Effects of parathyroid hormone (1–34) on tibia in an adult rat model for chronic alcohol abuse
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.
References (50)
- et al.
Time course of epiphyseal growth plate fusion in rat tibiae
Bone
(2003) - et al.
Mechanisms of hypocalcemia and markers of bone turnover in alcohol-intoxicated drinkers
Bone Miner.
(1994) - et al.
Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats
Bone
(1995) - et al.
Bone disease in alcohol abuse
Ann. Intern. Med.
(1985) - et al.
Alcohol-induced bone disease in the absence of severe chronic liver damage
J. Bone Miner. Res.
(1994) - et al.
Assessment of bone status in intermittent and continuous alcoholics, without evidence of liver damage
Rev. Med. Chil.
(1996) Skeletal response to alcohol
Alcohol.: Clin. Exp. Res.
(2000)- et al.
Alcohol consumption by young actively growing rats: a histomorphometric study of cancellous bone
Alcohol.: Clin. Exp. Res.
(1997) - et al.
Alcohol consumption inhibits bone growth and development in young actively growing rats
Alcohol.: Clin. Exp. Res.
(1996) - et al.
Chronic alcohol treatment results in disturbed vitamin D metabolism and skeletal abnormalities in rats
Alcohol.: Clin. Exp. Res.
(1988)
Demonstration that ethanol inhibits bone matrix synthesis and mineralization in the rat
J. Bone Miner. Res.
Effect of alcohol consumption on adult and aged bone: a histomorphometric study of the rat animal model
Alcohol.: Clin. Exp. Res.
Moderate alcohol consumption suppresses bone turnover in adult female rats
J. Bone Miner. Res.
The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment
Alcohol.: Clin. Exp. Res.
Osteopenia due to chronic alcohol consumption by young actively growing rats is not completely reversible
Alcohol.: Clin. Exp. Res.
A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1–34)] with alendronate in postmenopausal women with osteoporosis
J. Clin. Endocrinol. Metab.
The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats
Endocrinology
Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial
J. Clin. Invest.
Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration
Endocrinology
Effects of parathyroid hormone on bone formation in a rat model for chronic alcohol abuse
Alcohol.: Clin. Exp. Res.
The feeding of alcohol in liquid diets: two decades of applications and 1982 update
Alcohol.: Clin. Exp. Res.
Dietary ethanol does not accelerate bone loss in ovariectomized rats
Alcohol.: Clin. Exp. Res.
Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee
J. Bone Miner. Res.
The effects of chronic alcohol consumption and exercise on the skeleton of adult male rats
Alcohol.: Clin. Exp. Res.
Ethanol-induced changes in morphology and strength of femurs of rats
Alcohol.: Clin. Exp. Res.
Cited by (29)
Epigenetic regulation of bone remodeling by natural compounds
2019, Pharmacological ResearchCitation Excerpt :Therefore, future development of new therapeutic options for bone loss should focus on both bone resorption and bone formation. Currently, there are few treatments known to build bone, but these include the anabolic agents, estrogen replacement therapies, and intermittent parathyroid hormone (IPTH) [29–32]. While all of these treatments are available, they have serious adverse events associated with their use, and thus are not routinely recommended for the treatment of osteoporosis and other bone remodeling disorders [31].
Effect of sequential treatments with alendronate, parathyroid hormone (1-34) and raloxifene on cortical bone mass and strength in ovariectomized rats
2014, BoneCitation Excerpt :Our qualitative examination of the periosteal surfaces of these animals suggests that any PTH effect on periosteal bone formation that ever occurred was no longer evident. The use of a ten day fluorochrome interlabel time period that is more appropriate for studying the cancellous and endocortical surfaces than the periosteal surface, may also have limited the ability to properly study periosteal bone formation [99]. Cortical area and thickness declined by six–nine months after OVX [105].
Low dose parathyroid hormone maintains normal bone formation in adult male rats during rapid weight loss
2011, BoneCitation Excerpt :Approved for treatment of postmenopausal osteoporosis, PTH was shown to be effective in stimulating bone formation in rat models for a variety of metabolic bone diseases. These included disuse, chronic alcohol abuse, and deficiencies in estrogen, androgen and growth hormone [16,19–22]. To our knowledge, the efficacy of PTH in preventing the detrimental skeletal effects of weight loss has not been investigated.