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From the Townsend Letter
February / March 2012

Women's Health Update
Osteoporosis: Therapeutic Interventions
by Tori Hudson, ND
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Osteoporosis is the most common bone disease in humans and poses a serious health threat for postmenopausal women. It is characterized by diminished bone strength, which leads to an increased risk of fracture. Bone mineral density (BMD) is a major determinant of bone strength and is the most commonly measured quality of bone. Osteoporosis is determined by bone densitometry and, according to the World Health Organization (WHO), is defined by a BMD T-score less than or equal to −2.5 at the total hip, femoral neck, or lumbar spine (with at least two vertebral levels in the posteroanterior position) in a postmenopausal woman or a man over age 50.1,2 Most other organizations support this description. The presence of a fragility fracture also justifies a clinical diagnosis of osteoporosis.

Osteoporosis most commonly occurs in postmenopausal women, and the risk increases with age. Although the prevalence is 4% in women between 50 and 59 years of age, it rises to 52% in women age 80 and above.3 Osteoporosis of the hip occurs in 13% to 18% of white American women, and another 37% to 50% have low bone mass (often called osteopenia) of the hip.4

Osteoporosis is responsible for approximately 90% of all hip and spine fractures in white American women ages 65 to 84.5 However, most postmenopausal women who have fractures at any site do not actually have a diagnosis of osteoporosis.6

Hip fractures occur at age 82 on average and cause up to a 25% increase in mortality within 1 year of the fracture; an additional 25% of such patients require long-term care after a hip fracture, and 50% will have some long-term loss of mobility. The hip is not the only site where fractures result in serious morbidity. Vertebral fractures occur in a woman's mid-70s and cause significant pain as well as loss of height and an exaggerated kyphosis or deformity of the thoracic spine. In addition to pain, vertebral fractures of the thoracic or lumbar region or both can cause restricted range of motion, changes in posture, restricted lung function, and digestive problems. Other tolls can accumulate because of osteoporosis. Depression, anxiety, low self-esteem, changed body image, and loss of independence are other burdens of this disease. Once a vertebral fracture has occurred, there is at least a five- to sevenfold increase in the risk of subsequent vertebral fractures.7,8

Economically, osteoporosis imposes enormous costs – estimated at $14 billion annually – on the health-care system. Hip fractures are the most costly, owing to the expense of initial hospital care, first-year postfracture care, and long-term treatment.

Although it is not commonly recognized, men are also at risk of osteoporosis as they age. Hip fractures in men account for one-third of all hip fractures and have a higher mortality than those in women.9

Therapeutic Considerations
Osteoporosis is a complex condition involving medical, genetic, hormonal, lifestyle, nutritional, and environmental factors. A comprehensive plan that addresses these factors offers the greatest protection.

The primary goals in the treatment and prevention of osteoporosis are as follows:

  • preserve adequate bone mass
  • preserve bone strength
  • prevent skeletal fragility
  • prevent deterioration of the microarchitecture
  • prevent or reduce the risk of fractures

The primary role of alternative therapies is to prevent osteoporosis and, fortunately, osteoporosis is largely a preventable disease. Alternative therapies can also be considered part of a strategy to slow progression of bone loss and to reduce fractures. It is important to identify women who are at risk for not only osteoporosis, but more important, fractures. Alternative therapies alone may not be prudent in women at higher risk for fractures. Pharmacologic therapy reduces the risk of vertebral and hip fractures by about 50%. According to the North American Menopause Society and its 2010 position statement on osteoporosis, the following guidelines are indications for pharmacologic therapy10:

  • all postmenopausal women who have had an osteoporotic vertebral or hip fracture
  • all postmenopausal women who have BMD values consistent with osteoporosis (i.e., BMD T-score values equal to or worse than -2.5) at the lumbar spine, femoral neck, or total hip region
  • all postmenopausal women who have T-scores from −1.0 to −2.5 and a 10-year risk based on the FRAX calculator of major osteoporotic fracture (spine, hip, shoulder, or wrist) of at least 20% or of hip fracture of at least 3%

Individuals with secondary causes of bone loss require individualized management. Older postmenopausal women with a history of a previous nontraumatic nonpathologic vertebral fracture are at high risk of having another spine or hip fracture. These women in particular are candidates for treatment with proven conventional pharmacologic treatments regardless of their bone density.

