Is there a role for combination therapy for osteoporosis?

Abstract

There is no single agent currently available that represents a cure for osteoporosis. Various anabolic and antiresorptive therapies have been combined, following different protocols, to attempt to attain superior bone mass and strength compared to monotherapy. There is a great deal of misunderstanding about results of these trials. The small randomized, blinded study in men with osteoporosis in this issue of the journal [1], evaluating a previously untested combination of teriparatide and risedronate compared with either agent alone, might help encourage some reconsideration of combination therapy for treatment of osteoporosis. In trying to interpret the many different combination therapy studies [2, 3], it is important to make some distinctions between the populations that have been studied: previously untreated individuals receiving two agents concomitantly and individuals on established antiresorptive therapy where the anabolic agent is combined with continued antiresorptive therapy. While there are some parallels between these two populations, differences in the magnitude of active bone surface, effects of acute antiresorptive agents on parathyroid dynamics, and perhaps unique acute effects of antiresorptive agents on osteoblast function might all play a role in producing distinct responses to combination therapy in previously treated vs treatment naive individuals. A third population of individuals who have been on prior bisphosphonates in the recent or remote past has not been adequately studied. Several lines of work suggested that in patients who had already been treated with an oral bisphosphonate such as alendronate, there might be different effects in those who switched to teriparatide [4–6] vs those in whom teriparatide was added [7]. In general, hip BMD declines in the first 6–12 months when teriparatide is given alone to these pretreated patients, whereas bone density increases modestly in those on combination treatment. In the only study to directly compare the effects of switching to teriparatide vs combining teriparatide with ongoing alendronate (in women who had already received prior alendronate for an average of over 4 years), DXA BMD changes in both spine and hip were greater in those randomized to combination therapy than teriparatide alone [8]. Furthermore, volumetric BMD of the hip declined in those who switched to teriparatide and increased in those who received combination therapy [9]. Although strength of the hip did not actually decline in the teriparatide alone group, hip strength increased in the combination group [9]. These findings have very important implications for the clinical use of teriparatide in patients who have received prior antiresorptive therapy and are at high risk for hip and other skeletal sites that are rich in cortical bone. It may be that the withdrawal of the bisphosphonate actually facilitates an exaggerated bone resorption response to teriparatide [8] and offsets the expected positive bone balance, particularly in the cortical skeleton where there is little incorporated bisphosphonate. Some of the findings in this pretreated population can be applied to those of combination therapy studies in the treatment naive population. In several of these studies, there was no apparent difference at 12 months in the response of spine BMD measured by DXA to combination treatment versus PTH or teriparatide monotherapy [10, 11], whereas a greater increase in hip BMD was seen with combination treatment compared to teriparatide alone. Even a short-term study of teriparatide plus raloxifene was consistent with these findings [12]; there was no difference F. Cosman (&) Helen Hayes Hospital, West Haverstraw, NY, USA e-mail: cosmanf@helenhayeshosp.org