Michele F. Bellantoni
The 2000 National Institutes of Health (NIH) Consensus Conference defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Osteoporosis, like other medical conditions associated with aging, is common, underrecognized as a public health problem, underdiagnosed, and inadequately treated by medical providers. Both men and women can develop osteoporosis, but women bear a disproportionate burden of this illness because of their lower peak bone mass in adulthood and the dramatic impact of menopause on bone mass. From the age of 50 years, the lifetime risk for any fracture of the hip, spine, or distal forearm is 39% in white women (1). Because late-life fractures significantly affect the duration and quality of life, risk assessment, prevention, and treatment of osteoporosis are important components of comprehensive primary health care in women.
Epidemiology
Using the World Health Organization (WHO) criteria, 30% of Caucasian postmenopausal women in the United States have osteoporosis, and 54% have osteopenia. The prevalence of low bone mass increases with age. Using the WHO definition of osteoporosis, the prevalence in the United States of osteoporosis in Caucasian postmenopausal women based on the lowest bone mass at any site is estimated to be 14% of women age 50 to 59 years, 22% of women age 60 to 69 years, 39% of women age 70 to 79 years, and 70% of women age 80 years or older (1).
Bone mass predicts fracture risk. For every 1 standard deviation (SD) below peak bone mass, the risk of vertebral fracture is two times that of normal bone mass, and for the hip the risk is 2.5 times greater (2). Vertebral fractures are the most common osteoporotic fractures. Although they are often asymptomatic, multiple vertebral fractures can result in spinal kyphosis, the so-called “dowager's hump,” and chronic pain. Hip fractures, however, result in institutionalization and excess mortality. The 1-year mortality rate according to age at hip fracture is estimated to be roughly 20% in individuals younger than 70 years of age; 30% for those age 70 to 79 years, and almost 40% for those age 80 to 89.9 years (3). More than half of hip fracture survivors fail to return to independent living (4).
Risk Factors
To assess a woman's risk for osteoporosis, the clinician should consider those factors that affect peak bone mass, which occurs by the early thirties, and those factors that are associated with accelerated bone loss. Fracture risk has also been shown to increase independently of bone mass for those women with (a) a maternal history of hip fracture, (b) greater height, and (c) increased likelihood of falling.
Genetic factors play the greatest role in determining peak bone mass. African American women have on average greater bone mineral density than Caucasian women do (5). There are clinically significant contributions to bone mass from nutrition, drug exposures, endocrine health after puberty, and weight-bearing status (Table 103.1). For
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example, most teenagers and young adults do not receive the recommended daily allowance (RDA) for calcium of 1200 mg. Beverages high in phosphate (e.g., carbonated sodas) and a high protein diet result in excessive urinary excretion of calcium. Caffeine, alcohol, and smoking are harmful to bone metabolism. The use of systemic glucocorticoids in dosages equivalent to prednisone 7.5 mg daily or greater impairs bone formation. Phenytoin and other antiseizure medications impair vitamin D metabolism. Oligomenorrhea and amenorrhea cause accelerated bone loss, as does hyperthyroidism or oversupplementation of thyroxine (see Chapter 80). Immobility is associated with thin bone, so any condition that limits daily activity can promote osteoporosis.
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TABLE 103.1 Determinants of Peak Bone Mass and Bone Loss |
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A slow loss of bone mass begins as a natural conse-quence of aging in the fourth decade of life. The meno-pausal transition has the greatest impact on bone health in women, with rates of bone loss that can exceed 4% per year and extend for 10 years or longer. There is individual variation in the rate and duration of bone loss. It appears that body fat, a nonovarian source of circulating estrogens, influences the rate of bone loss, with higher amounts of body fat protecting against menopausal bone loss. Studies of African American women have shown that, although on average they have higher peak bone mass than Caucasian women, they experience comparable rates of menopausal bone loss that are clinically significant for lean African American women (6).
