Critique 086: Mechanisms for a beneficial effect of moderate alcohol consumption on osteoporosis in women — 1 August 2012
Marrone JA, Maddalozzo GF, Branscum AJ, Hardin K, Cialdella-Kam L, Philbrick KA, Breggia AC, Rosen CJ, Turner RT, Iwaniec UT. Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women. Menopause 2012;19: DOI: 10.1097/gme.0b013e31824ac071
Objective: Epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. However, the underlying cellular mechanisms responsible for the putative beneficial effects of alcohol on bone are unknown. Excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause.
Methods: Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean ± SE age, 56.3 ± 0.5 y) who consumed alcohol at 19 ± 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning.
Results: Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 ± 1.6%, P = 0.01 and 5.8 ± 2.6%, P = 0.02 compared with baseline, respectively). Ostocalcin and CTx decreased after alcohol readministration, compared with the previous day (- 3.4 ± 1.4%, P = 0.01 and – 3.5 ± 2.1%, P = 0.05, respectively), to values that did not differ from baseline (P > 0.05).
Conclusions: Abstinence from alcohol results in increased markers of bone turnover, whereas resumption of alcohol reduces bone turnover markers. These results suggest a cellular mechanism for the increased bone density observed in postmenopausal moderate alcohol consumers. Specifically, the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause.
Background: In 2011, the Forum prepared a summary of the existing data on this subject in response to the proposed US Dietary Guidelines (See Recent Reviews, Critique 011, on the Forum web-site: www.bu.edu/alcohol-forum). In that summary, we stated: “A number of recent prospective studies have confirmed that moderate alcohol consumption is positively associated with bone mineral density (BMD). While studies in the young indicate an increase in the risk of falls above a certain level of intake, most studies in the elderly actually show a lower risk of falls and fractures among moderate drinkers in comparison with non-drinkers.”1-5
We continued in our comments: “The special properties of beer might deserve a mention.6 The effect on BMD by silicon is about twice the effect seen with other dietary elements such as calcium. Beer appears to be a major contributor to Si intake. Diets that are high in Si may contribute to beneficial effects on bone which, for moderate beer intake, may be in addition to, or separate from, the effect of ethanol.”6 The study by Tucker et al from Framingham concluded that “Moderate consumption of alcohol (especially of beer and wine) may be beneficial to bone in men and postmenopausal women.”5
Other recent studies have similarly shown that moderate drinking is associated with improved BMD. In a study from Japan in men, a J-shaped curve was seen, with better measures of BMD in moderate drinkers but poorer BMD in heavier drinkers.7 Fini et al,8 in a study from Italy, concluded that moderate alcohol consumption may have a protective effect on bone mineral density, whereas excessive consumption is an important risk factor for harm. A recent study from Finland9 showed that alcohol consumption was significantly associated with BMD in elderly women. That study found that women drinking >3 alcoholic drinks/week had significantly higher BMD than abstainers, 12.0 % higher at the femoral neck and 9.2 % higher at the lumbar spine.9
The present study is from an intervention trial in which measures of bone metabolism that affect the development of osteoporosis after menopause were evaluated while subjects were consuming alcohol, after they had stopped drinking, and after they had resumed their alcohol consumption. It concludes that alcohol decreases the turnover of bone in post-menopausal women, which leads to less resorption of bone, hence less osteoporosis. It describes a cellular mechanism for the observed lower risk of osteoporosis among women who consume moderate amounts of alcohol.
Specific comments on paper: In general, Forum reviewers thought that the paper presented useful and interesting results. Several members suggested that a longer term study is called for, to study both these markers and others, but also actual bone mineral density (BMD). Stated one reviewer: “The results of the study suggest an effect of moderate alcohol consumption similar to the effects of biphosphonates. A longer term study would be important, but there would be a problem with the monitoring of bone mineral density with bone densitometry. In The Fracture Intervention Trial,10 a randomised controlled trial that compared the effects of alendronate and placebo in 6,459 postmenopausal women with low bone mineral density, the mean effect of three years’ treatment with alendronate was to increase hip bone mineral density by 0.030 g/cm2. In comparison there was a considerable within-person variation of bone mineral density over time: SD 0.014 g/cm2. Routine monitoring in the first three years of bisphosphonate treatment was discouraged as unnecessary and possibly misleading.11 Accordingly a longer term study would need to be of more than 3 years duration which would be very long for a controlled diet study.”
