Fragility of results from randomized controlled trials supporting the guidelines for the treatment of osteoporosis: a retrospective analysis.

This is the first report on the fragility of results from randomized controlled trials (RCTs) for the treatment of osteoporosis. The results of aforementioned RCTs appear to depend on a small number of events and are generally statistically fragile. INTRODUCTION: Osteoporosis remains a health concern worldwide. Evidence-based guideline recommendations that are mainly based on results of clinical trials are important to clinical decision-making. The fragility index (FI) is a novel statistical metric to measure the fragility of results from an RCT. Our study aimed to analyze the fragility of the clinical trials referenced in the guidelines for the treatment of osteoporosis. METHODS: Trials were included if they investigated primary osteoporosis, randomized patients to treatment or control in a 1:1 design, and reported fracture outcome as the primary endpoint. The FI and fragility quotient (FQ) were calculated for assessing the robustness of results from the eligible RCTs. An FI was defined as the minimum number of events in the intervention group that needs to change from a non-event to an event in order to render a significant result non-significant (or vice versa). The FQ was calculated by dividing the FI by the sample size of the trial. RESULTS: Of the 372 RCTs identified from the guidelines, 42 were eligible for analyses. Their median FI was 10 (25th-75th percentile [Q1-Q3]: 4-18), with a median FQ of 0.007 (Q1-Q3: 0.0017-0.019). Approximately one third of the RCTs had a FI of less than or equal to 5. There were 17 (40.5%) trials where the number of patients lost to follow-up was greater than the FI. The FI was significantly associated with sample size, journal impact factor, and the percent of patients lost to follow-up. CONCLUSION: Results from some RCTs supporting guideline recommendations for the treatment of osteoporosis depend on a small number of events. The FI and FQ may provide additional, intuitive metrics to help interpret the robustness of trial results.

Exploring changes in bone mass in individuals with a chronic spinal cord injury.

People experience rapid bone loss shortly after a spinal cord injury (SCI), but the long-term bone changes are yet to be confirmed. This study showed that trabecular bone may have reached a steady state, whereas cortical bone continued to decline in people with a chronic SCI (mean time post injury: 15.5 ± 10 years). INTRODUCTION: (1) To explore changes in bone [primary measure: trabecular volumetric bone mineral density (vBMD); secondary measures: cortical vBMD, cortical thickness, cortical cross-sectional area (CSA), and polar moment of inertia] over 2 years in individuals with a chronic spinal cord injury (SCI). (2) To explore whether muscle density changes were potential correlates of the observed bone changes. METHODS: This study is a secondary data analysis of a prospective, observational study involving 70 people with a chronic SCI (≥ 2 years post injury). The study included 4 strata of participants with diverse impairments: (1) Paraplegia (T1-T12) motor complete American Spinal Injury Association Impairment Scale (AIS) A/B (n = 23), (2) Paraplegia motor incomplete AIS C/D (n = 11), (3) Tetraplegia (C2-C8) AIS A/B (n = 22), and (4) Tetraplegia AIS C/D (n = 14). Peripheral quantitative computed tomography scans were taken at the 4% (distal tibia), 38% (diaphyseal tibia), and 66% (muscle cross-sectional area) tibia sites by measuring from the distal to proximal tibia starting at the inferior border of the medial malleolus. The tibia sites were assessed annually over a span of 2 years. Comparisons were made using a paired-samples t test and simple linear regression was used to adjust for sex, time post injury, and bisphosphonate use. RESULTS: We observed no changes in trabecular vBMD at the 4% tibia site, but there was a statistically significant decline in cortical vBMD, cortical thickness, and CSA at the 38% tibia site. Changes in muscle density were not associated with the decreases observed in cortical bone. CONCLUSION: Our findings suggest that individuals with chronic SCI (mean duration of injury: 15.5 ± 10 years) may have reached a plateau in bone loss with respect to trabecular bone, but cortical bone loss can continue well into the chronic stages.

Incremental costs of fragility fractures: a population-based matched -cohort study from Ontario, Canada.