Many pharmacologic therapies are available for osteoporosis treatment, including bisphosphonates, the selective estrogen receptor modulator (SERM), raloxifene, parathyroid hormone, estrogens, and calcitonin. There are currently no prospective studies comparing these therapies for antifracture efficacy. All of the therapies mentioned above except estrogen have been studied for their effect on fracture only in patients with either a clinical or BMD diagnosis of osteoporosis. With all of these therapies, the absolute reduction in fracture risk is greatest in women who are at high risk for a fracture

Pharmacologic Therapy
Hormone Replacement Therapy
As estrogen levels decline, bone remodeling increases and bone resorption outpaces bone formation. Both estrogen replacement therapy (ERT) and hormone replacement therapy of estrogen/progestogens (HRT) reduce the rate of bone turnover and resorption.11

ERT can return the high resorption rates in postmenopausal women to those of the rates in premenopausal women. Long-term data on the effects of ERT and HRT on bone density and fracture risk come mainly from observational and epidemiologic studies. Epidemiologic research found a 54% reduction in risk of fractures in current users of ERT/HRT compared with those who never used it.12 Researchers also found that ERT/HRT is more effective in reducing the fracture risk if it is begun within 5 years of menopause. If it was used more than 10 years earlier, it produced an even greater risk reduction – 75% for wrist fractures and 73% for hip fractures.

A 2002 meta-analysis of 57 randomized clinical trials of systemic oral or transdermal estrogen and estrogen/progestogen at standard doses found BMD increases at all sites in postmenopausal women.13 In trials of 2 years in length, the average difference in BMD after estrogen or estrogen/progestogen was 6.8% at the lumbar spine and 4.1% at the femoral neck.

The two largest and best-controlled trials are the Postmenopausal Estrogen/Progestin Interventions (PEPI) trials and the Women's Health Initiative (WHI). In the PEPI trials, 0.625 mg daily doses of conjugated equine estrogens with or without a progestogen (either medroxyprogesterone acetate or oral micronized progesterone) for 3 years significantly increased spinal BMD by 3.5% to 5.0%; there was also a 1.7% increase in hip BMD.14 In the WHI, a 5-year randomized controlled trial, HRT significantly increased spine BMD by 4.5% and total hip BMD by 3.7% in comparison with placebo; it also reduced the risk of hip fractures (34%), vertebral fractures (34%), and total body fractures (24%).15

Dosages even lower than the standard dosages of estrogen have produced significant increased in spine and hip BMD in the range of 1% to 3%, as has systemic estrogen via a vaginal ring (the Femring).16-21

In addition to increases in BMD, randomized trials and observational studies have indicated that standard doses of estrogen or estrogen/progestogen reduce fracture risk in postmenopausal women. Two meta-analyses found up to a 27% reduction in fracture risk.22,23 Two large observational studies, the National Osteoporosis Risk Assessment study of over 200,000 women and the Million Women Study of over 138,000 women, both reported significantly reduced risks for fractures.24,42 Despite these studies and more, estrogen-only or estrogen-plus-progestogen products are approved for prevention but not treatment of postmenopausal osteoporosis.

Now more than ever, it is important to individualize treatment options and more clearly identify the risk-benefit ratio. Generally, ERT/HRT is believed to work best during the first 5 to 10 years after menopause. The optimal duration and maximal duration have not yet been clearly determined and for this reason, in the face of the studies that show slight increases in risk of breast cancer and other potential issues, ERT/HRT will not be seen as a primary long-term treatment for osteoporosis except in those who do not tolerate bisphosphonates or who have menopausal symptoms that are not responding to other therapies.

