Comparative Resistance to Teriparatide-Induced Bone Resorption With Denosumab or Alendronate

Context: In postmenopausal osteoporotic women, denosumab fully inhibits teriparatide-induced bone resorption at approved doses. This property of denosumab is distinct from that of alendronate and likely contributes to the efficacy of combination denosumab and teriparatide therapy. Whether denosumab fully inhibits bone resorption when challenged by a higher dose of teriparatide is unknown. Objective: We aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose teriparatide. Design, Setting, and Participants: In this randomized controlled trial, bone resorption (serum C-telopeptide [CTX]) wasmeasured in 25 postmenopausal women prior to and 4 hours after a single 40-mu g sc teriparatide injection. Subjects then received either a single injection of denosumab 60 mg or oral alendronate 70 mg weekly for 8 weeks. After 8 weeks, serum CTX was again measured before and 4 hours after a teriparatide a 40-mu g injection. Outcomes: The primary outcome was the between-group difference in the teriparatide-induced change in CTX from baseline to week 8. Results: At baseline, 40 mu g of teriparatide induced similar 4-hour increases in mean CTX in both groups (alendronate 47% +/- 14%, denosumab 46% +/- 16%). After 8 weeks, teriparatide was still able to stimulate bone resorption in women treated with alendronate (mean CTX increase of 43% +/- 29%) but not in women treated with denosumab (-7% (+/-) 11%; P < .001 for between group comparison). Conclusions: Denosumab, but not alendronate, fully inhibits the ability of high-dose teriparatide to increase bone resorption acutely. These results suggest that combining denosumab with a more potent anabolic stimulus may result in greater separation between bone resorption and formation and hence greater increases in bone mass.