Inhibition of bone matrix apposition by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (AHPrBP) in the mouse

Abstract

To elucidate the mechanism of action of (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (AHPrBP, formerly APD) on bone metabolism, we have studied the influence of low doses of AHPrBP on bone resorption and formation in the mouse. Thirty-five-day-old mice were given daily injections of 0.16, 1.6, or 16 μ mol kg BW per day of AHPrBP for 10 days. At sacrifice biochemical parameters were measured in serum and bone ash, and histomorphometric parameters of bone formation and resorption were determined on undecalcified sections of caudal vertebrae after double 3H-proline and double tetracycline labelings. Serum calcium and 1,25-dihydroxyvitamin D levels remained normal at all dosage levels. Compared to controls, AHPrBP at doses of 1.6 and 16 μ mol kg per day increased the number of osteoclasts and the number of nuclei per osteoclast but markedly decreased the number of acid phosphatase-stained osteoclasts. Thus, AHPrBP appears to inhibit osteoclastic activity in vivo in part through reduction of acid phosphatase activity. At doses of 1.6 and 16 μ mol kg per day AHPrBP reduced serum alkaline phosphatase and the osteoblastic surface and decreased the endosteal osteoid surface and thickness. Both the matrix apposition rate and the mineral apposition rate were progressively reduced at the endosteal level, although they were not significantly changed at the periosteal level. Greater inhibition of bone resorption than bone formation resulted in increased endosteal bone density and bone mineral content. AHPrBP at a dose of 0.16 μ mol kg per day did not alter either the osteoclastic bone resorption or the mineral and matrix apposition rates. Despite unchanged bone resorption, the osteoid surface and thickness and the osteoblastic surface were found to be decreased. The results show that AHPrBP at low dose reduced the osteoblastic formation of bone without affecting the osteoclastic bone resorption, whereas higher doses of AHPrBP inhibited bone resorption and secondarily reduced the endosteal bone matrix and mineral apposition rates. It is concluded that the reduction of endosteal bone formation by AHPrBP involved both direct and indirect effects of the bisphosphonate on bone-forming cells.