Calcium and Vitamin D Don't Work Without Magnesium — So Why Do Researchers Continue to Ignore That Fact?

By Wayne Persky

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A major new review published in The BMJ has concluded that calcium supplements, vitamin D supplements, or both taken together provide little to no meaningful protection against fractures or falls in older adults. The analysis pooled data from 69 randomized controlled trials involving nearly 154,000 people, and its conclusions were blunt — routine supplementation with calcium or vitamin D doesn't appear to prevent the fractures it's been promoted to prevent for decades (Massé et al., 2026).1

​The findings have been widely reported, and the medical establishment is once again debating whether guidelines recommending these supplements should be revised. What's largely missing from that debate, however, is an obvious question that keeps getting overlooked in study after study — if vitamin D can't be properly activated without adequate magnesium, and calcium can't be properly transported into bone without adequate vitamin D, what exactly are we measuring when we run these trials without first establishing whether the study subjects have enough magnesium?

The answer, it turns out, is that we may be measuring the performance of a system with a critical missing part, and then concluding that the parts we did supply don't work.​

What magnesium does, and why it matters:

Magnesium isn't a peripheral player in bone metabolism. It's a central one. Every enzyme involved in converting vitamin D into its biologically active form depends on magnesium as a cofactor. This includes the two key hydroxylase enzymes — 25-hydroxylase in the liver, and 1-alpha-hydroxylase in the kidneys — that carry out the sequential steps required to transform inactive vitamin D (either from supplements or sunlight) into the hormone-like compound the body can actually use (Uwitonze and Razzaque), 2018; Deng et al., 2025).2, 3​

A 2018 review published in The Journal of the American Osteopathic Association put it plainly — all of the enzymes that metabolize vitamin D appear to require magnesium, which acts as a cofactor in the enzymatic reactions in both the liver and kidneys (Uwitonze and Razzaque). The review's co-author, Mohammed S. Razzaque, PhD, a professor of pathology at Lake Erie College of Osteopathic Medicine, was equally direct — "Without magnesium, vitamin D is not really useful or safe." (American Osteopathic Association. 2018, February 26)4

The implications for calcium are just as significant. Vitamin D's primary job in bone health is to regulate the absorption of calcium from the intestine and control its transport into bone tissue. If vitamin D can't be activated because magnesium is inadequate, calcium absorption is impaired, regardless of how much calcium a person takes in. The calcium goes somewhere — but it may not go to bone. Research has shown that vitamin D supplementation can raise calcium and phosphate levels in the blood even when a person remains functionally vitamin D deficient, raising concerns about deposits in soft tissue and blood vessels when magnesium is too low to keep the process regulated (American Osteopathic Association. (2018, February 26).

​Magnesium also plays a direct role in bone structure and formation that doesn't depend on vitamin D at all. It makes up a component of bone mineral itself, it's required for the activation of alkaline phosphatase (an enzyme essential for forming new bone crystals), and it stimulates the activity of osteoblasts, the cells responsible for building bone (Qureshi, 2015).5 Magnesium depletion alone causes cessation of bone growth, decreased osteoblast activity, and bone fragility, independent of calcium or vitamin D status (US Patent 8,324,191).6

How widespread is the problem?

If magnesium deficiency were rare, its absence from clinical trials might be a minor oversight. But it isn't rare at all. It may be one of the most common nutritional deficiencies in the developed world, and it's particularly prevalent in exactly the population that fracture prevention research targets — older adults.

NHANES data covering more than 5,600 U.S. adults aged 65 and older found that 83.3% were not meeting the recommended daily intake for magnesium from dietary sources (Jackson et al., 2018).7 A separate analysis from Oregon State University's Linus Pauling Institute found that 52.2% of the entire U.S. population fails to meet the daily requirement for magnesium (Linus Pauling Institute. n.d.).8 Among elderly adults aged 71 and over, more than two-thirds fall short (Grassroots Health, 2025, January 23).9

A 2018 randomized trial published in The American Journal of Clinical Nutrition offered a telling statistic: according to NHANES data, 79% of U.S. adults don't meet the Recommended Dietary Allowance for magnesium (Dai et al,. 2018).10 That same paper noted that a large portion of the unexplained variation in circulating vitamin D levels between individuals — something that has frustrated researchers trying to interpret vitamin D trial results for years — may actually be explained by differences in magnesium status.

In other words, when a vitamin D trial enrolls hundreds or thousands of subjects and gives them all the same dose, those subjects may be getting wildly different biological results depending on how much magnesium their bodies have available to activate what they've been given. Some subjects can activate the vitamin D they receive. Others, with depleted magnesium stores, can't. The trial then averages across both groups and concludes: vitamin D doesn't work.

The research that should have changed the conversation:

The magnesium-vitamin D connection isn't new or obscure. It has been described in the scientific literature for decades and has been the subject of multiple peer-reviewed investigations.

