The Danish HD Registry-a nationwide family registry of HD families in Denmark.

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.

Bone turnover predicts change in volumetric bone density and bone geometry at the radius in men.

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 (ß-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.

Health economic aspects of vertebral augmentation procedures.

We reviewed all peer-reviewed papers analysing the cost-effectiveness of vertebroplasty and balloon kyphoplasty for osteoporotic vertebral compression fractures. In general, the procedures appear to be cost effective but are very dependent upon model input details. Better data, rather than new models, are needed to answer outstanding questions. Vertebral augmentation procedures (VAPs), including vertebroplasty (VP) and balloon kyphoplasty (BKP), seek to stabilise fractured vertebral bodies and reduce pain. The aim of this paper is to review current literature on the cost-effectiveness of VAPs as well as to discuss the challenges for economic evaluation in this research area. A systematic literature search was conducted to identify existing published studies on the cost-effectiveness of VAPs in patients with osteoporosis. Only peer-reviewed published articles that fulfilled the criteria of being regarded as full economic evaluations including both morbidity and mortality in the outcome measure in the form of quality-adjusted life years (QALYs) were included. The search identified 949 studies, of which four (0.4 %) were identified as relevant with one study added later. The reviewed studies differed widely in terms of study design, modelling framework and data used, yielding different results and conclusions regarding the cost-effectiveness of VAPs. Three out of five studies indicated in the base case results that VAPs were cost effective compared to non-surgical management (NSM). The five main factors that drove the variations in the cost-effectiveness between the studies were time horizon, quality of life effect of treatment, offset time of the treatment effect, reduced number of bed days associated with VAPs and mortality benefit with treatment. The cost-effectiveness of VAPs is uncertain. In answering the remaining questions, new cost-effectiveness analysis will yield limited benefit. Rather, studies that can reduce the uncertainty in the underlying data, especially regarding the long-term clinical outcomes of VAPs, should be conducted.

Bone turnover markers predict hip bone loss in elderly European men: results of the European Male Ageing Study (EMAS).

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

Management of osteoporosis of the oldest old.

UNLABELLED: This consensus article reviews the diagnosis and treatment of osteoporosis in geriatric populations. Specifically, it reviews the risk assessment and intervention thresholds, the impact of nutritional deficiencies, fall prevention strategies, pharmacological treatments and their safety considerations, the risks of sub-optimal treatment adherence and strategies for its improvement. INTRODUCTION: This consensus article reviews the therapeutic strategies and management options for the treatment of osteoporosis of the oldest old. This vulnerable segment (persons over 80 years of age) stands to gain substantially from effective anti-osteoporosis treatment, but the under-prescription of these treatments is frequent. METHODS: This report is the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores some of the reasons for this and presents the arguments to counter these beliefs. The risk assessment of older individuals is briefly reviewed along with the differences between some intervention guidelines. The current evidence on the impact of nutritional deficiencies (i.e. calcium, protein and vitamin D) is presented, as are strategies to prevent falls. One possible reason for the under-prescription of pharmacological treatments for osteoporosis in the oldest old is the perception that anti-fracture efficacy requires long-term treatment. However, a review of the data shows convincing anti-fracture efficacy already by 12 months. RESULTS: The safety profiles of these pharmacological agents are generally satisfactory in this patient segment provided a few precautions are followed. CONCLUSION: These patients should be considered for particular consultation/follow-up procedures in the effort to convince on the benefits of treatment and to allay fears of adverse drug reactions, since poor adherence is a major problem for the success of a strategy for osteoporosis and limits cost-effectiveness.

Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study.

UNLABELLED: Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. INTRODUCTION: We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures. RESULTS: In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities. CONCLUSIONS: Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.

The impact of different health dimensions on overall quality of life related to kyphoplasty and non-surgical management.

UNLABELLED: This study uses data from a previously published randomised trial where balloon kyphoplasty was compared to non-surgical management. Of the improved overall quality of life, 60 % was caused by decreased pain. However, ignoring other dimensions of quality of life would underestimate the procedure's effect. INTRODUCTION: Acute back pain has been viewed as the most important factor lowering quality of life (QoL) for patients suffering vertebral fractures. The objective of this study was to quantify the impact of different health dimensions on overall QoL using patient-reported outcome measurements (PROMs) collected in Fracture Reduction Evaluation (FREE) trial. METHODS: The analysis was based on patients included in the 2-year-long randomised controlled FREE trial studying the efficacy and safety of balloon kyphoplasty procedure (BKP) compared to non-surgical management (NSM). The PROMs included were EQ-5D, Short Form (SF)-36, visual analogue scale (VAS) pain and the Roland-Morris Disability Questionnaire (RMDQ). The health dimensional contribution to the overall QoL improvements was analysed by isolating the impact of each dimension on QoL in the SF-36 and EQ-5D, respectively. A correlation analysis of the QoL improvement was performed to investigate the relationships between the four instruments. RESULTS: Changes in pain explained 60 % of the quality-adjusted life years (QALY) gained in BKP vs. NSM followed by self-care (17 %), mobility (16 %) and usual activities (10 %) (EQ-5D). Health dimensions capturing the mental state had little impact on the QALY gained. The SF-36 dimensional analysis showed similar results. The correlation analysis showed that the correlation between VAS pain, RMDQ and QALY improvement was fairly weak. CONCLUSIONS: Changes in the pain dimension of health are the most important drivers for changes of overall QoL in patients treated with BKP or NSM. However, ignoring the impact of other dimensions would lead to an underestimation of the actual improvement in overall QoL.

