The ratio of osteoprotegerin ligand (OPGL) to osteoprotegerin (OPG) determines the delicate balance between bone resorption and synthesis. The main objective of the present study is to investigate the possible role of OPGL and OPG in the bone metabolism of rats exposed to fluoride and the protective or aggravating effect of calcium (Ca). In a 6-month study, 270 weanling male Sprague–Dawley rats weighing between 70 and 90 g were divided randomly into six groups of 45 rats in each group. Three groups (groups I, III, and V)served as controls and drank deionized water and were fed purified rodent diets containing either 1,000 mg Ca/kg (low Ca), 5,000 mg Ca/kg (normal Ca), or 20,000 mg Ca/kg (high Ca). The three experimental groups (groups II, IV, and VI) were given the same diets but they drank water containing 100 mg?F ion/L (from NaF). Every 2 months 15 rats were randomly selected from each group and sacrificed for the study. The ratio of OPGL mRNA to OPG mRNA was significantly increased by the sixth month in the distal femur joints of the F-exposed rats. Serum tartrate-resistant acid phosphatase activity and serum calcitonin activity in the F-exposed groups was increased, although changes were not apparent in the serum alkaline phosphatase or Gla-containing proteins, especially in the low calcium and high calcium diet F-exposed groups. The results indicated that OPG and OPGL may play important roles in skeletal fluorosis, and that fluoride may enhance osteoclast formation and induce osteoclastic bone destruction. A high Ca diet did not play a protective role, but rather may aggravate the damage of fluoride.