Chapter 194 Osteoporosis
Diagnostic Summary
General Considerations
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 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, restricted range of motion, changes in posture, restricted lung function, and digestive problems can all be caused by vertebral fractures of the thoracic or lumbar region or both. 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 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
Pathophysiology
The process of bone resorption (breakdown) and bone formation is called bone remodeling. Osteoclasts stimulate the production of acids and enzymes that dissolve minerals and protein in bone and thus promote bone resorption. Osteoblasts create a protein matrix primarily of collagen, resulting in the remineralization of the bone and thereby promoting bone formation. Bone remodeling is normally a balance of bone resorption and bone formation. An imbalance between bone removal and bone replacement results in bone loss and an increase in the risk of bone fracture.
In childhood, bone mass rapidly increases and then slows in the late teens, but it continues to increase during the 20s. In women, the bone-building process is nearly complete by age 17. After achieving a peak bone mass, around age 28, women slowly lose an average of 0.4% of bone mass in the femoral neck each year. After menopause, the rate of loss is faster, with an average 2% loss annually during the first 5 to 10 years. Bone loss continues in older women past age 70 but at a much slower rate.
Risk Factors
Risk factors for osteoporosis are distinguished from risk factors for osteoporotic fracture. Major risk factors for osteoporosis in postmenopausal women are advanced age, genetics, lifestyle issues (low calcium, low vitamin D intake, and smoking), thinness, and menopausal status. The most common risk factors are as follows:
• Thinness—weight below 127 pounds
• Parental history of hip fracture
• Long-term use of glucocorticoids
• Other causes of secondary osteoporosis (e.g., primary hyperparathyroidism, renal calcium leak)
Genetic Factors
The level of peak bone mass is greatly influenced by genetic factors. Earlier studies suggest that up to 80% of the determination of peak bone mass might be due to genetic factors.10-12 Young daughters of women with osteoporotic fractures have lower bone mass compared with other children their age, and first-degree relatives of women with osteoporosis tend to have lower bone mass when compared with other women who do not have such a family history.13 A history of fracture in a first-degree relative also increases fracture risk. A family history of fracture was found to be associated with a significant increase in osteoporotic fractures at any site.14 In this same meta-analysis, hip fractures were almost 50% higher if a family had a history of fractures and 127% higher if a hip fracture had occurred in a parent. The greater bone mass of black women compared with white women also suggests a genetic influence.
One key genetic factor now being recognized is polymorphisms of the vitamin D receptor site. Some of these polymorphisms significantly increase the need for vitamin D.
Vitamin D Deficiency
The importance of vitamin D sufficiency in bone health has been underappreciated in the past. Emerging research is showing a direct correlation between both bone density and serum 25(OH)D3, with a corresponding inverse correlation with fractures of virtually all types.15
Lifestyle
Calcium and vitamin D intake, exercise, age at menarche, menstrual regularity, and alcohol and tobacco use also affect peak bone mass. All women lose bone mass in menopause, but several lifestyle factors affect the risk of developing osteoporosis, including physical activity, animal protein intake, acid-base homeostasis, calcium and vitamin D intake, smoking, and alcohol consumption. In order for a woman to achieve her genetically determined peak bone mass, she requires a balanced diet including adequate calories, protein, and calcium.16 Good nutrition throughout life is necessary to maintain bone mass and strength. Adequate calcium and vitamin D have crucial roles in maintaining bone mass in older women. Calcium requirements change with age; during and after menopause, the need for calcium increases. After age 65, women absorb 50% less calcium than younger women. The renal enzymatic activity that produces vitamin D metabolites and thus controls calcium absorption also decreases.
Dietary Protein
Not all studies have been consistent regarding whether or not excess dietary protein contributes to osteoporosis. The Nurses’ Health Study showed that a high intake of animal protein but not plant protein was associated with an increased risk of forearm fracture.17 Diets high in red meat are acid producing, and salts from bone may be mobilized to balance the acid and maintain the acid-base homeostasis the body requires. Diets high in fruits, vegetables, and plant proteins are alkaline forming.
Smoking
Female smokers tend to lose bone more rapidly and have a lower bone mass than those who do not smoke.18,19 Some studies show that smokers also have a higher fracture rate.20,21 In addition, female smokers reach menopause up to 2 years earlier than nonsmokers. It may be that smoking interferes with estrogen metabolism, although the mechanism is not clearly known.