Impact of nutrition on muscle mass, strength, and performance in older adults.

Muscle strength plays an important role in determining risk for falls, which result in fractures and other injuries. While bone loss has long been recognized as an inevitable consequence of aging, sarcopenia-the gradual loss of skeletal muscle mass and strength that occurs with advancing age-has recently received increased attention. A review of the literature was undertaken to identify nutritional factors that contribute to loss of muscle mass. The role of protein, acid-base balance, vitamin D/calcium, and other minor nutrients like B vitamins was reviewed. Muscle wasting is a multifactorial process involving intrinsic and extrinsic alterations. A loss of fast twitch fibers, glycation of proteins, and insulin resistance may play an important role in the loss of muscle strength and development of sarcopenia. Protein intake plays an integral part in muscle health and an intake of 1.0-1.2 g/kg of body weight per day is probably optimal for older adults. There is a moderate [corrected] relationship between vitamin D status and muscle strength. Chronic ingestion of acid-producing diets appears to have a negative impact on muscle performance, and decreases in vitamin B12 and folic acid intake may also impair muscle function through their action on homocysteine. An adequate nutritional intake and an optimal dietary acid-base balance are important elements of any strategy to preserve muscle mass and strength during aging.

Sarcopenia and its relationship with bone mineral density in middle-aged and elderly European men.

UNLABELLED: The aim of this study was to determine the relationship between reduced muscle mass (sarcopenia) and areal bone mineral density (BMD(a)) in middle-aged and elderly community-dwelling European men. Men with sarcopenia had significantly lower BMD(a) and were more likely to have osteoporosis compared with men without sarcopenia. INTRODUCTION: In men, the relationship between reduced muscle mass (sarcopenia) and BMD(a) is unclear. This study aimed to determine this relationship in middle-aged and elderly community-dwelling men. METHODS: Men aged 40-79 years from the Manchester (UK) and Leuven (Belgium) cohorts of the European Male Ageing Study were invited to attend for assessment including dual-energy X-ray absorptiometry, from which appendicular lean mass (aLM), fat mass (FM) and whole-body, spine and hip BMD(a) were determined. Relative appendicular skeletal muscle mass (RASM) was calculated as aLM/height². Muscle strength was assessed in subjects from Leuven. Sarcopenia was defined by RASM at <7.26 kg/m² and by the recent definition of the European Working Group on Sarcopenia in Older People (RASM at <7.26 kg/m(2) plus low muscle function). Linear regression was used to determine the associations between aLM, FM, muscle strength and BMD(a) and logistic regression to determine the association between sarcopenia and osteoporosis. RESULTS: Six hundred seventy-nine men with a mean age of 59.6 (SD = 10.7), contributed data to the analysis; 11.9 % were sarcopenic by the conventional definition. After adjustment for age and centre, aLM, RASM and FM were positively associated with BMD(a). Men with RASM at <7.26 kg/m² had significantly lower BMD(a) compared with those with RASM at ≥7.26 kg/m(2). In a multivariable model, aLM was most consistently associated with BMD(a). Men with sarcopenia were more likely to have osteoporosis compared with those with normal RASM (odds ratio = 3.0; 95 % CI = 1.6-5.8). CONCLUSIONS: Sarcopenia is associated with low BMD(a) and osteoporosis in middle-aged and elderly men. Further studies are necessary to assess whether maintaining muscle mass contributes to prevent osteoporosis.

Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data.

