Friday, July 6, 2012

Vitamin D – Current Research Roundup

Research RoundupAs regular readers of these Pain-Topics UPDATES know, we have long advocated for the potential benefits of adequate vitamin D in persons with chronic pain conditions of various types. Recent research studies shed more light on the advantages as well as some concerns about vitamin D supplementation that are of importance for clinicians and patients.

Vitamin D Improves Chronic Pain, Sleep, and QoL

Researchers from Emory University School of Medicine recently reported a case series that found, after supplementation with vitamin D, patients with multiple areas of chronic pain and low serum 25-hydroxyvitamin D concentrations at baseline (25[OH]D <30 ng/mL) reported improvements in pain, lack of sleep, and quality of life, or QoL [Huang et al. 2012]. Writing in an advance online edition of the Clinical Journal of Pain, the authors report on 28 U.S. veterans supplemented with oral vitamin D 1,200 IU/day if serum 25(OH)D was in the insufficient range (20 to 29 ng/mL) or 50,000 IU/week if it was in the deficient range (<20 ng/mL).

Participants reported no side effects during the study and the improvements were significant, compared with baseline, in terms of pain score (P<0.001), sleep latency (P=0.019), sleep duration (P=0.012), bodily pain (P=0.014), general health (P=0.006), vitality (P=0.048), and social functioning (P=0.017). Significance of improvements persisted after controlling for age, sex, race, body mass index, season, baseline serum 25(OH)D concentration, and whether or not participants received additional interventions during the supplementation period.

[This small study lends further support to the benefits of vitamin D supplementation as an aid for various types of chronic pain. However, it is important to note that this was a case series, without a control group, and in a select population of patients. — Ed.]

How Much Vitamin D is Enough?

Heike Bischoff-Ferrari, MD, DrPH, from the Center on Aging and Mobility at the University of Zurich, Switzerland, and colleagues conducted a meta-analysis of studies examining the relationship between vitamin D supplementation and reductions in painful bone fractures [Bischoff-Ferrari et al. 2012]. Writing in the New England Journal of Medicine, they pooled results from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or every 4 months), with or without calcium, as compared with placebo or calcium alone in persons 65 years of age or older.

Results included observations in 31,022 persons (mean age, 76 years; 91% women) with 1,111 incident hip fractures and 3,770 nonvertebral fractures. Reduction in the risk of fracture was demonstrated only at the highest vitamin D intake level (median, 800 IU/day; range, 792 to 2000 IU/day), with a significant 30% reduction in the risk of hip fracture and a 14% reduction in the risk of any nonvertebral fracture. Benefits at this level of vitamin D intake were fairly consistent across subgroups defined by age, type of dwelling, and additional calcium intake.

[Note: results across all studies incorporating various daily doses of vitamin D, from low to high, showed only a nonsignificant 10% reduction in hip fracture risk and a 7% reduction in the risk of nonvertebral fracture. So, the higher dosing made a difference. — Ed.]

In an accompanying editorial, well-known vitamin D authority, Robert P. Heaney, MD, observes that results of the Bischoff-Ferrari et al. analyses might have been more robust if all of the included studies had accounted for baseline 25(OH)D concentrations and subsequent change in vitamin D status, which few studies did [Heaney 2012]. Focusing on vitamin D dose alone, he contends, does not depict the true effects and potential benefits of supplementation.

VitD-ResponseCurveHeaney asserts that vitamin D shares a dose-response relationship that is typical of most nutrients. As the graph [from Heaney 2012] depicts, depending on the initial baseline level, a particular intake/dose of vitamin D may or may not produce a meaningful response. Given exactly the same dose, persons with either very low or very high 25(OH)D initially, at baseline, may show very little increase in 25(OH)D level. In other words, giving additional amounts of vitamin D to persons who already have enough, or not giving enough to stimulate a response in persons with deficiencies, is likely to have little beneficial effect.

Most research investigations have not taken this into account, and it could explain weak outcomes of vitamin D supplementation in some studies. The message is, when it comes to daily dosing of vitamin D, one size does not fit all.

