propeptide of type I procollagen (PINP) and osteocalcin (P < 0.0001) and higher total hip, femoral neck, and lumbar spine a BMD (P ≤ 0.03). Among MetS components, only hypertriglyceridaemia and hyperglycaemia were independently associated with PINP and β-CTX. Hyperglycaemia was negatively associated with BUA, hypertriglyceridaemia with hip a BMD and radius cross-sectional area (CSA) and stress-strain index. HOMA-S was similarly associated with PINP and β-CTX, BUA, and radius CSA in BMI-adjusted models., Conclusions: Men with MetS have higher a BMD in association with their greater body mass, while their lower bone turnover and relative deficits in heel BUA and radius CSA are mainly related to correlates of insulin sensitivity. Our findings support the hypothesis that underlying metabolic complications may be involved in the bone's failure to adapt to increasing bodily loads in men with MetS.

Summary: There is a wide variation in fracture probabilities estimated by Asian FRAX models, although the outputs of South Asian models are concordant. Clinicians can choose either fixed or age-specific intervention thresholds when making treatment decisions in postmenopausal women. Cost-effectiveness of such approach, however, needs to be addressed., Purpose: This study examined suitable fracture probability intervention thresholds (ITs) for Sri Lanka, based on the Sri Lankan FRAX model., Methods: Fracture probabilities were estimated using all Asian FRAX models for a postmenopausal woman of BMI 25 kg/m² and has no clinical risk factors apart from a fragility fracture, and they were compared. Age-specific ITs were estimated based on the Sri Lankan FRAX model using the method followed by the National Osteoporosis Guideline Group in the UK. Using the age-specific ITs as the reference standard, suitable fixed ITs were also estimated., Results: Fracture probabilities estimated by different Asian FRAX models varied widely. Japanese and Taiwan models showed higher fracture probabilities while Chinese, Philippine, and Indonesian models gave lower fracture probabilities. Output of remaining FRAX models were generally similar. Age-specific ITs of major osteoporotic fracture probabilities (MOFP) based on the Sri Lankan FRAX model varied from 2.6 to 18% between 50 and 90 years. ITs of hip fracture probabilities (HFP) varied from 0.4 to 6.5% between 50 and 90 years. In finding fixed ITs, MOFP of 11% and HFP of 3.5% gave the lowest misclassification and highest agreement., Conclusion: Sri Lankan FRAX model behaves similar to other Asian FRAX models such as Indian, Singapore-Indian, Thai, and South Korean. Clinicians may use either the fixed or age-specific ITs in making therapeutic decisions in postmenopausal women. The economical aspects of such decisions, however, need to be considered.

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head "offset" data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies., (Copyright © 2012 American Society for Bone and Mineral Research.)

