To study the pathogenesis of osteoporosis in patients with chronic liver disease, we performed dynamic bone histomorphometry and measured serum bone Gla-protein in 80 patients with various types of chronic liver disease. These results were compared with results obtained in 40 healthy controls. Mean trabecular bone volume and mean trabecular thickness were significantly reduced in both men and women with chronic liver disease (p less than 0.001 for both measurements in men and p less than 0.01 for both measurements in women). Osteoporosis as defined by histologic parameters was present in 17 (21%) patients with no significant differences in prevalence rates among the various hepatic disorders. No patient had histologic evidence of osteomalacia, although mineralization lag times were prolonged (p less than 0.01 for men and women). Bone formation rates were significantly reduced in 46 (57%) patients, and unlike the static measurements, were related to the type and severity of the underlying liver disease. Patients with alcoholic liver disease, hemochromatosis, and cholestatic liver disease had lower bone turnover rates and osteoblastic surfaces (p less than 0.001 and p less than 0.05, respectively) than patients with chronic active hepatitis. Furthermore, the presence of hepatic cirrhosis was associated with diminished bone formation and lower osteoblast surfaces. Serum bone Gla-protein levels were significantly correlated with bone formation rates and osteoblast surfaces (r = 0.585 and r = 0.434, respectively). A reduction in osteoblast surfaces has not previously been demonstrated in liver disease. This reduction and the associated impairment of osteoblastic activity may contribute to the pathogenesis of osteoporosis and can be assessed by the measurement of serum bone Gla-protein.