UNLABELLED: This study showed that risedronate 150-mg once a month provides similar efficacy and safety at 2 years compared with risedronate 5-mg daily for the treatment of postmenopausal osteoporosis. This adds to the range of risedronate dosing options and provides an alternative for patients who prefer once-a-month dosing. INTRODUCTION: Risedronate is effective in the treatment of postmenopausal osteoporosis in oral daily, weekly, or on two consecutive days per month doses. This 2-year randomized, double-blind, multicenter study assesses the efficacy and safety of a single risedronate 150-mg once-a-month oral dose compared with the 5-mg daily regimen. METHODS: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5-mg daily (n = 642) or 150-mg once a month (n = 650) for 2 years. Bone mineral density (BMD), bone turnover markers, new vertebral fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine BMD after 1 year. RESULTS: Four hundred ninety-eight subjects in the daily group (77.6 %) and 513 subjects in the once-a-month group (78.9 %) completed the study. After 24 months, the mean percent change in lumbar spine BMD was 3.9 % (95 % confidence interval [CI], 3.43 to 4.42 %) and 4.2 % (95 % CI, 3.68 to 4.65 %) in the daily and once-a-month groups, respectively. The once-a-month regimen was determined to be non-inferior to the daily regimen. The mean percent changes in BMD at the hip were similar in both dose groups, as were changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the two treatment groups. CONCLUSIONS: After 2 years, treatment with risedronate 150-mg once a month provided similar efficacy and tolerability to daily dosing and provides an alternative for patients who prefer once-a-month oral dosing.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Tools in the assessment of sarcopenia.

This review provides a framework for the development of an operational definition of sarcopenia and of the potential end points that might be adopted in clinical trials among older adults. While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate end points for determining outcomes of clinical importance which might be utilized in intervention studies. We review current approaches to the definition of sarcopenia and the methods used for the assessment of various aspects of physical function in older people. The potential end points of muscle mass, muscle strength, muscle power, and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these end points in clinical trials. Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomized clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area.

The transcription intermediary factor 1ß coactivates the androgen receptor.

The androgen receptor (AR) is a ligand-inducible transcription factor. Its transcription activation domain consists of the two transcription activation units called Tau-1 and Tau- 5. Tau-5 interacts with p160 coactivators like the transcription intermediary factor 2 (TIF2), which in their turn recruit histone modifiers and chromatin-remodelling complexes. The mechanism of action of Tau-1, however, remains elusive. Here, we demonstrate that transcription intermediary factor 1ß (TIF1ß) can induce the activity of the AR up to five fold when tested in vitro. Although there is no evidence for direct interactions between TIF1ß and AR, mutation studies show that the activity of TIF1ß depends on the integrity of Tau-1 in AR on the one hand, and the so-called tripartite motif domain in TIF1ß on the other. Surprisingly, the coactivation by TIF1ß via Tau-1 seems additive rather than cooperative with the AR coactivation by TIF2. Some mutations naturally occurring in androgen-insensitivity syndrome patients that reside in Tau-1 seem to impair the TIF1ß coactivation of the AR, indicating that TIF1ß could also be relevant for the in vivo androgen response in humans. Moreover, since TIF1ß is well expressed in prostate cancer cells, its functional interaction with androgen signalling could in the long run be a therapeutic target for this disease.

Poor bone microarchitecture in older men with impaired physical performance--the STRAMBO study.

UNLABELLED: In 810 men ≥ 60 years, poor physical performance of lower limbs was associated with lower areal bone mineral density (aBMD) of total hip and poor bone microarchitecture at the distal tibia (assessed by HR-pQCT). Men who reported falls had lower hip aBMD and lower cortical density at the distal tibia. INTRODUCTION: The aim of this study was to assess the association between bone microarchitecture and physical performance in older men. METHODS: Volumetric bone mineral density (vBMD) and bone microarchitecture were assessed in 810 men ≥ 60 years at the distal radius and tibia by high resolution pQCT. aBMD was measured at the spine, hip, whole body, and distal radius by dual energy X-ray absorptiometry. Clinical tests included chair stands and tests of static and dynamic balance. We calculated a composite score summarizing abilities and time required to perform the tests. RESULTS: In multivariable models, men who failed in ≥ one test had lower total hip aBMD than men who accomplished all the tests. They had lower total vBMD (Tt.vBMD), cortical thickness (Ct.Th), trabecular vBMD (Tb.vBMD), and more heterogenous trabecular distribution (Tb.Sp.SD) at the distal tibia (p < 0.05). Men who failed in ≥ two tests had lower aBMD at the total hip, femoral neck, and trochanter as well as lower Tt.vBMD, cortical vBMD (Ct.vBMD), Ct.Th and trabecular number (Tb.N), and higher Tb.Sp.SD at the distal tibia (p < 0.05). Men in the lowest quartile of the composite score had lower aBMD (total hip, distal radius), lower Tb.vBMD and Tb.N at the distal radius, and lower Tt.vBMD, Ct.vBMD, Ct.Th, Tb.vBMD, and Tb.N, and higher Tb.Sp.SD at the distal tibia compared with the highest quartile. In multivariables models, men reporting falls had lower total hip aBMD and lower distal tibia Ct.vBMD (p < 0.01). CONCLUSION: In older men, poor physical performance is associated with lower hip aBMD and poor bone microarchitecture (mainly at the distal tibia).

