➢ Numerous clinical and epidemiological studies have investigated the correlation between cigarette smoking and disc degeneration; several investigators have cited possible confounding factors as the reason for the insignificant correlations.
➢ Experimental studies investigating the effects of cigarette smoking on the intervertebral disc using both in vivo and in vitro models have found reduced nutritional supply, histological and morphological changes, and altered cellular activity and viability in the disc following exposure to cigarette smoke and/or its constituents.
➢ Additional studies are necessary to better identify the pathological mechanisms of smoking-induced disc degeneration and spine pain and to better establish the correlation between these factors.
The treatment of low back pain is a major socioeconomic dilemma, resulting in billions of dollars in expenditures each year in the United States alone and affecting 15% to 45% of the population annually1-3. Back pain is the second most common reason for seeing a primary care physician, behind only upper respiratory infections. Although the origins of low back pain remain unclear, degenerative changes in the intervertebral disc of the spine have been strongly associated with the onset of pain1,4-6.
Despite persistent warnings regarding the health hazards associated with cigarette smoking, more than one-third of the population of industrialized countries smokes; in the United States, more than 20% of adults are smokers7. Cigarette smoking has been linked to numerous diseases, most notably respiratory and cardiovascular disease. The detrimental effects of tobacco use are also apparent in many orthopaedic issues, including delayed fracture-healing, decreased bone density, and risk of nonunion of fractures and spinal fusions8-10.
Although the exact pathophysiology of disc degeneration is not fully understood, an imbalance in anabolic and catabolic activity by the small cellular population of outer fibroblast-like anulus fibrosus cells and inner chondrocyte-like nucleus pulposus cells has been implicated as a major contributing factor11-15. Many factors influence the extracellular environment around intervertebral disc cells, which plays a central role in regulating cellular activity; these factors include nutrient levels, mechanical loading, and chemical environment. Alteration in disc cellular viability and activity could influence the ability of anulus fibrosus and nucleus pulposus cells to produce appropriate extracellular matrix components and to thus maintain the health of the tissue13. Several possible causes of disc degeneration have been investigated, such as inadequate nutritional supply to the intervertebral disc, abnormal mechanical loading, and genetic factors. The degeneration of the intervertebral disc is marked by a number of changes to the tissue, including alterations in morphology, biochemistry, function, and material properties, which lead to a loss of disc function and subsequent pain.
The correlation between cigarette smoking and low back pain and disc degeneration requires further elucidation. Three systematic epidemiologic studies have been published to determine the clinical relationship between back pain and smoking16-18: the systematic reviews by Leboeuf-Yde and Goldberg et al. and the recent meta-analysis performed by Shiri et al. Leboeuf-Yde16 reviewed forty-one original research studies, published between 1974 and 1996, and concluded that smoking was a weak risk indicator and not a cause of low back pain; there was no conclusion as to the association between smoking and herniated discs or sciatica. Goldberg et al.17 reviewed thirty-eight epidemiological studies and found that smoking was associated with the incidence and prevalence of nonspecific back pain, but acknowledged that this could be a statistical artifact arising from selection or confounding factors. Shiri et al.18 found that both current and former smokers have a higher prevalence and incidence of low back pain as compared with individuals who had never smoked; the association was determined to be modest. That study also determined that the association between smoking and back pain was stronger in the adolescent population as compared with adults.
Although the relationship between nonspecific low back pain and smoking has been reported in the literature, only a few studies have investigated the link explicitly between disc degenerative changes and cigarette smoking. Clinical and/or epidemiological studies are important for identifying the association between low back pain and disc degeneration and cigarette smoking. Such studies generally evaluate the end stages of disc degeneration, when patients experience low back pain and when evidence of degeneration can be seen via imaging modalities. Biological studies are critical and necessary endeavors to assess the effect of cigarette smoking on the initiation and progression of disc degeneration, particularly at the cellular level. These studies include those investigating changes in nutrient supply at the disc periphery, histological and morphological changes to the disc tissue and cells, and alterations to the cellular activity and gene expression. Our study is a first-time review of the literature from both the clinical or epidemiological and experimental or biological perspective, with the objective of more clearly understanding the association linking smoking to degenerative disc disease.
