A Comparison of Bone-Targeted Exercise Strategies to Reduce Fracture Risk in Middle-Aged and Older Men with Osteopenia and Osteoporosis: LIFTMOR-M Semi-Randomized Controlled Trial

The Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men (LIFTMOR-M) trial examined efficacy and safety of two novel exercise programs in older men with low BMD. Men with low hip and/or LS BMD were randomized to high-intensity progressive resistance and impact training (HiRIT) or machine-based isometric axial compression (IAC) and compared to a nonrandomized matched control (CON). Outcomes included: hip and LS BMD; calcaneal ultrasound parameters; anthropometry; body composition; function (timed up-and-go [TUG], five-times sit-to-stand [FTSTS]); back extensor strength (BES); leg extensor strength (LES); compliance and adverse events. Ninety-three men (67.1 ± 7.5 years; 82.1 ± 11.6 kg; 175.2 ± 6.7 cm; FN T-score −1.6 ± 0.6) were randomized to HiRIT (n = 34) or IAC (n = 33), or allocated to CON (n = 26). HiRIT improved trochanteric BMD (2.8 ± 0.8%; −0.1 ± 0.9%, p = .024), LS BMD (4.1 ± 0.7%; 0.9 ± 0.8%, p = .003), BUA (2.2 ± 0.7%; −0.8 ± 0.9%, p = .009), stiffness index (1.6 ± 0.9%; −2.0 ± 1.1%, p = .011), lean mass (1.5 ± 0.8%; −2.4 ± 0.9%, p = .002), TUG, FTSTS, BES, and LES (p < .05) compared with CON. IAC improved lean mass (0.8 ± 0.8%; −2.4 ± 0.9%, p = .013) and FTSTS (−4.5 ± 1.6%; 7.5 ± 2.0%, p < .001) compared with CON. HiRIT improved LS BMD (4.1 ± 0.7%; 2.0 ± 0.7%, p = .039), stiffness index (1.6 ± 0.9%; −1.3 ± 0.9%, p = .025), and FTSTS (−10.7 ± 1.6%; −4.5 ± 1.7%, p = .010) compared with IAC. Exercise compliance was high (HiRIT 77.8 ± 16.6%; IAC 78.5 ± 14.8%, p = .872). There were five minor adverse events (HiRIT, 2; IAC, 3). HiRIT was well-tolerated and improved bone, function and fracture risk more than CON or IAC. © 2020 American Society for Bone and Mineral Research.     

High-Impact Exercise Increased Femoral Neck Bone Density With No Adverse Effects on Imaging Markers of Knee Osteoarthritis in Postmenopausal Women

High-impact exercise can improve femoral neck bone mass but findings in postmenopausal women have been inconsistent and there may be concern at the effects of high-impact exercise on joint health. We investigated the effects of a high-impact exercise intervention on bone mineral density (BMD), bone mineral content (BMC), and section modulus (Z) as well as imaging biomarkers of osteoarthritis (OA) in healthy postmenopausal women. Forty-two women aged 55 to 70 years who were at least 12 months postmenopausal were recruited. The 6-month intervention consisted of progressive, unilateral, high-impact exercise incorporating multidirectional hops on one randomly assigned exercise leg (EL) for comparison with the contralateral control leg (CL). Dual-energy X-ray absorptiometry (DXA) was used to measure BMD, BMC, and Z of the femoral neck. Magnetic resonance imaging (MRI) of the knee joint was used to analyze the biochemical composition of articular cartilage using T2 relaxometry and to analyze joint pathology associated with OA using semiquantitative analysis. Thirty-five participants (61.7 ± 4.3 years) completed the intervention with a mean adherence of 76.8% ± 22.5%. Femoral neck BMD, BMC, and Z all increased in the EL (+0.81%, +0.69%, and +3.18%, respectively) compared to decreases in the CL (−0.57%, −0.71%, and −0.75%: all interaction effects p < 0.05). There was a significant increase in mean T2 relaxation times (main effect of time p = 0.011) but this did not differ between the EL and CL, indicating no global effect. Semiquantitative analysis showed high prevalence of bone marrow lesions (BML) and cartilage defects, especially in the patellofemoral joint (PFJ), with no indication that the intervention caused pathology progression. In conclusion, a high-impact exercise intervention that requires little time, cost, or specialist equipment improved femoral neck BMD with no negative effects on knee OA imaging biomarkers. Unilateral high-impact exercise is a feasible intervention to reduce hip fracture risk in healthy postmenopausal women. © 2019 American Society for Bone and Mineral Research.     

