Vitamin D, race, and experimental pain sensitivity in older adults with knee osteoarthritis

Authors


Abstract

Objective

Low circulating serum levels of 25-hydroxyvitamin D (referred to hereafter as vitamin D) have been correlated with many health conditions, including chronic pain. Recent clinical practice guidelines define vitamin D levels <20 ng/ml as deficient and levels of 21–29 ng/ml as insufficient. Vitamin D insufficiency, including the most severe levels of deficiency, is more prevalent in black Americans. Ethnic and race group differences have been reported in both clinical and experimental pain, with black Americans reporting increased pain. The purpose of this study was to examine whether variations in vitamin D levels contribute to race differences in knee osteoarthritis pain.

Methods

The sample consisted of 94 participants (74% women), including 45 blacks and 49 whites with symptomatic knee osteoarthritis. Their average age was 55.8 years (range 45–71 years). Participants completed a questionnaire on knee osteoarthritis symptoms and underwent quantitative sensory testing, including measures of sensitivity to heat-induced and mechanically induced pain.

Results

Blacks had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat-induced and mechanically induced pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but did not predict self-reported clinical pain. Group differences in vitamin D levels significantly predicted group differences in heat pain and pressure pain thresholds at the index knee and ipsilateral forearm.

Conclusion

These data demonstrate that race differences in experimental pain are mediated by differences in the vitamin D level. Vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in black Americans.

The last decade has witnessed a dramatic increase in research related to the nonskeletal effects of vitamin D. In its known role as a vitamin, this micronutrient aids calcium absorption. However, recent research on vitamin D has focused on its hormonal actions. Recommended daily intake of vitamin D has historically been aimed at primary prevention of osteomalacia and osteoporosis. In its biologically active form, vitamin D is a secosteroid involved in regulating cell differentiation, proliferation, angiogenesis, and apoptosis (1). Vitamin D is synthesized through the skin with adequate exposure to ultraviolet B (UVB) light. Following synthesis and conversion, vitamin D is hydroxylated in the liver, then in the kidneys. Vitamin D receptors can be found on nearly all nucleated cells (2). Vitamin D deficiency has been correlated with diabetes, cancer, and decreased immunity (1).

Less than sufficient circulating serum levels of 25-hydroxyvitamin D (referred to hereafter as vitamin D) have been noted across populations in epidemiologic studies. Seasonal variation in the angle of the sun's UVB rays decreases opportunities for vitamin D synthesis in northern latitudes and in the winter months. Other factors contributing to inadequate vitamin D levels include more time spent indoors, increased use of sunscreen, and the prevalence of obesity (3). As a fat-soluble nutrient, vitamin D is sequestered in fat cells, decreasing its availability for hormonal actions in the bloodstream. The body's ability to synthesize vitamin D in the skin lessens with aging (3); thus, older adults are at greater risk of inadequate vitamin D levels. Additionally, vitamin D synthesis requires longer periods of sun exposure for those with dark skin pigmentation. Thus, low levels of vitamin D are prevalent in black Americans, including the most severe levels of deficiency. Estimates indicate that 70% of white Americans and >95% of black Americans have insufficient levels of vitamin D (4). Greater vitamin D deficiency in black Americans may, in part, explain their increased incidence of chronic health conditions and provide a key to reducing health disparities (3–5).

The optimal serum concentration of vitamin D is currently debated but is believed to be between 30 and 60 ng/ml. Recent clinical practice guidelines define vitamin D levels <20 ng/ml as deficient and levels of 21–29 ng/ml as insufficient (6). It has been suggested that different normative values of vitamin D may be warranted for black and white Americans based on the inverse relationship between vitamin D and parathyroid hormone levels (7). However, variation in the vitamin D–parathyroid hormone relationship by race and age is not fully understood, and clinical trials on vitamin D supplementation are needed (7–10). In 2011, the Institute of Medicine report, Dietary Reference Intakes for Calcium and Vitamin D (11), increased the recommended daily intake of vitamin D from 400 to 600 IU per day. Many experts believe that this dose is still too low (12). The Institute of Medicine report recommended interventional research on vitamin D supplementation to ascertain its effect on disease, aging, and racial health disparities and therefore raised the maximum safe daily dose to 4,000 IU. Although vitamin D has been correlated with many health conditions, few studies have considered the relationship of vitamin D to chronic pain (13–17).