A 2013 analysis using NHANES data found that magnesium intake significantly interacted with vitamin D intake in affecting vitamin D status, and also interacted with serum vitamin D levels in the risk of cardiovascular disease and colorectal cancer mortality (Deng et al., 2013).11 A subsequent randomized controlled trial by the same research group, published in The American Journal of Clinical Nutrition in 2018, confirmed that magnesium supplementation significantly influenced vitamin D metabolism, with effects that differed depending on participants' baseline vitamin D levels (Dai et al., 2018).

The 2018 trial found that among participants with lower baseline vitamin D levels, magnesium supplementation increased circulating active vitamin D. Among those with higher baseline levels, it reduced unnecessary conversion to inactive metabolites, suggesting that adequate magnesium helps the body use vitamin D more efficiently rather than simply producing more of it. The researchers concluded that optimal magnesium status may be important for optimizing vitamin D status (Dai et al., 2018).

A Finnish cohort study and a mouse study produced consistent findings. Yet when the authors of the BMJ's new 154,000-person review (mentioned in the first paragraph of this article) designed their analysis of 69 trials, there's no indication that magnesium status was measured, controlled for, or considered as a variable in any of them.

A flaw built into the design:

What we're dealing with here isn't a case of researchers ignoring a minor detail. It's a systematic blind spot that has been baked into the design of calcium and vitamin D research for decades. Are researchers unable to read research published by other researchers?

Consider what these trials are actually doing. They're taking populations in which the majority of older adults are already magnesium deficient, giving them vitamin D (which cannot be properly activated without magnesium) and calcium (which cannot be properly directed into bone without activated vitamin D), and then measuring whether fracture rates decline. When the fracture rates don't decline, the conclusion drawn is that vitamin D and calcium don't prevent fractures.

But an equally valid interpretation of the same data notes that vitamin D and calcium can't do their jobs when the cofactor required to activate them is missing, and the study populations were largely deficient in that cofactor from the start. The trials weren't testing whether vitamin D and calcium work. They were testing whether vitamin D and calcium work in people who are probably too magnesium-depleted to use them properly. Those are very different situations.

It's worth noting that the inconsistency of results across vitamin D fracture trials has itself been a persistent puzzle. Some meta-analyses have found modest benefits; others have found none. Some find benefits only at higher doses; others at lower. Some find benefits only in institutionalized populations. This kind of nonuniformity is exactly what you'd expect if the key variable determining outcomes — magnesium status — were different across study populations but unmeasured and uncontrolled in each trial (Izaks, 2007; Chakhtoura et al., 2022).12, 13

What the research actually supports:

None of this is to say that vitamin D and calcium are useless. What the evidence suggests is that they don't work in isolation, and that the nutritional context in which they're taken matters enormously.
​
A person with adequate magnesium who takes vitamin D and calcium may well be supporting their bone health. A person who is magnesium deficient and takes the same supplements may see little benefit, and may actually be at increased risk of calcium depositing in the wrong places, such as the arteries and soft tissues, rather than in bone, because the regulatory machinery that vitamin D and magnesium together provide isn't functioning (American Osteopathic Association. 2018, February 26).

The BMJ review itself acknowledges that its findings may not apply to people receiving medication for osteoporosis or those with certain bone disorders. But it doesn't raise magnesium as a variable, even though the biochemistry is well established and the prevalence of magnesium deficiency in the study-age population is well documented.​

The researchers suggest that resources and attention be directed toward balance training, resistance exercise, and personalized fall prevention programs, which are all legitimate recommendations. What they don't suggest is that future trials should simply account for the magnesium status of their participants before they start, which seems like an obvious and inexpensive place to begin.

The takeaway:

For those of us who are taking calcium and vitamin D supplements, or considering them, the practical takeaway from the emerging research isn't to stop. It's to ask whether we're completing the picture.
​
Vitamin D supplementation without adequate magnesium may leave a large portion of the vitamin D inactive and stored, unavailable to the body. Calcium supplementation without activated vitamin D to regulate its absorption and transport may not deliver calcium to bone effectively, and may carry its own risks if calcium ends up in the wrong tissues. Adding magnesium to the regimen, in a form the body can absorb, addresses the rate-limiting step that the trials continue to ignore.

Those of us with MC have additional reasons to pay attention to magnesium status. Chronic diarrhea depletes magnesium, and many of us tend to avoid many magnesium-rich foods, especially during flares. Some of us also take proton pump inhibitors, which are known to significantly reduce magnesium absorption. The combination of MC-related losses and inadequate dietary intake means that magnesium deficiency is likely to be much more prevalent in our group than in the general population.​

The conclusion that calcium and vitamin D don't prevent fractures may well be accurate for people who don't have enough magnesium to activate the system. What we're still waiting for is a large, well-designed trial that actually checks for magnesium deficiency before drawing any conclusions.

