Elsevier

Bone

Volume 98, May 2017, Pages 54-58
Bone

Full Length Article
Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: The Denosumab and Teriparatide Follow-up study (DATA-Follow-up)

https://doi.org/10.1016/j.bone.2017.03.006Get rights and content

Highlights

  • In women discontinuing denosumab or teriparatide, prompt antiresorptive therapy maintains or further increases hip and spine BMD.

  • Conversely, the lack of such therapy is associated with bone loss.

  • In those receiving consolidation therapy, hip BMD increases more in women treated with denosumab compared to bisphosphonates.

  • In untreated women, femoral neck BMD decreases more in those discontinuing denosumab than those discontinuing teriparatide.

  • Prior exposure to bisphosphonates may offer partial protection from post-teriparatide or post-denosumab bone loss.

Abstract

When teriparatide and denosumab are discontinued, bone mineral density (BMD) abruptly decreases. To compare rates of bone loss in postmenopausal women who discontinue denosumab or teriparatide and receive no additional prescription osteoporosis medications to women who discontinue these drugs followed by prompt antiresorptive therapy, we asked women concluding the Denosumab and Teriparatide Administration (DATA) study and its extension, DATA-Switch, to return for BMD measurements 1–2 years after study completion. In these studies, women received 2-years of either teriparatide, denosumab or both medications followed by 2-years of the alternate therapy (women who received combination therapy initially received an additional 2-years of denosumab alone).

Fifty of 69 women who completed DATA-Switch returned after a mean of 15.4 ± 3.5 months. Of the 28 women who received antiresorptive therapy (10 denosumab, 10 oral bisphosphonates, 8 intravenous zoledronic acid), the mean interval between ending DATA-Switch and beginning antiresorptive therapy was 3.8 ± 3.1 months. In the 22 women not receiving follow-up therapy, femoral neck, total hip, and spine BMD decreased by − 4.2 ± 4.3%, − 4.5 ± 3.6%, and − 10.0 ± 5.4%, respectively, while BMD was maintained in those who did receive follow-up antiresorptive drugs (femoral neck, total hip, and spine BMD changes of − 0.6 ± 2.7%, − 0.8 ± 3.1%, and − 1.2 ± 4.7%, respectively, P < 0.001 for all between-group comparisons). Among untreated women, femoral neck BMD decreased more in those discontinuing denosumab (− 5.8 ± 4.0%) than in those discontinuing teriparatide (− 0.8 ± 2.6%, P = 0.008). Total hip BMD, but not spine BMD, showed a similar pattern. Among treated women, denosumab increased femoral neck and total hip BMD more than bisphosphonates while BMD changes at the spine did not differ significantly.

In summary, the large teriparatide and denosumab-induced gains in BMD achieved with 4 years of intensive therapy in the DATA and DATA-Switch studies were maintained in patients who received prompt antiresorptive therapy but not in those left untreated. These results demonstrate the negative consequences of delaying consolidation therapy in women treated with these drugs and underscore the importance of timely medication transitions in such patients.

Introduction

Current osteoporosis medications, while effective at reducing the rates of some types of fractures in certain populations, are unable to restore skeletal integrity in most patients with established disease. Moreover, prolonged use of these agents has been associated with reduced efficacy and rare but serious side effects, or has been prohibited by regulatory agencies [1], [2], [3], [4] Thus, many patients with osteoporosis are treated with several different medications in sequence, often with intervening “drug holidays” [5], [6] Two of the most potent agents in use today, teriparatide and denosumab, act by different mechanisms but share a common property in that their biological effects are reversed when they are discontinued. This property contrasts with the more commonly used bisphosphonate class of osteoporosis drugs that reside in the skeletal matrix and exert biological effects long after their administration has been discontinued [7]. Teriparatide (parathyroid hormone 1–34), the only currently approved anabolic agent indicated for the treatment of osteoporosis, acts via the parathyroid hormone receptor to stimulate coupled bone remodeling, decrease osteoblast apoptosis, decrease osteocytic sclerostin production, and activate lining cells [8], [9], [10]. Denosumab is a monoclonal antibody that blocks the binding of receptor activator of NFκB (RANK)-ligand to its osteoclast-derived receptor, RANK, inhibiting osteoclast formation, activation and survival [11], [12] When teriparatide is discontinued, bone mineral density (BMD) at both the spine and hip progressively decrease while biochemical markers of bone turnover, which had been stimulated during the course of therapy, revert towards baseline [13], [14]. The discontinuation of denosumab is associated with an even more rapid decrease in BMD and a transient “rebound” in bone turnover markers to levels exceeding the pre-treatment baseline [15]. In the Denosumab and Teriparatide Administration (DATA) and DATA-Switch studies, postmenopausal osteoporotic women received a total of 4 years of treatment with denosumab and teriparatide in combination or in sequence. At the conclusion of DATA-Switch, we then asked patients who had completed all visits to return for BMD assessment at least 12 months after they had completed the study. At this follow-up visit, we assessed the efficacy of physician-prescribed antiresorptive medications in maintaining the large gains in hip and spine BMD achieved during the study as well as the consequences of discontinuing treatment without further antiresorptive drug therapy.

Section snippets

Patients and methods

The Denosumab and Teriparatide Administration (DATA) study and its extension, DATA-Switch, originally recruited postmenopausal women aged 45 or older through targeted mailings, advertisements, and physician referrals between September 2009 and January 2011 (clinicaltrials.gov identifier: NCT00926380). Detailed inclusion and exclusion criteria have been published previously [16], [17] In brief, subjects were required to be 36 + months since last menses and at high fracture risk (defined as a BMD

Results

Of the 69 postmenopausal osteoporotic women who completed all visits in DATA and DATA-Switch, 50 returned for follow-up DXA assessments (fig. 2). Of these 50, 20 had received 2 years of teriparatide followed by 2 years of denosumab, 17 received 2 years of denosumab followed by 2 years of teriparatide, and 13 received 2 years of combined teriparatide plus denosumab followed by 2 years of denosumab alone. Twenty-eight subjects were prescribed an antiresorptive agent at some point between the conclusion

Discussion

The results of this study underscore the importance of avoiding “drug holidays” in postmenopausal osteoporotic women who are discontinuing either teriparatide or denosumab. These findings also demonstrate the capacity of bisphosphonates and denosumab to consolidate the large gains in BMD accrued during initial phase of sequential or combination therapy.

When parathyroid hormone analogs are discontinued in postmenopausal women, BMD reverts to pre-treatment levels within 1–2 years [13], [14], [20]

Acknowledgments

We wish to thank the staff at the Massachusetts General Hospital Bone Density Center, and our dedicated study volunteers. Study support was received by NIH (NAIMS) grant K24-AR067847 (to BZL).

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