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

Abstract

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 µg/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 µCT. 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.

Introduction

Intermittent parathyroid hormone (PTH) is the only FDA approved bone anabolic therapy for treatment of established osteoporosis [1]. PTH has also been investigated for its potential to accelerate fracture healing by increasing bone formation [2], [3]. However, PTH is not effective in increasing bone mineral density (BMD) in all patients, suggesting that “life-style” factors may modulate the skeletal response to this bone anabolic therapy [4]. The prevalent use of alcohol may represent one of those factors.

Chronic alcohol abuse inhibits bone growth and turnover, results in a negative bone remodeling balance, decreases bone mass, increases fracture risk and, should a fracture occur, may impair bone healing [5]. Chronic alcohol abuse leads to delayed fracture repair, and a higher incidence of delayed unions and non-unions [6], [7]. Overall, fractures in alcoholics are associated with longer hospitalization and increased morbidity and mortality [8], [9].

The effects of ongoing alcohol consumption on therapies to treat osteoporosis or accelerate bone healing are uninvestigated in humans and only a small number of studies have been performed in animal models [10], [11]. Animal studies to date suggest a detrimental effect of alcohol on the skeletal response to PTH. However, only very high dose rates of the hormone have been modeled. Recent dose response studies suggest that high doses of PTH impair the ability to detect and model “life-style” factors that influence the skeletal response to PTH in humans [10], [11]. Additional studies that better model the human therapeutic application of PTH are warranted due to the high prevalence of alcohol consumption in countries with high rates of osteoporosis.

PTH is effective in reducing fractures in postmenopausal osteoporotic women. However, the fracture incidence in postmenopausal women is still much greater than in young women. Therefore, the potential of PTH for accelerating fracture repair is of great interest. Bone healing following a fracture is a complex process. A defect in any one of a number of critical steps could delay or prevent healing. Following a fracture, bone resorption results in the release of osteoinductive growth factors stored in bone matrix. We have recently shown that osteoinduction by demineralized allogeneic bone matrix (DABM) is impaired by alcohol in the rat model for chronic alcohol abuse [12]. PTH is under investigation as a therapy to improve fracture repair [2], [3]. The most likely benefit of PTH on bone healing would be increased bone formation at the fracture site, which is in part mediated by matrix-derived growth factors. However, the effects of a therapeutic dose of PTH on the osteoinductive capacity of bone matrix have not been evaluated.

Based on the above considerations, we assessed the effects of PTH on cancellous and cortical bone metabolism and osteoinduction in a rat model for chronic alcohol abuse using a dose rate of the hormone (1 µg/kg/d) that closely approximates the human therapeutic dose rate used to treat osteoporosis. We believe that this low-dose PTH models the human skeletal response to the hormone much better than the high dose rates commonly used in rodents. We also measured serum levels of insulin-like growth factor-I (IGF-I). IGF-I is a key mediator of PTH action and is decreased by alcohol consumption [13], [14], [15]. The results indicate that alcohol consumption and PTH have opposite effects on cancellous bone formation, mass, and architecture in the tibia. They also show that a therapeutic dose of PTH in young adult male rats has minimal effects on cortical bone or ectopic osteoinduction in either the presence or absence of alcohol. In contrast, alcohol consumption inhibits cortical bone formation and osteoinduction.