Alcohol
Alcohol consumption of 7 ounces or more daily, which is considered heavy, has been shown to increase the risk of falls and hip fractures. However, moderate alcohol consumption seems to lower the risk of hip fractures in older women.11 It is thought that moderate amounts of alcohol inhibit bone resorption by increasing estradiol concentrations and calcitonin excretion.22,23
Physical Activity
The effect of physical activity on the risk of osteoporosis cannot be overlooked. Highly active individuals have higher bone mass,24 and those who have undergone prolonged bed rest or are confined to a wheelchair experience a rapid and dramatic loss of bone. Exercise functions primarily to reduce osteoporosis risk by stimulating osteoblasts.
Hormonal Factors
A woman’s hormonal status clearly influences bone mass and the rate of bone resorption. At menopause, all women lose bone, and this loss is especially accelerated in the first 5 years. The drop in estrogen production that comes with menopause, no matter the age, increases the rate of bone resorption. The earlier that occurs before the average age of menopause (51 years), the sooner the bones lose the protective effect of endogenous estrogen.
Women who have premature menopause (before age 40), late onset of menarche in adolescence, surgical menopause, or experienced periods of amenorrhea due to low estrogen levels in their reproductive years (ex/hypothalamic amenorrhea), are at greater risk of osteoporosis if they have not taken longer term estrogen replacement therapy. Women who had missed up to half of their expected menstrual periods had 12% less vertebral bone mass than did those with normal menstrual cycles; those who missed more than half had 31% less bone mass than healthy controls.25
The concentration of calcium in the blood is strictly maintained within narrow limits. If levels start to decrease, there is an increase in the secretion of parathyroid hormone by the parathyroid glands and a decrease in the secretion of calcitonin by the thyroid and parathyroids. If calcium levels in the blood start to increase, there is a decrease in the secretion of parathyroid hormone and an increase in the secretion of calcitonin. An understanding of how these hormones increase (parathyroid hormone) and decrease (calcitonin) serum calcium levels is necessary in order to understand osteoporosis.
Parathyroid hormone increases serum calcium levels primarily by increasing the activity of the osteoclast catabolism of bone, although it also decreases the excretion of calcium by the kidneys and increases the absorption of calcium in the intestines. In the kidneys, parathyroid hormone increases the conversion of 25-(OH)D3 to 1,25-(OH)2D3.
Additional Factors
No one risk factor or combination of risk factors will accurately predict which patients will or will not experience osteoporosis or osteoporotic fractures. The more risk factors present, the greater the potential for lower bone mass and the higher the risk of fracture. Risk factors alone do not provide adequate assessment of low bone mass but rather are important guides in the clinical assessment of osteoporosis and fracture risks, and these contribute to optimal preventive strategies. Ultimately, an individual woman’s risk of fracture is the most relevant parameter for her future with regard to osteoporosis. Various medical conditions and medications can interrupt normal bone physiology and lead to osteoporosis. Endocrine disorders, malignancies, and collagen metabolism disorders can have a direct effect on the ability of bones to remodel.
Diagnostic Considerations
All postmenopausal women should be assessed for risk factors associated with osteoporosis. This assessment requires a history, physical examination, and diagnostic tests. The more recent World Health Organizations (WHO) FRAX risk factors (personal history of fracture after age 40, history of hip fracture in a parent, current cigarette smoking, excess alcohol consumption, glucocorticoid use, rheumatoid arthritis or other secondary causes of osteoporosis), bone density testing and the FRAX risk calculator are tools used to establish risk of fracture. The FRAX risk calculator is used for postmenopausal women who have low bone density but not osteoporosis. It determines the 10-year probability of any osteoporotic fracture and 10-year probability of a hip fracture. The FRAX risk calculator is available online. The goals of evaluation should be to identify those women at risk for osteoporosis or fracture; establish a diagnosis of osteoporosis, determine the severity of the diagnosis, or both; rule out secondary causes of bone loss in patients with osteoporosis; and identifying risk factors for falls and injuries.
The history and physical examination should focus on identifying the woman’s risk factors. There can be physical signs of osteoporosis. Loss of height greater than 1.5 inches may be associated with compression of vertebrae due to fractures on the anterior vertebral body. Measurement of height annually is the simplest of procedures that can be used to identify the risk of osteoporosis. Excessive kyphosis of the thoracic spine, dowager’s hump, dental caries, tooth loss, receding gums, and back pain should raise suspicion of osteoporosis. Weight should also be recorded to identify women with low BMI and thus increased risk for low bone density. Other aspects of evaluation should including the solicitation of acute or chronic back pain, signs of percussion tenderness on exam, and bone density testing. The risk of falls should be assessed and is increased by the following: medications that affect balance and coordination, muscle weakness, impaired vision, a history of falls/fainting or loss of consciousness, difficulty standing or walking, arthritis of the lower extremities, and neuropathy of the lower extremities.
