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