Potential Usefulness of BMD and Bone Turnover Monitoring of Zoledronic Acid Therapy Among Women With Osteoporosis: Secondary Analysis of Randomized Controlled Trial Data

We aimed to compare the clinical validity and the detectability of response of short‐term changes in bone mineral density (BMD; hip and spine) and bone turnover markers (serum PINP and CTX) through secondary analysis of trial data. We analyzed data on 7765 women with osteoporosis randomized to 5‐mg once‐yearly infusions of zoledronic acid or placebo in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON‐PFT; trial ran from 2002 to 2006) and the first extension trial (trial ran from 2006 to 2009). We assessed the clinical validity and detectability of response for 1‐year measurements of the following monitoring tests: total hip and lumbar spine BMD, serum N‐terminal propeptide of type I collagen (sPINP), and serum C‐telopeptide of type I collagen (sCTX; 6‐month measurement used). Clinical validity was assessed by examining prediction of clinical fracture in Cox models; detectability of response to treatment was assessed by the ratio of signal to noise, estimated from the distributions of change in zoledronic acid and placebo groups. Baseline measurements were available for 7683 women with hip BMD, 558 with spine BMD, 1246 with sPINP, and 517 women with sCTX. Hip BMD and sPINP ranked highly for prediction of clinical fracture, whereas sPINP and sCTX ranked highly for detectability of response to treatment. Serum PINP had the highest overall ranking. In conclusion, serum PINP is potentially useful in monitoring response to zoledronic acid. Further research is needed to evaluate the effects of monitoring PINP on treatment decisions and other clinically relevant outcomes. © 2016 American Society for Bone and Mineral Research.     

Longitudinal Associations of High-Volume and Vigorous-Intensity Exercise With Hip Fracture Risk in Men

Maintenance of vigorous exercise habits from young to old age is considered protective against hip fractures, but data on fracture risk in lifelong vigorous exercisers are lacking. This longitudinal cohort study examined the hazard of hip fractures in 1844 male former athletes and 1216 population controls and in relation to exercise volume and intensity in later years. Incident hip fractures after age 50 years were identified from hospital discharge register from 1972 to 2015. Exercise and covariate information was obtained from questionnaires administered in 1985, 1995, 2001, and 2008. Analyses were conducted using extended proportional hazards regression model for time-dependent exposures and effects. During the mean ± SD follow-up of 21.6 ± 10.3 years, 62 (3.4%) athletes and 38 (3.1%) controls sustained a hip fracture. Adjusted hazard ratio (HR) indicated no statistically significant difference between athletes and controls (0.84; 95% confidence interval [CI], 0.55–1.29). In subgroup analyses, adjusted HRs for athletes with recent high (≥15 metabolic equivalent hours [MET-h]/week) and low (<15 MET-h/week) exercise volume were 0.83 (95% CI, 0.46–1.48) and 1.04 (95% CI, 0.57–1.87), respectively, compared with controls. The adjusted HR was not statistically significant between athletes with low-intensity exercise (<6 METs) and controls (1.08; 95% CI, 0.62–1.85). Athletes engaging in vigorous-intensity exercise (≥6 METs at least 75 minutes/week) had initially 77% lower hazard rate (adjusted HR 0.23; 95% CI, 0.06–0.86) than controls. However, the HR was time-dependent (adjusted HR 1.04; 95% CI, 1.01–1.07); by age 75 years the HRs for the athletes with vigorous-intensity exercise reached the level of the controls, but after 85 years the HRs for these athletes increased approximately 1.3-fold annually relative to the controls. In conclusion, these data suggest that continuation of vigorous-intensity exercise is associated with lower HR of hip fracture up to old age. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