Using a matched cohort design, the 1-year excess cost of incident fragility fractures at any site was $26,341 per patient, with 43% of total excess costs attributed to hospitalization. The high economic burden of fractures in Ontario underscores the urgency of closing the secondary fracture prevention gap. INTRODUCTION: This retrospective real-world observational study was conducted to document the incremental costs associated with fragility fractures in Ontario, Canada. METHODS: Patients aged >65 years with an index fragility fracture occurring between January 2011 and March 2015 were identified from administrative databases and matched 1:1 to a cohort of similar patients without a fracture. Healthcare resource utilization data were extracted from healthcare records and associated costs were calculated on a per-patient level and for the province of Ontario. Costs were presented as 2017 Canadian dollars. RESULTS: The eligible cohort included 115,776 patients with a fragility fracture. Of these, 101,773 patients were successfully matched 1:1 to a non-fracture cohort. Overall, hip fractures (n = 31,613) were the most common, whereas femur fractures (n = 3002) were the least common type. Hospitalization and continuing care/home care/long-term care accounted for more than 60% of 1-year direct costs, whereas 5% was attributed to medication costs. First-year costs per patient in the fracture cohort were approximately threefold higher versus the non-fracture cohort (mean $37,362 versus $11,020, respectively). The incremental first-year direct healthcare costs of fragility fractures for the province of Ontario were calculated at $724 million per year. CONCLUSIONS: Fragility fractures were associated with a threefold increase in overall mean healthcare costs per patient compared to patients without fractures. With an aging population, there is an urgent need for improved prevention strategies for patients at high-risk of fracture to decrease the economic burden of fragility fractures on the Canadian healthcare system.

A scorecard for osteoporosis in Canada and seven Canadian provinces.

The scorecard evaluates the burden and management of osteoporosis in Canada and how care pathways differ across Canadian provinces. The results showed there are inequities in patients' access to diagnosis, treatment, and post-fracture care programs in Canada. Interventions are needed to close the osteoporosis treatment gap and minimize these inequities. INTRODUCTION: The purpose of this study was to develop a visual scorecard that assesses the burden of osteoporosis and its management within Canada and seven Canadian provinces. METHODS: We adapted the Scorecard for Osteoporosis in Europe (SCOPE) to score osteoporosis indicators for Canada and seven provinces (British Columbia, Alberta, Saskatchewan, Ontario, Quebec, New Brunswick, and Newfoundland). We obtained data from a comprehensive literature review and interviews with osteoporosis experts. We scored 20 elements across four domains: burden of disease, policy framework, service provision, and service uptake. Each element was scored as red, yellow, or green, indicating high, intermediate, or low risk, respectively. Elements with insufficient data were scored black. RESULTS: Canada performed well on several elements of osteoporosis care, including high uptake of risk assessment algorithms and minimal wait times for hip fracture surgery. However, there were no established fracture registries, and reporting on individuals with high fracture risk who remain untreated was limited. Furthermore, osteoporosis was not an official health priority in most provinces. Government-backed action plans and other osteoporosis initiatives were primarily confined to Ontario and Alberta. Several provinces (Saskatchewan, New Brunswick, Newfoundland) did not have any registered fracture liaison service (FLS) programs. Access to diagnosis and treatment was also inconsistent and reimbursement policies did not align with clinical guidelines. CONCLUSION: Government-backed action plans are needed to address provincial inequities in patients' access to diagnosis, treatment, and FLS programs in Canada. Further characterization of the treatment gap and the establishment of fracture registries are critical next steps in providing high-quality osteoporosis care.

Advanced 2D image processing technique to predict hip fracture risk in an older population based on single DXA scans.

