Menopausal Medicine: For clinicians who provide care for women

Vitamin D: The sunshine hormone How and when to treat deficiencies

Professor of Medicine, Professor of Obstetrics & Gynecology and Women’s Health, Division of Reproductive Endocrinology, Albert Einstein College of Medicine of Yeshiva University, Director of Bone Densitometry, Montefiore Medical Center, Bronx, New York

Vitamin D was discovered as the factor in cod-liver oil that prevented rickets in children in the early 20th century.¹ Soon thereafter it was discovered that exposure to sunlight gave equivalent protection.² Based on findings in the 1920s and 1930s, the dose of 400 units of vitamin D was established as essential for prevention of rickets. In the last 10 years, as treatments for osteoporosis have become available, many patients given such treatments did not respond as expected. One of the likely causes is that 52% of patients treated for osteoporosis had insufficient levels (<30 ng/mL 25-hydroxyvitamin D) of vitamin D.³ Based on data from the National Health and Nutrition Examination Survey (NHANES), the extent of vitamin D insufficiency in the population at large has been estimated to vary between 50% to 75%, depending on the ethnic group.⁴ Levels of vitamin D decline with age despite equal intake of vitamin supplements or equal exposure to sunlight.²

As measurement of the blood levels of vitamin D has become available, many other disorders, besides metabolic bone diseases, have been shown to be worse in people with insufficient vitamin D levels. The simple administration of adequate vitamin D may in fact prevent a number of chronic diseases as well as disability in the elderly.⁵

The skin is the major natural source of vitamin D. Exposure to UVB rays from sunshine and heat converts 7-dehydrocholesterol to cholecalciferol (vitamin D3). It is secreted into the blood and rapidly hydroxylated in liver microsomes at the 25 position, resulting in 25-hydroxycholecalciferol (hereafter referred to as 25 OH vit D). This is the major form of vitamin D, which is stored in the liver and secreted into the circulation. In blood, 25 OH vit D, which is a steroid, is carried on a vitamin D-binding protein.⁶ The liver stores vitamin D for many months, providing the vitamin when no sunshine is present. Several factors reduce the ability of the skin to produce vitamin D: sunscreen containing USP 8 will decrease active vitamin D formation by 97.5%; USP 15 sunscreen or higher will decrease formation of vitamin D3 by 99.9%. Aging itself reduces the skin’s ability to form vitamin D3 even when exposed to adequate sunshine.^2,7 Skin pigmentation also plays a role, with much lower levels of vitamin D found in people with darker pigmented skin. People who only go outdoors fully covered and get no exposure of their skin to sunshine have been found to have very low levels of vitamin D.⁸

The other main source of vitamin D is diet: Vitamin D is present in fish livers (therefore, the former intake of fish liver oil was common). Vitamin D has been added to many products. Milk contains 100 units of vitamin D3 in each cup. Orange juice that has added calcium may also contain 100 units of vitamin D3. There are two forms of the vitamin provided by foods or supplements. One is vitamin D3, which is the form in fish liver or in animals; the other is vitamin D2, ergocalciferol, which is present in vegetables and is estimated to be less potent, one-third to one-fourth as effective as vitamin D3. Vitamin D2 has to be converted into vitamin D3. The daily requirement of 400 units of either vitamin D has been shown to be inadequate for normal maintenance of adequate blood levels (see below).