The Associations Between Seven Different Types of Physical Activity and the Incidence of Fracture at Seven Sites in Healthy Postmenopausal UK Women

There is a paucity of information on associations between specific types of physical activity and fracture risk at different sites in otherwise healthy postmenopausal women. Therefore, we examined risk of fracture at seven different sites associated with seven different types of physical activity in the population-based prospective UK Million Women Study. A total of 371,279 postmenopausal women (mean age 59.8 years), rating their health as good or excellent and reporting participation in walking, cycling, gardening, doing housework, yoga, dance, and sports club activities, were followed for site-specific incident fracture through record linkage to national databases on day-case and overnight hospital admissions. Cox regression yielded adjusted relative risks (RRs) and, because of the large number of statistical tests done, 99% confidence intervals (CIs) for fracture at seven different sites in relation to seven different physical activities. During an average follow-up of 12 years, numbers with a first site-specific fracture were as follows: humerus (2341), forearm (1238), wrist (7358), hip (4354), femur (not neck) (617), lower leg (1184), and ankle (3629). For upper limb fractures there was significant heterogeneity across the seven activity types (test for heterogeneity p = 0.004), with gardening more than 1 hour/week associated with a lower risk (RR = 0.91; 99% CI, 0.86 to 0.96; p < 0.0001), whereas cycling more than 1 hour/week was associated with an increased risk (RR = 1.11; 99% CI, 1.00 to 1.23; p = 0.008). For fractures of the lower limb (including hip) there was no significant heterogeneity by type of activity, with significant approximately 5% to 15% reductions in risk associated with most activities, except cycling. For hip fractures, there was no significant heterogeneity by type of activity, but with significant 15% to 20% reductions in risk associated with walking for 1 hour/day and participating in yoga and sporting activities. Physical activity is a modifiable risk factor for fracture, but the effects differ between different types of activities and different fracture sites. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

The Vitamin D Metabolite Ratio Is Associated With Changes in Bone Density and Fracture Risk in Older Adults

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH)₂D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D–binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR) <60 mL/mL/1.73m². In fully adjusted models, a 50% lower VMR was associated with 0.3% (0.2%, 0.6%) more rapid decline in total hip bone mineral density (BMD). We found similar relationships with thoracic and lumbar spine BMD. In contrast, 25(OH)D₃ concentrations were not associated with longitudinal change in BMD. There were 178 fractures during a mean follow-up of 10 years. Each 50% lower VMR was associated with a 49% (95% confidence interval [CI] 1.06, 2.08) greater fracture risk, whereas lower 25(OH)D₃ concentrations were not significantly associated with fracture risk (hazard ratio [HR] per 50% lower 1.07 [0.80, 1.43]). In conclusion, among a diverse cohort of community-dwelling older adults, a lower VMR was more strongly associated with both loss of BMD and fracture risk compared with 25(OH)D₃. Trials are needed to evaluate the VMR as a therapeutic target in persons at risk for worsening BMD and fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Leisure‐Time Physical Activity and Risk of Fracture: A Cohort Study of 66,940 Men and Women