How Much Magnesium and Vitamin D Should We Be Taking for Optimum Results​?

​Acknowledging that magnesium is essential for vitamin D to work, and that vitamin D is essential for calcium to reach bone, raises a practical question that needs to be addressed. Specifically, what amounts are appropriate for MC patients? The honest answer is that there is no single evidence-based dose that applies to everyone with MC, because requirements vary considerably depending on disease activity, diet, medication use, and blood levels. The information that follows is based on the ranges that the available evidence and the collective experience of the MC community support as reasonable starting points, not fixed recommendations.

The form of magnesium selected matters:

Not all magnesium supplements are equivalent, and for MC patients this distinction is particularly important. Magnesium oxide, the form used most commonly in multivitamins because it's cheap and compact, has roughly one-quarter the bioavailability of organic magnesium salts, meaning much of what's on the label is never actually absorbed. To add insult to injury, it can have a laxative effect, which is the last thing most of us need.

Magnesium glycinate is generally the preferred form for MC patients. It's a chelated compound in which magnesium is bound to the amino acid glycine, which improves absorption through a separate intestinal pathway, and significantly reduces the laxative effect that makes other forms much more problematic for people who have inflammatory bowel disease (IBD)(Uwitonze, and Razzaque, 2018). ​

Magnesium citrate is also well absorbed but is more likely to loosen stools, which is useful for MC patients who have constipation-predominant symptoms, but counterproductive for those who have diarrhea-predominant MC. For those who find even magnesium glycinate tablets difficult to tolerate in larger doses, spreading smaller amounts throughout the day by sipping on an electrolyte solution achieves a similar effect with better individual tolerance.

During active MC:

When MC is active and diarrhea is ongoing, magnesium losses through the stool can be substantial. The body's stores are being depleted faster than a normal diet can replenish them, and malabsorption compounds the problem. A reasonable starting range for most MC patients with active disease is 200 to 400 mg of elemental magnesium per day, divided into two or more doses if possible. Some patients with more severe or persistent diarrhea may need 400 to 600 mg per day in order to maintain an adequate level, while others find that even the lower end of the range causes symptoms — particularly those who have impaired kidney function, low blood pressure, or arrhythmia sensitivity. For those individuals, caution with any magnesium supplementation is warranted.​

For vitamin D during active MC, the picture is similar, and standard recommended daily allowances (RDAs) are often insufficient. Chronic diarrhea reduces fat-soluble vitamin absorption, meaning the 600 to 800 IU (of vitamin D) that official guidelines recommend for the general public is unlikely to be even close to adequate for someone who has active IBD. Research in IBD patients has found that 5,000 IU of vitamin D3 daily is often required simply to achieve and maintain adequate serum levels during active disease, and some patients need more (Garcia, Moore, Kahan, and Hong, 2020).13 A study in IBD patients found that 2,000 IU per day produced a meaningfully larger improvement in vitamin D levels and disease activity scores than 1,000 IU per day — a finding consistent with the general principle that higher doses are needed when absorption is compromised (Garcia, Moore, Kahan, and Hong, 2020.

During remission:

Once diarrhea has resolved, magnesium losses slow considerably, and many MC patients can maintain adequate status with 200 to 300 mg of elemental magnesium per day. Those who use proton pump inhibitors, which are known to reduce magnesium absorption across the intestinal wall, may need to stay at the higher end of that range or beyond. The same applies to anyone who has had bowel resections, has a history of osteoporosis or osteopenia, or experiences ongoing mild loose stools. These are all situations in which maintenance requirements remain elevated even without a full flare.​

For vitamin D dosing when the disease is in remission, a daily dose of 2,000 to 5,000 IU is the range most commonly supported by both the research literature and the practical experience of the MC community. The right dose within that range isn't determined by guesswork — it's determined by a blood test. A 25-hydroxyvitamin D test (commonly written as 25(OH)D) measures the storage form of vitamin D in the blood and is the standard way to assess vitamin D status. Most MC patients appear to do best when their level falls between 40 and 60 ng/mL (100 and 150 mmol/l). Some practitioners who specialize in IBD prefer a target of 50 to 70 ng/mL (125 to 175mmol/l). Levels substantially above 80 to 100 ng/mL (200 to 250 mmol/l) provide little additional benefit and begin to carry their own risks, so more is not always better once the level is adequate.

Why testing is important:

One reason blood testing matters so much for MC patients — more than for the general population — is that our situation changes. During a flare, we may need supplemental doses that would be unnecessary in remission. If we raise our vitamin D significantly without ensuring magnesium is adequate, we may find that the vitamin D fails to produce the expected benefit, because there isn't enough magnesium available to activate it. Members of the Microscopic Colitis Foundation discussion and support forum have observed this pattern repeatedly over the years. Raising vitamin D levels without correcting magnesium deficiency sometimes worsens symptoms, while correcting both together reliably improves fatigue, muscle cramps, and overall well-being.