Bone effects

The major function of vitamin D has always been the adequate growth and mineralization of bone. This requires the further conversion of 25 OH vit D by the addition of a hydroxyl group at the 1 position, which occurs in the kidney mitochondria under stimulation by parathyroid hormone, resulting in 1,25-dihydroxycholecalciferol, or 1,25 OH vit D (FIGURE 1).^6,7 It is this compound that acts in the gastrointestinal (GI) system to activate calcium absorption. To prevent excessive calcium absorption, the 1 hydroxylation enzyme is modulated by blood calcium levels. High levels of blood calcium shut off 1 hydroxylation but cause the 25 OH vit D to be hydroxylated at the 24 position, resulting in the formation of 24,25-dihydroxyvitamin D, which does not increase GI absorption of calcium. In animal studies, bone can be adequately mineralized if the animal is given sufficient calcium systemically, suggesting that the key role of vitamin D is adequate calcium absorption. In fact, the amount of calcium absorbed is largely dependent on adequate vitamin D levels and not on which preparation of calcium has been ingested.⁹ Other lesser effects of vitamin D occur at the kidney, with slight increased reabsorption of calcium, and at the bone for both mineralization and resorption. The adequate calcium allows new bone matrix to become calcified normal bone tissue. Patients who are vitamin D deficient may have low bone density, but they are not lacking bone matrix. Their bone disorder is osteomalacia and not osteoporosis (in which there is loss of bone matrix as well as low mineral content). When given adequate vitamin D and calcium, their bone density (which measures only mineral content of bone) may go up 10% to 15% in one year. Some have both osteomalacia and osteoporosis. In older patients, supplementation of vitamin D to adequate levels (≥800 units vitamin D3/day) has been shown to decrease hip and other nonvertebral fractures.¹⁰ Adequate nutrition and physical therapy for balance training and fall prevention have been shown to decrease hip fractures in older people.

FIGURE 1

Actions of vitamin D

Schematic representation of the multitude of other potential physiologic actions of vitamin D for cardiovascular health, cancer prevention, regulation of immune function, and decreased risk of autoimmune diseases (Copyright Michael F. Holick, 2003, used with permission).

Non-bone effects

Over the last decade it has been demonstrated that many cells can add the 1 hydroxyl group to 25 OH vit D. Therefore, local effects in those tissues seem reasonable. The following are areas in which such effects have been suggested:

Muscle. Vitamin D increases muscle strength. In older people who had vitamin D deficiency, measurements of speed of walking a specific distance were markedly improved after vitamin D administration. Children with rickets have been shown to have muscle weakness.¹¹

Immune system. Vitamin D may improve immunity to infectious diseases. It has been specifically implicated in reducing tuberculosis (TB) infections.⁷ In the past, TB patients were known to improve when exposed to sunshine. This effect is likely due to vitamin D, which can be given directly, improving resistance to the disease. Increased resistance to other immune disorders has also been shown.¹²

Chronic diseases. Recent data suggest that people who have adequate vitamin D develop diabetes later than those deficient in this vitamin.¹³ Newer information has also implicated vitamin D deficiency as a risk factor for hypertension and heart disease.^7,14 Most of these studies are based on population observational studies. Whether vitamin D can effectively improve or reduce the risk of developing certain diseases is being tested actively.

Reproduction. Women who had rickets were known to have difficulty during delivery due to deformities of the pelvis. Merewood et al have recently documented a higher incidence of primary cesarean sections in women who have vitamin D deficiency.¹⁵

Cancer prevention. A new area of research suggests that adequate vitamin D reduces the risk of developing a variety of cancers. It has been implicated in reducing the incidence of colon cancer, breast cancer, prostate cancer, and other malignancies, as well as cancer mortality.¹⁶

The blood level of 25-hydroxyvitamin D reflects the intake of the vitamin, since this is the major form that is consistently carried in blood. Although this is a stable level, it is not necessarily an accurate measure of vitamin intake for two reasons.

First of all, this vitamin is a steroid and is carried on a protein (vitamin D-binding globulin). The active vitamin is the free material, not necessarily the total protein-bound vitamin D.⁷ Conditions that affect the protein will alter the total vitamin D but not necessarily the active free vitamin D. There are no adequate measurements available of the free form. Obesity, a rather common problem at present, reduces binding proteins and, therefore, may lower total 25 OH vit D levels.

The second problem concerns measurement of the total blood level of this vitamin. There are many different methods of measuring vitamin D. Some are immunoassays, others are some form of direct assay, and the only sure one is the most expensive, the chromatographic double MS method (Quest presently uses this method for its 25-hydroxyvitamin D assay as do many medical centers). The cost of the assay, runs from $244 (Quest 2009) to $288. Most insurance plans cover the cost. None of these methods have been sufficiently standardized, resulting in confusing and often incorrect results. For a comprehensive review of the assay methods, see Binkley et al.¹⁷

Measuring 1,25-dihydroxycholecalciferol, although this is the active form of the vitamin, reflects kidney function and not vitamin D sufficiency. It is abnormal in people with significant renal disease who are commonly given calcitriol (1,25 [OH]₂ vitamin D) replacement.

