[Frontiers in Bioscience E4, 2586-2606, June 1, 2012]

Role of obesity, alcohol and smoking on bone health

Fini Milena1, Salamanna Francesca1, Veronesi Francesca1,Torricelli Paola1,Nicolini Andrea2,Benedicenti Stefano3,Carpi Angelo4, Giavaresi Gianluca1

1Laboratory of Preclinical and Surgical Studies-Rizzoli Orthopaedic Institute, Bologna, Italy, 2Department of Internal Medicine, University of Pisa, Pisa, Italy, 3Department of Medical Science, Dentistry, and Biophysics, University of Genoa, Genoa, Italy, 4Department of Reproduction and Ageing, University of Pisa, Pisa, Italy


1. Abstract
2. Introduction
3. Search strategies
4. Obesity and bone
4.1. Clinical studies
4.2. Experimental studies
4.3. Pathophysiology and the role of cytokines
5. Alcohol-related bone disorders
5.1. Clinical studies
5.2. Experimental studies
5.3. Pathophysiology and the role of cytokines
6. Cigarette smoking and nicotine effects on bone
6.1. Clinical studies
6.2. Experimental studies
6.3. Pathophysiology and the role of cytokines
7. Perspective
8. Acknowledgement
9. References


The burden of osteoporosis is increasing in all societies. In comparison with other organs or apparatuses fewer studies have focused on incorrect lifestyles and bone. This article reviews clinical and experimental studies on the effects of obesity, alcohol abuse and smoking on bone. Overweight and obesity protect bone, thus reducing the fracture risk and the development of osteoporosis in older adults. However, extreme obesity (body mass index > 40 kg/m�) seems to be a risk factor for osteoporosis. Moderate alcohol consumption may have a protective effect, whereas excessive consumption is an important risk factor. Cytokines are the main mediators of the detrimental effects of obesity and alcohol. Smoking contributes to bone loss and fracture probably by interfering with estrogens, calcium and vitamin D. Health information campaigns against these harmful lifestyles should be strengthened by using available scientific information to increase awareness about their consequences on the bone.


Lifestyle may be defined as a pattern of individual practices and personal behaviors that are related to increased or reduced health risk and over which people may have more or less control. Harmful lifestyles represent avoidable risk factors that negatively impact health and wellbeing, average life expectancy and the onset of many diseases (1). In particular, among these risk factors, overweight and obesity, alcoholism and tobacco smoking are the most common cause of adverse effects on health and consequently constitute an increasing economic burden (2, 3, 4,5).

Overweight, defined as a body mass index (BMI) equal to or more than 25, and obesity, defined as a BMI equal to or more than 30, result from a chronic imbalance between energy intake and energy expenditure. They may impair health thus reducing life expectancy and/or increasing chronic diseases such as cardiovascular disease, diabetes, musculoskeletal disorders - especially osteoarthritis, and cancers (uterus, colorectal, breast, kidney and gallbladder) (2, 3, 4, 5). The World Health Organization further projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese (6).

Alcoholism is a global health problem facing many countries, involving about 140 million people suffering from alcohol dependence (7). The lifetime risk of developing alcohol-use disorders for men is more than 20%, with a risk of about 15% for alcohol abuse and 10% for alcohol dependence (8). The link between alcohol consumption and consequences depends on a) the two main dimensions of alcohol consumption: average volume of consumption and patterns of drinking; and b) the mediating mechanisms: biochemical effects, intoxication, and dependence (9). Referring to alcohol consumption volume, moderate drinkers tend to have better health and live longer than those who are either abstainers or heavy drinkers (10). The adverse health effects of alcohol have been shown for many disorders, including liver cirrhosis, pancreatitis, mental illness, several types of cancers (mouth, gullet, liver, colon and breast), cardiovascular disease, and damage to the fetus among pregnant women (7).

Finally, the damage and disease risks connected to tobacco smoking, proportional to the amount and duration of smoking, affect the duration of life and cause many diseases such as cardiovascular diseases, chronic obstructive pulmonary disease, renal failure and cancers (lung, bladder, oesophagus, kidney, pancreas) (11-12, 5). These diseases are significantly related to mortality and most of them to disability. Statistics show that chronic tobacco smoking reduces the life expectancy by an average of 7 years (11). Unfortunately, most of the damage done by tobacco to health does not become evident until years or even decades after the onset of use. Therefore, whereas tobacco use is rising globally, the epidemic of tobacco-related disease and death has yet to reach its peak.

Since limited and heterogeneous scientific information has been made available on the possible marked effects of these harmful lifestyles on bone over the last decade, this review should be seen as a synthetic update of data in support of the hypothesis that obesity, alcoholism and tobacco smoking, may be important risk factors for osteoporosis and fractures. Even though a great deal on the effect of physical activity on bone status is available in the literature, the range of risk factors considered does not include these because attention has been focused on three harmful lifestyles belonging to addictive behaviors. To the current authors knowledge there are no specific articles where the former lifestyles and physical activity were considered together as risk factors for bone health status, but physical activity was found to be related at least to body weight and tobacco smoking,(13-14) or to tobacco smoking and alcohol intake (13,15).


On January 2011, a literature search of the entire MEDLINE database (PubMed research engine) using the following MeSH database terms was carried out:

("Obesity"(MeSH)) AND ("Bone and Bones"(Mesh) OR "Bone Density"(Mesh) OR "Fractures, Bone"(Mesh) OR "Osteoporosis"(Mesh)).

("Smoke"(MeSH) OR "Smoking"(MeSH)) AND ("Bone and Bones"(Mesh) OR "Bone Density"(Mesh) OR "Fractures, Bone"(Mesh) OR "Osteoporosis"(Mesh)).

("Alcoholism"(Mesh) OR "Alcohol Drinking"(Mesh) OR "Alcohol-Related Disorders"(Mesh)) AND ("Bone and Bones"(Mesh) OR "Bone Density"(Mesh) OR "Fractures, Bone"(Mesh) OR "Osteoporosis"(Mesh)).

All papers on the effects of obesity, alcohol and smoking on bone implant osseointegration rate were excluded (NOT "Osseointegration"(MesH)) as well as those on dentistry (NOT "Dentistry"(MeSH)). The search was limited to the last 10 years (from 2001/01/01 to 2010/12/31), English language, and abstract availability. Then, the references of these studies and pertinent reviews were manually assessed by three reviewers using predefined criteria. In particular, papers related to cannabis smoking and metabolic and degenerative pathologies or syndromes (i.e. diabetes, Prader-Willi, etc...), infectious diseases and cancer were excluded. Citations regarding human subjects aged less than 19 years were excluded, considering that primary osteoporosis and related fractures are more common in the elderly. Physical activity was not included in the search, but yielded citations, considering this lifestyle is an alternative to improving bone health status.

The number of unique papers from the electronic search was 1470, which after abstract review was reduced by 1264. Two hundred six (14.0%) papers were included in the final paper, which belonged to different types of articles as defined in PubMed. These papers included 70% human, 22% animal and 8% in vitro studies (Figure 1). Most of the human studies were observational (63%, 90 out of 144) and controlled studies (15%, 21 out of 144) (Figure 2). Few meta-analyses were yielded by the electronic search (n = 9) and only 5 matched the selection criteria (n = 2 for alcohol and n = 3 for smoking).


4.1 Clinical studies

It is generally accepted that bone mineral density (BMD) is closely and positively related to body weight (BW) according to different mechanisms: a) an accommodation mechanism to a greater mechanical loading on bone, that also stimulates osteoblast activity; b) adipocytes produce estrogen that inhibits osteoclast activity and thus bone resorption; and c) obesity has been associated with insulin resistance, characterized by high plasma levels of insulin that may contribute to increased sex hormone levels, leading to an increased bone mass due to the reduction and augmentation of osteoclast and osteoblast activity, respectively (16-19). Another positive effect of increased BW is the reduced fracture rate and a cushioning effect produced by a greater thickness of adipose tissue during a fall (20). Finally, a recent review showed an indirect relationship between body weight/BMI and fracture risk. Therefore, overweight and obesity have a protective effect on bone thus reducing the fracture risk and the development of osteoporosis in older adults, however this protection is overtaken by age and long standing deficiency of estradiol (21- 22).

However, even if body weight is one of the strongest predictors of BMD, the relative contribution of fat mass (FM), the most important index of obesity, and lean mass (LM) to the weight-bone relationship has not yet been well defined (23). LM measures muscle mass and its changes during physical activity may have a greater effect on bone mass than changes in FM (24). The relationship between FM, LM and bone is reported to be different according to gender (FM is more important for BMD in women), age (LM has a greater effect on BMD in young women, whereas FM has a greater effect after pubertal growth and in postmenopausal women), skeletal site (LM is found to be strongly related to BMD of proximal femur), menopausal state (LM is a positive predictor of BMD in pre-menopausal women, whereas FM in post-menopausal women), and activity (LM influences BMD positively in exercising subjects, whereas FM has a positive influence in sedentary ones); however discordant results have been reported in the literature (23-25).

The positive relationship between BMD and BW has not been confirmed in extreme obesity (BMI > 40 kg/m�) where the relationship between body weight and bone mass is inverted (21). In particular, human and animal studies showed that extremely high levels of obesity are associated with a greater loss of BMD in estrogen-deficient osteopenia (21). These results suggest a complex interaction between fat and bone metabolism at cellular and molecular levels. On one hand, FM has a beneficial effect on increasing bone mass and "rapid" bone losers have significantly lower FM than the "slow" bone losers. On the other hand, excessive FM may not protect against decreases in bone mass, thus suggesting that when the mechanical loading effect of total body weight is removed, FM is negatively correlated with bone mass.

Moreover, obesity is reported to be responsible for peripheral or axial joint osteoarthritis. The risk of developing knee osteoarthritis in patients with BMI ≥ 30 is 6.8 times higher than that of healthy patients. The pathogenesis of osteoarthritis in obese patients is due not only to the increased mechanical load but also metabolic changes induced by an interaction between insulin-resistance and systemic inflammation (26). Acute joint inflammation determines increased levels of Thelper-1 and tumor necrosis factor (TNF), cytokines that produce an insulin-resistance condition by suppressing the sensitivity of insulin receptors on the membrane of muscle cells and adipocytes. This decreases glycogen production and, consequently, a muscle weakness leads to further traumatic events of peripheral or axial joints, thus resulting in stretching and breaking of the tenoperiosteal junction with abrasive damage to cartilage. As far as cartilage is concerned, increased BMI, BW and adiposity in healthy adults with no clinical knee osteoarthritis have been found to be associated with an increased annual rate of patella cartilage volume loss due to increased loading and dysregulation of lipid homeostasis (27).(Table 1)

4.2. Experimental studies

Few experimental studies have been performed on the effect of increased BMI on bone status. Increased BMI has been reported to have a positive effect on bone mass in wild type mice and in ob/ob mice, independently of leptin signaling that exerts its positive effects on cancellous bone volume. (28) In a model of Growth Hormone (GH)-deficient rats, increasing adiposity and circulating leptin by maintenance on a high-fat diet (HFD) had no effect on femoral strength, thus indicating that obesity and hyperleptinemia do not influence the strength of cortical bone in the absence of GH (29). Some studies focused on the negative correlation between BW and bone mass, thus indicating that biomechanical loading, due to BW in growing mice, decreased BMD because of a reduction in the number of trabecolae without thickening them (30). A significant reduction in material and structural trabecular bone properties in growing rats fed on an HFD was observed and FM was morphologically and mechanically inversely correlated with bone mass. Moreover, obese mice on HFD had increased osteoclast formation and decreased osteocalcin and femoral bone mass, thus suggesting that bone resorption augments more than formation. In fact, a decreased femoral trabecular bone mass by increasing trabecular separation and reducing trabecular number and connectivity density was observed in obese mice (31).

