Vitamin D and knee OA: Many theories, few answers

Several patient populations with an increased risk of knee osteoarthritis also are at increased risk for vitamin D deficiency, and research suggests vitamin D levels may be related to knee OA symptoms. The exact nature of the relationship, however, remains perplexing.

By Greg Gargiulo

Knee osteoarthritis (OA) remains one of the most common musculoskeletal disorders and represents a major burden to patients and the healthcare industry.^1,2 Despite its prevalence—up to 16% of adults older than 45 years have symptomatic knee OA³—and ongoing research efforts to manage its progress, no medical treatment has yet been demonstrated to significantly alter its course.⁴

The pathogenesis of knee OA is still not completely understood and is most likely multifactorial by nature, but risk factors that may contribute to its development and progression include ethnicity, bone density, gender, diet, previous injury and occupation, and older age and obesity are two leading predictors.¹

Research interests have also been growing recently in 25-hydroxyvitamin D 25(OH)D, or vitamin D, an important micronutrient that aids primarily in calcium absorption.⁵ Normal bone and cartilage metabolism depend on the presence of vitamin D,⁶ yet an estimated one billion people worldwide are vitamin D-deficient or insufficient, making it another international health concern.¹ Although some controversy exists and no consensus has yet been reached for optimal serum levels of vitamin D, most experts define 25(OH)D levels less than 20 ng/mL as deficient, levels of 21 to 29 ng/mL as insufficient, and levels greater than 30 ng/mL as sufficient.⁵

Conflicting evidence

Due to its vital biological role, research has linked low levels of vitamin D with a host of conditions, including rickets (children), osteomalacia (adults), osteoporosis, fracture risk, diabetes, cancer, and decreased immunity.⁵ Researchers have theorized that vitamin D deficiency may also impact the course of knee OA, since it’s known to influence bone quality and could affect cartilage as well. However, while some studies have identified a connection between vitamin D levels and factors related to knee OA,^7-12 others have found minimal or no association.^4,13-16 These conflicting reports have made it difficult for medical professionals to establish confident positions or provide appropriate recommendations for patients based on the available literature.

To some extent, this is typical of discussions related to dietary supplements, according to David Felson, MD, director of the Clinical Epidemiology Research & Training Unit at Boston University’s School of Medicine.

“I don’t think there’s really one explanation for the inconsistencies in the literature,” Felson said. “It’s not unlikely for us to find conflicting results on things for a long time before we can actually make sense of them.”

The first major clinical trial on the topic took place in 1996, when McAlindon et al¹² found that both low intake and serum levels of vitamin D were associated with an increased risk for the progression of knee OA. The findings suggested that people with inferior serum levels (≤ 30 ng/mL) and low intake were about three times more likely to experience radiographic progression of preexisting knee OA than those with sufficient levels, but found no evidence that lower levels also increased the risk for OA development in a previously normal knee.

Although the trial’s radiographic method is somewhat outdated and would probably not be considered acceptable by today’s standards,¹⁴ this seminal paper went on to be referenced regularly in a number of subsequent studies on the topic.

Since 1996, evidence has emerged both for and against an association. On the supportive end, one study found low dietary vitamin D increased the risk of radiographic knee OA progression,¹¹ while another established a clear relationship between knee OA and serum vitamin D deficiency in individuals younger than 60 years.¹⁰ Similar outcomes were reported for the hip, too, as Lane et al showed vitamin D-insufficient elderly men were twice as likely as those with normal vitamin D levels to have prevalent radiographic hip OA.¹⁷

Population associations

Taking the research further, some studies have investigated the role of known risk factors for knee OA in populations typically affected by low vitamin D levels.