Stated another Forum member: “Although bone density determinations are very specific, this method is not sensitive enough to measure short-term improvements in BMD. Other methods to consider would be determining the bone turnover markers, such as bone formation markers: bone-specific alkaline phosphatase (BSALP), osteocalcin, and bone resorption markers such as urine deoxypiridoline, U-DPD.” The reviewer added: “In our own studies, within 6 months we detected increased osteoblastic activity with an alkaline diet supplement in an intervention study.”
Another reviewer commented: “While the findings from this study suggest that alcohol consumption increases levels of bone formation markers (osteocalcin and CTx), it does not translate that it will necessarily increase bone density. Longitudinal studies are required to determine if regular moderate alcohol consumption increases bone density, and more importantly, if it could reduce the risk of fracture.”
Invited comments on the paper: Invited comments were also obtained from two scientists from the MRC Human Nutrition Research Group at Cambridge University who work in related fields: Professor Jonathan Powell and Dr. Ravin Jugdaohsingh. We are especially appreciative of their following comments:
“The study is novel and methods appear robust. The authors seem to know what they are doing. Our previous work on this topic had the advantage of multiple sampling for kinetics that allowed us to dissect out the dual mechanism on suppression of bone resorption by alcohol viz a non-specific calorie-driven effect and a novel, delayed, ethanol effect – however, the present study has a greater number of subjects. The different design used in the present study may have allowed effects to be seen in bone formation markers which are likely secondary to the inhibition of resorption. The moderate alcohol effect on bone is really quite potent. This is the “big issue” in determining the relation of moderate alcohol intake and bone that needs resolving.
“The effect on bone turnover markers is interesting. As noted above, we have previously reported12 that ingestion of 28 g of alcohol acutely (over 0- 6 h) significantly suppresses serum CTx but not serum bone formation markers (osteocalcin, CICP or bALP). CTX level was still suppressed 6 h after ingestion of alcohol due to that novel latent effect noted above.
“In the present study, blood samples were collected 12-14 h after ingestion of alcohol. The CTx results thus seem to confirm our previous reported findings and extend the period that it must be being sustained (for what is actually an impressive effect). It would be interesting to investigate just how long the levels of the bone turnover markers remain suppressed – if for 24 hours, then the regular, modest consumption (versus the 3 days a week modest consumption) debate for alcohol has some ‘data’ that supports the former – at least for bone. However the authors found no correlation between baseline serum levels of the turnover makers and alcohol intake (in fairness this either needs very good/perfect records of actual recent consumption or the numbers of subjects seem in epidemiologic studies). They did see osteocalcin suppression – a formation marker – hence turnover per se is being suppressed. This could be a direct effect, and that they had the power to see it with 40+ subjects and we didn’t with our far fewer subjects (certainly the trend in our average direction of change of osteocalcin would be consistent with this). Alternatively, it could be an inevitable consequence of suppression of resorption and thus not a direct ethanol/alcohol effect.
“Finally, just to note, abstaining from alcohol ingestion had no effect on serum estradiol concentration and ingestion of alcohol apparently decreased serum estradiol levels (in any case, we do not believe is the target through which moderate ethanol consumption mediates its effect on bone). Estradiol type studies are bedevilled by kinetics.”
1. Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP. Alcohol intake and bone mineral density in elderly men and women. The Framingham Study. Am J Epidemiol 1995;142:485-492.
2. Macdonald HM, New SA, Golden MH, Campbell MK, Reid DM. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr 2004;79:155-165.
3. Mukamal KJ, Robbins JA, Cauley JA, Kern LM, Siscovick DS. Alcohol consumption, bone density, and hip fracture among older adults: the Cardiovascular Health Study. Osteoporos Int 2007;18:593-602.
4. Berg KM, Kunins HV, Jackson JL, Nahvi S, Chaudhry A, Harris KA Jr, Malik R, Arnsten JH. Association between alcohol consumption and both osteoporotic fracture and bone density. Am J Med 2008;121:406-418.
5. Tucker KL, Jugdaohsingh R, Powell JJ, Qiao N, Hannan MT, Sripanyakorn S, Cupples LA, Kiel DP. Effects of beer, wine, and liquor intakes on bone mineral density in older men and women. Am J Clin Nutr 2009;89:1188-1196.
6. Sripanyakorn S, Jugdaohsingh R, Elliott H, Walker C, Mehta P, Shoukru S, Thompson RP, Powell JJ. The silicon content of beer and its bioavailability in healthy volunteers. Brit J Nutrition 2004;91:403-409.
