Combination Antiresorptive Therapy

Dennis Black, PhD


November 10, 2005


I have heard some experts say that 2 antiresorptive agents should not be given to a patient with severe osteoporosis because we do not know the quality of the bone produced, even though there are data showing that the combination of estrogen plus a bisphosphonate improves bone mineral density (BMD) more than either one by itself. Is there a consensus among the experts on this issue?

Kathleen Griffin, MD

Response from Dennis Black, PhD

Dennis Black, PhD 
Professor of Epidemiology & Biostatistics, University of California, San Francisco

There are no definitive data to answer this question. However, there are some small studies that show that various combinations of antiresorptives increase BMD to a slightly greater degree than monotherapy.[1,2,3,4,5,6,7] For example, in a study of estrogen and alendronate, the group receiving both agents over 2 years had increases in BMD of about 1% more than either of the monotherapy groups (for whom BMD increased by about 6%).[6] However, how beneficial such a small added increment in BMD is in terms of risk reduction for fracture is unknown, as there have been no studies with fracture as the outcome measure. Furthermore, the decreases in bone remodeling rates that occur with the combination therapy are larger than those with either agent alone, which is a concern with regard to possible over-suppression and potential decreases in bone quality. Given a small potential benefit and some (probably small) potential risk, most experts do not recommend combining antiresorptive agents. There would be less concern with combining a milder agent (eg, calcitonin or even raloxifene) with a stronger agent, but it is unclear whether this would provide any benefit compared with either agent alone.

It is worth noting that there is an accumulating body of evidence that bisphosphonates are much more effective in reducing nonvertebral and hip fractures in those with more severe disease. For example, there are several studies (clinical fracture arm of FIT (alendronate),[8] the recent BONE study (ibandronate),[9] and the HIP study (risedronate)[10]) that suggest that for a given bisphosphonate, the reductions in fracture risk are accentuated among those with lower BMD. Thus, a patient with severe osteoporosis -- a BMD T-score below -3.5 at the hip, for example -- might be expected to have large risk reductions in nonvertebral and hip fracture with bisphosphonate therapy alone and would not need combination therapy, even if it provided some advantage.


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