Physical activity has been associated with reduced risk of fracture, but it is not known how the intensity or frequency of physical activity influences this risk reduction. We aim to compare the risk of hip fracture and fracture of any locale between men and women with different levels of leisure‐time walking/bicycling and exercise. A total of 37,238 women (born 1914–1948) from the Swedish Mammography Cohort and 45,906 men (born 1918–1952) from the Cohort of Swedish Men were followed for a maximum of 17 years. Exposure and covariate information was collected through a self‐administered questionnaire in 1997. Incident fractures (5153 individuals with hip fracture and 15,043 with any type of fracture) and comorbidities were gathered from national and local patient registries. Hazard ratios (HRs) were calculated using Cox proportional hazards regression. Individuals who walked/bicycled less than 20 minutes per day had a lower rate of hip fracture (multivariable adjusted HR = 0.77; 95% confidence interval [CI] 0.70 to 0.85) and any fracture (HR = 0.87; 95% CI 0.82 to 0.92) compared with those who hardly ever walked/bicycled. These reduced rates were also evident in both sexes, in different age categories, for vertebral fractures and for non‐hip, non‐vertebral fractures. Those who reported exercise 1 hour per week had a lower rate of hip fracture (HR = 0.87; 95% CI 0.80 to 0.96) and any fracture (HR = 0.94; 95% CI 0.89 to 0.99) compared with those who exercised less than 1 hour per week. Only minor differences in HRs were observed in individuals with moderate compared with higher levels of walking/bicycling or exercise. Walking/bicycling and exercise showed almost equal reductions in rate of fracture when compared with those in a joint category with lowest activity. In conclusion, both moderate and high self‐reported frequency of physical activity is associated with reduced future risk of fracture. © 2017 American Society for Bone and Mineral Research.     

The Effects of Age,Adiposity, and Physical Activity on the Risk of Seven Site‐Specific Fractures in Postmenopausal Women

Risk factors for fracture of the neck of the femur are relatively well established, but those for fracture at other sites are little studied. In this large population study we explore the role of age, body mass index (BMI), and physical activity on the risk of fracture at seven sites in postmenopausal women. As part of the Million Women Study, 1,154,821 postmenopausal UK women with a mean age of 56.0 (SD 4.8) years provided health and lifestyle data at recruitment in 1996 to 2001. All participants were linked to National Health Service (NHS) hospital records for day‐case or overnight admissions with a mean follow‐up of 11 years per woman. Adjusted absolute and relative risks for seven site‐specific incident fractures were calculated using Cox regression models. During follow‐up, 4931 women had a fracture of the humerus; 2926 of the forearm; 15,883 of the wrist; 9887 of the neck of the femur; 1166 of the femur (not neck); 3199 a lower leg fracture; and 10,092 an ankle fracture. Age‐specific incidence rates increased gradually with age for fractures of forearm, lower leg, ankle, and femur (not neck), and steeply with age for fractures of neck of femur, wrist, and humerus. When compared to women with desirable BMI (20.0 to 24.9 kg/m²), higher BMI was associated with a reduced risk of fracture of the neck of femur, forearm, and wrist, but an increased risk of humerus, femur (not neck), lower leg, and ankle fractures (p < 0.001 for all). Strenuous activity was significantly associated with a decreased risk of fracture of the humerus and femur (both neck and remainder of femur) (p < 0.001), but was not significantly associated with lower leg, ankle, wrist, and forearm fractures. Postmenopausal women are at a high lifetime risk of fracture. BMI and physical activity are modifiable risk factors for fracture, but their associations with fracture risk differ substantially across fracture sites. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

Physical Activity and Psychosocial Factors Associated With Risk of Future Fractures in Middle-Aged Men and Women

Identification of risk factors for fractures is important for improving public health. We aimed to identify which factors related to physical activity and psychosocial situation were associated with incident fractures among 30,446 middle-aged women and men, followed from 1991–1996 to 2016, in a prospective population-based cohort study. The association between the baseline variables and first incident fracture was assessed by Cox regression models, and significant risk factors were summed into fracture risk scores. Any first incident fracture affecting spine, thoracic cage, arms, shoulders, hands, pelvis, hips, or legs was obtained from the National Patient Register, using the unique personal identity number of each citizen. A total of 8240 subjects (27%) had at least one fracture during the follow-up of median 20.7 years. Age, female sex, body mass index, previous fracture, reported family history of fracture >50 years (all p < .001), low leisure-time physical activity (p = .018), heavy work (p = .024), living alone (p = .002), smoking (p < .001), and no or high alcohol consumption (p = .005) were factors independently associated with incident fracture. The fracture risk score (0–9 points) was strongly associated with incident fracture (p for trend <.001). Among men without risk factors, the incidence rate was 5.3/1000 person-years compared with 23.2 in men with six or more risk factors (hazard ratio [HR] = 5.5; 95% confidence interval [CI] 3.7–8.2). Among women with no risk factors, the incidence rate was 10.7 compared with 28.4 in women with six or more risk factors (HR = 3.1; 95% CI 2.4–4.0). Even moderate levels of leisure-time physical activity in middle age are associated with lower risk of future fractures. In contrast, heavy work, living alone, smoking, and no or high alcohol consumption increase the risk of fracture. Our results emphasize the importance of these factors in public health initiatives for fracture prevention. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Change in Trabecular Bone Score (TBS) With Antiresorptive Therapy Does Not Predict Fracture in Women: The Manitoba BMD Cohort

