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Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study

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Summary

Background

Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis.

Methods

We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (≥7·5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of −2·0 or less, or −1·0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (−0·7 and −1·1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed.

Findings

Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4·4% [95% CI 3·8–5·0] vs 2·3% [1·7–2·9]; p<0·0001) and glucocorticoid-initiating (3·8% [3·1–4·5] vs 0·8% [0·2–1·5]; p<0·0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group.

Interpretation

Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures.

Funding

Amgen.

Introduction

Despite advances in targeted therapies for many immune-mediated diseases, glucocorticoids are still used long term by an estimated 1% of the population.1 Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis2 and is associated with an estimated annual fracture rate of 5%.3 Fracture risk in glucocorticoid users is related to dose and duration of glucocorticoid use,3, 4, 5 and the underlying disease necessitating glucocorticoid therapy.5 The pathophysiology of glucocorticoid-induced osteoporosis is mediated via accelerated bone resorption, particularly in the early phase, and a reduction in bone formation. Therefore, both antiresorptive and anabolic drugs have been investigated, with small but significant increases in bone mineral density noted in the spine and, to a lesser extent, the hip.6, 7, 8, 9

RANKL has an important role in the pathogenesis of glucocorticoid-induced osteoporosis. Its production is increased by glucocorticoid use, which results in overwhelming of the natural decoy receptor osteoprotegerin, leading to accelerated bone resorption.10 Denosumab is a fully human monoclonal antibody that binds and neutralises the activity of human RANKL, similar to the action of endogenous osteoprotegerin. Denosumab inhibited cortical bone loss without impairing biomechanical strength in a murine model of glucocorticoid-induced osteoporosis.11 In a phase 2 trial12 in patients with rheumatoid arthritis who were taking glucocorticoids, 60 or 180 mg of denosumab every 6 months was associated with significant gains in bone mineral density at 12 months compared with placebo. Denosumab also increases bone density and reduces vertebral, non-vertebral, and hip fracture risk in postmenopausal women with osteoporosis.13 This pathophysiological and clinical evidence, coupled with low adherence to treatment and prevention strategies for glucocorticoid-induced osteoporosis in long-term users of glucocorticoids,14, 15 provided the rationale for this study of denosumab compared with risedronate, which is an efficacious treatment for glucocorticoid-induced osteoporosis,7, 16 in patients who are either beginning or on sustained glucocorticoid therapy.

Research in context

Evidence before this study

Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis, and increases the risk of vertebral and non-vertebral fractures. However, treatment rates are low, despite the availability of therapies. We searched PubMed with the terms “glucocorticoid-induced osteoporosis” and “denosumab”, “risedronate”, “bisphosphonate”, “teriparatide”, or “PTH analog” for articles published in any language in peer-reviewed journals up to Nov 7, 2017. We reviewed all publications in which the results of randomised clinical trials were reported. Randomised controlled trials have been done to assess several therapies for glucocorticoid-induced osteoporosis, including alendronate, risedronate, zoledronic acid, and teriparatide. The results of these trials suggest that these drugs efficaciously maintain or increase bone mass.

Added value of this study

To our knowledge, ours is the first large, randomised controlled trial of denosumab in patients with glucocorticoid-induced osteoporosis who were either prevalent glucocorticoid users or newly initiating glucocorticoid therapy. The 12-month results of this 24-month study showed that denosumab was superior to risedronate, a commonly used bisphosphonate for glucocorticoid-induced osteoporosis, in increasing bone mineral density at the lumbar spine. The two treatment groups had similar safety profiles.

Implications of all the available evidence

Our findings suggest that denosumab is efficacious and well tolerated as a treatment option in glucocorticoid-induced osteoporosis.

Section snippets

Study design and participants

We did a phase 3, international, randomised, double-blind, double-dummy, active-controlled, non-inferiority study at 79 primary care and specialist centres in 16 countries in Europe, Latin America, Asia, and North America (appendix). Eligible participants were aged 18 years or older and were taking glucocorticoids (≥7·5 mg prednisone, or its equivalent daily). Participants who had been taking glucocorticoids for at least 3 months were classed as glucocorticoid continuing; those who were taking

Results

Between March 28, 2012, and June 30, 2015, 795 patients (505 glucocorticoid-continuing patients and 290 glucocorticoid-initiating patients) were enrolled in the study (appendix). The last patient's 12-month visit was on June 29, 2016. 691 (87%) patients across both the glucocorticoid-continuing and the glucocorticoid-initiating subpopulations completed the first 12 months of the study (figure 1). The leading causes of study discontinuation were withdrawal of consent and adverse events in both

Discussion

In this randomised, active-controlled trial, denosumab was both non-inferior and superior to risedronate, a commonly used bisphosphonate for glucocorticoid-induced osteoporosis, in increasing bone mineral density at the lumbar spine at 12 months in patients already taking or newly initiating glucocorticoid therapy. Superiority of denosumab over risedronate was also shown at the total hip. Denosumab was associated with a significant reduction in concentrations of markers of bone turnover

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