7. Kouda K, Iki M, Fujita Y, Tamaki J, Yura A, Kadowaki E, Sato Y, Moon JS, Morikawa M, Tomioka K, Okamoto N, Kurumatani N. Alcohol intake and bone status in elderly Japanese men: baseline data from the Fujiwara-kyo osteoporosis risk in men (FORMEN) study. Bone 2011;49:275-280.
8. Fini M, Salamanna F, Veronesi F, Torricelli P, Nicolini A, Benedicenti S, Carpi A, Giavaresi G. Role of obesity, alcohol and smoking on bone health. Front Biosci (Elite Ed) 2012;4:2686-2706.
9. Sommer I, Erkkilä AT, Järvinen R, Mursu J, Sirola J, Jurvelin JS, Kröger H, Tuppurainen M. Alcohol consumption and bone mineral density in elderly women. Public Health Nutr 2012; Jul 17:1-9. [Epub ahead of print]
10. Black DM, Cumings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.
11. Bell KJL, Hayen A, Macaskill P, Irwig L, Crain JC, Ensrud K, Bauer DC. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ 2009;338:b2266; doi:10.1136/bmj.b2266.
12. Sripanyakorn S, Jugdaohsingh R, Mander A, Davidson SL, Thompson RPH, Powell JJ. Moderate ingestion of alcohol is associated with acute ethanol-induced suppression of circulating CTX in a PTH-independent fashion. J Bone Miner Res 2009;24:1380-1388.
Women after menopause tend to develop weaker bones from what is known as osteoporosis, which may lead to fractures (especially hip fractures) from falling. The weakness of the bones results from an imbalance between the normal resorption (a type of dissolving of old bone) and the laying down of new bone, an ongoing process for both men and women referred to as “bone turnover.” For poorly understood reasons, after menopause the resorption of old bone in women continues but new bone is laid down less well, leading to a decrease in the density of bone. A variety of substances (calcium, vitamin D, various medications) have been used in an attempt to prevent the development of osteoporosis; in epidemiologic studies, moderate drinking of alcohol has been shown to lower this risk.
An intervention trial evaluating the association of alcohol intake with indices of bone metabolism shows beneficial effects of moderate alcohol intake on factors that relate to osteoporosis in post-menopausal women. The authors state that excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause of post-menopausal bone loss. This study among 40 healthy post-menopausal women investigated the hypothesis that moderate alcohol intake (an average of 19 grams per day, or approximately 1 and ½ typical drinks per day in this study) attenuates bone turnover after menopause. Measurements were carried out while the women were consuming alcohol, after they had stopped drinking as part of the trial, and following resumption of alcohol. The study showed that abstinence from alcohol resulted in increased markers of bone turnover (hence, higher risk of developing osteoporosis), whereas resumption of alcohol reduced bone turnover markers.
Forum reviewers considered this to be an innovative and well-done study. The key questions raised were how alcohol may affect bone metabolism in a longer period of time than was tested in this study. Reviewers realized that such long-term intervention trials are very difficult and expensive to carry out. On the other hand, many prospective epidemiologic studies in the elderly have shown greater bone mineral density and a lower risk of fractures among regular moderate drinkers than among abstainers. The most important aspect of this study may be that it has helped identify cellular mechanisms for the increased bone density observed in post-menopausal women who are moderate alcohol consumers.
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The following members of the International Scientific Forum on Alcohol Research provided comments on this review:
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA
Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
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In addition, invited comments were obtained from the following scientists:
Professor Jonathan Powell, MRC Human Nutrition Research Group, Cambridge University, UK
Dr. Ravin Jugdaohsingh, MRC Human Nutrition Research Group, Cambridge University, UK
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ADDENDUM: 15 August 2012
After our critique of this paper was published on our web-site, we have been notified by Professor Powell, who had not seen the final version of our critique, that our editing of the material he provided may have mis-represented his views. Hence, we are happy to publish this Addendum to Forum Critique 086 that has been provided by Professor Powell.
‘The issue of moderate alcohol ingestion being positively correlated with bone mineral density in older adults, especially post-menopausal women, is now of little doubt, and is observed even when great care is taken to correct for confounding factors (e.g. Am J Clin Nutr. 2012 May;95(5):1261-9). Moreover, mechanistic studies, and logic, dictate that this must be a cause-and-effect relationship. However, whether this effect tracks to reduced fracture risk has not been sufficiently established but it is clearly important to do so. It was this translation of moderate alcohol-BMD findings to fracture risk that we referred to as “…….the big issue” in determining the relation of moderate alcohol intake and bone that needs resolving”.
Jonathan Powell and Ravin Jugdaohsingh