Both plasma level of 1,25-dihydroxyvitamin D [1,25(OH)2D] and intestinal Ca absorption increase after biphosphonate-induced inhibition of bone resorption. Parathyroid hormone (PTH) has been considered a key mediating element of this homeostatic response. In the present work, the role of PTH was assessed by studying the influence of 1-hydroxypentane-1,1-bisphosphonate (HPeBP) on vitamin D and Ca metabolism in both intact and thyroparathyroidectomized (TPTX) rats. In intact rats, HPeBP given at 0.1 mg P/kg body wt sc for 10 days strongly inhibited bone resorption without affecting bone formation. This effect was associated with a marked stimulation of intestinal Ca absorption and Ca balance. In this condition, HPeBP caused a marked rise in plasma 1.25(OH)2D without affecting the level of 25-hydroxyvitamin D. In TPTX rats, HPeBP given at same dose also inhibited bone resorption and enhanced plasma 1,25(OH)2D, intestinal Ca absorption and Ca balance. In summary, this study shows that bisphosphonates such as HPeBP with prevailing inhibitory activity on bone resorption induce a marked stimulation of both 1,25(OH)2D production and intestinal Ca absorption. This homeostatic response is not attenuated after PTH removal. Thus, as previously shown for the response to low Ca diet, PTH does not appear to be an essential mediating factor for stimulating 1,25(OH)2D production in response to an increase in bone mineral retention.