Cost-effectiveness of 3 versus 6 years of zoledronic acid treatment before bisphosphonate holiday for women with osteoporosis.

We evaluated the cost-effectiveness of recurrent periods of 3 versus 6 years of zoledronic acid treatment prior to 3-year bisphosphonate holidays for US postmenopausal women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5. We found that cycles of 3 years of treatment followed by holidays is likely to be the more cost-effective option. INTRODUCTION: We compared the effectiveness and cost-effectiveness of cycles of 3 years versus 6 years of zoledronic acid treatment prior to 3-year bisphosphonate holidays for US postmenopausal women with osteoporosis. METHODS: We developed an individual-level state-transition microsimulation cost-effectiveness model to compare treatment strategies over the lifetime of recurrent periods of 3 years of zoledronic acid followed by 3-year holidays (zoledronic acid 3/3), recurrent periods of 6 years of zoledronic acid followed by 3-year holidays (zoledronic acid 6/3), and no zoledronic acid treatment for women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5. RESULTS: Base-case analysis and all key parameter sensitivity analysis findings for every treatment initiation age evaluated (50, 60, 70, and 80) revealed that zoledronic acid 3/3 was consistently the most cost-effective strategy, assuming a willingness-to-pay of $100,000 per quality-adjusted life-year (QALY). In general, the zoledronic acid 3/3 and 6/3 strategies were relatively close in effectiveness (QALYs) over the lifetime; however, lifetime direct health care costs were on average approximately $2000 lower for the 3/3 strategy. Probabilistic sensitivity analysis results revealed that the zoledronic acid 3/3 strategy was favored in greater than 70% of the iterations for a willingness-to-pay threshold of $100,000/QALY for all treatment initiation ages evaluated. CONCLUSIONS: After 3 years of zoledronic acid treatment for postmenopausal women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5, taking 3-year holidays before restarting another treatment cycle is likely to be more cost-effective over the lifetime than cycles of 6 years of treatment prior to 3-year holidays.

Zoledronic acid and bone health in older adults with cognitive impairment.

Fracture prevention in cognitively impaired individuals is lacking. This work highlights the benefits of zoledronic acid on bone health in cognitively impaired older adults. Demonstrating benefits of therapy may increase treatment uptake and reduce fracture risk in this group. INTRODUCTION: Osteoporosis has detrimental consequences for frail older adults. The effects on those with both osteoporosis and cognitive impairment are compounded due to increased risk of falls and changes in mobility, both of which can lead to fracture. However, there are limited data on treatment benefits for osteoporotic individuals with cognitive impairment. METHODS: This post hoc, secondary analysis of data from a randomized, double-blind, placebo-controlled clinical trial of single-dose zoledronic acid included 179 women age ≥ 65 years residing in assisted living facilities or nursing homes, 43 of whom had mild to severe cognitive impairment. We assessed bone mineral density (BMD) of the total hip, femoral neck, and lumbar spine by dual-energy x-ray absorptiometry and serum bone turnover markers (C-terminal telopeptide of type I collagen and procollagen type I N propeptide) at 6 and 12 months. RESULTS: In participants with cognitive impairment, those who received zoledronic acid had 4.3% greater BMD at the total hip (p=.005) and 5.3% greater BMD at the femoral neck (p<.001) after 12 months compared to those in the placebo group. Bone turnover markers demonstrated significant decreases at 6 months in those with cognitive impairment who received active treatment compared to the placebo group. Improvements in bone health measures with zoledronic acid were similar to those seen in participants without cognitive impairment. CONCLUSION: Zoledronic acid improves bone health in frail older women with cognitive impairment similar to those without impairment. Further studies are warranted to assess the benefit for fracture reduction in this undertreated population.

The clinician's guide to prevention and treatment of osteoporosis.