Bone loss in women continues into older age: the Study of Osteoporotic Fractures showed clinically significant bone loss occurring in women 65 years of age and older (7). Factors contributing to this bone loss include inadequate intake of calcium and vitamin D, lack of weight-bearing exercise, and possibly age-related changes in endocrine functions beyond those of estrogen deficiency, including age-related decreases in circulating growth hormone and adrenal androgens (8).
Disease states that alter gastrointestinal (GI) absorption of calcium and vitamin D; hepatic and renal metabolism of vitamin D; the endocrine systems of the hypothalamus and pituitary, thyroid, parathyroid, adrenal, and pancreatic glands; and the paracrine functions of the bone marrow all regulate bone formation and/or bone resorption and contribute to disease-related osteoporosis. Common conditions such as rheumatoid arthritis, celiac disease, and hyperthyroidism increase the risk of osteoporosis. Recently, it was estimated that 15% of those with celiac disease have osteoporosis as their only clinical sign of this condition (9).
The WHO has proposed a clinical definition of osteoporosis based on epidemiologic data that link low bone mass with increased fracture risk. In study populations of Caucasian postmenopausal women, a bone mineral density that was more than 2.5 SD lower than normal peak bone mass was associated with a fracture prevalence of 50%, meaning that 50% of women with bone mass at this level had at least one bone fracture (10). Based on these data, the WHO defined osteoporosis as bone mineral density at least 2.5 SD lower than peak bone mass, osteopenia as bone mass between 1.0 and 2.5 SD lower than the peak, and normal as bone mineral density within 1.0 SD below the normal peak bone mass. The WHO criteria were initially applied only to Caucasian, postmenopausal women and not men, premenopausal women, or women of ethnicity other than Caucasian. More recently, the International Society for Clinical Densitometry has recommended the use of the above bone mineral density categories for all postmenopausal women and men age older than 55 years.
Screening
The U.S. Preventive Task Force recommends assessment of bone mass/density for all women aged 65 years or older or those aged 60 years or older who have one or more osteoporosis risk factors (11) (Table 103.2). The National Osteoporosis Foundation guidelines recommend an initial assessment at age 70 years for men with no risk factors other than advanced age (12). All adults receiving systemic glucocorticoids, and young adults with sex hormone deficiency for whatever cause should be assessed, including women treated with antiestrogens and men treated with androgen deprivation. Bone fracture that occurs from a fall at standing height and age-related height loss of more than 1.5 inches suggest fragility fractures for which osteoporosis or other metabolic bone disorders may be an underlying cause.
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TABLE 103.2 Recommendations for Osteoporosis Screening |
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Medicare guidelines for bone densitometry became effective July 1, 1998 (13). Criteria for the need for bone densitometry are as follows: (a) An estrogen-deficient woman at clinical risk for osteoporosis (the clinician can refer a postmenopausal woman who is receiving hormone replacement if there is concern that the therapy may not be preventing bone loss); (b) vertebral abnormalities demonstrated radiographically to be indicative of osteoporosis, osteopenia, or vertebral fracture; (c) chronic glucocorticoid use, defined as prednisone 7.5 mg/day or greater (or equivalent steroid) for 3 months or longer, or anticipated use of such therapy; (d) primary hyperparathyroidism; and (e) an individual being monitored to assess the response to, or efficacy of, an osteoporosis drug therapy approved by the U.S. Food and Drug Administration (FDA). Medicare will cover a bone mass measurement for a beneficiary once every 2 years. More frequent screening is covered if it is medically necessary, such as with steroid use or to confirm the findings of a screening study (e.g., ultrasound, peripheral bone densitometry). Medicare reimbursement for central bone densitometry is roughly $150; peripheral densitometry and ultrasound studies are reimbursed at approximately $50.
It is now possible for patients to receive peripheral densitometry at locations such as pharmacies and health fairs. Again, because bone mass at peripheral sites changes more slowly with time and there is discordance in bone mass among various anatomic sites, a normal peripheral bone mass measurement in a patient with significant risk factors for osteoporosis should be confirmed with a bone mass measurement of the spine and hip.
