Elsevier

Bone

Volume 40, Issue 4, April 2007, Pages 1013-1020
Bone

Effects of parathyroid hormone (1–34) on tibia in an adult rat model for chronic alcohol abuse

https://doi.org/10.1016/j.bone.2006.11.002Get rights and content

Abstract

Chronic alcohol abuse is a risk factor for osteoporosis in men. Human recombinant parathyroid hormone (1–34) (PTH) therapy increases bone mass in patients with osteoporosis. The purpose of the present study was to determine whether PTH is effective in increasing bone formation and bone mass in a rat model for established osteopenia caused by chronic alcohol abuse. Eight-month-old male Sprague Dawley rats were fed the Lieber–DeCarli liquid diet in which 35% of the calories were derived from either maltose–dextran or ethanol. Measurements were performed 16 weeks later to establish the magnitude of bone changes in the rats fed alcohol. High dose PTH (80 μg/kg/day) was administered 5 days/week for 6 weeks to establish the differential efficacy of hormone therapy on bone formation in alcohol consuming and alcohol withdrawn rats. The effects of alcohol and PTH on cancellous and cortical bone mass, architecture and turnover were determined by densitometry and histomorphometry. Rats fed alcohol had reduced bone mineral contents and densities, cancellous and cortical bone areas and cancellous bone formation rates compared to pair-fed controls. Following the withdrawal of alcohol, indices of bone formation increased compared to baseline values. PTH treatment increased bone mineral content and density, bone formation rates, cortical bone area, cancellous bone area and trabecular number and thickness, but several indices of bone formation were reduced in the presence of continued alcohol consumption. These results suggest that alcohol consumption, in addition to inducing bone loss, may reduce the efficacy of PTH therapy to reverse osteoporosis.

Introduction

Excessive alcohol consumption is an independent risk factor for osteoporosis [1], [2], [3]. However, the cellular and molecular mechanisms for the detrimental actions of alcohol on the human skeleton are poorly understood. In this regard, the rat has been proven to be a useful model for investigating the skeletal response to alcohol consumption [4].

Alcohol is a potent inhibitor of bone growth in rats and can result in a decrease in peak bone mass [5], [6], [7], [8]. A less then optimal peak bone mass in humans may predispose the skeleton to osteoporosis during aging. In addition to reducing the accumulation of bone during growth, chronic alcohol consumption results in bone loss in skeletally mature female rats [9], [10]. Thus, alcohol could contribute to osteoporosis by multiple mechanisms. It is important therefore to determine whether the detrimental skeletal effects of chronic alcohol abuse are reversible.

In growing rats, alcohol decreased bone mass by inhibiting periosteal bone formation [5], [6], [7], [8]. In skeletally mature female rats moderate alcohol consumption decreased indices of bone formation and bone resorption to similar extents [10]. As a result, there was no net change in bone mass. Bone formation was further decreased and bone loss occurred at the higher alcohol intakes associated with alcohol abuse in humans [9], [10]. In contrast, the higher blood alcohol levels associated with binge drinking have been reported to stimulate bone resorption [11]. Alcohol withdrawal partially reversed osteopenia in growing rats [12] but the effect of alcohol withdrawal on the skeleton in adult rats with established bone loss is unknown.

The effects of prior and ongoing alcohol abuse on therapies to prevent and treat osteoporosis are largely uninvestigated. Such studies are warranted because alcohol consumption is common and because of the potentially deleterious effects of alcohol on bone metabolism. Parathyroid hormone (PTH) therapy (once daily) increases bone formation in rats and humans [13], [14], [15], [16]. In growing rats, PTH prevented the decrease in bone formation associated with short-duration alcohol abuse [17]. However, the skeletal response to PTH was diminished by ongoing alcohol consumption compared to rats fed an alcohol-free diet [17]. The effects of PTH on bone formation in an adult rat model for chronic alcohol abuse are unknown, as are the effects of the hormone on bone mass in alcohol-fed animals with established bone loss.

The present study investigates the effects of PTH treatment on bone metabolism in an alcohol abuse model in which the detrimental skeletal effects were established by feeding skeletally mature rats a diet containing alcohol for 4 months. We then investigated the respective effects of cessation of alcohol consumption and PTH treatment on bone mass, architecture and turnover.

Section snippets

General

PTH (1–34), also known as teriparatide, was generously provided by Eli Lilly Co. (Indianapolis, IN); Lieber–DeCarli liquid diet and maltose were supplied by BioServe (Frenchtown, NJ); bone fluorochromes, tetracycline–hydrochloride and calcein, were obtained from Sigma Chemicals (St. Louis, MO). The Lieber–DeCarli diet has been described in detail [18].

Eight-month-old (BW 595 ± 7 g, mean ± SE), skeletally mature [19], male, Sprague Dawley rats (Harlan, Indianapolis, IN) were used in the study. The

General

The animals were healthy. Pair-fed control groups consisting of animals that never consumed alcohol were sacrificed at 12 months of age, following the 16-week-long “Bone Loss Phase,” and at 13.5 months of age, following the 6-week-long “Recovery Phase.” The values for the two control groups did not differ significantly for any measured endpoint, which included body weight, seminal vesicle weight, bone densitometry and cancellous bone histomorphometry. The one exception was an age-related

Discussion

We investigated the detrimental skeletal effects of excessive drinking in an animal model for chronic alcohol abuse using skeletally mature male rats. In addition, we investigated spontaneous and PTH-mediated recovery following alcohol withdrawal. Chronic alcohol consumption resulted in cortical and cancellous osteopenia associated with reduced bone formation. Alcohol withdrawal resulted in normalization of bone formation but the animals remained osteopenic. PTH treatment increased bone

Acknowledgments

These studies were supported by NIH grants AA011140 and AR48833, and DOD grant PR043181.

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