Chronic pain is a disease. The 2011 Institute of Medicine report, Relieving Pain in America (18), estimates annual spending on pain to be between $560 billion and $635 billion. Many older adults contend with pain from osteoarthritis—the most common joint condition and the leading cause of disability in older adults (19–21). Research suggests that the brain reorganizes in the presence of chronic pain, which may reflect fundamental changes in how the brain processes pain-related information (22). Despite advances in the basic science understanding of pain pathways and processing, there remain vast individual differences in response to the clinical treatment of pain. Furthermore, pain remains undertreated, especially for older adults and nonwhite populations (23–27). Previous research in our laboratory has found ethnic differences in quantitative sensory testing results, with blacks reporting increased pain sensitivity (28, 29).

The triage theory, proposed by Ames (30), hypothesizes that long-term micronutrient deficiencies trigger chronic inflammation. In turn, chronic inflammation leads to chronic health conditions, many of which are characterized by pain as a disabling symptom. Recent research by Lee et al (31) supports the hypothesis that the etiology of osteoarthritis includes a systemic inflammatory component. Heaney (32) theorizes that long-latency chronic diseases are related to insufficient micronutrients over extended periods. The US nutritional recommendations for micronutrients are based on preventing short-latency diseases and not on optimizing the preventive health effects of micronutrient therapy. These theories may help to explain relationships between vitamin D level and chronic pain. The purpose of this study was to examine whether variations in vitamin D levels contribute to race differences in symptomatic knee osteoarthritis pain. We hypothesized that low levels of vitamin D would contribute to self-reported and experimental knee pain and that vitamin D level would mediate the relationship between race (referred to as group differences) and knee pain.

PATIENTS AND METHODS

Study design.

This cross-sectional study design examined the relationship between low levels of vitamin D and symptomatic knee osteoarthritis pain among older adults. The project is a substudy of an ongoing study examining ethnic differences in knee osteoarthritis pain. The measures and procedures described are limited to those involved in the current study. Participants were recruited at the University of Florida between January 2010 and August 2011.

Participants.

Participants were recruited via posted fliers, radio and print media advertisements, clinic recruitment, and word-of-mouth referral. The inclusion criteria were as follows: 1) ages 45–85 years; 2) unilateral or bilateral symptomatic knee osteoarthritis based on American College of Rheumatology criteria (33), regardless of radiographic evidence of osteoarthritis; and 3) availability to complete the 2-session protocol. Participants were excluded if they met any of the following criteria: 1) prosthetic knee replacement or nonarthroscopic surgery to the affected knee; 2) uncontrolled hypertension (>150/95), heart failure, or history of acute myocardial infarction; 3) peripheral neuropathy; 4) systemic rheumatic disorders including rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia; 5) daily opioid use; 6) cognitive impairment (Mini-Mental State Examination [MMSE] [34] score ≤22); 7) excessive anxiety regarding protocol procedures (intravenous [IV] catheter insertion, quantitative sensory testing procedures); and 8) hospitalization within the preceding year for psychiatric illness. All procedures were reviewed and approved by the University of Florida Institutional Review Board. Participants provided informed consent and were compensated for their participation.

Procedures.

Within 1 week prior to the health assessment session, participants completed study questionnaires. At the health assessment session, the following measures were obtained: anthropometric data, vital signs, health history, current medications, MMSE score, and a bilateral joint examination of the hand and knee joints. Using the American College of Rheumatology criteria (33) for symptomatic knee osteoarthritis, a participant's most symptomatic/painful knee was designated the index knee. Within 4 weeks of the health assessment session, participants were scheduled for the quantitative sensory testing session. Additional questionnaires were completed prior to and during this session. Quantitative sensory testing procedures included vital signs, IV insertion for blood collection, and assessment of thermally induced and mechanically induced pain.

