Review Article | Open Access
The Effect of Tobacco Smoking on Musculoskeletal Health: A Systematic Review
This systematic review explored associations between smoking and health outcomes involving the musculoskeletal system. AMSTAR criteria were followed. A comprehensive search of PubMed, Web of Science, and Science Direct returned 243 articles meeting inclusion criteria. A majority of studies found smoking has negative effects on the musculoskeletal system. In research on bones, smoking was associated with lower BMD, increased fracture risk, periodontitis, alveolar bone loss, and dental implant failure. In research on joints, smoking was associated with increased joint disease activity, poor functional outcomes, and poor therapeutic response. There was also evidence of adverse effects on muscles, tendons, cartilage, and ligaments. There were few studies on the musculoskeletal health outcomes of secondhand smoke, smoking cessation, or other modes of smoking, such as waterpipes or electronic cigarettes. This review found evidence that suggests tobacco smoking has negative effects on the health outcomes of the musculoskeletal system. There is a need for further research to understand mechanisms of action for the effects of smoking on the musculoskeletal system and to increase awareness of healthcare providers and community members of the adverse effects of smoking on the musculoskeletal system.
Tobacco smoke has more than 7,000 harmful chemical compounds that enter a human body either directly through smoking, indirectly through secondhand exposure to smoke exhaled by a smoker, or through downstream smoke released from a cigarette or pipe . Both smokers and nonsmokers are at risk of exposure to the compounds of smoked tobacco that accumulate on the surfaces in a poorly ventilated environment; this method of exposure is known as thirdhand smoke exposure . In the United States, there are approximately 500,000 annual deaths causally related to smoking and secondhand exposure to smoke .
Tobacco smoking has known adverse consequences on most human body systems. Researchers have focused more attention on the deleterious effects of smoking for high mortality diseases, such as cancer and diseases of the cardiovascular and respiratory systems, with less research attention on other body systems, such as the musculoskeletal system . The musculoskeletal system is one of the largest human body systems, comprised of bones, joints, muscles, cartilage, tendons, ligaments, and other connective tissues . An intact and functioning musculoskeletal (locomotor) system is necessary to perform activities of daily living and maintain quality of life [5, 6]. Several studies have investigated the association between smoking and musculoskeletal disorders. According to the recent Surgeon General report, the causal relationship between tobacco smoking and rheumatoid arthritis, periodontitis, and hip fractures has been confirmed ; however, there is inconclusive evidence to support causality between smoking and many other musculoskeletal disorders.
Searching online databases revealed significant growth in the body of literature investigating relationships between tobacco smoking and the musculoskeletal system. During our comprehensive online search, we did not encounter any systematic reviews examining those relationships; however, we did find 10 systematic reviews of the effects of tobacco smoking on components of the musculoskeletal system. Five systematic reviews focused on smoking and the effects on dental implants and found smoking increases the risk of peri-implant bone loss and implant failure [7–11]. Another systematic review revealed an association between smoking and lumbar disc herniation . Three other reviews found smoking was related to negative postoperative outcomes on knee ligaments , higher complication rates after anterior cruciate ligament (ACL) reconstruction , and slowed healing of rotator cuff repair . Also, one review found smoking was associated with rotator cuff tears and other shoulder symptoms . Our review will be the first to collect and assess all the recent literature on the effects of smoking on the musculoskeletal system. This systematic review will orient scientists interested in the health effects of smoking about the state of the science over the last decade as they conduct more advanced research. Also, the amalgamation of these data in one document will be helpful to the research community as there is a high degree of similarity and shared characteristics between musculoskeletal system components.
This systematic review evaluated literature published in the last decade to summarize the evidence regarding the effect of smoking on the musculoskeletal system. This systematic review will answer two main questions: Is there an association between tobacco smoking and musculoskeletal health? What are the effects of tobacco smoking on the musculoskeletal health?
This systematic review followed the criteria of A Measurement Tool to Assess Systematic Review (AMSTAR). Before the onset of the systematic review, a specific protocol was developed to minimize bias. This protocol included a priori research questions, a comprehensive literature search, inclusion criteria for studies, screening methods and reasons for exclusion, data abstraction, scientific study quality, data analysis, and synthesis.
A comprehensive literature search using PubMed, Web of Science, and Science Direct was conducted. This search covered 10 years from January 1, 2007, to March 18, 2017, and included only articles written in English. The search strategies included a combination of the following key words: smoking, musculoskeletal system, bone, bones, joints, muscles, tendons, ligaments, and cartilage. Medical Subject Headings (MeSH) were used during the search of PubMed. This step was helpful to expand the search; for example, the entry terms for MeSH of smoking were as follows: smoking, cigar smoking, cigar, tobacco smoking, tobacco, hookah smoking, smoking, hookah, waterpipe smoking, waterpipe, pipe smoking, pipe, cigarette smoking, and cigarette. All retrieved records were pulled from databases using EndNote X7. Duplicated records were removed via EndNote or manually when EndNote failed to recognize duplicates discovered by the authors during title/abstract reviews. After that, abstracts of the retained records were screened for inclusion criteria: English language, human subjects, published January 1, 2007–March 18, 2017, and investigating effects of smoking on the musculoskeletal system. Retained records then underwent full-text screening and records that did not meet the inclusion criteria or were editorials, commentaries, dissertations, case studies, or reviews (e.g., overview, systematic review, and meta-analysis) were excluded. A total of 243 final full-text articles were included in the review and used for data abstraction.
Based on an a priori protocol, data abstraction from selected full-text articles included citation (authors, year), study design, sample characteristics (size, age, sex, race/ethnicity, and type of sampling), study purpose, findings, comments, and/or limitations on data quality and validity. Two independent authors (first and second) extracted data using a standard form. The data abstraction process was piloted for the first 10 articles; it was successful and was used for the remaining articles. Any disagreements between authors were resolved through discussion.
The findings in this review were synthesized qualitatively as there was heterogeneity in study designs and populations. Our narrative analyses considered study design and quality.
The comprehensive search of the literature identified 8,709 potentially relevant records; however, only 243 records met the inclusion criteria and underwent data abstraction and synthesis (Figure 1). The 243 articles were reviewed and the effects of tobacco smoking on musculoskeletal system were classified into 7 categories: (1) tobacco smoking and bones (n =132), which were subdivided into (a) bone mass: bone mineral density (BMD), bone mineral content (BMC), and bone turnover (n = 40); (b) fractures ( n = 16); (c) alveolar bone (n = 4); (d) periodontitis (n = 34); (e) implants (n = 33); and (f) grafts (n = 5); (2) tobacco smoking and joints (n = 54), which were divided into four subcategories: (a) rheumatoid arthritis (RA) (n = 29), (b) osteoarthritis (OA) (n = 14), (c) spondyloarthritis (SA) (n = 7), and (d) temporomandibular joint disorders (n = 4); (3) tobacco smoking and skeletal muscles (n = 20); (4) tobacco smoking and cartilage (n = 19), which were divided into two subcategories: (a) cartilage (n = 7) and (b) spinal cartilage (n = 12); (5) tobacco smoking and tendons (n = 6); (6) tobacco smoking and ligaments (n = 4); and (7) intrauterine and secondhand smoking effects on the musculoskeletal system (n = 8).