Several clinical studies have aimed to identify the association between smoking and disc degeneration, herniation, or sciatica. The findings of these studies are summarized in Table I, listed in chronological order. Only clinical studies in which disc degeneration was confirmed operatively or by imaging studies were included. Numerous studies have found evidence of increased signs of general degeneration in the intervertebral disc for current or previous cigarette smokers. Battié et al.19 evaluated lumbar spine magnetic resonance imaging (MRI) studies for changes of intervertebral disc degeneration in twenty pairs of male identical twins who were discordant for smoking and found that smokers had higher mean disc degeneration scores (by 18%) as compared with non-smokers. Another study showed that a history of smoking significantly increased (p < 0.01) the percentage of patients undergoing surgery for lumbar disc disease (56% in the smoker group compared with 37% in the control group) or cervical disc disease (64.3% in the smoker group compared with 37% in the control group)20. In a study by Livshits et al.21, analyses showed that the degenerative disc disease status of parents, age, and smoking were the main risk factors for disc disease; the odds ratio for smokers compared with non-smokers was particularly high at 3.44. Mattila et al.22 found that daily smoking was the strongest risk factor for lumbar discectomy in male patients (hazard ratio, 1.6).
Other studies have failed to find a significant correlation between disc degeneration and cigarette smoking23-30. Some of these failures to find correlations may be due to other confounding factors, such as inadequate sample size23 or improper imaging (i.e., use of roentgenogram rather than MRI to assess degenerative changes)29. Some studies were able to establish other factors that were related to increased incidence of degeneration, including strong genetic predisposition28,31,32, age25,26,30, whole body vibration25, facet joint arthritis, female sex, increased body mass index (BMI)26, and hours of sitting27.
Despite some clinical correlation between smoking and intervertebral disc disease, the exact etiology for the relationship between disc degeneration and low back pain and cigarette smoking is not well understood. Although clinical studies are indeed necessary and important for establishing this association, biological or experimental studies, particularly at the cellular level, can provide essential information about the mechanisms for the initiation and progression of disc degeneration following exposure to cigarette smoke and/or its constituents.
Numerous animal studies have elucidated the mechanisms underlying the association between cigarette or tobacco smoking and disc degeneration. These studies include both in vivo and in vitro models and different mechanisms of exposure to cigarette smoking. The results of these studies are summarized in Table II, listed in chronological order. Overall, the findings indicate that exposure to cigarette smoke and/or its constituent chemicals results in a reduction in the nutrient supply at the disc periphery, histological and morphological changes to the disc tissue and cells, and alterations to the cellular activity and gene expression.
Change in Nutritional Supply and Vasculature Due to Cigarette Smoking
Currently, there are two primary hypotheses as to the mechanism of tobacco-related low back pain and disc degeneration (Fig. 1); although neither has been definitively proven, both have supporting experimental evidence. The most widely accepted hypothesis is the indirect route in which carbon monoxide-induced anoxia or vascular disease resulting from cigarette smoking leads to malnutrition of the cells in the intervertebral disc (Fig. 2). There is strong evidence suggesting that poor nutritional supply plays a role in disc degeneration21,22,30-32; it is thought that the cigarette smoking may further exacerbate the precarious nutrition to the disc and may accelerate the degeneration cascade.
