Intermittent and Continuous Administration of the Bisphosphonate Ibandronate in Ovariohysterectomized Beagle Dogs: Effects on Bone Morphometry and Mineral Properties

Abstract

Bisphosphonates have emerged as a valuable treatment for postmenopausal osteoporosis. Bisphosphonate treatment is usually accompanied by a 3-6% gain in bone mineral density (BMD) during the first year of treatment and by a decrease in bone turnover. Despite low bone turnover, BMD continues to increase slowly beyond the first year of treatment. There is evidence that bisphosphonates not only increase bone volume but also enhance secondary mineralization. The present study was conducted to address this issue and to compare the effects of continuous and intermittent bisphosphonate therapy on static and dynamic parameters of bone structure, formation, and resorption and on mineral properties of bone. Sixty dogs were ovariohysterectomized (OHX) and 10 animals were sham-operated (Sham). Four months after surgery, OHX dogs were divided in six groups (n = 10 each). They received for 1 year ibandronate daily (5 out of 7 days) at a dose of 0, 0.8, 1.2, 4.1, and 14 µg/kg/day or intermittently (65 µg/kg/day, 2 weeks on, 11 weeks off). Sham dogs received vehicle daily. At month 4, there was a significant decrease in bone volume in OHX animals (p < 0.05). Doses of ibandronate ≥ 4.1 µg/kg/day stopped or completely reversed bone loss. Bone turnover (activation frequency) was significantly depressed in OHX dogs given ibandronate at the dose of 14 µg/kg/day. This was accompanied by significantly higher crystal size, a higher mineral-tomatrix ratio, and a more uniformly mineralized bone matrix than in control dogs. This finding lends support to the hypothesis that an increase in secondary mineralization plays a role in gain in BMD associated with bisphosphonate treatment. Moreover, intermittent and continuous therapies had a similar effect on bone volume. However, intermittent therapy was more sparing on bone turnover and bone mineral properties. Intermittent therapy could therefore represent an attractive alternative approach to continuous therapy. (J Bone Miner Res 1999;14: 1768-1778)

Vitamin D and ibandronate prevent cancellous bone loss associated with binge alcohol treatment in male rats

“…The loss of connectivity and trabecular architecture is not restored but accretion on bone surfaces thickens existing trabecular elements. The microarchitectural outcome of treatment with ibandronate after the development of post-ovariectomy osteoporosis is also trabecular thickening [20]. In the current investigation when vitamin D or ibandronate is co-administered with alcohol vertebral and tibial cancellous BMD remain at control values preventing alcohol-induced bone loss.…”

“…Ibandronate, a potent nitrogen-containing bisphosphonate with affinity for hydroxyapatite [19], inhibits osteoclast-mediated bone resorption and is effective in the treatment of estrogen-deficient osteoporosis. Its high in vivo potency prevents estrogen-dependent bone loss and it improves bone mass, bone strength and bone architectural parameters in rats [20][21][22]. In postmenopausal osteoporosis, ibandronate decreases the biochemical markers of bone turnover, including CTX and osteocalcin to levels similar to those before estrogen deficiency.…”

Infrared Assessment of Bone Quality: A Review

“…They have also proven useful in evaluating various therapeutic protocols, providing insight into the mechanisms by which the various drugs work and therefore assisting in the design of new and more targeted ones [7,13,17,22,26,49,52,55,56,58,62,71].…”

Bisphosphonates: Mode of Action and Pharmacology

“…However, a recent long-term study in a beagle dog model that simulated fracture repair has demonstrated that ibandronate treatment did not adversely affect normal bone healing. 140 Studies of repair processes after creating drill-hole defects in dogs also showed no impairment with ibandronate. 141 Several other recent studies raised the intriguing possibility that bisphosphonates may enhance fracture repair and related processes.…”