This review included studies using various designs: cohort studies (n = 106; 67 were prospective and 39 were retrospective), cross-sectional studies (n = 90), case-control studies (n = 16), randomized control trials (RCTs) (n = 14), and quasi-experimental studies (n = 10). Other study designs included secondary data analysis (n =5) and cross-sequential design (n = 2). Table 1 presents the classification of study designs and related information based on the categories and subcategories. Table 2 summarizes the effect of smoking on major outcomes of musculoskeletal health. Table 3 provides comprehensive information on each study in the review.
Note: Type of sample was mentioned when it is only random; otherwise the sample was nonrandom sample. Race/ethnicity was mentioned if it were given in the article.
3.1. Tobacco Smoking and Bones (n=132)
3.1.1. Bone Mass: BMD, BMC, and Bone Turnover (n = 40)
Overall characteristics of these studies were as follows: 15 studies were conducted in males, 12 studies were conducted in females, and 13 included both sexes; 22 studies used data or samples from large-scale longitudinal studies; all studies used self-report to assess smoking habits, with the exception of 6 studies that used objective measures in addition to self-report: 3 assessed level of cotinine [24, 48, 49] and 3 assessed level of exhaled carbon monoxide (EXCO) [22, 36, 41]. Table 3 provides comprehensive details on the findings from those studies for effects of smoking on selected bone-related outcomes.
According to a majority of studies, smoking had adverse effects on BMD across age categories and sex. In males, regardless of age, method, and site of measurement for bone density, the cross-sectional studies found smokers had significantly lower BMD than nonsmokers [27, 42–44, 46, 52, 54, 55]. The cohort studies found male smokers exhibited a significant decline in BMD [32, 33, 50, 54]. There was only one cross-sectional study that reported no significant difference in calcaneus BMD between 3 groups: an alcohol drinking-only group, combined alcohol drinking and smoking group, and control nondrinking/nonsmoking . In adolescent females, 2 cross-sectional studies found a high frequency of smoking was associated with lower rate of total body BMC  and hip BMD [28, 29]; these findings were supported by cohort studies that found initiation of smoking at age 13 affected bone accrual and was associated with low mean BMD at age 17 [33, 47]. Another cross-sectional study of adolescent females reported significant linear relationships between urinary cotinine and BMD of the femoral neck, total femur, and lumbar spine . However, only one cross-sectional study in adolescent females found no significant difference in BMC and BMD between smokers and nonsmokers . In premenopausal women, one cross-sectional study reported the BMD of smokers was not significantly different than the BMD of nonsmokers .
In postmenopausal women, cross-sectional study findings demonstrated postmenopausal women who smoked had significantly lower BMD than postmenopausal women who did not smoke [23, 56] and an increased risk of falls regardless of the BMD T-score . Two randomized control studies were conducted in postmenopausal women. One study found consumption of blackberries was effective in reducing bone loss of the total body BMD in a smokers’ group (P = 0.0284) . Another study found quitting smoking significantly associated with increased body weight, fat, muscles, and functional mass that affected BMD . A study using data from one RCT found administration of nasal estradiol for 2 years increased the lumbar spine BMD of smokers (P = 0.03) but did not increase total hip BMD (P = 0.89). Finally, two cross-sectional studies enrolled both males and females, and one reported BMD and BMC were significantly lower in smokers than those of nonsmokers ; the second study used a small sample and found no association between pack-years and BMD .
Biological mechanisms were examined in several studies, most of which were cross-sectional. A comparative analysis of smokers to nonsmokers found smokers had a higher receptor activator of nuclear factor-B ligand (RANKL-positive) CD4 (+) and CD8 (+) T cells (All P < 0.001) , a lower periosteal gene expression of bone morphogenetic proteins (BMP-2, BMP-4, and BMP-6) , and a lower mean concentration of bone marrow progenitor cells (BMPCs) (P = 0.004) . Both BMP and BMPCs are required for musculoskeletal healing and regeneration. Smokers also had lower antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and paraoxonase), higher levels of oxidative stress products (malondialdehyde, nitric oxide) (P < 0.001) , lower levels of parathyroid hormone (PTH) [34, 36], vitamin D [26, 36, 37], biomarkers of serum osteocalcin, and 24-hour urinary excretion of calcium .
The correlational analysis did not find a significant effect for serum osteocalcin (OC) or tartrate resistant acid phosphatase isoenzyme 5b (TRACP 5b) . The interaction between smoking and other compounds found smoking with calcium intake did not reach statistical significance for BMD ; however, elderly women with the lowest tertile of choline who were exposed to nicotine had the highest risk for low BMD (OR=4.56, 95%CI: 1.87-11.11) . One prospective study found growth hormone (GH) therapy after 3-5 years did not significantly improve total BMC of smokers (P = 0.09) .
The interaction between smoking and genetic factors was also investigated. A potential interaction was reported between smoking and receptor-related Protein 5 (LRP5) C135242T (rs545382) on osteoporosis in postmenopausal women  and between smoking and polymorphism of glutathione S-transferases (GSTT1) on bone quality index in young adult men . One cross-sectional study reported a relationship between PTH and hip BMD only for nonsmokers . Finally, in a cross-sectional methodological study, a strong correlation between bioelectrical impedance analysis (sBIA) and dual energy X-ray absorptiometry (DEXA)] regarding whole-body fat mass (FM) and lean mass (LM) (r > 0.9, p < 0.001) was found .
3.1.2. Fracture (n = 16)
The overall characteristics of these studies were as follows: 12 studies were conducted in both sexes: 2 studies in females only [61, 71] and 2 studies in males only [62, 70]; 12 studies were cohort studies; 3 obtained data or samples from large-scale longitudinal studies; all studies used self-report to assess smoking habits with the exception of one study that assessed levels of cotinine . Table 3 provides comprehensive details on studies which examined the prevalence of fracture in smokers, the association between smoking and fracture risk, fracture healing, the biological mechanism of fracture in smokers, and the interaction of smoking and other fracture risks.
Fracture was more prevalent in male smokers than in the males who never smoked (P < 0.05) . Smoking was also found to increase the likelihood of fracture. In one cohort study of elderly men, current smoking increased the risk of all new [hazard ratio (HR) = 1.76, 95% Cl: 1.19-2.61] and osteoporotic fractures (HR = 2.14, 95%Cl: 1.18-3.88) . Similar findings were reported in elderly women; former and current smokers compared to nonsmokers had increased risk for fracture [59, 71], including nonvertebral fractures in patients with diabetes (OR = 3.47, 95%CI: 1.82-6.62, P = 0.001) . Regardless of fracture site, six cohort studies and one case-control study examining both sexes found smoking was significantly associated with poor fracture outcomes, such as nonunion (P < 0.01) [57, 58, 60, 66], lower trabecular strength (beta = -0.323; P = 0.045) and toughness (beta = -0.403; P = 0.018) , and delayed mean healing time . No significant association was found between fracture and delay in filling  work absenteeism (P = 0.1177)  or low mental and physical-function scores on the Short Form 36 (SF-36) .