Bone mineral density (BMD) and trabecular bone score (TBS), along with additional clinical risk factors, can be used to identify individuals at high fracture risk. Whether change in TBS in untreated or treated women independently affects fracture risk is unclear. Using the Manitoba (Canada) DXA Registry containing all BMD results for the population we identified 9044 women age ≥40 years with two consecutive DXA scans and who were not receiving osteoporosis treatment at baseline (baseline mean age 62 ± 10 years). We examined BMD and TBS change, osteoporosis treatment, and incident major osteoporotic fractures (MOFs) for each individual. Over a mean of 7.7 years follow‐up, 770 women developed an incident MOF. During the interval between the two DXA scans (mean, 4.1 years), 5083 women initiated osteoporosis treatment (bisphosphonate use 80%) whereas 3961 women did not receive any osteoporosis treatment. Larger gains in both BMD and TBS were seen in women with greater adherence to osteoporosis medication (p for trend <0.001), and the magnitude of the increase was consistently greater for BMD than for TBS. Among treated women there was greater antifracture effect for each SD increase in total hip BMD change (fracture decrease 20%; 95% CI, 13% to 26%; p < 0.001), femoral neck BMD change (19%; 95% CI, 12% to 26%; p < 0.001), and lumbar spine BMD change (9%; 95% CI, 0% to 17%; p = 0.049). In contrast, change in TBS did not predict fractures in women who initiated osteoporosis treatment (p = 0.10). Among untreated women neither change in BMD or TBS predicted fractures. We conclude that, unlike antiresorptive treatment–related changes in BMD, change in lumbar spine TBS is not a useful indicator of fracture risk irrespective of osteoporosis treatment. © 2016 American Society for Bone and Mineral Research.     

Total Hip Bone Mineral Density as an Indicator of Fracture Risk in Bisphosphonate-Treated Patients in a Real-World Setting

Bone mineral density (BMD) is an established measure used to diagnose patients with osteoporosis. In clinical trials, change in BMD has been shown to provide a reliable estimate of fracture risk reduction, and achieved BMD T-score has been shown to reflect the near-term risk of fracture. We aimed to test the association between BMD T-score and fracture risk in patients treated for osteoporosis in a real-world setting. This retrospective, observational cohort study included Swedish females aged ≥55 years who had a total hip BMD measurement at one of three participating clinics. Patients were separated into two cohorts: bisphosphonate-treated and bisphosphonate-naïve prior to BMD measurement, stratified by age and prior nonvertebral fracture status. The primary outcome was cumulative incidence of clinical fractures within 24 months of BMD measurement, with other fracture types included as secondary outcomes. Associations between T-score and fracture risk were estimated using proportional hazards regression and restricted cubic splines. A total of 15,395 patients were analyzed: 11,973 bisphosphonate-naïve and 3422 bisphosphonate-treated. In the 24 months following BMD measurement, 6.3% (95% confidence interval [CI], 5.9–6.7) of bisphosphonate-naïve and 8.4% (95% CI, 7.5–9.4) of bisphosphonate-treated patients experienced a clinical fracture. Strong inverse relationships between BMD T-score and fracture incidence were observed in both cohorts. Among bisphosphonate-naïve patients, this relationship appeared to plateau around T-score −1.5, indicating smaller marginal reductions in fracture risk above this value; bisphosphonate-treated patients showed a more consistent marginal change in fracture risk across the evaluated T-scores (−3.0 to –0.5). Trends remained robust regardless of age and prior fracture status. This real-world demonstration of a BMD–fracture risk association in both bisphosphonate-naïve and bisphosphonate-treated patients extends evidence from clinical trials and recent meta-regressions supporting the suitability of total hip BMD as a meaningful outcome for the clinical management of patients with osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON‐Pivotal Fracture Trial (PFT)

