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We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Summary This systematic review summarizes the effect of\ud combined exercise and nutrition intervention on muscle mass\ud and muscle function. A total of 37 RCTs were identified.\ud Results indicate that physical exercise has a positive impact\ud on muscle mass and muscle function in subjects aged 65 years\ud and older. However, any interactive effect of dietary supplementation\ud appears to be limited.\ud Introduction In 2013, Denison et al. conducted a systematic\ud review including 17 randomized controlled trials\ud (RCTs) to explore the effect of combined exercise and\ud nutrition intervention to improve muscle mass, muscle\ud strength, or physical performance in older people.\ud They concluded that further studies were needed to provide\ud evidence upon which public health and clinical\ud recommendations could be based. The purpose of the\ud present work was to update the prior systematic review\ud and include studies published up to October 2015.\ud Methods Using the electronic databases MEDLINE and\ud EMBASE, we identified RCTs which assessed the combined\ud effect of exercise training and nutritional supplementation on\ud muscle strength, muscle mass, or physical performance in\ud subjects aged 60 years and over. Study selection and data\ud extraction were performed by two independent reviewers.\ud Results The search strategy identified 21 additional RCTs giving\ud a total of 37 RCTs. Studies were heterogeneous in terms of\ud protocols for physical exercise and dietary supplementation\ud (proteins, essential amino acids, creatine, β-hydroxy-β-methylbuthyrate, vitamin D, multi-nutrients, or other). In 79%\ud of the studies (27/34 RCTs), muscle mass increased with exercise\ud but an additional effect of nutrition was only found in 8\ud RCTs (23.5%). Muscle strength increased in 82.8% of the\ud studies (29/35 RCTs) following exercise intervention, and dietary\ud supplementation showed additional benefits in only a\ud small number of studies (8/35 RCTS, 22.8%). Finally, the\ud majority of studies showed an increase of physical performance\ud following exercise intervention (26/28 RCTs, 92.8%)\ud but interaction with nutrition supplementation was only found\ud in 14.3% of these studies (4/28 RCTs).\ud Conclusion Physical exercise has a positive impact on muscle\ud mass and muscle function in healthy subjects aged 60 years\ud and older. The biggest effect of exercise intervention, of any\ud type, has been seen on physical performance (gait speed, chair\ud rising test, balance, SPPB test, etc.). We observed huge variations\ud in regard to the dietary supplementation protocols.\ud Based on the included studies, mainly performed on wellnourished\ud subjects, the interactive effect of dietary supplementation\ud on muscle function appears limited.

Summary: Current intake recommendations of 200 to 600IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D. Introduction: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk. Methods and results: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000IU vitamin D per day or mean 25(OH)D between 75 and 110nmol/l (30-44ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000IU per day or achieved 25(OH)D up to 643nmol/l. Mean levels of 75 to 110nmol/l were reached in most RCTs with 1,800 to 4,000IU vitamin D per day without risk. Conclusion: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population

Summary: Higher physiologic testosterone levels among community dwelling older men and women may protect against falls, and this benefit may be further increased among those taking additional vitamin D plus calcium. Introduction: The aim of this study is to investigate sex hormone levels and fall risk in older men and women. Methods: One hundred and ninety-nine men and 246 women age 65+ living at home were followed for 3years after baseline assessment of sex hormones. Analyses controlled for several covariates, including baseline 25-hydroxyvitamin D, sex hormone binding globulin, and vitamin D plus calcium treatment (vitD+cal). Results: Compared to the lowest quartile, men and women in the highest quartile of total testosterone had a decreased odds of falling (men: OR = 0.22; 95% CI [0.07,0.72]/ women: OR = 0.34; 95% CI [0.14,0.83]); if those individuals also took vitD+cal, the fall reduction was enhanced (men: OR = 0.16; 95% CI [0.03,0.90] / women: OR = 0.15; 95% CI [0.04,0.57]). Similarly, women in the top quartile of dihydroepiandrosterone sulfate (DHEA-S) had a lower risk of falling (OR = 0.39; 95% CI [0.16,0.93]). Other sex hormones and SHBG did not predict falling in men or women. Conclusions: Higher testosterone levels in both genders and higher DHEA-S levels in women predicted a more than 60% lower risk of falling. With vitD+cal, the anti-fall benefit of higher physiologic testosterone levels is enhanced from 78% to 84% among men and from 66% to 85% among women

Summary: Our findings show that only about 20% of seniors receive vitamin D supplementation prior to their index hip fracture or after the event. We further confirm the high prevalence of severe vitamin D deficiency in this population and show that those who receive supplementation have significantly higher 25-hydroxyvitamin D (25(OH)D) status. Introduction: The aim of this study is to assess current practice in pre- and post-hip fracture care practice with respect to vitamin D supplementation. Methods: We surveyed 1,090 acute hip fracture patients age 65 and older admitted to acute care for hip fracture repair; 844 had serum 25-hydroxyvitamin D levels measured upon admission to acute care, and 362 agreed to be followed at 12month after their hip fracture. Prevalence of vitamin D supplementation was assessed upon admission to acute care (at the time of hip fracture), upon discharge from acute care, and at 6 and 12months follow-up. Results: Of 1,090 acute hip fracture patients (mean age 85years, 78% women, 59% community-dwelling), 19% had received any dose of vitamin D prior to the index hip fracture, 27% (of 854 assessed) at discharge from acute care, 22% (of 321 assessed) at 6month, and 21% (of 285 assessed) at 12month after their hip fracture. At the time of fracture, 45% had 25(OH)D levels below 10ng/ml, 81% had levels below 20ng/ml, and 96% had levels below 30ng/ml. Notably, 25(OH)D levels did not differ by season or gender but were significantly higher among 164 hip fracture patients, with any vitamin D supplementation compared with 680 without supplementation (19.9 versus 10.8ng/ml; p