A new technique to enhance hip fracture risk prediction in older adults was presented and assessed. The new method dramatically improved prediction at high specificity levels using only a standard clinical diagnostic scan. This has the potential to be implemented in clinical practice to enhance patient fragility diagnosis. INTRODUCTION: Diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) scans. However, studies have shown this to be insufficient to accurately predict hip fractures. Therefore, complementary methods are needed to enhance hip fracture risk prediction to identify vulnerable patients. METHODS: Hip DXA scans were obtained for 192 subjects from the Canadian Multicenter Osteoporosis Study (CaMos), 50 of whom had experienced a hip fracture within 5 years of the scan. 2D statistical shape and appearance modeling was performed to account for the effect of the femur's geometry and BMD distribution on hip fracture risk. Statistical shape modeling (SSM), and statistical appearance modeling (SAM) were also used separately to predict the fracture risk based solely on the femur's geometry and BMD distribution, respectively. Combined with BMD, age, and body mass index (BMI), logistic regression was performed to estimate the fracture risk over the 5-year period. RESULTS: Using the new technique, hip fractures were correctly predicted in 78% of cases compared with 36% when using the T-score. The accuracy of the prediction was not greatly reduced when using SSM and SAM (78% and 74% correct, respectively). Various geometric and BMD distribution traits were identified in the fractured and non-fractured groups. CONCLUSION: 2D SSAM can dramatically improve hip fracture prediction at high specificity levels and estimate the year of the impending fracture using standard clinical images. This has the potential to be implemented in clinical practice to estimate hip fracture risk.

Correction to: Comparison of the clinical effectiveness and safety between the use of denosumab vs bisphosphonates in renal transplant patients.

The original version of this article, published on 03 January 2020 contained a mistake. An author's name was misspelled.

Comparison of the clinical effectiveness and safety between the use of denosumab vs bisphosphonates in renal transplant patients.

A retrospective chart review was conducted on 85 renal transplant patients aged 19-88 years, treated with denosumab or bisphosphonate therapy. Bone densitometry measures were compared between treatment groups at baseline; at years 1, 2, and 3; and at final follow-up (average of 3.4 years). Both bisphosphonate and denosumab treatments increased lumbar spine bone density; however, the effect of denosumab was greater compared with that of bisphosphonate treatment. Denosumab treatment increased femoral neck BMD, whereas bisphosphonate treatment had a mean decrease in femoral neck BMD at final follow-up. Thus, our study provides evidence for the efficacy of denosumab treatment in renal transplant patients. Caution around hypocalcemia is warranted. We recommend more prospective studies to analyze the effects of long-term antiresorptive therapy in patients with a renal transplant. INTRODUCTION: To compare the clinical effectiveness and safety between the use of denosumab and bisphosphonates on bone density and incidence of adverse events in renal transplant patients. METHODS: A retrospective chart review was conducted on 85 renal transplant patients aged 19-88 years, treated with denosumab or bisphosphonate therapy. Bone densitometry measures were compared between treatment groups at baseline; years 1, 2, and 3; and at final follow-up (average of 3.4 years). RESULTS: Absolute change in lumbar spine and femoral neck BMD over the treatment period was 0.029 ± 0.075 g/cm2 and - 0.003 ± 0.064 g/cm2, respectively, in the bisphosphonate group. Absolute change in lumbar spine and femoral neck BMD at final follow-up was 0.072 ± 0.094 g/cm2 and 0.025 ± 0.063 g/cm2, respectively, in the denosumab group. Denosumab resulted in significantly greater increases in lumbar spine BMD (0.045 g/cm2 greater in the denosumab group). Similarly, the absolute change in BMD at the femoral neck was 0.022 g/cm2 greater in the denosumab group as compared with the bisphosphonate group. The denosumab group had one event of severe hypocalcemia following first injection and one report of hospitalized pneumonia. No serious adverse events were reported in the bisphosphonate group. CONCLUSIONS: Both treatments increased lumbar spine BMD; however, the effect of denosumab was greater compared with that of bisphosphonate treatment. Our study provides evidence for the efficacy of denosumab treatment in renal transplant patients. Caution around hypocalcemia is warranted. We recommend more prospective studies to analyze the effects of long-term antiresorptive therapy in patients with a renal transplant.

