New VITAL analyses shed light on vitamin D for bone health, fall prevention

Debate continues among endocrinologists regarding what constitutes the “optimal” level of vitamin D, and dozens of studies have assessed the benefits of vitamin D supplementation on everything from fracture risk to diabetes and autoimmune disease. Most recently, the large-scale VITAL trial, presented in November at the American Heart Association Scientific Sessions, suggested the supplement failed to prevent major cardiovascular events and the development of invasive cancers over 5 years, although a deeper dive into the findings reveals a signal for benefits with vitamin D for certain subsets of patients.

Meryl Susan LeBoff

At least 23 ancillary studies are expected from VITAL, according to researchers involved with the study, including analyses assessing the association between vitamin D and diabetes, cognitive function, depression and other health outcomes that could inform clinical decision-making.

At the American Society of Bone and Mineral Research annual meeting, Meryl Susan LeBoff, MD, chief of the calcium and bone section in the endocrinology, diabetes and hypertension division at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, presented new findings on the effect of supplemental vitamin D on bone density and structure, as well as risk for falls.

LeBoff spoke with Endocrine Today about the latest analyses to come out of the VITAL trial, what the findings mean for clinicians, and the importance of continuing to treat individuals with vitamin D deficiency.

Why is VITAL such an important study for th ese type s of ancillary analyses?

LeBoff: VITAL was a randomized, double-blind, placebo-controlled trial assessing the effects of 2,000 IU supplemental vitamin D, with or without an omega-3 fatty acid supplement vs. placebo, in the primary prevention of cancer and CVD in the United States. It included 25,871 healthy men and women across all 50 states, 20% African American, with no history of CVD or cancer. It had a hybrid design and was the largest randomized controlled trial for vitamin D, with a median 5.3-year duration. Study adherence in VITAL was 92%. Participants provided blood samples and completed yearly questionnaires on medical history and falls. To assess bone parameters, we looked at a VITAL subcohort of participants from the greater Boston area who underwent detailed phenotyping, including blood samples, bone imaging via DXA and assessment of bone structure and architecture, as well as the measurement of free vitamin D.

Why did you and your colleagues opt to assess free vitamin D levels in addition to total vitamin D ?

LeBoff: It is unclear whether free vitamin D level may better predict the effects of supplemental vitamin D on bone density and bone structure. We looked at that in this study in the subcohort, using a new assay that enables us to more easily measure free vitamin D. As endocrinologists, we have heard the “free hormone” hypothesis — that the free, circulating hormone is responsible for a lot of biological action. We know this about testosterone, cortisol and free thyroid hormone. We use those clinically. Less than 1% of vitamin D circulates as free vitamin D. It may be affected by clinical factors the same way other hormones are; however, there is no consensus on the optimal total and free vitamin D levels for bone.

What did VITAL analyses show for bone parameters ?

LeBoff: There was no effect of vitamin D vs. placebo on the absolute change in BMD at 2 years. There was similarly no effect of vitamin D vs. placebo on absolute change in areal BMD at 2 years. We adjusted for age, sex and race and looked at BMI, and there was not a different effect. Generally, in a healthy U.S. population not preselected for low vitamin D level, supplemental vitamin D had no effect on bone density or bone structural measures.

Vitamin D Pills 
Debate continues among endocrinologists regarding what constitutes the “optimal” level of vitamin D, and dozens of studies have assessed the benefits of vitamin D supplementation on everything from fracture risk to diabetes and autoimmune disease.
Source: Adobe Stock

In exploratory analyses, we did see that, for free vitamin D level, supplemental vitamin D had a slight benefit on spine and total hip BMD among participants with baseline free vitamin D levels below the median, and that was significant. However, that is considered a secondary outcome of an exploratory study and warrants further research. It suggests that free vitamin D may help identify those most likely to benefit from supplemental vitamin D.

Is it possible there is a threshold effect with vitamin D for healthy adults ?

LeBoff: We tried to look for a threshold effect. We looked at participants with a vitamin D level of less than 12 ng/mL, less than 20 ng/mL and less than 30 ng/mL. There were no differences for changes in bone density when we looked at those thresholds. However, the VITAL participants mirror the overall U.S. population. According to NHANES data, 2.9% of U.S. adults have a vitamin D level of less than 12 ng/mL, and 17.7% have levels less than 20 ng/mL. In general, vitamin D levels among older adults are not extremely low in the U.S., fortunately. In a primary prevention study, results are quite different vs. looking at a patient with vitamin D deficiency or osteoporosis.

