Elsevier

The Lancet

Volume 382, Issue 9886, 6–12 July 2013, Pages 50-56
The Lancet

Articles
Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial

https://doi.org/10.1016/S0140-6736(13)60856-9Get rights and content

Summary

Background

Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone.

Methods

From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 μg teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380.

Findings

94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9·1%, [SD 3·9]) than in the teriparatide (6·2% [4·6], p=0·0139) or denosumab (5·5% [3·3], p=0·0005) groups. Femoral-neck BMD also increased more in the combination group (4·2% [3·0]) than in the teriparatide (0·8% [4·1], p=0·0007) and denosumab (2·1% [3·8], p=0·0238) groups, as did total-hip BMD (combination, 4·9% [2·9]; teriparatide, 0·7% [2·7], p<0·0001; denosumab 2·5% [2·6], p=0·0011).

Interpretation

Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture.

Funding

Amgen, Eli Lilly, National Center for Research Resources.

Introduction

Therapeutic options for osteoporosis have greatly expanded over the past few decades. The introduction of nitrogen-containing bisphosphonates, which act by suppressing bone resorption, has been an important advance.1, 2, 3, 4 Parathyroid hormone (PTH) and teriparatide also help to prevent fractures, but are generally reserved for patients with severe disease because of multiple factors, including cost and the inconvenience of daily injections.5 The approval of denosumab has further expanded treatment options.6 Denosumab is a monoclonal antibody that potently blocks the binding of RANKL to its osteoclast-derived receptor (RANK), an interaction that is required for osteoclast formation, activation, and survival.7 By blocking this receptor binding, denosumab potently inhibits osteoclast-mediated bone resorption. This mechanism differs from that of amino bisphosphonates, which act via inhibition of the enzyme farnesyl pyrophosphate synthase, leading to decreased osteoclast activity and increased osteoclast apoptosis.8 Despite these advances, no currently approved therapy restores normal bone integrity in most patients with established osteoporosis, and options for those with severe osteoporosis remain limited.

Efforts to improve treatment efficacy by combining osteoporosis medications have been largely unsuccessful. Studies combining PTH or teriparatide and bisphosphonates have reported no benefit compared with PTH or teriparatide alone.9, 10, 11, 12 The pharmacological reasons for the lack of additive effects, however, remain unknown. Animal studies of combined RANKL inhibitors and teriparatide have yielded conflicting results. An early study done in rats suggested that the combination of teriparatide and osteoprotegerin, an endogenous molecule that blocks RANKL binding to RANK, increased bone-mineral density (BMD) and bone strength more than either agent individually, but this finding could not be consistently reproduced.13, 14, 15 To test the hypothesis that combined teriparatide and denosumab would have additive effects on BMD in human beings, we performed a randomised, controlled trial in postmenopausal women with osteoporosis.

Section snippets

Participants

Women aged 45 years or older were recruited to this open-label randomised, controlled trial from September, 2009, to January, 2011, through targeted mailings, advertisements, and referrals to Massachusetts General Hospital in Boston, MA, USA. Inclusion criteria were age over 45 years with at least 36 months since the last menses (or hysterectomy with a concentration of follicle-stimulating hormone in serum of 40 IU/L or higher) and a high risk of fracture. We defined high fracture risk

Results

Of the 100 women enrolled, six did not complete a visit after baseline and, therefore, 94 (94%) were included in this analysis (figure 1). Two additional women discontinued the study after completing at least one post-baseline visit. Of the eight women who did not complete all study visits, three withdrew for personal reasons (two in the teriparatide group and one in the combination-therapy group). Five women discontinued for medical reasons, four in the teriparatide group (rash n=1, nausea

Discussion

In this 12-month randomised, controlled trial we show that combined teriparatide and denosumab increased BMD at the PA spine, femoral neck, and hip significantly more than either drug alone (panel). These additive effects were, therefore, seen in sites of both trabecular and mixed cortical and trabecular bone. Moreover, the 12-month changes in femoral-neck and total-hip BMD in the combination-therapy group (4·2% and 4·9%, respectively) were greater than have been reported with approved

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    JNT and AVU contributed equally to the writing of the paper.

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