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Editorial |
Professor of Bone Medicine Department of Medicine Addenbrooke’s Hospital Cambridge CB2 2QQ, United Kingdom
Address all correspondence and requests for reprints to: Juliet Compston, Professor of Bone Medicine, Department of Medicine, Box 157, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. E-mail: jec1001{at}cam.ac.uk.
Smoking is harmful for many aspects of health, and the skeleton is no exception. A number of reports have documented decreased bone mineral density (BMD) and increased fracture risk in smokers, although the mechanisms responsible have not been clearly established. In particular, the relative effects of tobacco use on the attainment of peak bone mass and on age-related bone loss are uncertain, as are the contributions to bone loss and fracture of a number of lifestyle variables that are commonly linked to smoking.
The association between smoking and fracture is observed in both women and men (1). In both sexes, the increase in fracture risk appears to be greatest for hip fracture; in a recent meta-analysis of data from 10 large prospectively studied cohorts, the risk ratio for hip fracture was 1.82 (95% confidence intervals, 1.34–2.49) in men and 1.85 (1.46–2.34) in women (2). When all osteoporotic fractures, including hip fractures, were considered, the increase in risk was greater in men [1.53 (1.27–1.83)] than in women [1.20 (1.06–1.35)]. A greater risk in men has also been observed in other studies and may be attributable to their higher exposure to tobacco; evidence in favor of a dose response in current smokers has been reported in some studies, although smoking duration does not appear to be related to fracture risk (3, 4, 5). Interestingly, the increase in fracture risk associated with smoking in the study of Kanis et al. (2) was only partially explained by lower BMD levels, accounting for 23% of the increase in risk of hip fracture and 40% of the increase in risk of all osteoporotic fractures. For all osteoporotic fractures, the increase in risk associated with smoking remained significant after adjustment for BMD in men, but not in women. The BMD-independent factors contributing to fracture risk in smokers have not been established, but increased cardiovascular comorbidity resulting in a higher risk of falling and impairment of protective responses may play a role.
Although lower BMD values in smokers have been reported in many studies (6), the relative contributions of increased age-related bone loss and reduced peak bone mass are unclear. Some prospective studies of BMD in older smokers have demonstrated faster rates of bone loss in the radius and proximal femur (7, 8), although this finding has not been universal (9). Higher levels of biochemical markers of bone resorption have been reported in older smokers; in one study, this was most marked in men with low body weight and was associated with lower serum 25-hydroxyvitamin D and higher PTH levels than in nonsmokers (10). Reduced serum osteocalcin levels have also been reported in early postmenopausal women who smoked (11). Collectively, these observations indicate that rates of bone loss may be increased in smokers as a result of increased resorption and decreased formation.
Previous studies of the effects of smoking on bone mass in adolescents and young adults have produced conflicting results, possibly because the number of subjects studied has been relatively small (12, 13, 14, 15). However, in a large population-based study of over 1000 young men (mean age, around 19 yr), Lorentzon et al. (16) report significantly lower areal BMD, measured by dual energy x-ray absorptiometry, of the total body, lumbar spine, femoral neck, and trochanter in smokers than in nonsmokers. The magnitude of the differences was quite substantial, for example a mean difference of 3.3% in the spine and 5% in the trochanter after adjustment for age, height, weight, calcium intake, and physical activity. Peripheral quantitative computed tomography was also used in this study to measure cortical thickness and trabecular and cortical volumetric BMD of the tibia and radius. Cortical thickness was significantly lower in the smokers, and in multiple regression analysis, smoking was a significant negative predictor of cortical thickness at both sites; cortical thinning was the result of increased endosteal circumference, the periosteal circumference being unaffected. Smoking was also an independent predictor of the trabecular volumetric BMD of the tibia, which was lower in smokers, whereas no differences in cortical volumetric BMD were demonstrated between smokers and nonsmokers. Taken together, these data thus indicate that both reduced volumetric trabecular BMD and cortical thinning may contribute to the reduction in peak bone mass associated with smoking. The mean duration of smoking in this study of 4.1 yr suggests that these effects may occur quite rapidly, although, because this study was cross-sectional, a direct causal association remains unproven.
The mechanisms by which smoking affects the skeleton may include both direct and indirect effects. The effects of tobacco products on bone cells have not been clearly defined, both stimulation and inhibition of osteoblast formation and activity being reported; in other cell types tobacco products have been reported to induce apoptosis. It is likely that a number of lifestyle variables associated with smoking contribute to the observed effects. Smokers tend to be thinner, and those with a low body mass index appear to have greater rates of bone loss and fracture (10). Lower intake of specific dietary components including calcium and higher consumption of caffeine and alcohol may also contribute to the adverse skeletal effects of smoking. Another potential confounding factor is the lower levels of physical activity in smokers. Finally, lower serum 25-hydroxyvitamin D levels have been reported in smokers, although it is unclear whether there are accompanying changes in PTH production (10, 17). Many of these variables were adjusted for in the study of Lorentzon et al. (16) but did not change the significant associations demonstrated between smoking and the density and structure of bone.
There is also evidence to link altered sex hormone status to the association between smoking and osteoporosis. Women who smoke have an earlier menopause, and there is some evidence that the beneficial skeletal effects of hormone replacement therapy are reduced in smokers (18). Furthermore, reduced synthesis of estrogens by adipose tissue as a result of lower body weight in smokers is compounded by increased 2-hydroxylation of 17ß-estradiol, resulting in the formation of metabolites with minimal estrogenic activity (19). Tobacco also stimulates ACTH secretion and the production of adrenal steroids, resulting in increased serum levels of cortisol, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate (20). Lorentzon et al. (16) found that male smokers had significantly higher total and free testosterone levels than nonsmokers, but this did not influence the association between smoking and bone measurements. Serum estradiol levels were similar in smokers and nonsmokers in their study, although others have reported increased levels in current male smokers.
Smoking is clearly a modifiable risk factor but does stopping help the skeleton? Advice to stop smoking is supported by a large evidence base for other diseases and would routinely be offered by health professionals. Nevertheless, specific reassurance that cessation of smoking improves bone health may increase motivation in some individuals. Kanis et al. (2) showed that the association between fracture risk and smoking was weaker in ever smokers than in current smokers, although when data for men and women were combined, significant increases in osteoporotic fractures and in hip fracture were still observed in the former. In another study, women who stopped smoking did not experience any demonstrable reduction in hip fracture risk compared with smokers until 10 yr after cessation (3). However, in a prospective population-based cohort study of older men, fracture risk was more than halved during the first 10 yr after stopping smoking, although a significant increase compared with nonsmokers persisted until 30 yr after cessation (4). Thus, the adverse skeletal effects of smoking appear to be at least partially reversible, and patients can be reassured that if they stop, their fracture risk should decrease.
The demonstration that cortical thinning contributes to the reduction in peak bone mass associated with smoking in young men provides important additional information to the existing body of evidence linking smoking to increased fracture risk. The mechanisms by which these effects occur have not been fully elucidated but are likely to be related to associated lifestyle habits, changes in the hormonal environment, and perhaps also direct effects of tobacco products on bone cells. The partial independence from BMD of smoking as a risk factor for fracture can be exploited in case-finding strategies, and the persistence of effect on fracture risk argues for inclusion of both current and recent smokers. Most importantly, however, the potential for smoking to damage the young skeleton should be recognized in public health policies aimed at optimizing bone health in children and young adults.
Footnotes
Abbreviation: BMD, Bone mineral density.
Received November 30, 2006.
Accepted December 5, 2006.
References
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