Vitamin D Supplementation and Bone Health
By David Kiefer, MD, Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Adequate vitamin d intake never used to be a concern with the traditional daily tablespoon of cod liver oil and regular exposure to direct sunlight. But now, with cod liver oil falling out of favor for many people, and warnings about too much sunlight causing skin cancer, there may in fact be issues with vitamin D insufficiency, especially given what we know about the connection between vitamin D, calcium homeostasis, and bone health. This article will explore the scientific evidence for vitamin D supplementation for bone health and the prevention of bone-related pathology.
Physiology
The body is able to make its own vitamin D, produced when ultraviolet light (specifically UVB) contacts the skin and converts 7-dehydroxycholesterol to cholecalciferol, also called vitamin D3.1-3 Cholecalciferol is then hydroxylated in the liver to make 25-hydroxyvitamin D (calcitriol), which predominates in the human body;2 25-hydroxyvitamin D is the compound that can be measured to determine a person's overall vitamin D status.3 The more potent but less prevalent (0.1% concentration of calcitriol) form of vitamin D, 1,25-dihydroxyvitamin D, is created through further hydroxylation in the mitochondria of renal tubules in the kidney.
1,25-dihydroxyvitamin D is important for facilitating active calcium absorption from the lumen of the intestine into the systemic circulation;3 in deficiency states, secondary hyperparathyroidism may occur, resulting in increased bone turnover and cortical bone loss.
Vitamin D has many other interesting physiological effects, perhaps accounting for the evidence accumulating for the importance of adequate vitamin D levels in the prevention of such diseases as cancer,1,4 diabetes, and autoimmune disorders.3
Epidemiology
Vitamin D deficiency is thought by many experts to be an epidemic in the United States, leading to secondary hyperparathyroidism in some individuals and increasing their risk of osteoporosis and fractures.3 One demographic particularly at risk is the elderly. Vitamin D deficiency occurs in the elderly because of decreased sunlight exposure, suboptimal nutrition, and skin that is less efficient in producing vitamin D.5
Researchers have demonstrated that vitamin D supplementation can improve serum vitamin D and lower parathyroid hormone (PTH). For example, in one study of 553 community-dwelling women aged 65 and older, 16% were vitamin D-deficient (serum vitamin D < 10 ng/mL) and 48% had vitamin D insufficiency (serum vitamin D between 10 and 20 ng/mL).6 This can be corrected with vitamin D supplementation; the women were given 400 IU vitamin D as part of a multivitamin and 1-2 tablets of calcium carbonate (600 mg) plus 200 IU vitamin D, for a total of 400-800 IU vitamin D daily for three months. Though there are methodological problems with this study, especially the fact that it was not a placebo-controlled trial, the rate of deficiency and insufficiency dropped to 0% and 20%, respectively, with the supplementation regimen.
It may be possible to supplement with vitamin D and normalize serum levels, an important intervention given the connection between low serum vitamin D and bone pathology. For example, reviews of the topic have found that patients with osteoporosis often have calcium malabsorption, and more than half have low serum vitamin D,7 and women with osteoporotic hip fractures are more likely to have low serum 25-hydroxyvitamin D and higher PTH than women presenting for elective hip replacement, either osteoporotic or non-osteoporotic.8
Clinical Trials
The main areas of research for supplementation with vitamin D have been in fracture risk prevention and improvements in bone mineral density (BMD). One of the difficulties in interpreting the data is that some, but not all, trials also include calcium supplementation (in a variety of forms) with vitamin D as part of the treatment group; the effect of vitamin D itself may then be hidden. Representative trials are described in more detail below.
Bone Mineral Density
One placebo-controlled trial of 348 women aged 70 and older examined the effect of 400 IU daily vitamin D for two years on BMD (hips, distal radius) and biochemical markers of bone turnover (serum calcitonin, osteocalcin, alkaline phosphatase, bone alkaline phosphatase, urinary hydroxyproline/creatine).9 The treatment group had increased serum 25-hydroxyvitamin D and decreased PTH, with no change in bone turnover markers. Also, there was an increased density of the femoral neck (left 1.9 %, right 2.6%) after two years, though no change in the distal radius or femoral trochanter. There was a significant amount of attrition in this study (283 completed the first year, and 248 completed two years), but the dropout rates were similar between the two groups. The vitamin D treatment was well-tolerated. The researchers noted that the effects seemed to be independent of baseline vitamin D status but more prominent in the subgroup of women with less remaining estrogen activity.
Another study was undertaken on 187 recently postmenopausal women (mean age 56 years) who were randomized to take either 1,000 mg of calcium carbonate daily or 1,000 mg of calcium plus 10,000 IU vitamin D2 every week.10 Baseline serum 25-hydroxyvitamin D levels were found to be normal in both groups. The BMD at several sites was measured every six months, and no differences in the 153 women who completed the study in the two groups were noticed; both groups gained BMD in Ward's triangle and the femoral trochanter, lost BMD at the distal radius, and had no change in the lumbar spine or femoral neck.
There have been some studies examining the effect of vitamin D supplementation on bone health in healthy people. One double-blind, randomized controlled trial in 208 healthy African American women who were ingesting 1,200-1,500 mg of calcium daily tested placebo vs. 800 IU of vitamin D3 supplementation for two years on BMD, serum calcium, PTH, and 25-hydroxyvitamin D.11 The researchers reported no change in the rate of bone loss between the vitamin D group and placebo group, nor any correlation between serum 25-hydroxy-vitamin D levels and rates of bone loss. These results may be related to the calcium-replete status of these women, as well as ethnic differences in calcium physiology and metabolism.
Fracture Risk
One of the original studies examining fracture risk randomized 3,270 ambulatory women aged 69-106 living in nursing homes or apartments for the elderly to receive either 800 IU cholecalciferol and 1,200 mg elemental calcium (as tricalcium phosphate) or placebo daily for 18 months.12 The study outcomes were fracture rates, biochemical changes (various blood parameters), and bone density. There was significant attrition for the study: Only 1,765 women completed the 18-month trial term. Analysis of the data on the 1,765 women showed significant reductions in nonvertebral and hip fracture rates, results that held with an intention-to-treat analysis that included all 3,270 women. Furthermore, the placebo group had lower serum calcium, the treatment group had lower serum PTH, and the treatment group had significant improvements in BMD of the proximal femur.
A recent meta-analysis examined the efficacy of vitamin D supplementation for fracture prevention in people 60 years old and older.13 Randomized controlled trials (RCTs) using 700-800 IU daily of cholecalciferol led to a 26% decrease in the relative risk of hip fractures (three RCTs) and 23% decrease in relative risk of nonvertebral fractures (five RCTs). In these trials, calcium intake ranged from 500 to 1,200 mg daily, either from supplements or food intake. The researchers mention that the benefits in fracture risk reduction could be due to either decreases in bone loss or increases in muscle strength, another physiological benefit of vitamin D.14 Those trials using 400 IU daily of cholecalciferol showed no change in fracture risk (two RCTs).
A Cochrane review reported slightly different results.15 In their analysis, vitamin D only reduced fracture risk when it was combined with calcium supplementation; there was a 19% decreased relative risk for hip fractures (seven RCTs) and a 13% decreased relative risk for non-vertebral fractures (seven RCTs), but these benefits only occurred in people who were confined to institutions. There was no benefit with respect to vertebral fractures and no benefit when vitamin D was used alone.
A clinical trial hot off the press provides some information about vitamin D and fracture risk. A randomized controlled trial compared 1,000 mg calcium and 800 IU cholecalciferol plus a leaflet discussing calcium intake and fall prevention to a leaflet only in 3,314 women aged 70 and older with risk factors for hip fracture.16 A well-organized, intention-to-treat analysis did not demonstrate any difference in fracture rate between the two groups. The people in this study were more healthy and living independently in the community as compared to other studies documenting efficacy with vitamin D and fracture risk, perhaps accounting for the negative results.
This result agrees with a negative Dutch trial involving 2,578 people aged 70 and older, both community-dwelling and in homes for the elderly, who were randomized to receive 400 IU cholecalciferol or placebo daily for 3.5 years.17 Mean dietary calcium intake was estimated at 868 mg daily. Using an intention-to-treat analysis, no difference in hip or peripheral fracture rate was detected, though the vitamin D group did demonstrate an increase in serum 25-hydroxyvitamin D.
An interesting dosage regimen was used in a study of community-dwelling men and women over the course of five years; 2,686 people were randomized to receive 100,000 IU oral cholecalciferol or placebo every four months.18 In the treatment group, the relative risk of fracture was 0.67-0.78, significantly different from the placebo group. Neither calcium intake nor diet was assessed in this trial and it is unclear if either of these variables could have accounted for the results.
Dosing and Sources of Vitamin D
The Daily Reference Intake (DRI) for vitamin D is 200 IU/d for infants, children, adults through age 50, and pregnant and lactating women; adults age 50-69 have a DRI of 400 IU/d, and 70 and older, 600 IU/d.19 However, recent data presented in this review suggest that higher doses may be indicated in specific circumstances.
Sun exposure generally provides 90-95% of a person's vitamin D needs, and, even though conversion in the skin upon exposure to UVB radiation is less efficient as a person ages, it is usually sufficient.3 During the spring, summer, and fall, 5-15 minutes daily of sun exposure during the middle of the day on the arms and legs, or arms, hands, and face is usually enough to provide adequate vitamin D, after which people should cover themselves, stay in the shade, and use sunscreen.3 In the frail elderly, it is also possible to normalize vitamin D status by facilitating time outdoors, with 15-30 minutes daily being adequate in a temperate climate.20
Most supplements contain either vitamin D2, made by exposing ergosterol from yeast to UVB radiation, or cholecalciferol, both of which are used by the body to make 25-hydroxyvitamin D.3 There is some evidence that vitamin D3 in the same doses increases serum 25-hydroxyvitamin D more than vitamin D2.10
In addition to vitamin D-fortified foods such as milk and bread, oily fish (salmon, mackerel, herring), cod liver oil, and sun-dried mushrooms naturally contain vitamin D (approximately 400-500 IU per serving).3
Adverse Effects
Vitamin D supplementation as described in the above trials is well-tolerated, with adverse effect reports similar to those from the placebo groups in most cases. High doses of vitamin D (50 mcg or 2,000 IU) can lead to calcinosis and hypercalciuria. In people with these pre-existing conditions, vitamin D supplementation should be avoided.7
Conclusion
Vitamin D is important for the maintenance of bone health, with well-proven interactions with calcium metabolism. There are also studies showing that some people, primarily the elderly, are vitamin D-deficient. Clinical trials using vitamin D supplementation for the improvement of BMD and the prevention of fractures have shown some interesting results. Vitamin D supplementation appears to translate into increased serum 25-hydroxyvitamin D and lower serum PTH, and may increase BMD in the femur, though some clinical trials have failed to show changes in BMD; the overall effect on BMD may have to do with concomitant calcium supplementation and baseline serum levels of calcium, vitamin D, or estrogen. Meta-analyses and clinical trials show efficacy of vitamin D supplementation for reductions in fracture risk most convincingly for doses of 800 IU daily combined with calcium supplementation, with the best data for elderly people confined to institutions. Vitamin D is usually supplemented as cholecalciferol (vitamin D3), and appears to be well tolerated.
Recommendation
Vitamin D deficiency is a common problem, especially as people age. With a favorable side effect profile, and some convincing studies showing effects on blood parameters, BMD, and fracture risk, supplementation with 400-800 IU of cholecalciferol (vitamin D3) is recommended for people at risk of osteoporosis, but especially for elderly people living in nursing homes or other assisted living institutions. The positive effects of vitamin D supplementation on bone health appear to occur mostly with simultaneous calcium supplementation, so patients should be counseled about good dietary sources of calcium and advised regarding appropriate calcium supplementation. Given the evidence accumulating for bone and other problems associated with vitamin D deficiency, all people should ensure adequate vitamin D intake, whether from supplementation, enriched or high-vitamin D foods, or prudent sunlight exposure.
References
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15. Avenell A, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2005;3:CD000227.
16. Porthouse J, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003-1008.
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18. Trivedi DP, et al. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: Randomised double blind controlled trial. BMJ 2003;326:469-474.
19. Food and Nutrition Information Center. Daily Reference Intakes (DRI) and Recommended Daily Allowances (RDA). Available at: www.nal.usda.gov/fnic/etext/000105.html. Accessed Dec. 7, 2005.
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Kiefer D. Vitamin D supplementation and bone health. Altern Med Alert 2006;9(2):13-16.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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