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We have examined the effects of a potent inhibitor of carbonic anhydrase (CA), 5-(3-hydroxybenzoyl)2-thiophenesulfonamide (HTS), and compared them with the effects of acetazolamide (AZ) and ethoxzolamide (EX) on bone resorption in organ cultures in fetal rat long bones under control unstimulated conditions and in response to PTH, prostaglandin E2 (PGE2), 1,25-dihydroxyvitamin D [1,25-(OH)2D3], and interleukin-1 (IL-1). The relative potencies of HTS, EX, and AZ for inhibition of CA and bone resorption were similar. HTS inhibited control resorption at 10(-5) to 3 X 10(-5) M, while EX at 10(-4) M inhibited and AZ was ineffective. In the presence of PTH, the inhibitory effect of HTS was seen at concentrations as low as 3 X 10(-6) M and was maximal at 3 X 10(-5) M. EX was inhibitory at 10(-5) M and maximal at 10(-4) M, while AZ at 10(-4) M only partially inhibited PTH-stimulated bone resorption. The responses to PGE2 (10(-7) M), 1,25-(OH)2D3 (10(-9) M), and IL-1 (50 U/ml) were inhibited by HTS at 10(-5) M, while AZ at 10(-4) M was ineffective against PGE2 and 1,25-(OH)2D3. The effect of HTS did not appear to be due to nonspecific toxicity, since after 2 days of treatment at 3 X 10(-5) M and 3 days of recovery, the bone resorptive response to PTH was completely restored. Moreover, HTS at 3 X 10(-5) M did not inhibit the incorporation of labeled proline or thymidine into fetal rat long bones. HTS was more potent as an inhibitor when the CO2 concentration in the gas phase was reduced from 5% to 2% and the pH was increased from 7.2 to 7.5, consistent with an effect on CA-mediated hydrogen ion generation.