Osteoporosis is the most common metabolic bone disease in the USA and the world. It is a subclinical condition until complicated by fracture(s). These fractures place an enormous medical and personal burden on individuals who suffer from them and take a significant economic toll. Any new fracture in an adult aged 50 years or older signifies imminent elevated risk for subsequent fractures, particularly in the year following the initial fracture. What a patient perceives as an unfortunate accident may be seen as a sentinel event indicative of bone fragility and increased future fracture risk even when the result of considerable trauma. Clinical or subclinical vertebral fractures, the most common type of osteoporotic fractures, are associated with a 5-fold increased risk for additional vertebral fractures and a 2- to 3-fold increased risk for fractures at other sites. Untreated osteoporosis can lead to a vicious cycle of recurrent fracture(s), often resulting in disability and premature death. In appropriate patients, treatment with effective antifracture medication prevents fractures and improves outcomes. Primary care providers and medical specialists are critical gatekeepers who can identify fractures and initiate proven osteoporosis interventions. Osteoporosis detection, diagnosis, and treatment should be routine practice in all adult healthcare settings. The Bone Health and Osteoporosis Foundation (BHOF) - formerly the National Osteoporosis Foundation - first published the Clinician's Guide in 1999 to provide accurate information on osteoporosis prevention and treatment. Since that time, significant improvements have been made in diagnostic technologies and treatments for osteoporosis. Despite these advances, a disturbing gap persists in patient care. At-risk patients are often not screened to establish fracture probability and not educated about fracture prevention. Most concerning, the majority of highest risk women and men who have a fracture(s) are not diagnosed and do not receive effective, FDA-approved therapies. Even those prescribed appropriate therapy are unlikely to take the medication as prescribed. The Clinician's Guide offers concise recommendations regarding prevention, risk assessment, diagnosis, and treatment of osteoporosis in postmenopausal women and men aged 50 years and older. It includes indications for bone densitometry as well as fracture risk thresholds for pharmacologic intervention. Current medications build bone and/or decrease bone breakdown and dramatically reduce incident fractures. All antifracture therapeutics treat but do not cure the disease. Skeletal deterioration resumes sooner or later when a medication is discontinued-sooner for nonbisphosphonates and later for bisphosphonates. Even if normal BMD is achieved, osteoporosis and elevated risk for fracture are still present. The diagnosis of osteoporosis persists even if subsequent DXA T-scores are above - 2.5. Ongoing monitoring and strategic interventions will be necessary if fractures are to be avoided. In addition to pharmacotherapy, adequate intake of calcium and vitamin D, avoidance of smoking and excessive alcohol intake, weight-bearing and resistance-training exercise, and fall prevention are included in the fracture prevention armamentarium. Where possible, recommendations in this guide are based on evidence from RCTs; however, relevant published data and guidance from expert clinical experience provides the basis for recommendations in those areas where RCT evidence is currently deficient or not applicable to the many osteoporosis patients not considered for RCT participation due to age and morbidity.

How has COVID-19 affected the treatment of osteoporosis? An IOF-NOF-ESCEO global survey.

The effects of COVID-19 have the potential to impact on the management of chronic diseases including osteoporosis. A global survey has demonstrated that these impacts include an increase in telemedicine consultations, delays in DXA scanning, interruptions in the supply of medications and reductions in parenteral medication delivery. INTRODUCTION: The COVID-19 pandemic has had profound effects on the health of the global population both directly, via the sequelae of the infection, and indirectly, including the relative neglect of chronic disease management. Together the International Osteoporosis Foundation and National Osteoporosis Foundation sought to ascertain the impact on osteoporosis management. METHODS: Questionnaires were electronically circulated to a sample of members of both learned bodies and included information regarding the location and specialty of respondents, current extent of face to face consultations, alterations in osteoporosis risk assessment, telemedicine experience, alterations to medication ascertainment and delivery and electronic health record (EHR) utilisation. Responses were collected, quantitative data analysed, and qualitative data assessed for recurring themes. RESULTS: Responses were received from 209 healthcare workers from 53 countries, including 28% from Europe, 24% from North America, 19% from the Asia Pacific region, 17% from the Middle East and 12% from Latin America. Most respondents were physicians (85%) with physician assistants, physical therapists and nurses/nurse practitioners represented in the sample. The main three specialties represented included rheumatology (40%), endocrinology (22%) and orthopaedics (15%). In terms of the type of patient contact, 33% of respondents conducted telephone consultations and 21% video consultations. Bone mineral density assessment by dual-energy X-ray absorptiometry (DXA) usage was affected with only 29% able to obtain a scan as recommended. The majority of clinicians (60%) had systems in place to identify patients receiving parenteral medication, and 43% of clinicians reported difficulty in arranging appropriate osteoporosis medications during the COVID-19 crisis. CONCLUSIONS: To conclude through surveying a global sample of osteoporosis healthcare professionals, we have observed an increase in telemedicine consultations, delays in DXA scanning, interrupted supply of medications and reductions in parenteral medication delivery.