Two prospective cohort studies of both sexes investigating the postsurgery level of serum transforming growth factor-beta 1 (TGF-beta 1) found TGF-beta 1 was lower in smokers than in nonsmokers at 4 weeks  and 8 weeks . The trend of lower level of TGF-beta 1 in smokers than that of nonsmokers was observed in both groups of patients with normally healed fractures and delayed healed fractures . Finally, two studies examined interactional effect of smoking and other factors. In the first study, changes in BMI had an effect on fracture risk in nonsmokers, but not in smokers . In the second study, plasma dimethylglycine (DMG) increased the risk of hip fracture in cohort of elderly males and females (HR = 1.70, 95 % CI: 1.28-2.26), and such risks were noticeably increased in women exposed to nicotine (HR = 3.41, 95%CI: 1.40-8.28) .
3.1.3. Alveolar Bone (n = 4)
In two cross-sectional studies, one study found smokers had significantly lower alveolar bone density values (P ≤ 0.002) and a greater distance from cemento-enamel-junction to the alveolar bone crest (P < 0.0001) . The second study did not find smoking significantly correlated with alveolar crest height loss . The third cross-sectional study found smoking negatively affected the expression of bone sialoprotein (BSP) and osteocalcin (OC) mRNA (P< .05) and positively altered the expression of Type I collagen (COL-I) (P< .05); however, smoking was not statistically correlated with the expression of mRNA for tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), or osteoprotegerin (OPG) . The fourth study, an RCT, found that, despite involvement of smokers in dental hygiene program, smokers had significantly lower density of alveolar bone by Day 365 (P < 0.05) and Day 545 of follow-up during the dental hygiene program (P < 0.01) . Table 3 provides comprehensive details on the 4 studies that examined the effect of smoking on the alveolar bone.
3.1.4. Periodontitis (n=34)
Thirty-four studies examined the prevalence and clinical parameters of periodontitis in smokers, the biological mechanism of smoking, the interaction between smoking and periodontitis risk factors, and interventions to minimize periodontitis in smokers. The characteristics of these studies were as follows: 27 studies were conducted in both sexes; 7 studied males only. Twenty-four studies were cross-sectional, 5 studies were RCTs, 4 studies were cohort, and 1 study was a case-control. Two studies out of 34 obtained data or samples from large-scale longitudinal studies. All the studies used self-report to assess smoking, with the exception of three studies that assessed levels of cotinine [88, 99, 101]. Table 3 provides comprehensive details on the studies that examined the relationship between smoking and periodontitis.
Eleven studies investigated the prevalence and association of smoking on periodontitis and periodontal parameters. Ten studies were cross-sectional. The comparative analysis found smokers compared to nonsmokers had significantly deeper periodontal pockets [77, 89, 90, 92, 108], higher mean clinical attachment loss (CAL) [78, 91, 92, 108], higher mean plaque scores [78, 91, 92], greater fraction of teeth with apical periodontitis , higher marginal bone loss, and a greater number of missing teeth . In a correlational analysis, smoking was strongly associated with alveolar bone loss  and the percentage of palatal periodontal pockets ≥ 6 mm . Heavy smoking was also associated with higher prevalence [79, 94] and severity of periodontitis [77, 94]. A comparative study between different modalities of smoking found cigarette smokers had higher frequency of probing pocket depth ≥ 4 mm and a higher incidence of severe periodontitis compared to nontobacco users . Two studies compared cigarettes smokers to waterpipe and narghile users and found a similarity between groups on most periodontal parameters [92, 95].
Fourteen studies examined the potential biological mechanism for smoking in periodontitis and what potential biomarkers may be affected. Thirteen studies were cross-sectional designs and enrolled both sexes. Three studies examined smoking and nonsmoking subjects without periodontitis and found smokers had significantly higher synthesis of lipoxygenases and isoprostanes in the extracted periapical granuloma , higher whole salivary IL-1 beta and IL-6 (P < 0.05)  but a lower total amount of platelet-derived growth factor (PDGF-AB) (P = 0.014) in gingival crevicular fluid . Four studies were conducted in smokers and nonsmokers with periodontitis and found smokers had significantly lower levels of salivary osteocalcin (OC) (P < 0.001) ; a lower median serum level of OPG (P = 0.0006) ; higher levels of prostaglandin E-2, lactoferrin, albumin, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase . The groups had similar levels of salivary C-telopeptide pyridinoline cross-links of Type I collagen (P > 0.05) ; median serum receptor activator of nuclear factor kappa-B ligand (RANKL) (P = 0.0942) ; and gingival crevicular levels of RANKL and osteoprotegerin (OPG)  and similar proportion of identified pathogens . Seven studies enrolled both smokers and nonsmokers in groups with or without periodontitis. Based on periodontal status, the group with periodontitis (smokers and nonsmokers) had significantly higher plasma sRANKL, TNF, a proliferation-inducing ligand (APRIL and BAFF) and lower OPG (P < 0.01) , and higher salivary OC (P < 0.05)  than the healthy control group (smokers and nonsmokers without periodontitis). Interestingly, these two studies found levels for some of these markers were altered by smoking; sRANKL and TNF concentrations were significantly greater (P = 0.011, P = 0.001; respectively), and OPG concentration was significantly lower (P = 0.001) in smokers with periodontitis; however, such trend was not seen for salivary OC [101, 102]. The results from these studies indicated that smokers had more lymphocyte and higher levels of both IFN-γ and IL-13, regardless of periodontal status , had higher salivary sCD44 profiles (P < 0.001) with the highest levels recorded in smokers in the periodontitis group , and had significantly higher levels of salivary calcium level (P< 0.05) . A subgroup analysis for smoking and periodontal status found that smokers with chronic periodontitis exhibited significantly higher levels of sIgA  and lower plasma OPG concentrations (P = 0.007) but higher sRANKL/OPG ratio (P = 0.01) than smokers without periodontitis ; however, smokers and nonsmokers with periodontitis exhibited similar values for plasma sIgA, sRANKL, and OPG concentrations. Smoking is one of the greatest risks for periodontitis and may increase host susceptibility to tissue destruction especially in presence of other factors such as the functional defect of leukocyte and monocyte . These findings indicate periodontal inflammation in smoker with chronic periodontitis patients, as evidenced by high levels of sIgA, seems to lower plasma OPG levels and thereby increase the RANKL/OPG ratio and possibly play a role in the increased susceptibility for alveolar bone destruction in smoker subjects.