Bone Mineral Density Testing
BMD testing is the optimal method to establish a diagnosis of osteoporosis. There are several techniques to measure BMD, but the gold standard is dual energy x-ray absorptiometry (DEXA).26 Other methods of assessing bone mass include computed tomography (CT), ultrasounds of the heel, and radiographs, none of which is as useful for diagnosis and follow-up as the DEXA scan. The tests that measure BMD and their relative accuracy are shown in Table 194-1.
TABLE 194-1 Comparison of Tests Measuring Bone Density
| METHOD | SITE AND ACCURACY |
|---|---|
| DEXA | Hip, spine, total body: 90%-99% |
| PDXA | Forearm, finger, heel: 90%-99% |
| SXA | Heel: 98%-99% |
| QUS | Heel, shin: not available |
| QCT | Spine: 95%-97% |
| PQTC | Forearm: 92%-98% |
DEXA, Dual-energy x-ray absorptiometry; PDXA, peripheral dual-energy x-ray absorptiometry; PQTC, peripheral quantitative computed tomography; QCT, quantitated computed tomography; QUS, quantitative ultrasound; SXA, single-energy x-ray absorptiometry.
Data from Jergas M, Genant HK. Current methods and recent advances in the diagnosis of osteoporosis. Arthritis Rheum 1993;36:1649-1662.
In addition to providing the most reliable measurement of BMD, the DEXA scan requires less radiation exposure than a conventional radiograph or CT scan. Usually the DEXA scan is used to measure the density of both the hip and the lumbar spine. The hip is the preferred site for BMD testing, especially in women above age 60, because—owing to extraosseous ossification—the spinal measurements can be unreliable. The spine is useful in early postmenopausal women because the rates of bone loss then are greater because of lower estrogen levels. Although peripheral DEXA sites are accurate, they may be less useful because they may not correlate as well with fracture risk and BMD at the hip and spine. The use of DEXA testing in a postmenopausal woman should be based on her risk profile. Testing is not indicated unless the test results will influence management. The North American Menopause Society has established the following guidelines to determine for indications for BMD testing:
• All women 65 years of age and older
• Postmenopausal women with secondary causes of bone loss (e.g., steroid use, hyperparathyroidism)
• Postmenopausal women age 50 and above with additional risk factors (fracture after menopause, thinness or weight below 127 pounds, history of hip fracture in a parent, current smoker, rheumatoid arthritis, alcohol intake of more than two units per day [one unit being equal to 12 ounces of beer, 4 ounces of wine, or 1 ounce of liquor])
• Postmenopausal women regardless of age with postmenopausal fragility fractures, low body weight, or a family history of spine or hip fracture
Results of BMD tests are reported as standard deviations—either a Z-score or a T-score. A Z-score is based on the standard deviation from the mean BMD of women in the same age group. A T-score is based on the mean peak BMD of a normal young woman. The WHO criteria for the diagnosis of osteoporosis are based on T-scores, as shown in Table 194-2.
TABLE 194-2 Interpretation of Bone Mineral Density Score
| STATUS | T-SCORE | INTERPRETATION |
|---|---|---|
| Normal | Above -1 | BMD within 1 SD of a young normal adult’s T-score |
| Osteopenia | Between -1 and -2.5 | BMD between 1 and 2.5 SD below a young normal adult’s T-score |
| Osteoporosis | Below -2.5 | BMD 2.5 SD or more below a young normal adult’s T-score |
BMD, Bone mineral density; SD, standard deviation.
Laboratory Tests of Bone Metabolism
Biochemical markers of bone turnover appeal to some practitioners. A urine test measures the breakdown products of bone, such as cross-linked N-telopeptide of type I collagen or deoxypyridium. These tests measure bone turnover and can be correlated with the rate of bone loss, but they are not intended to be used for the diagnosis of osteoporosis or monitoring of bone loss. Such tests may be used to monitor the success (or failure) of therapy. They provide quicker feedback compared with DEXA, with which it can take up to 2 years to detect a therapeutic response. The DEXA test is best used to measure bone density, whereas urinary bone resorption assessments can be used to measure the rate of bone turnover. The reduction of urinary levels of these markers of bone breakdown over a 2-year period has produced increases in bone density measurements,27 but the value of these markers in clinical practice has yet to be definitively confirmed.