Self-report measures.

Center for Epidemiologic Studies Depression Scale (CES-D).

The CES-D is a 20-item self-report tool that measures symptoms of depression including depressed mood, guilt/worthlessness, helplessness/hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance (35). The total score of the CES-D (range 0–60) was used in the current study as an estimate of the degree of participants' depressive symptoms. The validity and internal consistency of the CES-D in the general population have been reported to be acceptable (36).

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

The WOMAC (37) is frequently used in research to assess symptoms of knee and hip osteoarthritis. The subscales measure pain, stiffness, and physical function. The total WOMAC score was used in analysis (range 0–96). High construct validity and test–retest reliability has been found in paper and computerized versions of the WOMAC (38).

Quantitative sensory testing.

Thermal testing procedures.

All thermal stimuli were delivered using a computer-controlled Medoc Pathway Thermal Sensory Analyzer (Ramat Yishai). Heat pain thresholds and heat pain tolerances were assessed using an ascending method of limits. From a baseline of 32°C, thermode temperature increased at a rate of 0.5°C per second until the participant responded by pressing a button on a handheld device. For heat pain threshold, participants were instructed to press the button when the sensation “first becomes painful,” and for tolerance, the instruction was to press the button when they “no longer feel able to tolerate the pain.” Three trials for threshold and 3 for tolerance were delivered to the index knee. The position of the thermode was moved among 3 sites (the medial joint line, the patella, and the tibial tuberosity distal to the joint) between trials to avoid sensitization and/or habituation of cutaneous receptors. The results of the 3 individual trials were averaged together to create overall heat pain threshold and heat pain tolerance scores for the index knee. Similarly, 3 trials for threshold and 3 for tolerance were delivered to the ipsilateral forearm. The position of the thermode was moved among 3 sites an inch above the ventral wrist and an inch below the antecubital space. The results of the 3 individual trials were averaged together to create overall heat pain threshold and heat pain tolerance scores for the ipsilateral forearm.

Mechanical testing procedures.

To determine sensitivity at the site of clinical pain, 6 total trials of pressure pain threshold were assessed at the medial (3 trials) and lateral (3 trials) joint lines of the index knee. Additionally, 3 pressure pain threshold trials were assessed at the dorsal ipsilateral forearm. A handheld Medoc digital pressure algometer (Ramat Yishai) was used for the mechanical procedures. An application rate of 30 kPa per second was used. To assess pressure pain threshold, the examiner applied a constant rate of pressure, and the participant was instructed to press a button when the sensation “first becomes painful,” at which time the device recorded the pressure in kPa. The average of the 3 trials was computed separately for the medial and lateral knee and subsequently combined to create an overall pressure pain sensitivity score for the index knee. Likewise, the average results of the 3 trials for the ipsilateral forearm were calculated to create an overall pressure pain sensitivity score. The overall pain index scores for the index knee and ipsilateral forearm were included in statistical analysis.

Vitamin D assay.

Serum was collected at the beginning of the quantitative sensory testing session. Following collection, plasma was stored in a freezer at −80°C. The analyte was subjected to analysis within 6 months of collection. Vitamin D analysis was performed by high-performance liquid chromatography (total 25-hydroxyvitamin D = 25[OH]D2 plus 25[OH]D3). Results were shared with participants, and if their vitamin D level was ≤30 ng/ml, they were encouraged to discuss this result with their primary care provider.

Statistical analysis.

Statistical analysis was performed using SPSS software, version 19.0 (IBM). Bivariate relationships among continuously measured variables were assessed using Pearson's correlations, while sex differences were assessed using analysis of variance. Group differences by race were adjusted for covariates and assessed using analysis of covariance (ANCOVA). The relationships between vitamin D level and pain were examined using multiple regressions. P values less than 0.05 were considered significant.