Bone Densitometry
The current standard for assessing bone mass is dual energy x-ray absorptiometry (DEXA). Measurement of the bone mass of the lumbar spine and hip is currently used for diagnostic purposes and for monitoring of treatment (Fig. 103.1). Measurement at peripheral sites (e.g., wrist, heel) can be a useful screening tool in older individuals; however, as said, there is discordance among bone sites in rates of loss with aging. Many newly postmenopausal women have a normal bone mass of the heel and yet have clinically significant low bone mass of the spine. Falsely normal readings of the spine may occur in older women who have significant degenerative changes of the spine that result in calcification of the posterior structures of the vertebrae and adjacent soft tissues. Vertebral compression fractures also result in falsely elevated bone density measurements.
Currently, the different manufacturers of bone densitometers all use different algorithms to calculate the area of bone. Thus, the absolute bone mineral density readings differ by device. Therefore, to monitor a patient's response to treatment, the same bone densitometer must be used. This is a challenge since patients are often referred to centers based on insurance coverage.
Whereas the T score is used to assess bone mass, diagnose osteoporosis, and predict fracture risk, the Z score, or comparison with age-matched individuals, is used to determine whether the patient's bone mass is unexpectedly low. A Z score of –2.0 or more is often used to determine whether a more extensive laboratory assessment should be done to assess for secondary causes of bone loss (e.g., myeloma, vitamin D deficiency, hyperpara-thyroidism).
The FDA has approved ultrasound techniques of the heel for use in screening tests for low bone mass. T scores of –1.8 or more are associated with significant risk of fracture (14), and T scores of –2.5 or more are considered to be diagnostic of osteoporosis. Peripheral ultrasound is accurate, but there are insufficient data to assess precision over time. Therefore, this technology is not currently used to monitor response to treatment, although this recommendation may change with more data. A positive screening result should be confirmed with DEXA of the spine and hip to obtain a baseline bone density measurement, from which treatments can be monitored for effectiveness. Also, because of discordance of bone loss with aging, a negative screening test result in the setting of significant risk factors should be confirmed with DEXA of the spine and hip. Recently, some DEXA devices have been upgraded to assess vertebral deformity associated with vertebral compression fractures, termed an instant vertebral assessment, which may be useful when the DEXA spine image shows de-formity.
A bone density study provides information on the patient's current bone mass but does not assess whether bone loss is accelerated. Blood and urine studies have been developed to assess bone turnover. Most of these measure markers that are breakdown products of proteins specific to bone, including n-telopeptide (NTX or Osteomark), C-telopeptide (CTX), and deoxypyridinoline crosslinks (Pyrilinks-D). The appropriate use of these markers in clinical practice is controversial (15). There are data to show that they predict perimenopausal bone loss as assessed by bone densitometry over 1 to 2 years. Small studies show that markers may be used to monitor response to treatments such as bisphosphonates and estrogen (16). Studies are repeated at 3 months after treatment. The variability in measurements is estimated at 20%, and a decrease in value of 30% is considered a treatment response. Older women typically have low bone turnover at baseline; yet they respond to current osteoporosis treatments. Therefore, the utility of monitoring bone biomarkers in states other than high turnover ones such as perimenopause, hyperparathyroidism, hyperthyroidism, or Paget disease of the bone is not established.
Previous fractures predict future fractures. One vertebral fracture is associated with a fivefold increase in
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risk for subsequent vertebral fracture and a twofold increase in risk for hip fracture. Two or more vertebral fractures increase the risk of subsequent vertebral fracture by 12-fold (17). Almost half of frail elders admitted to an inpatient rehabilitation unit after a fracture had experienced a previous fracture. The majority of the earlier fractures were of minimal or short-term impact on functional state, whereas the more recent fracture greatly affected physical function. Yet, none of the earlier fractures resulted in an effective treatment program that may have prevented the more recent fracture.
