ABSTRACT It is often difficult to obtain valid estimates of comparative treatment effectiveness and safety owing to differences across patient populations taking different medications in the real world. One approach for assessing comparability between treatment groups in effectiveness studies is to use negative control outcomes (NCOs). NCOs share similar sources of bias with the primary outcomes but have no plausible causal relationship to the treatment of interest. Observing differences in the risk of NCOs thus provides evidence for residual confounding between groups. This retrospective study assessed the comparability of postmenopausal women, treated with osteoporosis medications with various mechanisms of action such as denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor), zoledronic acid (bisphosphonate derivative), or oral bisphosphonates including alendronate. Administrative claims data were extracted from the US Centers for Medicare and Medicaid Services' Chronic Condition Warehouse database (May 2010–December 2016). Propensity scores were used to match denosumab patients 1:1 to comparators. Four nonfracture NCOs and three early fracture NCOs (before substantial biologic effects of treatment would be expected) were assessed over 1-year and 3-month follow-up periods, respectively. According to comparability decision rules established a priori, patients initiating denosumab were comparable to those initiating zoledronic acid or alendronate, irrespective of prior osteoporosis treatment experience. Among new users, new switchers, and in the historical fracture subgroup, no meaningful differences were observed in the cumulative incidence of the seven NCOs comparing denosumab to zoledronic acid. This empirical examination can assist in the selection of appropriate comparator groups for future comparability research using real-world data. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abstract Osteoporosis and cardiovascular disease are common in older adults. Treatment of osteoporosis reduces the burden of debilitating fractures; however, it is important to understand the benefit versus risk of treatment. This study evaluates the risk of stroke (ischemic or hemorrhagic) and myocardial infarction (MI) among postmenopausal women and men initiating osteoporosis treatment with denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor) or zoledronic acid (bisphosphonate) between October 2010 and June 2019. A retrospective cohort study employing the new user/active comparator design was conducted. Analyses were conducted separately in two national US commercial databases, MarketScan® and Optum® for reproducibility. Inverse probability of treatment and censoring weighting was employed to control for confounding and informative censoring. Cumulative risks at 6‐month, 12‐month, and 36‐month time points were calculated and adjusted risk ratios and differences (with 95% confidence intervals [CIs]) were estimated. In MarketScan® and Optum® databases, 96,611 and 73,127 patients met all study eligibility criteria, respectively. At 36 months, the risk ratio estimates (zoledronic acid referent group) were 1.22 (95% CI, 0.77–1.66) and 0.97 (95% CI, 0.63–1.32) for MI and 1.00 (95% CI, 0.61–1.40) and 0.87 (95% CI, 0.56–1.17) for stroke in MarketScan and Optum, respectively. Most of the treatment associations across the other time periods and outcomes also had 95% CIs including the null value. In these large samples of real‐world US patients, no increased risk in MI and stroke were identified for up to 36 months of treatment in denosumab users compared with zoledronic acid users. © 2023 Amgen. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

OBJECTIVE:To evaluate changes in bone turnover and bone mineral density (BMD) in patients with rheumatoid arthritis (RA) receiving glucocorticoids, after discontinuation of denosumab for 12 months.METHODS:We conducted a randomized, double-blind, placebo-controlled, phase II study of RA patients. Patients received placebo, denosumab 60 mg, or denosumab 180 mg every 6 months for 12 months and were followed up for an additional 12 months after discontinuation, during which no bone loss prevention therapy was instituted. Changes from baseline in serum C-terminal telopeptide of type I collagen (CTX), serum procollagen type I N-terminal propeptide (PINP), and lumbar spine and total hip BMD were evaluated.RESULTS:In this post hoc analysis of patients treated with glucocorticoids at study baseline (n = 82), levels of CTX and PINP decreased significantly from baseline in both denosumab groups. Following denosumab discontinuation, CTX returned to baseline and was not significantly different from the placebo group 6 and 12 months after discontinuation. Median percentage changes from baseline PINP in those treated with denosumab 60 mg were -0.16% and 15.3% at 6 and 12 months, respectively, after discontinuation (P = 0.062 and P = 0.017, versus placebo); corresponding changes with denosumab 180 mg were 9.0% and 75.8%, respectively (P = 0.018 and P = 0.002 versus placebo). Compared to placebo, lumbar spine and total hip BMD increased in patients receiving denosumab and returned to baseline 12 months after discontinuation. No osteoporotic fractures were reported during treatment or in the off-treatment period.CONCLUSION:In this analysis of short-term denosumab use in RA patients receiving glucocorticoids, denosumab discontinuation resulted in a gradual increase in bone turnover, which was associated with a return to baseline lumbar spine and total hip BMD.

The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term.

Abstract Context There are few studies on patients transitioning from denosumab to bisphosphonates. Objective To investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from denosumab to alendronate. Design Randomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531). Setting 25 study centers in the US and Canada. Patients Treatment-naïve postmenopausal women with BMD T-scores from −2.0 to −4.0. Interventions This post hoc analysis evaluated women randomized to subcutaneous denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2. Main Outcome Measure A 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate. Results Of 126 participants randomized to denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7% lost BMD at the lumbar spine, total hip, and femoral neck, respectively. Few participants fell below their pretreatment baseline BMD value; this occurred most often in those who lost BMD in year 2. Women who lost BMD with alendronate in year 2 also showed a greater percent change in BMD with denosumab in year 1. The BMD change in year 2 was similar regardless of baseline characteristics or adherence to oral alendronate. Conclusion Alendronate can effectively maintain the BMD gains accrued after 1 year of denosumab in most patients, regardless of baseline characteristics.