One cross-sectional study suggested the interaction between smoking and vitamin D receptor gene polymorphism (CC+CT genotypes of FokI) increased the risk of periodontitis (OR = 9.6, 95%CI: 4.5- 20.4). The combined effect was 3.7 times greater than expected from the sum of individual effects . Eight interventional studies examined therapies to manage periodontitis. One observational cohort study that monitored the effect of smoking cessation found quitters had a higher reduction of mean probing depth and CAL relative to nonquitters (P ≤ 0.05) . Another prospective observational study found periodontal maintenance therapy every 3-4 months inhibited the progression of CAL, probing depth, and tooth loss in smokers . Wan et al.  found in a prospective cohort study that anterior teeth, sites without plaque, and nonsmoking were significantly associated with a greater reduction in probing pocket depth . Three RCTs found adjunct treatments of low-dose doxycycline for 6 months , systemic azithromycin , or a daily dose of 325 mg of aspirin  did not significantly improve periodontal parameters in smokers with chronic periodontitis. In contrast, 2 RCTs in smokers with chronic periodontitis successfully improved some periodontal parameters. Compared with treatment using only scaling and root planing (SRP), the treatment using Simvastatin (1.2% biodegradable controlled-release gel) as an adjunct to scaling and root planing (SRP) significantly reduced probing depth and significantly increased bone filling (all P < 0.001) . Smoking is one of the greatest risks for periodontitis and is associated with poor periodontal parameters; such finding provides evidence that the treatment used Simvastatin besides SRP in smokers suffering from chronic periodontitis was more effective in reducing the negative effect of smoking on the periodontal parameter than the treatment using only SRP. The second RCT found the treatment using modified YJ (mYJ) Chinese medicinal herbs in a nonsurgical treatment for smokers suffering from periodontitis was associated with higher computer-assisted densitometry values than the treatment using original YJ Chinese medicinal herbs with nonsurgical treatments (P = 0.025) . Also, this finding provides evidence that the use of mYJ Chinese medicinal herbs in a nonsurgical treatment was effective in reducing the negative effect of smoking on the periodontal parameter as evidenced by the increases in radiographic alveolar bone density.
3.1.5. Bone Implants (n = 33)
There were 33 studies which investigated implant survival/failure rates, clinical parameters of success/failure, risk factors of implant survival, interaction between smoking and risk factors on the implant survival, effects of implants on surrounding tissue, complications associated with implants, biological mechanisms of smoking effect on implants, and interventions to reduce the effects of smoking and enhance implant survival rate in smokers. The characteristics of these studies were as follows: all 33 studies examined dental implants and enrolled both sexes; 19 were cohort studies; 7 were cross-sectional studies; 4 were RCTs; and 3 were case-control studies. Eleven studies had small samples. All studies used self-report to assess smoking. Table 3 provides comprehensive detail on these studies exploring the effects of smoking on bone implants.
Thirteen studies examined the effect of smoking on dental implant survival with special consideration of implant type and time of follow-up. Eleven studies were cohort studies. Two studies investigated smoking and early implant failure and the first study found early implant failure was threefold higher in smokers than nonsmokers  while the second study found frequency of tobacco smoking was not associated with early implant failure . Ten studies examined long-term survival/failure of dental implants. Two studies reported smoking did not influence implant survival rates [115, 123], although 8 studies provided contradictory findings. A correlation analysis found smoking status [112, 139], and pack-years  were inversely associated with dental implant survival. A comparative analysis between smokers and nonsmokers found smokers had lower implant survival rates [114, 119, 124, 130, 132, 142]. A subgroup analysis based on implant type found smokers had higher failure rates for turned  and smooth-surface implants . One study of only tobacco smokers found implant survival with turned or screw surfaces was similar in tobacco smokers regardless of periodontal status . Five of 13 studies measured marginal bone loss; 4 reported smokers demonstrated significantly greater marginal bone loss than nonsmokers [119, 123, 141, 142], and two studies did not report a significant difference [130, 131].
Six studies examined the clinical effects of implants on surrounding tissue in smokers. One retrospective cohort study found smoking was associated with overall complications (e.g., implant loss, infection, peri-implantitis, and mucositis) (P = 0.008) . Five studies examined histometric parameters for dental mini-implants, and one case-control study carried out on smokers found mean bone-to-implant contact (BIC%) better in sandblasted acid-etched surfaces than machined surfaces (22.19 ± 14.68% versus 10.40 ± 14.16%, P < 0.001) . Smoking is associated with increased risk of bone implant failure due to its negative effect on tissues surrounding the implant; such finding indicates that the negative effect of smoking on histometric measurements after dental mini-implants was significantly minimized through using of implants with sandblasted acid-etched but it was not improved with the use of implants with machined surfaces. The remaining 4 studies were prospective cohort studies and found smokers had significantly lower BIC% [120, 133], lower bone density in thread areas (BA%) , less stability at 3, 4, 6, and 8 weeks after surgery , and less regrowth of papillae and midfacial soft tissue .
Eight studies examined the biological mechanism of smoking on tissue surrounding dental implants and explored potential biomarkers that could be affected by this mechanism. Five of eight were cross-sectional studies; one study analyzed peri-implants fluid of smokers’ prior implant placements and found smoking negatively altered the mRNA expression of bone sialoprotein (BSP) and osteocalcin (OC) and positively affected the expression of Type I collagen (COL-I) (P < 0.05). However, smoking was not correlated with the expression of TNF-α, transforming growth factor-beat (TGF-β), or OPG (P > 0.05) . Four studies analyzed peri-implant fluid and found smokers and nonsmokers had similar levels of pathogens [113, 140], OPG, and RANKL/OPG . However, there were contradictory findings regarding the level of cytokines (IL-4, IL-8, or TNF- α) in smokers and nonsmokers, as they were reported to be similar in one study , significantly lower in one study , and significantly higher in yet another study . One case-control study found heavy smokers with an IL-1 polymorphism did not increase their risk for peri-implantitis . One short-term prospective study found a 7-day follow-up for the whole genome array of implant adherent cells was not different between smokers and nonsmokers . The long-term prospective cohort study found smokers with previous periodontal disease had significant clinical signs of inflammation and significantly higher counts of pathogenic bacteria .
Four studies were randomized control trials; 2 measured peri-implant parameters for implants with different configurations. One trial found smoking did not influence peri-implant soft tissue response (recession and the papilla index) ; a second study found smoking doubled marginal bone loss regardless of treatment . One methodological RCT using stereolithographic surgical guides found smoking was associated with inaccurate implant placement . A therapeutic RCT found mechanical debridement with adjunct antimicrobial did not significantly improve parameters of bleeding on probing, probing depth, or crestal bone loss in smokers . There were positive outcomes (high implant survival, bone level, and low rate of biological complications) reported by one retrospective cohort study where the authors monitored dental implant rehabilitation in patients with systemic disorders and smoking habits .