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FIGURE 103.1. Typical bone density report of hip and spine. WHO Classifications for DEXA Interpretation are based on T score, or standard deviations from normal peak bone mass at any one of the following bone sites: lumbar spine mean L1–L4, total hip, femoral neck, and proximal one-third radius. Normal bone density is defined as T score ≥-1.0 SD, osteopenia or “low bone mass” T score -1.0 to -2.5, osteoporosis T score ≤-2.5 SD. From Raisz LG. Clinical practice. Screening for osteoporosis. N Engl J Med 2005;353:164. |
The great majority of all fractures in older women result from falls (18). An elderly woman with a history of one or more falls should undergo a careful assessment of risk factors for falling and be helped to develop a strategy to prevent further falls (see Chapter 12).
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Once osteoporosis is diagnosed, further laboratory studies to assess for metabolic bone diseases are needed based on the clinical history and the degree of osteoporosis. A serum calcium determination and measurement of the alkaline phosphatase level are recommended at the time of initial diagnosis. If the Z score is –2.0 SD below the peak or more, or if the history is relevant, other studies should be considered, including serum protein electrophoresis, serum thyroxine (T4) and thyroid-stimulating hormone (TSH), serum parathyroid hormone, serum 25-hydroxyvitamin D, and 24-hour urinary calcium and cortisol excretion studies. Estrogen levels in blood or urine are not useful to predict bone loss.
Prevention
Primary health care should routinely address bone health (19). Young adults should be encouraged to achieve normal peak bone mass through adequate dietary calcium (1,000 mg daily), weight-bearing exercise, and maintenance of normal body weight and reproductive function. Young women who experience prolonged amenorrhea should receive hormone replacement, often in the form of estrogen-containing oral contraceptives.
The Women's Health Initiative Study published in 2003, presented compelling data that the long-term cardiovascular, thromboembolic, and breast cancer risks of conjugated equine estrogen in combination with the synthetic progestin, medroxyprogesterone acetate outweigh the benefits to bone health and to reduction in the incidence of colon cancer (20). For newly menopausal women at risk for accelerated bone loss from estrogen deficiency, the alternatives to estrogen replacement are increasing. Selective estrogen receptor modulators such as raloxifene, 60 mg daily, offer a choice to women who are unable to take estrogen. The effects of raloxifene on bone and lipids are comparable to those seen after estrogen replacement (21). There appear to be no growth-promoting effects on breast or endometrium, thus reducing the risk profile of hormone replacement. The downside to raloxifene is that hot flushes are not improved over placebo, and the risk of thromboembolic disease (see Chapter 57) is at least comparable to that associated with estrogen replacement. Cost is also an issue, with estrogen/progestin therapy costing roughly $30 per month, whereas raloxifene is more than $80 per month. Tamoxifen, an older selective estrogen receptor modulator currently used to treat breast cancer, has estrogenic effects on bone. A study of tamoxifen use in older nursing home residents found that those who took 10 mg of tamoxifen daily had a lower rate of hip fracture than women not receiving such therapy (22). However, raloxifene, an FDA-approved drug for treatment of osteoporosis, is recommended over tamoxifen for women who are not being treated for breast cancer.
Studies with endpoints of bone mineral density have not shown consistent benefit of the nutritional supplements that contain plant-derived estrogenic compounds to improve bone health. Currently, 50 mg per day of isoflavones is considered the minimum effective intake to prevent osteoporosis, though there are no clinical trials with fracture endpoints from which to base treatment (23).
Bisphosphonates such as alendronate, one 35-mg tablet once weekly, have been shown to prevent accelerated bone loss in newly postmenopausal women and may be useful for women who are unable to take estrogen, because of a history of estrogen-sensitive cancers, or raloxifene, because of clotting disorders (24). Bisphosphonate therapy is not recommended for women considering pregnancy, because the drug remains in bone for years after the last dose, and its potential to impair fetal bone development has not been adequately studied.