What's in a name? What constitutes the clinical diagnosis of osteoporosis?

Osteoporosis is a skeletal disorder in which reductions in bone strength predispose to an increased risk for fractures. Currently, the diagnosis is officially made based exclusively on bone mineral density T-scores that are ≤-2.5 at the spine or hip. Limiting the clinical diagnosis of osteoporosis solely to a T-score-based criterion, which is the official convention in the USA, creates uncertainty about the use of the term osteoporosis to diagnose older women and men who have T-scores >-2.5, but either have already sustained low-trauma fractures or are recognized as having high fracture risk based on absolute fracture risk calculations from FRAX or other algorithms. A failure to diagnose such patients as having osteoporosis may be one component of the well-documented underdiagnosis and undertreatment of this disease which limits our ability to reduce the burden of fractures worldwide. There is a need to expand the criteria for making a clinical diagnosis and to codify these changes in order to help patients, physicians, policy makers, and payers better understand who has this disease and the elevated risk for fracture that it represents.

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

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

Frailty and sarcopenia: definitions and outcome parameters.

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

Regional and age-related variations in the proportions of hip fractures and major fractures among postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women.

UNLABELLED: We examined variations in proportions of hip fractures and major fractures among postmenopausal women using the Global Longitudinal Study of Osteoporosis in Women (GLOW). The proportion of major fractures that were hip fractures varied with age and region, whereas variations in the proportion of fractures that were major fractures appeared modest. INTRODUCTION: In many countries, the World Health Organization fracture risk assessment tool calculates the probability of major fractures by assuming a uniform age-associated proportion of major fractures that are hip fractures in different countries. We further explored this assumption, using data from the GLOW. METHODS: GLOW is an observational population-based study of 60,393 non-institutionalized women aged ≥55 years who had visited practices within the previous 2 years. Main outcome measures were self-reported prevalent fractures after the age of 45 years and incident fractures during the 2 years of follow-up. RESULTS: The adjusted proportion of prevalent and incident major fractures after the age of 45 years that were hip fractures was higher in North America (16%, 17%) than in northern (13%, 12%) and southern Europe (10%, 10%), respectively. The proportion of incident major fractures that were hip fractures increased more than five-fold with age, from 6.6% among 55-59-year-olds to 34% among those aged ≥85 years. Regional and age-associated variations in the proportion of all incident fractures that were major fractures were less marked, not exceeding 16% and 28%, respectively. CONCLUSIONS: The data suggest that there may be regional differences in the proportion of major fractures that are hip fractures in postmenopausal women. In contrast, the regional and age-related variations in the proportion of fractures that are major fractures appear to be modest. However, because of the limited number of fractures in our sample, further studies are necessary to confirm these findings.

Impact of clinical fractures on health-related quality of life is dependent on time of assessment since fracture: results from the FREEDOM trial.

UNLABELLED: In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, women with incident clinical fractures reported significant declines in health-related quality of life (HRQoL). The largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. INTRODUCTION: In the FREEDOM trial, denosumab significantly reduced the risk of new vertebral, hip, and nonvertebral fractures. We evaluated the effect of denosumab on HRQoL and the association between incident clinical fractures and HRQoL. METHODS: The FREEDOM trial enrolled 7,868 women aged 60-90 years with a total hip and/or lumbar spine BMD T-score <-2.5 and not <-4.0 at either site. Women were randomized to receive denosumab 60 mg or placebo every 6 months, in addition to daily calcium and vitamin D. HRQoL was assessed with the Osteoporosis Assessment Questionnaire-Short Version (OPAQ-SV) at baseline and every 6 months for 36 months. The OPAQ-SV assesses physical function, emotional status, and back pain. Higher scores indicate better health status. RESULTS: No statistically significant differences in mean change in HRQoL from baseline to end of study were found when comparing treatment groups. Compared with women without any incident fractures during the study, women with incident clinical fractures reported significant declines in physical function (-4.0 vs. -0.5) and emotional status (-5.0 vs. -0.8) at month 36 (P < 0.001 for both). Importantly, time-dependent covariate analyses demonstrated that the largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. CONCLUSIONS: These findings not only demonstrate that incident clinical fractures impact HRQoL but also contribute new information regarding the impact of these fracture events on HRQoL over time.

Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).

UNLABELLED: Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. INTRODUCTION: There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. METHODS: We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. RESULTS: Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. CONCLUSION: This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.