Cost-effectiveness of five versus ten years of alendronate treatment prior to drug holiday for women with osteoporosis.

We performed a cost-effectiveness analysis comparing 5 versus 10 years of alendronate treatment prior to 5-year drug holiday for US postmenopausal women with hip BMD T-scores between - 2.5 and - 3.5. We found that for most postmenopausal women 5 years of treatment prior to drug holiday is the more effective and cost-effective option. INTRODUCTION: We performed a cost-effectiveness analysis to compare 5 versus 10 years of alendronate treatment prior to 5-year drug holiday for postmenopausal osteoporotic women. METHODS: We created an individual-level state-transition microsimulation model to compare 3 treatment strategies for US postmenopausal women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5 at baseline: recurrent periods of 5 years of alendronate followed by 5 years of drug holiday (alendronate 5/5), recurrent periods of 10 years of alendronate followed by 5 years of drug holiday (alendronate 10/5), and no alendronate treatment. RESULTS: Base-case analysis revealed for women initiating treatment at ages 50, 60, and 70, the alendronate 5/5 strategy dominated (was more effective and less costly than) the alendronate 10/5 strategy and no treatment. For women age 80, the alendronate 10/5 strategy dominated. When assuming a lower relative risk of nonvertebral fracture during years 6-10 of alendronate treatment than the base-case assumption, the alendronate 10/5 strategy became the most cost-effective strategy even at younger treatment initiation ages. Probabilistic sensitivity analysis results supported the base-case findings; for treatment initiation ages of 50, 60, and 70, the alendronate 5/5 strategy was favored, whereas for treatment initiation age of 80, the alendronate 10/5 strategy was favored; however, there was uncertainty in these findings. CONCLUSIONS: After 5 years of alendronate treatment, younger postmenopausal women (ages 50-70) with osteoporosis would likely benefit from a drug holiday, whereas older women (age 80) are likely to benefit from treatment for 10 years before a drug holiday.

Factors associated with the contemplative stage of readiness to initiate osteoporosis treatment.

We investigated the factors associated with readiness for initiating osteoporosis treatment in women at high risk of fracture. We found that women in the contemplative stage were more likely to report previously being told having osteoporosis or osteopenia, acknowledge concern about osteoporosis, and disclose prior osteoporosis treatment. INTRODUCTION: Understanding factors associated with reaching the contemplative stage of readiness to initiate osteoporosis treatment may inform the design of behavioral interventions to improve osteoporosis treatment uptake in women at high risk for fracture. METHODS: We measured readiness to initiate osteoporosis treatment using a modified form of the Weinstein Precaution Adoption Process Model (PAPM) among 2684 women at high risk of fracture from the Activating Patients at Risk for OsteoPOroSis (APROPOS) clinical trial. Pre-contemplative participants were those who self-classified in the unaware and unengaged stages of PAPM (stages 1 and 2). Contemplative participants were those in the undecided, decided not to act, or decided to act stages of PAPM (stages 3, 4, and 5). Using multivariable logistic regression, we evaluated participant characteristics associated with levels of readiness to initiate osteoporosis treatment. RESULTS: Overall, 24% (N = 412) self-classified in the contemplative stage of readiness to initiate osteoporosis treatment. After adjusting for age, race, education, health literacy, and major osteoporotic fracture in the past 12 months, contemplative women were more likely to report previously being told they had osteoporosis or osteopenia (adjusted odds ratio [aOR] (95% CI) 11.8 (7.8-17.9) and 3.8 (2.5-5.6), respectively), acknowledge concern about osteoporosis (aOR 3.5 (2.5-4.9)), and disclose prior osteoporosis treatment (aOR 4.5 (3.3-6.3)) than women who self-classified as pre-contemplative. CONCLUSIONS: For women at high risk for future fractures, ensuring women's recognition of their diagnosis of osteoporosis/osteopenia and addressing their concerns about osteoporosis are critical components to consider when attempting to influence stage of behavior transitions in osteoporosis treatment.

