The
enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast-mediated
bone resorption. In
humoral hypercalcemia of malignancy (HHM) intense osteoclastic
bone resorption is principally responsible for the observed
hypercalcemia. We therefore undertook to examine the effect of the
carbonic anhydrase inhibitor acetazolamide on the
hypercalcemia induced by the H500
Leydig cell tumor in Fisher rats, a well-described model of HHM.
Acetazolamide treatment for 10 h
at 10 mg/h resulted in a significant fall in serum
calcium in the five
drug-treated animals (14.2 +/- 0.9 to 11.5 +/- 0.1 mg/dl, p less than 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum
calcium (12.5 +/- 0.5 to 13.8 +/- 0.1 mg/dl, p less than 0.05). At the end of the infusion, the
acetazolamide-treated animals had a significantly lower mean serum
calcium than those receiving vehicle alone (11.5 +/- 0.1 versus 13.8 +/- 0.1, p less than 0.05). There was no significant change in serum
phosphorus, urine
calcium, urine
phosphorus, or nephrogenous
cyclic AMP excretion between the two groups. Acetazaolamide and HTS
5-(3-hydroxybenzoyl)-2-thiophenesulfonamide, another
carbonic anhydrase inhibitor, both significantly inhibited in vitro
bone resorption induced by 5 X 10(-9) M 36Tyr(1-36)-PTHrP-amide (
PTHrP,
parathyroid hormone-related protein).
Acetazolamide also inhibited the resorption induced by 10(-8) M (1-141)-PTHrP and 2.5 X 10(-9) M (1-74)-PTHrP. We conclude that
acetazolamide is effective in lowering the serum
calcium in animals with
humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast-mediated
bone resorption.