You and your colleagues also assessed the risk for falls with vitamin D supplementation. What did you find?

LeBoff: For generally healthy men and women aged at least 55 years enrolled in VITAL [mean age, 67 years], vitamin D supplementation did not result in a decrease in the number of falls as assessed by questionnaires. We stratified by vitamin D threshold because there are some data that suggest high vitamin D could be associated with falls. We did not see a threshold effect at all. We even looked at analyses adjusted for age, race, sex and baseline BMI.

These data, which are consistent with other data coming out from around the world, suggest that supplemental vitamin D is not effective in the primary prevention of falls in a healthy U.S. population not selected for low vitamin D levels. I was not surprised by this finding; however, some studies have suggested an association between low vitamin D and an increase in falls, though such studies are confounded. There are many other factors that impact falls — things like poor eyesight, neurogenerative disorders, depression, physical activity — and we did look at multiple risk factors. It is important to note that 74% of participants in VITAL reported very good or excellent health.

What is the takeaway from these latest VITAL analyses for endocrinologists?

LeBoff: In a healthy U.S. population, there was no benefit of daily supplemental vitamin D vs. placebo for 2 years on areal BMD or volumetric BMD at the radius or tibia or cortical thickness. However, it is important to note that this study was not designed to test whether supplemental vitamin D has a greater benefit in those who are markedly vitamin D deficient. We would treat those people. At very low vitamin D levels, there is rickets and osteomalacia. We do not want those people to stop taking their vitamin D. These results also cannot be applied to young adults or those with osteoporosis.

The main takeaway is, for vitamin D supplementation, more is not better, and a high level of vitamin D is associated with increased risk for falls and fractures. We were surprised by the findings, only because our original hypothesis was there would be small effects on bone. However, from a public health perspective, it is important to know that middle-aged adults do not need 2,000 IU of daily vitamin D if they are generally healthy. – by Regina Schaffer

For more information:

Meryl Susan LeBoff, MD, can be reached at Brigham and Women’s Hospital, Department of Medicine, Endocrinology, 75 Francis St., Boston, MA 02115; email: mleboff@bwh.harvard.edu.

Disclosure: LeBoff reports no relevant financial disclosures.

Debate continues among endocrinologists regarding what constitutes the “optimal” level of vitamin D, and dozens of studies have assessed the benefits of vitamin D supplementation on everything from fracture risk to diabetes and autoimmune disease. Most recently, the large-scale VITAL trial, presented in November at the American Heart Association Scientific Sessions, suggested the supplement failed to prevent major cardiovascular events and the development of invasive cancers over 5 years, although a deeper dive into the findings reveals a signal for benefits with vitamin D for certain subsets of patients.

Meryl Susan LeBoff

At least 23 ancillary studies are expected from VITAL, according to researchers involved with the study, including analyses assessing the association between vitamin D and diabetes, cognitive function, depression and other health outcomes that could inform clinical decision-making.

At the American Society of Bone and Mineral Research annual meeting, Meryl Susan LeBoff, MD, chief of the calcium and bone section in the endocrinology, diabetes and hypertension division at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, presented new findings on the effect of supplemental vitamin D on bone density and structure, as well as risk for falls.

LeBoff spoke with Endocrine Today about the latest analyses to come out of the VITAL trial, what the findings mean for clinicians, and the importance of continuing to treat individuals with vitamin D deficiency.

Why is VITAL such an important study for th ese type s of ancillary analyses?

LeBoff: VITAL was a randomized, double-blind, placebo-controlled trial assessing the effects of 2,000 IU supplemental vitamin D, with or without an omega-3 fatty acid supplement vs. placebo, in the primary prevention of cancer and CVD in the United States. It included 25,871 healthy men and women across all 50 states, 20% African American, with no history of CVD or cancer. It had a hybrid design and was the largest randomized controlled trial for vitamin D, with a median 5.3-year duration. Study adherence in VITAL was 92%. Participants provided blood samples and completed yearly questionnaires on medical history and falls. To assess bone parameters, we looked at a VITAL subcohort of participants from the greater Boston area who underwent detailed phenotyping, including blood samples, bone imaging via DXA and assessment of bone structure and architecture, as well as the measurement of free vitamin D.

Why did you and your colleagues opt to assess free vitamin D levels in addition to total vitamin D ?