To test whether vitamin D level significantly mediated (Figure 1) the association between race and clinical and experimental pain measures, we conducted a bootstrap analysis. Bootstrapping, as put forth by Hayes and Preacher (39, 40), is a nonparametric resampling procedure that has been shown to be a viable alternative to the Baron and Kenny (41) approach to testing intervening variable effects. Percentile bootstrap confidence intervals (CIs) were used to minimize Type I error rate (42). A percentile bootstrap 95% CI was calculated, using the SPSS macro for simple mediation (40) to determine the significance of the mediator. In the current study, path c represents the total effect of the independent variable (race) on the dependent variable (clinical and experimental pain measures). Path a denotes the effect of race on vitamin D level (mediator) and path b is the effect of vitamin D level on clinical and experimental pain measures. The bootstrapped mediation analysis indicates whether the total effect (path c) consists of a significant direct effect (path c′) of race on clinical and experimental pain measures and a significant indirect effect (path a × b) of race on clinical and experimental pain measures through the mediator—vitamin D level.

Figure 1.

Mediation model. The effect of race on vitamin D level is represented by a, the direct effect of vitamin D level on pain measures is represented by b, and the total effect of race on pain measures is represented by c.

RESULTS

Sample characteristics and examination of covariates.

A total of 107 participants with symptomatic knee osteoarthritis were recruited. Vitamin D data were available for 94 participants at the time of analyses. Figure 2 shows a flow diagram for participant matriculation through the study.

Figure 2.

Flow diagram of the study participants. QST = quantitative sensory testing; HAS = health assessment session; AA = African American.

Pearson's correlations for key study variables are shown in Table 1. Vitamin D level correlated significantly and inversely with the total WOMAC score, suggesting that lower vitamin D levels are associated with greater knee osteoarthritis pain and dysfunction. For experimental pain measures, vitamin D level correlated significantly with heat pain threshold and heat pain tolerance at the index knee and at the ipsilateral forearm. Finally, vitamin D level correlated significantly with pressure pain thresholds at the knee and at the ipsilateral forearm. Age and CES-D score did not correlate significantly with vitamin D level; however, the CES-D score correlated positively with WOMAC score and heat pain threshold at the knee.

Table 1. Pearson's correlations of variables among the 94 study participants*
 Age, yearsBMIVitamin D levelCES-D scoreWOMAC scoreKnee heat pain thresholdKnee heat pain toleranceForearm heat pain thresholdForearm heat pain toleranceKnee pressure painForearm pressure pain
  • *

    BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

  • P < 0.01.

  • P < 0.05.

Age, years          
BMI0.02         
Vitamin D level0.02−0.33        
CES-D score−0.18−0.010.07       
WOMAC score0.030.50−0.270.28      
Knee heat pain threshold−0.02−0.020.270.23−0.12     
Knee heat pain tolerance−0.11−0.140.270.07−0.220.61    
Forearm heat pain threshold−0.07−0.140.350.18−0.150.580.59   
Forearm heat pain tolerance−0.16−0.210.300.08−0.200.470.880.64  
Knee pressure pain−0.07−0.380.390.05−0.410.370.360.370.35 
Forearm pressure pain−0.19−0.160.340.06−0.220.360.350.410.370.67

Women demonstrated lower heat pain tolerance at the forearm (F[1,92] = 4.76, P = 0.03) and lower pressure pain thresholds at the knee (F[1,92] = 12.92, P = 0.001) and forearm (F[1,92] = 13.75, P < 0.001) compared to men. There was a greater proportion of black current smokers compared to white current smokers (χ2 = 4.64, P < 0.05). However, clinical and experimental pain, as well as vitamin D level, did not differ significantly according to smoking status (all P > 0.05 for current smokers versus nonsmokers). Participant age, sex, body mass index (BMI), and CES-D score correlated with pain response and were included as statistical controls in all subsequent data analyses.

