Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix.

Pretreatment of a long bone explant with P-C-P can prevent the osteoclastic resorption of its mineralized matrix, when it is entirely dependent upon activation and accession of extra-osseous osteoclast precursors. When treatment of the explant is postponed until after the development of mature osteoclasts, the P-C-P dose required for an inhibitory effect is increased 100-fold for the amino bisphosphonate APD, but not for EHDP and Cl2MDP. It is concluded that high doses of all P-C-Ps inhibit the resorbing osteoclast, but that low dose of the amino P-C-P can specifically inhibit the accession of osteoclast precursors to mineralized matrix. Both actions require P-C-P binding to the mineral. The relative potencies of the P-C-Ps in the precursor-dependent system correspond to their relative potencies in vivo. This suggests that inhibition of accession underlies the high potency which the aminobisphosphonate has in vivo.

Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).

The effects of 1.5-2 years oral administration of disodium (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) on bone metabolism were studied in male and female rats. APD was mixed in the food at levels of 500, 2,000 and 10,000 ppm. A dose-dependent increase in metaphyseal bone was found, indicative of continued inhibition of bone and cartilage resorption. APD did not affect mineralization of bone and cartilage, primary bone formation, or periosteal apposition. A short-term metabolic balance study was performed to compare the effects of oral with subcutaneous APD. Absorption of APD was in the order of 0.2%. Oral APD increased absorption of phosphate, probably by complexation of calcium with APD. The excess absorbed phosphate increased phosphaturia and decreased urinary calcium.