The practical management is straightforward. If we're going to supplement — and the evidence suggests that we probably should — then we should supplement with the right form of magnesium, in divided doses, alongside vitamin D3. And we should periodically check our 25(OH)D level, and where available, request testing for our red blood cell (RBC) magnesium level. The RBC magnesium test indicates actual cellular magnesium reserves much more accurately than a standard serum magnesium test, because the body automatically regulates the blood level of electrolytes within a relatively narrow range, including magnesium. Treating these supplements as a system rather than as isolated pills is the part that most of the research studies miss, and it may be the part that makes the difference.

References:

1. Massé, O., Mercurio, C. M., Dupuis, S., Sahwi, M. Al., Arruda, A., Dallaire, G., . . . Williamson, D. (2026). Calcium, vitamin D, or combined supplementation to prevent fractures and falls: systematic review and meta-analysis. BMJ, 393. e088050. Retrieved from https://www.bmj.com/content/393/bmj-2025-088050

2. Uwitonze, A. M. and Razzaque, M. S. (2018). Role of Magnesium in Vitamin D Activation and Function. The Journal of the American Osteopathic Association, 118(3). pp 181-189. Retrieved from https://pubmed.ncbi.nlm.nih.gov/29480918/

3. Deng, K., Liu, J., Miao, Y., Wang, G., Wang, X., Liu, S., and Yang, L. (2025).The effects of magnesium and vitamin D/E co-supplementation on inflammation markers and lipid metabolism of obese/overweight population: a systematic review and meta-analysis. Frontiers in Nutrition, 12. 1563604. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC12433974/

4. American Osteopathic Association. (2018, February 26). Researchers Find Low Magnesium Levels Make Vitamin D Ineffective. PR Newswire, Retrieved from https://www.prnewswire.com/news-releases/researchers-find-low-magnesium-levels-make-vitamin-d-ineffective-300603613.html

5. Qureshi, I. (2015, September 24). Bone-Health Cofactors: New Science on Vitamin D, K2, Magnesium, and Zinc. Nutritional Outlook, 18(7). Retrieved from https://www.nutritionaloutlook.com/view/bone-health-cofactors-new-science-vitamin-d-k2-magnesium-and-zinc

​6. US Patent 8,324,191. Combined calcium, magnesium and vitamin d supplements. Retrieved from https://patents.google.com/patent/WO2010008976A2/en

7. Jackson, S. E., Smith, L., Grabovac, I., Haider, S., Demurtas, J., López-Sánchez, G. F., . . . Yang, L. (2018). Ethnic Differences in Magnesium Intake in U.S. Older Adults: Findings from NHANES 2005⁻2016. Nutrients, 10(12). 1901. Retrieved from https://pubmed.ncbi.nlm.nih.gov/30518025/

8. Linus Pauling Institute. (n.d.). Micronutrient Inadequacies in the US Population: an Overview. Oregon State University, Retrieved from https://lpi.oregonstate.edu/mic/micronutrient-inadequacies/overview

9. Grassroots Health. (2025, January 23). Significant Roles of Magnesium Plus 7 Factors Contributing to Deficiency. GrassrootsHealth Nutrient Research Institute, Retrieved from https://www.grassrootshealth.net/blog/7-factors-make-people-likely-magnesium-deficient/

10. Dai, Q., Zhu, X., Manson, J. E., Song, Y., Li, X., Franke, A. A., . . . Shrubsole, M. J. (2018). Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. The American Journal of Clinical Nutrition, 108(6). pp 1249–1258. Retrieved from https://pubmed.ncbi.nlm.nih.gov/30541089/

11. Deng, X., Song, Y., Manson, J. E., Signorello, L. B., Zhang, S. M., Shrubsole, M. J., . . . Dai, Q. (2013). Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Medicine, 11, 187. Retrieved from https://pubmed.ncbi.nlm.nih.gov/23981518/

12. Izaks, G. J. (2007). Fracture prevention with vitamin D supplementation: considering the inconsistent results. BMC Musculoskeletal Disorders, 8. 26. Retrieved from https://pubmed.ncbi.nlm.nih.gov/17349055/

13. Chakhtoura, M., Bacha, D. S., Gharios, C., Ajjour. S., Assaad, M., Jabbour, Y., . . . El-Hajj Fuleihan, G. (2022).Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials. The Journal of Clinical Endocrinology and Metabolism, 107(3). pp 882–898. Retrieved from https://pubmed.ncbi.nlm.nih.gov/34687206/

14. Garcia, P. M., Moore, J., Kahan, D., and Hong, M. Y. (2020). Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review. Molecules, 25(10). 2300. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC7288056/