This is a class of drugs that work by inhibiting osteoclast activity, thereby reducing bone resorption. Clinical trials demonstrate that bisphosphonates can significantly increase BMD at the spine and hip in postmenopausal women no matter their age. Bisphosphonates have been shown to reduce the risk of vertebral fractures in women with osteoporosis by 40% to 70% and to reduce the incidence of hip fracture and other nonvertebral fractures by about half of this.25,26 Most of the bisphosphonates available in the US (alendronate, ibandronate, and risedronate) are intended for use in daily or intermittent oral doses. Zoledronic acid is available as an intravenous injection. Clinical trials that have demonstrated BMD responses show similar results for weekly oral dosing regimens of alendronate and risedronate, monthly oral dosing of ibandronate and risedronate, and intravenous dosing every 3 months of ibandronate.27-30

Bisphosphonates are not without problems, and they should be used with careful consideration – both for their potential benefit in women who have osteoporosis and are at higher risk for fracture (especially as they get older) and for their potential risk. Some questions have arisen regarding the quality of the bone and possibly increased fractures with bisphosphonates in longer-term use and in some individuals.31 There may be the potential for oversuppression of bone turnover with long-term therapy, resulting in a more brittle bone. Individual cases and small case series with unusual, poorly healing fractures have been reported recently, as well as atypical fractures of the femur. Research is under way to determine what is unique to these rare individuals.

Osteonecrosis of the jaw (ONJ) has been observed with bisphosphonate use.32 This has occurred mainly in individuals on high-dose intravenous bisphosphonates and in those being treated with radiation for head and neck cancers. ONJ is characterized by a delay in healing of an oral lesion after surgery or extraction for more than 6 to 8 weeks. The incidence of ONJ with intravenous bisphosphonates in those without neck radiation has been reported to be as high as 12%. Oral incidence is much lower, at 0.03% to 0.06%. However, oral surgery increases the incidence sevenfold.33 Currently there is controversy in the research on whether to discontinue bisphosphonate therapy before dental extraction. Many practitioners are recommending suspending bisphosphonate therapy until the oral lesion has healed.

Although this effect is not common, long-term bisphosphonate use is also associated with insufficiency fractures of the femoral shaft, which commonly presents with prodromal thigh pain and may be bilateral.34 This is one reason why the use of bisphosphonates is now being recommended for a maximum of 5 years, which then allows bone remodeling.35 Bone density should monitored closely to ensure stable or minimal bone loss after discontinuation. It appears that 5 years of use may provide long-term fracture protection just as effectively as if the drug were taken for more than 5 years.

Oral bisphosphonates may cause other problems such as upper gastrointestinal disorders, including dysphagia, esophagitis, and esophageal and gastric ulcers. All bisphosphonates carry precautions regarding hypocalcemia and renal impairment. There can also be a transient flulike illness, although infrequently, with large doses of oral or intravenous bisphosphonates. How and when to take these drugs require careful following of the directions.

In total, this class of drugs is an important option for selected individuals – they can be life-altering in terms of relieving pain and suffering and saving lives (especially in the case of hip fractures). Clinicians should become familiar with the FRAX tool for determining fracture risk in those who have low bone density but not osteoporosis; they should also inform themselves of the full scope of benefits and risks so as to be able to advise their patients. With proper care and monitoring for potential adverse events and loss of bone remodeling, bisphosphonates can be used when truly indicated and without adequate or appropriate alternative options in the context of a holistic/integrative approach to bone health and fracture protection.

Selective Estrogen-Receptor Modulators
Selective estrogen-receptor modulators (SERMs) are nonsteroidal estrogen agonists and/or antagonists. Raloxifene, at a dose of 60 mg/day, is approved for the prevention and treatment of osteoporosis. Currently this is the only SERM approved for the treatment of osteoporosis. In a 20-year study, raloxifene at 60 mg/day significantly improved BMD at the lumbar spine by 1.6% and at the femoral neck by 1.2%.36 In the Multiple Outcomes of Raloxifene Evaluation trial, 3 years of raloxifene therapy at 60 mg/day in postmenopausal women increased BMD by 2.6% at the spine and 2.1% at the femoral neck.37