Calcium absorption declines with estrogen deficiency and aging. Postmenopausal women younger than 65 years of age who are not receiving estrogen, as well as all men and women older than 65 years of age, should receive 1,500 mg elemental calcium daily (25). Dietary sources are less constipating and include milk, yogurt, calcium-fortified fruit juices, and breakfast cereals. Chocolate chews that contain 500 mg elemental calcium and 100 to 200 units of vitamin D are a low-caloric dietary supplement, though some contain 50% RDA of vitamin K and may not be appropriate for adults treated with warfarin. Tablets of calcium with and without vitamin D are available in chewable and nonchewable forms. No one source of calcium has been determined to be more effective clinically, although calcium citrate may be less constipating. Personal choice should be considered in planning strategies for calcium supplementation to achieve long-term compliance.
Vitamin D deficiency occurs when older individuals do not drink vitamin D–fortified milk, take a daily multiple vitamin that includes 400 units of vitamin D, or receive 15 minutes of daily sun exposure to the face. Vitamin D absorption declines with aging and with small bowel resection. Ideally, individuals older than 65 years of age should receive 800 units of vitamin D daily (see Chapter 84).
Weight-bearing exercise is recommended to maintain bone health with aging. Walking is excellent weight-bearing exercise for the hips. A weight-lifting program is recommended for the spine and arms under the guidance of an exercise physiologist to prevent neck and spine injuries due to excessive use of the weights. Strong muscles can absorb the physical forces associated with falls and reduce risk of bone fracture. Any physical activity that promotes muscle strength is helpful to bone, including swimming and water aerobics, both of which are well-tolerated forms of exercise, especially for women with osteoarthritis or other musculoskeletal conditions that limit their ability to walk or lift weights.
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Other behavioral strategies to prevent osteoporosis include smoking cessation and limiting phosphate-containing, caffeine-containing, and alcoholic beverages to two per day.
Treatment
Osteoporosis management is evolving. There is consensus that calcium intake should be achieved through diet and supplements equal to 1,500 mg of elemental calcium daily. Vitamin D recommendations are 800 to 1,000 units daily. Weight-bearing exercise has been shown to increase bone mass, but weight lifting should be performed under the guidance of a trained professional to prevent vertebral fractures. The National Osteoporosis Foundation has developed an exercise video tape that focuses on abdominal and back muscle exercises and is recommended even in the setting of severe osteoporosis and frailty.
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TABLE 103.3 Comparison of Established Osteoporosis Treatments |
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At present, there are four FDA-approved, non–sex-steroid treatments for postmenopausal osteoporosis, three of which act principally to inhibit bone resorption (Table 103.3). These include oral bisphosphonates, selective
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estrogen receptor modulators, and calcitonin. The fourth, recombinant parathyroid hormone polypeptide sequences, acts primarily to increase osteoblastic bone formation.
Age-related fracture risk and bone mineral density should be considered in making recommendations for pharmacologic intervention. A 50-year-old woman with osteoporosis diagnosed by screening DEXA has a 2.5% risk of fracture within 5 years, whereas a 65-year-old woman with the same bone density has a 13% 5-year fracture risk (26). The number of osteoporotic women needed to treat with pharmacologic therapy at age 50 to prevent one fracture is 100, but that number in the older woman is only 19. Recently, the cost-effectiveness of alendronate therapy for osteopenic postmenopausal women with femoral neck T-scores better than –2.5 and no history of clinical fractures or other bone mineral density-independent risk factors for fracture has been questioned. It is expected that future recommendations for pharmacologic therapy will advocate intervention when the 5 year fracture rate is 10% based on combination of age, a few easily identified clinical risk factors, and bone density.
