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What New Findings on Vitamin D and Bone Density Could Mean for Neurology Patients

Article In Brief

A study found high-dose vitamin D supplements did not improve bone density and strength. Specialists in multiple sclerosis and epilepsy discuss when and how they prescribe vitamin D.

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Researchers in Canada found that high daily doses of vitamin D were not more effective in maintaining bone density or bone strength than a low dose and that bone density actually decreased over three years, according to a paper published online in the August 27 issue of JAMA.

“We had expected that the higher doses of vitamin D (4,000 and 10,000 IU) would show a modest benefit in bone mineral density [BMD] over time, but the results suggested the opposite. Because our subjects were healthy with normal bone density, it was unlikely that the small amount of bone loss seen with the high doses of vitamin D would cause significant harm. However, a loss of BMD might be more important in an older person with osteoporosis and a high risk of fracture,” co-investigator David A. Hanley, MD, professor emeritus in the Cumming School of Medicine at the University of Calgary told Neurology Today.

The impetus for studying the effect of higher doses on BMD and bone strength was manifold: About 3 percent of Americans take more than the safe upper intake limit of 4,000 IU recommended by the Institute of Medicine, which exceeds the standard recommendation for vitamin D intake of 400 IU to 2,000 IU daily, Dr. Hanley said. Also, when the Calgary Vitamin D Study started in 2013, “some experts were suggesting a higher upper intake level of 10,000 IU daily.” The three-year study that ended in December 2017 was also longer than previous studies, Dr. Hanley added.

Neurologists who treat patients with multiple sclerosis (MS) and epilepsy said the findings were important as some of therapies, and the disorders themselves, have been linked with vitamin D deficiency and lower BMD.

“We don't want to conclude from this study that our patients on enzyme-inducing medications will never need high doses of vitamin D,” said Alison M. Pack, “But, the data doesn't support high maintenance doses in anyone,” said Dr. Pack, professor of neurology at Columbia Irving Medical Center in New York, who see patients with epilepsy, who was not involved with the study.

Study Design, Findings

To study the issue, the Canadian researchers conducted a randomized clinical trial in 311 healthy participants living in the community with a mean age of 62.2 years. The participants had normal baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L and serum calcium (2.10-2.55 mmol/L), and normal baseline DXA lumbar spine and total hip T-scores (greater than -2.5 SD).

People were excluded if they had osteoporosis or a high 10-year risk for osteoporotic fracture, used bone active medications in the past two years, or had disorders known to affect vitamin D metabolism.

The researchers randomly assigned the 311 participants to receive one of three doses of vitamin D3 (cholecalciferol): 400 IU (n=109), 4,000 IU (n=100), or 10,000 IU (n=102). Participants with total dietary calcium less than 1200 mg daily received calcium supplementation. Adherence was self-reported through daily diaries.

The researchers measured volume-based BMD and bone strength at the distal radius and tibia with high-resolution peripheral quantitative computed tomography. “This is a more sensitive method of measuring bone density and bone structure than the DXA scans used in clinical practice,” said Dr. Hanley.

The measurements were taken at baseline, six months and one, two and three years. Bone density was measured in milligrams of hydroxyapatite (the complex calcium phosphate bone mineral) per cubic centimeter (HA/cm3).

At the three-year mark, participants taking daily vitamin D doses of 4,000 IU and 10,000 IU had statistically significantly lower radial BMD (−3.9 mg HA/cm3) and (−7.5 mg HA/cm3) respectively compared with the 400 IU group. Only the participants receiving a daily dose of 10,000 IU had significantly lower tibial BMD than the 400 IU group (−4.1 mg HA/cm3), with a mean percent change of −1.7 percent.

Although bone strength decreased over the three-year study, there were no significant differences between the three vitamin D doses.

The main study limitation was that the supplier of the vitamin D solutions changed the manufacturing laboratory between 18 and 24 months, which affected the prescribed 10,000 IU dose. “We estimated that group instead received a dose between 2,000 IU and 10,000 IU daily. Despite the problem, we still found a significant dose-dependent difference in BMD between the groups,” said Dr. Hanley.

The study also excluded vitamin D-deficient individuals, which might have led to a different result with the higher doses of vitamin D and there was no placebo control group. “Our choice of 400 IU as the reference point, though, appears to have been appropriate since that groups' serum 25-OH vitamin D level remained stable throughout the three years of the study,” said Dr. Hanley.

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“We had expected that the higher doses of vitamin D (4,000 and 10,000 IU) would show a modest benefit in bone mineral density [BMD] over time, but the results suggested the opposite. ...However, a loss of BMD might be more important in an older person with osteoporosis and a high risk of fracture.”—DR. DAVID A. HANLEY

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“If the vitamin D level appears normal, I would then decrease the dose to 1000 IU daily. There isnt compelling data to support the ongoing use of higher doses, and excessive vitamin D can result in unwanted problems like kidney stones.”—DR. DAVID B. BURKHOLDER

Expert Commentary

Older antiepileptic drugs (AEDs)—phenytoin, phenobarbital, and carbamazepine—have been linked with vitamin D deficiency and lower BMD by increasing the metabolism of the vitamin. However, even valproate, an enzyme-inhibitor, has been associated with bone mineralization, said David B. Burkholder, MD, assistant professor of neurology at Mayo Clinic in Rochester, MN, who was not involved with the study.