The FRAX software developed by the World Health Organization provides a method to estimate fracture probability of old men and women based on their bone mineral density (BMD) and clinical risk factors (CRFs). The validity of 4 selected ethnic-specific FRAX tools in determining prevalent fracture or treatment decisions in a group of postmenopausal women from Sri Lanka was examined. Women with a history of fragility fracture/s and those who were detected to have femoral neck T-score<2.5 were considered eligible for specific osteoporosis treatment. Ten-year all osteoporotic fracture (vertebral and nonvertebral) probability (10y-AOFP) of 481 postmenopausal women were estimated on US Caucasian, US Asian, Japanese, and Chinese FRAX tools, first using CRFs alone and then combining with femoral neck T-scores. At 20% 10y-AOFP, Chinese tool showed a very low sensitivity in detecting prevalent fracture or detecting women needing intervention (1.3%). Sensitivities observed with US Asian and Japanese tools ranged from 33% to 42%, showing their limitations in predicting prevalent fracture in this group of women. The US Caucasian tool, either with CRFs alone or with BMD incorporated, showed a relatively higher sensitivity in detecting fractures or identifying those needing interventions (71% and 76%, respectively). Furthermore, the US Caucasian tool showed a relatively high specificity (ranging from 70% to 87%). In conclusion, this analysis showed the limitations of the current FRAX tools in predicting fractures when applied to a different ethnic group. Until a separate FRAX tool is developed, the US Caucasian tool can be used to predict fractures in Sri Lankan postmenopausal women., (Copyright (c) 2010 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: Osteoporosis is a chronic disease that presents a large economic burden both on the affected individual and on society. Osteoporotic fractures are a cause of significant morbidity and mortality. Given the high prevalence of osteoporosis and related costs, understanding the factors that determine the cost-effectiveness of osteoporosis therapy is important for physicians and managed-care organizations. Bisphosphonates are considered first-line therapy for osteoporosis, and pharmacological differences between them relate not only to differences in efficacy and safety, but also have an impact on health economics. Efficacy and persistence with therapy influence fracture risk-reduction and should be considered when determining the best osteoporosis therapy for each patient., Scope: This article synthesizes recent health economic data, assessing the impact of drug efficacy and persistence or dosing frequency on the cost-effectiveness of bisphosphonates as therapeutic agents for osteoporosis treatment. The author's interpretation of the available evidence is also discussed, from the perspective of a 'Commentary' article., Findings: Although treatment persistence is an important factor in reducing fracture risk, when comparing the health economic data of several treatment options, studies have shown that the cost-effectiveness of bisphosphonate therapy is mainly dependent on drug efficacy rather than persistence or dosing frequency. It should also be noted that fractures at different skeletal sites have different economic impacts. Non-vertebral fractures (and particularly those of the hip) are more costly than vertebral fractures., Conclusions: Although persistence with osteoporosis therapy is an important factor in reducing fracture risk, it has less of an impact on cost-effectiveness than treatment efficacy, in particular efficacy at non-vertebral sites.

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2-yr, randomized, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of 35 mg once-a-week risedronate in men with osteoporosis. Patients had to be men >or=30 yr old, with lumbar spine T-score

We examined the association between bone mineral density (BMD) and cardiovascular risk in a group of premenopausal women selected from the Southern province of Sri Lanka. One hundred six previously healthy premenopausal volunteers (aged 30-54 yr) were recruited by open invitations. Subjects with previous history of diabetes, hypertension, epilepsy, chronic renal or liver disease, hyperlipidemia, ischemic heart disease, endocrine diseases, or prolonged inflammatory conditions were excluded. Subjects who were taking medications that can affect bone density, blood sugar, serum lipids, or blood pressure (BP) were also excluded. Women with the history of previous fractures were not excluded. BMDs in the spine, hip, and total body (TB) were measured using a Hologic Discovery scanner (Hologic Inc, Bedford, MA). BP, fasting glucose, and fasting lipids were also measured. Independent of body mass index (BMI) and age, TB bone mineral content (BMC) and spine BMD showed inverse and significant correlations with total cholesterol (TC), low density cholesterol, and the ratio between TC and high density lipoprotein cholesterol (r ranged from -0.24 to -0.27, p<0.05 for all). The highest mean lipid levels were seen among the women in the lowest third of spine BMD, whereas women in the upper third of spine BMD had the lowest lipid levels. The number of women with metabolic syndrome in the 3 tirtiles of spine BMD was not significantly different. Fasting glucose or BP had no association with either BMD or BMC. In conclusion, our data demonstrates an association, independent of age and BMI, between BMD and BMC or lipid levels among previously healthy, premenopausal women. This may explain the high cardiovascular risk seen in women with osteoporosis in old age.