Describing the resource utilisation and costs associated withvertebral fractures: the Build Better Bones with Exercise (B3E) Pilot Trial.

This analysis examined costs/resources of 141 women with vertebral fractures, randomised to a home exercise programme or control group. Total, mean costs and the incremental cost-effectiveness ratio (ICER) were calculated. Quality of life was collected. Cost drivers were caregiver time, medications and adverse events (AEs). Results show adding an exercise programme may reduce the risk of AEs. INTRODUCTION: This exploratory economic analysis examined the health resource utilisation and costs experienced by women with vertebral fractures, and explored the effects of home exercise on those costs. METHODS: Women ≥ 65 years with one or more X-ray-confirmed vertebral fractures were randomised 1:1 to a 12-month home exercise programme or equal attention control group. Clinical and health system resources were collected during monthly phone calls and daily diaries completed by participants. Intervention costs were included. Unit costs were applied to health system resources. Quality of life (QoL) information was collected via EQ-5D-5L at baseline, 6 and 12 months. RESULTS: One hundred and forty-one women were randomised. Overall total costs (CAD 2018) were $664,923 (intervention) and $614,033 (control), respectively. The top three cost drivers were caregiver time ($250,269 and $240,811), medications ($151,000 and $122,145) and AEs ($58,807 and $71,981). The mean cost per intervention participant of $9365 ± $9988 was higher compared with the mean cost per control participant of $8772 ± $9718. The mean EQ-5D index score was higher for the intervention participants (0.81 ± 0.11) compared with that of controls (0.79 ± 0.13). The differences in quality-adjusted life year (QALY) (0.02) and mean cost ($593) were used to calculate the ICER of $29,650. CONCLUSIONS: Women with osteoporosis with a previous fracture experience a number of resources and associated costs that impact their care and quality of life. Caregiver time, medications and AEs are the biggest cost drivers for this population. The next steps would be to expand this feasibility study with more participants, longer-term follow-up and more regional variability.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Longitudinal assessment of health-related quality of life in osteoporosis: data from the population-based Canadian Multicentre Osteoporosis Study.

Little is known about the association between health-related quality of life (HRQOL) and osteoporosis in the absence of fracture, and how HRQOL may change over time. This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. INTRODUCTION: Fragility fractures have a detrimental effect on the health-related quality of life (HRQOL) of those with osteoporosis. Less is known about the association between HRQOL and osteoporosis in the absence of fracture. METHODS: Canadian Multicentre Osteoporosis Study participants completed the SF-36, a detailed health questionnaire and measures of bone mineral density (BMD) at baseline and follow-up. We report the results of participants ≥ 50 years with 10-year follow-up. Self-reported osteoporosis at baseline and BMD-based osteoporosis at follow-up were ascertained. Multivariable linear regression models were developed for baseline SF-36 domains, component summaries, and change over time, adjusting for relevant baseline information. RESULTS: Baseline data were available for 5266 women and 2112 men. Women in the osteoporosis group had substantially lower SF-36 baseline scores, particularly in the physically oriented domains, than those without osteoporosis. A similar but attenuated pattern was evident for the men. After 10-year follow-up (2797 women and 1023 men), most domain scores dropped for women and men regardless of osteoporosis status, with the exception of mentally-oriented ones. In general, a fragility fracture was associated with lower SF-36 scores and larger declines over time. CONCLUSIONS: This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. HRQOL should be thoroughly investigated even prior to fracture, to develop appropriate interventions for all stages of the disease.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Recommendations for the conduct of economic evaluations in osteoporosis: outcomes of an experts' consensus meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the US branch of the International Osteoporosis Foundation.