Parathyroid Hormone
Parathyroid hormone is given by subcutaneous injection once daily. This anabolic agent stimulates osteoblastic bone formation and increases trabecular bone density in women with osteoporosis.38-40 One medication in particular, teriparatide (Forteo), is approved for the treatment of osteoporosis in postmenopausal women. Nineteen months of teriparatide treatment (20 mcg/day) increased bone density in the spine by 8.6% and in the femoral neck by 3.5% compared with placebo.40 In addition, the incidence of new vertebral fractures was reduced by 65% and nonvertebral fractures by 53%.

Calcitonin is approved for postmenopausal osteoporosis treatment but not prevention. It is available as a nasal spray and a subcutaneous injection. In the randomized controlled trial Prevent Recurrence of Osteoporotic Fractures (PROOF), an intranasal spray containing calcitonin (delivering 200 IU/day) was used for 5 years by postmenopausal women with osteoporosis; this was found to reduce the risk of new vertebral fractures by 33% compared with placebo.41 No effect was seen on hip or nonvertebral fractures. Calcitonin spray may also be helpful in women with osteoporosis in that it can reduce bone pain from vertebral compression fractures.

New Therapies Being Researched
New drugs and treatments are being developed all the time, although some of them are not currently available in the US, such as tibolone and oral strontium ranelate (Protelos). Denosumab (Prolia), a human monoclonal antibody to receptor activator of the nuclear factor-kB ligand, has recently been approved and is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, have a history of an osteoporotic fracture, or have failed or are intolerant of other osteoporosis therapies. Other drugs are in development, including SERMs and full-length parathyroid hormone.

Lifestyle Factors
Certain lifestyle factors significantly affect bone health, but lifestyle approaches alone are not sufficient to prevent bone loss or fractures. Whether adequate alone or not, they do provide the foundation for nonpharmacologic and pharmacologic approaches to the prevention and management of osteoporosis. While this is not the focus of this article, nor is there space to refer to the in-depth research in many areas, including soy intake and exercise, readers should know a few basics. Smoking can lead to lower bone loss, more rapid bone loss, and higher fracture rates. Excess alcohol can increase the risk of falls and increase fracture rates.

Physical fitness is a major determinant of bone density, and certain kinds of exercise can slow bone loss and increase bone mass. Strength training has small but meaningful benefits to bone mass. In a meta-analysis of postmenopausal women, those who exercised increased their spine BMD by approximately 2%.42

Although nutritional factors are important, an effective regimen for strengthening bones and reducing fractures would fall short if it did not emphasize physical activity. Weight-bearing exercises can be simple, such as walking or tai chi. Strength-training exercises can also be simple, with home barbells or resistance bands. Women with osteoporosis should consult resources that give guidance about effective exercises, safe activities, and exercises to be avoided.

Many dietary factors can influence bone health. General guidelines are thought to include: adequate calcium, low phosphorus, average protein (not too high, not too low), lower salt, and lower sugar. Vegetarian diets appear to be beneficial to bone density and slowing of bone loss. The research on soy is fairly extensive and contradictory, but there is plenty of evidence to show at least small benefits.

Nutritional Supplementation
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 BMD 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 WHI study, there was no clear evidence that higher calcium intake decreased fracture risk.43 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.44 In a 2004 meta-analysis of randomized controlled trials, supplementation with 500 to 2000 mg/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.45 Two trials within this meta-analysis suggested a modest and nonsignificant benefit with calcium supplementation and the risk of nonvertebral fractures. In the WHI, which enrolled more than 36,000 postmenopausal women, supplementation with 1000 mg/day of calcium and 400 IU/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.46

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.47 In a study by Elders et al., a significant decrease in vertebral bone loss was observed with supplementation of 1000 to 2000 mg/day of calcium for 1 year.48 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 owing 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.49 Although consuming an adequate amount of calcium is important, it is too often overemphasized and supplemented at excessive doses, since calcium is only one of many nutritional and lifestyle factors that play a role in promoting bone health.

