Metabolic acidosis (MA) has been implicated in the pathogenesis of both osteomalacia and osteopenia. Alterations in the secretion of parathyroid hormone and in the metabolism of vitamin D may contribute to such skeletal changes. To minimize the influence of these factors, quantitative bone histology and measurements of bone formation using double tetracycline labeling were done in thyroparathyroidectomized (TPTX) rats with MA induced by ammonium chloride (TPTX-A), and in both non-acidotic TPTX (TPTX-C) and intact (C) controls. To evaluate the response of both cortical and trabecular bone to MA, histologic studies were done at three separate sites in the tibia, cortical bone from the mid-shaft, and trabecular bone from the epiphysis and from the metaphysis. Plasma pH was lower in TPTX-A, 7.24 +/- 0.10, than in either TPTX-C, 7.39 +/- 0.03, or C, 7.43 +/- 0.04, P less than 0.01, and urinary hydroxyproline excretion increased from 89.8 +/- 8.7 in TPTX-C to 150.2 +/- 25.9 micrograms/mg/creatinine in TPTX-A, P less than 0.01. Resorption surface at the epiphysis increased from 1.8 +/- 0.6% in TPTX-C to 4.0 +/- 1.6% in TPTX-A, P less than 0.05, values not different from those in C, 3.1 +/- 1.1%. Resorption surface was unchanged at other skeletal sites, but total bone volume at the metaphysis fell from 15.5 +/- 5.6% in TPTX-C to 9.0 +/- 4.3% in TPTX-A, P less than 0.05. Bone formation was reduced at each skeletal site in TPTX-A vs. TPTX-C, P less than 0.05 for all values, but histologic evidence of osteomalacia was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)