The vitamin D hype is just that — at least for now

The vitamin D receptor is ubiquitous and there are several basic science studies documenting a role for active metabolites of vitamin D in systems other than bone — inhibiting growth of MCF7 cancer cells in vitro and preventing adjuvant arthritis in mice — to name two.

There are also abundant epidemiologic studies documenting an association between levels of 25-hydroxyvitamin D in such diverse clinical conditions such as breast and prostate cancers, coronary artery disease, diabetes — you name it and it has been reported. As I am typing this a “DocAlert” loaded on my Epocrates linking vitamin D to autoimmune thyroiditis.

However, to the best of my knowledge, there are few, if any, randomized, double blind, placebo-controlled clinical trials documenting a role for vitamin D therapy for any organ system outside the musculoskeletal system. Yet, it has been estimated that major medical laboratories around the country have been performing upwards of 30,000 assays for 25-hydroxyvitamin D, each month.

The cost of a 25-hydroxyvitamin D assay is approximately $25 — the charge and reimbursement varies. For that money you can buy more than a year’s supply of vitamin D capsules 1,000 IU over-the-counter at your local pharmacy or supermarket. You can pay much more at "fancy shoppes”, but there is no evidence that you are buying a better product. Many patients think they are getting a better deal by using ergocalciferol (Deltalin, Eli Lilly) 50,000 units once weekly. With a $4 co-pay, it is hard to see much cost saving over the course of a year and there is little added clinical value for most of the population in a dose of about 7,000 units daily. Let me quickly add that doses of up to 10,000 units daily are rarely associated with vitamin D toxicity. (Caution your patients about getting all of their vitamin D via multivitamin preparations. Most multi-vitamins contain only 400 units of vitamin D, such that three tablets/capsules are required to get at least 1,000 units. That usually exposes the patient to 30,000 units of vitamin A which is detrimental to the skeleton.)

Also, remember that the reference interval for vitamin D is different in different ethnic groups. Blacks, for example, have lower mean levels of 25-hydroxyvitamin D than whites, but bone mineral density is higher in blacks.

Vitamin D itself is biologically inert and it is only after hydroxylation in the liver to 25-hydroxyvitamin D that a biologically active metabolite capable of binding to the vitamin D receptor becomes available. 25-hydroxyvitamin D is further metabolized in the kidney to 1-25 dihydroxyvitamin D (1-25-hydroxyvitamin D2), an action catalyzed by parathyroid hormone (PTH). The circulating concentration of 25-hydroxyvitamin D is about 1,000-fold that of 1-25OHD2, and 1-25OHD2 binds to the vitamin D receptor with about 100-fold the avidity of 25-hydroxyvitamin D, such that unless your patient has a malabsorption syndrome or is severely malnourished, it is difficult to become truly deficient in 1-25OHD2 — except in the absence of PTH or the presence of impaired renal function.

There are few, if any, clinical clues to vitamin D insufficiency. Some clinical clues to vitamin D sufficiency:

If your patient can walk unaided and without difficulty from the waiting room to the exam room vitamin D deficiency is unlikely.
If your patient can stand from a sitting position with his/her arms folded and does not have to “waddle” to the edge of the chair, vitamin D deficiency is unlikely.
If your patient can lift his/her thigh off the chair against pressure from your hand, vitamin D deficiency is unlikely.

Vitamin D deficiency is associated with proximal muscle weakness, but of course so are many other diseases. There are also many other reasons for a patient being unable to walk or stand unaided.

Bone tenderness, in the absence of known local trauma or metastases, is a common feature of rickets and osteomalacia.

In the lab data, hypocalcemia is a very late manifestation of vitamin D deficiency. Hypophosphatemia and/or an elevated alkaline phosphatase are earlier warning signs of possible vitamin D deficiency. There is no clear indication for measurement of bone specific alkaline phosphatase if vitamin D deficiency is strongly suspected after a history and physical. As I have mentioned in earlier blogs, I place a lot of attention to 24-hour urinary excretion of calcium, always measuring the creatinine and sodium as well — creatinine as a measure of the adequacy of collection and sodium, because a high sodium diet will increase both urinary sodium and calcium.

In an adequate collection, a urine calcium excretion of <100 mg should increase your suspicion of vitamin D deficiency. You won’t encounter that too often in patients who can walk into your exam room.

The bottom line is — the clinical indications for measuring 25-hydroxyvitamin D are limited while the safety and wisdom of recommending vitamin D supplementation is well established.