Vitamin D
Vitamin D enhances intestinal calcium absorption, thereby contributing to a favorable calcium balance. Increased calcium absorption also reduces parathyroid-hormone–mediated bone resorption. In the US, most infants and young children receive adequate vitamin D from fortified milk. During adolescence, however, the consumption of dairy products drops off and inadequate vitamin D intake is more likely to affect calcium absorption adversely.

Several large randomized controlled trials have found that the combination of calcium and vitamin D had no significant effect on fracture risk.43,47,50 However, virtually all of these use vitamin D dosages that were inadequate to raise serum 25(OH)D3 levels into the effective range.

Nonetheless, a meta-analysis of randomized controlled trials in elderly postmenopausal women found that a still inadequate dose of 700 to 800 IU/day of vitamin D was associated with significant reductions in the risk of hip and nonvertebral fractures.51 Especially in older women, vitamin D in combination with calcium supplementation reduced the rate of postmenopausal bone loss.52 Vitamin D has also been shown to improve muscle strength and balance, thereby reducing the risk of falling.53-55

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.56 Some women with reduced BMD do not have an increased fracture rate, possibly because their bone mineral crystals are of high quality owing in part to high levels of magnesium. In a group of postmenopausal women, supplementation with 250 to 750 mg/day of magnesium for 6 months followed by 250 mg/day for 6 to 18 months resulted in an increase in bone density in 71% of the women. This increase was noteworthy because it occurred without calcium supplementation.57

Strontium is a nonradioactive 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 US. Strontium in large doses stimulates bone formation and reduces bone resorption. In a phase 2 clinical trial, 2 g/day of oral strontium ranelate (containing 680 mg per day of elemental strontium) for 3 years was shown to reduce the risk of vertebral fractures and to increase BMD in 1649 postmenopausal women with osteoporosis.58

In the first year, there was a 49% reduction in the incidence of vertebral fractures in the strontium ranelate group and a 41% reduction at the end of 3 years. After adjusting for artifact effect on imaging, a 6.8% increase in BMD 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; therefore it is not clear 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.59 A small increase in lumbar BMD 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, versus 54.7%, 56.7%, and 42.0% in the placebo, 340 mg/day, and 680 mg per day groups respectively.

Strontium chloride is the most common form of strontium used in US supplements. This form of strontium has not been the subject of published research. Owing 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 has been 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.60

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.61,62 In a double-blind trial, supplementation with 3 mg/day of copper for 2 years significantly decreased bone loss in postmenopausal women.63

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.64

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.65

Boron supplementation reduces urinary excretion of calcium and magnesium and increases serum levels of 17 beta-estradiol and testosterone in postmenopausal women.66 These observations suggest that boron supplementation could help to 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, and supplemental silicon partially prevented trabecular bone loss in ovariectomized rats.67,68

Folic Acid and Vitamin B12
Accelerated bone loss in menopausal women may in part be due to increased levels of homocysteine, a breakdown product of methionine. Homocysteine has the potential to promote osteoporosis if it is not eliminated adequately. In a prospective study, women with high homocysteine levels had almost twice the risk of nonvertebral osteoporotic fractures as did women with low homocysteine levels. There was no association in that study between homocysteine levels and BMD at either the femoral neck or the lumbar spine, which suggests that the increase in fracture risk was due to poorer bone quality.69 Folic acid promotes the remethylation of homocysteine to methionine, and supplementing postmenopausal women with this nutrient results in significant reductions in homocysteine levels.70 Vitamin B12 has also been shown to reduce homocysteine levels. In a double-blind study of stroke victims with elevated homocysteine levels, daily supplementation with 5 mg of folic acid plus 1500 mcg of vitamin B12 for 2 years reduced hip fracture incidence by 78% compared with placebo.71

Vitamin B6
Vitamin B6 also plays a role in homocysteine metabolism. In people with the genetic disorder homocystinuria, vitamin B6 supplementation reverses the elevated levels of homocysteine.72 Animal studies have shown that vitamin B6 deficiency can prolong fracture healing time, impair cartilage growth, cause defective bone formation, and promote osteoporosis.73-75 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.76