4.3. Pathophysiology and the role of cytokines

To explain the pathophysiological linkage between obesity and osteoporosis, it has been thought that: a) both diseases are affected by genetic and environmental factors; b) bone remodeling and adiposity are both regulated through the hypothalamus and sympathetic nervous system; and c) adipocytes and osteoblasts derive from a common progenitor - the pluripotent mesenchymal stem cells found in bone marrow and adipose tissue (32). In fact, there is a large degree of plasticity between adipogenesis and osteoblastogenesis and this relationship is reciprocal in bone marrow stromal cells, leading to the concept that inhibition of adipogenesis might enhance bone formation (33). Numerous transcription factors and multiple extracellular and intracellular signals regulating adipogenesis and osteoblastogenesis have been identified. Briefly, the Wnt/beta-catenin pathway induces osteoblastogenesis and inhibits adipogenesis. TNF-alpha, interleukin-1 (IL-1) and trasforming growth factor-beta, (TGF-beta) induce a signaling cascade that attenuates peroxisome proliferator activated receptor-gamma (PPAR-gamma) functions, which is an adipogenesis inducer and osteoblastogenesis inhibitor. As a result of the previous signaling cascade, PPAR-gamma induces osteoblastogenesis (34).

Adipose tissue allows vertebrates to store excess calories such as lipids and acts as an endocrine tissue by secreting hormones known as adipokines. Numerous proteins are included under this heading, from proteins related to the immune system (TNF-alpha, IL-6) to growth factors (TGF-beta) and proteins of the alternative complement pathway (adipsin). Furthermore, other adipokines are involved in the regulation of pressure (angiotensinogen), blood coagulation (plasminogen activator inhibitor-1), glycemic homeostasis (adiponectin, resistin, visfatin, leptin) and angiogenesis (vascular endothelial growth factor) (35). Adipokines affect human energy homeostasis and may be involved in bone metabolism regulation even if their effect on bone is actually complex (35).

In all processes observed in obese and overweight patients and investigated with in vitro and in vivo experimental studies, leptin has an important pathophysiological role in the protective effect of increased FM on BMD and consequently on reducing the fracture risk and development of osteoporosis. Leptin is known to affect the immune system, reproduction, development, haemopoiesis and angiogenesis. Besides all these functions, leptin promotes the growth of osteoblasts and chondrocytes, and increases synthesis of bone matrix proteins such as type I collagen and OC (32). However, it is difficult to define the real effects of leptin on bone metabolism, because contrasting experimental and clinical results have been reported on the positive relationship between serum leptin levels and BMD (22, 32, 36). On one hand leptin can be a mediator of the protective effects of FM on bone tissue, as confirmed by the inverse relationship found between serum leptin and bone resorption markers; on the other hand, by adjusting BMD results for BMI or FM, the correlation between leptin and BMD is lost, thus suggesting that circulating leptin does not exert a protective effect on bone mass (36).

Briefly, it has been highlighted in in vitro models that leptin (a) induces the phosphorylation of PPAR-gamma, which prevents adipogenesis and enhances osteoblastic activity by inhibiting apoptosis (22); (b) induces MAPK-dependent cell proliferation by enhancing osteoblastic differentiation (22); and (c) increases osteoprotegerin (OPG) mRNA expression and decreases RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) mRNA expression, thus limiting osteoclastogenesis (37). Conversely, it has been shown in some clinical and experimental models that in vivo leptin does not act directly on osteoblasts, but through a central pathway (hypothalamic-pituitary axis), which mediates its antiosteogenic function (32). Finally, leptin effects on bone may result from a balance between negative central effects and positive peripheral effects (32). The latter seem to be predominant only when serum leptin levels rise above a certain threshold as a signal of elevated energic storage.

Finally, another adipose-specific protein that has a pathophysiological role in the protective effect of visceral FM on BMD is adiponectin, which regulates energy homeostasis and has anti-inflammatory and anti-atherogenic effects.(38, 39). Unlike leptin, adiponectin levels decrease in obesity and type 2 diabetes. It is present within normal bone marrow and inhibits fat cell formation by marrow-derived stromal cells through a COX-2-dependent mechanism (38).


5.1. Clinical studies

Conflicting results on the relationship between alcohol consumption and fracture risk are reported in the literature (Table 2). Two recent metanalyses confirmed that a reported history of high intake of alcohol carries a substantial risk for future fractures and that this risk is largely independent of BMD (40-41). A threshold effect was found above which fracture risk increases; individuals who took 2 units (8 g of pure alcohol; 1 unit) or less per day of alcohol presented no increased risk of osteoporotic fracture. In particular, J-shaped and U-shaped relationships between alcohol consumption and hip fracture risk or BMD was found; moderate drinkers had lower hip fracture risk, whereas heavier drinkers had a higher hip fracture risk both compared with abstainers (40-42). Recently, Pye et al. highlighted a U-shaped association between quantitative heel ultrasound parameters and frequency of alcohol consumption in middle-aged and elderly men (43) Except for the prospective studies that showed higher BMD levels at different sites in drinkers,(13, 44-45) most clinical trials performed in the general population found neither a decrease in BMD nor an increase in fracture incidence associated with alcohol consumption (43, 46-51).

Alcohol-related bone disorders seem to depend mainly on consumed volume, type of drinking and drinker gender. Various studies on alcohol-induced bone loss have highlighted that bone remodeling is disrupted, new bone formation is suppressed (decreased osteoblast activity, reduced serum osteocalcin, malnourished resulting in vitamin D deficiency) and only relatively small changes occur in bone resorption (52-54).

Excessive alcohol consumption is usually associated with liver toxicity, poor nutrition status, cigarette smoking and reduced physical activity, which have all been reported to interfere with human bone homeostasis and repair in several ways (52-54, 47). It has been found that high alcohol intake drinkers had higher concentrations of pro-inflammatory markers (IL-1, Il-6, TNF-alpha) responsible for severe damage to the vascular bed above all that of the liver (55). Increased alcohol consumption has addictive effects on bone formation, thus confirming that comorbidity factors may contribute to the high incidence of osteoporosis in alcoholics (56). Furthermore, heavy drinkers, above all binge drinkers, are at a higher risk of fracture, because excessive alcohol consumption also impairs balance and fractures occur when falling while intoxicated (10,47, 49, 57-58).

Conversely, moderate alcohol consumption has a modest protective effect against hip fracture (45, 48, 59-60). Alcohol at moderate levels seems to be a powerful stimulant of calcitonin secretion, which inhibits resorption and stimulates the formation of bone, and is positively correlated with the bone mass and BMD (10, 57, 61-62). In addition, moderate alcohol consumption might induce anti-inflammatory cytokines (TGF-beta and IL-10) and endogenous estrogen synthesis, thus promoting an increase in BMD, also in men, by the aromatization of androgens to estrogens; however the level of alcohol intake to produce this effect is not evidence-defined (55, 57, 61). Furthermore, some authors suggest that the beneficial effect of moderate doses of alcohol on bone health might be due to the presence of nonalcoholic constituents such as polyphenol compounds, including flavonols and proanthocyanidins, present in alcoholic beverages (45, 62-63). Polyphenols are typically considered as antioxidants, but most of them have also estrogen-mimetic properties which might plausibly influence bone metabolism (45, 62-63). Finally, two recent studies showed the positive effect of consciously-defined lifestyle conditions, regular physical activity and balanced diet, on moderate alcohol consumption that does not lead to unhealthy bone status (64-65). (Table 2)

5.2. Experimental studies

The mechanisms of action of alcohol on bone turnover have not been fully understood and may involve both direct and indirect actions. A few in vitro studies have shown that alcohol modifies human bone-forming cells (undifferentiated and differentiated) directly by reducing proliferation, extracellular matrix and mineralization index synthesis (54, 66-67). Alcohol diffuses into osteoblasts, where alcoholdehydrogenase class 1 is expressed, and is metabolized to acetaldehyde and produces reactive oxygen species (ROS) that can have biological effects: (1) it may activate the p53/p21 complex, a tumor suppressor gene regulating cell growth, apoptosis and genome integrity (p53) and a downstream effector of p53 (p21); (2) it may activate alcohol responsive elements; and/or (3) it may also block the estrogen receptor nuclear translocation (68-69). This action of alcohol and negative cross-talk between alcohol signaling and estrogen receptor-mediated pathways contributes to osteoporotic bone loss and protective effects of estrogens on alcohol bone loss (69).

Gong et al. observed a dose-dependent inhibition of stem cell proliferation, the down-regulation of type I collagen gene expression and consequently the decrease of type I collagen C-terminal propeptide synthesis (54). They also found that alcohol reduced alkaline phosphatases (ALP) levels without influencing ALP mRNA levels, which did not affect OC gene expression (Osf2/Cbfa1), and protein synthesis by induced stem cells (54). More recently, Torricelli et al. found that osteoblast proliferation rate, ALP and OC synthesis and TGF-beta1, IL-6 and TNF-alpha releases were all negatively affected after in vivo alcohol exposure. Rosa et al. showed that chronic alcohol intake in vivo and subsequent alcohol exposure in vitro inhibited the differentiation of osteoblasts by increasing their proliferation rate and reducing bone-like nodule formation (70).

In vivo studies have mainly focused on the effect of alcohol on BMD and fracture healing (71-73). Direct detrimental effects of chronic or binge alcohol abuse on bone health have been highlighted by various in vivo biomechanical and densitometric studies using alcohol-fed rat models. First of all, it was found that chronic alcohol intake produces progressive bone loss and an increased risk of secondary osteoporosis in adult rats, whereas it suppresses skeletal growth and reduces peak bone mass in young rats (52, 74). The inhibitory effect of alcohol consumption on bone formation occurred within 2 weeks of initiating treatment, and it was transient with the same time on steady-state mRNA levels for bone matrix proteins (75). In chronic alcohol-exposed models mechanical deficiencies of femoral and tibial cortical bone, disruption of femoral osteoblasts and reduction of bone mass in trabecular bone were found; the diaphysis expanded radially to create a higher cross-sectional moment of inertia to maintain the same flexural rigidity in response to the lower elastic modulus (52, 76-80). Secondly, Maddalozzo et al. highlighted that alcohol has effects on bone that are both dependent and independent of caloric intake (81): the self-imposed caloric restriction that occurs with high alcohol intake clearly plays an important role in the skeletal manifestations. Alcohol consumption decreased whole body fat and serum leptin levels, but increased bone marrow fat, producing a decrease in osteoblastogenesis and an increase in osteoclastogenesis (81). Site-specific differences in bone mass were found in a binge alcohol-exposed rat model (82). It was observed that bone loss did not recover during prolonged alcohol abstinence and suggested that young adults engaging in binge alcohol consumption may experience persistent changes in the skeleton leading to a greater susceptibility to fracture and osteoporosis in later decades of life (82). Furthermore, physical activity had no effect on the bone and did not attenuate any of the negative effects of alcohol (83). Finally, Chakkalakal et al. observed that alcohol exposure inhibited osteoid synthesis with the formation of a mixture of osteoid and fibrous tissue in fracture repair. Since fibrosis was predominant, they concluded that the inferior bone repair was due mostly to the inhibition of osteoblast number rather than to the inhibition of mineralization (77, 73).