Group differences in clinical and experimental pain.

Using the total WOMAC score, ANCOVA revealed a significant group difference (F[1,88] = 5.67, P = 0.02). As shown in Table 2, the mean ± SD WOMAC score for black participants was 41.5 ± 21.66, compared to a mean ± SD WOMAC score of 29.4 ± 18.76 for white participants, indicating that blacks reported more knee pain, stiffness, and limitations in physical function. Additionally, black participants demonstrated greater sensitivity to experimental pain measures compared to whites. For example, blacks demonstrated significantly lower mean heat pain threshold (F[1,88] = 5.36, P = 0.02) and heat pain tolerance (F[1,88] = 23.14, P < 0.001) at the index knee. Similar results were found for the ipsilateral forearm, such that blacks demonstrated significantly lower heat pain threshold (F[1,88] = 9.32, P = 0.003) and heat pain tolerance (F[1,88] = 17.81, P < 0.001) compared to whites. For mechanically induced pain, black participants demonstrated significantly lower mean pressure pain threshold at the index knee (F[1,88] = 10.13, P = 0.002) and at the ipsilateral forearm (F[1,88] = 3.96, P = 0.05) compared to whites.

Table 2. Descriptive data for key study variables across the groups*
 Blacks (n = 45)Whites (n=49)P
  • *

    Except where indicated otherwise, values are the mean ± SD (range). BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

No. of women/men31/1439/10
Age, years54.6 ± 5.4 (45–68)56.9 ± 7.7 (45–71)
Vitamin D level, ng/ml19.9 ± 8.6 (8–40)28.2 ± 8.6 (7–48)<0.001
BMI, kg/m232.4 ± 8.0 (18–50)29.0 ± 6.7 (19–49)<0.05
CES-D score (range 0–60)16.2 ± 6.5 (0–30)16.7 ± 5.2 (0–38)
WOMAC score (range 0–96)41.5 ± 21.7 (4–94)29.4 ± 18.8 (4–86)<0.05
Knee heat pain threshold, °C41.3 ± 3.0 (36–46)42.7 ± 2.9 (36–48)
Knee heat pain tolerance, °C44.6 ± 3.3 (35–49)47.0 ± 2.1 (38–51)<0.001
Forearm heat pain threshold, °C40.9 ± 3.3 (34–47)42.8 ± 2.7 (35–47)<0.05
Forearm heat pain tolerance, °C45.2 ± 2.7 (37–50)47.0 ± 2.1 (39–51)<0.001
Knee pressure pain threshold, kPa263.6 ± 149.0 (53–588)362.4 ± 164.4 (81–598)<0.05
Forearm pressure pain threshold, kPa233.3 ± 153.2 (51–748)275.9 ± 148.9 (77–677)<0.05

Group differences in vitamin D level.

Adjusted for covariates, ANCOVA revealed that black participants were characterized by significantly lower mean vitamin D levels than their white counterparts (F[1,88] = 16.03, P < 0.001). The mean ± SD vitamin D level in black participants was 19.9 ± 8.6 ng/ml, which based on the most recent guidelines (6) indicates vitamin D deficiency, compared to a mean ± SD vitamin D level of 28.2 ± 8.6 ng/ml in whites, which indicates vitamin D insufficiency. Low levels of vitamin D were observed across the sample but were found disproportionately in black participants; 38 of 45 black participants (84%) had vitamin D levels <30 ng/ml compared to 25 of 49 white participants (51%) (χ2 = 11.86, P < 0.001).

Vitamin D level and pain.

