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A vitamin D study which found virtually no benefits for seniors – probably due to candidate rejection – Aug 2015

Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial.

JAMA Intern Med. 2015 Aug 3. doi: 10.1001/jamainternmed.2015.3874. [Epub ahead of print]
Hansen KE1, Johnson RE2, Chambers KR1, Johnson MG1, Lemon CC1, Vo TN3, Marvdashti S1.
1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison.
2Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison2Quality and Patient Safety Analysis, Saint Luke's Health System, Kansas City, Missouri.
3Department of Computing and Biometry, University of Wisconsin College of Agriculture and Life Sciences, Madison.

  • This study rejected 500 candidates due to > 30 ng of vitamin D
    and another 235 candidates were rejected because they were taking > 400 IU of vitamin D
       Note: Only 230 people were finally accepted.
    This increased by about 5X the likelihood that the participants had Rheumatoid Arthritis
  • The following is an example of a previous study (which did not reject those with high vitamin D) which did find a benefit with much smaller dose of vitamin D
    Improved muscle function in postmenopausal women with just 1,000 IU of vitamin D daily – RCT May 2015
  • Note: the abstract failed to mention that 8% of the participants needed to take vitamin D more frequently: weekly, instead of bi-weekly
    I had wondered why the error bars of the response showed NONE with < 35 nanograms. Typically some fraction (say 10-20%) are poor or non-responders
  • The study rejected participants who had fragility fractures – which was not mentioned in abstract
  • Physical Activity decreased over the year long trial by only 2% in those getting 50,000 IU biweekly
    but decreased 13% by those getting 800 IU weekly (not statistically significant)
  • Calcium absorption INCREASED by 1% in those getting 50,000 IU weekly
    And DECREASED by 2% in those getting a mere 800 IU weekly
  • A response graph in the PDF shows that >35 ng was achieved by ALL participants of the 50,000 IU trial arm

See also VitaminDWiki

Reasons RCT might fail - from VitaminDWiki as of Oct 2012

  1. Not enough vitamin D3 was used in the trial - (much more is typically needed for treatment than for prevention)
  2. Too long of time between doses ( > 3 month between doses)
  3. Trial period too short, or failed to give loading dose. Especially important in groups at high risk of being vitamin D deficient
  4. Vitamin D2 was used, rather than D3
  5. Cofactor was needed - vitamin D monotheraphy is not always a good thing
  6. Vitamin A (or cod liver oil) inhibited the vitamin D dose
  7. The group was known to have mal-absorption problems - so a different vitamin D should have been used
  8. Individuals were using drugs which are known to inhibit vitamin D
  9. Participants had low compliance (people tend to forget to take the pill in trials which run for years, easy to remember if it is on the calendar)
  10. Participants already have enough Vitamin D and adding more does not provide any additional benefit - example RCT of colds Oct 2012

IMPORTANCE: Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health.

OBJECTIVE: To compare the effects of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption, bone mineral density, Timed Up and Go and five sit-to-stand tests, and muscle mass in postmenopausal women with vitamin D insufficiency.

This randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Madison, Wisconsin, from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied.

Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL.

MAIN OUTCOMES AND MEASURES: Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit-to-stand tests, functional status (Health Assessment Questionnaire), and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of P values to control for the false discovery rate.

RESULTS: After baseline absorption was controlled for, calcium absorption

  • increased 1% (10 mg/d) in the high-dose arm but
  • decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and
  • (decreased by) 1.3% in the placebo arm (P = .03 vs high-dose arm).

We found no between-arm changes in spine, mean total-hip, mean femoral neck, or total-body bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity, or functional status.

CONCLUSIONS AND RELEVANCE: High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00933244.

PMID: 26237520