Comparative effectiveness of combination osteoanabolic and antiresorptive therapy for osteoporosis: an update.

The combination of an osteoanabolic and antiresorptive agent for the treatment of osteoporosis has been a topic of interest for at least a decade. When used together, in theory, bone formation would be stimulated by the action of the osteoanabolic drug, while bone resorption would be reduced by the action of the antiresorptive agent. Based upon these two different mechanisms, combination therapy, at least in concept, would be expected to be more efficacious than monotherapy with either agent alone. The earliest studies used alendronate in combination with teriparatide [PTH(1–34)] or PTH(1–84) [1,2]. With regard to bone mineral density (BMD) of the lumbar spine as assessed by dual-energy x-ray absorptiometry (DXA), combination therapy was similarly effective as PTH monotherapy, with these two arms of the trials showing densitometric advantages over alendronate alone. When BMD was measured by quantitative computed tomography, teriparatide monotherapy gave even greater improvement in BMD than either combination therapy or alendronate alone. At the hip, by DXA, gains in BMD at 1 year were greater with combination therapy than teriparatide alone, but similar to alendronate monotherapy. When carried out to 2 years, however, there was no longer an advantage to combination therapy over PTH alone. At the distal 1/3 radius site, combination therapy helped to mitigate reductions in BMD seen when teriparatide was used alone, but again provided results similar to alendronate alone. These studies in men and women did not provide support for the idea that combination therapy provides greater densitometric advantages over monotherapy with either an osteoanabolic or antiresorptive agent [1,2]. A clue to these results could be seen in the bone turnover markers influenced by combination therapy. Both formation and resorption markers were reduced, mirroring the effect of alendronate, not PTH. It was expected, on the contrary, that combination therapy would reveal the dominating effects of osteoanabolic therapy on skeletal dynamics, leading to an increase in bone turnover markers. The results of these studies led to the idea that an antiresorptive agent with a smaller effect on bone resorption might enhance – or at the very least not impair – the osteoanabolic actions of PTH to increase bone formation. Encouraging results were noted in a short-term study using raloxifene [3], a selective estrogen receptor modulator that is indeed less potent than alendronate in reducing bone turnover. More recently, Walker et al. studied the combination of teriparatide with risedronate, a bisphosphonate that does not reduce bone resorption to the same extent as alendronate or zoledronic acid [4]. The study randomized 29 men with low BMD to risedronate or teriparatide alone or in combination. Lumbar spine BMD, the primary end point, was significantly increased in all three treatment groups with out any advantage gained by combination therapy. At the total hip, however, BMD increased to a greater extent in the combination group (+3.9%) versus teriparatide alone (+0.3%) or risedronate alone (+0.8%; p < 0.05 for both comparisons). Femoral neck BMD also increased to a greater extent in the combination group 1