3.1.6. Bone Graft (n = 5)
Two of the 5 studies were randomized clinical trials. The first trial found smokers who received an acellular dermal matrix graft (ADMG) with enamel matrix derivative (EMD) had a higher mean gain in recession height and root coverage than smokers who received ADMG alone . This finding indicates that the treatment combining EMD with ADMG was found to be more effective in reducing the negative effect of smoking on root coverage than the treatment using only ADMG. A second trial found regenerative treatment of platelet-rich plasma combined with a bovine-derived xenograft did not improve periodontal parameters in smokers . Three long-term prospective cohorts compared smokers to nonsmokers and found smokers had significantly higher marginal bone loss up to 4 years after onlay bone grafting in the atrophic maxilla . These patients also had higher tissue inflammation around augmentation sites once they received bone graft titanium- reinforced ePTFE membranes  and had similar survival rates for dental implants after A Le Fort I osteotomy and interpositional bone graft in combination with implants in the atrophic maxilla . Table 3 provides comprehensive details on the 5 studies that examined the effects of smoking on bone graft.
3.2. Tobacco Smoking and Joints (n = 54)
3.2.1. Rheumatoid Arthritis (n = 29)
The overall characteristics for these 29 studies were as follows: all studies enrolled males and females, 17studies were cohort studies, 7 were cross-sectional studies, 3 were case-control studies, 1 was an RCT, and 1 was a secondary analysis. Twelve studies obtained data or samples from large-scale longitudinal studies and all used self-report to assess smoking habits with an exception of one study that assessed level of cotinine . Table 3 provides comprehensive detail about studies that examined the effect of smoking on several outcomes in patients with RA.
Five studies of varying design (2 cross-sectional studies, 2 prospective cohort studies, and 1 case-control study) enrolled patients from both sexes of similar age. These studies examined the effect of smoking on RA clinical outcomes, such as disease activity, functional capacity, radiographic damage, serology, and existence of extraarticular manifestations. Overall, the collective results were that smokers had significantly higher scores on the Disease Activity Score of 28 joints (DAS 28) [162, 167], the functional disability score (Health Assessment Questionnaire) , the simple erosion narrowing score , CRP , and a rheumatoid factor titer . These patients demonstrated severe extraarticular RA  and took significantly more disease-modifying antirheumatic drugs (DMARD) . One study reported no difference in DAS28 and radiographic scores between smokers and nonsmokers . Smoking was found to be independently associated with DAS28-CRP3 in human leukocyte antigen-shared epitope (HLA-SE-positive) patients, but not in HLA-SE-negative patients (P for interaction = 0.02) , higher Modified Health Assessment Questionnaire  scores, and greater number of rheumatoid nodules . Smoking and RA remission were investigated in two studies. A cross-sectional study reported current smokers had higher remission rates than persons who had never smoked or former smokers ; however, a prospective cohort study reported lower remission rates in current smokers compared to persons who had never smoked or former smokers at 12-month follow-up . Two prospective studies examined smoking on RA progression, and one study with a large sample size reported radiographic progression for joint damage was not significantly different between smokers and nonsmokers (P = 0.26), but further analysis by authors found smoking intensity (pack-day) to be inversely associated with radiographic progression . Meanwhile, a second study with a small sample size found current smoking associated with radiographic progression .
There were 10 studies that examined the effect of smoking on response to RA therapies. A first group of 5 cohort studies was conducted in patients with early stage RA. Four studies found smoking associated with poor response after 3 months of methotrexate or anti-TNF-α therapy , after 6 months of combined therapy of methotrexate and sulfasalazine , and after 12 months of glucocorticoids and DMARDs [169, 170]. One study reported no difference in response to therapy after 12 months’ follow-up in patients who continued or quit smoking . Similar findings were reported in 5 studies that enrolled RA patients regardless of disease stage. Four studies reported current smoking was associated with poor response after 3 months [148, 160, 171] and 12 months  of anti-TNF-α therapy and after 48 and 102 weeks of therapy that included methotrexate . One of the 5 studies reported exposure to secondhand smoking did not influence the response to RA therapy after 3, 6, and 12 months and 2 years .
Seven studies (2 case-control studies, 3 cohort studies, 1 cross-sectional study, and 1 secondary analysis) investigated the interaction between smoking and other factors on RA. The results of these studies found a significant increase in disease activity when there was an interaction between heavy smoking and HLA-DR beta 1 4-amino acid haplotype primarily Positions 11 and 13 , between smoking and all positive anti-citrullinated peptide antibodies (ACPA) [153, 157, 164], and between ever smoking and mannose-binding lectin (MBL2) genotype YA/YA . Further results were increased signs of joint inflammation in first-degree relatives who were younger than 50 and had smoked more than 10 pack-years . There was no interaction found between smoking and endothelial growth factor A haplotype [VEGFA-2578 AA genotype and (A_2578-C_460-G+405)], but endothelial growth factor A haplotype was found to be associated with reduced disease activity in patients of RA who had never smoked . Four studies investigated smoking effects on certain mechanisms and biological markers in patients with RA. One prospective cohort study found smoking and ACPA predicted persistence of high levels of survivin (OR = 4.36, 95% CI: 2.64-7.20, P < 0.001, positive predictive value 0.66, and specificity 0.83) . Two cross-sectional studies compared level of essential and trace elements of smoker and nonsmokers with RA and matched healthy controls of smokers and nonsmokers to determine if there were any associations between toxic elements, cigarette smoking, deficiency of essential trace elements, and risk of arthritis. One study found smokers and nonsmokers RA patients had significantly higher hair levels of toxic elements (Cd and Pb) and lower hair levels of trace elements (Zn, Cu, and Mn) than those of smokers and nonsmokers healthy individuals . The second study found smokers with RA had significantly higher hair and blood levels of toxic element (Cd, Pb, Hg, and AS) and lower hair and blood levels of trace elements (Zn, Cu, Mn, and Se) . Finally, another cross-sectional study reported smoking pack-years was inversely correlated to body fat composition in patients with RA .
3.2.2. Osteoarthritis (n = 14)
Three cross-sectional studies provided disparate findings on the effects of smoking and OA. One study reported smoking was not significantly associated with hand OA in a Chuvashian community ; two other studies reported an inverse relationship between smoking and radiographic knee OA (P = 0.019)  and between indirect smoking and knee and hip OA (OR = 0.271; 95% CI: 0.088-0.828) . One prospective study reported smoking was not significantly associated with the prevalence or incidence of radiographic knee OA . Three prospective studies found smoking associated with higher pain scores [177, 178], increased risk for cartilage loss at the medial tibiofemoral joint (OR = 2.3, 95% CI:1.0 - 5.4), and increased risk for cartilage loss at the patellofemoral joint (OR = 2.5, 95% CI: 1.1 - 5.7) ; however, smoking reduced the risk of total joint replacement (TJR) in presence of [rs1051730 T] alleles (HR = 0.84, 95% CI: 0.76 – 0.98, per T allele) . Two prospective studies found smoking significantly associated with higher complication rates , but not with functional outcomes after a tibial osteotomy in patient with RA . There were five studies that examined the association of smoking with the risk for joint replacement and the risk for complications after joint surgery. Two cohort studies investigated the risks for joint surgery: one prospective cohort study reported smoking increased the risk for total joint replacement (TJR) in males ; however, conflicting evidence was reported by another retrospective cohort study that found an inverse association between smoking and TJR (adjusted-HRs: 0.60; 95% CI: 0.48-0.75, and 0.70; 95% CI: 0.56-0.86 in men and women, respectively), but this study investigated the risk for only primary TJR and included both sexes . Another prospective study of patients who underwent total hip or knee arthroplasty found no difference in perioperative mortality rates between smokers and nonsmokers; however, smokers had a higher complication rate . In two retrospective studies, smoking significantly increased the risk for early failure of total hip arthroplasty  and wound breakdown after total ankle replacements . Table 3 provides comprehensive details on the 14 studies in this subsection.