A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk.

We performed a systematic review on the effect of drug holidays (discontinuation) on bone mineral density (BMD) and fracture risk. Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3-5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation. INTRODUCTION: We performed a systematic review and meta-analysis on the effect of drug holidays (discontinuation) on BMD and fracture risk. METHODS: We searched PubMed, Embase, and Cochrane Library databases to locate controlled clinical trials and cohort studies evaluating the effect of drug holidays/discontinuation versus osteoporosis treatment continuation. We performed random-effects meta-analyses of hazard ratios of hip and any clinical osteoporotic fracture for individuals who discontinued bisphosphonates compared to persistent users. RESULTS: Thirteen records reporting results from eight different studies met inclusion criteria. The FLEX study found a reduced clinical vertebral fracture risk with 10 years of alendronate therapy compared to 5 (RR 0.45, 95% CI 0.24-0.85), and the HORIZON extension studies found a reduced risk of morphometric vertebral fracture with 6 years of zoledronic acid therapy compared to 3 (OR = 0.51, 95% CI 0.26-0.95); subgroup analyses showed that women with low hip BMD T-scores after the initial treatment period benefitted from continued treatment in terms of reduced vertebral fracture risk. Meta-analysis of adjusted hazard ratios of hip and any clinical osteoporotic fracture for women who discontinued bisphosphonates revealed no significant differences in the risk of hip fracture (summary estimate of HR 1.09, 95% CI 0.87-1.37) or any clinical fracture (summary estimate of HR 1.13, 95% CI 0.75-1.70) compared to persistent users. CONCLUSIONS: Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3 to 5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.

Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur.

The Fracture Improvement with Teriparatide (Fix-IT) study randomized 13 women with an atypical femur fracture to immediate vs delayed teriparatide therapy; all were followed for 12 months. Results suggested a trend for superior healing and lesser bone mineral density declines in the immediate vs delayed group with no differences in adverse events. PURPOSE: Little clinical data are available on the use of teriparatide for the treatment of bisphosphonate-associated atypical femur fractures (AFF). The goal of the Fix-IT study was to determine if immediate therapy with teriparatide was superior for fracture healing after an AFF compared to a 6-month delay in teriparatide therapy. METHODS: This randomized pilot clinical trial included 13 women with an AFF who were randomized to immediate teriparatide vs a delay of 6 months. All were followed for 12 months on teriparatide. The primary outcomes included individual and composite measures of radiologic bone healing (scored 1 point [no healing] to 4 points [complete healing]) at 6 and 12 months. Secondary outcomes included bone mineral density of the unfractured contralateral hip, spine, 1/3 distal radius, and adverse events. RESULTS: We found there was a trend for superior healing with the composite score (12.6 vs 11.2 at 6 months and 15.4 vs 13.2 at 12 months), and lesser bone mineral density declines at the 1/3 distal radius (12-month change - 1.9 vs - 6.1%) in the immediate vs the delayed group. There were no differences in adverse events. There was one implant failure in the delayed group. CONCLUSIONS: There is a preliminary signal for greater improvements with immediate teriparatide therapy vs delayed therapy. However, because an AFF is a rare event, and only a small number of patients were included, the results must be interpreted with caution.

Implementing a fracture liaison service open model of care utilizing a cloud-based tool.