5.3. Pathophysiology and the role of cytokines

Alcohol decreases blood insulin growth factor levels by decreasing insulin growth factor-I mRNA levels and increases insulin growth factor-I-binding proteins by reducing insulin growth factor-I bioavailability; bone loss and muscle wasting follow (79, 84-85). Alcohol interferes with liver enzymes that are necessary for converting the inactive into the active form of vitamin D. Finally, alcohol increases the release of catecholamines (norepinephrine and epinephrine) and glucorticoids (cortisol, corticosterone), which negatively influence bone metabolism (86).

Chronic alcohol intake (a) increases the local expression of mRNA transcripts of both TNF-alpha and IL-1beta with a consequent enhancement of RANK-ligand induced bone resorption; (b) inhibits the proliferation of osteoblasts and their precursors; (c) increases RANKL mRNA expression in bone marrow cells and osteoblasts; (d) increases protective effects of OPG on alcohol-induced bone loss by blocking increased bone resorption; and (e) increases proinflammatory cytokines (76, 87-89).

By using a binge alcohol rat model, some authors highlighted the relationship between bone damage and modulation of bone transcriptome (82, 72). Acute binging affects the integrin-signaling pathway with a significant increase in mRNA levels of beta3 integrin (Itgb3), which consequently increases alphavbeta3 integrin, the main integrin expressed by osteoclasts (72). The alphavbeta3 integrin enhances both alphavbeta3-mediated matrix attachments and intracellular signaling, leading to the organization of the osteoclast cytoskeleton and formation of the protected resorptive microenvironment required for bone resorption (72). Chronic alcohol binging affects the Wnt signaling pathway at different levels. This deactivates Wnt/beta-catenin signaling, which is important for the trasformation of mesenchymal progenitor cells into the osteoblast lineage (72). Callaci et al. reported that chronic alcohol binging influences the expression of several "bone-forming" genes and the modulation of important regulators of bone resorption: (a) a general decrease in gene expression of bone morphogenetic proteins; (b) a decrease in parathyroid hormone receptor expression levels on osteoblasts by more than 40%; (c) an increase in sclerostin mRNA, a Wnt inhibitor, with a consequent decrease in the maturation of osteoblast precursors and thus in bone formation; (d) a differential expression of RANKL-OPG system by osteoblasts with an increase in RANKL-mediated signaling that decreases the attenuating effect of OPG leading to bone resorption; (e) a decrease in RANK expression as a possible negative feedback loop modulating alcohol-induced osteoclast over-activity; and (f) an increase in IL-6 and oncostatin M expression levels that stimulate bone resorption by increasing expression of RANKL and decreasing OPG expression (82).


6.1. Clinical studies

The literature is full of reports highlighting smoking as a risk factor for primary and secondary osteoporosis, bone fracture incidence and increased nonunion rates (90-105). 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 (106-113). However, it was clearly shown that smoking cessation decreases fracture risk, thus indicating that the detrimental effects of smoking are reversible (114-116). It was also highlighted that the effect of smoking on bone is mainly time and not dose dependent. (116-119) The clinical implication of all these studies was that even moderate smoking has a harmful effect on bone, and thus it should be stopped.(104, 115, 117)

Clinical studies performed on post-menopausal women have shown decreased BMD and increased fracture risk in smokers (15, 13, 107, 120-125). However, the biological mechanisms by which smoking influences bone loss have not been clearly understood (106, 117). Tobacco smoking also contributes to bone loss by interfering with calcium and vitamin D homeostasis, which are vital for bone metabolism (127-128). A negative effect of smoking on BMD has been found in different skeletal sites such as the spine, femoral neck and total body (47, 103, 109, 128-135), but some authors did not find any negative effects on BMD (108, 136-138). In particular, it has been reported that former smokers had similar BMD to that of current smokers and lower compared with that of never smokers at most skeletal sites and lifetime smoking seems to be an independent predictor of BMD.(108-139)

Both current smokers and lifetime tobacco smoking were associated with a deterioration in bone structure and elasticity that were found differently influenced by sex and menopausal status (60, 140-144). Recently, Wust et al. found that smoking compromises bone strength by diaphyseal marrow cavity expansion and epiphyseal trabecular bone content reduction, and that these effect seem to wane with age (145). Smoking-induced changes in gonadal hormones appears to be an unlikely explanation for the gender differences found in many studies. (116-117, 146-147). Nevertheless, the antiestrogenic effects in women are responsible for an increased incidence of early menopause and osteoporosis (113, 135, 146, 148-156).

In recent years there has been increasing interest in the possible adverse effects of cigarette smoke on soft tissue and bone healing following injury (41, 91, 157-163). It has been found that smoking can influence the fracture healing process by reducing blood supply to the injury site, increasing reactive oxygen species in the circulation, and reducing endothelial nitric oxide synthase (94,157, 164-165). A higher incidence of delayed union in fracture healing (43, 60, 91-92, 94, 166-173) and nonunion following spinal fusion (94) have been highlighted. Conversely, a prospective case-control series reported that smoking appears not to affect the preoperative or postoperative course of hip fracture patients(174). Moghaddam et al. showed that tobacco smoking reduces the osteoblast release of TGF-beta1 during fracture healing, and advocated the use of this growth factor as a marker of fracture healing in smokers soon after injury (93). (Table 3).

6.2. Experimental studies

Many experimental studies were performed on the effect of smoking on bone status but most of them were focused mainly on the nicotine effect. Recent studies analyzing the effect of global tobacco smoke suggest that smoking significantly decreases bone mineral density and alters bone structure (175-176). A recent study examined how the duration and cessation of cigarette smoke exposure affects lymphocyte distribution and function in normal mice and in mice predisposed to low or high bone mass due to disruption or mutation of gene Lrp5, a gene involved in canonical Wnt signaling that regulates bone metabolism.(177) This study provided the first evidence that smoke exposure reduces bone marrow B cells, providing a plausible mechanism for how smoking contributes to osteoporosis.(177) Regarding cigarette smoking effects on fracture healing, it has been found that acute cigarette smoke inhalation delays but does not prevent spinal fusion, (178-180) and delays chondrogenesis, and thus, fracture healing.(181) Akhter et al showed the negative effects of high nicotine dose exposure on bone biomechanical properties (decrease in most of the structural strength and apparent material properties of the femoral mid-shaft), bone mass and structure in growing female mice (182-184). Conversely, lower nicotine doses in growing adult female rats, producing serum concentrations similar to those in smokers, had no effect on the biomechanical properties of bone (182).

A link between environmental toxicants found in the tar fraction of tobacco smoke and bone loss was reported by Lee et al. using an ovariectomized rat model (185). They focused on the polycyclic aromatic hydrocarbons interacting with the aryl hydrocarbon receptor as the potential mediators of the toxic effects of tobacco smoking. Benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene are two polycyclic aromatic hydrocarbons found in high concentrations in the tar fraction of tobacco smoke (94). The study suggested that Benzo(a)pyrene / 7,12-dimethylbenz(a)anthracene reduced bone mechanical properties and lowered the BMD and bone connectivity, while stepping up bone formation; these changes are the result of an antiestrogenic effect, leading to an increase in bone turnover.

6.3.Pathophysiology and the role of cytokines

The mechanism of detrimental effects of smoking on bone is complex and probably includes a combination of factors. Nicotine is a potent vasoconstrictor that reduces blood flow and delivery of essential nutriments to injured tissue. It has been shown to increase platelet aggregation, decrease microvascular prostacyclin levels and inhibit the biological function of fibroblasts, red blood cells and macrophages (186). Nicotine inhibits the cell growth of various cell types, including skin fibroblasts, gingival fibroblasts, lung cancer cells and osteosarcoma cells (186). Nicotine modulates osteoblast cell proliferation and differentiation by specific receptors, and reduces collagen synthesis and ALP activity (90, 186-189). Conversely, a study by Gullihorn et al. suggests that nicotine acts as a direct stimulant of ALP activity, total protein and collagen syntheses (190). Recently, Rothem et al. demonstrated that the addiction of nicotine concentrations analogous to those acquired by a light-to-moderate smoker yields increased osteoblast proliferation and bone metabolism (191). Nicotine has a direct effect on human bone cells up-regulating c-fos oncoprotein and osteopontin synthesis, a bone matrix protein indicator of bone turnover and degradation, IL-6 and TNF-alpha (90, 186-189). The high expression of osteopontin might be associated with nicotine effects on bone turnover and, after long-term administration, determining a decrease in BMD or reducing fracture healing rate (90). Recently, Katono et al. observed that nicotine stimulated bone matrix turnover thereby tipping the balance between bone matrix formation and resorption toward the latter process (193). Additionally, smoking was also associated with lower osteocalcin levels indicating a slow and reduced osteoblasts formation and regeneration leading to a decrease in BMD (194).

Furthermore, in in vitro models Nakayama et al. identified three different elements in the rat bone sialoprotein proximal gene promoter that mediate the negative effects of nicotine on bone sialoprotein transcription, a sulphated and phosphorylated glycoprotein involved in osteoblast differentiation and bone matrix mineralization, with a consequent decrease in bone turnover (186).

In relation to the effect of other toxic smoke components, moieties contained in tobacco smoke extract can influence bone cell recruitment and contraction of extracellular matrices through the inhibition of bone cell fibronectin production (188).


While for years we have been witnessing the progressive education on smoking and the risk of lung cancer and cardiovascular disease, obesity, diabetes and hypertension, and alcohol or severe liver disease, there is a lack of information about the serious side effects on bone metabolism such as osteoporosis and fractures. Numerous pre-clinical and clinical studies have begun to explore these issues, taking into account many factors, which may negatively influence the effect of these harmful lifestyles on bone (20-21, 32, 43, 60, 120-122,169-171). In this article the authors collected evidence that lifestyles that includes non-smoking, no alcohol abuse and avoidance of weight loss is advantageous for maintaining bone heath through life. Documentation of not only the association, but also the size of the effect between lifestyles and bone health can be helpful in promoting public health advice.

The risk factors analyzed by most of the clinical studies selected are related to hip fracture or less frequently to decrease in BMD. Concerning the risk factors associated with BMD variations, it has been reported to be OR=2.84 with a BMI=25-30 kg/m2 and OR=5.94 with a BMI>30 kg/m2 for postmenopausal women (195). Korpelainen et al. reported in postmenopausal women significant RR for low daily physical exertion and daily dietary calcium intake in relation to different ranges of BMI (Table 1) (19). It appears that daily physical activity and modification of dietary intake contribute positively to BMD results. Weight loss is important for the reduction of chronic conditions, such as heart diseases and osteoarthrosis (196), but weight loss or repeated cycles of weight loss and regaining weight increase fracture risk (197) and reduce BMD, mainly by malnutrition (198-201). Therefore, a balanced diet with correct intakes of protein and calcium is mandatory. In fact, inadequate or excessive protein intakes adversely affect BMD (202-203) through calcium mobilization from bone to balance endogenous acidity produced during protein intake, increasing urinary calcium excretion and stimulating PTH hormone circulation (203). Conversely, a high-protein diet may protect against bone loss during weight reduction (204), because overweight patients who consume energy-restricted diets with protein do not experience adverse changes in markers of bone turnover, preventing some of the inevitable loss of lean body mass (205). Calcium supplementation attenuates these changes in bone metabolism during energy restriction (198, 206) by the activation of calcium-parathyroid hormone axis (207) and it is recommended during weight loss (200). Furthermore, physical activity may help to prevent bone loss through both direct effects on skeleton and indirect effects on muscle mass (19, 32); however the literature shows discordant results (32, 208).

