The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment.

A history of alcohol abuse is an important risk factor for bone pathologies such as osteoporosis and fracture (Turner, 2000). Most alcoholics exhibit radiographic evidence of osteopenia (Bilke et al., 1985). The regulation of bone remodeling, which occurs throughout life and is essential for maintenance of normal bone mass and architecture in the adult skeleton, may be disrupted by alcohol exposure (Turner, 2000). Most studies examining the relationship between alcohol abuse and bone remodeling have focused on the formation phase of the remodeling cycle, leading to a hypothesis that reduced osteoblast activity resulting in under filling of resorptive lacunae is primarily responsible for alcohol-induced bone loss (Turner, 2000). There are reports in the literature supporting the concept that osteoblast proliferation and activity are negatively affected by alcohol treatment (Chavassieux et al., 1993; Klein et al., 1996). Chronic alcohol exposure also impairs skeletal development affecting bone mineral density, bone strength as well as perturbing osteoblast gene expression profiles (Wezeman et al., 1999). Thus, the process of bone formation appears to be a primary target of alcohol-induced bone loss (Turner, 2000). Less is known about the effects of alcohol exposure on osteoclast function and resorption during bone remodeling and its potential contribution to alcohol-induced bone loss. Studies in this area have clinical relevance given the availability of effective inhibitors of bone resorption (Compston, 2002). Antiresorptive agents such as risedronate, a third generation aminobisphosphonate, reduce bone loss by inhibiting osteoclast-mediated bone resorption (Compston, 2002) and are commonly used in the treatment of osteoporosis (Russel and Rodgers, 1999). These compounds are also highly effective inhibitors of resorption in rat models of bone loss (Wezeman et al., 2000). Human studies examining the relationship between alcohol abuse and markers of bone resorption have been somewhat contradictory. Several studies reported increased bone resorptive markers in both long-term alcoholic patients as well as during alcohol withdrawal (Laitinen et al., 1994; Nyquist et al., 1996; Pepersack et al., 1992). However, Bikle and coworkers (1985) reported decreased resorption in alcoholics with radiologic evidence of osteopenia, while others (Crilly et al., 1988; Diamond et al., 1989; Laitinen et al., 1992) reported no change in bone resorption markers in alcoholics. Most animal studies have shown that alcohol exposure does increase markers of bone resorption both in vitro (Cheung et al., 1995; Farley et al., 1985) and in vivo (Zhang et al., 2002). Early studies of the effect of alcohol on bone remodeling found direct effects on both formation and resorption in an embryonic chick tibia in vitro model system (Farley et al., 1985), and suggested alcohol-induced alterations in bone cell membrane fluidity as a potential contributory mechanism. More recent reports using in vitro resorption assays found primary cultured osteoclasts exposed to different concentrations of alcohol exhibited greater in vitro resorption activity than control cultures (Cheung et al., 1995). Zhang and coworkers, using a model of chronic alcohol consumption in mice, observed both alcohol-induced bone loss and increased urinary markers of bone resorption (Zhang et al., 2002). This effect was diminished by concurrent treatment with osteoprotegerin (OPG), an osteoblast-derived factor that inhibits osteoclastogenesis, suggesting that alcohol has a stimulatory effect on bone resorption. However, decreases in bone resorption after chronic alcohol consumption in rats have also been reported (Preedy et al., 1991). Approximately 90% of the organic matrix of bone is type 1 collagen helical protein (Seyed and Rosen, 1990). Type 1 collagen is cross-linked by specific molecules, pyridinolone and deoxypyridinolone, which provide rigidity and strength. During bone resorption type 1 collagen is degraded and the carboxyterminal cross-linked telopeptide region (ICTP) is liberated into the serum as an immunologic intact fragment, which resists further degradation (Eriksen et al., 1993). This trimeric antigen constitutes the collagen-derived precursor for pyridinolone and deoxypyridinolone (Dpd) crosslinks measurable in urine and serum (Eriksen et al., 1993). Current generation assays measure Dpd’s as a diagnostic for the increased bone resorptive activity that occurs in metabolic bone diseases such as osteoporosis (Robins, 1995). Binge alcohol drinking is a pattern of alcohol consumption resulting in highly intoxicating blood alcohol concentrations (BAC’s) (Witt, 1994) coupled with repeated withdrawal phases (Lundquvist et al., 1995). Alcoholic binge drinkers can achieve extremely high BAC’s (Penland et al., 2001). Sober-appearing alcohol users seen in emergency rooms had BAC’s averaging close to 300 mg/dL, with some individuals exceeding 500 mg/dL (Urso et al., 1981). Cartlidge and Redmund (1990) reported approximately 10% of individuals admitted to an alcohol detoxification unit had BAC’s higher than 500 mg/dL, with one patient who was alert with a BAC of 894 mg/dL. Other studies have also reported high BAC’s in alcoholics (Lindblad and Olsson, 1976; Teplin et al., 1989). Thus, although very high BAC’s appear to be common among alcoholics (Penland et al., 2001), the effects of BAC’s of this magnitude on bone health parameters have not been studied to date. The consequences of binge alcohol consumption are not limited to alcoholics as weekend binge drinking of high alcohol content beverages by nonalcoholics is a commonly observed phenomenon in many cultures (Lundquvist et al., 1995). One recent study attempted to examine effects of more modest binge drinking episodes on bone in an actively growing rat model, but no definitive conclusions were reached (Sampson et al., 1999). In the current study an alcohol exposure model system was developed using intraperitoneal (IP) injection to administer alcohol to adult male rats in a binge-like pattern, generating high blood alcohol concentrations seen in alcoholic humans. The model was used to examine the effects this level and pattern of alcohol exposure would have on markers of bone health. Our hypothesis was that binge alcohol exposure would induce bone loss, at least in part by increasing bone resorption, detectable by serum markers of bone collagen degradation and affecting bone mineral density (BMD) as well as the biomechanical properties and microarchitecture of bone. We further hypothesized that if bone resorption does play a role in alcohol-induced bone loss, concurrent treatment with an antiresorptive agent would attenuate these effects. As such, we examined the effect of concurrent treatment with an aminobisphosphonate (risedronate) and binge alcohol on bone health parameters.