Long Term Cyclic Pamidronate Reduces Bone Growth by Inhibiting Osteoclast Mediated Cartilage-to-Bone Turnover in the Mouse

K.D Evans,D.I Grossman,A.M Oberbauer,R.B Martin,L.E Sheppard,S.H Rao

doi:10.2174/1874325000802010121

Abstract

Bisphosphonates, used to treat diseases exhibiting increased osteoclast activity, reduce longitudinal bone growth through an as yet undefined mechanism. Pamidronate, an aminobisphosphonate, was given weekly to mice at 0, 1.25, or 2.50 mg/kg/wk beginning at 4 weeks of age. At 12 weeks of age, humeral length, growth plate area, regional chondrocyte cell numbers, chondrocyte apoptosis, TRAP stained osteoclast number, and osteoclast function assessed by cathepsin K immunohistochemistry were quantified. Humeral length was decreased in pamidronate treated mice compared to vehicle control mice, and correlated with greater growth plate areas reflecting greater proliferative and hypertrophic chondrocyte cell numbers with fewer hypertrophic cells undergoing apoptosis. Pamidronate treatment increased TRAP stained osteoclast numbers yet decreased cathepsin K indicating that pamidronate repressed osteoclast maturation and function. The data suggest that long term cyclic pamidronate treatment impairs bone growth by inhibition of osteoclast maturation thereby reducing cartilage-to-bone turnover within the growth plate.

Highlights

One preferred treatment for human diseases characterized by increased osteoclast activity, such as osteoporosis and osteogenesis imperfecta, is bisphosphonate therapy [1]
In this study we evaluated the effect of long term cyclic pamidronate treatment, a clinically relevant bisphosphonate, on bone elongation parameters including length, growth plate area, chondrocyte apoptosis, osteoclast numbers, and osteoclast function in a mouse model in an effort to understand how bisphosphonate inhibition of osteoclasts influences bone elongation at the growth plate
Growth plate area and height were affected by pamidronate dose while sex (p > 0.2) was not significant sexes were combined for further growth plate dimensional analysis

Summary

Introduction

One preferred treatment for human diseases characterized by increased osteoclast activity, such as osteoporosis and osteogenesis imperfecta, is bisphosphonate therapy [1]. Bisphosphonates primarily affect bone remodeling through inhibition of the osteoclast by reducing osteoclast formation and chemotaxis, or increasing osteoclast apoptosis [2,3,4], increased osteoblast growth factor expression and lowered articular chondrocyte apoptosis have been documented [5]. Treatment with bisphosphonates during the growth period could inhibit the normal osteoclast and chondroclast function necessary for that cartilage-tobone turnover, thereby impairing linear bone growth. Studies employing bisphosphonates have reported decreased bone formation rate and increased accumulation of mineralized growth plate tissue in the metaphyseal secondary spongiosa [6]. Abnormal bone remodeling and accumulation of mineralized cartilage remnants have been reported for individuals treated with bisphosphonates during growth [79]

Results

Discussion

Conclusion