In a two-year randomized controlled trial, patients with painful knee osteoarthritis taking vitamin D supplements did not have improved knee pain or less structural damage compared with patients receiving placebo, according to a recent report in the Journal of the American Medical Association. However, this was only a single study, the amount of vitamin D may have been inadequate, and further research is needed to confirm results.
Knee osteoarthritis (OA) is a common age-related musculoskeletal disorder with significant impact on quality of life and high costs to society. There are no medical treatments proven to alter the course of the disease, although some studies have suggested that vitamin D may help to relieve pain and protect against the progression of structural damage to the knee.
To further explore potential benefits of vitamin D in knee OA, Timothy McAlindon, DM, MPH, of Tufts Medical Center, Boston, and colleagues conducted a 2-year, randomized, double-blind, placebo-controlled clinical trial [McAlindon et al. 2013]. Between March 2006 and June 2009, they enrolled 146 participants with symptomatic knee OA (mean age 62 years, 61% women), and these patients were randomized to receive either placebo or 2,000 IU/day of oral vitamin D3 (cholecalciferol). Dose escalations up to 8,000 IU/day were allowed as necessary for increasing vitamin D serum levels — measured as 25-hydroxyvitamin D, or 25(OH)D — to at least 36 ng/mL. Participants and investigators were blinded as to group assignment and, overall, 85% of patients completed the study with a high 96.5% adherence to taking assigned placebo or vitamin D tablets.
The primary outcomes included knee pain severity measured on the Western Ontario and McMaster Universities [WOMAC] pain scale (0-20; 0=no pain, 20=extreme pain), and cartilage volume loss measured by magnetic resonance imaging (MRI). Secondary outcomes included measures of physical function, knee function, cartilage thickness, bone marrow lesions, and joint space width. Assessments were made at 4-month intervals throughout the 2-year period.
Results indicated that 25(OH)D levels increased by an average of about 16 ng/mL in the vitamin D treatment group and by an average 2 ng/mL in the placebo group. Knee pain at the beginning of the study was slightly but not significantly worse in the treatment group (mean 6.9 on 0-20 scale) than in the placebo group (mean 5.8). During the course of the study, pain outcome effects were generally similar in the two groups (see figure, adapted from McAlindon et al. 2013, showing mean scores with 95% Confidence Intervals). Knee pain decreased by -2.3 points in the treatment group and -1.5 points in the placebo group, but there were no statistically significant differences between groups on this measure at any time point (note that all CIs overlap).
The percentage of cartilage volume decreased to the same extent in both groups, by about 4%, and there were no differences between groups in any of the secondary clinical end points. Sixteen participants in each group experienced adverse events and to the same extent, but only 1 event was considered as possibly related to vitamin D — a hip fracture. There were no episodes of hypercalcemia, and the frequency of hypercalciuria (calcium in urine, 10 events) or kidney stones (2 events) were comparable in the two groups.
The researchers conclude from their data that daily vitamin D supplementation at a dose sufficient to elevate 25(OH)D levels to 36 ng/mL does not have major beneficial effects on painful symptoms of knee OA or on structural progression of the disease.
COMMENTARY: Overall, this was a good-quality study of reasonable size, long-term, and well designed, executed, and analyzed. Interim, 12-month, outcomes of this 2-year trial had been presented in abstract form in November 8, 2010 at the American College of Rheumatology Annual Scientific Meeting in Atlanta, Georgia. These results were discussed in a prior UPDATE article [here], and it is important to avoid confusing that earlier report as being a completely separate trial.
At first glance, this study does not appear to endorse vitamin D as beneficial for knee OA; however, there are some questions worth considering:
- Was the level of knee pain severe enough to benefit from vitamin D? At the outset, participants’ arthritis pain in this study population was rather modest, ranging across the 95% Confidence Intervals of the treatment and placebo groups from roughly 4.5 to 7.5 on a 0-to-20 scale [see figure above]. It also is interesting that pain scores decreased slightly over the 2 years, rather than increasing due to progressing structural damage, in both groups and to approximately an equal amount, which may suggest the natural course of mild OA knee pain.