Background\ud All proposed definitions of sarcopenia include the measurement of muscle mass, but the techniques and threshold values used vary. Indeed, the literature does not establish consensus on the best technique for measuring lean body mass. Thus, the objective measurement of sarcopenia is hampered by limitations intrinsic to assessment tools. The aim of this study was to review the methods to assess muscle mass and to reach consensus on the development of a reference standard.\ud \ud Methods\ud Literature reviews were performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis working group on frailty and sarcopenia. Face‐to‐face meetings were organized for the whole group to make amendments and discuss further recommendations.\ud \ud Results\ud A wide range of techniques can be used to assess muscle mass. Cost, availability, and ease of use can determine whether the techniques are better suited to clinical practice or are more useful for research. No one technique subserves all requirements but dual energy X‐ray absorptiometry could be considered as a reference standard (but not a gold standard) for measuring muscle lean body mass.\ud \ud Conclusions\ud Based on the feasibility, accuracy, safety, and low cost, dual energy X‐ray absorptiometry can be considered as the reference standard for measuring muscle mass.

Objective To test whether daily high-dose Vitamin D improves recovery after unilateral total knee replacement. Methods Data come from a 24-month randomised, double-blind clinical trial. Adults aged 60 and older undergoing unilateral joint replacement due to severe knee osteoarthritis were 6-8 weeks after surgery randomly assigned to receive daily high-dose (2000 IU) or standard-dose (800 IU) Vitamin D 3. The primary endpoints were symptoms (Western Ontario and McMaster Universities Arthritis Index pain and function scores) assessed at baseline, 6, 12, 18 and 24 months in both knees, and the rate of falls over 24 months. The secondary outcomes were sit-to-stand performance, gait speed, physical activity and radiographic progression in the contralateral knee. Results We recruited 273 participants, 137 were randomised to receive 2000 IU and 136 were randomised to receive 800 IU Vitamin D per day. 2000 IU Vitamin D increased 25-hydroxyVitamin D levels to 45.6 ng/mL and 800 IU Vitamin D to 37.1 ng/mL at month 24 (p

The place of calcium supplementation, with or without concomitant vitamin D supplementation, has been much debated in terms of both efficacy and safety. There have been numerous trials and meta-analyses of supplementation for fracture reduction, and associations with risk of myocardial infarction have been suggested in recent years. In this report, the product of an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF), we review the evidence for the value of calcium supplementation, with or without vitamin D supplementation, for healthy musculoskeletal ageing. We conclude that (1) calcium and vitamin D supplementation leads to a modest reduction in fracture risk, although population-level intervention has not been shown to be an effective public health strategy; (2) supplementation with calcium alone for fracture reduction is not supported by the literature; (3) side effects of calcium supplementation include renal stones and gastrointestinal symptoms; (4) vitamin D supplementation, rather than calcium supplementation, may reduce falls risk; and (5) assertions of increased cardiovascular risk consequent to calcium supplementation are not convincingly supported by current evidence. In conclusion, we recommend, on the basis of the current evidence, that calcium supplementation, with concomitant vitamin D supplementation, is supported for patients at high risk of calcium and vitamin D insufficiency, and in those who are receiving treatment for osteoporosis

Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest group on falls and fracture prevention of the European union geriatric medicine society (EUGMS), in collaboration with the International association of gerontology and geriatrics for the European region (IAGG-ER), the European union of medical specialists (EUMS), the Fragility fracture network (FFN), the International osteoporosis foundation (IOF) – European society for clinical and economic aspects of osteoporosis and osteoarthritis (ECCEO), outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people.

The International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) convened the FRAX® Position Development Conference (PDC) in Bucharest, Romania, on November 14, 2010, following a two-day joint meeting of the ISCD and IOF on the "Interpretation and Use of FRAX® in Clinical Practice." These three days of critical discussion and debate, led by a panel of international experts from the ISCD, IOF and dedicated task forces, have clarified a number of important issues pertaining to the interpretation and implementation of FRAX® in clinical practice. The Official Positions resulting from the PDC are intended to enhance the quality and clinical utility of fracture risk assessment worldwide. Since the field of skeletal assessment is still evolving rapidly, some clinically important issues addressed at the PDCs are not associated with robust medical evidence. Accordingly, some Official Positions are based largely on expert opinion. Despite limitations inherent in such a process, the ISCD and IOF believe it is important to provide clinicians and technologists with the best distillation of current knowledge in the discipline of bone densitometry and provide an important focus for the scientific community to consider. This report describes the methodology and results of the ISCD-IOF PDC dedicated to FRAX®. © 2011 The International Society for Clinical Densitometry.

Summary Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods Clinical perspective and updated literature search. Results The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions.