Medical Hypotheses (2001) 56(5), 553557 2001 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1164, available online at http://www.idealibrary.

com on

Smokeless tobacco and osteoporosis: a new relationship?

J. G. Spangler,1 S. Quandt,2 R. A. Bell3
Department of Family and Community Medicine Department of Public Health Sciences 3 Department of Public Health Sciences, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27517
2 1

Summary Osteoporosis is a common disorder of bone predominantly affecting postmenopausal women in which bone mineral density declines making bone more likely to break. Although cigarette smoking is a well-established risk factor for osteoporosis, smokeless tobacco (ST) use has never been suggested or evaluated as a risk factor for this bone disorder. This would be important to consider since in certain regions of the world, ST use is more prevalent than cigarette smoking, particularly among women. This paper reviews the animal and human evidence lending support to this new hypothesis, as well as the epidemiology of ST use that underscores the potential impact this modifiable behavior might have on osteoporosis world wide. 2001 Harcourt Publishers Ltd

INTRODUCTION Osteoporosis, a disease of increased bone fragility and likelihood of fracture, is extremely common, affecting many millions of patients world wide. Lowering an individuals risk for osteoporotic fracture must focus not only on treatment but also on modification of risk factors. While some risk factors for this condition cannot be changed (e.g., family history of osteoporosis, age, gender, and Asian or Caucasian descent), many behavioral factors are modifiable. One such potentially modifiable risk factor that has never been evaluated or suggested as a risk factor for osteoporosis is smokeless tobacco use. Despite a lack of research connecting smokeless tobacco use to osteoporosis, there is strong theoretical support for considering this behavior as a possible risk factor for low bone mineral density. Smokeless tobacco, also called spit tobacco, is used orally and includes snuff and chewing tobacco. Snuff is sold as moist or dry preparations, and

Received 9 February 2000 Accepted 1 June 2000 Correspondence to: Dr John Spangler, Department of Family and Community Medicine, Medical Center Blvd., Winston-Salem, NC 27517, USA. Phone: (336)-716-2238; Fax (336)-716-9126; E-mail: jspangle@bgsm.edu

also in sachets similar to tea bags. Chewing tobacco is usually sold in pouches as whole or coarsely chopped, flavored leaves. Smokeless tobacco use is increasing among certain populations, and remains high in certain geographic areas. This paper will review the evidence lending credence to this new hypothesis of smokeless tobacco as a contributor to a patients risk for developing osteoporosis. Osteoporosis is a disease characterized by progressive decline in the structural integrity of bone, eventually progressing to the point that fracture can occur. The risk for such fractures increases with age and is especially pronounced among post-menopausal women, due largely to the imbalance in bone remodeling that occurs with declines in estrogen levels. The economic, disability, and mortality costs of osteoporosis and fractures are well documented (1). It is estimated that 15 to 20 million persons in the US have osteoporosis and that 1.5 million fractures per year can be attributed to the condition (2). In the United Kingdom and Scandinavia, osteoporotic fracture accounts for 20% of orthopedic bed occupancy (3). Further, after the age of 45, hip fracture accounts for a higher proportion of bed occupancy in the U.K. than many other disorders of women including breast cancer (3). Research suggests that the prevalence of hip fracture among White European versus Indian patients in the United Kingdom is equivalent, (4) and that if current 553

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trends continue, the number of hip fractures occurring each year will more than double (5). The National Osteoporosis Foundation estimates that direct and indirect costs for this disease are $18 billion annually in the U.S. alone, and increasing annually (6). Low bone mineral density (BMD) is an important predictor of fracture risk. Numerous determinants for BMD have been identified (6), including low body weight, smoking, excessive alcohol intake, physical inactivity, and low dietary calcium intake (6). Epidemiologic studies have found low BMD more prevalent among Caucasian women and women of Asian decent. There is also increasing attention being given to osteoporosis in women of other minority ethnic groups and in men. The development of low-cost peripheral BMD screening technology has made screening for osteoporosis feasible in populations that do not have access to more expensive central BMD screening modalities. TOBACCO USE AND OSTEOPOROSIS Cigarette smoking and osteoporosis Numerous studies have linked smoking with low BMD (714), osteoporosis (6,13,1523) and osteoporotic fracture (6,15,1723). Initial reports (8,9,11,15) indicated that men and women who smoked had lower BMD than nonsmokers of the same age and sex. In 1989, Pocock (14) performed a cross-sectional study of BMD at the lumbar spine and proximal femur in identical twins who smoked and compared them to their non-smoking twin. The amount of bone lost among these twins who smoked was significant equivalent to 3 or 4 years of bone loss experienced by postmenopausal women. Several case-control studies (15,17,2022) have evaluated smoking and osteoporotic fracture risk. All but one found a 2- to 4-fold increased odds for osteoporotic fractures among smokers compared to nonsmokers at the hip, vertebral column or forearm. The one study that did not find an increase in risk failed to consider age as a confounding variable in the relationship between smoking and osteoporosis (22). The mechanism by which smoking affects BMD is likely mediated through estrogen. Several lines of evidence point to this. First, it is known that estrogen stabilizes the skeleton and that estrogen deficiency (premature ovarian failure, bilateral oophorectomy or menopause) is associated with accelerated bone loss at all skeletal sites (6,16,18,19). While estrogen replacement therapy prevents or reverses this process of bone loss, cigarette smoking opposes this beneficial effect. Cigarette smokers, for example, undergo earlier menopause (9,2428) primarily because of lower estrogen levels (9,13) and altered estrogen metabolism (12,13,29,30). In the liver, smoking induces 2-hydroxylation of estradiol
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leading to increased production of 2-hydroxyestrogen compounds which possess minimal peripheral estrogen activity (30). This effect can be bypassed by percutaneous estrogen administration avoiding first pass hepatic metabolism (12). It is important to emphasize that the component within cigarette smoke responsible for these metabolic changes is not known. Smokeless tobacco and osteoporosis Although the effects of cigarette smoking on BMD and osteoporosis have been described, a similar effect of chewing tobacco or snuff use on osteoporosis has never been investigated. This is an important topic to consider given that in certain regions of the world, the prevalence of ST use among women is much greater than cigarette smoking (3142). Furthermore, the component in cigarette smoke responsible for these effects at the bone has never been identified, and conceivably could be consumed by individuals who used ST. If a relationship between ST and low bone density were to exist, ST use would be a common modifiable risk factor for osteoporosis among women 65 years and older. Finally, and most importantly, the typical single dose of nicotine from snuff use is twice that of cigarettes and the typical single dose of nicotine from chewing tobacco is 15 times that of cigarettes (43). Thus, if nicotine or another component from ST use has similar adverse effects on the bone as cigarette smoking, it is possible that ST users are exposed to levels of the offending compound(s) which are many times higher than levels from cigarette smoke. Animal studies provide justification for investigating the relationship between ST use and osteoporosis. Galvin and colleagues (44), in chick embryo tibiae preparations, found that both a smokeless tobacco extract (STE) and a nicotine-free STE inhibited bone oxygen consumption, increased glycolysis and lactate production, and reduced collagen synthesis; these effects reversed after removal of the STE. High concentrations of nicotine by itself decreased bone oxygen consumption and collagen synthesis, but glycolysis was not altered leading the investigators to conclude that nicotine was not responsible for all of the effects of the STE. The authors acknowledged that this acute STE-bone metabolism model would be most relevant to the oral cavity where high concentrations of ST come in direct contact with bone, but they also pointed out that systemic skeletal effects of longterm exposure to ST remain unknown. In a mouse model, Paulson and colleagues (45) showed that maternal exposure to very high doses of ST delayed ossification and caused skeletal anomalies (e.g., supranumary ribs) in fetal mice. Paradoxically, low doses of maternal exposure to ST actually increased fetal ossification rates. With these contradictory results, Paulson et al. urged caution in extrapolating these results
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to humans. This seems warranted given the varied interspecies responses in bone to maternal exposure to nicotine and ST (4652). Again, no animal model has evaluated potential osteoporotic effects of ST use. In the human dental literature, it is well documented that any tobacco use increases bone loss in the oral cavity. Cigarette smokers, for example, have increased alveolar bone loss (5357) and this relationship is dose dependent (56,58). Fewer studies have evaluated alveolar bone loss among ST users but this, too, is known to occur (53,58,59). This effect may have to do with nicotines known inhibition of collagen synthesis (44,45,6063), but ST also causes increased levels locally of inflammatory mediators that can promote alveolar bone loss (53). Whether ST acts systemically to inhibit bone metabolism is not known, nor is it known if chronic ST use exerts anti-estrogenic effects. In summary, cigarette smoking has been clearly linked to postmenopausal osteoporosis and osteoporotic fracture, a relationship mediated by this products effect on liver metabolism of estrogen. Unfortunately, while ST use is a very common habit in certain populations of elderly women, no study to date has evaluated its relationship to osteoporosis. EPIDEMIOLOGY OF SMOKELESS TOBACCO USE Smokeless tobacco use remains a problem in both the U.S. and other countries. While the prevalence of cigarette smoking has been declining in the United States, annual consumption of ST has nearly tripled in the past 20 years (64). In 1997, 121 million pounds of ST (chewing tobacco and snuff) were consumed in the United States (65). Documented rates vary, but one of the most comprehensive estimates, the National Health Interview Survey, indicated that in 1991, approximately 5.3 million American adults (2.9%) were current ST users (66). Highest rates of ST use occurred among men (5.6%) with prevalence rates ranging from 3.6% for 4564-year-old men to 8.2% for 1824-year-old men. ST use is greater among those individuals with 12 or fewer years of education, individuals of southern or rural residence, those living below the poverty level, and among Native Americans (66). Research has also shown higher ST prevalence in areas with strong economic ties to tobacco such as rural Kentucky (67), North Carolina (3135), and other southeastern states (3135, 6062, 6668). Among American women, 0.6% of the total 1991 population used ST. Older age groups had the highest prevalence of ST use with 1.3% of women 6574 years old and 2.3% of women 75 years old reporting current use (66). In addition, African American women reported higher rates of use compared to whites (2.3% vs. 0.3%, respectively), and certain Native American populations of
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women have extremely high rates of ST use. For example, among women 65 years and older, 1% of whites and 9% of African Americans reported current use (66), while up to 1951% of elderly Native American report current use (32,34). Because median age of initiation of use among ST users is as young as 10 to 11 years old (32,34,69), exposure to this tobacco product has been both long term and has occurred before women achieved peak bone mass. Since peak bone mass is a future predictor of osteoporosis (6), it is important to know if ST use is related to bone metabolism as this may help prevent childhood exposure to this product. ST use is also common in other areas of the world. In India and in the Sudan, for example, oral use of tobacco (often mixed with betel nut) is very high among women (3740) with rates up to 30% (37). In the U.K., ST use is most common among women of Indian or Bangladeshi ethnicity (41,42), occurring in up to 70% of low-income Bangladeshi women (41). Since hip fracture rates are approximately equivalent between Caucasian and Asian women in the U.K. (4), and are expected to double within the next 15 years (3), ST use as a modifiable risk factor for low BMD has important public health implications for the U.K. CONCLUSION Based on the existing literature, ST appears to be a potential risk factor for osteoporosis. Historically, its use among women seems to have been concentrated in the tobaccoproducing region of the southeastern U.S., and among specific ethnic populations around the world. Women who use ST in these areas often have done so from an early age, maximizing exposure to its potential bone effects. If ST use has an effect on bone metabolism, this effect is likely mediated through the antiestrogenic effect known to occur among cigarette smokers. Unfortunately, the compound(s) within cigarette smoke responsible for this antiestrogenic effect is (are) unknown. Because ST use is associated with exposure to nicotine levels many times higher than cigarette smoking, it is likely ST users are exposed to other offending tobacco-related compound(s) at exceptionally high levels as well. Given the epidemiology of ST use and its possible effect on bone metabolism, this tobacco product should be evaluated systematically for effects on BMD and risk for osteoporosis and fracture. With the increase nationally of ST use among youth (33), this risk factor may also be of increasing importance for women in the future. REFERENCES
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