Additional tests may be used to determine secondary causes of bone loss. These include serum calcium, 24-hour urinary calcium, parathyroid hormone, thyroid-stimulating hormone, free thyroxine level, serum albumin, serum alkaline phosphatase, erythrocyte sedimentation rate, complete blood cell count, and 25(OH)D3 levels.
Management Approaches Based on Testing
A therapeutic and management strategy focusing on lifestyle and supplementation may be all that is necessary for postmenopausal women who have been determined to be at low risk for osteoporotic fractures. The North American Menopause Society recommends adding proven osteoporosis drug therapy for the following patients:
1. All postmenopausal women who have had an osteoporotic vertebral or hip fracture
2. All postmenopausal women who have BMD values equal to or less than -2.5 at the lumbar spine, femoral neck, or total hip region.
3. 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 a hip fracture of at least 3% are at high risk, and drug therapy is recommended.
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:
The primary role of alternative therapies is to prevent osteoporosis and, fortunately, osteoporosis is largely a preventable disease. Pharmacologic therapy reduces the risk of vertebral and hip fractures by about 50%. According to the North American Menopause Society and their 2010 position statement on osteoporosis, the following guidelines are indications for pharmacologic therapy28:
• 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 less 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 proved 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 anti fracture 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) with estrogen only and hormone replacement therapy (HRT), with estrogen and progestogen, reduce the rate of bone turnover and resorption.29
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.30 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.31 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.32 In the 5-year randomized controlled trial, the WHI 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%).33
Doses even lower than the standard dosages of estrogen have produced significant increased in spine and hip BMD in the range of 1% to 3%,34-38 as has systemic estrogen via a vaginal ring (the Femring).39
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.40,41 Two large observational studies, the National Osteoporosis Risk Assessment study42 of over 200,000 women and the Million Women Study43 of over 138,000 women both reported significantly reduced risks for fractures. 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.
Bisphosphonates
This class of drugs is thought to 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.44,45 Most of the bisphosphonates available in the United States (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.46-49
Bisphosphonates are not without problems and they should only 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 for serious risk. Some questions have arisen regarding the quality of the bone and possibly increased fractures with bisphosphonates in longer-term use in some individuals.50 There may be the potential for over suppression 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. Many clinicians are responding to these concerns by “drug holidays.” Understanding the frequency and duration of these drug holidays is under investigation in ongoing studies.
Osteonecrosis of the jaw (ONJ) has been observed with bisphosphonate use.51 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.52 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 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.53 This is one reason why the use bisphosphonates is now being recommended for a maximum of 5 years, which then allows bone remodeling.54 Bone density should be 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 the drug 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 requires careful following of the directions.
In total, this class of drugs is an important option for selected individuals—it 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 that have low bone density but not osteoporosis; they should also informed 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.
(The editors recommend using the bisphosphonates only if the natural interventions described in this chapter have not produced satisfactory results.)
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%.55 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.56
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.57-59 One medication in particular, teriparatide (Forteo) is approved for the treatment of osteoporosis in postmenopausal women. Nineteen months of teriparatide treatment (20 mcg/injection per day) increased bone density in the spine by 8.6% and in the femoral neck by 3.5% compared with placebo.59 In addition, the incidence of new vertebral fractures was reduced by 65% and nonvertebral fractures by 53%.
Calcitonin
Calcitonin is approved for postmenopausal osteoporosis treatment but not prevention. It is available as a nasal spray and a subcutaneous injection. The randomized controlled trial Prevent Recurrence of Osteoporotic Fractures (PROOF),60 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. 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 United States, 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.