Lifestyle changes to address modifiable risk factors are beneficial and defining an intake limit of alcohol beverages is mandatory. The risk associated with alcohol consumption has been reported to be J-shaped or U-shaped for hip fracture (RR = 0.84 for ≤ 0.5 drinks/day, RR=0.80 for 0.5 - 1.0 drinks/day, and RR=1.39 for > 2 drinks/day) in that abstainers from alcohol have a higher risk that that of individuals consuming 1 or 2 units daily (40,41). Even though the beneficial association between moderate drinking of alcohol and bone health is consistent across many studies, this association deserves further exploration. Evidence is insufficient to determine relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers. In addition, clinical human studies that are aimed at delineating more fully the etiology and mechanisms of the effects of alcohol are often complicated by difficulties in carefully controlling for lifestyle factors such as nutrition and activity level (209).

Finally, as far as the risk associated with smoking is concerned, it has been reported to be linear for osteoporosis and fracture. In particular, the hip fracture risk was RR = 1.41 in smokers, RR = 1.59 in smokers with osteoporosis (98) and up to RR = 2.20 in ever-smokers (163). Trimpou et al. reported a linear association for HR in hip fracture: HR = 1.00 in never smokers, HR = 1.06 in ex-smokers e di HR = 1.58 in smokers (105). Osteoporosis also is associated with higher odds of femoral neck bone loss: OR=1.0 in never smokers; OR = 1.02 ex smokers; and OR=2.09 in smokers. However, many of these surveys suffer from an incorrect, usually underestimated number of cigarettes smoked. Furthermore, the number of cigarettes considered as a risk varies among studies.

Smoking is again generating controversy in the medical press even though there is now adequate evidence from this and other studies to advise patients to stop smoking to minimize these complications. There are many factors that contribute to the smoking habit, unrealistic perception of personal susceptibility to the health hazards of smoking may be an important determinant of cigarette smoking and a barrier to smoking cessation. Perception of the risk is important in several well-established models of preventive behavior (1-2, 12). The available evidence largely shows that smokers in general acknowledge the health risk associated with smoking but underestimate the magnitude and personal relevance. Despite large-scale public health campaigns to inform the public of the heath risk of smoking, the majority of smokers in the population did not perceive that they were at increased risk produced by the effects of cigarette smoking. Although communication of the risk is one aspect of the campaign to decrease smoking, the extent of the role of communicating the risk to stop smoking cannot be known until researchers are able to show an accurate perception of the risk of smoking (1-2, 12).

As for future preclinical studies, the pathophysiological mechanisms of harmful lifestyles underlying the metabolic alterations of bone tissue occurring in some osteoporotic patients should be clarified. In particular, preclinical models resolving some problems such as experimental models and setup, routes of administration, dosages and methods of assessment should be further developed. However, health information campaigns on these harmful lifestyles should be strengthened by using available scientific information to increase the awareness of their consequences on the musculoskeletal system.


This work was supported by the Italian Ministry of Education, University and Research - FIRB Project RBAP10KCNS "Pathogenesis and molecular targets for degenerative diseases of the musculoskeletal. The authors wish to thank Mr. Keith Smith for his assistance in language supervision


1.H.W. Sampson: Alcohol and other factors affecting osteoporosis risk in women. Alcohol Res Health 26, 292-298 (2002)
PMid:12875040 (doi not found)

2.R. Doll, R. Peto and J. Boreham, I. Sutherland: Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ 328(7455), 1-9 (2004) (doi not found)
PMid:14703521    PMCid:313879

3.T. Pischon, U. Nöthlings and H. Boeing: Obesity and cancer. Proc Nutr Soc 67(2), 128-45 (2008)

4.Prospective Studies Collaboration, G . Whitlock, S. Lewington, P. Sherliker, R. Clarke, J. Emberson, J. Halsey, N. Qizilbash, R. Collins, R. Peto: Prospective Studies Collaboration: Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet, 373,1083-1096 (2009) (doi not found)
PMid:19299006    PMCid:2662372

5.S.T. Stewart, D.M. Cutler, A.B. Rosen: Forecasting the effects of obesity and smoking on U.S. life expectancy. N Engl J Med, 361, 2252-2260 (2009)

6.Department of Nutrition for Health and Development (NHD) Fact sheet N�311 September 2006:Obesity and overweight. World Health Organization,Geneva (2006) (doi not found)

7.Department of Mental Health and Substance Dependence Noncommunicable Diseases and Mental Health Cluster World Health Organization: International guide for monitoring alcohol consumption and related harm. World Health Organization, Geneva (2000) (doi not found)

8.M. Schuckit: Alcohol-use disorders. Lancet, 373, 492-501 (2009)

9.World Health Organization Department of Mental Health and Substance Abuse Geneva 2004: WHO Global Status Report on Alcohol 2004. © World Health Organization 2004 - Geneva. (doi not found)

10.J.A. Papadakis, E.S. Ganotakis and D.P. Mikhailidis: Beneficial effect of moderate of alcohol consumption on vascular disease: myth or reality? J R Soc Promot Helath, 120, 111-53 (2000)

11.D.M. Burns: Tobacco-related diseases. Semin Oncol Nurs, 19, 244-49 (2003)

12.World Health Organization Report on the Global Tobacco Epidemic, 2009: Implementing smoke-free environments. World Health Organization Tobacco Free Initiative Non communicable Diseases and Mental Health. World Health Organization - Geneva 2009. (doi not found)

13.L.N. Bakhireva, E. Barrett-Connor, D. Kritz-Silverstein and D.J. Morton: Modifiable predictors of bone loss in older men: a prospective study. Am J Prev Med, 26(5), 436-42 (2004).

14.S.E. Woods, J. Springett, L. Porcellato and L. Dugdill: 'Stop it, it's bad for you and me': experiences of and views on passive smoking among primary-school children in Liverpool. Health Educ Res 20(6):645-55 (2005)

15.S. Muraki, S. Yamamoto, H. Ishibashi, H. Oka, N. Yoshimura, H. Kawaguchi and K. Nakamura: Diet and lifestyle associated with increased bone mineral density: cross-sectional study of Japanese elderly women at an osteoporosis outpatient clinic. J Orthop Sci 12(4), 317-20, (2007)

16.L.J. Zhao, Y.J. Liu, P.Y. Liu, J. Hamilton, R.R. Recker and H.W. Deng: Relationship of obesity with osteoporosis. J Clin Endocrinol Metab, 92, 1640-46 (2007)

17.S. Morin and W.D. Leslie: High bone mineral density is associated with high body mass index. Osteoporos Int 20, 1267-1271 (2009)

18.J.S. Lee, K. Kawakubo, H. Sato, Y. Kobayashi and Y. Haruna: Relationship between total and regional bone mineral density and menopausal state, body composition and life style factors in overweight Japanese women Int J Obese Relat Metab Disord 25, 880-886 (2001) (doi not found)

19.R. Korpelainen, J. Korpelainen, J. Heikkinen, K. Väänänen and S. Keinänen-Kiukaanniemi: Lifestyle factors are associated with osteoporosis in lean women but not in normal and overweight women: a population-based cohort study of 1222 women. Osteoporos Int 14, 34-43 (2003)

20.M.O. Premaor, L. Pilbrow, C. Tonkin, R.A. Parker and J. Compston: Obesity and fractures in postmenopausal women. J Bone Miner Res 25, 292-297 (2010)

21.N.P. Nunez, C.L. Carpenter, S.N. Perkins, D. Berrigan, S.V. Jaque and S.A. Ingles, L. Bernstein, M.R. Forman, J.C. Barrett, S.D. Hursting: Extreme obesity reduces bone mineral density: complementary evidence from mice and women. Obesity15, 1980-87 (2007)

22.H.G. Valente da Silva, L.M.C. MendonçaII, F.L. ConceiçãoI, S.E.V. ZaharIII and M.L.F. FariasI: Influence of obesity on bone density in postmenopausal women. Arq Bras Endocrinol Metabol 51/6, 943-949 (2007) (doi not found)

23.C.G. Gjesdal, J.H. Halse, G.E. Eide and J.G. Brun, G.S. Tell: Impact of lean mass and fat mass on bone mineral denity. The Hordaland Health Study. Maturitas 59, 191-200 (2008)

24.L.T. Ho-Pham, N.D. Nguyen, T.Q. Lai and T.V Nguyen: Contributions of lean mass and fat mass to bone mineral density: a study in postmenopausal women. Musculoskelet Disord 11, 1-9 (2010) (doi not found)

25.K.J. Stewart, J.R. Deregis, K.L. Turner, A.C. Bacher, J. Sung, P.S. Hees, M. Tayback and P. Ouyang: Fitness, fatness and activity as predictors of bone mineral density in older persons. J Intern Med 252, 381-388 (2002)

26.Buchholz AL, Niesen MC, Gausden EB, Sterken DG, Hetzel SJ, Baum SZ, Squire MW, Kaplan LD: Metabolic activity of osteoarthritic knees correlates with BMI. Knee 17, 161-166 (2010)

27.A.J. Teichtahl, A.E. Wluka, Y. Wang, F. Hanna, D.R. English, G.G. Giles and F.M. Cicuttini: Obesity and adiposity are associated with the rate of patella cartilage volume loss over 2 years in adults without knee osteoarthritis. Ann Rheum Dis 68, 909-913 (2009)

28.U.T. Iwaniec, M.G. Dube, S. Boghossian, H. Song, W.G. Helferich, R.T. Turner and S.P. Kalra: Body mass influences cortical bone mass independent of leptin signaling. Bone 44, 404-412 (2009)

29.A.E. Stevenson, B.A. Evans, E.F. Gevers, C. Elford, R.W. McLeod, M.J. Perry, M.M. El-Kasti, K.T. Coschigano, J.J. Kopchick, S.L. Evans and T. Wells: Does adiposity status influence femoral cortical strength in rodent models of growth hormone deficiency? Am J Physiol Endocrinol Metab 296, 147-156 (2009)
PMid:19001545    PMCid:2636985

30.H. Heep, G. Hilken, S. Hofmeister and C. Wedemeyer: Osteoarthritis of leptin-deficient ob/ob mice in response to biomechanical loading in micro-CT. Int J Biol Sci 5(3), 265-275 (2009) (doi not found)
PMid:19343112    PMCid:2664549

31.J.J. Cao, L. Sun and H. Gao: Diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice. Ann NY Acad Sci 1192, 292-297 (2010)

32.D.T. Villareal, K. Shah, M.R. Banks, D.R. Sinacore and S. Klein: Effect of weight loss and exercise therapy on bone metabolism and mass in obese older adults: a one-year randomized controlled trial. J Clin Endocrinol Metab 93, 2181-2187 (2008)

33.R.A. Samra, N.H. Baba, N. Torbay, L. Dib and G.E.H. Fuleihan: High plasma Leptin is not associated with higher bone mineral density in Insulin-Resistant premenopausal obese women. J Clin Endocrinol Metab, 90, 2588-2594 (2005)

34.M. Pirro, G. Fabbriciani, C. Leli, L. Callarelli, M.R. Manfredelli, C. Fioroni, M.R. Mannarino, A.M. Scarponi and E. Mannarino: High weight or body mass index increase the risk of vertebral fractures in postmenopausal osteoporotic women. J Bone Miner Metab 28, 88-93 (2010)

35.G. Fruhbeck, J. Gómez-Ambrosi, F.J. Muruzábal and M.A. Burrell: The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metabol 280, 827-847 (2001) (doi not found)

36.R. Filip and G. Raszewski: Bone mineral density and bone turnover in relation to serum leptin, alpha-ketoglutarate and sex steroids in overweight and obese postmenopausal women. Clin Endocrinol 70, 214-20 (2009)

37.S.A. Shapses and C.S. Riedt: Bone, body weight, and weight reduction: what are the concerns? J Nutr 136, 1453-1456 (2006) (doi not found)

38.L. Lenchik, T.C. Register, F.C. Hsu, K. Lohman, B.J. Nicklas, B.I. Freedman, C.D. Langefeld, J.J. Carr and D.W. Bowden: Adiponectin as a novel determinant of bone mineral density and visceral fat. Bone 33, 646-651 (2003)

39.J.P. Despres and I. Lemieux: Abdominal obesity and metabolic syndrome. Nature 444(14), 881-887 (2006).

