Bisphosphonate action on bone structure and strength: Preclinical and clinical evidence for ibandronate

Bisphosphonates are the mainstay of treatment for postmenopausal osteoporosis. Their efficacy and safety have been assessed in animal models of osteoporosis, from which effects of treatment on bone mass, remodeling and strength can be measured. For example, the nitrogen-containing bisphosphonate, ibandronate, has been assessed in intact, ovariectomized (OVX) and ovariohysterectomized rats, dogs and monkeys. Ibandronate increases bone mineral density (BMD) and bone strength, and studies using clinically relevant dosing regimens in non-human primates have shown that treatment can prevent osteopenia and decrease activation frequency, bone formation rate and biochemical markers of bone turnover in OVX animals. Regression analyses have shown that, while bone mineral content is an important predictor of bone strength, combining it with structural parameters can further increase predictive power.The material and structural properties of bone during ibandronate treatment of postmenopausal osteoporosis have been evaluated in bone biopsies from human patients in two large-scale trials. BONE was a 3-year randomized, double-blind trial of placebo vs. daily oral ibandronate (2.5 mg/day) or intermittent oral ibandronate (20 mg every other day for 12 doses every 3 months), and DIVA was a randomized, double-blind trial comparing two intermittent, intravenous (IV) ibandronate injection regimens (2 mg every 2 months and 3 mg every 3 months) with a 2.5 mg/day oral ibandronate regimen of proven fracture efficacy. Analysis of osteoid thickness showed no evidence of impairment of bone mineralization with oral or IV therapy. Mineral apposition rate in ibandronate-treated patients was similar, regardless of dosing regimen, and was also similar to that in healthy postmenopausal women. Activation frequency was reduced significantly by ibandronate treatment, to levels observed in premenopausal women, and bone microarchitecture was maintained. Studies have also been carried out with daily oral alendronate and risedronate, and results for the ibandronate regimens are within the range of those seen with these agents. Overall, preclinical and clinical data show that ibandronate reduces bone turnover and increases BMD, without adversely affecting the material and structural properties of bone. Thus the risk of fracture may be reduced in patients receiving ibandronate for the treatment of postmenopausal osteoporosis.