Smoking tends to cause more rapid bone loss and lower bone mass. Smokers also tend to experience menopause 2 years earlier than nonsmokers.61-63
Postmenopausal smokers have higher fracture rates,64 and meta-analyses have suggested that hip fracture risk may be increased in current smokers.65 Such fractures may be a particular risk for women over the age of 60. The WHO reports that a history of smoking causes a substantial risk for future fracture independently of BMD.66
Moderate alcohol consumption is associated with an increased BMD in postmenopausal women,67,68 but alcohol consumption greater than seven units a week is associated with an increase risk of falls.69 It appears that consuming more than two units a day of alcohol is associated with an increased risk of osteoporotic fracture (one unit is the equivalent of 12 ounces of beer, 4 ounces of wine, or 1 ounce of liquor).70
Exercise
Numerous studies have demonstrated that physical fitness is the major determinant of bone density. Physical exercise consisting of 1 hour of moderate activity three times a week has been shown to prevent bone loss and actually increase bone mass in postmenopausal women.71-76 Both weight-bearing and strength-training exercises are beneficial to the development of bone and maintenance of bone health and function.77-79 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%.80
In surgically menopausal women who have used estrogen therapy, the addition of strength training provides further benefits to BMD compared with estrogen alone.81 If a particular exercise does not increase BMD, it can at least reduce the risk of falling and subsequent fractures. Muscle-strengthening and balancing exercises have been shown to reduce the risk of falls and fall-related injuries by 75% in women 75 years of age and older.82 In contrast to exercise, immobilization doubles the rate of urinary and fecal calcium excretion, resulting in a significant negative calcium balance.83 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.
General Dietary Factors
Many dietary factors have been suggested as causes of osteoporosis, including the following84-86:
A vegetarian diet (both lacto-ovo and vegan) is associated with a lower risk of osteoporosis.87,88 Although bone mass in vegetarians does not differ significantly from that in omnivores in the third, fourth, and fifth decades, there are significant differences in the later decades. These findings indicate that the decreased incidence of osteoporosis in vegetarians is not due to increased initial bone mass but rather to decreased bone loss.
Several factors are probably responsible for the decrease in bone loss observed in vegetarians. The most important of these is probably a lowered intake of protein. One point of view holds that a high-protein diet or a diet high in phosphates is associated with increased excretion of calcium in the urine. Raising daily protein from 47 to 142 g doubles the excretion of calcium in the urine.89 A diet this high in protein is common in the United States and may be a significant factor in the increasing number of people suffering from osteoporosis in this country. The opposing point of view is that high-protein diets resulting in increased urinary calcium excretion and increased acid production—in essence, a negative calcium balance—may result only if the daily calcium intake is inadequate. Rather than reduce protein intake, it would be advisable to increase calcium intake and increase the dietary intake of fruits and vegetables for their alkalinizing effect.90 A reasonable guide and compromise might be to assure a minimum of 20 g/day of protein, especially in elderly patients over age 80, and limit the upper end to 60 g or so.
The issue here is not protein per se but rather the pH effects of the diet. When the diet induces acidosis—which is typical of a diet high in protein and salt—the body maintains pH by buffering with calcium, which is taken from the bones. Although calcium supplementation can prevent bone loss, for those at risk and in excess doses, it poses an increase in calcium kidney stones. A possible strategy to reduce this risk of kidney stones is to supplement with calcium citrate.91
Gastric Acid
It has long been believed that the absorption of calcium depends on it becoming ionized in the intestines, largely on the basis of the secretion of gastric acid. Furthermore, it has been believed that the poor ionization of calcium is a major problem with calcium carbonate—the most widely used form of calcium for nutritional supplementation, as it has been thought that in order for calcium carbonate to be absorbed it must first be solubilized and ionized by stomach acid.
Although decreased gastric acidity may be seen in as many as 40% of postmenopausal women,91a a critical review of available human studies indicates that the effects of increased gastric pH are apparent only when poorly soluble calcium salts (like calcium carbonate) are taken after an overnight fast.92 In a fasting state, patients with insufficient stomach acid output can absorb only about 4% of an oral dose of calcium as calcium carbonate, whereas a person with normal stomach acid can typically absorb about 22%.93 Patients with low stomach acid secretion need a form of calcium that is already in a soluble and ionized state, such as calcium citrate, calcium lactate, or calcium gluconate. About 45% of the calcium is absorbed from calcium citrate in patients with reduced stomach acid, compared with an absorption of only 4% for calcium carbonate.92 However, when any form of calcium is taken with meals, there is little difference in its absorption even in elderly subjects with atrophic gastritis or those taking H2-receptor antagonists.
Sugar
Another dietary factor that increases the loss of calcium from the body is refined sugar. Following sugar intake, there is an increase in the urinary excretion of calcium.94 Considering that the average American consumes, in 1 day, 125 g of sucrose, 50 g of corn syrup, plus other refined simple sugars, and a glass of a carbonated beverage loaded with phosphates, along with the high amount of protein, it is little wonder that so many suffer from osteoporosis.