Adjusted multiple regression analyses, controlling for the effects of age, sex, BMI, CES-D score, and group, revealed that vitamin D level was not significantly associated with the total WOMAC score (β coefficient −0.06, P = 0.56). However, low levels of vitamin D predicted increased pain sensitivity and lower experimental pain thresholds. Diminished vitamin D levels were significantly associated with lower heat pain thresholds at the index knee (β coefficient 0.23, P = 0.05) and ipsilateral forearm (β coefficient 0.25, P = 0.03). Additionally, lower vitamin D levels were significantly associated with greater sensitivity to pressure pain (i.e., lower threshold) at the index knee (β coefficient 0.23, P = 0.02) and the ipsilateral forearm (β coefficient 0.31, P < 0.01). However, the vitamin D level was not significantly related to heat pain tolerance at the index knee (β coefficient 0.10, P = 0.37) or the ipsilateral forearm (β coefficient 0.13, P = 0.22). Accordingly, only heat pain thresholds and pressure pain thresholds at the index knee and ipsilateral forearm were examined in the mediational analyses.

Testing vitamin D level as a simple mediator.

We tested the indirect effects of group differences in heat pain thresholds and pressure pain thresholds through vitamin D level (i.e., simple mediation). Table 3 displays the results of the analyses that examined whether vitamin D level mediated group differences in heat pain thresholds at the index knee (model 1) and ipsilateral forearm (model 2) after adjusting for covariates. The vitamin D level was found to significantly mediate the group difference in heat pain threshold at the index knee (percentile bootstrap 95% CI 0.01–1.11) and at the ipsilateral forearm (percentile bootstrap 95% CI 0.09–1.22) using the percentile bootstrap 95% CI, with 5,000 resamples. These results indicate that indirect effects through vitamin D level are significantly different from zero. Thus, group differences in heat pain thresholds are mediated by group differences in vitamin D levels. More specifically, blacks possessed lower vitamin D levels than whites and, in turn, lower vitamin D levels significantly predicted lower heat pain thresholds at the index knee and ipsilateral forearm.

Table 3. Vitamin D mediation of group differences in heat pain threshold at the index knee (model 1) and ipsilateral forearm (model 2)*
EffectCoefficientSEtPPercentile bootstrap 95% CI
  • *

    Shown are unstandardized coefficients for the mediated effect of group differences in heat pain threshold at the index knee and ipsilateral forearm through vitamin D level, controlling for age, sex, body mass index, and Center for Epidemiologic Studies Depression Scale score. Path c =total effect of race on heat pain threshold; path a =effect of race on vitamin D level; path b =direct effect of vitamin D level on heat pain threshold; path c′ = direct effect of race on heat pain threshold, controlling for vitamin D level; path a × b = indirect effect of race on heat pain threshold through vitamin D level. 95% CI = 95% confidence interval.

  • A P value for the indirect effect is not provided because such a P value is contingent upon a normal distribution of the indirect effect. Given that the product of the path a and path b coefficients is always positively skewed, interpretation of this P value can be misleading (40).

Model 1     
 Path c1.490.642.320.0229
 Path a7.391.854.000.0001
 Path b0.070.041.960.0531
 Path c′0.960.691.390.1667
 Path a × b0.510.280.01–1.11
Model 2     
 Path c1.970.643.050.0030
 Path a7.391.854.000.0001
 Path b0.080.042.270.0258
 Path c′1.360.681.980.0506
 Path a × b0.600.290.09–1.22

Table 4 displays the results of the analyses that examined whether the vitamin D level also mediated group differences in pressure pain thresholds at the index knee (model 3) and ipsilateral forearm (model 4) after adjusting for covariates. Vitamin D level was shown to significantly mediate the group differences in pressure pain threshold at the index knee (percentile bootstrap 95% CI 3.43–60.86) and at the ipsilateral forearm (percentile bootstrap 95% CI 12.44–67.55) using the percentile bootstrap 95% CI, with 5,000 resamples. As mentioned above, these results indicate that indirect effects through the vitamin D level are significantly different from zero. Thus, group differences in pressure pain thresholds are mediated by group differences in vitamin D levels.