40.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 121(5), 406-18 (2008)
PMid:18456037    PMCid:2692368

41.J.A. Kanis, H. Johansson, O. Johnell, A. Oden, C. De Laet, J.A. Eisman, H. Pols and A. Tenehouse: Alcohol intake as a risk factor for fracture. Osteoporos Int 16, 731-742 (2005)

42.K.J. Mukamal, J.A. Robbins, J.A. Cauley, L.M. Kern and D.S. Siscovick: Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study. Osteoporos Int 18(5), 593-602 (2007)

43.S.R. Pye, V. Devakumar, S. Boonen, H. Borghs, D. Vanderschueren, J.E. Adams, K.A. Ward, G. Bartfai, F.F. Casanueva, J.D. Finn, G. Forti, A. Giwercman, T.S. Han, I.T. Huhtaniemi, K. Kula, M.E. Lean, N. Pendleton, M. Punab, A.J. Silman, F.C. Wu and T.W. O'Neill: EMAS Study Group. Influence of lifestyle factors on quantitative heel ultrasound measurements in middle-aged and elderly men. Calcif Tissue Int 86(3), 211-219 (2010)

44.P.M. Cawthon, S.L. Harrison, E. Barrett-Connor, H.A. Fink, J.A. Cauley, C.E. Lewis, E.S. Orwoll and S.R. Cummings: Alcohol intake and its relationship with bone mineral density, falls, and fracture risk in older men. J Am Geriatr Soc 54, 1649-1657 (2006)

45.Tucker KL, R. Jugdaohsingh, J.J. Powell, N. Qiao, M.T. Hannan, S. Sripanyakorn, L.A. Cupples and D.P. Kiel: Effects of beer, wine, and liquor intakes on bone mineral density in older men and women. Am J Clin Nutr 89, 1188-1196 (2009)
PMid:19244365    PMCid:2667462

46.T.E. Hefferan, A.M. Kennedy, G.L. Evans and R.T. Turner: Disuse exaggerates the detrimental effects of alcohol on cortical bone. Alcohol Clin Exp Res 27, 111-117 (2003)

47.M. Lunt, P. Masaryk, C. Scheidt-Nave, J. Nijs, G. Poor, H. Pols, J.A. Falch, G. Hammermeister, D.M. Reid, L. Benevolenskaya, K. Weber, J. Cannata, T.W. O'Neill, D. Felsenberg, A.J. Silman and J. Reeve: The effects of lifestyle, dietary dairy intake and diabetes on bone density and vertebral deformity prevalence: the EVOS study. Osteoporos Int 12(8), 688-98 (2001).

48.E.M. Lau, P. Suriwongpaisal, J.K. Lee, S. Das De, M.R. Festin, S.M. Saw, A. Khir, T. Torralba, A. Sham and P. Sambrook: Risk factors for hip fracture in Asian men and women: the Asian osteoporosis study. J Bone Miner Res 16(3), 572-80 (2001).

49.J.J.E. Johnston and McGovern: Alcohol related falls: an interesting pattern of injuries. Emerg Med J 21, 185-188 (2004)
PMid:14988344    PMCid:1726307

50.L. Wang, G. Van Belle, W.B. Kukull and E.B. Larson: Predictors of functional change: a longitudinal study of nondemented people aged 65 and older. J Am Geriatr Soc 50(9), 1525-34 (2002)

51.J. Huuskonen, S.B. Väisänen, H. Kröger, J.S. Jurvelin, E. Alhava and R. Rauramaa: Regular physical exercise and bone mineral density: a four-year controlled randomized trial in middle-aged men. The DNASCO study. Osteoporos Int 12(5), 349-55 (2001)

52.R.T. Turner: Skeletal response to alcohol. Alcohol Clin Exp Res 24(11), 1693-701 (2000)

53.J.J. Callaci, D. Juknelis, A. Patwardhan, M. Sartori, N. Frost and F.H. Wezeman: The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment. Alcohol Clin Exp Res 28, 182-91 (2004)

54.Z. Gong and F.H. Wezeman: Inhibitory effect of alcohol on osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Alcohol Clin Exp Res 28, 468-79 (2004)

55.A. Imhof, M. Woodward, A. Doering, N. Helbecque, H. Loewel, P. Amouyel, G.D. Lowe, W. Koenig: Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: results from three MONICA samples (Augsburg, Glasgow, Lille). Eur Heart J 25(23), 2092-100 (2004)

56.J. Alvisa-Negrín, E. González-Reimers, F. Santolaria-Fernández, E. García-Valdecasas-Campelo, M.R. Valls, R. Pelazas-González, M.C. Durán-Castellón and M. de Los Angeles Gómez-Rodríguez: Osteopenia in alcoholics: effect of alcohol abstinence. Alcohol 44(5), 468-75 (2009) (doi not found)

57.K.S. Wosje and H.J. Kalkwarf: Bone density in relation to alcohol intake among men and women in the United States. Osteoporos Int 18, 391-400 (2007)

58.Z. Yuan, N. Dawson, G.S. Cooper, D. Einstadter, R. Cebul and A.A. Rimm: Effects of alcohol-related disease on hip fracture and mortality: a retrospective cohort study of hospitalized Medicare beneficiaries. Am J Public Health 91(7), 1089-93 (2001)
PMid:11441736    PMCid:1446699

59.J.A. Baron, B.Y. Farahmand, E. Weiderpass, K. Michaëlsson, A. Alberts, I. Persson and S. Ljunghall: Cigarette smoking, alcohol consumption, and risk of hip fracture in women. Arch Intern Med 161(7), 983-8 (2001)

60.F.M. Williams, L.F. Cherkas, T.D. Spector and A.J. MacGregor: The effect of moderate alcohol consumption on bone mineral density: a study of female twins. Ann Rheum Dis 64(2), 309-10 (2004)
PMid:15231511    PMCid:1755353

61.P.B. Rapuri, J.C. Gallagher, K.E. Balhorn and K.L. Ryschon: Alcohol intake and bone metabolism in elderly women. Am J Clin Nutr 72, 1206-13 (2000) (doi not found)

62.R. Jugdaohsingh, M.A. O'Connell, S. Sripanyakorn and J.J. Powell: Moderate alcohol consumption and increased bone mineral density: potential ethanol and non-ethanol mechanisms. Proc Nutr Soc 65, 291-310 (2006)

63.J.D. Pedrera-Zamorano, J.M. Lavado-Garcia, R. Roncero-Martin, J.F. Calderon-Garcia, T. Rodriguez-Dominguez and M.L. Canal-Macias: Effect of beer drinking on ultrasound bone mass in women. Nutrition 25(10), 1057-63 (2009)

64.L.J. Tivis and R.D. Tivis: One-per-occasion or less: are moderate-drinking postmenopausal women really healthier than their nondrinking and heavier-drinking peers? Alcohol Clin Exp Res 32(9), 1670-80 (2008)
PMid:18616686    PMCid:2579961

65.K.K. Venkat, M.M. Arora, P. Singh, M. Desai and I. Khatkhatay: Effect of alcohol consumption on bone mineral density and hormonal parameters in physically active male soldiers. Bone 45(3), 449-54 (2009)

66.R.C. Vignesh, S. Sitta Djody, E. Jayasudha, V. Gopalakrishnan, R. Ilangovan, M. Balaganesh, S. Veni, M. Sridhar and N. Srinivasan: Effect of ethanol on human osteosarcoma cell proliferation, differentiation and mineralization. Toxicology 220, 63-70 (2006)

67.P. Torricelli, M. Fini, G. Giavaresi, V. Borsari, L. Rimondini, R. Rimondini, A. Carrassi and R. Giardino: Intermittent exposure to ethanol vapor affects osteoblasts behaviour more severely than estrogen deficiency does. In vitro study on rat osteoblasts. Toxicology 237, 168-76 (2007)

68.J.R. Chen, O.P. Lazarenko, R.L. Haley, M.L. Blackburn, T.M. Badger and M.J. Ronis: Ethanol impairs estrogen receptor signaling resulting in accelerated activation of senescence pathways, whereas estradiol attenuates the effects of ethanol in osteoblasts. J Bone Miner Res 24(2), 221-30 (2009).

69.J.R. Chen, K. Shankar, S. Nagarajan, T.M. Badger and M.J. Ronis: Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-kappaB ligand signaling cascade. J Pharmacol Exp Ther 324(1), 50-9 (2008).

70.M.L. Rosa, M.M. Beloti, N. Prando, R.H. Queiroz, P.T. de Oliverira and A.L. Rosa: Chronic ethanol intake inhibits in vitro osteogenesis induced by osteoblasts differentiated from stem cells. J Appl Toxicol 28, 205-11 (2008)

71.R. Himes, F.H. Wezeman and J.J. Callaci: Identification of novel bone-specific molecular targets of binge alcohol and ibandronate by transcriptome analysis. Alcohol Clin Exp Res 32, 1167-80 (2008)
PMid:18537941    PMCid:2728683

72.J.J. Callaci, R. Himes, K. Lauing, F.H. Wezeman and K. Brownson: Binge alcohol-induced bone damage is accompanied by differential expression of bone remodeling-related genes in rat vertebral bone. Calcif Tissue Int 84, 474-84 (2009)
PMid:19330277    PMCid:2693714

73.D.A. Chakkalakal, J.R. Novak, E.D. Fritz, T.J. Mollner, D.L. McVicker, K.L. Garvin, M.H. McGuire and T.M. Donohue: Inhibition of bone repair in a rat model for chronic and excessive alcohol consumption. Alcohol 36, 201-14 (2005)

74.P.D. Broul�k, J. Vondrov�, P. Růzicka, R. Sedl�cek and T. Z�ma: The effect of chronic alcohol administration on bone mineral content and bone strength in male rats. Physiol Res 59(4), 599-604 (2010) (doi not found)

75.R.T. Turner, G.L. Evans, M. Zhang and J.D. Sibonga: Effects of parathyroid hormone on bone formation in a rat model for chronic alcohol abuse. Alcohol Clin Exp Res 25(5), 667-71 (2001)

76.D.S. Perrien, Z. Liu, E.C. Wahl, R.C. Bunn, R.A. Skinner, J. Aronson, J. Fowlkes, T.M. Badger and C.K. Lumpkin Jr: Chronic ethanol exposure is associated with a local increase in TNF-alpha and decreased proliferation in the rat distraction gap. Cytokine 23, 179-89 (2003)