PURPOSE: Although half of women and one-quarter of men aged 50 and older will sustain an acute low-trauma fracture, less than a quarter receive appropriate secondary fracture prevention. The goal of this quality improvement demonstration project was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in three open health care systems aided by a cloud-based tool. METHODS: The pre-post study design examined the proportion of men and women over age 50 who received appropriate assessment (bone mineral density, vitamin D levels) and treatment (calcium/vitamin D, pharmacologic therapy) in the six months following a recently diagnosed fracture. The pre-study (Pre FLS) included a retrospective chart review for baseline data (N = 344 patients) within each health care system. In the post-evaluation (Post FLS, N = 148 patients), the FLS coordinator from each health care system examined these parameters following enrollment and for 6 months following the recently diagnosed fracture. Data were managed in the cloud-based FLS application tool. RESULTS: Ninety-three participants completed the program. The FLS program increased the percentage of patients receiving bone mineral density testing from 21% at baseline to 93% (p < 0.001) Post FLS implementation. Assessments of vitamin D levels increased from 25 to 84% (p < 0.001). Patients prescribed calcium/vitamin D increased from 36% at baseline to 93% (p < 0.001) and those prescribed pharmacologic treatment for osteoporosis increased on average from 20 to 54% (p < 0.001) Post FLS. CONCLUSIONS: We conclude that the FLS model of care in an open health care system, assisted by a cloud-based tool, significantly improved assessment and/or treatment of patients with a recently diagnosed osteoporotic fracture. Future studies are necessary to determine if this model of care is scalable and if such programs result in prevention of fractures. Mini-Abstract: The goal was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in open health care systems aided by a cloud-based tool. This model significantly improved assessment and/or treatment of patients with a recently diagnosed fracture.

Vitamin D deficiency is associated with functional decline and falls in frail elderly women despite supplementation.

We examined the impact of daily supplementation on vitamin D deficiency, function, and falls in female long-term care residents. Initial vitamin D deficiency was associated with greater functional decline and increased fall risk despite guideline-recommended supplementation, highlighting the importance of preventing vitamin D deficiency in frail elderly. INTRODUCTION: Institute of Medicine (IOM) guidelines recommend 800 IU vitamin D daily for older adults and maintaining serum 25-hydroxyvitamin D [25(OH) D] above 20 ng/ml for optimal skeletal health. The adequacy of IOM guidelines for sustaining function and reducing falls in frail elderly is unknown. METHODS: Female long-term care residents aged ≥65 enrolled in an osteoporosis clinical trial were included in this analysis (n = 137). Participants were classified based on baseline 25(OH) D levels as deficient (<20 ng/ml, n = 26), insufficient (20-30 ng/ml, n = 40), or sufficient (>30 ng/ml, n = 71). Deficient women were provided initial vitamin D repletion (50,000 IU D3 weekly for 8 weeks). All were supplemented with 800 IU vitamin D3 daily for 24 months. Annual functional assessments included Activities of Daily Living (ADLs), Instrumental ADL (IADL), physical performance test (PPT), gait speed, cognition (SPMSQ), and mental health (PHQ-9). We used linear mixed models for analysis of functional measures and logistic regression for falls. RESULTS: Daily supplementation maintained 25(OH) D levels above 20 ng/ml in 95% of participants. All groups demonstrated functional decline. Women initially deficient had a greater decline in physical function at 12 (IADL -2.0 ± 0.4, PPT -3.1 ± 0.7, both p < 0.01) and 24 months (IADL -2.5 ± 0.6, ADL -2.5 ± 0.6, both p < 0.01), a larger increase in cognitive deficits at 12 months (1.7 ± 0.4: p = 0.01) and more fallers (88.5%, p = 0.04) compared to those sufficient at baseline, despite supplementation to sufficient levels. CONCLUSIONS: IOM guidelines may not be adequate for frail elderly. Further study of optimal 25(OH) D levels for maintaining function and preventing falls is needed.

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.

Systematic review and meta-analysis of the performance of clinical risk assessment instruments for screening for osteoporosis or low bone density.