Cigarette smoke contains many constituents that may alter the nutrient supply in the bloodstream, thereby reducing nutrition at the disc periphery. The particulate matter, or tar, found in cigarette smoke has been shown to reduce the oxygen diffusion across the pulmonary membrane, leading to a reduction in the oxygen tension in arterial blood33. Likely the most important factor resulting in diminished oxygen levels is the elevated carbon monoxide levels in blood following cigarette smoking. Carbon monoxide is known to bind more readily with hemoglobin than oxygen does, thereby displacing oxygen from hemoglobin. Indeed, carbon monoxide has an affinity for hemoglobin that is approximately 225 times higher than that of oxygen, so the bound oxygen content in hemoglobin is greatly reduced when carbon monoxide is present34. A previous study has found that carboxyhemoglobin levels in the blood of smokers (∼4%) are higher than those for non-smokers (∼1.3%)35. These elevated levels of carbon monoxide lead to a reduced quantity of oxygen carried by hemoglobin because of fewer available binding sites.
Vascular disease resulting from cigarette smoking can also reduce the supply of nutrients at the disc periphery and can also limit the ability to remove harmful waste from the disc. Given the avascular nature of the intervertebral disc, disc cells receive nutrition from the vasculature in the adjacent vertebral bodies and surrounding the anulus region of the disc. A decreased quality of the vasculature at the disc periphery (e.g., a reduction in the quantity of vascular buds described below) translates to a poor supply of both oxygen and glucose to the disc. The uptake of lactic acid waste from the tissue can also be hindered, leading to a buildup within the intervertebral disc and a subsequent decrease in the pH to detrimental levels. Previous studies have shown that a reduced vertebral blood flow is associated with the presence of disc degeneration36 and that viable cell density in the disc is related to the density of blood vessels in the adjacent vertebral bodies37.
Several studies have shown that cigarette smoking results in a decreased nutritional supply at the disc edge, which supports the primary hypothesis that smoking causes degeneration via the indirect route of malnourishment of disc cells. This has been reported by Frymoyer et al., who suggested that cigarette smoking may alter blood flow38. They also reported preliminary results, which showed that injecting the amount of nicotine equivalent to one cigarette into the blood stream of dogs caused a reduction in vertebral body blood flow. Holm and Nachemson showed that smoking induced a constriction of the capillary network surrounding the intervertebral disc in a porcine model39. Hambly and Mooney found significantly reduced intradiscal pH levels (p < 0.005) in the intervertebral disc of rabbits exposed to cigarette smoking40. The authors suggested that the acidic pH was a consequence of the altered circulatory system at the disc periphery, which includes a reduction in the solute exchange capacity and transport.
Iwahashi et al. also found that nicotine treatment, administered via injection under the skin in rabbits, led to a decrease in the density of vascular buds in the vicinity of the vertebral end plate, as well as a narrowing of the vascular lumen41. The authors suggested that these changes may result in a decrease in the local oxygen tension levels in the tissue, thereby altering the cellular activity in the disc. Such changes may have detrimental effects on the intervertebral disc, such as lowered production of collagen and proteoglycan; these alterations may, in turn, lead to the degeneration of the disc and subsequent low back pain.
Cellular-Level Changes in Intervertebral Disc Following Exposure to Cigarette Smoke
As an alternative hypothesis to the indirect pathway, in which poor nutritional supply resulting from cigarette smoking leads to degeneration in the intervertebral disc, others have proposed that disc degeneration is caused by the direct effects of the toxic chemical compounds found in cigarette smoke on intervertebral disc cells42-44. Cigarette smoke contains thousands of chemicals, including nicotine, which may impact the homeostasis within the tissue and may result in degeneration. Disc degeneration is the manifestation of an imbalance in anabolic and catabolic activities in the disc, which favors the breakdown of the tissue matrix11-15. Thus, the cellular population of the tissue is responsible for the overall health of the tissue. Changes in cellular activity and viability may trigger the degeneration cascade in the intervertebral disc13-15,45.