Table 4. Vitamin D mediation of group differences in pressure pain threshold at the index knee (model 3) and ipsilateral forearm (model 4)*
EffectCoefficientSEtPPercentile bootstrap 95% CI
  • *

    Shown are unstandardized coefficients for the mediated effect of group differences in pressure pain threshold at the index knee and ipsilateral forearm through vitamin D level, controlling for age, sex, body mass index, and Center for Epidemiologic Studies Depression Scale score. Path c =total effect of race on pressure pain threshold; path a =effect of race on vitamin D level; path b =direct effect of vitamin D level on pressure pain threshold; path c′ = direct effect of race on pressure pain threshold, controlling for vitamin D level; path a × b = indirect effect of race on pressure pain threshold through vitamin D level. 95% CI = 95% confidence interval.

  • A P value for the indirect effect is not provided because such a P value is contingent upon a normal distribution of the indirect effect. Given that the product of the path a and path b coefficients is always positively skewed, interpretation of this P value can be misleading (40).

Model 3     
 Path c95.8830.123.180.0020
 Path a7.391.854.000.0001
 Path b4.001.702.360.0205
 Path c′66.3131.932.080.0408
 Path a × b29.1014.843.43–60.86
Model 4     
 Path c60.2130.261.990.0497
 Path a7.391.854.000.0001
 Path b4.951.682.960.0040
 Path c′23.6131.540.750.4561
 Path a × b36.3414.2712.44–67.55

DISCUSSION

In the present study, we examined the extent to which the vitamin D level mediated the relationship between race and pain in older adults with symptomatic knee osteoarthritis. The results revealed that group differences in response to experimental pain, but not self-reported pain, for blacks and whites are mediated by group differences in vitamin D level. Low levels of vitamin D mediated the relationship between race and experimental pain in older adults with symptomatic knee osteoarthritis. The study hypothesis expected these findings at the painful knee. Similar results were demonstrated at a nonpainful testing site at the forearm. Even in a sunny southern environment, low levels of vitamin D were endemic across the sample, with black participants having more pronounced vitamin D deficiency. Black participants demonstrated greater pain sensitivity in thermal and mechanical testing at the index knee and the ipsilateral forearm. These findings are consistent with previous research demonstrating significant differences in responses to quantitative sensory testing in black Americans (28, 29, 43).

Although there is an established link between low levels of vitamin D and pain due to osteomalacia (1), no clear biologic or psychological mechanisms explain how low levels of vitamin D may affect pain sensitivity or relate causally to other chronic pain conditions. Interestingly, significant mediation was found for heat pain threshold but not for pain tolerance. This outcome suggests that vitamin D level may be related to pain pathways involved in initial perception of pain but not to how much pain an individual can tolerate. Pain tolerance is dependent, in part, on individuals' willingness to endure noxious stimulation, which is not necessarily related to vitamin D level.

In contrast, since there are vitamin D receptors in nucleated cells throughout the peripheral and central nervous system, less than sufficient levels of vitamin D could affect both the transmission and modulation of painful stimuli (16, 21, 31, 44). Using a rodent model, Tague and colleagues (45) found that vitamin D–deficient rats had increased muscle innervation by nociceptors, leading to reduced pain threshold for mechanical stimulation in hindlimb musculature. In vitro cultures revealed that vitamin D level was inversely correlated with growth of sensory neurons, leading the authors to hypothesize that vitamin D deficiency may induce muscle pain by stimulating nociceptor growth. Furthermore, inflammatory processes contribute to increased pain sensitivity among individuals with osteoarthritis (21, 31). Sufficient levels of cellular vitamin D have a protective effect on cell function and are believed to reduce inflammation (1, 46). Thus, alterations in inflammation attributable to low levels of vitamin D may precipitate increased pain among individuals with osteoarthritis. Less than sufficient levels of vitamin D may explain the increase in symptomatic osteoarthritis without a concurrent increase in radiographic osteoarthritis (47).