Soft Drinks
Soft drinks may be a major contributor to osteoporosis, as they are high in phosphates but contain virtually no calcium. This leads to lower calcium levels and higher phosphate levels in the blood. The United States ranks first among countries for soft drink consumption, with a per capita consumption of approximately 15 ounces a day.
The link between soft drink consumption and bone loss is going to be even more significant as children practically weaned on soft drinks reach adulthood. Soft drink consumption among children poses a significant risk factor for impaired calcification of growing bones. Because there is such a strong correlation between maximum BMD and the risk of osteoporosis, the rate of osteoporosis may eventually reach even greater epidemic proportions.
The severely negative effect that soft drinks have on bone formation in children was clearly demonstrated in a study that compared 57 children with low blood calcium, aged 18 months to 14 years, with 171 matched controls with normal calcium levels.95 The goal of the study was to assess whether the intake of at least 1.5 quarts per week of soft drinks containing phosphates is a risk for the development of low blood calcium levels. Of the 57 children with low blood calcium levels, 38 (66.7%) drank more than four bottles (12 to 16 ounces) per week, but only 48 (28%) of the 171 children with normal serum calcium levels drank as many soft drinks. For all 228 children, a significant inverse correlation between serum calcium level and the amount of soft drinks consumed each week was found.96
Green Leafy Vegetables
Consumption of green leafy vegetables (e.g., kale, collard greens, parsley, lettuce) offers significant protection against osteoporosis. These foods are a rich source of a broad range of vitamins and minerals that are important to maintaining healthy bones, including calcium, vitamin K1, and boron.
Soy Isoflavones
The potential for soy protein or soy isoflavones to alter bone metabolism and bone resorption is currently contradictory and inconclusive.97 The lack of agreement in the literature is thought to be related to variations in study design. These variations include differences in the dose and form of soy products studied (i.e., soy protein isolate, whole soy foods, or extracted soy isoflavones), differences in the menopausal status of the women studied (i.e., perimenopausal, early menopausal, or late postmenopausal), differences in the duration of the various trials, and differences in the tests used to assess bone density and bone metabolism. All of these different approaches and study designs make it very difficult to determine the effectiveness of soy for bone health and make the decision to include soy in a protocol for supporting bone health more difficult for the practitioner.
Soybeans contain a class of compounds called phytoestrogens, comprising mostly genistein, daidzein and glycitein, all of which have a biochemical structure similar to that of 17 beta-estradiol. The binding of isoflavones to estrogen receptors is preferential for the estrogen receptor beta and thus indicates that soy isoflavones act as selective estrogen modulators.98 Daidzein is similar in shape to a drug called ipriflavone, which is used in Europe to treat osteoporosis. In the United States, ipriflavone is available as a nutritional supplement.
BMD is the gold standard for determining fracture risk due to nontraumatic events. Bone turnover is an independent predictor of fracture risk.99
Although the research on the effects of soy on bone metabolism has been inconsistent, many positive studies exist that suggest a role for soy in slowing bone turnover and increasing bone density in women. According to some experimental evaluations, soy appears to have an estrogenic effect on bone. The bone density of ovariectomized rats was evaluated in a study in which soy replaced casein in the diet; these rats were then compared with another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as achieved with the estrogen treatment.100 Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen genistein in maintaining bone.101
These authors also reported that genistein suppresses osteoclasts, the cells responsible for bone resorption, both in the test tube and in vivo. Arjmandi also did a double-blind randomized, controlled trial using 40 g of soy protein containing isoflavones over 3 months in postmenopausal women.102 Bone resorption was decreased with soy protein as compared with milk protein.
Several human studies have provided further insight and comfort in the possible role of soy in our bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55 to 90 mg of soy isoflavones for 6 months.103
The placebo group showed the lowest bone density and the greatest bone loss, whereas the estrogen group showed the highest bone density and the slowest bone loss. The isoflavone diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip. Soy isoflavones seem to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soy did not show as great an ability to prevent bone loss as the estrogen group, but the positive effect it showed is encouraging.
An analysis of the relationship of soy isoflavone intake and BMD was conducted from the Study of Women’s Health Across the Nation, a U.S. cohort study of women aged 42 to 52 years.104
For African American and white women, median intakes of genistein were too low to be analyzed. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. The mean spinal bone density of those women in the highest group was 7.7% greater than that of women in the lowest group. Bone density of the femoral neck was 12% greater in the group with the highest intake versus that with the lowest.