77.D.A. Chakkalakal, J.R. Novak, E.D. Fritz, T.J. Mollner, D.L. McVicker, D.L. Lybarger, M.H. McGuire and T.M. Donohue Jr.: Chronic ethanol consumption results in deficient bone repair in rats. Alcohol 37(1), 13-20 (2002) (doi not found)

78.H. Chen, D. Hayakawa, S. Emura, Y. Ozawa, H. Taguchi, R. Yano and S. Shoumura: Effects of ethanol on the ultrastructure of the hamster femur. Histol Histopathol 16(3), 763-70 (2001) (doi not found)

79.F.H. Wezeman and Z. Gong: Bone marrow triglyceride accumulation and hormonal changes during long-term alcohol intake in male and female rats. Alcohol Clin Exp Res 25(10), 1515-22 (2001)

80.F.H. Wezeman, D. Juknelis, N. Frost and J.J. Callaci: Spine bone mineral density and vertebral body height are altered by alcohol consumption in growing male and female rats. Alcohol 31(1-2), 87-92 (2003)
PMid:14615015    PMCid:3065176

81.G.F. Maddalozzo, R.T Turner, C.H. Edwards, K.S. Howe, J.J. Widrick, C.J. Rosen and U.T. Iwaniec: Alcohol alters whole body composition, inhibits bone formation, and increases bone marrow adiposity in rats. Osteoporos Int 20, 1529-38 (2009)

82.J.J. Callaci, D. Juknelis, A. Patwardhan and F.H. Wezeman: Binge alcohol treatment increases vertebral bone loss following ovariectomy: compensation by intermittent parathyroid hormone. Alcohol Clin Exp Res 30, 665-72 (2006)
PMid:16573585    PMCid:3065175

83.A.H. Reed, H.L. McCarty, G.L. Evans, R.T. Turner and K.C. Westerlind: The effects of chronic alcohol consumption and exercise on the skeleton of adult male rats. Alcohol Clin Exp Res 26(8), 1269-74 (2002)

84.D.V. Rai, G. Kumar, P. Tewari and D.C. Saxena: Acute and chronic dose of alcohol affect the load carrying capacity of long bone in rats. J Biomech 41(1), 20-4 (2008)

85.K. Keiver, S. Duggal and M.E. Simpson: Ethanol administration results in a prolonged decrease in blood ionized calcium levels in the rat. Alcohol 37(3), 173-8 (2005)

86.P. Patterson-Buckendahl, L.A. Pohorecky, L. Kubovcakova, O. Krizanova, R.B. Martin, D.A. Martinez and R. Kvetnanský: Ethanol and stress activate catecholamine synthesis in the adrenal: effects on bone. Ann N Y Acad Sci 1148, 542-51(2008)

87.J. Zhang, J. Dai, J. Dai, D.L. Lin, P. Habib, P. Smith, J. Murtha, Z. Fu, Z. Yao, Y. Qi and E.T. Keller: Osteoprotegerin abrogates chronic alcohol ingestion-induced bone loss in mice. J Bone Miner Res 17, 1256-63 (2002)

88.E.C. Brown, D.S. Perrien, T.W. Fletcher, D.J. Irby, J. Aronson, G.G. Gao, W.J. Hogue, R.A. Skinner, L.J. Suva, M.J. Ronis, R. Hakkak, T.M. Badger and C.K. Lumpkin Jr: Skeletal toxicity associated with chronic ethanol exposure in a rat model using total enteral nutrition. J Pharmacol Exp Ther 301(3), 1132-8 (2002)

89.E.C. Wahl, L. Liu, D.S. Perrien, J. Aronson, W.R. Hogue, R.A. Skinner, M. Hidestrand, M.J. Ronis, T.M. Badger and C.K. Lumpkin Jr: A novel mouse model for the study of the inhibitory effects of chronic ethanol exposure on direct bone formation. Alcohol 39(3), 159-67 (2006)

90.L.M. Walker, M.R. Preston, J.L. Magnay, P.B. Thomas and A.J. El Haj: Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone 28, 603-08 (2001)

91.C.I. Adams, J.F. Keating and C.M. Court-Brown: Cigarette smoking and open tibial fractures. Injury 32, 61-65 (2001)

92.E.J. Harvey, J. Agel, H.S. Selznick, J.R. Chapman and M.B. Henley: Deleterious effect of smoking on healing of open tibia-shaft fractures. Am J Orthop 31, 518-21 (2002) (doi not found)

93.A. Moghaddam, S. Weiss, C.G. Wölfl, K. Schmeckenbecher, A. Wentzensen, P.A.Grützner and G. Zimmermann: Cigarette smoking decreases TGF-beta1 serum concentrations after long bone fracture. Injury 41, 1020-1025 (2010)

94.A. Sloan, I. Hussain, M. Maqsood, O. Eremin and M. El-Sheemy: The effects of smoking on fracture healing. Surgeon 8, 111-16 (2010)

95.A.O. Mueck and H. Seeger: Smoking, estradiol metabolism and hormone replacement therapy. Arzneimittelforschung 53(1), 1-11 (2003) (doi not found)

96.K. Tansavatdi, B. McClain and D.M. Herrington: The effects of smoking on estradiol metabolism. Minerva Ginecol 56(1), 105-14 (2004) (doi not found)

97.C. Kessenich: An approach to postmenopausal osteoporosis treatment: a case study review. J Am Acad Nurse Pract 15(12), 539-45 (2003)

98.P. Stolee, J. Poss, R.J. Cook, K. Byrne and J.P. Hirdes: Risk factors for hip fracture in older home care clients. J Gerontol A Biol Sci Med Sci 64(3), 403-10 (2009)
PMid:19196903    PMCid:2654998

99.H. Hermizi, O. Faizah, S. Ima-Nirwana, S. Ahmad Nazrun and M. Norazlina: Beneficial effects of tocotrienol and tocopherol on bone histomorphometric parameters in sprague-dawley male rats after nicotine cessation. Calcif Tissue Int 84(1), 65-74 (2009)

100.H. Jutberger, M. Lorentzon, E. Barrett-Connor, H. Johansson, J.A. Kanis, O. Ljunggren, M.K. Karlsson, B.E. Rosengren, I. Redlund-Johnell, E. Orwoll, C. Ohlsson and D. Mellström: Smoking predicts incident fractures in elderly men: Mr OS Sweden. J Bone Miner Res 25(5), 1010-6 (2010) (doi not found)

101.A. Papaioannou, C.C. Kennedy, G. Ioannidis, J.P. Brown, A. Pathak, D.A. Hanley, R.G. Josse, R.J. Sebaldt, W.P. Olszynski, A. Tenenhouse, T.M. Murray, A. Petrie, C.H. Goldsmith and J.D. Adachi: Determinants of health-related quality of life in women with vertebral fractures. Osteoporos Int 17(3), 355-63 (2006)

102.A. Papaioannou, C.C. Kennedy, A. Cranney, G. Hawker, J.P. Brown, S.M. Kaiser, W.D. Leslie, C.J. O'Brien, A.M. Sawka, A. Khan, K. Siminoski, G. Tarulli, D. Webster, J. McGowan andJ.D. Adachi: Risk factors for low BMD in healthy men age 50 years or older: a systematic review. Osteoporos Int 20(4), 507-18 (2009)

103.R. Bensen, J.D. Adachi, A. Papaioannou, G. Ioannidis, W.P. Olszynski, R.J. Sebaldt, T.M. Murray, R.G. Josse, J.P. Brown, D.A. Hanley, A. Petrie, M. Puglia, C.H. Goldsmith and W. Bensen: Evaluation of easily measured risk factors in the prediction of osteoporotic fractures. BMC Musculoskelet Disord 6 (47), 1-9 (2005) (doi not found)
PMid:15777484    PMCid:547908

104.P. Vestergaard and L. Mosekilde: Fracture risk associated with smoking: a meta-analysis. J Intern Med 254(6), 572-83 (2003)

105.P. Trimpou, K. Landin-Wilhelmsen, A. Odén, A. Rosengren and L. Wilhelmsen: Male risk factors for hip fracture-a 30-year follow-up study in 7,495 men. Osteoporos Int 21(3), 409-16 (2010)

106.Compston J: Smoking and the Skeleton. J Clin Endocrinol Metab 92, 428-429 (2007)

107.Y. Taes, B. Lapauw, G. Vanbillemont, V. Bogaert, D. De Bacquer, S. Goemaere, H. Zmierczak and J.M. Kaufman: Early smoking is associated with peak bone mass and prevalent fractures in young, healthy men. J Bone Miner Res 25(2), 379-87 (2010)

108.P. Szulc, P. Garnero, B. Claustrat, F. Marchand, F. Duboeuf and P.D. Delmas: Increased bone resorption in moderate smokers with low body weight: the Minos study. J Clin Endocrinol Metab 87(2), 666-74 (2002)

109.M. Lorentzon, D. Mellström, E. Haug and C. Ohlsson: Smoking is associated with lower bone mineral density and reduced cortical thickness in young men. J Clin Endocrinol Metab 92, 497-503 (2007)

110.C.W. Kuo, T.H. Chang, W.L. Chi and T.C. Chu: Effect of cigarette smoking on bone mineral density in healthy Taiwanese middle-aged men. J Clin Densitom 11(4), 518-24 (2008)

111.J. Porthouse, Y.F. Birks, D.J. Torgerson, S. Cockayne, S. Puffer and I. Watt: Risk factors for fracture in a UK population: a prospective cohort study. QJM 97(9), 569-74 (2004)

112.D.J. Van der Voort, P.P. Geusens and G.J. Dinant: Risk factors for osteoporosis related to their outcome: fractures. Osteoporos Int 12(8), 630-8 (2001)

113.D.J. Van Der Voort, P.H. van Der Weijer and R. Barentsen: Early menopause: increased fracture risk at older age. Osteoporos Int 14(6), 525-30 (2003)

114.C. Oncken, K. Prestwood, A. Kleppinger, Y. Wang, J. Cooney and L. Raisz: Impact of smoking cessation on bone mineral density in postmenopausal women. J Womens Health 15, 1141-50 (2006)

115.C. Oncken, K. Prestwood, J.L. Cooney, C. Unson, P. Fall, M. Kulldorff and L.G. Raisz: Effects of smoking cessation or reduction on hormone profiles and bone turnover in postmenopausal women. Nicotine Tob Res 4(4), 451-8 (2002)

116.K.D. Ward and R.C. Klesges: A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif Tissue Int 68(5), 259-70 (2001)

117.M. Sneve, N. Emaus, R.M. Joakimsen and R. Jorde: The association between serum parathyroid hormone and bone mineral density, and the impact of smoking: the Tromso Study. Eur J Endocrinol 158(3), 401-9, (2008)

118.A. Supervía, X. Nogués, A. Enjuanes, J. Vila, L. Mellibovsky, S. Serrano, J. Aubía and A. Díez-Pérez: Effect of smoking and smoking cessation on bone mass, bone remodeling, vitamin D, PTH and sex hormones. J Musculoskelet Neuronal Interact 6(3), 234-41 (2006) (doi not found)

119.P. Gerdhem and K.J. Obrant: Effects of cigarette-smoking on bone mass as assessed by dual-energy X-ray absorptiometry and ultrasound. Osteoporos Int 13(12), 932-6 (2002)

120.J.Z. Ilich, R.A. Brownbill, L. Tamborini and Z. Crncevic-Orlic: To drink or not to drink: how are alcohol, caffeine and past smoking related to bone mineral density in elderly women? J Am Coll Nutr 21(6), 536-44 (2002) (doi not found)