Data from the National Health and Nutrition Examination Survey of 2001-2004 indicate that approximately 70% of white Americans have insufficient or deficient vitamin D levels, while about 97% of black Americans fall into this category, a factor researchers believe may be partially responsible for race-related disparities in the incidence of chronic health conditions linked to vitamin D insufficiency.¹⁸ Glover et al, for example, found that black patients with symptomatic knee OA had significantly lower levels of vitamin D and greater clinical pain and sensitivity to mechanically and heat-induced pain than their white counterparts.⁹

Another study concluded there was an association in older adults between both sunlight exposure and serum vitamin D levels and loss of knee cartilage volume, a hallmark of established knee OA, suggesting that reaching sufficient vitamin D levels may therefore prevent or delay cartilage loss in knee OA.⁷

Two other studies assessed the connection between vitamin D and body mass index (BMI), with one reporting that those who were overweight (BMI 25-29.9 kg/m²) or obese (BMI ≥ 30 kg/m²) had significantly lower serum vitamin D levels than those of normal weight.¹⁶ The other highlighted this connection to a greater extent by showing a significant decrease of vitamin D levels as BMI increased, and finding the highest prevalence of vitamin D deficiency in patients with BMIs of 40 kg/m² or higher (32% of women, 46% of men); this study did not control for knee osteoarthritis.¹⁹

Toni Glover, PhD, assistant professor in the College of Nursing at the University of Florida in Gainesville, offered an explanation for this connection: “Obesity is related to OA—through mechanical forces on the knee—and also to vitamin D, which tends to get sequestered in fat cells,”²⁰ she said.

So evidence does suggest obesity is associated with both OA and vitamin D, but it’s yet to be determined if they share a causal relationship beyond this commonality.

Older age is another risk factor consistently identified with knee OA and, in addition to the previously mentioned outcomes of one paper,⁷ Jansen et al provided further insight by showing a significant relationship between vitamin D deficiency and lower preoperative function in elderly patients with advanced knee OA.²¹

The available research suggests race, weight, and age may be confounding factors in the potential relationship between vitamin D and knee OA and should therefore be controlled for in future studies, but there are some important points surrounding these factors.

According to recent estimates, 35.9% of adults are obese and 69.2% are overweight or obese.²² Vitamin D insufficiency and deficiency have also experienced a significant upswing recently, and researchers have suggested that increased inactivity and obesity have contributed to the observed rise in vitamin D insufficiency.¹⁸ Glover has also suggested that race, age, and lifestyle modifications may help explain this trend.²³

Following the sun

Some authors point out that modern lifestyles have moved humans indoors, and when we do spend time outside, we’re told to cover ourselves with sunscreen. Taking such precautions against skin conditions such as melanoma also deprives the body of its primary source of vitamin D, which comes from exposure to the ultraviolet B (UVB) rays of the sun;²³ sunscreen with sun protection factor 15 decreases vitamin D synthesis by 99%.²⁴

This problem is compounded by weight, which increases the requirements for vitamin D;²⁵ age, since older adults spend less time outdoors and are less able to synthesize vitamin D;²³ and race, as dark skin absorbs UVB rays and slows vitamin D synthesis, meaning those of African ethnicity must spend more time in the sun to make sufficient vitamin D.²⁶

So, if these factors are all somehow involved in both vitamin D deficiency and knee OA, does it indicate there is in fact a causal connection between the two conditions, or are they related in a more indirect manner? Some studies have proposed that the association is based more on coincidence than causality.

Konstari et al conducted a study¹⁶ in Finland, where sunlight exposure varies drastically each season, and determined that vitamin D insufficiency did not increase the risk of developing hip or knee OA; however, the results suggested that high serum vitamin D levels in summer were associated with a decreased risk of OA, but high serum vitamin D levels in winter were associated with an elevated risk of OA. The authors did not feel they could conclude with certainty whether seasons modify the effect of vitamin D on OA, though, and recommended that future research focus on this correlation.¹⁶

Additional studies concluded with no association, yet some of these contained caveats. Al-Jarallah et al found a high level of vitamin D deficiency in patients with knee OA but did not find a relationship between vitamin D level and OA severity,¹⁵ while Muraki et al showed vitamin D levels were not significantly associated with radiographic knee OA but were significantly associated with knee pain.¹³

Another oft-referenced 2007 paper by Felson et al reviewed data from two longitudinal cohort studies, the Framingham Osteoarthritis Study and the Boston Osteoarthritis of the Knee Study. Researchers suggested that, while vitamin D had no significant effect on cartilage loss, it’s possible a deficiency could directly impact other elements of knee OA, such as pain and weakness.¹⁴

Supplemental roles

More recently, in early 2013 McAlindon et al published results from a randomized controlled trial (RCT) in which vitamin D supplementation was given to patients with knee OA for two years.⁴ This RCT is frequently cited to disprove association, as it found that supplementation had no major effects on clinical or structural outcomes in knee OA. Some limitations of this study, however, are worth noting:²³ only 61% of the sample reached the target level of vitamin D, many participants were not vitamin D-deficient to begin with, and the trial may have been too small (146 participants) for its findings to reach statistical significance.

