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Introduction: Palovarotene is a retinoic acid receptor gamma agonist that was studied in phase-2 and phase-3 clinical trials for the inhibition of new heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP). Despite numerous setbacks and regulatory delays, palovarotene is now the first approved FOP treatment in the U.S.A., Canada and Australia but remains unapproved in Europe where concerns surrounding the drug and its path to regional market authorization persist. Areas covered: The developmental history of palovarotene and an overview of the clinical trials and the regulatory approval journey are discussed by global FOP experts. Expert opinion: While post hoc analyses indicate that palovarotene may have modest benefits for the inhibition of new HO formation in FOP, a number of limitations and concerns remain about its generalized use. Although the long-term risks and benefits of treatment with palovarotene remain unknown, the regional approval of palovarotene marks a milestone for the FOP community at the very beginning of a new era of clinical trials. [ABSTRACT FROM AUTHOR]

Increased fracture risk has been associated with weight loss in postmenopausal women, but the time course over which this occurs has not been established. The aim of this study was to examine the effects of unintentional weight loss of ≥10 lb (4.5 kg) in postmenopausal women on fracture risk at multiple sites up to 5 years after weight loss. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed the relationships between self-reported unintentional weight loss of ≥10 lb at baseline, year 2, or year 3 and incident clinical fracture in the years after weight loss. Complete data were available in 40,179 women (mean age ± SD 68 ± 8.3 years). Five-year cumulative fracture rate was estimated using the Kaplan-Meier method, and adjusted hazard ratios for weight loss as a time-varying covariate were calculated from Cox multiple regression models. Unintentional weight loss at baseline was associated with a significantly increased risk of fracture of the clavicle, wrist, spine, rib, hip, and pelvis for up to 5 years after weight loss. Adjusted hazard ratios showed a significant association between unintentional weight loss and fracture of the hip, spine, and clavicle within 1 year of weight loss, and these associations were still present at 5 years. These findings demonstrate increased fracture risk at several sites after unintentional weight loss in postmenopausal women. This increase is found as early as 1 year after weight loss, emphasizing the need for prompt fracture risk assessment and appropriate management to reduce fracture risk in this population. © 2016 American Society for Bone and Mineral Research.

ContextSeveral fracture prediction models that combine fractures at different sites into a composite outcome are in current use. However, to the extent individual fracture sites have differing risk factor profiles, model discrimination is impaired.ObjectiveThe objective of the study was to improve model discrimination by developing a 5-year composite fracture prediction model for fracture sites that display similar risk profiles.DesignThis was a prospective, observational cohort study.SettingThe study was conducted at primary care practices in 10 countries.PatientsWomen aged 55 years or older participated in the study.InterventionSelf-administered questionnaires collected data on patient characteristics, fracture risk factors, and previous fractures.Main outcome measureThe main outcome is time to first clinical fracture of hip, pelvis, upper leg, clavicle, or spine, each of which exhibits a strong association with advanced age.ResultsOf four composite fracture models considered, model discrimination (c index) is highest for an age-related fracture model (c index of 0.75, 47 066 women), and lowest for Fracture Risk Assessment Tool (FRAX) major fracture and a 10-site model (c indices of 0.67 and 0.65). The unadjusted increase in fracture risk for an additional 10 years of age ranges from 80% to 180% for the individual bones in the age-associated model. Five other fracture sites not considered for the age-associated model (upper arm/shoulder, rib, wrist, lower leg, and ankle) have age associations for an additional 10 years of age from a 10% decrease to a 60% increase.ConclusionsAfter examining results for 10 different bone fracture sites, advanced age appeared the single best possibility for uniting several different sites, resulting in an empirically based composite fracture risk model.

Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p

Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.

Antiosteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining two or more fractures while on AOM. GLOW is a prospective, observational cohort study of women aged ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow-up, 73 of 5550 women in the AOM group (1.3%) and 123 of 21,368 in the non-AOM group (0.6%) reported occurrence of two or more fractures. The following variables were associated with treatment failure: lower Short Form 36 Health Survey (SF-36) score (physical function and vitality) at baseline, higher Fracture Risk Assessment Tool (FRAX) score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss ≥10 lb (≥4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF-36 vitality score (odds ratio [OR] per 10-point increase, 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004); two or more falls in the past year (OR, 2.40; 95% CI, 1.34-4.29; p = 0.011), and prior fracture (OR, 2.93; 95% CI, 1.81-4.75; p

ObjectiveTo examine when, where and how fractures occur in postmenopausal women.MethodsWe analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3.ResultsAmong 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68-86% of NHNV and 68-83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling.ConclusionIn this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year.

