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