LeBoff: It is unclear whether free vitamin D level may better predict the effects of supplemental vitamin D on bone density and bone structure. We looked at that in this study in the subcohort, using a new assay that enables us to more easily measure free vitamin D. As endocrinologists, we have heard the “free hormone” hypothesis — that the free, circulating hormone is responsible for a lot of biological action. We know this about testosterone, cortisol and free thyroid hormone. We use those clinically. Less than 1% of vitamin D circulates as free vitamin D. It may be affected by clinical factors the same way other hormones are; however, there is no consensus on the optimal total and free vitamin D levels for bone.

What did VITAL analyses show for bone parameters ?

LeBoff: There was no effect of vitamin D vs. placebo on the absolute change in BMD at 2 years. There was similarly no effect of vitamin D vs. placebo on absolute change in areal BMD at 2 years. We adjusted for age, sex and race and looked at BMI, and there was not a different effect. Generally, in a healthy U.S. population not preselected for low vitamin D level, supplemental vitamin D had no effect on bone density or bone structural measures.

Vitamin D Pills 
Debate continues among endocrinologists regarding what constitutes the “optimal” level of vitamin D, and dozens of studies have assessed the benefits of vitamin D supplementation on everything from fracture risk to diabetes and autoimmune disease.
Source: Adobe Stock

In exploratory analyses, we did see that, for free vitamin D level, supplemental vitamin D had a slight benefit on spine and total hip BMD among participants with baseline free vitamin D levels below the median, and that was significant. However, that is considered a secondary outcome of an exploratory study and warrants further research. It suggests that free vitamin D may help identify those most likely to benefit from supplemental vitamin D.

Is it possible there is a threshold effect with vitamin D for healthy adults ?

LeBoff: We tried to look for a threshold effect. We looked at participants with a vitamin D level of less than 12 ng/mL, less than 20 ng/mL and less than 30 ng/mL. There were no differences for changes in bone density when we looked at those thresholds. However, the VITAL participants mirror the overall U.S. population. According to NHANES data, 2.9% of U.S. adults have a vitamin D level of less than 12 ng/mL, and 17.7% have levels less than 20 ng/mL. In general, vitamin D levels among older adults are not extremely low in the U.S., fortunately. In a primary prevention study, results are quite different vs. looking at a patient with vitamin D deficiency or osteoporosis.

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You and your colleagues also assessed the risk for falls with vitamin D supplementation. What did you find?

LeBoff: For generally healthy men and women aged at least 55 years enrolled in VITAL [mean age, 67 years], vitamin D supplementation did not result in a decrease in the number of falls as assessed by questionnaires. We stratified by vitamin D threshold because there are some data that suggest high vitamin D could be associated with falls. We did not see a threshold effect at all. We even looked at analyses adjusted for age, race, sex and baseline BMI.

These data, which are consistent with other data coming out from around the world, suggest that supplemental vitamin D is not effective in the primary prevention of falls in a healthy U.S. population not selected for low vitamin D levels. I was not surprised by this finding; however, some studies have suggested an association between low vitamin D and an increase in falls, though such studies are confounded. There are many other factors that impact falls — things like poor eyesight, neurogenerative disorders, depression, physical activity — and we did look at multiple risk factors. It is important to note that 74% of participants in VITAL reported very good or excellent health.

What is the takeaway from these latest VITAL analyses for endocrinologists?

LeBoff: In a healthy U.S. population, there was no benefit of daily supplemental vitamin D vs. placebo for 2 years on areal BMD or volumetric BMD at the radius or tibia or cortical thickness. However, it is important to note that this study was not designed to test whether supplemental vitamin D has a greater benefit in those who are markedly vitamin D deficient. We would treat those people. At very low vitamin D levels, there is rickets and osteomalacia. We do not want those people to stop taking their vitamin D. These results also cannot be applied to young adults or those with osteoporosis.

The main takeaway is, for vitamin D supplementation, more is not better, and a high level of vitamin D is associated with increased risk for falls and fractures. We were surprised by the findings, only because our original hypothesis was there would be small effects on bone. However, from a public health perspective, it is important to know that middle-aged adults do not need 2,000 IU of daily vitamin D if they are generally healthy. – by Regina Schaffer

For more information:

Meryl Susan LeBoff, MD, can be reached at Brigham and Women’s Hospital, Department of Medicine, Endocrinology, 75 Francis St., Boston, MA 02115; email: mleboff@bwh.harvard.edu.

Disclosure: LeBoff reports no relevant financial disclosures.

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