Other positive studies on soy and bone density also give some credence to the role of soy and bone health. In a study estimating the daily intakes of soy isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption, high consumption of soy products was associated with increased bone mass.105
A recent meta-analysis further increases our optimism about using soy to inhibit bone resorption. Nine studies comprising a total of 432 menopausal women were evaluated in this meta-analysis.106
The amount of soy intake varied among the nine studies from 37 to 118 mg of isoflavones per day. Testing for urinary peptides (deoxypyridinoline), a marker of bone turnover, demonstrated that those who consumed isoflavones had a decrease in these biomarkers of 2.08 nmol/mmol compared with those who did not consume isoflavones. In five of the studies where isolated soy protein was used, there was no significant effect on urinary deoxypyridinoline. In the current analysis, a significant reduction in urinary deoxypyridinoline was not observed in those studies with isoflavones of less than 90 mg/day. In a review of the research in 2003, the author concluded that 90 mg/day of isoflavones day would be required to achieve benefits on bone health.107
In contrast to the positive studies, several clinical trials using a variety of soy protein isolate formulations found no clinically important effects of soy on bone metabolism or markers of bone turnover.108-110
Further inconsistent research can be seen with several clinical trials using soy protein or isoflavones that demonstrated a positive effect on BMD,111-115 whereas others had no positive findings.116,117
Variations in dosing, duration, soy formulation used, and different study populations are possible reasons for inconsistent results on the effects of soy isoflavones on bone turnover and bone density. But another significant consideration may be how the isoflavones are metabolized in the gut. In the meta-analysis mentioned above, which included nine studies,106 the significant effects on urinary peptides occurred in Asian women but not white women. This may be due to the conversion of daidzein into its active metabolite equol by intestinal flora and to the fact that only one third of white women can metabolize isoflavones into equol, whereas more than half of Asian women possess this ability.
Soy isoflavones may also have more of an effect in postmenopausal women than in pre- or perimenopausal women. In one study, 53.3 mg/day of isoflavones was associated with an increase in bone density in postmenopausal women but not in premenopausal women.118
A nutritional influence of soy foods that may be overlooked is the amount of calcium in some of these foods or in diets that contain soy foods. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much or more calcium as a serving of dairy products (Table 194-3).
TABLE 194-3 Calcium Content of Select Soy Foods
| SOY PRODUCT | SERVING SIZE | MG OF CALCIUM |
|---|---|---|
| Tofu, firm | ¼ block | 553 |
| Tofu, regular | ¼ block | 406 |
| Soy milk, calcium-fortified | 1 cup | 80-300 |
| Soy milk | 1 cup | 7 |
| Soybeans, roasted | ¼ cup | 119 |
| Soybeans, boiled | ¼ cup | 88 |
| Tempeh | ¼ cup | 77 |
With the inconsistent research, it is difficult to draw confident conclusions about the role of soy in bone health. Prudent clinical advice might be to increase soy foods as part of a regular diet in prevention strategies for all premenopausal, perimenopausal, and postmenopausal women. For all women who have significant risk factors for osteoporosis, soy supplementation could be added so that their total daily soy isoflavone intake would amount to approximately 90 mg/day. For treatment of perimenopausal and postmenopausal women who already have osteoporosis, this alone would not be considered adequate treatment.
Nutritional Supplementation
Calcium
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 perimenopausal 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.119 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.120 In a 2004 meta-analysis of randomized controlled trials, supplementation with 500 to 2000 mg a 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.121 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 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.122
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.123 In a study by Elders et al,124 a significant decrease in vertebral bone loss was observed with supplementation of 1000 to 2000 mg/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 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 postmenopausal, calcium supplementation again becomes effective in reducing age-related bone loss.125 Although consuming an adequate amount of calcium is important, it is too often overemphasized and supplemented at excessive doses, because 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 United States, 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.119,123,126 However, virtually all of these use vitamin D doses 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.127 Especially in older women, vitamin D in combination with calcium supplementation reduced the rate of postmenopausal bone loss.128 Vitamin D has also been shown to improve muscle strength129 and balance,130 thereby reducing the risk of falling.131
Magnesium
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.132 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.133
Strontium
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 United States. 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.134
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.135 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 deformities 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 U.S. 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
Zinc is essential for the formation of osteoblasts and osteoclasts, and it enhances the biochemical action of vitamin D. Zinc is also 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.136
Copper
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.137,138 In a double-blind trial, supplementation with 3 mg/day of copper for 2 years significantly decreased bone loss in postmenopausal women.139
Manganese
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.140
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.141
Boron
Boron supplementation reduces urinary excretion of calcium and magnesium and increases serum levels of 17 beta-estradiol and testosterone in postmenopausal women.142 These observations suggest that boron supplementation could help to prevent bone loss.