UNLABELLED: We performed a systematic review and meta-analysis of the performance of clinical risk assessment instruments for screening for DXA-determined osteoporosis or low bone density. Commonly evaluated risk instruments showed high sensitivity approaching or exceeding 90% at particular thresholds within various populations but low specificity at thresholds required for high sensitivity. Simpler instruments, such as OST, generally performed as well as or better than more complex instruments. INTRODUCTION: The purpose of the study is to systematically review the performance of clinical risk assessment instruments for screening for dual-energy X-ray absorptiometry (DXA)-determined osteoporosis or low bone density. METHODS: Systematic review and meta-analysis were performed. Multiple literature sources were searched, and data extracted and analyzed from included references. RESULTS: One hundred eight references met inclusion criteria. Studies assessed many instruments in 34 countries, most commonly the Osteoporosis Self-Assessment Tool (OST), the Simple Calculated Osteoporosis Risk Estimation (SCORE) instrument, the Osteoporosis Self-Assessment Tool for Asians (OSTA), the Osteoporosis Risk Assessment Instrument (ORAI), and body weight criteria. Meta-analyses of studies evaluating OST using a cutoff threshold of <1 to identify US postmenopausal women with osteoporosis at the femoral neck provided summary sensitivity and specificity estimates of 89% (95%CI 82-96%) and 41% (95%CI 23-59%), respectively. Meta-analyses of studies evaluating OST using a cutoff threshold of 3 to identify US men with osteoporosis at the femoral neck, total hip, or lumbar spine provided summary sensitivity and specificity estimates of 88% (95%CI 79-97%) and 55% (95%CI 42-68%), respectively. Frequently evaluated instruments each had thresholds and populations for which sensitivity for osteoporosis or low bone mass detection approached or exceeded 90% but always with a trade-off of relatively low specificity. CONCLUSIONS: Commonly evaluated clinical risk assessment instruments each showed high sensitivity approaching or exceeding 90% for identifying individuals with DXA-determined osteoporosis or low BMD at certain thresholds in different populations but low specificity at thresholds required for high sensitivity. Simpler instruments, such as OST, generally performed as well as or better than more complex instruments.

Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial.

UNLABELLED: In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months. INTRODUCTION: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD). METHODS: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety. RESULTS: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 µg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p < 0.05). The oral therapy was safe and well tolerated. CONCLUSION: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health.

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Performance of risk assessment instruments for predicting osteoporotic fracture risk: a systematic review.

UNLABELLED: We systematically reviewed the literature on the performance of osteoporosis absolute fracture risk assessment instruments. Relatively few studies have evaluated the calibration of instruments in populations separate from their development cohorts, and findings are mixed. Many studies had methodological limitations making susceptibility to bias a concern. INTRODUCTION: The aim of this study was to systematically review the literature on the performance of osteoporosis clinical fracture risk assessment instruments for predicting absolute fracture risk, or calibration, in populations other than their derivation cohorts. METHODS: We performed a systematic review, and MEDLINE, Embase, Cochrane Library, and multiple other literature sources were searched. Inclusion and exclusion criteria were applied and data extracted, including information about study participants, study design, potential sources of bias, and predicted and observed fracture probabilities. RESULTS: A total of 19,949 unique records were identified for review. Fourteen studies met inclusion criteria. There was substantial heterogeneity among included studies. Six studies assessed the WHO's Fracture Risk Assessment (FRAX) instrument in five separate cohorts, and a variety of risk assessment instruments were evaluated in the remainder of the studies. Approximately half found good instrument calibration, with observed fracture probabilities being close to predicted probabilities for different risk categories. Studies that assessed the calibration of FRAX found mixed performance in different populations. A similar proportion of studies that evaluated simple risk assessment instruments (≤5 variables) found good calibration when compared with studies that assessed complex instruments (>5 variables). Many studies had methodological features making them susceptible to bias. CONCLUSIONS: Few studies have evaluated the performance or calibration of osteoporosis fracture risk assessment instruments in populations separate from their development cohorts. Findings are mixed, and many studies had methodological limitations making susceptibility to bias a possibility, raising concerns about use of these tools outside of the original derivation cohorts. Further studies are needed to assess the calibration of instruments in different populations prior to widespread use.

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.