Several investigators have used in vitro and in vivo studies to investigate the effects of cigarette smoke and/or its constituents on the viability, morphology, and activity of intervertebral disc cells. Numerous investigators have reported changes in the morphology of intervertebral disc cells following exposure to cigarette smoke and/or its constituents. Akmal et al. cultured bovine nucleus pulposus cells seeded in 2% alginate beads in the presence of nicotine and found that there was a reduction in cell proliferation and a change in the cell architecture as compared with control groups42. Vo et al. found that human intervertebral disc cells exposed to tobacco smoke extract (containing all water soluble components inhaled by smokers) had dramatic morphological changes that were dose-dependent; that is, exposure to low tobacco smoke extract concentrations resulted in cells taking on an elongated appearance, and high concentrations resulted in a densely compacted appearance43. Interestingly, the same study also showed that exposure to nicotine alone produced different morphological changes, suggesting that the thousands of other compounds46 found in cigarette smoke may also play an important role in the mechanism of disc degeneration following smoking. Wang et al. found that cellular senescence had a twofold increase for discs in mice exposed to cigarette smoke for six months, in a model intended to simulate chronic heavy smoking47.
The activity and viability of the cells in the intervertebral disc have also been shown to be affected by cigarette smoke or its constituents. Of principal concern is the alteration in the expression and/or production of major extracellular matrix macromolecules (e.g., collagen, aggrecan) in response to exposure to cigarette smoke, given that improper matrix production is seen in early-stage degeneration and thus may be an initiating factor13-15,48. It has been shown that nicotine exposure to bovine nucleus pulposus cells seeded in alginate leads to a reduction in cell density as well as lowered levels of DNA as compared with control groups. Furthermore, the same study also found that cells exposed to high doses of nicotine stained positively for collagen type I, but stained negatively for collagen type II and chondroitin-6-sulfate, which was the opposite of staining for control groups42. This indicates that both the cell viability and activity are altered in response to nicotine exposure.
Other studies have investigated the alterations in gene expression of intervertebral disc cells exposed to cigarette smoke or its constituents. Multiple investigators have found that interleukin-1β (IL-1β) is more strongly expressed in cells exposed to nicotine or cigarette smoking49,50, but one study showed that IL-1β expression was not affected51. Previous investigators have shown that intervertebral disc cells produce IL-1β during degeneration; IL-1β has been shown to lead to an upregulation of the expression of matrix-degrading matrix metalloproteinases, which play a key role in the imbalance in the matrix synthesis and degradation that results in degenerative changes to the tissue13. This alteration in cellular activity resulting from exposure to cigarette smoke may be a mechanism for disc degeneration in smokers.
Disc Herniation and/or Prolapse and Cigarette Smoking
As noted, several clinical studies have found signs of general degeneration in the intervertebral disc that is increased by cigarette smoking. In addition to these findings, there are numerous, more specific links between cigarette smoking and particular degeneration signs that have been noted. Several clinical studies have found an association between the incidence of disc herniation or prolapsed disc and cigarette smoking. Kelsey et al. found that patients who had smoked cigarettes in the past year were more at risk of having an acute prolapsed lumbar disc (odds ratio, 1.7) than patients who had not smoked in the past year (odds ratio, 1.0)52. They computed that, for every ten cigarettes smoked per day in the past year, the risk of developing a prolapsed disc increased by 20%. The authors also found that that current smokers had about twice the risk for a prolapsed cervical disc as compared with past smokers or non-smokers53. More recently, Saberi et al.54 found that cigarette smoking and age were associated with upper lumbar nucleus pulposus displacement (odds ratio, 2.29; p = 0.007). Schumann et al.55 showed that men who had smoked for a length of between twenty and forty pack-years showed significantly increased odds ratios (1.7) for lumbar intervertebral disc herniation. However, there was no clear dose-response relationship between the extent of smoking and disc disease, as smoking for forty pack-years or more was not associated with a higher risk of disc herniation (odds ratio, 0.8). A higher risk of lumbar intervertebral disc herniation was seen in women smoking for a length of between eight and twenty pack-years (odds ratio, 1.7). Lumbar intervertebral disc herniation was confirmed on MRI or computed tomography (CT).