To be adequate, blood levels of 25 OH vit D must be greater than 30 ng/mL. Deficiency is defined as levels below 10 ng/mL (previously known to be the level at which children develop rickets and adults have osteomalacia). Between 10 ng/mL and 29 ng/mL has been described as vitamin D insufficiency (TABLE 1). These are the insufficiency levels that are seen in many patients who have low bone density.

The resultant low calcium absorption causes secondary increases in parathyroid hormone, which then resorbs calcium from bone in order to maintain the blood level of calcium that is essential for many physiologic and enzymatic activities. Blood levels below 30 ng/mL have been associated with increasing parathyroid hormone levels.¹⁸

Although bone mineral is low at the vitamin D insufficiency level, specific symptoms are only seen when levels go below 10 ng/mL. Such individuals may have aches and pains all over their bodies, particularly over muscles and bones. They have general tenderness all over, not related to any specific organ system. Some also have joint pains. On providing adequate vitamin D, all symptoms disappear promptly. Patients with osteoporosis who have extremely low vitamin D levels and are started on a bisphosphonate may develop hypocalcemia.

Diagnosis and management of low, normal, and high serum levels of vitamin D

If the individual is deficient in vitamin D, with blood levels below 15 ng/mL, the administration of large amounts of vitamin D is warranted. The only prescription preparation of vitamin D in the United States is vitamin D2 in 50,000 unit capsules. This can be given weekly for at least 8 weeks, which will bring levels to normal in most patients who have normal absorption capacity (ie, no gastrointestinal illness).

Thereafter, patients will most likely continue to need the high-dose capsules 2 or 3 times per month (personal observation suggests that about one-third of patients will need the 50,000 unit vitamin D2 every 10 days). Maintenance with 1000 to 2000 units of vitamin D3 daily may be adequate but has not been tested. For those with higher levels, every 400 units of vitamin D3 will raise the level of 25 OH vit D by about 5 ng/mL.

The average person (ie, one who does not have low levels of vitamin D) needs to take at least 1000 units of vitamin D3 daily.¹⁹ These over-the-counter preparations are available at very reasonable cost (some are sold for $6 or less for 100 pills).

In people with adequate vitamin D levels, calcium intake need only be 1000 mg/day in food or supplements. Overdosage is unlikely, as the administered vitamin D is not the final effective material.

The kidney can modulate how much 1,25-dihydroxyvitamin D is produced depending on the patient’s blood calcium levels. Levels over 5000 units of vitamin D3 per day have been associated with elevated blood calcium and/or elevated urinary calcium levels (TABLE 2). Excessive absorption of calcium may, however, ultimately lead to kidney stones. Measurement of the calcium content of 24-hour urine should contain less than 280 mg of calcium per 24 hours. Reduction of the supplemental calcium may be all that is needed to prevent the high calcium excretion. Vitamin D requirements for children have also been increased, as reported by Gordon et al in 2008.²⁰

Monitoring therapy

Vitamin D is an essential ingredient in everyone’s daily diet unless they get a significant amount of sun exposure without sunscreen. It is important for normal bone strength, fracture prevention, and muscle activity. Recent information has implicated low vitamin D levels as being associated with increased rates of developing diabetes, coronary heart disease, hypertension, immune disorders, and increases in primary cesarean section rates. At this time, vitamin D is good for many systems, including preventing the common cold.²¹ Further investigation will show us which areas of disease are truly related to, or caused by, vitamin D deficiency. At present, the main effects clearly show improvement of calcium absorption from the bowel, improvement in bone and muscle strength, and the prevention of osteoporotic fractures.

Sexuality, Reproduction & Menopause ©2009 Lebhar-Friedman, Inc.