Combination therapy for osteoporosis: a reappraisal.

Combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent alone. A large number of relatively small clinical trials have been performed evaluating combinations of PTH1-34 or PTH1-84 with a variety of antiresorptives, including hormone/estrogen therapy, raloxifene, alendronate (Aln), risedronate, ibandronate, zoledronic acid and denosumab (Dmab). Most of the studies evaluate dual-X-ray densitometry outcomes, with a few trials reporting volumetric bone mineral density (BMD) by quantitative computed tomography followed by finite element modeling of bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary depending on the timing of introduction of the anabolic agent (before, during or after antiresorptive treatment), as well as according to the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site dependent. The most consistent effect of combining antiresorptive agents with parathyroid hormone (PTH) is a superior hip BMD outcome compared with PTH alone. This is most evident when PTH is combined with a bisphosphonate or Dmab. In contrast to findings in the hip, in the majority of studies there is no benefit to spine BMD with combination therapy when compared with monotherapy. The two exceptions to this are when PTH is combined with Dmab and when PTH is given as monotherapy first for 9 months followed by the addition of Aln and continuation of PTH as combination treatment. On the basis of what we now know, in patients on bisphosphonates who suffer hip fractures or who have very low hip BMD, strong consideration should be given to starting teriparatide and continuing a bisphosphonate (possibly switching to zoledronic acid or even Dmab) to maximize hip BMD and strength. Furthermore, in treatment-naive individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with PTH and Dmab or PTH followed by combination treatment with a potent bisphosphonate or Dmab should be considered to maximize early increases in BMD.