- Top of page
- MATERIALS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
Osteoarthritis (OA) is a common, complex disorder with multiple risk factors. It carries a large community health burden, especially for hip and knee OA (). The first studies that examined smoking as a possible risk factor reported a negative association between smoking and the development of OA ([2, 3]) and subsequently with the progression of OA ([4-7]). However, this negative association was not supported by a number of other studies ([8-14]). Evidence about the possible mechanism for the negative association between smoking and OA is currently sparse. In contrast, there is some evidence that smoking is detrimental for both cartilage and bone, resulting in uncertain effects on the progression of OA ([15, 16]).
Our group recently published a meta-analysis showing no overall association between smoking and the incidence of OA (). Smoking was found to have a positive association with OA only in case–control studies where controls were recruited from a hospital setting (e.g., a cardiovascular clinic) where smoking-related conditions predominate in the population from which the controls were selected. As a result, the control group had a higher exposure to smoking, which led to the negative association with OA ().
This meta-analysis attempts to address the related question of whether smoking is associated with the progression of OA. Differentiating incident from progressive OA is clinically relevant because they are related to different stages of the disease (development and progression) and prevention (primary or secondary prevention) of the outcomes ([18, 19]). Some studies have found that risk factors for development and progression of OA may differ (). Whether smoking has different effects on the different stages in the natural history of the disease remains unknown. The objective of this study was to examine the association between smoking and the progression of OA through a meta-analysis of observational studies.
Box 1. Significance & Innovations
- This meta-analysis finds no compelling evidence that smoking has a protective effect on the progression of osteoarthritis (OA).
- The results concur with a previous meta-analysis published by this group that showed no association between smoking and the incidence of OA.
- Top of page
- MATERIALS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
Our meta-analysis of 16 observational studies of progression of OA with 976,564 participants shows no negative association between smoking and the progression of OA. Some statistically negative associations were observed in the subgroup analyses, e.g., in community-based studies, radiographic OA studies, and studies adjusted for confounding factors (age, sex, and/or BMI, etc.). However, these associations were marginal. The ORs ranged from 0.85–0.96, with the upper limit of the 95% CIs very close to 1. This suggests that even if there is truly a statistically negative association, it is not clinically significant (). In addition, they were not confirmed in the meta-regression when multiple covariates were adjusted, suggesting that smoking is very unlikely to be beneficial for the progression of OA.
This meta-analysis follows our previous meta-analysis, which examined the association between smoking and the incidence of OA (). Both meta-analyses accord in finding no association between smoking and the incidence or progression of OA. Unlike our previous study, we did not observe the negative association in hospital-based case–control studies; therefore, we were unable to attribute the bias (). However, according to the marginal statistical significance and the distribution of the study outcomes around a null association (i.e., OR 1) in the forest plot (Figure 3), the negative association in some studies is more likely to be a random error.
There has been no previous meta-analysis of whether smoking is associated with the progression of OA. Previous large cohort studies have provided conflicting conclusions, with a negative association found in some (the Framingham study in the US , the Swedish construction workers study , the Million Women Study in the UK , and a large community-based cohort in Australia ), but not others (the Clearwater  and Nurses Health  Studies in the US, the Chingford Study  in the UK, the Zoetermeer Study in The Netherlands , and 2 recent community-based cohorts in Japan [[12, 13]]). Most recently, a very large community-based cohort of more than 23,500 people in Sweden followed up for 30 years showed no association ().
One study showed a significant positive association of smoking with the progression of OA, but this was the only study using MRI assessment of cartilage loss as the definition of OA progression (). This accorded with 2 other studies (with 3 reports [[25, 26, 31]]) of cartilage loss assessed by MRI, albeit in subjects mostly with normal knees, in which smokers showed significantly increased total knee cartilage volume loss compared to nonsmokers even over a short (2–3 years) time period.
The mechanisms by which smoking potentially might affect the progression of OA are unclear. There are conflicting in vitro data of the effect of smoking on chondrocytes at a cellular level. Nicotine may have a beneficial effect on chondrocyte function ([33, 34]), whereas in other studies, components of tobacco have a deleterious effect on chondrocyte function ([15, 35-38]). Smoking has a detrimental effect on bone health (), including new bone growth after fracture (), so it may inhibit osteophyte formation. Smoking is known to be associated with progression of other chronic musculoskeletal conditions, such as low back pain, and intervertebral disc disease ([41-43]) as well as inflammatory diseases such as rheumatoid arthritis ([44, 45]), but the mechanism has not been elucidated. Finally, smoking may be seen as a wider proxy marker of a person's social demographics, lifestyle, weight, etc., which may be involved in the different pathways during the development and progression of OA.
This meta-analysis has several limitations. First, the meta-analysis included the smaller number of studies (16 studies) in the published literature that address the question of the association of smoking with the progression of OA compared with the incidence of OA (44 studies). This may influence the power of the meta-regression analysis, especially when multiple exploratory factors were included. Sixteen studies are obviously underpowered to examine 5 covariates. The results are likely to be false-positive if the analysis detects any significant effect modifier (). Fortunately, no significant variable was identified in this analysis, so the conclusion may be drawn in conjunction with the main analyses. Second, progression of OA itself is difficult to define, and there is also no consensus in the literature of what constitutes progression or the best way to measure it (radiographs, MRI, surrogate of clinical and radiologic progression such as TJR) (). This heterogeneity in the definition of OA progression may account for some of the heterogeneity of the results. Third, there was also diversity in the study design (cohort, case–control, or cross-sectional), study setting (hospital or community), OA site (hip or knee only was included), and definition of smoking (ever, past, or current), which may make the overall meta-analysis suboptimal. We therefore undertook a number of subgroup analyses and meta-regression analysis to examine the contribution of each of these factors and to give an adjusted overall OR. Furthermore, using TJR as a surrogate marker for OA progression may not be legitimate because it is in fact not truly a progression marker (but a measure of severe OA) and is influenced by numerous other factors apart from OA itself.
However, using TJR as a progression measure has some advantages. It will avoid index event bias, a paradox that is often caused by the selection of people with an index event (e.g., OA) to investigate risk factors of the subsequent event (e.g., progression). The paradox has been observed in OA where BMI appears to be a stronger risk factor for development than for the progression of OA (). It has also been observed in other conditions (e.g., stroke, cardiac events) in which factors that appear to predispose to the development of the condition paradoxically are reported not to be associated with its recurrence or progression (). The index event bias normally dilutes the association between the risk factors and the recurrent or progressive events because the selection of the cases with the index event means (to some extent) the selection of the risk factors. The best way to avoid this bias is to recruit cohorts of healthy subjects (rather than after an index event has occurred) and follow up with them for both index and subsequent outcomes (e.g., both development and progression) of interest. This is often not possible; therefore, an alternative approach is to use a severe marker of the disease such as TJR to bypass the bias (). Several other caveats apply to all meta-analyses of this sort: despite rigorous attempts to search the literature, it is possible that some eligible data were not included, and language bias may apply because English search terms were used, although returned studies in all languages were considered eligible.
In summary, this meta-analysis shows no compelling evidence to support the reported negative association between smoking and progression of OA. It aligns with the results of the previous meta-analysis published by this group that showed no association between smoking and the incidence of OA.