There is paucity of studies related to parity and bone mineral density in South Asian countries. We recruited 713 healthy, community dwelling post-menopausal women from seven provinces in Sri Lanka for this survey. The number of pregnancies, including miscarriages beyond 20 weeks of gestation, was recorded. Women with diseases and those who have taken drugs that can affect bone mineral density (BMD) were excluded (n = 15). Phalangeal BMD and bone mineral content (BMC) were measured using AccuDEXA in 713 women. Mean (SE) BMD of nulliparous women (n = 32), women with one to two pregnancies (n = 284), three to four pregnancies (n = 290) and more than four pregnancies (n = 107) were 0.437(0.014), 0.454(0.005), 0.455(0.005) and 0.417(0.006) g/cm(2), respectively (P < 0.001). Corresponding mean (SE) BMCs were 1.30(0.063), 1.41(0.021), 1.43(0.022) and 1.32(0.033) g, respectively (P < 0.001). Women with more than four pregnancies were older and lighter when compared with other groups. When results were adjusted for current age and current weight, differences in mean BMD and BMC between groups became non-significant. BMD of nulliparous women remained low in all analyses. We report a significant difference in unadjusted phalangeal BMD in women categorized according to their parity. Women with one to four pregnancies had the highest phalangeal BMD and BMC, while multi-parous (more than four pregnancies) and nulliparous women had lower values. However, in an adjusted analysis, the differences in BMD and BMC were partially explained by the differences of age and body weight between the groups and the unique effect of parity was difficult to determine. Women with lower BMD may have a higher risk of future fractures.

To establish normative reference values and to study the age-related trends in phalangeal bone mineral density (BMD), 4504 male and 5215 female volunteers aged 20 yr or more were recruited from 7 provinces from October 2004 to October 2005. Subjects suffering from diseases and those who were taking medications, which could affect BMD were excluded from the analysis (n=530). Phalangeal BMD was measured in the nondominant hand using an AccuDXA. Men and women were categorized to age groups of 20-29 (1087 men and 1079 women), 30-39 (1122 men and 1146 women), 40-49 (1148 men and 1455 women), 50-59 (810 men and 1111 women), 60-69 (250 men and 335 women), and 70 yr or more (87 men and 94 women). Mean BMDs (SD) of men in above categories were 0.595 (0.057), 0.603 (0.061), 0.591 (0.066), 0.576 (0.069), 0.558 (0.077), and 0.522 (0.079) g/cm2, respectively. The corresponding BMDs (SD) in women were 0.495 (0.057), 0.506 (0.062), 0.502 (0.064), 0.462 (0.072), 0.406 (0.072), and 0.340 (0.055) g/cm2, respectively. Peak BMD was seen in 30-39-age category in both sexes. Women after 50 yr lost BMD at a rate of 0.006 (standard error 0.0003) g/cm2/yr, whereas the corresponding value in men was 0.002 (standard error 0.0001) g/cm2/yr. These data provide normative reference data for the calculation of T-score and Z-score for phalangeal BMD in Sri Lankan men and women aged more than 20 yr.

Associations between lean mass, fat mass, and bone mass have been reported earlier; however, most of those studies have been done in Caucasian populations, and data from Asian countries, especially those in South Asia, are limited. We examined the associations between lean mass, fat mass, bone mineral density (BMD), and bone mineral content (BMC), determined by dual-energy X-ray absorptiometry technology, in a group of healthy, middle-aged, premenopausal female volunteers. The mean (SD) age of the women (n = 106) was 42.1 (6.1) years and the mean (SD) body mass index was 24.3 (3.6) kg/m(2). Total body BMD, total body BMC, and BMD in total spine, total hip, and femoral neck showed statistically significant partial correlations (adjusted for age) with total fat mass (r = 0.19-0.43, P < 0.05) and lean body mass (r = 0.28-0.54, P < 0.05). Truncal fat mass correlated positively with total body BMC and BMD at total hip and femoral neck (r = 0.33-0.40, P < 0.001). When a stepwise regression model was fitted, lean mass remained the strongest predictor of total body BMD, total body BMC, and total spine BMD (regression coefficients = 0.004-0.008 g/cm(2) per 1-kg change in lean mass, P < 0.001). Similarly, crude BMD and BMC increased across the tertiles of lean mass (P trend < 0.05). We show that lean mass is the strongest predictor of total body BMC and BMD at different sites, although positive correlations with fat mass also exist.

Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.