The study was adequately powered to detect a significantt difference in pain scores between groups of as little as 2.2 points, and the researchers indicated that a minimal clinical improvement would be about 4 points. Therefore, it seems possible that pain scores were too low at baseline — representing a “floor effect” — for realizing meaningful and statistically significant pain-relieving effects of vitamin D therapy over time.
- Was the vitamin D dose sufficient? In the vitamin D group, the researchers set a target 25(OH)D serum level of at least 36 ng/mL as necessary to achieve improved outcomes. At 24 months, the mean level in the treatment group overall was 38.5 ng/mL; however, only 61.3% of patients actually reached the targeted 36 ng/mL. Therefore, more than a third of subjects fell below what the researchers thought would be needed for efficacy and, at that, some authorities in the field have suggested that persons with pain may require 50 ng/mL to 75 ng/mL of 25(OH)D circulating in their serum to benefit from vitamin D3 supplementation.
- Were outcomes confounded by analgesic use? Overall, 54% of participants in both groups reported using NSAIDs and 6% used opioids for pain throughout the study, which might have accounted for the modest pain scores at baseline and thereafter. For each visit, patients receiving vitamin D reported greater NSAID use, but this was significantly different from the placebo group only at the 16-month visit. It seems possible that ongoing analgesic use — and perhaps other therapies that patients were engaged in, unknown to the researchers — may have lowered pain scores sufficiently to attenuate demonstrable effects of vitamin D.
- Is 2 years sufficient time to realize benefits of vitamin D? Results in the interim report at 12 months remained essentially unchanged in the full report spanning 24 months. Yet, the researchers questioned in their discussion of outcomes if 2 years was an adequate period of time to accrue clinically important outcomes. This can only be determined by further research; however, it seems that most patients would reasonably expect to achieve some degree of favorable results of a therapy within weeks or months rather than years. Therefore, the duration of this trial was already longer than most in the pain field and likely represented a more than sufficient and clinically practical amount of time to realize any benefits.
The fact that vitamin D did not appear to retard or ameliorate anatomic structural damage from OA, or benefit any of the other secondary outcomes needs further investigation. Subjects were older patients from a single clinical center in the United States and were carefully selected; as noted above, the severity of pain and extent of structural damage may have been such that vitamin D therapy might not be efficacious in such cases.
Along those lines, in a Reuters Health interview, Robert Heaney, MD — at Creighton University School of Medicine in Omaha, Nebraska, and a widely acknowledged authority on vitamin D — commented, “It's almost certain that vitamin D's effects are different from person to person. It's very important for some people, but may not make any difference for others.”
Genetics and other factors that have yet to be discovered may affect responses to vitamin D. However, Heaney suggests, because vitamin D may have other health benefits — and with virtually no side effects at appropriate doses and relatively little expense — he believes it is still worth a try for patients with osteoarthritis.
Meanwhile, this was but one study and it is hoped that further good-quality research studies of vitamin D for osteoarthritis, like the McAlindon et al. trial, will be conducted. There have been countless cases where individual studies of a treatment — whether results were negative or favorable — later became overshadowed and refuted once a larger body of evidence addressing the issue could be subjected to data meta-analyses [see UPDATE here discussing meta-analysis].
Unfortunately, funding for such research is always problematical since vitamin D is a generic product, available over-the-counter (at least in the U.S.), and economically priced. This present trial was funded by 3 separate grants from public organizations: (a) the U.S. National Institutes of Health, NIAMS, and the Office of Dietary Supplements; (b) the National Center for Research Resources; and (c) the Houston Veterans Affairs Health Services Research and Development Service.
REFERENCE: McAlindon T, LaValley M, Schneider E, et al. Effect of Vitamin D Supplementation on Progression of Knee Pain and Cartilage Volume Loss in Patients With Symptomatic Osteoarthritis: A Randomized Controlled Trial. JAMA. 2013;309(2):155-162 [abstract here].
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