Vitamin D deficiency and osteoporosis
: Weibo Xia, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sicences, Peking Union Medical College, Beijing 100730, China. Email: firstname.lastname@example.org
Osteoporosis is a disease of disequilibrium between bone formation and bone loss, and vitamin D is one of the key hormones in the regulation of bone metabolism, the major role of which is to provide the proper micro-environment for bone mineralization. Vitamin D deficiency which has been defined by most experts as circulating 25-hydroxyvitamin D levels of less than 20 ng/mL (50 nmol/L) is widespread all over the world. As shown by the results of recent studies, vitamin D deficiency could increase the risk of low bone mineral density or osteoporosis, muscle disorders, falls, and as a matter of course, fractures due to both osteoporosis and falls. Long-term supplementation of vitamin D and calcium are good prevention measures for osteoporosis, falls and fractures. At the same time, they are essential components of osteoporosis management. Many studies show that sufficient vitamin D intake could increase bone mass, and decrease the risk of falls and fractures.
Osteoporosis is a chronic, progressive disease characterized by reduced bone mass and microarchitectural deterioration of bone, involving an extensive fragility and a subsequent increase in fracture risk.1 1,25 dihydroxy vitamin D is the biologically active form of vitamin D, the major role of which in bone is to provide the proper microenvironment for bone mineralization. Although foods may be fortified with vitamin D or vitamin D is supplemented, vitamin D deficiency remains common in children and adults. Inadequate serum vitamin D [25(OH)D] concentrations are associated with secondary hyperparathyroidism, increased bone turnover and bone loss, which increase fracture risk. Vitamin D and calcium are essential components of osteoporosis management. Many studies have shown that sufficient vitamin D intake can increase bone mass, muscle capacity and adjust muscle function. It is also effective to prevent osteoporosis and fracture. The recommended dose is at least 1200 mg of calcium in addition to 800 IU of vitamin D per day.
VITAMIN D METABOLISM AND FUNCTION
Vitamin D discovery
From the mid-1600s, most children who lived in crowded and polluted industrialized cities of northern Europe developed a severe bone-deforming disease which was later called rickets. Although cod liver oil had been used medicinally for a long time, D. Scheutte2 in 1824 was the first to prescribe it for the treatment of rickets. It was not until 1906 that Hopkins3 postulated the existence of essential dietary factors necessary for the prevention of diseases such as scurvy or rickets. The key experiment was performed by McCollum and his coworkers in 1922; they concluded that fat-soluble factor was the newly discovered antirickets factor, and they named the new factor vitamin D.4 After vitamin D was structurally identified and chemically synthesized inexpensively from yeast, people found that it was not as effective as cod liver oil in children with rickets, and they were therefore not the same thing. When vitamin D was isolated and identified from pig skin and was shown to originate from 7-dehydrocholesterol, the vitamin D from yeast was called vitamin D2 and the one from pig and human skin vitamin D3.4
Vitamin D production, hydroxylation and metabolism
Vitamin D originates from 7-dehydrocholesterol. During exposure to solar ultraviolet B (UVB) radiation, 7-dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to vitamin D3 in a heat-dependent process. Vitamin D2 and vitamin D3 from dietary sources are incorporated into chylomicrons and transported by the lymphatic system into the venous circulation. Vitamin D made in the skin or ingested in the diet can be stored and then released from fat cells. Vitamin D in the circulation is bound to the vitamin D-binding protein, which transports it to the liver, where vitamin D is converted by vitamin D-25-hydroxylase to 25-hydroxy vitamin D.5 This form of vitamin D is biologically inactive and must be converted to the active form. Since the pioneering work of Liu and Chu6 in the 1930s and the subsequent studies of others, it has been recognized that many patients with renal insufficiency demonstrate both features of a deficiency of calciferol and a resistance to treatment with doses of calciferol which are physiologically effective in normal individuals. These studies indicated a close association between vitamin D metabolism and kidneys. Up to 1972 Deluca et al.7 found 25 hydroxy vitamin D-1α hydroxylase in the kidney, and clarified that 25 hydroxy vitamin D must be converted in kidneys by this enzyme to the biologically active form – 1,25 dihydroxy vitamin D.8,9 1,25 dihydroxy vitamin D can increase the expression of 25 hydroxy vitamin D-24 hydroxylase to catabolize 1,25 dihydroxy vitamin D to the water-soluble, biologically inactive calcitroic acid, which is excreted in the bile.8
VITAMIN D NUTRITION AND DEFICIENCY
Optimal vitamin D level and vitamin D deficiency
The serum concentration of 25(OH)D3 is 1000 times of that of serum 1,25(OH)D3, and this excess concentration constitutes a storage facility similar to that of other steroid hormones. 25(OH)D3 is used by clinicians to determine vitamin D status.10 Although it is generally agreed that vitamin D status is most accurately reflected by serum 25(OH)D3 concentrations, evidence regarding adequate serum concentrations is inconclusive.
Vitamin D deficiency has classically been defined as circulating concentrations of 25 hydroxy vitamin D [25(OH)D] < 10 ng/mL11 but subsequent studies have indicated that concentrations < 20 ng/mL are insufficient for blood parathyroid hormone (PTH) homeostasis. More recently, it was recommended that nutritional vitamin D deficiency be defined as concentrations of circulating 25(OH)D < 32 ng/mL, based on optimization of PTH concentrations, calcium absorption, and bone mineral density.12 Although there is no consensus on optimal levels of 25 hydroxy vitamin D as measured in serum, vitamin D deficiency is defined by most experts as a 25 hydroxy vitamin D level of less than 20 ng/mL (50 nmol/L). a level of 25 hydroxy vitamin D of 21–29 ng/mL (52–72 nmol/L) can be considered to indicate a relative insufficiency of vitamin D, and a level of 30 ng/mL or greater can be considered to indicate sufficient vitamin D: the so-called optimal vitamin D level. Vitamin D intoxication is observed when serum levels of 25 hydroxyl vitamin D are greater than 150 ng/mL (374 nmol/L).13
Alternatively, a gradual scale was proposed in which hypovitaminosis D is defined as a 25(OH)D3 concentration < 100 nmol/L (40 ng/mL), vitamin D insufficiency as a 25(OH)D3 concentration < 50 nmol/L (20 ng/mL), and vitamin D deficiency as a 25(OH)D3 concentration < 25 nmol/L (10 ng/mL).4
Vitamin D deficiency prevalence in populations
With the use of the above definitions, it has been estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency. In 1990s studies, many elderly people had serum 25 hydroxy vitamin D levels below 50 nmol/L (20 ng/mL); in some centres, the percentage achieved 90%, that is to say, they were vitamin D deficient. Also, there were a few centres in the US, UK, and so on where elderly people had accepted vitamin D supplementation, so the percentage of vitamin D deficiency was near to zero. High latitude, low outdoor activity, hip fracture history, and so on were shown to increase the risk of vitamin D deficiency.14
According to several recent studies, 40–100% of US and European elderly men and women still living in the community (not in nursing homes) are deficient in vitamin D. More than 50% of postmenopausal women taking medication for osteoporosis have relative insufficiency of vitamin D – below 30 ng/mL (75 nmol/L). Children and young adults are also potentially at high risk for vitamin D deficiency.15 Results from the third National Health and Nutrition Examination Survey (NHANES III)16 show that 42% of African-American women and 4.2% of White women had serum 25(OH)D concentrations < 15 ng/mL. Other studies in the US, generally conducted in northern latitudes, have found that up to 30% of healthy, non-institutionalized adults had vitamin D insufficiency, with higher rates in those with darkly pigmented skin. A recent study has been conducted in regions of the southern US (southern Arizona)17 where ultraviolet (UV) exposure is relatively high. The mean serum 25(OH)D concentration for the total population was 26.1 ± 9.1 ng/mL. Of 637 participants, 25.4% had 25(OH)D concentrations < 20 ng/mL, and 2.0% had concentrations < 10 ng/mL. Blacks (55.5%) and Hispanics (37.6%) were more likely to have deficient 25(OH)D concentrations (< 20 ng/mL) than were non-Hispanic Whites (22.7%).
Zhou and Meng18 compared the serum 25 hydroxy vitamin D levels between people living in the Lhasa area in Tibet and in Beijing; 30.5 ± 14.5 ng/mL in people from Lhasa, significantly higher than 18.9 ± 6.5 ng/mL in people from the Beijing area. These differences are contributed to the different latitude of these two areas. These results also implicate that vitamin D inadequacy is in high prevalence among Chinese people. Exposure to sunlight is the most important protection against vitamin D deficiency, but nowadays, even in sunnier areas, vitamin D deficiency is still common because of the widespread popularity of sunscreen products. When adults topically apply a sunscreen, the amount of vitamin D3 produced in the skin may be reduced by 95%.19
VATAMIN D AND BMD
The relationship of BMD and vitamin D
1,25 dihydroxy vitamin D can promote bone mineralization indirectly by stimulating calcium and phosphate supply, mainly by absorption from the gut. Without vitamin D, only 10–15% of dietary calcium and about 60% of phosphorus is absorbed. The interaction of 1,25 dihydroxy vitamin D with the vitamin D receptor increases the efficiency of intestinal calcium absorption to 30–40% and phosphorus absorption to approximately 80%.4
In cross-sectional studies20 a positive relationship has been observed between serum 25 hydroxy vitamin D and bone mineral density (BMD) of the hip. In 330 elderly women in Amsterdam, a threshold of serum 25 hydroxy vitamin D was observed on BMD changes. There was positive correlation between BMD and serum 25 hydroxy vitamin D levels lower than 30 nmol/L, but above this level the relationship was no longer significant. This study showed that BMD at the femoral neck was 5% or 10% lower than average when serum 25 hydroxy vitamin D was 20 or 10 nmol/L, respectively. A positive relationship between serum 25 hydroxy vitamin D and BMD of the hip was also observed in middle-aged women in the UK (45–65 years) and in elderly women in New Zealand.11
Bischoff-Ferrari et al.21 found that serum levels of 25 hydroxy vitamin D were directly related to bone mineral density in White, Black, and Mexican-American men and women, with a maximum density achieved when the 25 hydroxy vitamin D level reached 40 ng/mL or more. Wat et al.22 reported the prevalence and impact of vitamin D insufficiency in southern Chinese adults. The mean 25(OH)D level was 28.3 ± 10.8 ng/mL, with 62.8% of subjects having levels < 30 ng/mL, and 6.3% of the subjects had elevated PTH levels. Although subjects with vitamin D < 30 ng/mL had significantly lower BMD, only sex, age and PTH but not 25(OH)D were predictors of BMD at the spine and hip. Vitamin D insufficiency and its complication of secondary hyperparathyroidism is common even in subtropical regions and is an important risk factor for low bone mass, falls and fractures. A more recent study23 points out a high prevalence of vitamin D inadequacy in Belgian postmenopausal osteoporotic women, even among subjects receiving vitamin D supplements. This prevalence of 25(OH)D inadequacy was 91.3%, 87.5%, 43.1% and 15.9% when considering cutoffs of 80, 75, 50 and 30 nmol/L, respectively. There is a significant positive relation between age and PTH (r = 0.16), serum 25(OH)D and femoral neck BMD (r = 0.07, P < 0.05). However, the OFELY study24 concluded that in a population of home-dwelling healthy postmenopausal women, few of them had severe vitamin D deficiency, and that vitamin D status may not be an important determinant of bone health.
When patients are vitamin D deficient, the decrease of intestinal calcium absorption will increase the serum PTH, which can activate osteoblasts, and stimulate preosteoclasts differentiating into mature osteoclasts. Osteoclasts dissolve the mineralized collagen matrix in bone, causing the loss of bone mass and the low BMD.
Another interpretation of the association between low serum 25 hydroxy vitamin D and low BMD is a sedentary lifestyle. This would cause bone loss due to immobility as well as reduced exposure to sunlight. Indeed, frail elderly subjects are often vitamin D deficient and are physically not very active. However, immobility is associated with increased bone resorption, which causes loss of bone mass.4
The association of vitamin D receptor gene polymorphism and BMD
Bone mineral density is known to have strong genetic determinants. On the basis of studies of twins and mother-daughter pairs, it is estimated that heredity accounts for up to 70% of the variance in BMD in both women and men.11
In 1994, Morrison et al.25 reported that normal allelic variations in the vitamin D receptor (VDR) gene could account for up to three quarters of the genetic effect on BMD in normal Australian male and female twins. They found a similar association in a group of 311 normal Australian women. VDR genotype was based on the presence (b) or absence (B) of the BsmI restriction site, and there are two kind of homozygote (BB and bb) and one kind of heterozygote (Bb). In homozygotes, the more common b allele was associated with higher BMD, and the less common B allele with lower BMD. In twins, the difference between genotypes corresponded to a difference in BMD of 13% for the lumbar spine and 9% for the hip, whereas in the 311 women the corresponding values were 8% and 4%, respectively. Basically, the b allele is relative to high BMD.26
Zhao et al.27 reported on vitamin D receptor polymorphisms and BMD in Chinese in 1997; they studied polymorphisms of VDR gene of three restriction enzyme sites (namely BsmI, ApaI and TaqI) in 223 subjects, Chinese had high frequencies of ‘b,a,T’ alleles, 95%, 75% and 95%, respectively, which were very different from Caucasians. ‘BB’ or ‘AA’ genotype had tendencies for higher BMD at some sites in this group of young women, whereas in the group of postmenopausal women, ‘bb’ or ‘aa’ genotype were related to lower BMD at femoral neck and trochanter. Kung et al.28 reported allelic frequencies of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms (RFLPs) in 144 normal healthy southern Chinese premenopausal women aged between 30 and 40 years, and correlated their peak bone mass with the VDR genotypes. Analysis of the VDR genotype revealed that subjects with BbAaTt and BbAATt haplotypes had the lowest peak bone mass.
Although some recent studies show that there is no significant difference in the polymorphisms of VDR for the BMD basal level, after vitamin D supplements in vitamin D-deficient elderly, the increase of BMD may depend on genetic characteristics of the VDR. One study shows that the VDR polymorphisms BB and Bb were associated with a 3% gain of BMD in the femoral neck after vitamin D supplementation in comparison with no change in the bb genotype. Another study showed that the mean increase of BMD in the vitamin D group relative to the placebo group, expressed as percentage of baseline BMD, was significantly higher (P = 0.03) in the BB (δBMD: 4.4%, P = 0.04) and the Bb genotype (δBMD: 4.2%, P = 0.007) compared with the bb genotype (δBMD: –0.3%, P = 0.61), providing evidence for functional roles of VDR gene variants in relation to bone mass. The VDR genotype might help in explaining the variance in response to vitamin D supplementation.29
Vitamin D and active vitamin D treatment and BMD changes
Vitamin D supplementation may increase BMD in several regions of the skeleton, especially in people who are vitamin D deficient. The increase of BMD may be explained by mineralization of excess osteoid in cases with more severe vitamin D deficiency and by decreasing parathyroid function and bone turnover which will decrease bone loss in the long-term.
In 1997, the results of a 3-year, double-blind, placebo-controlled trial to identify the effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older were reported: 176 men and 213 women received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. The mean (± SD) changes in bone mineral density in the calcium + vitamin D and placebo groups were as follows: femoral neck, +0.50 ± 4.80 and –0.70 ± 5.03%, respectively (P = 0.02); spine, +2.12 ± 4.06 and +1.22 ± 4.25% (P = 0.04); and total body, +0.06 ± 1.83 and –1.09 ± 1.71% (P = 0.001). The difference between the calcium + vitamin D and placebo groups was significant at all skeletal sites after 1 year, but it was significant only for total-body BMD in the second and third years.30
A lot of studies have confirmed this conclusion. A supplementation of vitamin D of 800 IU increased BMD of the lumbar spine during winter months in postmenopausal women in comparison with the control group. In a later study from the same centre, vitamin D (100 IU/day and 700 IU/day) were compared in a double-blind trial in postmenopausal women. The group receiving the higher vitamin D dose experienced less bone loss from the femoral neck than the group on the lower dose (–1.0%vs –2.5%, P = 0.01). In the Amsterdam vitamin D study, vitamin D3 (400 IU/day) increased BMD of the femoral neck by 1.9% after 1 year and 2.2% after 2 years (P = 0.01), whereas BMD of the trochanter did not change significantly. This suggests a greater effect on cortical than on trabecular bone. The combined effect of vitamin D3 (800 IU/day) and calcium (1200 mg/day) in the Qualyos study in French nursing home residents increased BMD of the total hip by more than 6%. In California, 12 elderly subjects with vitamin D deficiency (serum 25 hydroxy vitamin D < 35 nmol/L) were supplemented with vitamin D2 (50,000 IU) twice weekly and calcium carbonate (1000 mg/day) for 5 weeks. The BMD showed significant increases in the lumbar spine (4.1%) and femoral neck (4.9%). In a recent study in Indiana, 316 elderly women and 122 elderly men were randomized to 25 hydroxy vitamin D (15 µg/day) or calcium (750 mg/day), or placebo. The effect of 25 hydroxy vitamin D on bone loss was intermediate between that of calcium and placebo. In this study, baseline median serum 25 hydroxy vitamin D was 59 nmol/L, a relatively high value. This study confirms that the effect of vitamin D treatment is small when vitamin D status is adequate.11
In the Women's Health Initiative (WHI) study, 18,176 women were assigned to active supplementation (calcium 1000 mg with vitamin D400 IU), and 18,106 to placebo. They were 50–79 years of age. The result showed that hip bone density was 1.06% higher in the calcium plus vitamin D group than in the placebo group (P < 0.01) after 5 years treatment. No significant difference favouring the calcium with vitamin D group were observed in spine and whole-body BMD.31 Papadimitropoulos et al.32 reviewed the effect of vitamin D on bone density and fractures in postmenopausal women. They found hydroxylated vitamin D had a consistently larger impact on bone density than did standard vitamin D. For instance, total body differences in percentage change between hydroxylated vitamin D and control were 2.06 (0.72, 3.40) and 0.40 (0.25, 1.06) for standard vitamin D. At the lumbar spine and forearm sites, hydroxylated vitamin D doses above 0.5 µg yielded larger effect than lower doses. Xia et al. observed the efficacy of calcitriol (1,25(OH)2D3)on bone mass in ageing Chinese women with osteopenia or osteoporosis. BMD of L2–4 were significantly increased after 12 months treatment compared with baseline. Changes of BMD in L2–4 and femur neck were 2.8% (P < 0.01) and 2.0% (P < 0.05), respectively.
The response to treatment with vitamin D will depend on the degree and severity of vitamin D deficiency and the secondary changes in mineral and bone metabolism. Supplements of vitamin D at 400 IU or more daily slightly increases serum 1,25-(OH),D and lowers PTH secretion without side-effects. Therefore vitamin D supplementation may be a safe method for the prevention of bone loss, especially in vitamin D-deficienci populations.
VITAMIN D AND MUSCLE FUNCTION AND FALLS
Vitamin D and muscle function
Vitamin D can affect muscle metabolism through many different mechanisms. In the past decade, various cases have been described in which prolonged vitamin D deficiency was associated with some muscle weakness that would be improved with a period of vitamin D supplementation.
In an elderly population (65–95 years of age), of whom 12% of women and 18% of men had a serum 25 hydroxy vitamin D3 concentration < 30 nmol/L, a significant correlation was found between vitamin D metabolites and leg extension power.33 In a cross-sectional study of 349 elderly people (≥ 70), of whom 246 were hospitalized, serum 25 hydroxy vitamin D3 concentrations were significantly lower in those with less handgrip strength and falls in the previous month. In another similar study, a low serum 25 hydroxy vitamin D3 concentration (< 40 nmol/L) was associated with reduced handgrip strength and walking distance in 63 community-dwelling elderly (82.5 ± 5.4 years of age). However, cross-sectional studies cannot infer a causal relation.
There is also evidence from intervention studies which do indicate causality. Muscle strength and mobility were measured in 10 vitamin D-deficient (< 20 nmol/L), elderly women (mean age: 76 years) who were treated for 6 months with 0.5 µg α-calcidiol/day. Both knee extension strength and walking distance improved significantly compared with a vitamin D-replete control group who received no therapy. Many similar studies have been performed, but more random controlled trials are needed to provide fair evidence.
In comparison, in some studies of healthy, vitamin D-replete, elderly populations, no correlation was found between serum 1,25-hydroxy vitamin D3 concentration and knee-extension strength, and after α-calcidiol treatment there was no significant change. The level of serum 25 hydroxy vitamin D3 in such people remains stable, but muscle strength declines year by year.34
Although many other conditions may cause muscle weakness, vitamin D supplements can benefit the vitamin D-deficient patients whose serum 25 hydroxy vitamin D3 concentrations are lower than normal.
Vitamin D and falls
Besides low BMD, falls are also important in the pathogenesis of osteoporotic fractures. Any condition which can increase the fall risk can also increase the risk of fractures.
More than a third of people aged over 65 fall each year; the most important risk factor is muscle weakness which may be associated with vitamin D deficiency. A significant correlation between serum 25 hydroxy vitamin D3 concentration and the occurrence of falls in elderly people was reported in 1999.35
There is more evidence that supplementation of vitamin D can reduce the incidence of falls. When used properly, it is more effective than other treatments. Eight weeks of vitamin D and calcium in 148 elderly women with a serum 25 hydroxy vitamin D3 concentration < 50 nmol/L resulted in a decrease of 9% (P < 0.05) in body sway and fewer falls as compared with calcium only. In the STOP/IT (Sites Testing Osteoporosis Prevention and Intervention Treatments) trial, 489 women (mean age: 71 years) were randomly assigned to receive estrogen, calcitriol, both estrogen and calcitriol, or a placebo for 3 years The subjects who took calcitriol experienced fewer fractures from falls than did the group who took estrogen (OR: 0.78 and 0.94, respectively).30
Also, there is evidence that the effectiveness of vitamin D supplementation is dose-respondant, and the reported adequate dose is 800 IU per day. Two randomized controlled trials have found 400 IU/day of vitamin D to be ineffective in reducing the frequency of fractures; one trial of high-dose treatment showed no evidence of reduction in falls among frail outpatients. However, in a randomized controlled trial elderly women given 800 IU vitamin D daily with calcium had a 47% reduction in falls and fractures compared with controls receiving calcium alone over 12 months. In another trial, the incidence of falls was almost halved and musculoskeletal function improved among elderly people who had 800 IU vitamin D with calcium compared with calcium alone.31
We must know clearly that vitamin D deficiency is only one risk factor for falls and fractures among elderly people. Vitamin D supplementation has little benefit in the vitamin D-replete population for they may have other disabilities. But it is one of the most important and common risk factors, and intervention in the vitamin D-deficient population do reduce falls and relative fractures, although more randoized controlled trials are needed.
VITAMIN D AND FRACTURES
Vitamin D deficiency as a risk of fracture
Bone mineral density reduction and falls are the most important risks for fracture. As we have discussed above that vitamin D deficiency is associated with both of these, so vitamin D deficiency becomes an important fracture risk and supplementation of vitamin D may reduce fracture incidence. Still, people have done many studies to prove the relationship.
In the case-control Study of Osteoporotic Fractures,36 133 women with first hip fracture and 138 women with a new vertebral fracture were studied. However, the results were negative. In this study, vitamin D deficiency was not associated with an increased risk for hip or vertebral fracture. That may be because severe vitamin D deficiency was rare. But there was a positive result that low serum 1,25 dihydroxy vitamin D (< 57 pmol/L) was associated with an increased risk for hip fracture (RR 2.1 adjusted for age and weight).
In Oslo, Norway, 246 patients with hip fracture and a similar number of controls were studied for risk factors. A vitamin D intake (including food and supplements) lower than 100 IU/day was associated with an increased risk for hip fracture (RR 3.9, CI 1.7–9.3).37
Vitamin D deficiency is the risk of fracture which is the most important cause of morbidity and mortality in elderly people. So, the treatment of vitamin D becomes more and more important for people's health.
Vitamin D treatment and fracture reduction
Controversy persists whether low-level trauma or osteoporotic fractures can be prevented with vitamin D supplementation. In 1992, Chapuy et al. reported that among 3270 elderly French women given 1200 mg of calcium and 800 IU of vitamin D3 daily for 3 years, the risk of hip fracture was reduced by 43% and the risk of non-vertebral fracture by 32%.38 A 58% reduction in non-vertebral fractures was observed in 389 men and women over the age of 65 years who were receiving 700 IU of vitamin D3 and 500 mg of calcium per day.6 A review on the effect of vitamin D on bone density and fractures in postmenopausal women which included 25 trials concluded that vitamin D reduced the incidence of vertebral fractures (RR 0.63, P < 0.01) and showed a trend toward reduced incidence of non-vertebral fractures (RR 0.77, 95%,P = 0.09).32 In 2005,39 the divergent findings were addressed in a meta-analysis and the results were hopeful. A meta-analysis of seven randomized clinical trials that evaluated the risk of fracture in older persons given 400 IU of vitamin D3 per day revealed little benefit with respect to the risk of either non-vertebral or hip fractures. But in studies using doses of 700–800 IU of vitamin D3 per day, the relative risk of hip fracture was reduced by 26% (pooled relative risk, 0.74; 95% CI, 0.61–0.88), and the relative risk of non-vertebral fracture by 23% (pooled relative risk, 0.77; 95% CI, 0.68–0.87) with vitamin D3 as compared with calcium or placebo.27 But a Women's Health Initiative large-scale, randomized, double-blind, placebo controlled trial study that compared the effects of 400 IU of vitamin D3 plus 1000 mg of calcium per day with placebo in more than 36,000 postmenopausal women reported an increased risk of kidney stones but no benefit with respect to the risk of hip fracture. That may be because that the dose of vitamin D of the WHI study (400 IU/day) was low. Jackson et al.40 evaluated the effect of supplementation with vitamin D3 (excluding the potential effect of calcium supplementation) on the risk of falls and fractures, primarily in postmenopausal women from nine studies. The review found that the pooled relative risk (RR) for vitamin D3 preventing falls was 0.88 (95% CI 0.78–1.00). For fractures, the pooled RR for vitamin D3 preventing non-vertebral fractures was 0.96 (95% CI 0.84–1.09) and the pooled RR for vitamin D3 preventing vertebral fractures was 1.22 (95% CI 0.64–2.31). In a subgroup analysis of postmenopausal women, the pooled RR for vitamin D3 preventing falls was 0.92 (95% CI 0.75–1.12) and in preventing non-vertebral fractures the pooled RR was 0.81 (95% CI 0.48–1.34). There is a trend towards a reduction in the risk of fall among patients treated with vitamin D3 alone compared with placebo, suggesting that vitamin D3 should be an integral part of effective osteoporosis management. It is likely that the inconsistency between the meta-analysis and the recent trials is, at least partially, due to publication bias and differences in target populations. High-dose vitamin D may be effective in institutionalized persons but probably is not effective in the general population.41
Because vitamin D plays a major role in calcium absorption, bone health, muscle performance, balance, and risk of falling,42 the clinician's guide to prevention and treatment of osteoporosis 2008 of the National Osteoporosis Foundation recommends an intake of 800–1000 international units (IU) of vitamin D3 per day for adults over age 50. This intake will bring the average adult's serum 25(OH)D concentration to the desired level of 30 ng/mL (75 nmol/L) or higher.
We thank Professor Xueying Zhou (Department of endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College) and ProfessorAnnie Kung (Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China) who provided helpful discussion and modifications.