Instead of choosing an older AED, Dr. Burkholder would start a patient with epilepsy on one of the newer drugs such as levetiracetam or lamotrigine, which have not been linked to bone demineralization.

If an older patient has done well on phenytoin or phenobarbital for many years but developed osteoporosis, Dr. Burkholder suggests switching to a newer medication such as lamotrigine and provides lifestyle counseling, if needed. “I would also suggest that the patient see a primary care doctor who could prescribe a bisphosphonate.”

He screens patients with epilepsy for vitamin D levels when they are older than 60, postmenopausal, have used older AEDs, or are not exposed to the sun or engaging in weight-bearing physical activity. Depending on their age and other factors, he might order a DXA scan.

When a patient's vitamin D level is below normal (less than 20 nmol/mL), Dr. Burkholder typically supplements between 400 and 2000 IUs of vitamin D. If someone's vitamin D level is in the single-digits, he would start with a higher daily dose and recheck in about three months.

“If the vitamin D level appears normal, I would then decrease the dose to 1000 IU daily. There isn't compelling data to support the ongoing use of higher doses, and excessive vitamin D can result in unwanted problems like kidney stones,” said Dr. Burkholder.

Studies have also shown that people prescribed antiseizure medications, particularly the older enzyme-inducing ones, are at increased risk of falls, Dr. Pack of Columbia Irving Medical Center in New York, told Neurology Today.

For example, an Australian study published in Epilepsia in 2015 found that siblings who took long-term antiseizure medications were more likely to have poorer balance when standing, which can increase the risk of falling, than their siblings not on the medications, said Dr. Pack.

“The risks for fracture are related to multiple factors including the potential effects of certain antiseizure medications on vitamin D status and BMD, and fall risk especially in people with convulsive seizures.”

She routinely checks vitamin D levels in patients with epilepsy, especially those on enzyme-inducing medications. Depending on their baseline levels, she counsels them on how to get at least 400 IUs through their diet and prescribes vitamin D supplements up to 2000 IUs as a maintenance dose. If a patient has very low vitamin D levels, she might start at a dose higher than 2000 IUs for a brief time and then return to a lower maintenance dose.

Several studies have shown that people with MS are more likely to have low levels of vitamin D compared with healthy controls and that the deficiency is both a risk factor for MS and for relapse, said Bianca Weinstock-Guttman, MD, professor of neurology in the Jacobs School of Medicine and Biomedical Science at the University of Buffalo, in an email.

“People with MS also have a higher risk of osteoporosis, primarily related to their physical disability, although there may be other contributing factors,” said Dr. Weinstock-Guttman.

“Therefore, supplementing with vitamin D is recommended to control the disease activity and maintain bone health,” she said.

Dr. Weinstock-Guttman screens new MS patients for vitamin D levels. She checks chronic MS patients twice a year for vitamin D and calcium levels and recommends supplementation if their adherence is low.

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“People with MS also have a higher risk of osteoporosis, primarily related to their physical disability, although there may be other contributing factors. Therefore, supplementing with vitamin D is recommended to control the disease activity and maintain bone health.”—DR. BIANCA WEINSTOCK-GUTTMAN

When the patient's vitamin D level is between 20-30 ng/mL (insufficient), she recommends a supplement between 1,000 and 2,000 IU. When the level drops below 20 ng/mL (deficient), she supplements with 4,000 IUs and conducts repeat testing in two months, which usually is enough time to reach normal levels (30-40 ng/mL).

Dr. Weinstock-Guttman pointed out that a 2018 Cochrane review did not find a significant benefit of vitamin D supplementation on MS disease activity, although no side effects were identified. “Additional larger ongoing vitamin D supplementation studies may shed more light on this well accepted approach.”

Disclosures

Dr. Hanley received a research grant and speaking honorarium from Amgen and a research grant from Eli Lilly. Dr. Pack had no relevant disclosures. Dr Weinstock-Guttman received honoraria for educational programs, advisory boards, and research grants from Biogen, EMD Serono, Novartis and Genentech.

Link Up for More Information

• Burt LA, Billington EO, Rose MS, et al. Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength: A randomized clinical trial https://jamanetwork.com/journals/jama/fullarticle/2748796. JAMA 2019;322(8):736–745.
    • Institute of Medicine. Dietary reference intakes for calcium and vitamin D https://www.nap.edu/catalog/13050/dietary-reference-intakes-for-calcium-and-vitamin-d. Washington, DC: The National Academies Press 2011.
      • Ahmad et al. Changes in balance function with chronic antiepileptic drug therapy: A twin and sibling study https://onlinelibrary.wiley.com/doi/full/10.1111/epi.13136. Epilepsia 2015;56(11):1714–1722.
        • Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis https://journals.sagepub.com/doi/abs/10.1177/1352458508094399. Mult Scler 2008;14(9):1220–1224.
          • Weinstock-Guttman B, Gallagher E, Baier M, et al. Risk of bone loss in men with multiple sclerosis https://journals.sagepub.com/doi/abs/10.1191/1352458504ms993oa. Mult Scler 2004;10(2):170–175.
            • Jagannath VA, Filippini G, Di Pietrantonj C, et al. Vitamin D for the management of multiple sclerosis https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008422.pub2/full. Cochrane Database Syst Rev 2018;9:CD008422.