Another fallacious approach involves studies that use vastly different frequencies and dosages of vitamin D, especially massive single dosing, or Stosstherapy. For example, Heaney mentions a trial that administered a single, yearly dose of 500,000 IU, which was biologically flawed since that annual dose was 12 times as long as the half-life of vitamin D in the body and such a large dose probably induced transient vitamin D intoxication during the first 2 to 3 weeks after its administration. He suggests that this sort of therapy is not the proper way to evaluate vitamin D efficacy; rather, dosing at the upper end of the range at which Bischoff-Ferrari et al. found benefits, or about 2,000 IU/day, is more apropos — at least for evaluating reductions in facture risks.

Concerns About Vitamin D, Calcium, & Kidney Stones

Many clinicians are reluctant to treat vitamin D deficiency in patients who are prone to developing kidney stones because of the theoretical risk of increasing urinary calcium excretion. Writing in the Clinical Journal of the American Society of Nephrology, a team of researchers examined the effect of vitamin D supplementation on urinary calcium excretion among so-called stone formers [Leaf et al. 2012].

Participants included 29 patients with a history of nephrolithiasis (kidney stone disease), urinary calcium excretion between 150 and 400 mg/day —normal ≈300 mg/day — and 25(OH)D levels <30 ng/mL. They were given 50,000 IU/week of oral vitamin D2 (ergocalciferol) for 8 weeks. Resulting levels of 25(OH)D increased significantly from 17±6 ng/mL at baseline to 35±10 ng/mL (P<0.001). However, mean 24-hour urinary calcium excretion did not change significantly (257±54 baseline vs 255±88 mg/d at follow-up); although, 11 participants did have an increase in urinary calcium excretion ≥20 mg/d. No participant experienced adverse effects from vitamin D, including hypercalcemia (excessive serum calcium).

The authors conclude that, among kidney stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not seem to generally increase mean urinary calcium excretion, although a subset of individuals may have an increase. The data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of prioir nephrolithiasis, but 24-hour urinary calcium excretion should be monitored after 25(OH)D repletion.

It is important to note that subjects in the above study were not administered supplemental calcium. Other recent research has suggested that vitamin D taken with calcium supplements can be associated with elevated calcium levels in both serum and urine, potentially increasing the risk of kidney stones.

In a study presented at the 94th Annual Meeting of the Endocrine Society, researchers from Creighton University Medical Center in Omaha, Nebraska, enrolled 163 Caucasian postmenopausal women, ages 57-85 years, who were randomized to one of the several doses of vitamin D3 — 400, 800, 1600, 2400, 3200, 4000, 4800 IU/day — or placebo [Yalamanchili and Gallagher 2012]. Calcium intake was increased from a baseline average of 691 mg/d up to 1400 mg/d using calcium citrate. All subjects had vitamin D insufficiency (25[OH]D < 20 ng/mL) at baseline.

Mean baseline serum 25(OH)D was 15.6 ng/mL and increased on the highest dose of vitamin D to 45 ng/mL. Mean baseline serum calcium was 9.47 mg/dL and increased to 9.52 mg/dL (normal range = 8.9-10.3 mg/dL); mean 24-hour urine calcium was 142 mg/d and increased to 186 mg/d (normal ≈300 mg/d). However, during the study, about a third of participants experienced episodes of hypercalciuria (88 episodes in 48 subjects) and about 10% had an episode of hypercalcemia (25 episodes in 16 subjects). Prolonged hypercalciuria led to discontinuation of calcium in 2 participants and vitamin D in 1 subject.

The episodes of excessive calcium in urine and serum did not appear to be directly related to a particular vitamin D dose, and there were no incidents of kidney stones during the study. However, the researchers express concern that, if these changes occur frequently with long-term vitamin D and calcium supplementation, it could lead to an increase in kidney stones.

[The second study was a conference abstract and should be considered preliminary until publication in a peer-reviewed journal. However, taken together, both studies suggest that unless a patient has a specific need for extra calcium, it may always be best to recommend supplements containing vitamin D alone, rather than calcium/vitamin D combinations. Furthermore, if there are concerns regarding nephrolithiasis potential during long-term use of supplements, monitoring of calcium levels should be considered. — Ed.]

Vitamin D2 vs D3 Debate Settled?

There has been an ongoing debate in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in raising serum 25(OH)D levels. Therefore, a research team from the United Kingdom conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the effects of D2 and D3 on serum 25(OH)D concentrations in humans [Tripkovic et al. 2012].

