CHAPTER 29—OSTEOPOROSIS AND OSTEOMALACIA
EPIDEMIOLOGY AND IMPACT OF OSTEOPOROSIS
BONE REMODELING AND BONE LOSS IN AGING
DIAGNOSIS OF OSTEOPOROSIS AND PREDICTION OF FRACTURE
PREVENTION AND TREATMENT OF OSTEOPOROSIS
MANAGEMENT OF VERTEBRAL FRACTURES
Osteoporosis was defined previously by a consensus panel as a “disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture incidence.” According to this definition, the diagnosis of osteoporosis requires the presence of a fracture. The World Health Organization now defines osteoporosis by bone mineral density (BMD) measurement, which allows diagnosis and treatment of osteoporosis prior to incident fracture. If a woman has a BMD measurement at any site < 2.5 standard deviations below the young adult standard (a T score of < −2.5), the diagnosis of osteoporosis can be made. Further, women with osteopenia (low bone mass, with a T score of ≥ −2.5 but < −1) and normal bone mass (with a T score of ≥ −1) can also be identified. Thus, the clinician can make the diagnosis of osteoporosis and begin the appropriate therapy before fracture in the older adult occurs. In addition, women with osteopenia can be placed on a preventive regimen and then followed carefully for further bone loss. Specific standards for definitions of osteoporosis have not been established for men or for racial and ethnic groups other than white persons, although it appears that similar standards apply to men and to Hispanic women.
In 1990 more than 1.25 million hip fractures were reported worldwide in women, and 500,000 in men. In the United States the estimated numbers of hip and vertebral fractures in women annually are more than 250,000 and 500,000, respectively. To this number must be added fragility fractures in men, which occur at about one third the rate seen in women. Thus, approximately 1 million Americans suffer fragility fractures each year, at a cost of more than $14 billion. The consequences of osteoporosis include diminished quality of life, decreased independence, and increased morbidity and mortality. The pain and kyphosis, height loss, and other changes in body habitus that occur as a result of vertebral compression fractures erode quality of life for both women and men. In addition, the functional status of patients who have had vertebral crush fractures may also decrease. These patients may be unable to bathe, dress, or walk independently. Increased mortality is related primarily to hip fractures; 20% excess mortality occurs in older persons in the year following hip fracture. In addition, approximately 50% of women with hip fracture do not fully recover prior function. Thus, in older adults, it is important to prevent as many fractures as possible.
Bone is able to repair itself by actively remodeling, a coupled process (also called bone turnover) of bone resorption followed by bone formation; bone remodeling continues throughout life. Local signals, not yet fully understood, bring osteoclasts to specific areas of bone where resorption is initiated and resorption cavities are formed. Once osteoclasts have completed the resorption process, osteoblasts move into the area and begin to lay down osteoid and, later, to calcify the matrix. Under optimal conditions, once bone remodeling is completed in a specific area, the resorption spaces are completely filled with new bone. However, after menopause in women, and with aging in men and women, the remodeling cycle becomes unbalanced, and bone resorption increases more than formation does, resulting in net bone loss. The majority of treatments for osteoporosis act to inhibit bone resorption rather than to increase bone formation.
Bone mass changes over the life span of an individual. In women, bone mass increases rapidly from the time of puberty until approximately the mid-20s to mid-30s, at which time peak bone mass is reached. Once women reach peak bone mass, a few years of stability are followed by a slow rate of bone loss, beginning well before the onset of menopause. After menopause, the rate of bone loss is quite rapid––as much as 7% per year––for up to 7 years, as a consequence of estrogen deficiency. In later life, bone loss continues, albeit at a slower rate, generally 1% to 2% per year; however, some older women may lose bone density at a higher rate. Data strongly suggest that terminating bone loss at any time will decrease fracture risk. It has been estimated that a 14% increase in bone density in 80-year-old women would halve the hip fracture risk. This 14% increase would also be realized if bone loss were prevented in 70-year-old women.
Although studies thus far have focused mostly on women, it is well documented that men lose bone with age. Cross-sectional studies have detected a slower rate of bone loss in men than in women, but in a longitudinal study the rates of bone loss in men were found to equal those of older women, although men start from a higher bone mass. It is estimated that men aged 30 to 90 years lose approximately 1% per year in the radius and spine; some men with risk factors lose as much as 6% per year. These data suggest that older men lose bone at rates similar to those of older women; however, vertebral fracture rates in men are lower.