Background: Osteoporosis is a major and costly global public health problem. It is a chronic disease in which fracture is the main outcome, and the impact of these fractures can vary depending on the age of the individual and the severity of the fracture., Scope: Using literature review, this paper discusses and summarizes the information available regarding the individual and socio-economic consequences associated with the several types of osteoporotic fractures., Findings: Different types of osteoporotic fractures are generally associated with different age groups. The health-economic impact of vertebral and hip fractures has been extensively explored and it is well known that these fractures are associated with morbidity/disability and increased mortality; they also account for a substantial portion of the direct fracture costs. However, to accurately estimate the individual and socio-economic burden of the disease, further research is needed on the morbidity/disability, mortality, and costs associated with non-hip, nonvertebral fractures, which account for more than half of the total fractures. More data are also required on the indirect costs associated with all fracture types., Conclusions: Understanding the socio-economic consequences of each fracture type will be important to fully estimate the burden of osteoporosis and may help clinicians tailor management plans for individual patients.

Introduction: EUROFORS was a 2-yr prospective, randomized trial of postmenopausal women with established osteoporosis, designed to investigate various sequential treatments after teriparatide 20 microg/d for 1 yr. The present secondary analysis examined the effects of 2 yr of open-label teriparatide in women previously treated with antiresorptive drugs for at least 1 yr., Methods: A subgroup of 245 women with osteoporosis who had 2 yr of teriparatide treatment were stratified by previous predominant antiresorptive treatment into four groups: alendronate (n=107), risedronate (n=59), etidronate (n=30), and non-bisphosphonate (n=49). Bone mineral density (BMD) at the lumbar spine and hip was determined after 6, 12, 18, and 24 months, and bone formation markers were measured after 1 and 6 months., Results: Significant increases in bone formation markers occurred in all groups after 1 month of teriparatide treatment. Lumbar spine BMD increased at all visits, whereas a transient decrease in hip BMD, which was subsequently reversed, was observed in all groups. BMD responses were similar in all previous antiresorptive groups. Previous etidronate users showed a higher increase at the spine but not at the hip BMD. Duration of previous antiresorptive therapy and lag time between stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal site. Treatment-emergent adverse events were similar to those reported in treatment-naive postmenopausal women with osteoporosis treated with teriparatide., Conclusions: Teriparatide induces positive effects on BMD and markers of bone formation in postmenopausal women with established osteoporosis, regardless of previous long-term exposure to antiresorptive therapies.

Although it is generally recommended that patients keep their hips flexed by 90 degrees during the measurement of spinal bone mineral density (BMD), there is no uniform agreement among the manufacturers of dual-energy X-ray absorptiometry (DXA) scanners regarding the positioning of legs while scanning the spine. We measured spinal BMD in 54 postmenopausal women, from L1 to L4 in posterior-anterior projection, using a Hologic Discovery scanner, first with their legs elevated as recommended by the manufacturer and then with their legs flat on the scanning table. Differences of bone mineral content (BMC), area of the region of interest (ROI), BMD, and T-score of the total spine between the 2 scans were compared. The mean (SD) age of the women was 54.3 yr (15 yr). Between the 2 scans, BMC, area of the ROI, BMD, and T-scores showed high correlations (r=0.98, 0.94, 0.99, and 0.99, respectively). BMC and the area of the ROI changed significantly between the 2 scans, but the changes of BMD and T-scores were not significant. The percentage changes of BMC and the area of the ROI were similar (2.6% and 2.4%, respectively), whereas T-scores showed no change and change of BMD was only 0.6%. The absolute difference in BMD between the 2 scans was only 0.005 (p=0.09). When spinal BMD was measured with their legs elevated, 31 women were found to have osteoporosis and further 13 were found to have osteopenia. When spinal BMD was measured with their legs flat, 32 women were found to have osteoporosis and further 12 were found to have osteopenia. In conclusion, no clinically or statistically significant difference in the total spinal BMD was found when the BMD in a group of women was measured on a Hologic Discovery DXA scanner with their legs positioned flat.