121.L. Sewón, M. Laine, S. Karjalainen, A. Doroguinskaia and M. Lehtonen-Veromaa: Salivary calcium reflects skeletal bone density of heavy smokers. Arch Oral Biol 49(5), 355-8 (2004)

122.E.M. Lau, P.C. Leung, T. Kwok, J. Woo, H. Lynn, E. Orwoll, S. Cummings and J. Cauley: The determinants of bone mineral density in Chinese men--results from Mr. Os (Hong Kong), the first cohort study on osteoporosis in Asian men. Osteoporos Int 17(2), 297-303 (2006)

123.A. Baheiraei, N.A. Pocock, J.A. Eisman, N.D. Nguyen and T.V. Nguyen: Bone mineral density, body mass index and cigarette smoking among Iranian women: implications for prevention. BMC Musculoskelet Disord 6 (34), 1-9 (2005) (doi not found)
PMid:15777484    PMCid:547908

124.J.D. Lin, J.F. Chen, H.Y. Chang and C. Ho: Evaluation of bone mineral density by quantitative ultrasound of bone in 16,862 subjects during routine health examination. Br J Radiol 74(883), 602-6 (2001) (doi not found)

125.A. Stewart, D. Felsenberg, R. Eastell, C. Roux, C.C. Glüer and D.M. Reid: Relationship between risk factors and QUS in a European Population: The OPUS study. Bone 39(3), 609-15 (2006)

126.J. Sirola, H. Kröger, R. Honkanen, L. Sandini, M. Tuppurainen, J.S. Jurvelin and S. Saarikoski: Smoking may impair the bone protective effects of nutritional calcium: a population-based approach. J Bone Miner Res 18(6), 1036-42 (2003)

127.A.G. Need, A. Kemp, N. Giles, H.A. Morris, M. Horowitz and B.E. Nordin: Relationships between intestinal calcium absorption, serum vitamin D metabolites and smoking in postmenopausal women. Osteoporos Int 13(1), 83-8 (2002)

128.E.A. Krall and B. Dawson-Hughes: Smoking increases bone loss and decreases intestinal calcium absorption. J Bone Miner Res 14, 215-20 (1999)

129.J. Tamaki, M. Iki, Y. Sato, E. Kajita, S. Kagamimori, Y. Kagawa and H. Yoneshima: Smoking among premenopausal women is associated with increased risk of low bone status: the JPOS Study. J Bone Miner Metab 28(3), 320-7 (2010)

130.S. Forsmo, B. Schei, A. Langhammer and L. Forsén: How do reproductive and lifestyle factors influence bone density in distal and ultradistal radius of early postmenopausal women? The Nord-Trøndelag Health Survey, Norway. Osteoporos Int 12(3), 222-9 (2001)

131.H.J. Seo, S.G. Kim and C.S. Kim: Risk factors for bone mineral density at the calcaneus in 40-59 year-old male workers: a cross-sectional study in Korea. BMC Public Health 8 (253), 1-5 (2008) (doi not found)
PMid:18173844    PMCid:2254612

132.E. Atalar, G. Aydin, I. Keles, E. Inal, G. Zog, A. Arslan and S. Orkun: Factors affecting bone mineral -density in men. Rheumatol Int 29(9), 1025-30 (2009)

133.H. Kaji, R. Kosaka, M. Yamauchi, K. Kuno, K Chihara and T. Sugimoto: Effects of age, grip strength and smoking on forearm volumetric bone mineral density and bone geometry by peripheral quantitative computed tomography: comparisons between female and male. Endocr J 52(6), 659-66 (2005)

134.B.W. Benson and J.D. Shulman: Inclusion of tobacco exposure as a predictive factorfor decreased bone mineral content. Nicotine Tob Res 7(5), 719-24 (2005)

135.T. Tanaka, M.R. Latorre, P.C. Jaime, A.A. Florindo, M.G. Pippa and C.A. Zerbini: Risk factors for proximal femur osteoporosis in men aged 50 years or older. Osteoporos Int 12(11), 942-9 (2001)

136.J.A. Cauley, R.L. Fullman, K.L. Stone, J.M. Zmuda, D.C. Bauer, E. Barrett-Connor, K. Ensrud, E.M. Lau and E.S. Orwoll; Mr. OS Research Group: Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 16(12), 1525-37 (2005)

137.Y. Yahata, K. Aoyagi, K. Okano, I. Yoshimi, Y. Kusano, M. Kobayashi, K. Moji and T. Takemoto: Metacarpal bone mineral density, body mass index and lifestyle among postmenopausal Japanese women: relationship of body mass index, physical activity, calcium intake, alcohol and smoking to bone mineral density: the Hizen-Oshima study. Tohoku J Exp Med 196(3), 123-9 (2002)

138.D.R. Gore, G.F. Carrera and S.T. Glaeser: Smoking and degenerative changes of the cervical spine: a roentgenographic study. Spine J 6(5), 557-60 (2006)

139.R.J. MacInnis, C. Cassar, C.A. Nowson, L.M. Paton, L. Flicker, J.L. Hopper, R.G. Larkins and J.D. Wark: Determinants of bone density in 30- to 65-year-old women: a co-twin study. J Bone Miner Res 18, 1650-6 (2003)

140.M. Fukuharu, J. Sato, I. Ohsawa, Y. Oshida, K. Kuriki, K. Shibata, T. Tamagawa, T. Nagaya, N. Fujiwara, S. Tokudome and Y. Sato: Effects of lifestyle factors on ultrasonographically determined bone health in Japanese women. Public Health 115(2), 146-51 (2001)

141.S. Adami, S. Giannini, R. Giorgino, G. Isaia, S. Maggi, L. Sinigaglia, P. Filipponi, G. Crepaldi and O. Di Munno: The effect of age, weight, and lifestyle factors on calcaneal quantitative ultrasound: the ESOPO study. Osteoporos Int 14(3), 198-207 (2003) (doi not found)

142.Y. Zhang, K. Aoyagi, S. Honda, Y. Yahata, I. Yoshimi, Y. Kusano, N. Takamura, M. Kobayashi, K. Moji and T. Takemoto: Effects of lifestyle factors on stiffness index of calcaneus measured by quantitative ultrasound system among Japanese women aged 40 years and over: the Hizen-Oshima Study. Tohoku J Exp Med 201(2), 97-107 (2003)

143.C.M. Bernaards, J.W. Twisk, J. Snel, W. Van Mechelen, P. Lips and H.C. Kemper: Smoking and quantitative ultrasound parameters in the calcaneus in 36-year-old men and women. Osteoporos Int 15(9), 735-41 (2004)

144.M. Blum, S.S. Harris, A. Must, S.M. Phillips, W.M. Rand and B. Dawson-Hughes: Household tobacco smoke exposure is negatively associated with premenopausal bone mass. Osteoporos Int 13(8), 663-8 (2002)

145.R.C. Wüst, K. Winwood, D.C. Wilks, C.I. Morse, H. Degens and J. Rittweger: Effects of smoking on tibial and radial bone mass and strength may diminish with age. J Clin Endocrinol Metab 95(6), 2763-71 (2010)

146.S.S. Rao, M. Singh, M. Parkar and R. Sugumaran: Health maintenance for postmenopausal women. Am Fam Physician 78(5), 583-91 (2008) (doi not found)

147.A. Cetin, Y. Gökçe-Kutsal and R. Celiker: Predictors of bone mineral density in healthy males. Rheumatol Int 21(3), 85-8 (2001)

148.P.K. Wong, J.J. Christie and J.D. Wark: The effects of smoking on bone health. Clin Sci (Lond), 113(5), 233-41 (2007)

149.N.E. Lane: Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 194(2 Suppl), 3-11 (2006)

150.M.F. Delaney: Strategies for the prevention and treatment of osteoporosis during early postmenopause. Am J Obstet Gynecol 194(2 Suppl), 12-23 (2006)

151.Progetto Menopausa Italia Study Group: Risk of low bone density in women attending menopause clinics in Italy. Maturitas 42(2), 105-11 (2002)

152.T. Manabe, S. Takasugi and Y. Iwamoto: Positive relationship between bone mineral density and low back pain in middle-aged women. Eur Spine J 12(6), 596-601 (2003)

153.E.J. Rhee, K.W. Oh, W.Y. Lee, S.W. Kim, E.S. Oh, K.H. Baek, M.I. Kang, C.Y. Park, M.G. Choi, H.J Yoo and S.W. Park: Age, body mass index, current smoking history, and serum insulin-like growth factor-I levels associated with bone mineral density in middle-aged Korean men. J Bone Miner Metab 22(4), 392-8 (2004)

154.D. Demirbag, F. Ozdemir and M. Ture: Effects of coffee consumption and smoking habit on bone mineral density. Rheumatol Int 26(6), 530-5 (2006)

155.P.F. Giampietro, C. McCarty, B. Mukesh, F. McKiernan, D. Wilson, A. Shuldiner, J. Liu, J. LeVasseur, L. Ivacic, T. Kitchner and N. Ghebranious: The role of cigarette smoking and statins in the development of postmenopausal osteoporosis: a pilot study utilizing the Marshfield Clinic Personalized Medicine Cohort. Osteoporos Int 21, 467-77 (2010)

156.S. Moran, G. Glazier and K. Armstrong: Women smokers' perceptions of smoking-related health risks. J Womens Health (Larchmt) 12(4), 363-71 (2003)

157.E. Serena-Gómez and L.A. Passeri: Complications of mandible fractures related to substance abuse. J Oral Maxillofac Surg 66(10), 2028-34 (2008)

158.S.N. Ishikawa, G.A. Murphy and E.G. Richardson: The effect of cigarette smoking on hindfoot fusions. Foot Ankle Int 23(11), 996-8 (2002) (doi not found)

159.F. Chen, A.L. Osterman and K. Mahony: Smoking and bony union after ulna-shortening osteotomy. Am J Orthop (Belle Mead NJ) 30(6), 486-9 (2001) (doi not found)

160.T. Andersen, F.B. Christensen, M. Laursen, K. Høy, E.S. Hansen and C. Bünger: Smoking as a predictor of negative outcome in lumbar spinal fusion. Spine 26(23), 2623-8 (2001)

161.A. Peolsson, L. Vavruch and B. Oberg: Predictive factors for arm pain, neck pain, neck specific disability and health after anterior cervical decompression and fusion. Acta Neurochir (Wien) 148(2), 167-73 (2006)

162.S. Sharma, M. Fraser, F. Lovell, A. Reece and A.R. McLellan: Characteristics of males over 50 years who present with a fracture: epidemiology and underlying risk factors. J Bone Joint Surg Br 90(1), 72-7 (2008)

163.A.H. Holmberg, O. Johnell, P.M. Nilsson, J.A. Nilsson, G. Berglund and K. Akesson: Risk factors for hip fractures in a middle-aged population: a study of 33,000 men and women. Osteoporos Int 16(12), 2185-94 (2005)

164.M.D. McKee, D.J. DiPasquale, L.M. Wild, D.J. Stephen, H.J. Kreder and E.H. Schemitsch: The effect of smoking on clinical outcome and complication rates following Ilizarov reconstruction. J Orthop Trauma 17(10), 663-7 (2003)

165.C.P. Little, B.J. Burston, J. Hopkinson-Woolley and P. Burge: Failure of surgery for scaphoid non-union is associated with smoking. J Hand Surg Br 31(3), 252-5 (2006)