3.2.3. Spondyloarthritis (n = 7).
Three of these seven studies investigated the effects of smoking on biological markers in patients with SA; 5 studies investigated effect of smoking on clinical, functional, and imaging outcomes of SA. Three cross-sectional studies found smoking was associated with lower matrix metalloproteinase-generated Type II collagen fragment in patients with SA (P = 0.02)  and higher level of vascular endothelial growth factor in patients with ankylosing spondylitis (VEGF) (P < 0.05) [195, 196]. Three cross-sectional studies, two in patients with ankylosing spondylitis and one in patients with early axial spondyloarthritis, and one prospective cohort study in patients with early axial spondyloarthritis reported smoking was associated with higher pain scores [191, 192], disease activity and functional status [191, 192, 195], poor quality of life [191, 192], and spinal radiographic/MRI progression [191, 194]. Also, pack-years were positively correlated with duration of inflammatory back pain (r = 0.628, P < 0.001), Bath AS Functional Index (BASFI) (r = 0.443, P < 0.001), and the severity of radiographic damage assessed by the modified Stroke AS Spine Score (mSASSS) (r = 0.683, P < 0.001) . Finally, one case-control study found collagen IX tryptophan (Trp+2) alleles and smoking status did not influence the risk for cervical spondylotic myelopathy (OR = 1.34, 95% CI = 0.85-2.18, P > 0.05); however, smoking intensity with collagen IX tryptophan (Trp+2) exhibited a dose-response relationship with cervical spondylotic myelopathy . Table 3 provides comprehensive details about the 7 studies that examined the effects of smoking on SA.
3.2.4. Temporomandibular Joint Disorders (n = 4)
Of the four studies in this subsection, 4 studies with varying designs compared smokers to nonsmokers and found smokers had higher temporomandibular joint disorder (TMD) pain intensity [198–201]. Further analysis of these studies found no differences in pain intensity between smokers and nonsmokers after adjustment for demographic variables . The number of cigarettes was associated with pain intensity only in females  and females younger than 30 were more likely to develop TMD symptoms than females over the age of 30 . Table 3 provides comprehensive details on the four studies in this subsection.
3.3. Tobacco Smoking and Skeletal Muscles (n = 20)
Compared to bones and joints, few studies investigated the effect of tobacco smoking on skeletal muscles. The overall characteristics of these 20 studies were as follows: 11 studies enrolled both sexes, 8 enrolled only males, and 1 enrolled only females, 10 studies were quasi-experimental, 5 were cross-sectional studies, 4 were cohort studies, and 1 was a case-control study, and all studies used self-report to assess smoking habits. Table 3 provides comprehensive details on these studies which examined the effects of smoking on the anatomical, biological, metabolic, physical, and functional outcomes of skeletal muscles.
Two studies investigated the association between smoking and the anatomy of skeletal muscles. A cross-sectional study reported smokers had lower Types I and IIa muscle fibers than nonsmokers indicating smokers’ skeletal muscles had oxidative fiber atrophy . The prospective cohort study of only males reported rectus femoris volume (RFVOL) at baseline (prior training) was lesser in smokers than in nonsmokers, although RFVOL was significantly increased with training, and due to those authors suggested that training reversed the effects of smoking . Three quasi-experimental studies investigated the biological effects of smoking. The results of those studies reported smokers had decreased local muscle O2Hb , thiobarbituric acid , and catalase  levels, an increase in inflammatory markers (sTNFR1)  and similar VO2 [206, 211], lactate , superoxide dismutase (SOD) , and succinate dehydrogenase (SDH) activity , inflammatory cytokines (IL-6, IL-10, and sTNFR2), myoglobin concentration , and capillarization  during leg muscle exercises.
Twelve studies examined the effects of smoking on physical and functional properties of skeletal muscle: 7 studies examined muscle strength, 2 studies examined muscle thickness, and 3 focused on maximal voluntary contraction. The findings of the 3 pretest/posttest, 2 prospective cohort, and 2 cross-sectional studies on muscle strength were that smoking was significantly associated with a reduction in back extensor muscle strength [202, 208], grip strength [203, 215], and knee muscle strength . One prospective cohort study reported that parameters of body composition and muscle strength were increased in subjects who quit smoking compared to subjects who continued smoking . One study reported an inverse correlation between pack-years and muscle strength . Two pretest/posttest studies were not congruent in terms of findings regarding percentage of change in muscle thickness (PCMT) and relative contribution ratio (RCR) of both internal oblique (IO) and transversus abdominis (TrA) muscles [205, 209]. The first study reported PCMT and RCR were not significantly different between smokers and nonsmokers ; however, the second study reported significant differences between smokers and nonsmokers in regard to PCMT of the TrA and in RCR of both TrA and IO . Three pretest/posttest studies of male smokers and nonsmokers had similar findings regarding the maximal voluntary contraction for quadriceps muscles [210, 221], rectus abdominis, and external oblique ; however, maximal voluntary contraction was significantly higher in smokers than in nonsmokers .
Three studies (case-control, cross-sectional, and prospective cohort) investigated the interaction of smoking and obstructive lung disease on skeletal muscles. Those studies found smoking in the presence of obstructive lung disease to be significantly associated with increased muscle injury  and lower weight and lean mass ; however, smoking, regardless of patient spirometry status, was the only independent variable associated with lower quadriceps Klotho levels .
3.4. Tobacco Smoking and Cartilage (n = 19)
3.4.1. Knee Joint Cartilage (n = 7)
Four studies (2 prospective cohorts, 1 case-control, and 1 cross-sectional) described the effect of smoking on knee joint cartilage. A cross-sectional analysis of these studies found both smoking and pack-years were positively associated with the volume of tibia cartilage  and femoral medial, intercondylar, and lateral cartilage . There was an inverse association between smoking and cartilage strain ratio .There was no consensus regarding the risk of tibiofemoral cartilage defects; one study reported smokers experienced a higher risk for medial and lateral tibiofemoral cartilage defect (OR: 4.91, P < 0.05), and such risk was increased with pack-years (OR 9.90 and OR 12.98, respectively, for heavy smoking versus never smoked, P < 0.05) ; another study reported smoking was not associated with tibiofemoral cartilage defect . Interestingly, the prospective cohort study found both smoking and pack-years associated with an increased annual loss of medial but not lateral tibia or patellar cartilage . There were 3 studies (2 cohorts and 1 case-control) that reported on the postoperative effects of smoking. Smokers experienced significant early meniscus repair failure (P = 0.0076) , less improvement in Modified Cincinnati Knee score after 2 years of autologous chondrocyte implantation surgery for full-thickness chondral defects of the knee (P < 0.05) , and a lower satisfaction rate after knee microfracture intervention . Table 3 provides comprehensive details on the 7 studies in this subsection.