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly?Pivotal Fracture Trial (HORIZON?PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer‐term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double‐blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was ?0.54% in Z9 vs. ?1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: ?0.37%, 1.93%; p = 0.183). BTMs showed small, non‐significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non‐serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research.     

The Cost‐Effectiveness of Screening in the Community to Reduce Osteoporotic Fractures in Older Women in the UK: Economic Evaluation of the SCOOP Study

The SCOOP study was a two‐arm randomized controlled trial conducted in the UK in 12,483 eligible women aged 70 to 85 years. It compared a screening program using the FRAX® risk assessment tool in addition to bone mineral density (BMD) measures versus usual management. The SCOOP study found a reduction in the incidence of hip fractures in the screening arm, but there was no evidence of a reduction in the incidence of all osteoporosis‐related fractures. To make decisions about whether to implement any screening program, we should also consider whether the program is likely to be a good use of health care resources, ie, is it cost‐effective? The cost per gained quality adjusted life year of screening for fracture risk has not previously been demonstrated in an economic evaluation alongside a clinical trial. We conducted a “within trial” economic analysis alongside the SCOOP study from the perspective of a national health payer, the UK National Health Service (NHS). The main outcome measure in the economic analysis was the cost per quality adjusted life year (QALY) gained over a 5‐year time period. We also estimated cost per osteoporosis‐related fracture prevented and the cost per hip fracture prevented. The screening arm had an average incremental QALY gain of 0.0237 (95% confidence interval –0.0034 to 0.0508) for the 5‐year follow‐up. The incremental cost per QALY gained was £2772 compared with the control arm. Cost‐effectiveness acceptability curves indicated a 93% probability of the intervention being cost‐effective at values of a QALY greater than £20,000. The intervention arm prevented fractures at a cost of £4478 and £7694 per fracture for osteoporosis‐related and hip fractures, respectively. The current study demonstrates that a systematic, community‐based screening program of fracture risk in older women in the UK represents a highly cost‐effective intervention. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

The Effect of Discontinuing Treatment With Blosozumab: Follow‐up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1‐year randomized, placebo‐controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow‐up; 88 women completed 1 year of follow‐up. At the beginning of follow‐up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow‐up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow‐up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C‐terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti‐drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment

Although treat-to-target strategies are being discussed in osteoporosis, there is little evidence of what the target should be to reduce fracture risk maximally. We investigated the relationship between total hip BMD T-score and the incidence of nonvertebral fracture in women who received up to 10 years of continued denosumab therapy in the FREEDOM (3 years) study and its long-term Extension (up to 7 years) study. We report the percentages of women who achieved a range of T-scores at the total hip or femoral neck over 10 years of denosumab treatment (1343 women completed 10 years of treatment). The incidence of nonvertebral fractures was lower with higher total hip T-score. This relationship plateaued at a T-score between -2.0 and -1.5 and was independent of age and prevalent vertebral fractures, similar to observations in treatment-naïve subjects. Reaching a specific T-score during denosumab treatment was dependent on the baseline T-score, with higher T-scores at baseline more likely to result in higher T-scores at each time point during the study. Our findings highlight the importance of follow-up BMD measurements in patients receiving denosumab therapy because BMD remains a robust indicator of fracture risk. These data support the notion of a specific T-score threshold as a practical target for therapy in osteoporosis. © 2019 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

Addressing the Crisis in the Treatment of Osteoporosis: A Path Forward

Considerable data and media attention have highlighted a potential “crisis” in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this “gap” in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short‐, intermediate‐, and long‐term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual‐energy X‐ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high‐risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. © 2016 American Society for Bone and Mineral Research.