166.R.A. Rajan, M. Ong, S. Jones and J. Fernandes: Does smoking affect the quality of bone regenerate in paediatric limb reconstructive surgery? J Child Orthop 1, 365-7 (2007)
PMid:19308533    PMCid:2656748

167.R.C. Castillo, M.J. Bosse, E.J. MacKenzie, B.M. Patterson and LEAP Study Group: Impact of smoking on fracture healing and risk of complications in limb-threatening open tibia fractures. J Orthop Trauma 19(3), 151-7 (2005)

168.S. Mpofu, R.J. Moots RJ and R.N. Thompson: Bilateral distal fibular and tibial stress fractures associated with heavy smoking. Ann Rheum Dis 62(3), 273-4 (2003)
PMid:12594122    PMCid:1754481

169.T. Wilsgaard, N. Emaus, L.A. Ahmed, G. Grimnes, R.M. Joakimsen, T.K. Omsland and G.R. Berntsen: Lifestyle impact on lifetime bone loss in women and men: the Tromsø Study. Am J Epidemiol 169(7), 877-86 (2009)

170.N.M. Peel, R.J. McClure and J.K. Hendrikz: Health-protective behaviours and risk of fall-related hip fractures: a population-based case-control study. Age Ageing 35(5), 491-7 (2006)

171.A.F. Dinah and R.H. Vickers: Smoking increases failure rate of operation for established non-union of the scaphoid bone. Int Orthop 31(4), 503-5 (2007)
PMid:16947049    PMCid:2267625

172.E. Rightmire, D. Zurakowski and M. Vrahas: Acute infections after fracture repair: management with hardware in place. Clin Orthop Relat Res 466(2), 466-72 (2008)
PMid:18196433    PMCid:2505119

173.H. Olofsson, L. Byberg, R. Mohsen, H. Melhus, H. Lithell and K. Michaëlsson: Smoking and the risk of fracture in older men. J Bone Miner Res 20(7), 1208-15 (2005)

174.P. Johnston, K.S. Gurusamy and M.J. Parker: Smoking and hip fracture; a study of 3617 cases. Injury 37(2), 152-6 (2006)

175.J.B. César-Neto, B.B. Benatti, F.R. Manzi, E.A. Sallum, A.W. Sallum and F.H. Nociti: The influence of cigarette smoke inhalation on bone density. A radiographic study in rats. Braz Oral Res 19(1), 47-51 (2005) (doi not found)

176.Y. Ajiro, Y. Tokuhashi, H. Matsuzaki, S. Nakajima and T. Ogawa: Impact of passive smoking on the bones of rats. Orthopedics 33(2), 90-5 (2010)

177.J.S. Fusby, M.D. Kassmeier, V.L. Palmer, G.A. Perry, D.K. Anderson, B.T. Hackfort, G.K. Alvarez, D.M. Cullen, M.P. Akhter and P.C. Swanson: Cigarette smoke-induced effects on bone marrow B-cell subsets and CD4+:CD8+ T-cell ratios are reversed by smoking cessation: influence of bone mass on immune cell response to and recovery from smoke exposure. Inhal Toxicol 22(9), 785-96 (2010)

178.T.C. Lee, S.W. Ueng, H.H. Chen, K. Lu, H.Y. Huang, P.C. Liliang, T.M. Su and L.C. Yang:The effect of acute smoking on spinal fusion: an experimental study among rabbits. J Trauma 59(2), 402-8 (2005)

179.H. Oda, H. Matsuzaki, Y. Tokuhashi, K. Wakabayashi, Y. Uematsu and M. Iwahashi: Degeneration of intervertebral discs due to smoking: experimental assessment in a rat-smoking model. J Orthop Sci 9(2), 135-41 (2004)

180.H. Uei, H. Matsuzaki, H. Oda, S. Nakajima, Y. Tokuhashi and M. Esumi: Gene expression changes in an early stage of intervertebral disc degeneration induced by passive cigarette smoking. Spine 31(5), 510-4 (2006)

181.H.B. El-Zawawy, C.S. Gill, R.W. Wright and L.J. Sandell: Smoking delays chondrogenesis in a mouse model of closed tibial fracture healing. J Orthop Res 24(12), 2150-8 (2006)

182.M.P. Akhter, A.D. Lund and C.G. Gairola: Bone Biomechanical Property Deterioration Due to Tobacco Smoke Exposure. Calcif Tissue Int 77, 319-26 (2005)

183.M.P. Akhter, U.T. Iwaniec, G.R. Haynatzki, Y.K. Fung, D.M. Cullen and R.R. Recker: Effects of nicotine on bone mass and strength in aged female rats. J Orthop Res 21, 14-19 (2003)

184.U.T. Iwaniec, Y.K. Fung, M.P. Akhter, M.C. Haven, S. Nespor, G.R. Haynatzki and D.M. Cullen: Effects of nicotine on bone mass, turnover, and strength in adult female rats. Calcif Tissue Int 68(6), 358-64 (2001)

185.L.L. Lee, J.S. Lee, S.D. Waldman, R.F. Casper and M.D. Grynpas: Polycyclic aromatic hydrocarbons present in cigarette smoke cause bone loss in an ovariectomized rat model. Bone 30, 917-23 (2002)

186.Y. Nakayama, M. Mezawa, S. Araki, Y. Sasaki, S. Wang, J. Han, X. Li, H. Takai and Y. Ogata: Nicotine suppresses bone sialoprotein gene expression. J Periodontal Res 44, 657-63 (2009)

187.A.R. Kamer, N. El-Ghorab, N. Marzec, J.E. Margarone 3rd and R. Dziak: Nicotine induced proliferation and cytokine release in osteoblastic cells. Int J Mol Med 17, 121-7 (2006) (doi not found)

188.X. Liu, T. Kohyama, T. Kobayashi, S. Abe, H.J. Kim, E.C. Reed and S.I. Rennard: Cigarette smoke extract inhibits chemotaxis and collagen gel contraction mediated by human bone marrow osteoprogenitor cells and osteoblast-like cells. Osteoporos Int 14, 235-42 (2003) (doi not found)

189.T. Sato, T. Abe, N. Nakamoto, Y. Tomaru, N. Koshikiya, J. Nojima, S. Kokabu, Y. Sakata, A. Kobayashi and T. Yoda: Nicotine induces cell proliferation in association with cyclin D1 up-regulation and inhibits cell differentiation in association with p53 regulation in a murine pre-osteoblastic cell line. Biochem Biophys Res Commun 377(1), 126-30 (2008)

190.L. Gullihorn, R. Karpman and L. Lippiello: Differential effects of nicotine and smoke condensate on bone cell metabolic activity. J Orthop Trauma 19(1), 17-22 (2005)

191.D.E. Rothem, L. Rothem, M. Soudry, A. Dahan and R. Eliakim: Nicotine modulates bone metabolism-associated gene expression in osteoblast cells. J Bone Miner Metab 27(5), 555-61 (2009)

192.D.G. Yanbaeva, M.A. Dentener, E.C. Creutzberg, G. Wesseling and E.F. Wouters: Systemic effects of smoking. Chest 131(5),1557-66 (2007)

193.T. Katono, T. Kawato, N. Tanabe, N. Suzuki, K. Yamanaka, H. Oka, M. Motohashi and M. Maeno: Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. Acta Biochim Biophys Sin (Shanghai) 38(12), 874-82 (2006)

194.M.M. Hla, J.W. Davis, P.D. Ross, A.J. Yates and R.D. Wasnich: The relation between lifestyle factors and biochemical markers of bone turnover among early postmenopausal women. Calcif Tissue Int 68(5), 291-6 (2001)

195.J. Pesonen, J. Sirola, M. Tuppurainen, J. Jurvelin, E. Alhava, R. Honkanen and H. Kröger: High bone mineral density among perimenopausal women. Osteoporos Int 16, 1899-1906 (2005)

196.J.S. Brach, J.M. VanSwearingen, S.J. FitzGerald, K.L. Storti and A.M. Kriska: The relationship among physical activity, obesity, and physical function in community-dwelling older women Preventive Medicine 39, 74-80 (2004)

197.L. Bacon, J.S. Stern, N.L. Keim and M.D. Van Loan: Low bone mass in premenopausal chronic dieting obese women European journal of Clinical Nutrition 58, 966-971 (2004)

198.S.A. Shapses, N.L. Von Thun, S.B. Heymsfield, T.A. Ricci, M. Ospina, R.N. Jr Pierson and T. Stahl: Bone turnover and density in obese premenopausal women during moderate weight loss and calcium supplementation. J Bone Miner Res 16, 1329-1336 (2001)

199.T.A. Ricci, S.B. Heymsfield, R.N. Pierson, J.T. Stahl, H.A. Chowdhury and S.A. Shapses: Moderate energy restriction increases bone resorption in obese postmenopausal women. Am J Clin Nutr 73, 347-52 (2001) (doi not found)

200.L.B. Jensen, G. Kollerup, F. Quaade and O.H. SØRensen: Bone mineral changes in obese women during a moderate weight loss with and without calcium supplementation. J Bone Miner Res 16, 141-147 (2001)

201.K. Uusi-Rasi, A. Rauhio, P. Kannus, M. Pasanen, K. Kukkonen-Harjula, M. Fogelholm and H. Sievänen: Three-month weight reduction does not compromise bone strength in obese premenopausal women. Bone 46, 1286-1293 (2010)

202.J.E. Kerstetter, K.O. O'Brien and K.L Insogna: Low protein intake: the impact on calcium and bone homeostasis in humans. J Nutr 133, 855S-861S (2003) (doi not found)

203.W.W. Campbell and M. Tang: Protein intake, weight loss, and bone mineral density in postmenopausal women. J Gerontol A Biol Sci Med Sci 65A(10), 1115-1122 (2010)

204.J. Bowen, M. Noakes and P.M. Clifton: A high dairy protein, high-calcium diet minimized bone turnover in overweight adults during weight loss. J Nutr 134, 568-573 (2004) (doi not found)

205.M. Noakes, J.B. Keogh, P.R. Foster and P.M. Clifton: Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women. Am J Clin Nutr 81, 1298-306 (2005) (doi not found)

206.C.S. Riedt, M. Cifuentes, T.Stahl, H.A. Chowdhury, Y. Schlussel and S.A. Shapses: Overweight postmenopausal women lose bone with moderate weight reduction and 1g/day calcium intake. J Bone Miner Res 20, 455-463 (2005)

207.M. Cifuentes, C.S. Riedt, R.E. Brolin, M.P. Field, R.M. Sherrell and S.A. Shapses: Weight loss and calcium intake influence calcium absorption in overweight postmenopausal women. Am J Clin Nutr 80, 123-30 (2004) (doi not found)

208.Y. Nakata, K. Ohkawara, D.J. Lee, T. Okura and K. Tanaka: Effects of additional resistance training during diet-induced weight loss on bone mineral density in overweight premenopausal women. J Bone Miner Metab 26, 172-7 (2008)

209.H.A. Hogan, F. Argueta, L. Moe, L.P. Nguyen and H.W. Sampson: Adult-onset alcohol consumption induces osteopenia in female rats. Alcohol Clin Exp Res 25(5), 746-54 (2001)

Key Words: Bone Density, Osteoporosis, Fractures, Alcoholism, Alcohol-Related Disorders, Obesity, Smoking, Review

Send correspondence to: Giavaresi Gianluca, Laboratorio Studi Preclinici e Chirurgici, Istituto di Ricerca Codivilla-Putti, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy, Tel: 39-051-6366730, Fax: 39-051-6366580, E-mail: gianluca.giavaresi@ior.it