3.4.2. Spinal Cartilage (n = 12)
Twelve studies examined the effects of smoking on spinal cartilage. One secondary data analysis reported smoking was not associated with disc degeneration and low back pain; however, the combination of smoking and hard physical work increased risk of vertebral inflammatory processes (OR = 4.9, 95%CI: 1.6-13.0) . There were 11 cohort (10 retrospective, 1 prospective) studies of patients who underwent spinal surgery. Interestingly, these studies found smoking was significantly associated with an increased risk of reoperation [230, 237, 238], higher infection rates [235, 239], higher risk of 30-day morbidity (P = 0.04) , and use of analgesic medication [234, 240], but there was no consensus on spinal fusion rate, length of stay, or complication rate. Three studies reported smoking was significantly associated with a lower spinal fusion rate [232, 234, 235]; however, one study reported spinal fusion rate was not affected by smoking status . One study reported smoking was associated with longer length of hospital stay (P < 0.001) , whereas the other study reported no association with length of hospital stay (P = 0.99) [233, 237]. Two studies reported smoking was not associated with overall complications [229, 233]. Table 3 provides comprehensive details for the 12 studies that enrolled both sexes and investigated the association of smoking with vertebral disc degeneration, pain, and the effect of smoking on spinal surgery outcomes.
3.5. Tobacco Smoking and Tendons (n = 6)
Three studies investigated rotator cuff tendons; two cross-sectional studies reported smokers presented with more advanced degenerative changes in their supraspinatus tendons (P < 0.001)  and reported that a higher total of smoked cigarettes was associated with the severity of rotator cuff tears (Type II versus Type I, P = 0.032) . The retrospective cohort study in patients with calcified calcific tendinitis of the rotator cuff found smoking was significantly associated with a failure of needle aspiration of calcific deposits (nACD) (adjusted OR = 1.7, 95% CI: 1.0-2.7, P = 0.04) . One case-control study reported smokers had significantly thinner patellar and Achilles tendons in the proximal, middle, and distal thirds region of the tendons and significant lower strain ratio measurements in the same regions (P < 0.05); pack-years were inversely related to patellar tendon thickness (P < 0.05) . One cross-sectional study reported smokers had significant improvement in finger range of motion over nonsmokers after tendon grafting . Finally, one prospective study reported that the Constant score was significantly lower in smokers than nonsmokers 1 year postoperatively after rotator cuff reconstruction (71 versus 75, P = 0.017) . Table 3 provides comprehensive details on the 6 studies that investigated the effects of smoking on the anatomical or functional characteristics of tendons.
3.6. Tobacco Smoking and Ligaments (n = 4)
Compared to nonsmokers, smokers were found to have significantly poorer outcomes regarding stability , Lysholm Knee Score, International Knee Documentation Committee (IKDC) subjective score, and IKDC objective grade [249, 250] after ACL reconstruction. A dose-dependent association was noted between pack-years and postoperative anterior translation (P = 0.015) and IKDC objective grade (P = 0.002) . Tobacco use was associated with a significantly increased risk of postoperative venous thromboembolism (OR = 1.9; P = 0.035)  and subsequent ACL reconstruction (OR = 1.7; P < 0.0001) ; but it was not found to be significant for postoperative stiffness (OR = 0.9; P = 0.656) . There was no consensus regarding risks of postoperative infection. One study reported tobacco use increased risk infection (OR = 2.3; P < 0.0001) , and another study reported smoking was not a significant risk factor (OR=2.5; P = 0.167) . Table 3 provides more details on the 4 cohort studies that enrolled both sexes and investigated effect of smoking on the clinical outcomes and complications after ACL reconstruction.
3.7. Intrauterine and Secondhand Smoking Effect on Musculoskeletal System (n = 8)
These studies were classified into two groups: first group investigated associations between secondhand smoke and musculoskeletal system disorders, and the second investigated the effects of intrauterine exposure by mothers who smoked or mothers exposed to secondhand smoke and the long-term outcomes on the musculoskeletal system of offspring. The first group had two cross-sectional studies that reported subjects exposed to passive secondhand smoking had significantly lower phalangeal BMD (P < 0.01)  and higher risk for femoral neck osteoporosis (OR, 3.68; 95%CI: 1.23-10.92) than unexposed subjects . The second group consisted of 6 studies; 3 studies were cohort studies and reported maternal smoking was significantly associated with lower aerobic fitness of male adolescents  and lower total body BMC in male adolescents, but not female adolescents . Maternal smoking was not found to be associated with BMD [254, 257] or fractures in adolescents . One prospective cohort and one cross-sectional study reported smoking by both parents during pregnancy had a significant effect on relative leg length (shorter) of offspring at ages 7-10 , increased spine BMC, and BMD in girls, but not boys at a mean age of 9.9 years . Finally, one article, a secondary data analysis, reported exposure of nonsmoking pregnant mothers to secondhand smoke from paternal grandmothers was associated with taller girls, and greater bone and lean mass of both sexes at age 17, while exposure of nonsmokers pregnant mothers to secondhand smoking from maternal grandmothers was associated with increased weight of boys at age 17 . Table 3 provides comprehensive details about the 8 studies.
This systematic review provides evidence of the substantive negative effects of tobacco smoking on the musculoskeletal system. A majority of studies reviewed (132 of 243) focused on the deleterious effect of tobacco smoking on bones, followed by joints (54 of 243), with less emphasis on muscles, cartilage, tendons, and ligaments. At the bone level, there is sufficient evidence demonstrating tobacco smoking is associated with low BMD, an increased likelihood of fracture, delayed fracture healing, increased alveolar bone loss, increased risk of periodontitis, increased peri-implant bone loss, and implant failure. The inverse association for tobacco smoking with BMD was evident in males across ages, in adolescents of both sexes, and in postmenopausal females; however, these associations were not fully explained by biomarkers monitored to understand the mechanisms of smoking effects on bone metabolism. Studies investigating biological mechanisms were few and were limited by a lack of power or a failure to adjust for confounding variables.
The research on periodontitis provided general agreement on clinical outcomes and monitored biomarkers proposed to be affected by tobacco smoking. This may indicate different mechanisms for effects on the alveolar bone than the rest of the body or there may be factors other than smoking that have an isolated effect or interact with the effects of smoking to synergize or diminish the negative effect on human BMD. Our findings regarding the negative outcomes of smoking on bone implants and surrounding tissues were consistent with 5 systematic reviews conducted previously on smoking effects on dental implants [7–11].