Economic evaluations are increasingly used to assess the value of health interventions, but variable quality and heterogeneity limit the use of these evaluations by decision-makers. These recommendations provide guidance for the design, conduct, and reporting of economic evaluations in osteoporosis to improve their transparency, comparability, and methodologic standards. INTRODUCTION: This paper aims to provide recommendations for the conduct of economic evaluations in osteoporosis in order to improve their transparency, comparability, and methodologic standards. METHODS: A working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis to make recommendations for the design, conduct, and reporting of economic evaluations in osteoporosis, to define an osteoporosis-specific reference case to serve a minimum standard for all economic analyses in osteoporosis, to discuss methodologic challenges and initiate a call for research. A literature review, a face-to-face meeting in New York City (including 11 experts), and a review/approval by a larger group of experts worldwide (including 23 experts in total) were conducted. RESULTS: Recommendations on the type of economic evaluation, methods for economic evaluation, modeling aspects, base-case analysis and population, excess mortality, fracture costs and disutility, treatment characteristics, and model validation were provided. Recommendations for reporting economic evaluations in osteoporosis were also made and an osteoporosis-specific checklist was designed that includes items to report when performing an economic evaluation in osteoporosis. Further, 12 minimum criteria for economic evaluations in osteoporosis were identified and 12 methodologic challenges and need for further research were discussed. CONCLUSION: While the working group acknowledges challenges and the need for further research, these recommendations are intended to supplement general and national guidelines for economic evaluations, improve transparency, quality, and comparability of economic evaluations in osteoporosis, and maintain methodologic standards to increase their use by decision-makers.

The impact of GI events on persistence and adherence to osteoporosis treatment: 3-, 6-, and 12-month findings in the MUSIC-OS study.

The goal of this multinational, prospective, observational study was to examine the relationship between gastrointestinal (GI) events and self-reported levels of medication adherence and persistence in postmenopausal women. A total of 73.9% of patients remained on their osteoporosis (OP) therapy at month 12, although the presence of a GI event at baseline, month 3, and month 6 significantly reduced month 12 persistence among new users. The odds of a month-12 ADEOS score ≥ 20 were significantly lower among patients who experienced a GI event between baseline and month 6. The occurrence of GI events was observed to be associated with a lower likelihood of patient adherence and persistence to OP medication. INTRODUCTION: This study examines the relationship between gastrointestinal (GI) events and self-reported adherence and persistence with initial osteoporosis (OP) therapy over the course of the first 12 months of treatment. METHODS: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study was a multinational, prospective, observational study examining the impact of GI events on OP management in postmenopausal women. Information regarding GI events was collected at the time of enrollment and at months 3, 6, and 12 of follow-up. Patients reported GI events and medication persistence and completed the 12-item Adherence Evaluation of Osteoporosis treatment (ADEOS) questionnaire. Multivariate logistic and general linear models examined the association between GI events at various time points and persistence and adherence at month 12. RESULTS: The study enrolled 2943 women; 22.8% were classified as new users of OP therapy and the remainder were considered experienced users. Across all patients, 68.1% reported GI events at baseline; by month 12, over 80% of subjects who completed follow-up reported at least one GI problem. The majority of patients (86.7%) were treated only with bisphosphonates at baseline. At month 12, 73.9% of patients remained on therapy; logistic regression revealed that those with GI problems by month 6 were significantly less likely to persist with treatment, after adjusting for other factors. The odds of a month 12 ADEOS score ≥ 20 (considered predictive of adherence) were significantly lower among patients who experienced a GI event between baseline and month 6. CONCLUSIONS: The occurrence of GI events was associated with a lower likelihood of patient adherence to and persistence with OP medication.

Build better bones with exercise (B3E pilot trial): results of a feasibility study of a multicenter randomized controlled trial of 12 months of home exercise in older women with vertebral fracture.