IntroductionGreater awareness of the relationship between co-morbidities and fracture risk may improve fracture-prediction algorithms such as FRAX.Materials and methodsWe used a large, multinational cohort study (GLOW) to investigate the effect of co-morbidities on fracture risk. Women completed a baseline questionnaire detailing past medical history, including co-morbidity history and fracture. They were re-contacted annually to determine incident clinical fractures. A co-morbidity index, defined as number of baseline co-morbidities, was derived. The effect of adding the co-morbidity index to FRAX risk factors on fracture prevention was examined using chi-squared tests, the May-Hosmer test, c index and comparison of predicted versus observed fracture rates.ResultsOf 52,960 women with follow-up data, enrolled between October 2006 and February 2008, 3224 (6.1%) sustained an incident fracture over 2 years. All recorded co-morbidities were significantly associated with fracture, except for high cholesterol, hypertension, celiac disease, and cancer. The strongest association was seen with Parkinson's disease (age-adjusted hazard ratio [HR]: 2.2; 95% CI: 1.6-3.1; P

Previous fractures of the hip, spine, or wrist are well-recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow-up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow-up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8-, 3.0-, and 4.8-fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1-fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR] = 7.3) and hip (HR = 3.5). Prior rib fractures were associated with a 2.3-fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2-fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8-fold risk of future fracture of a weight-bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.

ObjectivesTo determine the proportion of untreated women who reported receiving treatment after incident fracture and to identify factors that predict treatment across an international spectrum of individuals.DesignProspective observational study. Self-administered questionnaires were mailed at baseline and 1 year.SettingMultinational cohort of noninstitutionalized women recruited from 723 primary physician practices in 10 countries.ParticipantsSixty thousand three hundred ninety-three postmenopausal women aged 55 and older were recruited with a 2:1 oversampling of women aged 65 and older.MeasurementsData collected included participant demographics, medical history, fracture occurrence, medications, and risk factors for fracture. Anti-osteoporosis medications (AOMs) included estrogen, selective estrogen receptor modulators, bisphosphonates, calcitonin, parathyroid hormone, and strontium.ResultsAfter the first year of follow-up, 1,075 women reported an incident fracture. Of these, 17% had started AOM, including 15% of those with a single fracture and 35% with multiple fractures. Predictors of treatment included baseline calcium use (P = .01), baseline diagnosis of osteoporosis (P < .001), and fracture type (P < .001). In multivariable analysis, women taking calcium supplements at baseline (odds ratio (OR) = 1.67) and with a baseline diagnosis of osteoporosis (OR = 2.55) were more likely to be taking AOM. Hip fracture (OR = 2.61), spine fracture (OR = 6.61), and multiple fractures (OR = 3.79) were associated with AOM treatment. Age, global region, and use of high-risk medications were not associated with treatment.ConclusionMore than 80% of older women with new fractures were not treated, despite the availability of AOM. Important factors associated with treatment in this international cohort included diagnosis of osteoporosis before the incident fracture, spine fracture, and to a lesser degree, hip fracture.

Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self-reported clinical risk factors, excluding BMD, to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged 55 years or older from 723 primary-care practices in 10 countries. The population comprised 19,586 women aged 60 years or older who were not receiving antiosteoporosis medication and were followed annually for 2 years. Self-administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the C index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 "major fractures" (as defined by FRAX), and 583 "osteoporotic fractures" (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed a moderate ability to correctly order hip fracture times (C index for hip fracture 0.78 and 0.76, respectively). C indices for "major" and "osteoporotic" fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age + fracture history alone (C index for hip fracture 0.78). In conclusion, estimation of fracture risk in an international primary-care population of postmenopausal women can be made using clinical risk factors alone without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population.

ObjectiveTo investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW).MethodsThis was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications.ResultsBody mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women.ConclusionsOur results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.

PurposeTo determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors.MethodsThe Global Longitudinal Study of Osteoporosis in Women is an observational study of women ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status.ResultsAmong 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in U.S.A. and Australia (32%). Between 48% (U.S.A., Southern Europe) and 68% (Northern Europe) of women aged ≥65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45-52% versus 62-65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in U.S.A. (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, U.S. women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5-3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4-1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment.ConclusionsThe likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis.

ObjectiveTo examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease).Patients and methodsFractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36).ResultsReductions in EQ-5D health-utility scores and SF-36-measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for >/=3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease).ConclusionPrevious fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life.

The efficiency of strontium in the quantitative analysis of intestinal calcium absorption was evaluated during the preclinical screening of adult rats after the administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The intestinal absorption of strontium across the intestinal wall exhibited a linear relationship with the dose of 1,25(OH)2D3 that was administered to adult rats during preclinical screening. Furthermore, the intervention of 1,25(OH)3D2 exhibited the similarity of strontium intestinal absorption with calcium intestinal absorption which are both mediated by active and passive components.