Purpose: The purpose of this study was to extend the metaanalysis of Bischoff-Ferrari et al., which found that 700-800 IU/d vitamin D reduced hip fracture risk in elderly individuals by 25%, by defining the need for additional calcium supplementation in individuals receiving vitamin D for the prevention of hip fractures., Data Sources: MEDLINE and EMBASE.com (search terms: "vitamin D" and "hip fracture"), bibliographies of articles retrieved, and the authors' reference files were used as data sources., Study Selection: Selected studies were randomized controlled trials (RCTs) of oral vitamin D with or without calcium supplementation vs. placebo/no treatment in postmenopausal women and/or older men (>or=50 yr) specifically reporting a risk of hip fracture., Data Extraction: Independent extraction was performed by two authors using predefined criteria, including study quality indicators., Data Synthesis: All pooled analyses are based on random-effects models. Based on four RCTs (9083 patients), the pooled relative risk (RR) of hip fracture for vitamin D alone was 1.10 [95% confidence intervals (CI) 0.89, 1.36]. No between-trial heterogeneity was observed. For the six RCTs (45,509 patients) of vitamin D with calcium supplementation, the pooled RR for hip fracture was 0.82 (95% CI 0.71, 0.94). There was no heterogeneity between trials. In an adjusted indirect comparison of the summary RRs from the two metaanalyses, the RR for hip fracture for vitamin D with calcium vs. vitamin D alone was 0.75 (95% CI 0.58, 0.96)., Conclusions: Our analyses, designed to extend the findings of Bischoff-Ferrari et al., suggest that oral vitamin D appears to reduce the risk of hip fractures only when calcium supplementation is added.

Indices of hip geometry are known to be predictive of hip fractures while sex and ethnic differences in hip geometry have been previously demonstrated. Age-related trends in hip geometry among Asians, however, have not been studied sufficiently. A total of 280 healthy, perimenopausal women, aged between 32 and 97 years, were selected from the Community Study Area of the Faculty of Medicine, Galle, Sri Lanka. Hip DXA images were analyzed further to calculate the hip axis length, neck-shaft angle, and femoral neck width at the narrowest point of the femoral neck. Standard formulae were used to calculate cross-sectional area, cross-sectional moment of inertia, and section modulus in the femoral neck region. Mean (SD) age, weight, height, femoral neck bone mineral density (BMD), hip axis length, neck-shaft angle, neck width, cross-sectional area, and cross-sectional moment of inertia of the study sample were 56.8 (13.0) years, 47.8 (10.1) kg, 1.48 (0.06) m, 0.704 (0.147) g/cm(2), 90.6 (5.6) mm, 123.2 (5.7) degrees, 2.99 (0.24) cm, 2.00 (0.42) cm(2), and 1.62 (0.47) cm(4), respectively. Height and weight of subjects had positive correlations with most of the indices of hip geometry. Femoral neck BMD, cross-sectional area and section modulus showed a rapid reduction during the postmenopausal period. With advancing age, there was a marginal but statistically nonsignificant expansion of the neck width, increase in the hip axis length, and narrowing of the neck-shaft angle. In conclusion, this study demonstrated a gradual loss of BMD in postmenopausal age, accompanied by thinning of the cortical shell and deterioration of the resistance to bending in the femoral neck of this group of healthy women. The clinical relevance of the marginal changes seen in other indices such as neck-shaft angle, hip axis length, and neck width is not known.

Male osteoporosis is associated with a significant burden in terms of morbidity, mortality, and economic cost. Despite recent advances in the understanding of the male osteoporotic syndrome, the evaluation and treatment of men suffering from osteoporosis remains a clinical challenge. In men with osteoporosis, it remains particularly critical to exclude underlying pathological causes as these are much more likely to be present than in women. There is increasing evidence that the approaches developed to diagnose and treat the disorder in women may be equally useful in men. The available evidence suggests that the anti-fracture efficacy of treatment with alendronate, risedronate, or teriparatide is similar in both sexes. Additional research is warranted to prospectively address the usefulness of BMD measurements to predict fracture risk, to identify those men who are likely to benefit the most from therapy, and to monitor individual responses to therapy.

