Mega Vitamin D Harms Bone in Women, Not Men, Without Osteoporosis

Marlene Busko

September 14, 2020

"More is not necessarily better" when it comes to vitamin D supplements for women with adequate serum levels, new research suggests.

In a study of healthy 55- to 70-year-old women who took very high-dose vitamin D supplements — either 4000 IU/day or the previously identified "upper safe limit" of 10,000 IU/day — for 3 years had a significantly greater loss of total bone mineral density (BMD) at the radius and tibia than women who took 400 IU/day. However, this effect was not seen in men.

And the higher-dose vitamin D supplements did not improve bone strength in men or women.

But this was an exploratory post-hoc analysis, and these were healthy community-dwelling adults with sufficient serum vitamin D levels (and no osteoporosis) at study entry, stressed lead researcher Lauren A. Burt, PhD, from the University of Calgary, in Alberta, Canada.

Burt presented these findings September 11 at the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting, and the study was also recently published online in the Journal of Bone and Mineral Research.

Lauren A. Burt

The results suggest that "if you have normal bone density and adequate levels of vitamin D, there is no bone benefit in taking doses of vitamin D above the standard recommendations designed to prevent vitamin D deficiency, and doses at or above 4000 IU/day might even be detrimental to bone, especially in females," Burt told Medscape Medical News.

"These results are clinically relevant," Burt and her coauthors write, "as vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention."

"Our findings do not support a benefit of high-dose vitamin D supplementation for bone health and raise the possibility of harm for females."

Invited to comment, Meryl S. LeBoff, MD, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that this finding "warrants further research," because it is "important" to discover sex differences in bone responses to vitamin D.

"This Doesn't Apply to Osteoporosis"

LeBoff was lead author of a subanalysis of the Vitamin D and Omega-3 Trial (VITAL).

As she reported at last year's ASBMR meeting, that analysis showed that in healthy adults who did not have vitamin D insufficiency, taking vitamin D3 supplements for 2 years did not improve BMD compared with placebo (recently published), nor was this linked with fewer fractures. 

LeBoff pointed out that the current study investigated "very high doses of vitamin D" — at least double the 2000 IU/day doses examined in VITAL.

Dr Meryl S. LeBoff

Also, the serum vitamin D levels in this study were "above what we considered the upper normal limit for our assay in our hospital," she noted, and there was no placebo control.

"We did not see any adverse effects of 2000 IU/day vitamin D," LeBoff stressed.

"At the same time, we didn't see any significant benefits in terms of bone density, because they already had achieved a normal level of vitamin D sufficient for bone."

But "this doesn't apply to patients with vitamin D deficiency, patients with osteoporosis, or low bone mass, in which case we would recommend vitamin D."

Some patients take more vitamin D than they need, because they think more is better, said LeBoff, but this study suggests "more is not necessarily better."

"There's been a concern for several years that too much vitamin D may be associated with increased fractures," she emphasized.

Post-Hoc Analysis

The current study analyzed new data from the Calgary Vitamin D study.

That study found no benefit in BMD or bone strength (JAMA. 2019;322:736-45), contrary to the researchers' hypothesis that high-dose vitamin D supplements would be associated with greater calcium absorption and parathyroid hormone suppression, and thus reduced age-related bone loss (improved bone density and strength).

Instead, they found a negative dose–response relationship, which "should be regarded as hypothesis generating, requiring confirmation with further research," they write.

The current study sought to determine if there were sex differences in the effect of vitamin D supplements on bone health in this population.  

From October 2013 to December 2017, the Canada Vitamin D study enrolled 311 participants (53% male). To be eligible for the study, participants had to have serum 25-hydroxyvitamin D levels > 30 nmol/L and < 125 nmol/L.

They also needed to have adequate calcium intake (1200 mg/day, as defined by the US Institute of Medicine), or if not, they were instructed to take an appropriate calcium supplement dose.

Patients were randomized to receive 400, 4000, or 10,000 IU/day of vitamin D3 cholecalciferol, given as 5 drops/day of liquid (Ddrops), with roughly 50 men and 50 women in each dose group.

Researchers selected the 400 IU/day dose as the comparator because the Institute of Medicine recommends a vitamin D intake of 600 IU/day for adults under age 70 to provide the vitamin D needed for bone health.

The typical Canadian diet includes 200-300 IU/day of vitamin D, so individuals would need a supplement of 400 IU/day to reach the recommended intake.

The 4000 IU/day dose is the recommended tolerable upper intake level, according to the Institute of Medicine.

And the 10,000 IU/day dose is the tolerable upper intake level of vitamin D as identified in a review by Hathcock and colleagues (Am J Clin Nutr. 2007;85:6-18).

Participants underwent scans with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD at the radius and tibia at baseline, 6, 12, 24, and 36 months.

Finite element analysis was used to estimate bone strength.

After 3 years, women had lost significantly more BMD at the radius after taking high-dose vs 400 IU/day of vitamin D. Losses in BMD at the tibia followed a similar trend but were smaller (Figure 1). There were no significant changes in this measure among men (Figure 2). 

There were also no significant changes in bone strength among men or women.

Figure 1. BMD Loss in Women at 3 Years

  Vitamin D supplement, IU/day
Bone 400 4000 10,000
Radius, % 1.8 3.8 5.5
Tibia, % 0.9 1.3 1.9


Figure 2. BMD Loss in Men at 3 Years

  Vitamin D supplement, IU/day
Bone 400 4000 10,000
Radius, % 1.0 2.0 3.2
Tibia, % 0.1 0.0 0.6


Biological Mechanism Remains to Be Determined

LeBoff said a "possible biological explanation" for the findings is that "women, particularly when they are younger, lose more bone than men."

"Postmenopausal females do lose bone at an accelerated rate compared with males," Burt agreed, "but at the time the study was designed, there was no reason to believe that high-dose vitamin D supplementation would accelerate the problem."

"The biological mechanism of the vitamin D-related bone loss needs further investigation," Burt added, "but there are laboratory data suggesting that supraphysiologic doses of active metabolites of vitamin D may stimulate bone resorption."

The study was funded by the Pure North S'Energy Foundation. Burt has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. LeBoff has reported receiving grants from the National Institutes of Health for the VITAL analysis.

ASBMR 2020 annual meeting. Presented September 11, 2020.

J Bone Miner Res. Published online August 10, 2020. Full Text

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