Effect of Bisphosphonates on the Rapidly Growing Male Murine Skeleton

Abstract

Bisphosphonates are effective for preventing and treating skeletal disorders associated with hyperresorption. Their safety and efficacy has been studied in adults where the growth plate is fused and there is no longitudinal bone growth and little appositional growth. Although bisphosphonate use in the pediatric population was pioneered for compassionate use in the treatment of osteogenesis imperfecta, they are being increasingly used for the treatment and prevention of bone loss in children at risk of hyperresorptive bone loss. However, the effect of these agents on the growing skeleton in disorders other than osteogenesis imperfecta has not been systematically compared. Studies were, therefore, undertaken to examine the consequences of bisphosphonate administration on the growth plate and skeletal microarchitecture during a period of rapid growth. C57Bl6/J male mice were treated from 18 to 38 days of age with vehicle, alendronate, pamidronate, zoledronate, or clodronate at doses selected to replicate those used in humans. Treatment with alendronate, pamidronate, and zoledronate, but not clodronate, led to a decrease in the number of chondrocytes per column in the hypertrophic chondrocyte layer. This was not associated with altered hypertrophic chondrocyte apoptosis or vascular invasion at the growth plate. The effects of pamidronate on trabecular microarchitecture were less beneficial than those of alendronate and zoledronate. Pamidronate did not increase cortical thickness or cortical area/total area relative to control mice. These studies suggest that bisphosphonate administration does not adversely affect skeletal growth. Long-term investigations are required to determine whether the differences observed among the agents examined impact biomechanical integrity of the growing skeleton.

Effect of alendronate on the mandible and long bones: an experimental study in vivo

“…This observation is at odds with a study (32) (2.5 mg/kg ALN dose) showing a dose-dependent decrease in hypertrophic chondrocyte apoptosis. However, our finding is partly in agreement with a report (35) that showed a decrease in the number of hypertrophic chondrocytes per column, but no changes in vascular invasion or apoptosis rate (0.1 mg/kg ALN twice a week). It could be posited that higher doses of ALN might impair apoptosis increasing hypertrophic zone thickness, whereas lower doses would not.…”

Bisphosphonate Treatment of Children and Adults with Osteogenesis Imperfecta: Unanswered Questions

“…In growing wild-type mice, treatment with alendronate, pamidronate, and zoledronate led to a decrease in the number of chondrocytes in the hypertrophic chondrocyte layer. This was not associated with altered chondrocyte apoptosis or altered vascular invasion at the growth plate [16]. However, this may differ in OI.…”

PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology

“…43 Other studies have demonstrated substantial increases in both cortical and trabecular bone with bisphosphonate treatments in young male mice. 21 Further investigation is needed into the sex-dependent effects of these drugs in pediatric models. Secondly, only one dosing strategy was evaluated in this study for each of the proof-of-concept drugs.…”

“…18–20 In growing male mice, alendronate, zoledronic acid, pamidronate, and clodronate treatment resulted in substantial increases in cortical and trabecular bone mass, suggesting that bone strength could be improved, but changes in mechanical strength were not measured. 21 …”