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Summary: To determine persistence with subcutaneous denosumab every 6 months in women being treated for osteoporosis, we conducted a single-arm prospective, observational study in the United States and Canada. Among 935 patients enrolled, 12-month persistence was 82 %, with 66 patients (7 %) reporting serious adverse events and 19 patients (2 %) reporting fractures. Introduction: Increased persistence with osteoporosis therapy is associated with reduced fracture risk. Denosumab reduced fracture risk in clinical trials; persistence in community settings is undetermined. This study evaluates persistence with denosumab in community practice in the United States (US) and Canada. Methods: In a 24-month multicenter, prospective, single-arm, observational study, women being treated for osteoporosis were enrolled ≤4 weeks after the first subcutaneous injection of denosumab. For this 12-month prespecified interim analysis, endpoints include persistence (one injection at study entry and another within 6 months + 8 weeks), attributes associated with persistence (univariate analysis), and serious adverse events (SAEs). Results: Among 935 patients (mean age 71 years), mean baseline T-scores were −2.18 (femoral neck) and −2.00 (lumbar spine); 50 % of patients had experienced osteoporotic fracture(s). At 12 months, 82 % of patients were persistent with denosumab. Baseline factors significantly ( p < 0.05) associated with higher persistence included use of osteoporosis medications >5 years previously, lumbar spine T-score > −2.5, and treatment by female physicians (US). Lower persistence was associated ( p < 0.05) with psychiatric diagnoses including depression, southern US residence, being divorced, separated, or widowed (US), and prior hip fracture (Canada). SAEs were reported in 66 patients (7 %); no SAEs of osteonecrosis of the jaw, atypical femoral fracture, fracture healing complications, hypocalcemia, eczema, or hypersensitivity were reported. Nineteen patients (2 %) reported osteoporotic fractures. Conclusions: The 12-month persistence observed in this single-arm open-label study of US and Canadian community practice extends the evidence regarding denosumab's potential role in reducing fracture risk in postmenopausal women with osteoporosis. [ABSTRACT FROM AUTHOR]

Summary: Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. Introduction: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). Methods: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months ( N = 852) or oral BP 150 mg monthly ( N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. Results: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine ( p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) ( p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 ( p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. Conclusions: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment. [ABSTRACT FROM AUTHOR]

Summary: The Safe Functional Motion test (SFM) was developed to document movement strategies used to perform everyday activities that may increase the risk for osteoporotic fracture. After adjusting for variables known to predict vertebral compression fracture (VCF), baseline score on the SFM was a significant independent predictor of incident VCF at 1- and 3-year follow-ups. Introduction: Functional movements may contribute to risk for VCF. We hypothesize that scores on the SFM, a performance-based test of physical function, are associated with incident VCF. Methods: An osteoporosis clinic database was queried for men and women ≥50 years with an initial SFM and corresponding data for prevalent VCF, history of injurious falls, femoral neck bone mineral density (fnBMD), osteoporosis medication use, and incident morphometric VCF at 1-year ( n = 878) and 3-year follow-ups ( n = 503). Multiple logistic regressions, adjusted for gender, age, injurious fall(s), fnBMD, prevalent VCF at baseline, and osteoporosis medication use, were used to determine whether SFM score was associated with incident VCF at follow-up visits. Results: Baseline SFM score was a significant independent predictor of incident VCF at 1-year follow-up (adjusted odds ratio (95 % confidence intervals (CI)) = 0.818 (0.707, 0.948); p < 0.008) and 3-year follow-up (adjusted odds ratio (95 % CI) = 0.728 (0.628, 0.844); p < 0.0001). Baseline fnBMD and osteoporosis medication use were significant predictors at 1-year ( p = 0.05 and < 0.0001, respectively) and 3-year ( p < 0.01 and 0.001, respectively) follow-ups. At 3-year follow-up, gender and prevalent VCF were also significant predictors ( p = 0.003 and 0.007, respectively). Conclusions: For every 10-point increase in SFM score, the odds of future VCF decreases by 18 % at 1 year and 27 % at 3 years after adjusting for known covariates. The SFM may aid in the identification of modifiable functional risk factors for VCF. [ABSTRACT FROM AUTHOR]

Summary: The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. Introduction: This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. Methods: In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 μg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. Results: At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine ( p = 0.001) and femoral neck ( p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe ( p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. Conclusions: Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate. [ABSTRACT FROM AUTHOR]

Summary: Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Introduction: Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. Methods: In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia ( n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol ( n = 135), ibuprofen ( n = 137) or placebo ( n = 137), or placebo + placebo ( n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. Results: The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. Conclusion: Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg. [ABSTRACT FROM AUTHOR]

Summary: This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. Introduction: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). Methods: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg ( n = 1,065) or placebo ( n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. Results: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. −1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. −1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs . −0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). Conclusion: ZOL significantly improves HRQoL in patients with low-trauma hip fracture. [ABSTRACT FROM AUTHOR]

Summary: Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. Introduction: Intravenous zoledronic acid 5 mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing. Methods: In the HORIZON Recurrent Fracture Trial, patients were randomized within 90 days of a low-trauma hip fracture to receive either once-yearly ZOL ( n = 1,065) or placebo ( n = 1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6 months and 12 months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9 years. Results: The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72-1.90; p = 0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74-1.99; p = 0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2 weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49-4.39; p < 0.001). Conclusions: ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. [ABSTRACT FROM AUTHOR]

