Each year, the hottest tickets at ENDO are the various debates and ENDO 2023 was no exception when experts weighed in on the pros and cons of using vitamin D supplements in female patients at risk for osteoporotic fracture.

One ENDO 2023 session that proved popular in June was “Is there a role for vitamin D supplementation for women at risk for osteoporotic fracture?” which was quite an important (not to mention exciting) debate.

By now, in 2023, the vitamin supplementation industry grosses billions of dollars annually, and vitamin D is one of the most sought after. As a transcription factor, vitamin D can partner with a host of cellular receptors, hence the tremendous interest in uncovering just want it can and cannot do.

Always somewhat of a gray area, whether to prescribe vitamin D supplementation became more controversial when the results of the Vitamin D and Omega-3 Trial (VITAL) were published in the New England Journal of Medicine in 2019. The highly powered VITAL trial sought to determine whether supplementation with vitamin D reduced the risk of cancer or cardiovascular disease (CVD) and concluded that it did not result in a lower incidence of invasive cancer or cardiovascular events than placebo, despite formerly inconclusive or mixed findings. A substudy found that vitamin D supplementation also does not improve bone mineral density.

But does vitamin D help prevent fracture in women with osteoporosis? On the “Pro side” was Ghada El-Hajj Fuleihan, MD, MPH, physician-scientist and professor of medicine, founding director of the Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, and one of the Scholars in HeAlth Research Program (SHARP), at  the American University of Beirut, in Lebanon. 

“In any debate, arguments would depend on how one evaluates the data, examines its limitations, and assesses its generalizability to the population of interest. Although VITAL’s editorial has attempted to provide a ‘decisive verdict’ and to ‘put the nail in the coffin’ on vitamin D supplementation, that topic is still full of life.”

Ghada El-Hajj Fuleihan, MD, MPH, American University of Beirut, Lebanon

On the “Con side” was Steven R. Cummings, MD, director, San Francisco Coordinating Center; research scientist, California Pacific Medical Center Research Institute; and professor of medicine, epidemiology and biostatistics, emeritus of the University of California in San Francisco (UCSF).

Dolores M. Shoback, MD, professor of medicine, also at UCSF, and endocrinologist at the VA Medical Center in San Francisco, Calif., served as the debate’s moderator.

Supplementation: Thumbs Up

The El-Hajj Fuleihan and her laboratory focus on generating evidence on the pathophysiology, prevention, and treatment of hypovitaminosis D, osteoporosis, and other metabolic bone disorders. She leads a team that conducts clinical trials, systematic reviews, and meta-analyses, and translates findings into prevention and treatment strategies. She closely collaborates with the Ministry of Health officials and international experts to generate evidence-based national and international care pathways and guidelines.

“The increasing number of systematic reviews and meta-analyses regarding the effect of vitamin D in fractures with contradicting results over the last decade led us to lead an umbrella review of systematic reviews published during this timeline,” El-Hajj Fuleihan says. “Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials,” published in The Journal of Clinical Endocrinology & Metabolism in March 2022, allowed them to dissect the evidence available, rate its quality, and assess relevance of the findings reported to specific populations.

“Some of the important considerations to guide practice guidelines in subjects at high risk for osteoporotic fractures is evidence from adequately powered randomized trials conducted in subjects representative of the population of interest,” El-Hajj Fuleihan states. “Other considerations are nutritional status of study participants at study entry. Does VITAL and other negative large trials published today fulfill such criteria? I will argue they do not.”

“If you look at the number of citations and publications of vitamin D over the last two decades, it’s obvious that there is a need to do something,” she says. “What I’m hoping this debate will achieve is to bring some granularity to the discussion and some important details to light. Is there another role for vitamin D? I think the debate will be constructive and positive.”

Supplementation: Thumbs Down

For Cummings, who wrote “VITAL Findings — A Decisive Verdict on Vitamin D Supplementation,” published in NEJM in July of last year, the proof has to be in the pudding. Cummings is an internal medicine specialist and epidemiologist who has more than 30 years’ experience designing and leading major trials for prevention of fractures, including pivotal studies of alendronate, raloxifene, and denosumab, and large cohort studies about the epidemiology and causes of osteoporosis and fracture, including the Study of Osteoporotic Fractures (SOF), MrOs, and others. He is also an expert in clinical research methods and the design of clinical trials and elected as a member of the National Academy of Medicine.

“The value of vitamin D supplements must be established by randomized placebo-controlled trials,” he says. “Other types of evidence are misleading.” Although VITAL’s primary outcomes were cancer and CVD, Cummings points out that it also failed to show benefit of vitamin D supplementation in the setting of fracture risk. “In 25,871 people age ≥55 years (women) and ≥50 years (men), VITAL showed that vitamin D supplements have no effect risk of fractures. Even those at ‘high’ risk had low levels of vitamin D. VITAL has also found that they have no benefit for preventing falls or improving bone density. Additionally, large rigorous trials have found no benefit of vitamin D supplements on mortality, CVD, cancer, and numerous other health conditions.”

This debate, he says, was “an opportunity … to hear about the physiology of vitamin D, previous studies about vitamin D and fractures, the importance of trusting randomized placebo-controlled trials about the evidence from such trials about the efficacy and safety of vitamin D supplements, and what to advise patients and the public.”

Closing Remarks

Interestingly, despite VITAL’s conclusions, “clearly there are experts with divided opinions on both ends of the camp, and I think this debate will be instrumental in identifying some of the issues that have led to this confusion,” El-Hajj Fuleihan says. “In any debate, arguments would depend on how one evaluates the data, examines its limitations, and assesses its generalizability to the population of interest. Although VITAL’s editorial has attempted to provide a ‘decisive verdict’ and to ‘put the nail in the coffin’ on vitamin D supplementation, that topic is still full of life.”

“Millions of people take vitamin D supplements, many based on the recommendation of their doctors. It is important that physicians give them accurate evidence-based advice. I believe that they should advise patients to focus on treatments and lifestyle changes that work. I hope that is the message those attending the debate will bring back to their patients and friends.”

Steven R. Cummings, MD, California Pacific Medical Center Research Institute, San Francisco, Calif.

For Cummings’ part, he says, “millions of people take vitamin D supplements, many based on the recommendation of their doctors. It is important that physicians give them accurate evidence-based advice. I believe that they should advise patients to focus on treatments and lifestyle changes that work. I hope that is the message those attending the debate will bring back to their patients and friends.” 

The bottom line is: clinicians must both use evidence-based approaches in the care they provide and think carefully about the individual and their comorbidities to individualize care. This coming debate may help endocrinologists strike that balance. “Please come listen to the arguments,” agrees Shoback. “They’re both fiercely data-driven people and two of the most respected people in the field.”

Horvath is a freelance writer based in Baltimore, Md. In the March issue, she undertook the herculean effort of conducting the “Women in Endocrinology” roundtable, speaking with 10 outstanding Endocrine Society members.