Oral Bisphosphonates
Bisphosphonates, although limited in GI absorption, are bone specific and have little systemic effects, hence their overall more desirable benefit-to-risk profile compared with estrogens and selective estrogen receptor modulators. The mechanism of action is impairment in cholesterol synthesis, although specific to osteoclasts secondary to the hydroxyapatite side chains. Alendronate (27), risedronate (28), and ibandronate (29) reduce the risk of new vertebral fractures in osteoporotic postmenopausal women by about 50% when dosed daily, and are FDA-approved for alternate dosing regimens of once weekly or once monthly based on bone density increases that were comparable to once daily dosing. The less frequent dosing may result in better tolerance than daily dosing, as the most common side effects are GI, including nausea, acid reflux symptoms, and constipation, all potentially resulting from GI exposure to the drug, with case reports of severe ulcerations of the esophagus. Dosing instructions, including administration with a minimum of 8 oz of water and remaining upright for 30 to 60 minutes postdosing, are aimed at reduction of esophageal complications. To maximize absorption, oral bisphosphonate must be taken on an empty stomach with only water, and the patient must wait 30 to 60 minutes before eating or drinking. Adequate calcium and vitamin D (see Treatment) are essential for optimizing treatment response. Postmarketing case reports of osteonecrosis of the jaw have been published (30). The frequency of this adverse experience and the role of vitamin D and/or calcium deficiency in this complication of therapy are unknown. Cycled etidronate is no longer recommended as the newer agents have more proven efficacy.
Data support the use of alendronate or risedronate in the prevention and treatment of steroid-induced osteoporosis in women and men (31), and idiopathic osteoporosis in men (32).
Clinical trials of bisphosphonates such as ibandronate and zolendronic acid (33) administered intravenously are ongoing or are under FDA review. The goals of these therapies are to provide acceptable fracture risk reduction with less frequent drug administration and GI side effects. Intravenous therapies may pose an additional risk of renal insufficiency not seen with oral therapies due to the concentrated drug exposure to the kidneys following intravenous administration. The risks of osteonecrosis as compared with oral dosing are also being considered.
Other Treatments
Calcitonin, given in a nasal spray (200 units) or one metered puff daily, alternating nostrils, is a second-line treatment for those who do not tolerate bisphosphonate therapy. This therapy has been shown to reduce the risk of vertebral fractures, but the effects on the hip appear to be less than that of bisphosphonate therapy (34). Calcitonin is considered second-line therapy to bisphosphonates for both postmenopausal and steroid-induced osteoporosis.
Selective estrogen receptor modulators such as raloxifene and tamoxifen are considered less effective than bisphosphonates and are best employed for prevention or treatment of mild osteoporosis.
Parathyroid hormone, at low doses, increases new bone formation, but in excess it leads to bone loss, as seen in hyperparathyroid syndromes. Recently, nightly subcutaneous injections of parathyroid hormone were reported to increase bone density and to reduce vertebral fractures, similar to the effects that were found in previous studies of currently available oral bisphosphonates (35). Trials combining parathyroid hormone injections with bisphosphonates are ongoing.
Sodium monofluorophosphate plus calcium has been shown to reduce the incidence of vertebral fractures; however, as with calcitonin, the effects on bone mineral density of the total hip were not significant (36). Fluoride therapy does not have approval of the FDA, and older studies in which it was taken without vitamin D supplementation resulted in osteomalacia. Successful clinical trials of a second mineral, strontium (37), in combination with adequate calcium and vitamin D, have resulted in clinical use of this mineral in Europe.
Hormonal therapies such as testosterone, dehydro-epiandrosterone, and growth hormone have been studied, but without fracture endpoints required for FDA approval. Growth factors that are specific to bone formation rather than systemic in effect are under clinical investigation.
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Postfracture Treatment Program
An osteoporosis treatment program can often be implemented in the setting of new fracture, a time when many patients who were previously unwilling to consider osteoporosis management become interested. Calcium supplementation should be prescribed, although 1500 mg daily may not be tolerated initially because of constipation from narcotics prescribed for fracture pain. Vitamin D, 800 to 1000 units, is recommended. Bisphosphonate therapy in this setting has been difficult to implement because of the high prevalence of gastroesophageal reflux and constipation, although once-weekly and once-monthly dosing may be tolerated. Calcitonin therapy has less adverse effects and is used routinely in the management of acute vertebral fractures.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.