In an RCT by Sanghi et al⁸ published in summer 2013, knee OA patients who had vitamin D insufficiency (≤ 20 ng/mL) were given either placebo or 60,000 international units (IU) of oral vitamin D daily for 10 days, then once a month for 12 months. That level of supplementation is much higher than most recommended daily doses, but, according to Felson, “Sixty thousand IU is recommended for people who are very vitamin D deficient, and you just take that amount for a limited period of time to replenish your stores.”

Sanghi et al’s⁸ results showed the vitamin D group had significantly less knee pain than a placebo group as indicated by scores on both the Western Ontario and McMaster Universities Osteoarthritis Index and a visual analog scale, suggesting there could be a clinical benefit of vitamin D treatment in knee OA patients.

Regardless of the uncertainty surrounding a possible vitamin D-knee OA connection, experts say it may still be beneficial for deficient individuals to increase their vitamin D intake to improve overall health.²³

“My general suggestion is that this is a deficiency that is common and has other ill health effects, like [decreased] bone density for example, and that it’s therefore reasonable for people to get their vitamin D levels checked,” Felson said. “If you supplement and that happens to have a favorable effect on your OA, then that’s great; but even if it has no direct impact, you’ve lost nothing and still receive the benefit of having good health effects from supplementation.”

The only way to determine personal vitamin D levels is by getting a 25(OH)D blood test, which can be performed by a practitioner or by the patient using an in-home version. For those with vitamin D insufficiency or deficiency, taking supplements is the best way to increase serum levels, but not the only way.

“Other means of vitamin D supplementation by diet and outdoor activity in the sun are vital as well,” said Joris Jansen, MD, an orthopedic surgeon and clinical fellow in trauma and orthopedics at University College Hospital in London who has conducted research on vitamin D and knee OA.

Although fatty fish such as Atlantic herring, salmon, and oysters and fortified cereals can provide sizable amounts of vitamin D, it’s extremely difficult to reach sufficient levels from food alone.^27,28

Glover concurs with the sunlight recommendation.

“Prudent sun exposure can be an effective way to help reach adequate vitamin D levels,” she said. “There are even apps to calculate how much sun exposure is needed based on geographic location. Even with this, though, for most people supplementation is still the best way to improve levels.”

This appears to be the general consensus of most experts.²⁹ The Food and Nutrition Board, which provides the official recommendations to the US government, suggests 600 IU a day for adults and 800 IU a day for seniors,²⁵ while the Endocrine Society recommends 1500 to 2000 IU per day.³⁰

For John Cannell, MD, executive director of the Vitamin D Council, a nonprofit organization that educates the public with the latest research on the health benefits of vitamin D and sun exposure, though, those figures are still too low.

“I think all adults should take five thousand IU a day, regardless of whether they are vitamin D-deficient or not,” he said. “That amount will eventually get people the same blood level distribution as exists in free-living hunter-gatherers in Tanzania.”

Cannell’s recommendation may be on the upper end and evidence is still needed to definitively support those elevated numbers; however, even though vitamin D is fat soluble and can be toxic at extremely high doses, though this is quite rare—requiring approximately 40,000 IU a day for multiple months—it’s generally considered a very safe supplement.^31,32 Middle-of-the-road figures of 1000 to 2000 IU a day seem to be reasonable targets for most people, but the safest way to guarantee these amounts are right for each person is consulting a physician experienced in evaluating vitamin D levels.²⁵

Conclusion

Current research suggests it’s likely vitamin D levels are at least somewhat related to symptoms of knee OA, such as pain and weakness, and that African Americans, seniors, and obese individuals are at an increased risk for both vitamin D deficiency and knee OA. However, researchers say it is still not possible to declare causality or establish a definitive association between the two conditions, and additional evidence is needed before stronger conclusions can be reached. Other large-scale trials on this topic are already in progress.²⁹ Researchers have also recommended more RCTs investigating musculoskeletal effects of vitamin D with race as a variable.⁹

Greg Gargiulo is a freelance medical writer based in the San Francisco Bay Area.