Vitamin C
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 osteoporosis, and it has been known for decades that scurvy, a disease caused by vitamin C deficiency, is also associated with abnormalities of bone.77

Vitamin K
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.78 Vitamin K plays a key role in the formation, remodeling, and repair of bone by attracting calcium to the site of this protein matrix.79 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.80

There are various forms of vitamin K, but the human trials have been done on vitamin K1 (phylloquinone), MK4, (MK4, a form of vitamin K2), and menaquinone-7 (longer-chain MK7).

In a double-blind study, 452 men and women (aged 60–80 years) received a multivitamin/multimineral supplement providing 600 mg/day of calcium and 400 IU/day of vitamin D, plus either 500 mcg/day of vitamin K1 or no vitamin K1.81 BMD (determined by DEXA) and bone turnover were measured at 6, 12, 24, and 36 months. There were no differences in BMD 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, or other nutrients in this patient population. In the double-blind ECKO trial, a daily 5 mg supplement of vitamin K1 for 2 to 4 years did not protect against an age-related decline in BMD in postmenopausal women with osteopenia, but significantly fewer women in the vitamin K1 group than in the placebo group had fractures.82

Epidemiologic 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 trials that gave vitamin K1 or MK4 supplements for longer than 6 months reported data on bone loss and fracture rates.83 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 MK4. Most of these trials used a high dose, 45 mg/day.

Although the recommended dietary intake of vitamin K is 90 to 120 mcg/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 MK4 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 be influenced by 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 seven positive Japanese studies, in a double-blind trial, 381 postmenopausal women received phylloquinone 1 mg/day, MK4 45 mg/day, or placebo for 12 months.84 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/day of vitamin K1 plus calcium and vitamin D for 3 years in postmenopausal women aged 50 to 60 years, bone loss was reduced at the femoral neck, but there was no beneficial effect on spinal bone density.85 In a second study, 200 mcg/day of vitamin K1 plus calcium and vitamin D given for 2 years to nonosteoporotic women aged 60 years or above resulted in a modest increase in BMD of the radius but not the femoral neck.86

MK7 is found in natto (highest concentration in fermented soybeans) and cheese and in lower concentrations in meat and other dairy products; a very small amount is produced by gut bacteria from dietary vitamin K1.87 MK7 has been found in animal studies to be more potent and more bioavailable as well as to have a longer half-life than MK4. When taken as a daily supplement (0.22 µmol/day), MK7 is more effective than K1 in carboxylating osteocalcin. This is thought to be due to MK-7's much longer residence time and the higher serum concentrations of MK7 achieved during its prolonged intake.88 The longer-chain menaquinones such as MK7 are much more hydrophobic, which contributes to their much longer half-lives (8 hours for K1 and MK4 vs. 96 hours for MK7).89 In a study of Japanese postmenopausal women, a significant inverse association was found between natto consumption and the incidence of hip fractures.90 In a study of osteoporosis after organ transplantation, 1 year of MK7 supplementation (180 mcg/day) resulted in increased bone mineralization compared with placebo.91 However, a study of early menopausal women given 1 year of supplementation of 360 mcg/day of MK7 in the form of natto capsules did not show a significant improvement in bone density despite a reduction in uncarboxylated osteocalcin.92 A likely reason for these inconsistent results is the confounding effect of vitamin D status. The study in posttransplant patients noted a high incidence of vitamin D deficiency, which was found to affect the results.

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 minimizing subsequent bone loss in elderly women. To maximize peak bone mass (even in the context of hereditary and other nonmodifiable risk factors), lifestyle, proper nutrition with a whole-foods diet, and moderate exercise should begin during childhood and adolescence; thereafter the avoidance of smoking and excessive alcohol consumption should be added to this regimen 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 lower patients' risk and provide optimal bone strength, bone architecture, and bone density, thus reducing the risk of fractures later in life.

Tori Hudson, ND

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