The effect of teriparatide (20 μg/day) on serum calcium was examined in postmenopausal women previously treated with alendronate or raloxifene. Women previously treated with alendronate or raloxifene who added teriparatide or switched to teriparatide did not have clinically meaningful increases in mean predose serum calcium. The effects of a 6-month treatment with teriparatide (20 μg/day; rhPTH(1–34), TPTD) on serum calcium (Ca) was examined in a prospective study of postmenopausal women previously treated with alendronate (70 mg/week or 10 mg/day [ALN] or raloxifene 60 mg/d [RLX]) for ≥18 months. Women continued their usual ALN or RLX during a 2-month antiresorptive phase. Women previously treated with ALN were randomized to add TPTD ( n = 52) or switch to TPTD ( n = 50) and women previously treated with RLX were randomized to add TPTD ( n = 47) or switch to TPTD ( n = 49). All were to take at least 500 mg/day of elemental Ca and 400–800 IU/day of vitamin D. Predose mean serum Ca did not significantly change in groups adding TPTD to either RLX or ALN treatment. In patients who switched from RLX or ALN to TPTD, mean serum Ca increased by 0.05 mmol/L and 0.04 mmol/L respectively. Only 1 patient had the predefined calcium endpoint of serum calcium > 2.76 mmol/L (11 mg/dL) at more than one visit. Women previously treated with ALN or RLX who added TPTD or switched to TPTD did not have clinically meaningful increases in mean predose serum Ca. [ABSTRACT FROM AUTHOR]

Summary: In clinical practice, the frequency of patients achieving improved T-scores and the expected change in bone mineral density (BMD) according to osteoporosis drugs is unknown. We found that osteoporosis medications infrequently achieve improved femoral neck T-scores over 1.2 years. BMD increases were more often seen with IV bisphosphonates and denosumab.Purpose: To determine the frequency of osteoporosis patients achieving improvement in T-scores and quantify the change in bone mineral density (BMD) over time according to osteoporosis medication use.Methods: The study included all patients receiving clinical care at United Osteoporosis Centers, Gainesville, GA, 1995-2015, who had at least two measures of femoral neck BMD (N = 1232). We evaluated successive pairs of BMD tests to describe the distribution of transitions between T-score categories. Generalized estimating equations were used to estimate %BMD change between successive pairs of BMD tests according to osteoporosis medication, adjusted for age, sex, height, weight, baseline BMD, previous fracture, and follow-up time.Results: Mean (±SD) age was 68 (±10) years, and 90% of patients were women. Mean baseline T-score was − 2.04 (± 0.85). In total, 1232 patients had 4918 pairs of successive BMD tests, with a mean 1.2 years (± 0.9) between assessments. Frequency of transition to an improved T-score category was 41% when prior T-score ≤ − 3.5, and 15% when prior T-score − 1.99 to − 1.50. Most individuals (69%) remained in the same T-score category. BMD increased 0.54% (95% CI 0.23-0.85%) with IV bisphosphonates and 1.23% (95% CI 0.56-1.90%) with denosumab, whereas no significant change was seen with oral bisphosphonates, teriparatide, or raloxifene.Conclusions: Osteoporosis patients are unlikely to improve femoral neck T-scores over 1.2 years. Additional studies are needed to determine the optimal time to repeat BMD testing while receiving osteoporosis treatment and to determine whether fracture risk is reduced in patients who achieve target T-scores. [ABSTRACT FROM AUTHOR]

Summary: Persistence with prescribed medications for chronic diseases is important; however, persistence with osteoporosis treatments is historically poor. In this prospective cohort study of postmenopausal women treated for osteoporosis in real-world clinical practice settings in the USA and Canada, 24-month persistence with denosumab was 58%.Purpose: Patients who persist with their prescribed osteoporosis treatment have increased bone mineral density (BMD) and reduced risk of fracture. Twelve-month persistence with denosumab in routine clinical practice is as high as 95%, but there are limited data on longer-term persistence with denosumab in this setting.Methods: This single-arm, prospective, cohort study evaluated 24-month persistence with denosumab administered every 6 months in postmenopausal women receiving treatment for osteoporosis in real-world clinical practice in the USA and Canada. Endpoints and analyses included the percentage of patients who persist with denosumab at 24 months (greater than or equal to four injections with a gap between injections of no more than 6 months plus 8 weeks), the total number of injections received by each patient, changes in BMD in persistent patients, and the incidence of serious adverse events (SAEs) and fractures.Results: Among 935 enrolled patients, 24-month persistence was 58% (50% in US patients and 75% in Canadian patients). A majority of patients received at least four injections over the observation period (62% of US patients and 81% of Canadian patients). Among patients who were persistent at 24 months and who had a baseline, 12-month, and 24-month DXA scan, mean BMD increased from baseline to 24 months by 7.8% at the lumbar spine and 2.1% at the femoral neck. SAEs and fractures were reported for 122 (13.0%) patients and 54 (5.8%) patients, respectively.Conclusions: Persistence with denosumab for 24 months yields improvement in BMD among postmenopausal women with osteoporosis treated in routine clinical practice in the USA and Canada. [ABSTRACT FROM AUTHOR]