The literature search uncovered 10 RCTs with a collective total of 1,016 participants ages 18-97; studies included a range of different dosages and administration methods. The data meta-analysis indicated that supplementation with vitamin D3 had a significant and positive effect in raising serum 25(OH)D concentrations compared with the effect of vitamin D2 (P=0.001). When frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P=0.0002) compared with administration of vitamin D2, but the effect was not as pronounced with daily supplementation of either D2 or D3.

Overall, the authors conclude the evidence suggests that D3 is more favorable than D2 in terms of potency, and should be the preferred choice for supplementation. However, additional research is needed to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.

[This has been a confusing issue, which is exacerbated by research studies variously using vitamin D2 and/or D3. Furthermore, D2 often is prescribed for larger dosing, such as 50,000 IU once weekly, both clinically and in research designs, making it difficult to assess the relative advantages of D3 for this purpose. However, the preponderance of evidence seems to favor D3 for daily or less frequent dosing and, hopefully, researchers will focus on this form in further investigations. — Ed.]

Newest Vitamin D Tests Inaccurate

Two new blood tests for vitamin D are inaccurate in at least 40% of laboratory specimens analyzed, according to a study reported at the Endocrine Society’s 94th Annual Meeting [Holmes et al. 2012]. A research team at Loyola University Stritch School of Medicine in Maywood, IL, assessed results of two new 25(OH)D immunoassay tests: 1) the reagent kit and Architect lab testing platform from Abbott Laboratories, and 2) the reagent kit and Advia Centaur2 platform from Siemens Healthcare Diagnostics. Results in 163 randomly selected clinical samples were compared with definitive 25(OH)D testing via liquid chromatography - tandem mass spectrometry (LC/MS).

In 40% of the Architect-tested specimens and in 48% those tested by Centaur2, the results were at least either 25% too high or 25% too low, compared with LC/MS testing. The absolute sizes of the observed errors ranged from a remarkable –60% to +80%.

With the Centaur2 test, 71 of 163 test results indicated vitamin D deficiency, or 25(OH)D < 20 ng/mL, while the Architect results indicated deficiency in 45 of the 163 samples. Meanwhile, LC/MS results indicated Vitamin D deficiency in only 33 of the samples. “Both of the immunoassays erred on the side of overestimating vitamin D deficiency, which could lead to overtreatment,” one of the researchers said in a news release [here].

[Serum testing for 25(OH)D has become an important clinical tool in everyday practice; however, it also is costly. As we previously observed in our research review of vitamin D [PDF here, pp 13-14] the reliability and precision of 25(OH)D assays have been of some concern. Apparently, these apprehensions have not been resolved by the latest two products described above. — Ed.]


  • Bischoff-Ferrari HA, Willett WC, Oray EJ, et al. A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention. N Engl J Med. 2012(Jul); 367:40-49 [abstract here].
  • Heaney RP. Vitamin D — Baseline Status and Effective Dose. N Engl J Med. 2012(Jul);367:77-78 [abstract here].
  • Holmes EW, Garbincius J, McKenna KMAnalytical Performance Characteristics of Two New Automated Immunoassays for 25 Hydroxy Vitamin D. Presentation at ENDO2012, the Endocrine Society’s 94th Annual Meeting, June 23-26, Houston, TX; abstract MON-372 [available here].
  • Huang W, Shah S, Long Q, et al. Improvement of Pain, Sleep, and Quality of Life in Chronic Pain Patients With Vitamin D Supplementation. Clin J Pain. 2012(Jun 13); online ahead of print [abstract here].
  • Leaf DE, Korets R, Taylor EN, et al. Effect of Vitamin D Repletion on Urinary Calcium Excretion among Kidney Stone Formers. Clin J Am Soc Nephrol. 2012(Mar);7(5):829-834 [abstract here].
  • Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012(Jun);95(6):1375-1364 [article here].
  • Yalamanchili V, Gallagher J. Incidence of Hypercalciuria and Hypercalcemia during a Vitamin D Trial in Postmenopausal Women. Presentation at ENDO2012, the Endocrine Society’s 94th Annual Meeting, June 23-26, Houston, TX; abstract OR38-1 [available here].

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