Bisphosphonates inhibit 1,25-dihydroxyvitamin D3-induced increase of osteocalcin in plasma of ratsin vivo and in culture medium of rat calvariain vitro

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Abstract
In order to test whether bisphosphonates, which are potent inhibitors of osteoclastic bone resorption, may also act upon osteoblasts, we studied the effect of dichloromethylenebisphosphonate (Cl2MBP) and 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) onin vivo levels andin vitro release of osteocalcin, a bone-specific protein produced by osteoblasts. In rats, 161 μmol/kg of Cl2MBP or 1.61 μmol/kg AHBuBP strongly inhibited the increase of plasma osteocalcin induced by 1,25(OH)2D3. The inhibition was measurable within 24 hours after the administration of bisphosphonate and was independent of any change in bone resorption. The effect upon osteocalcin release was also present in calvaria cultures. 250 μM Cl2MBP strongly inhibited the osteocalcin release induced by 10−8 M 1,25(OH)2D3. In the presence of 1,25(OH)2D3, protein synthesis and DNA synthesis were also decreased, whereas in the absence of 1,25(OH)2D3, protein synthesis was increased. Thus, bisphosphonates affect the production of a bone-specific protein by osteoblasts in addition to their inhibitory action on osteoclasts.

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