Although disc herniation or displacement is indicative of the late stages of disc degeneration, several of the biological or experimental findings investigating the pathways and/or mechanisms of cigarette smoking-related disc degeneration have shown precursors to such an occurrence. Cigarette smoking has been linked with various histological changes to intervertebral disc tissues. Alterations to the gross morphological structure of disc tissue include necrosis, fibrosis, and hyalinization of the nucleus pulposus tissue, as well as cracks, separation, and disruption of the layered structure of the anulus fibrosus41,56. Additional studies have shown that these morphological changes became more marked and occur more frequently after longer exposure to cigarette smoke49,51. Such alterations in the tissue structure can initiate a degenerative cascade at the tissue or organ level, because the weakening of the anulus fibrosus tissue hinders its ability to withstand tensile strains during compressive loading. As the anulus fibrosus continues to break down, the nucleus pulposus tissue is allowed to enter the annular region of the disc, and eventually disc bulging and/or herniation will occur. Thus, biological changes in the disc morphology resulting from the exposure to cigarette smoke and/or its constituents can directly lead to intervertebral disc herniation or prolapse.
Spinal Loading and Smoking Lead to Degeneration
Several previous studies have linked high occupational loading, such as heavy lifting or vibrational loading, with the incidence of low back pain clinically. Videman et al.57 found that higher occupational lifting and more smoking during follow-up were predictors of increased disc height reduction in a longitudinal study assessing quantitative MRI measures of disc degeneration in 134 male monozygotic twins of the ages of thirty-five to sixty-nine years. The loss of disc height is one of the hallmarks of disc degeneration and is often used in MRI diagnosis of the condition. Additionally, in a population-based cross-sectional study, Leboeuf-Yde et al.24 evaluated the association of self-reported physical hard work, smoking, and obesity in 412 forty-year-old Danes with MRI findings, back pain, and a vertebral inflammatory process. They found that there were no significant associations between the single variables and intervertebral disc degeneration, although they did find that hard physical work in combination with either heavy smoking or obesity was strongly associated with a vertebral inflammatory process.
Both smoking and back pain have been accepted as important public health concerns. Although the link between these two has not been fully established, several epidemiological and clinical studies have shown a correlation. There is difficulty in fully interpreting results of these studies because of the possible confounding factors involved. For instance, it may be that cigarette smokers may be more likely to make other lifestyle choices that are closely associated with disc degeneration or low back pain; although some studies have investigated such factors, not all have taken them into account. It is also possible that smokers exhibit more symptomatic disc degeneration and are thus more likely to see a doctor because of the onset of pain.
A better understanding of the mechanism of the association between smoking and intervertebral disc degeneration can be achieved through experimental evidence supporting the indirect and direct mechanisms linking the two. It should be noted that both direct and indirect mechanisms have only been hypothesized, with limited experimental evidence to support each. Nonetheless, studies have shown that exposure to cigarette smoke or its constituents can lead to alterations in tissue and cellular morphology, changes in disc cell activity and metabolism, and a reduction in the nutritional supply at the disc periphery. Although experimental studies have been carried out in controlled settings that may not fully reflect the in vivo environment in the intervertebral disc of a smoking individual, changes seen may detrimentally affect the homeostasis within the tissue either directly or indirectly, thus leading to degenerative changes and a subsequent loss of disc function and back pain. More studies are necessary to further elucidate the molecular and biological effects and pathways involved in the degenerative process of the intervertebral disc in connection with cigarette smoking, so that we can better understand the pathobiology of the intervertebral disc more generally. This will greatly enhance our ability to design innovative strategies for the treatment and/or prevention of disc degeneration and low back pain in all patients.
Source of Funding: Two authors (A.R.J. and M.D.B.) received funding for this research from the Miami Center for Orthopaedic Research and Education (CORE) at the University of Miami Miller School of Medicine. Funds were used to pay for partial salary support.
Investigation performed at the Departments of Biomedical Engineering and Orthopaedics, University of Miami, Miami, Florida
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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