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The Effects of Combination of Alendronate and Human Parathyroid Hormone(1–34) on Bone Strength Are Synergistic in the Lumbar Vertebra and Additive in the Femur of C57BL/6J Mice

The Regional Bone Center (S.J., S.A., D.W.D., A.I.-K.) and Clinical Research Center (F.C., R.L.), Helen Hayes Hospital, West Haverstraw, New York 10993; MDS Pharma Services Inc. (V.S.), Bothell, Washington 98021; and Departments of Medicine (F.C., R.L.) and Pathology (D.W.D., A.I.-K.), Columbia University, College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Akiko Iida-Klein, Ph.D., Helen Hayes Hospital, Regional Bone Center, 51 North Route 9W, West Haverstraw, New York 10993. E-mail: iida-kleina{at}helenhayeshosp.org.

A cyclic PTH regimen is as effective as a daily regimen on bone density gain in humans and in improving bone quality in mice. Our previous murine study evaluated the effects of a cyclic PTH regimen in the absence of a bisphosphonate, whereas our human study addressed the effects of a cyclic PTH regimen in the presence of ongoing alendronate (ALN) treatment. Accordingly, the current study examined the effects of cyclic or daily PTH regimens in combination with ALN on bone quality and bone density in mice. Twenty-week-old, female C57BL/6J mice were treated with the following sc injections (n = 10): 1) vehicle for 5 d/wk (control); 2) ALN (20 µg/kg·d) 3 d/wk (ALN); 3) human PTH(1–34) (40 µg/kg·d) 5 d/wk (daily PTH); 4) daily PTH in addition to ALN (daily PTH plus ALN); 5) PTH 5 d/wk and vehicle 5 d/wk alternating weekly (cyclic PTH); 6) cyclic PTH in addition to ALN (cyclic PTH plus ALN); and 7) PTH and ALN alternating weekly (alt PTH and ALN). Bone mineral density was measured weekly by dual-energy x-ray absorptiometry, and at 7 wk, bone markers, bone structure, and bone strength were evaluated by biochemical assays, peripheral quantitative computed tomography and mechanical testing, respectively. At 7 wk, all treatments significantly increased femoral and vertebral bone mineral density. ALN slightly decreased endosteal circumference, whereas PTH increased periosteal circumference, resulting in significant increases in femoral cortical thickness in all groups. PTH and ALN enhanced bone strength synergistically in the lumbar vertebrae and additively in the femur. Combined therapy, however, had no effects on bone markers. The results show that combinations of ALN and PTH, in both daily and cyclic regimens, produce more beneficial effects than treatment with either agent alone, suggesting that the mechanisms of actions of ALN and PTH on bone quality may be complementary.