Effects of low-dose parathyroid hormone on bone mass, turnover, and ectopic osteoinduction in a rat model for chronic alcohol abuse.

Parathyroid hormone (PTH) is used clinically in osteoporotic patients to increase bone mass by enhancing bone formation. PTH therapy is not uniformly effective at all skeletal sites and "life-style" factors may modulate the skeletal response to PTH. Alcohol may represent one of these factors. Chronic alcohol abuse is associated with osteoporosis and impaired fracture healing. Therefore, the present study investigated the effects of alcohol on the bone anabolic response to a dose of PTH similar to a human therapeutic dose 1) during normal cancellous and cortical bone growth and turnover, and 2) in a model of demineralized allogeneic bone matrix (DABM)-induced osteoinduction. Three-month-old male Sprague Dawley rats were fed a Lieber-DeCarli liquid diet with 35% of the calories derived from ethanol. The controls were pair-fed an alcohol-free isocaloric diet containing maltose-dextran. Following adaptation to the liquid diets, the rats were implanted subcutaneously with DABM cylinders prepared from cortical bone of rats fed normal chow. The rats were subsequently treated daily with PTH (1 microg/kg/d sc, 5 d/week) or vehicle and measurements on bone and DABM implants performed 6 weeks later. Total bone mass was evaluated on the day of necropsy using DXA. Tibiae were processed for histomorphometry. Bone mass and architecture in tibial diaphysis and DABM implants were evaluated by muCT. PTH treatment increased whole body bone mineral content (BMC) and bone mineral density (BMD). The hormone also increased bone formation and bone area/tissue area in the proximal tibial metaphysis. In contrast, PTH treatment had no effect on periosteal bone formation and minimal effects on DABM-induced osteoinduction. Alcohol consumption decreased whole body BMC. Alcohol also decreased cancellous as well as cortical bone formation and bone mass in tibia and impaired DABM-mediated osteoinduction. There was no interaction between PTH treatment and alcohol consumption for any of the endpoints evaluated. Our results indicate that the bone anabolic response to a therapeutic dose of PTH in the rat is largely confined to cancellous bone. In contrast, alcohol consumption inhibits bone formation at all sites. Furthermore, alcohol inhibits osteoinduction and reduces periosteal and cancellous bone formation, irrespective of therapeutic PTH administration. Based on the animal model, our findings suggest that alcohol consumption could impair the beneficial effects of PTH therapy in osteoporosis.

Impaired osteoinduction in a rat model for chronic alcohol abuse.

Alcohol abuse is a risk factor for bone fractures. Following a fracture, alcoholics have a higher risk for impaired fracture healing. However, the specific alcohol-induced defect(s) in bone healing are not known. Alcohol is a potent inhibitor of bone formation during bone growth and turnover. Thus, the purpose of this study was to determine the effects of alcohol consumption on induction of new bone formation. Demineralized allogeneic bone matrix (DABM) cylinders were used to model osteoinduction in a rat model for chronic alcohol abuse. DABM cylinders, prepared from femurs and tibiae of rats fed a normal diet, were implanted into sexually mature male rats adapted to alcohol (ethanol contributed 35% of caloric intake) or control liquid diets. Food intake in the control rats was restricted to match food intake of alcohol-fed animals. The implants were recovered 6 weeks later and analyzed by histology, muCT and chemical analysis. Histological evaluation revealed a robust osteoinductive response, resulting in mature bone ossicle formation, in DABM implants in rats fed the control diet. Alcohol consumption affected bone mass and architecture of the DABM implants but not volumetric density or mineral composition. Specifically, alcohol consumption resulted in significant decreases in DABM-induced bone volume, bone volume/mg original cylinder weight, connectivity density, trabecular number and thickness, ash weight and % ash weight. There were no changes in mineral (ash) density nor in the relative amounts of calcium, magnesium, iron, selenium and zinc (microg/mg ash), indicating that alcohol consumption did not impair mineralization. Taken together, these results show that alcohol abuse resulted in decreased bone formation within the DABM implant. We conclude that reduced osteoinduction may contribute to impaired bone healing in alcoholics.