Combined calcium and vitamin D supplementation is an essential component of the management of osteoporosis, supported by a strong scientific rationale. The types of individuals who should receive calcium and vitamin D supplements are those: (i) patients with documented osteoporosis receiving antiresorptive or anabolic treatment; (ii) patients receiving glucocorticoids; and (iii) individuals with or at high risk of calcium and/or vitamin D insufficiencies, in particular older women and men. This article describes the evidence base that supports targeting these groups. Benefits are most apparent when 800 IU day(-1) vitamin D is complemented with a dose of 1000-1200 mg day(-1) elemental calcium. Compliance is also key to optimizing clinical efficacy.

Patients with osteoporosis need a safe and effective treatment that reduces the risk of vertebral and non-vertebral fractures, leading to clinical benefits such as reduced back pain and height loss. Strontium ranelate corrects bone turnover, producing a more physiological state. Double-blind, placebo-controlled studies in postmenopausal osteoporosis show it to be effective in reducing vertebral and non-vertebral fracture risks. Treatment efficacy has been documented across a wide range of patient profiles, and appears to be independent of all the major determinants of fracture risk, including the severity of the disease at baseline, the number of prevalent fractures, and the age of the patient. This antifracture efficacy translates into clinical benefits, such as a 20% reduction in the rate of height loss and a 29% increase in the number of patients free of back pain. The effect of treatment with strontium ranelate on well-being has been assessed using the Quality-of-Life Questionnaire in Osteoporosis, which is a supplement to the 36-question Short-Form Health Survey. Treatment with strontium ranelate had a significant beneficial effect on the emotional, physical, and global Quality-of-Life Questionnaire in Osteoporosis scores compared with placebo. The rates of compliance with treatment were over 80% in phase III studies, reflecting the tolerability and safety profile and the ease of administration of this agent. Together with the antifracture data, the clinical benefits and quality of life data endorse the treatment of postmenopausal osteoporosis with strontium ranelate.

Objectives: To assess the safety and efficacy of teriparatide in patients aged 75 and older and compare these findings with those of women younger than 75 using data from the Fracture Prevention Trial (FPT)., Design: The FPT was a randomized, multicenter, double-blind, placebo-controlled study., Setting: The FPT multicenter international study., Participants: Postmenopausal women aged 42 to 86 were randomized to placebo (N=544) or teriparatide 20 mug (N=541) by daily self-injection for a median of 19 months. Patients received daily oral supplements of 1,000 mg calcium and 400 to 1,200 IU vitamin D. For this analysis, subgroups were defined according to patient age younger than 75 (N=841) and 75 and older (N=244)., Measurements: The effects of teriparatide on bone mineral density (BMD) of the lumbar spine and femoral neck; the incidence of new vertebral and new nonvertebral fragility fractures; bone turnover markers, including bone-specific alkaline phosphatase; and urinary deoxypyridinoline corrected for creatinine clearance, as well as the safety of teriparatide, were investigated., Results: There were no significant treatment-by-age interactions for the bone turnover markers, femoral neck BMD, vertebral fractures, nonvertebral fragility fractures, height loss, hyperuricemia, or hypercalcemia. A significant treatment-by-age interaction for lumbar spine BMD (P=.08) was due to an increase in BMD observed in the placebo group aged 75 and older. There were no treatment-by-age interactions for important treatment-emergent adverse events (TEAEs), including back pain, nausea, leg cramps, and dizziness. The most important TEAEs in women aged 80 and older (23 patients from the placebo group and 25 patients from the teriparatide group) were also reviewed; no unexpected TEAEs were found in the patients treated with teriparatide. These results indicate that the clinical effects of teriparatide were consistent in the older and younger women., Conclusion: Age does not affect the safety and efficacy of teriparatide in postmenopausal women with osteoporosis.

