Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial

Summary

Background

Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy.

Methods

This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of −2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301.

Findings

Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and −0·6% (−1·0 to −0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal.

Interpretation

Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture.

Funding

Amgen, Astellas, and UCB Pharma.

Introduction

Patients with osteoporosis are usually treated with bisphosphonates as first-line therapy because of medium to high effectiveness, long-term experience, and price considerations. For patients who do not respond sufficiently, such as those who have persistently low bone mineral density (BMD) or those who develop fractures on therapy, switching to a bone-forming agent is common clinical practice.

Bone-forming agents are important in the management of patients with osteoporosis at high risk for fracture because they are associated with large BMD gains that can address both the bone mass and microarchitectural deficits responsible for the increased fracture risk. In practice, the use of bone-forming agents such as teriparatide is often reserved for patients with a very high fracture risk (eg, two or more prevalent fractures) or those who have been previously exposed to bisphosphonate therapy; however, data suggest that the clinical benefit of teriparatide might be reduced in patients transitioning from bisphosphonates compared with bisphosphonate-naive patients. Indeed, the use of teriparatide in patients who were previously exposed to antiresorptives, such as oral bisphosphonates, results in a blunting of BMD gains compared with treatment-naive patients, particularly at the hip, with decreases in areal BMD seen in the first year.1, 2, 3, 4, 5 Thus, transitioning patients at high risk for fracture from a bisphosphonate to teriparatide poses a clinical challenge.

Research in context

Evidence before this study

We searched PubMed for papers in any language published up to May 30, 2016 with the terms “bone anabolic”, “bisphosphonate”, “osteoporosis”, “romosozumab”, and “teriparatide”. We restricted the search to papers published in peer-reviewed journals only. We reviewed all publications that reported the results of randomised clinical trials and relevant preclinical studies. Although randomised controlled trials have investigated the effects of sequential bisphosphonate and bone-forming osteoporosis therapy, none have addressed the sequential use of alendronate and a sclerostin monoclonal antibody.

Added value of this study

Bone-forming agents are important for the treatment of patients at high risk of fracture because they can improve deficits in both mass and microstructure that contribute to fracture risk. Teriparatide, a parathyroid hormone analogue, is a bone-forming agent, approved for human use by the US Food and Drug Administration. Teriparatide is often prescribed to patients who have been previously exposed to bisphosphonates. However, the use of parathyroid hormone therapy after bisphosphonate might have limitations; a blunting of the bone-forming effect of teriparatide on bone mineral density (BMD) has been reported in women with previous bisphosphonate use compared with bisphosphonate-naive patients. The reduced effect of teriparatide during sequential administration is most notable at the hip, where losses in areal bone density have been documented in patients transitioning from bisphosphonate to teriparatide, particularly in the year following transition. Thus, it is important to understand the effects of the bone-forming agent romosozumab compared with teriparatide on bone density and estimated strength in patients with osteoporosis who were previously treated with antiresorptive agents, such as bisphosphonates, in routine clinical practice. To our knowledge, STRUCTURE is the first large, randomised, phase 3 trial to directly compare the effects of romosozumab and teriparatide on BMD, bone turnover, and estimated bone strength in postmenopausal women with osteoporosis who were previously treated with oral bisphosphonates. Our findings showed that 12 months of treatment with romosozumab in patients transitioning from oral bisphosphonate therapy resulted in BMD gains and improved estimated hip strength compared with teriparatide, and that romosozumab was well tolerated in this population.

Implications of all the available evidence

These findings are clinically relevant because many patients are considered candidates for bone-forming agents after bisphosphonate therapy. Our findings suggest that romosozumab might be an effective treatment option for patients at increased risk for fracture who are transitioning from oral bisphosphonate therapy.

Romosozumab (AMG 785) is a bone-forming agent that inhibits sclerostin with a dual effect on bone, increasing bone formation and decreasing bone resorption.6, 7 In a 12-month, phase 2, placebo-controlled study of postmenopausal women with low bone mass treated with romosozumab, alendronate, or teriparatide, romosozumab treatment significantly increased mean areal BMD from baseline (11·3% at the lumbar spine and 4·1% at the total hip) and was well tolerated.⁷ In this treatment-naive population, areal BMD gains were larger in patients treated with romosozumab than in those treated with teriparatide. Additionally, findings from a pivotal fracture study in women with postmenopausal osteoporosis showed that the rapid and large gains in BMD associated with romosozumab treatment reduced the risk of new vertebral fractures and clinical fractures at 12 months compared with placebo.⁸

Here, we report the results of a phase 3 study comparing the effects of romosozumab versus teriparatide treatment for 12 months in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy.