Clinical Nutrients for Osteoporosis
by Tori Hudson, ND
Numerous modifiable and non-modifiable factors influence the risk of developing osteoporosis. This article provides the practitioner with an understanding of supplementary clinical nutrients and their effect on bone loss and fractures. Lifestyle modifications and nutrient supplementation may be able to reduce the risk of osteoporosis and the associated debilitating fractures. For women who have already been diagnosed with osteoporosis, these nutritional factors can serve as an adjunct to conventional therapies to slow bone loss and, more importantly, decrease the risk of fractures.
Adequate calcium intake has an established role in maintaining bone health, primarily in very young women and the elderly. However, calcium is only modestly effective for slowing the loss of bone mineral density in peri- and early postmenopausal women. Calcium supplementation also appears to have an important role in improving the efficacy of pharmaceutical agents used to treat bone loss and osteoporosis.
Prior to the Women's Health Initiative study, there was no clear evidence that higher calcium intake decreased fracture risk.1 A meta-analysis of prospective cohort studies and clinical trials found that higher calcium intake and calcium supplementation were not associated with a lower incidence of hip fractures.2 In a 2004 meta-analysis of randomized controlled trials, supplementation with 500-2,000 mg per day of calcium had only a modest benefit on bone density in postmenopausal women: the difference in the amount of bone loss between calcium and placebo was 2.05% for the total body, 1.66% for the lumbar spine, and 1.64% for the hip.3 Two trials within this meta-analysis suggested a modest and nonsignificant benefit with calcium supplementation and the risk of nonvertebral fractures. In the Women's Health Initiative, which enrolled more than 36,000 postmenopausal women, supplementation with 1,000 mg per day of calcium and 400 IU per day of vitamin D decreased the risk of hip fractures nonsignificantly by 12%, when compared with placebo. However, when the analysis was restricted to women who took the tablets at least 80% of the time, calcium plus vitamin D significantly decreased hip fractures by 29% compared with placebo.4
Other calcium studies also showed a beneficial effect on bone loss. In postmenopausal women, calcium supplementation has been shown to decrease bone loss by as much as 50% at nonvertebral sites. The effects were greatest in women whose baseline calcium intake was low, in older women, and in women with established osteoporosis.5 In a study by Elders et al,6 a significant decrease in vertebral bone loss was observed with supplementation of 1,000 to 2,000 mg per day of calcium for 1 year. Bone loss was also less in the calcium group than in the control group after 2 years, but the difference was no longer statistically significant.
Dietary calcium is essential throughout a woman's life, and requirements increase with advancing age, in part due to reduced calcium absorption and decreased renal calcium conservation. However, calcium supplementation by itself is not effective in preventing the accelerated bone loss that occurs in the first few years after menopause. Ten years postmenopausally, calcium supplementation again becomes effective in reducing age-related bone loss.7 While consuming an adequate amount of calcium is important, it is too often overemphasized, supplemented at excessive doses, and is only one of many nutritional and lifestyle factors that play a role in promoting bone health.
Vitamin D enhances intestinal calcium absorption, thereby contributing to a favorable calcium balance in the body. Increased calcium absorption also reduces parathyroid-hormone-mediated bone resorption. In the United States, most infants and young children have adequate vitamin D consumption from fortified milk. During adolescence, however, the consumption of dairy products drops off, and inadequate vitamin D intake is more likely to adversely affect calcium absorption.
Several large randomized controlled trials have found that the combination of calcium and vitamin D had no significant effect on fracture risk.1,8,5
However, a meta-analysis of randomized controlled trials in elderly postmenopausal women found that a dose of 700 – 800 IU per day of vitamin D was associated with significant reductions in the risk of hip and nonvertebral fractures.9 Especially in older women, vitamin D in combination with calcium supplementation reduced the rate of postmenopausal bone loss.10 Vitamin D has also been shown to improve muscle strength11 and balance12, thereby reducing the risk of falling.13
Magnesium is a cofactor for alkaline phosphatase, which plays a role in bone mineralization. Low magnesium status is common in women with osteoporosis, and magnesium deficiency is associated with abnormal bone mineral crystals.14 Some women with reduced bone mineral density do not have an increased fracture rate, possibly because their bone mineral crystals are of high quality, due in part to high levels of magnesium. In a group of postmenopausal women, supplementation with 250-750 mg per day of magnesium for 6 months, followed by 250 mg per day for 6-18 months, resulted in an increase in bone density in 71% of women. This increase was noteworthy, because it occurred without calcium supplementation.15
Strontium is a non-radioactive earth element physically and chemically similar to calcium. Strontium ranelate is the specific strontium salt used in clinical trials for osteoporosis, but this form of strontium is not available in the U.S. Strontium in large doses stimulates bone formation and reduces bone resorption. In a phase 2 clinical trial, 2 g per day of oral strontium ranelate (containing 680 mg per day of elemental strontium) for three years was shown to reduce the risk of vertebral fractures and to increase bone mineral density in 1,649 postmenopausal women with osteoporosis.16
In the first year, there was a 49% reduction in the incidence of vertebral fractures in the strontium ranelate group and 41% reduction at the end of three years. After adjusting for artifact effect on imaging, a 6.8% increase in bone mineral density was seen at the lumbar spine after 3 years of strontium supplementation.. There was also an 8.3% increase at the femoral neck, but there was insufficient data to adjust it for an artifact effect, and therefore it is not clear as to how accurate this is.
In a two year trial 353 postmenopausal women with osteoporosis and a history of at least one vertebral fracture received a placebo or one of three different doses of strontium: 170 mg per day, 340 mg per day or 680 mg per day.17 A small increase in lumbar bone mineral density was seen with each dose of strontium, but the difference compared with placebo was statistically significant only for the highest dose. The incidence of new vertebral fractures was lowest (38.8%) with the lowest dose of strontium, vs. 54.7%, 56.7% and 42.0% in the placebo, 340 mg per day and 680 mg per day groups, respectively.
Strontium chloride is the most common form of strontium used in U.S. supplements. This form of strontium has not been the subject of published research. Due to potential adverse effects of higher doses of strontium, including rickets, bone mineralization defects, and interference with vitamin D metabolism, it may be prudent to use low doses until more research is conducted.
Zinc is essential for the formation of osteoblasts and osteoclasts, and it enhances the biochemical action of vitamin D. Zinc is also is necessary for the synthesis of various proteins found in bone. Low zinc levels have been found in the serum and bone of elderly people with osteoporosis.18
A deficiency of copper is known to produce abnormal bone development in growing children, and may be a contributing cause of osteoporosis. In vitro studies have shown that copper supplementation inhibits bone resorption.19,20 In a double-blind trial, supplementation with 3 mg per day of copper for 2 years significantly decreased bone loss in postmenopausal women.21
A deficiency of manganese may be one of the lesser known but more important nutritional factors related to osteoporosis. Manganese deficiency causes a reduction in calcium deposition in bone. Manganese also stimulates mucopolysaccharide production, which provides a framework for the calcification process.22
Zinc, Copper, and Manganese
In a double-blind study of postmenopausal women, the combination of zinc, copper, manganese, and calcium appeared to be more effective than calcium alone for preventing bone loss in postmenopausal women.23
Boron supplementation reduces urinary excretion of calcium and magnesium and increases serum levels of 17beta-estradiol and testosterone in postmenopausal women.24 These observations suggest that boron supplementation could help prevent bone loss.
During bone growth and the early phases of bone calcification, silicon has an essential role in the formation of cross-links between collagen and proteoglycans. In animals, silicon-deficient diets have produced abnormal skull development and growth retardation,25 and supplemental silicon partially prevented trabecular bone loss in ovariectomized rats.26
Other Nutritional Factors
Folic Acid and Vitamin B12
Accelerated bone loss in menopausal women may in part be due to increased levels of h***cysteine, a breakdown product of methionine. H***cysteine has the potential to promote osteoporosis if it is not eliminated adequately. In a prospective study, women with high h***cysteine levels had almost twice the risk of nonvertebral osteoporotic fractures as did women with low h***cysteine levels. There was no association in that study between h***cysteine levels and bone mineral density at either the femoral neck or the lumbar spine, which suggests that the reduction in fracture risk was due to an improvement in bone quality.27 Folic acid promotes the remethylation of h***cysteine to methionine, and supplementing postmenopausal women with this nutrient results in significant reductions in h***cysteine levels. Vitamin B12 has also been shown to reduce h***cysteine levels.28 In a double-blind study of stroke victims with elevated h***cysteine levels, daily supplementation with 5 mg of folic acid plus 1,500 mcg of vitamin B12 for two years reduced hip fracture incidence by 78%, compared with placebo.29
Vitamin B6 also plays a role in h***cysteine metabolism. In people with the genetic disorder h***cystinuria, vitamin B6 supplementation reverses the elevated levels of h***cysteine.30 Animal studies have shown that vitamin B6 deficiency can prolong fracture healing time,31 impair cartilage growth, cause defective bone formation,32 and promote osteoporosis.33 Vitamin B6 may also influence progesterone production and exert a synergistic effect on estrogen-sensitive tissue. Laboratory evidence of low vitamin B6 status appears to be common, even among healthy individuals.34
Vitamin C promotes the formation and cross-linking of some of the structural proteins in bone. Animal studies have shown that vitamin C deficiency can cause osteoporosis35 and it has been known for decades that scurvy, a disease caused by vitamin C deficiency, is also associated with abnormalities of bone.
Vitamin K is required for the production of the bone protein, osteocalcin. Osteocalcin draws calcium to bone tissue, enabling calcium crystal formation. Osteocalcin provides the protein matrix for mineralization and is thought to act as a regulator of bone mineralization.36 Vitamin K plays a key role in the formation, remodeling, and repair of bone by attracting calcium to the site of this protein matrix.37 A low dietary intake of vitamin K seems to increase the risk of osteoporotic hip fractures in women, according to data from the Nurses' Health Study.38
There are various forms of vitamin K, but the human trials have been done on vitamin K1 (phylloquinone) and menaquinone-4, (MK4, a form of vitamin K2).
In a double-blind study, 452 men and women (ages 60-80 years) received a multiple vitamin/mineral supplement that provided 600 mg per day of calcium and 400 IU per day of vitamin D, plus either 500 mcg per day of vitamin K1 or no vitamin K1.39 Bone mineral density (determined by dual-energy x-ray absorptiometry) and bone turnover were measured at 6, 12, 24 and 36 months. There were no differences in bone mineral density at the femoral neck, lumbar spine, or total body, between the two treatment groups, indicating that vitamin K1 did not enhance the effects of calcium, vitamin D, and other nutrients in this patient population. In the double-blind ECKO trial,40 a daily 5-mg supplement of vitamin K1 for 2 to 4 years did not protect against age-related decline in bone mineral density in postmenopausal women with osteopenia, but significantly fewer women in the vitamin K group than in the placebo group had fractures.
Epidemiological evidence has shown associations between low dietary intake of vitamin K and increased bone loss in elderly men and women. A 2006 meta-analysis of 13 randomized controlled trials41 that gave vitamin K1 or menaquinone-4 (a form of vitamin K2) supplements for longer than 6 months reported data on bone loss and fracture rates. All but one study showed a reduction in bone loss with supplemental vitamin K. All 7 of the 13 studies that reported fracture data were in Japanese individuals and used menaquinone-4. Most of these trials used a high dose, 45 mg/day.
While the recommended dietary intake of vitamin K is 90-120 mcg per day, the optimal dose and form of vitamin K supplementation to achieve a protective effect on bone loss and fracture reduction is not known. The majority of studies used menaquinone-4 at doses approximately 400-fold higher than dietary recommendations for vitamin K1. An additional issue is that these studies have been conducted almost exclusively in Japanese postmenopausal women. This population group may have unique dietary, environmental, and/or genetic factors, so it is not clear whether the findings from these studies can be generalized to other populations. In contrast to the 7 positive Japanese studies, a double-blind trial in 381 postmenoapusal women received either phylloquinone 1 mg/day, MK4 45 mg/day or placebo for 12 months.42 No effect of phylloquinone or MK4 on the bone density of the lumbar spine or proximal femur was observed.
Two long-term trials have previously been done evaluating the effect of vitamin K1 supplementation on bone loss. In one study using 1 mg per day of vitamin K1 plus calcium and vitamin D for 3 years in postmenopausal women ages 50-60 years,43 bone loss was reduced at the femoral neck but there was no beneficial effect on spine bone density. In a second study,44 200 mcg per day of vitamin K1 plus calcium and vitamin D given for two years to non-osteoporotic women aged 60 years or older resulted in a modest increase in bone mineral density of the radius, but not the femoral neck.
Menaquinone-7 (a form of vitamin K2), which is derived from natto (fermented soybeans) has been found in animal studies to be more potent and more bioavailable, and to have a longer half-life, than menaquinone-4. In a study of Japanese postmenopausal women, a significant inverse association was found between natto consumption and the incidence of hip fractures.45
The most effective approach to osteoporosis is prevention. The risk of developing osteoporosis may be reduced by optimizing peak bone mass in the younger years and by minimizing subsequent bone loss in elderly women. In order to maximize peak bone mass (even in the context of hereditary and other non-modifiable risk factors), lifestyle habits, proper nutrition with a whole foods diet, moderate exercise, and avoiding tobacco and excessive alcohol consumption should begin during childhood and adolescence and continue throughout life. The physician is encouraged to maintain a key interest in dietary habits that promote optimal bone health, and include nutritional supplementation that may favorably alter patients' risk and provide optimal bone strength, bone architecture, and bone density with reduced risk for fractures later in life.
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