We pilot-tested a trial of home exercise on individuals with osteoporosis and spine fracture. Our target enrollment was met, though it took longer than expected. Participants stayed in the study and completed the exercise program with no safety concerns. Future trials should expand the inclusion criteria and consider other changes. PURPOSE: Osteoporotic fragility fractures create a substantial human and economic burden. There have been calls for a large randomized controlled trial examining the effect of exercise on fracture incidence. The B3E pilot trial was designed to evaluate the feasibility of a large trial examining the effects of home exercise on individuals at high risk of fracture. METHODS: Community-dwelling women ≥ 65 years with radiographically confirmed vertebral compression fractures were recruited at seven sites in Canada and Australia. We randomized participants in a 1:1 ratio to a 12-month home exercise program or equal attention control group, both delivered by a physiotherapist (PT). Participants received six PT home visits in addition to monthly phone calls from the PT and a blinded research assistant. The primary feasibility outcomes of the study were recruitment rate (20 per site in 1 year), retention rate (75% completion), and intervention adherence rate (60% of weeks meeting exercise goals). Secondary outcomes included falls, fractures and adverse events. RESULTS: One hundred forty-one participants were recruited; an average of 20 per site, though most sites took longer than anticipated. Retention and adherence met the criteria for success: 92% of participants completed the study; average adherence was 66%. The intervention group did not differ significantly in the number of falls (IRR 0.97, 95% CI 0.58 to 1.63) or fragility fractures (OR 1.11, 95% CI 0.60 to 2.05) compared to the control group. There were 18 serious adverse events in the intervention group and 12 in the control group. CONCLUSION: An RCT of home exercise in women with vertebral fractures is feasible but recruitment was a challenge. Suggestions are made for the conduct of future trials.

Facilitators and barriers to exercise adherence in patients with osteopenia and osteoporosis: a systematic review.

The aim of this study was to categorize the facilitators and barriers of exercise and identify methods to promote exercise adherence in the osteoporosis population. Despite the fair methodological quality of included randomized controlled trials (RCTs), less than 75 % identified facilitators and barriers to exercise. Methods to promote and measure exercise adherence were poorly reported. INTRODUCTION: Several studies have shown exercise to be successful in maintaining or increasing BMD in individuals with low bone mass. Yet, adherence to exercise is poor, with 50 % of those registered in an exercise program dropping out within the first 6 months, lack of time being the number one barrier in many populations. However, in the osteoporosis population, the main facilitator and barrier to exercise is still unclear. The aim of this study is to examine the extent to which RCTs reported the facilitators and the barriers to exercise and identified methods to promote adherence to an exercise program. METHODS: PubMed, CINHAL, EMBASE, and the Cochrane Review were queried using a predefined search criterion, and the resulting citations were imported into DistillerSR. Screening was carried out by two independent reviewers, and articles were included in the analysis by consensus. The methodological quality of included studies was assessed using the PEDro scale. RESULTS: Fifty-four RCTs examining exercise interventions in patients with osteopenia or osteoporosis were included. A spectrum of facilitators and barriers to exercise for osteoporotic patients were identified; however, no one facilitator was more frequently reported than the other. The most commonly reported barriers were lack of time and transportation. In most RCTs, methods to promote and measure exercise adherence were unsatisfactory. Of the 54 papers, 72 % reported an adherence rate to an exercise program; the lowest reported rate was 51.7 %, and the highest 100 %. CONCLUSIONS: Most RCTs found were of fair quality; however, less than three quarters identified facilitators and barriers to exercise. Reporting of methods to promote and measure exercise adherence were low. Future work should be directed toward identifying major facilitators and barriers to exercise adherence within RCTs. Only then can methods be identified to leverage facilitators and overcome barriers, thus strengthening the evidence for efficacy of optimal interventional exercise programs. This review has been registered in PROSPERO under registration number CRD42016039941.

Association of gastrointestinal events with quality of life and treatment satisfaction in osteoporosis patients: results from the Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS).