In this cohort, the participants' CES-D score did not correlate significantly with vitamin D level. However, other research has found an association between low levels of vitamin D and increased symptoms of depression. In a 4-year study of nearly 12,600 participants, low levels of vitamin D were associated with depression, especially in those who had had previous episodes (48). Higher levels of vitamin D were associated with fewer symptoms of depression, even among those with a history of depression. It is possible that vitamin D has a direct effect on mood, since vitamin D supplementation in a placebo-controlled double-blind trial was shown to improve the mood and affect of individuals diagnosed as having seasonal affective disorder (49). Vitamin D receptors are ample in structures and cells of the brain and may contribute to overall brain health and enhanced nerve conduction (50). Given the substantial overlap between negative mood and chronic pain, vitamin D insufficiency may modulate pain perception through affective pathways (51).

As in most research, these findings should be interpreted in light of the study limitations. Participants represented a convenience sample of community-dwelling adults and older adults. The age range of participants was 45–71 years; however, the average age of 55.8 years represents a younger cohort. Although black participants were slightly younger than whites, they reported higher levels of osteoarthritis-related pain. The cross-sectional examination of vitamin D level and clinical and experimental pain does not permit a full understanding of the direction of the relationship between vitamin D level and chronic pain. It is possible that people with osteoarthritis pain spend less time outdoors and thus have reduced opportunities for vitamin D synthesis. However, it is unlikely that experimental pain affected participants' vitamin D levels, thus lending credence to our study model, namely, that vitamin D mediates the relationship between race and experimental pain. Finally, although participants using regularly scheduled opioids were excluded from the study, and those using opioids as needed were asked to refrain from taking their medication 2 days prior to quantitative sensory testing, we did not account for other analgesic medication use, which may have affected the results of pain testing.

It is unclear why race differences in vitamin D level mediate group differences in experimental pain outcomes but do not mediate clinical osteoarthritis pain intensity, stiffness, or physical function on the WOMAC. This outcome may be related to the fact that osteoarthritis pain intensity measures were assessed retrospectively (i.e., pain over the past 48 hours) and were therefore subject to recall bias. Alternatively, vitamin D may influence certain aspects of pain processing reflected by pain thresholds, while osteoarthritis-related symptoms assessed by the WOMAC are likely driven by multiple factors over and above nociceptive processes. Moreover, a clinical threshold of vitamin D insufficiency may be necessary to better understand the relationship between low levels of vitamin D, clinical knee pain, and total WOMAC score. In a systematic review of research on vitamin D and chronic pain, Straube and colleagues (16) did not find evidence to support a relationship between vitamin D and chronic pain. Results may have been affected by methodologic considerations, such as study design weakness and limited sample size. Similarly, in a review of 7 studies, Straube and colleagues (14) found insufficient evidence to support treating chronic pain in ethnic minority patients by correcting vitamin D deficiency. However, none of the studies were randomized controlled trials, and only 2 case studies investigated vitamin D supplementation.

Additional research is needed to strengthen these findings. High-quality observational studies and randomized controlled trials with rigorous methodologic control and adequate numbers of black participants are needed to understand the relationship between low levels of vitamin D, pain, and pain disparities experienced by black Americans. Improving vitamin D status is inexpensive and with low risk of adverse events. Thus, if additional research demonstrates that improving vitamin D status lessens knee osteoarthritis pain, identifying and treating vitamin D insufficiency and deficiency may improve function for older adults with osteoarthritis and reduce health disparities for black Americans.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Ms Glover had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Glover, Horgas, Riley, Staud, Bradley, Fillingim.

Acquisition of data. Glover, Goodin, Kindler, King, Sibille.

Analysis and interpretation of data. Glover, Goodin, Peloquin, Fillingim.

Acknowledgements

We would like to thank the participants and staff of the Understanding Pain and Limitations in Osteoarthritic Disease study and the staff of the University of Florida Clinical Research Center, without whom this research would not have been possible.

Ancillary