Silicon
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,143 and supplemental silicon partially prevented trabecular bone loss in ovariectomized rats.144
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.145 Folic acid promotes the remethylation of homocysteine to methionine, and supplementing postmenopausal women with this nutrient results in significant reductions in homocysteine levels.146 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.147
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.148 Animal studies have shown that vitamin B6 deficiency can prolong fracture healing time,149 impair cartilage growth, cause defective bone formation,150 and promote osteoporosis.151 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.152
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,153 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
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.154 Vitamin K plays a key role in the formation, remodeling, and repair of bone by attracting calcium to the site of this protein matrix.155 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.156
There are various forms of vitamin K, but the human trials have been done on vitamin K1 (phylloquinone), MK-4, (MK-4, a form of vitamin K2) and menaquinone-7 (longer-chain MK-7).
In a double-blind study, 452 men and women (ages 60-80 years) received a multiple vitamin/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 K1.157 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,158 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.
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 trials159 that gave vitamin K1 or MK-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 MK-4. 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 MK-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 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 either phylloquinone 1 mg/day, MK-4 45 mg/day, or placebo for 12 months.160 No effect of phylloquinone or MK-4 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,161 bone loss was reduced at the femoral neck, but there was no beneficial effect on spinal bone density. In a second study,162 200 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.
Menaquinone-7, or MK-7 (a longer-chain form of vitamin K2), 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 K1.163 MK-7 has been found in animal studies to be more potent and more bioavailable as well as to have a longer half-life than MK-4. When taken as a daily supplement (0.22 µmol/day), MK-7 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 MK-7 achieved during its prolonged intake.164 The longer-chain menaquinones such as MK-7 are much more hydrophobic, which contributes to their much longer half-lives (8 hours for K1 and MK-4 vs 96 hours for MK-7).165 In a study of Japanese postmenopausal women, a significant inverse association was found between natto consumption and the incidence of hip fractures.166 In a study of osteoporosis after organ transplantation, 1 year of MK-7 supplementation (180 mcg/day) resulted in increased bone mineralization compared with placebo.167 However, a study of early menopausal women given 1 year of supplementation of 360 mcg/day of MK-7 in the form of natto capsules did not show a significant improvement in bone density despite a reduction in uncarboxylated osteocalcin.168 A likely reason for these inconsistent results is the confounding effect of vitamin D status. The study in post-transplant patients noted a high incidence of vitamin D deficiency, which was found to affect the results.
Botanical Medicine
Camellia sinensis (Green Tea)
Population-based studies, as well as experimental studies, have demonstrated that green tea consumption may offer significant protection against osteoporosis.169 Green tea is rich not only in health promoting polyphenols, but is also a major source of vitamin K1. In order to take advantage of this protection it requires 3 to 5 cups per day, providing a minimum of 250 mg per day of polyphenols (also referred to as catechins), or alternatively a green tea extract providing the same level of polyphenols. In the experimental studies, the basic mechanism of green tea polyphenols was to impair bone resorption while at the same time stimulating osteoblast activity.170-172 This effect would have tremendous significance if confirmed in human clinical trials.
Therapeutic Approach
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. In order 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.
Numerous modifiable and non-modifiable factors influence the risk of developing osteoporosis. For the majority of women, osteoporosis is a preventable illness if dietary and lifestyle measures are implemented. Lifestyle modifications and nutrient supplementation may reduce the risk of osteoporosis and the associated debilitating fractures in many women but not all. For women who have already been diagnosed with osteoporosis, these nutritional and lifestyle factors can serve as an adjunct to conventional therapies to slow bone loss and, more importantly, decrease the risk of fractures.
The primary goals are the prevention of excessive bone loss and reduction of risk for fractures. In cases of actual osteoporosis (vs osteopenia), the recommendations given in this chapter should be used in conjunction with appropriate medical care, which may include the use of various prescription drugs.
Exercise
Weight-bearing exercise four times a week plus strength training/weight training two or more times a week is recommended.
Diet
A balanced diet with a particular focus on adequate protein, daily soy isoflavones, green leafy vegetables, adequate calcium and vitamin D, vitamin K, and magnesium. A holistic approach also recommends that patients avoid dietary factors that promote calcium excretion, such as salt, sugar, excessive protein, and soft drinks.
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