The purpose of this study was to assess the association of GI events with HRQoL and treatment satisfaction. The effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D, OPAQ-SV, and treatment satisfaction scores among patients with vs without baseline GI events. The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. INTRODUCTION: The goal of this study was to assess the association of gastrointestinal (GI) events with health-related quality of life (HRQoL) and treatment satisfaction in patients being treated for osteoporosis. METHODS: MUSIC OS was a multinational, prospective, observational study examining the impact of GI events on osteoporosis management in postmenopausal women. In this analysis, HRQoL and treatment satisfaction were assessed at baseline, 6, and 12 months and compared between patients with and without GI events. Covariate-adjusted scores were calculated using multivariate least-squares regression analysis, and differences between the mean scores of patients with and without baseline and post-baseline GI events were determined. RESULTS: Among the 2959 patients in the analysis, unadjusted scores at each time point were lower (i.e., worse) for patients with GI events than patients without GI events. In adjusted analyses, the effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D and OPAQ-SV scores at 12 months among patients with vs without baseline GI events (-0.04 for the EQ-5D utility score, -5.07 for the EQ-5D visual analog scale, -3.35 for OPAQ physical function, -4.60 for OPAQ emotional status, and -8.50 for OPAQ back pain; P ≤ 0.001 for all values). Decrements in month 12 treatment satisfaction scores were -6.46 for patients with baseline GI events and -7.88 for patients with post-baseline GI events. CONCLUSIONS: The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis.

Biologic therapies and bone loss in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. METHODS: Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." CONCLUSION: Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Self-perception of fracture risk: what can it tell us?

In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.

Single, double, and triple Auger decays from 1s shake-up states of the oxygen molecule.

The single, double, and triple Auger decays from the 1s shake-up states of O2 have been studied using a multi-electron coincidence method. Efficient populations of two-hole final states are observed in single Auger decays of the π-π* shake-up states, which is understood as a characteristic property of the Auger transitions from shake-up states of an open-shell molecule. The O23+ populations formed by double Auger decays show similar profiles for both the O1s-1 and shake-up states, which is due to the contributions from cascade double Auger processes. While the cascade contributions to the double Auger decays increase with the initial shake-up energy, the probability of direct double Auger processes remains unchanged between the O1s-1 and shake-up states, which implies a weak influence of the excited electron on the double Auger emission that originates from the electron correlation effect.

Muscle and Myotendinous Tissue Properties at the Distal Tibia as Assessed by High-Resolution Peripheral Quantitative Computed Tomography.

High-resolution peripheral quantitative computed tomography (HR-pQCT) quantifies bone microstructure and density at the distal tibia where there is also a sizable amount of myotendinous (muscle and tendon) tissue (MT); however, there is no method for the quantification of MT. This study aimed (1) to assess the feasibility of using HR-pQCT distal tibia scans to estimate MT properties using a custom algorithm, and (2) to determine the relationship between MT properties at the distal tibia and mid-leg muscle density (MD) obtained from pQCT. Postmenopausal women from the Hamilton cohort of the Canadian Multicenter Osteoporosis Study had a single-slice (2.3 ± 0.5 mm) 66% site pQCT scan measuring muscle cross-sectional area (MCSA) and MD. A standard HR-pQCT scan was acquired at the distal tibia. HR-pQCT-derived MT cross-sectional area (MTCSA) and MT density (MTD) were calculated using a custom algorithm in which thresholds (34.22-194.32 mg HA/cm3) identified muscle seed volumes and were iteratively expanded. Pearson and Bland-Altman plots were used to assess correlations and systematic differences between pQCT- and HR-pQCT-derived muscle properties. Among 45 women (mean age: 74.6 ± 8.5 years, body mass index: 25.9 ± 4.3 kg/m2), MTD was moderately correlated with mid-leg MD across the 2 modalities (r = 0.69-0.70, p < 0.01). Bland-Altman analyses revealed no evidence of directional bias for MTD-MD. HR-pQCT and pQCT measures of MTCSA and MCSA were moderately correlated (r = 0.44, p < 0.01). Bland-Altman plots for MTCSA revealed that larger MCSAs related to larger discrepancy between the distal and the mid-leg locations. This is the first study to assess the ability of HR-pQCT to measure MT size, density, and morphometry. HR-pQCT-derived MTD was moderately correlated with mid-leg MD from pQCT. This relationship suggests that distal MT may share common properties with muscle throughout the length of the leg. Future studies will assess the value of HR-pQCT-derived MT properties in the context of falls, mobility, and balance.