Osteoporotic fractures are an extremely common and serious health problem in the elderly. This article presents the rationale for calcium and vitamin D supplementation in the prevention and treatment of osteoporotic fractures and reviews the literature evidence on the efficacy of this strategy. Two musculoskeletal risk factors are implicated in osteoporotic fractures in the elderly: the loss of bone mass due to secondary hyperparathyroidism and the increased propensity to falls. Calcium and vitamin D reverse secondary hyperparathyroidism with resultant beneficial effects on bone mineral density (BMD). Additionally, calcium and vitamin D supplementation significantly improves body sway and lower extremity strength, reducing the risk of falls. The effects of combined calcium and vitamin D on parathyroid function and BMD provide a strong rationale for the use of this therapy in the prevention and treatment of osteoporosis and osteoporotic fractures. There is general agreement that, in patients with documented osteoporosis, calcium and vitamin D supplementation should be an integral component of the management strategy, along with antiresorptive or anabolic treatment. Frail elderly individuals constitute another major target population for calcium and vitamin D because evidence from randomized studies in institutionalized elderly subjects demonstrates that these supplements reduce osteoporotic fracture risk, particularly in the presence of dietary deficiencies. However, the results of trials in community-dwelling subjects have been equivocal. Within the primary-care setting, further research is required to establish appropriate target subgroups for calcium and vitamin D supplementation; overall, the data are consistent with a benefit individuals with insufficient calcium and/or vitamin D, although patients with documented osteoporosis will derive further benefit in terms of fracture prevention from the addition of an antiresorptive agent.

Osteoporosis is a major cause of morbidity, mortality, and healthcare costs. The socioeconomic burden of osteoporosis is likely to increase dramatically if improvements in prevention are not made. Calcium supplementation effectively reduces the rate of bone loss in postmenopausal women, yet most women do not achieve an adequate calcium intake. In fact, use of calcium supplementation appears to have declined as the more effective antiresorptive therapies, such as bisphosphonates, have become available. Among patients prescribed bisphosphonates, calcium intake is often insufficient, despite the fact that adequate calcium intake may be necessary to gain the maximum benefits from antiresorptive therapy. In addition, because calcium interferes with bisphosphonate absorption, incorrect use of calcium may limit the efficacy of bisphosphonate therapy. This underscores the need for new initiatives to reduce the confusion surrounding appropriate calcium use during antiresorptive therapy. Co-packaging of bisphosphonates with calcium supplements is one strategy to help ensure that patients taking bisphosphonates not only achieve adequate calcium intake but also gain the maximum benefit from bisphosphonate therapy.

Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P < or =0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76-0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71-0.92, P =0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.

It is recommended that the hip joints be flexed to 90 degrees during dual-energy X-ray absorptiometry scanning of the lumbar spine in the anteroposterior projection; however, some patients are unable to maintain this position because of the presence of degenerative changes in lower limb joints. This study examines the effect of a lesser degree of hip flexion on the lumbar spine bone mineral density (BMD) measurement and its interpretation. Fifty women were scanned on the Norland Eclipse XR, initially in the standard position with the hips flexed to 90 degrees and then in the adjusted position after allowing for some degree of hip extension to keep them comfortable (hip flexion of 60 degrees -70 degrees ). Higher bone mineral content (BMC), surface area, and BMD values were seen in the standard position compared to the adjusted position, but none of the differences was statistically significant. There were strong correlations for BMC,surface area, and BMD measured in the two positions. In the standard position, 26 women were found to have osteoporosis and 18 had osteopenia. In the adjusted position, osteoporosis was noted in 27 women, and 18 had osteopenia. Four women showed a reduction, whereas 12 women showed an increase in BMD in excess of the least significant change at the 95% confidence level, defined as 2.77 times the precision error (0.008 g/cm(2) x 2.77 = 0.120 g/cm(2)). Our study demonstrates that a lesser degree of hip flexion in women who find it difficult to maintain the recommended 90 degrees hip flexion during the lumbar spine BMD measurement would not affect the patient classification based on T-scores recommended by the World Health Organization; however, variation in hip flexion can be a major confounding factor when interpreting a change in BMD over time.