The research on joints was more segregated and investigated the effects of smoking on specific joint disorders rather than whole joints. Most studies were focused on RA (29 of 54). There was consensus that smoking is associated with increased disease activity, functional disability, and poor response to therapy. There was also evidence of an interaction between smoking and HLA-DR beta 1 4-amino acid haplotype and ACPA. This interaction was significantly associated with increased RA disease activity. There was evidence of a negative effect on OA outcomes; however, findings were inconsistent. There was evidence that supported the association between smoking and increased pain in patients with TMD, increased disease activity, pain, and poor response to therapy in patients with spondylarthrosis in a pattern similar to that exhibited by patients with RA.
Studies of smoking effects on skeletal muscles provided clear evidence that smoking was associated with poor outcomes, particularly decreased muscle strength. However, these findings were inconsistent on whether smoking is associated with changes in muscle thickness or maximal voluntary contraction. For the effects of smoking on cartilage, this review provided evidence of a harmful association of smoking and pack-years with knee cartilage (increased in cartilage volume, decreased strain ratio, and poor postoperative outcome), low spinal fusion rate, and increased risk of spinal reoperation. A limited number of studies investigated the effect of smoking on tendons and ligaments. For tendons, the results found smoking and pack-years associated with thinner patellar and Achilles tendons, severe rotator cuff tears, and poor postoperative functional outcomes. The results of this review regarding the effect of smoking on tendons are consistent with the findings reported in a previous systematic review by Bishop et al. . For ligaments, smoking was associated with poor functional and stability scores after ACL reconstruction, consistent with the findings in systematic reviews by Kanneganti et al.  and Novikov et al.  that reported negative effects of smoking on postoperative outcomes.
This systematic review identified few articles on secondhand (4 studies) or intrauterine exposure to smoke (6 studies). In terms of secondhand smoke, reviewed studies reported varying effects. There was an inverse association between secondhand smoke exposure and phalangeal BMD and a positive association with risk of femoral neck osteoporosis. A positive effect reported was the reduction in OA risk, and no effects were found in relation to response to RA therapy. Studies on intrauterine exposure were focused on long-term effects of exposure on the musculoskeletal outcomes of offspring. There was no consensus in the evidence on the effects of smoking on BMD, BMC, relative leg length, or other body composition parameters in male and female offspring.
This systematic review provided evidence of the negative effects of smoking on the musculoskeletal system. Table 3 provides essential information to be considered in future studies. Definitions of smoking status and intensity of smoking based on self-report were inconsistent across studies. For example, when smoking status was treated as binomial category (smoking versus nonsmoking), one study may have added former smokers to the smoking category, while another may have placed former smokers in the nonsmoking category. Similar observations were noted regarding measurement of smoking intensity; one study may define a heavy smoker as an individual who smoked 10 cigarettes or more a day over the last 10 years, while another study may define a heavy smoker as an individual who smoked 10 or more cigarettes a day over the last 5 years. Such variations in classification may lead to a misinterpretation of overall smoking effects and introduce inconsistencies among reported findings. Objective measurements are considered more reliable assessments of smoking exposure; however, objective measurements were reported in only 12 of 243 studies, 9 of these studies measured level of cotinine, and 3 assessed levels of EXCO. We did not encounter any study in this review that measured nicotine dependence (e.g., the Fagerstrom Test for Nicotine Dependence), so we cannot conclude if there were differences in patterns of effects for use or dependence of tobacco smoking. There were a limited number of studies investigating the effects of secondhand smoke and other smoking modalities, such as hookahs, narghiles, or electronic cigarettes. This review encountered only 4 studies on secondhand smoking with varying effects reported. We also only encountered only 2 studies regarding waterpipe smoking and no studies investigated the effects of smoking electronic cigarettes on the musculoskeletal system.
This systematic review demonstrates the need for further research to understand the effects of smoking on the musculoskeletal system. Due to the limited evidence on muscles, cartilage, tendons, and ligaments, more studies using different research designs are needed. The need for studies using various research designs naturally extends to study the effects of waterpipe, electronic cigarettes, and secondhand smoke on the musculoskeletal system. Longitudinal observational and experimental studies are needed to conclusively understand the effects of smoking on bone and joint-related outcomes.
There are several factors to be considered in the design of future studies. There needs to be a consistent approach to evaluate self-reported exposure for smoking and a more objective assessment for smoking exposure. There is also a need to assess for other smoking products (polycyclic aromatic hydrocarbons, nitrosamines, etc.) rather than to assess only levels of cotinine or EXCO. There need to be more information and analysis of confounders and genetic factors that may interact with smoking effects on the musculoskeletal system. There is also a need for more and frequent monitoring for changes in smoking status in longitudinal studies. Future research should endeavor to examine more than one musculoskeletal component to shed light on the development and differentiation of cell types of the musculoskeletal system. Finally, there is a need for further research to provide insight into how to minimize the effects of smoking in patients who undergo musculoskeletal surgery. Also, we recommend more ancillary studies as part of large longitudinal studies such as Population Assessment of Tobacco and Health (PATH).
Our research had several limitations. First, this review included only English language articles. Second, in vitro studies were not included. Third, we did not search for specific diseases or disorders under the term musculoskeletal system; however, we believe our search was able to comprehensively capture these disorders that are subcategorized under each section in Table 3. Fourth, this review was focused primarily on the effect of tobacco smoking on musculoskeletal system, and due to that the search method in this review may have missed other studies that have smoking as variable. Finally, we did not find any research on electronic cigarettes with only 2 studies on waterpipes. We believe these areas warrant research and will likely attract attention in the future.
This systematic review provided clear evidence of the negative effects of smoking on the musculoskeletal system. Evidence found smoking associated with lower BMD, and increased risk for fracture, periodontitis, alveolar bone loss and implant failure, increased joint disease, poor functional outcomes, and poor therapeutic response. We also found evidence of adverse effects on muscles, tendons, cartilage, and ligaments, despite the scarcity of studies. As smoking continues to be an important public health concern, there is a need for further research to understand mechanisms of action for the effects of smoking on the musculoskeletal system and to increase awareness of healthcare providers and community members about the deleterious effects of smoking on the musculoskeletal system.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this article.
Ahmad M. AL-Bashaireh conducted the literature search, reviewed the articles, and prepared the original draft of the main sections. Ahmad M. AL-Bashaireh and Linda G. Haddad participated in the interpretation and writing the result sections. Michael Weaver and Linda G. Haddad reviewed and edited draft manuscripts and the final manuscript and contributed to manuscript improvement. Debra Lynch Kelly participated in the study design and reviewed and edited all versions of manuscript. Xing Chengguo validated the literature search and assisted in editing the manuscript. Saunjoo Yoon reviewed and edited the final manuscript. All authors approved the final manuscript.
The authors would like to acknowledge the staff of the Health Science Center Libraries at University of Florida for their support obtaining full-text articles included in this review.
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