Alcohol intake in rheumatic disease

Alcohol intake in rheumatic disease: good or bad?

by N. Sofat and A. Keat

( rheumatology news ) Alcohol is a major cause of morbidity and mortality. In 1983 the World Health Organization (WHO) declared alcohol-related problems to be among the world's major health concerns . Recent developments in basic science and clinical research have led to an improved understanding of the mechanisms of the effects of alcohol on musculoskeletal diseases. These vary from the site of action of the cytokine–hormone axis on the development of osteoporosis to the variety of epidemiological studies of alcohol in diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and seronegative arthropathies.

Alcohol might be beneficial in rheumatic disease. There are examples of reduced alcohol-related deaths in RA and SLE . However, acute and chronic alcohol intake is known to result in myopathies, which may lead to falls and consequent fractures . There is a body of data emerging about the link between vertebral osteoporotic fractures and alcohol, particularly in men . Alcohol has also been implicated in the increased death rate from violence and accident-related deaths in ankylosing spondylitis . This review will discuss recent data obtained regarding alcohol intake in the above conditions.

Alcohol can have harmful effects on the musculoskeletal system. It is associated with osteoporosis and an increased incidence of fractures. The strongest link is seen in spinal osteoporosis, where alcoholic men are most at risk. In one study, 38% of mobile chronic alcoholics demonstrated radiological evidence of spinal and/or forearm bone loss . Riggs et al. found the risk of spinal osteoporosis with vertebral fracture was significantly greater among men who drank alcoholic beverages (relative risk=2.4) than those who did not . The risk increased by a factor of 1.007 for each ounce year of cumulative exposure. In this study, a multiple logistic model was used to show a multiplied risk in drinkers who also smoked. An Australian study also found that drinkers had diminished bone formation rates. However, factors such as gonadal status, body mass and physical activity may also alter osteoblast function in these patients.

In women, there are conflicting data, particularly regarding ethanol use and spinal osteoporosis. In the European Vertebral Osteoporosis Study, alcohol consumption appeared to reduce the risk of vertebral fractures in women who consumed alcohol more than five days a week. Others have found reduced bone formation rates in women with established alcoholic liver disease. The conflicting results may be attributed to varying doses of alcohol intake in the two studies. However, the risk factors of late menarche, early menopause, a low dairy product consumption, low physical activity and family history of hip fracture do appear to be stronger predictors of vertebral fracture in women .

The mechanism by which ethanol promotes bone loss in both men and women is not fully understood. Some work has proposed that ethanol promotes osteoporosis through the alteration of production and resorption pathways of bone remodelling. Osteoblasts derive from the mesenchymal lineage marrow stroma and osteoclasts from the haemopoietic lineage. Ethanol inhibits proliferation of human osteoblasts. In one study, ethanol increased bone resorption in rat trabecular bone , suggesting that the osteoclastic phase is also affected by ethanol.

The development of osteoclasts from their progenitors is dependent on stromal–osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis. In vitro studies using human osteoblasts show that cytokine mediators include interleukin (IL)-1 (IL-1), tumour necrosis factor (TNF-), IL-6 and IL-11 . In humans, sex steroids regulate IL-6 production by stromal-osteoblastic cells, including the response of bone marrow cells to this cytokine and IL-11. The production of IL-6 by cultured bone marrow stromal and osteoblastic cell lines is inhibited by oestrogens . Others have not found a regulatory effect of 17ß-oestradiol in osteoblast cell preparations stimulated with IL-1b and TNF- . The inhibitory effect of oestrogen on IL-6 production is mediated by inhibition of IL-6 gene transcription through an oestrogen receptor-mediated effect on the transcriptional activity of an identified promoter sequence.

Inhibition of sex steroids, such as is seen in the low serum free testosterone concentration in male drinkers , may affect osteoclast activity . Androgens have already been shown to have an effect on IL-6 transcription, which is similar to oestrogen receptor-mediated effects, by acting through androgen-specific receptors . Furthermore, in a study using IL-6 knockout mice, Dai et al. found that mice that produced IL-6 and were fed ethanol for 4 months had reduced bone mineral density and cancellous bone formation compared with IL-6 knockouts, which had no change in these parameters with ethanol. Ethanol may therefore achieve its effect by inducing bone loss through IL-6 mediation. They proposed that this process may occur by IL-6 inducing increased receptor activation of NFB ligand messenger RNA expression in IL-6 mice, promoting granulocyte–macrophage colony-forming units and osteoclastogenesis.

Studies in mice with oophorectomies show that osteoclast formation increases in response to IL-6 or the combination of the soluble IL-6 receptor and IL-11 in bone marrow cultures. These findings suggest that osteoclast precursors have an enhanced response to IL-6 and IL-11 in oestrogen-deficient states, which correlates with clinical scenarios. Furthermore, in mice that have undergone orchidectomy, there is increased replication of granulocyte–macrophage colony-forming units with increased formation of osteoclasts . These effects are prevented by testosterone or IL-6-neutralizing antibody . It follows that the bone loss occurring through loss of gonadal function in both sexes may be mediated in both sexes through mechanisms involving IL-6.

The results from the studies described above show that there is clearly a complex interaction between ethanol use, sex hormones, cytokines and the osteoblastic and osteoclastic processes that contribute to osteoporosis in susceptible individuals. ( parterns : www.rheumatology.oxfordjournals.org )