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 while 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 subcutaneous injections (n=10), A) vehicle for 5 days a week [Control], B) ALN (20 µg/kg/day) 3 days a week [ALN], C) hPTH(1-34) (40 µg/kg/day) 5 days a week [daily PTH], D) daily PTH in addition to ALN [daily PTH plus ALN], E) PTH 5 days a week and vehicle 5 days a week alternating weekly [cyclic PTH], F) cyclic PTH in addition to ALN [cyclic PTH plus ALN], and G) PTH and ALN alternating weekly [alt PTH and ALN]. BMD was measured weekly by DXA, and at 7 weeks, bone markers, bone structure and bone strength were evaluated by biochemical assays, pQCT and mechanical testing, respectively. At 7 weeks, all treatments significantly increased femoral and vertebral BMD. ALN slightly decreased endosteal circumference, while 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.