The association between respiratory function and bone mineral density (BMD) among women living in the community has been reported previously. We examined the association between forced expiratory volume in 1 s (FEV(1)) and BMD measured at hip using dual-energy X-ray absorptiometry in a group of 947 men (aged 65 to 76 years) recruited from general practice age-sex registers in Cambridge between 1991 and 1995. A positive and significant correlation was seen between FEV(1) and BMD measured at total hip, femoral neck, and trochanter. A unit change (1 l) in FEV(1) was associated with a change of BMD by 0.019, 0.017, and 0.026 g/cm(2) in the total hip, femoral neck, and tochanteric region, respectively. These associations were independent of possible confounding factors such as age, height, weight, smoking habit, major disease prevalence, and medications, which might affect bone metabolism. In categorical analyses, the highest BMD was seen in the highest FEV(1) quartile, while the lowest BMD was seen in the lowest FEV(1) quartile. This pattern was seen in all three skeletal sites and was independent of covariates listed above. Compared with the bottom FEV(1) quartile, mean hip BMDs in the top quartile were 2-3.5% higher. The exact mechanism of this association is not clear to us. One plausible explanation is that respiratory function and bone health both reflect common but as yet unknown determinants.

Identifying women with osteoporosis remains a clinical challenge, as it may not be feasible or cost-effective to recommend dual-energy X-ray absorptiometry (DXA) for all postmenopausal women. In this regard, quantitative ultrasound (QUS) has emerged as an attractive screening tool because of the (relatively) low cost and because QUS and DXA-assessed BMD appear to be equally predictive of future (hip) fracture risk. The objective of this study was to compare the ability of calcaneal QUS to identify osteoporosis with two alternative potential screening methods: digital X-ray radiogrammetry (DXR) and radiographic absorptiometry (RA). We enrolled a total of 221 postmenopausal community-dwelling Caucasian women aged 50-75 years. Bone mineral density (BMD) was measured at the lumbar spine and the total hip regions using DXA. Calcaneal ultrasound attenuation and velocity were assessed using QUS and metacarpal and phalangeal bone density were estimated by the use of DXR and RA, respectively. Receiver operating characteristic (ROC) curves were constructed by calculating the specificity and sensitivity of QUS, DXR, and RA at different cut-point values in discriminating osteoporosis, as defined by a T-score below -2.5 at the spine or hip using DXA, and the areas under the curves (AUCs) were computed. The sensitivity for identifying women with osteoporosis was 67.6% [95% confidence interval (CI), 50.2-82.0%] using QUS and was 76.9% (95% CI, 60.7-88.8%) and 82.9% (95% CI, 67.9-92.8%), respectively, using DXR and RA. The negative predictive value (NPV, the proportion of patients with a negative test who have no osteoporosis) was 90% for QUS, compared with an NPV of 94% for both DXR and RA. These data suggest that metacarpal DXR and phalangeal RA may be as effective as calcaneal QUS for targeting DXA testing in high-risk postmenopausal women.

Objectives: To determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older with osteoporosis., Design: Pooled analysis of data from three randomized, double-blind, controlled, 3-year-fracture-endpoint trials conducted from November 1993 to April 1998: Hip Intervention Program (HIP), Vertebral Efficacy with Risedronate Therapy-Multinational (VERT-MN), and VERT-North America (NA)., Setting: Office-based practices, research centers, and osteoporosis clinics in Europe, North America, and Australia., Participants: Osteoporotic (femoral neck bone mineral density T-score < -2.5 standard deviations or at least one prevalent vertebral fracture) women aged 80 and older., Intervention: Patients received placebo (n=688) or risedronate 5 mg/d (n=704) for up to 3 years. All patients received 1,000 mg/d calcium and, if baseline levels were low, up to 500 IU/d vitamin D., Measurements: Cumulative incidence of new vertebral fractures., Results: After 1 year, the risk of new vertebral fractures in the risedronate group was 81% lower than with placebo (95% confidence interval=60-91%; P<.001). The number of women who needed to be treated to prevent one new vertebral fracture after 1 year was 12. This early onset of efficacy was consistent across the clinical programs, and antifracture efficacy was confirmed over 3 years. Risedronate was well tolerated, with a safety profile comparable with that of placebo., Conclusion: These findings provide the first evidence that, even in the very old, reducing bone resorption rate remains an effective treatment strategy for osteoporosis. Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, the observations made in this study should not be assumed to apply to other bisphosphonates.