Both men and women lose predominantly cancellous bone, which is concentrated in the vertebral spine. Cortical bone accounts for 45% to 75% of the mechanical resistance to compression of the vertebral spine, and men actually gain cortical bone through periosteal bone deposition. Men also increase the cross-sectional area of their vertebrae by 15% to 20%, increasing maximum load levels until the age of 75. The increased bone strength seems to be reversed by thinning of the cortical ring by age 75, the age at which men begin to present with vertebral fractures. Although bone loss at the hip has not been extensively studied in men, in cross-sectional analyses healthy men were found to lose 40% of femoral neck BMD between the ages of 20 and 90 years.
The pathogenesis of osteoporosis in women is complex. Factors that affect the level of peak bone mass, the rate of bone resorption, and the rate of bone formation need to be considered. Peak bone mass appears to be 75% to 80% genetically determined, although which genes are involved is not clear. A number of candidate genes that may be important to osteoporosis are being explored currently: vitamin D receptor, estrogen receptor, transforming growth factor, interleukin-6, interleukin-1 receptor 2, type I collagen genes, and collagenases. Several factors may work to increase bone resorption in older women. After menopause, and with estrogen deficiency, a variety of factors that act locally on bone may lead to increased bone resorption. Factors thought to play a role in the bone loss of estrogen deficiency include interleukin-1, interleukin-1 receptor antagonist, interleukin-6, and tumor necrosis factor, as well as their binding proteins and receptors.
The mechanism by which older men and women continue to lose bone is likely related to calcium deficiency, which produces secondary hyperparathyroidism. Parathyroid hormone (PTH) is a potent stimulator of bone resorption when chronically elevated. Aging skin and decreased exposure to sunlight reduce the conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) by ultraviolet light, and the result is vitamin-D insufficiency in older adults. Vitamin-D insufficiency, in turn, reduces the absorption of calcium. Further, older adults tend to ingest inadequate amounts of vitamin D and calcium. As a result of decreased serum levels of calcium, PTH—acting to maintain serum levels of calcium—increases, which leads to increased bone resorption. In one study, older women (mean age 79 years) hospitalized with a hip fracture were found to have lower 25(OH)D levels and higher PTH, higher bone resorption, and lower bone formation than women in the control group (mean age 77 years). Further, data from the Study of Osteoporotic Fractures indicate that women with low fractional absorption of calcium are at increased risk for hip fracture. (See also Endocrine and Metabolic Disorders, for more on disorders of calcium metabolism.)
Androgens are important determinants for peak bone mass in men. Bone accretion is closely related to sexual maturity, and men who have abnormal puberty or delayed puberty have reduced bone mass. In addition, men with estrogen deficiency or resistance have decreased bone mass and failure of epiphyseal closure. Several studies have demonstrated that late-onset hypogonadism can also play a role in osteoporosis in men. Although it is evident that severe male hypogonadism can cause osteoporosis, the effect of moderate decreases in testosterone levels in aging men on rates of bone loss is uncertain. One study found that more than 60% of men presenting with hip fracture had low testosterone levels, compared with about 20% of those in the control group.
In men and women, osteoblast activity appears to decrease with aging, compounding the bone loss that results from increased resorption seen with aging and, for women, with menopause. Growth factors, such as transforming growth factor B and insulin-like growth factor 1, may be impaired with estrogen deficiency or with aging, resulting in decreased osteoblast function.
Risk factors for osteoporosis and osteoporotic fracture have been identified and have been used to determine who should be placed on preventive or therapeutic regimens. Risk factors, however, are mediocre predictors of low bone density and fractures, and it is more useful to identify modifiable risk factors and to implement change as part of a treatment or preventive program. Table 29.1 lists modifications of risk factors of osteoporosis; all of these risk factors should be addressed by the clinician as part of the routine care of an older adult. Risk factors can also be used to identify women younger than 65 years of age who should have BMD screening.
The diagnosis of idiopathic or primary osteoporosis is made by bone density measurement prior to fracture or by incident fracture. Exclusion of other diseases that may present as fracture or with low bone mass is important in the evaluation of women and men with osteoporosis, since different treatment would be required. The major secondary causes of osteoporosis are listed in Table 29.2, along with laboratory tests used to exclude each disease. These laboratory tests should be considered for persons who present with acute compression fracture or who present with a diagnosis of osteoporosis by BMD measurement. The most common causes of secondary osteoporosis in women are primary hyperparathyroidism and glucocorticoid use. Men are more likely to have a secondary cause of osteoporosis than women; as many as 50% of osteoporotic men may have a secondary cause. The most commonly reported secondary causes of osteoporosis in men are hypogonadism and malabsorption syndromes, including gastrectomy. Medications that might have a detrimental effect on bone should be given with adjusted doses or discontinued. Medications that have been shown to adversely affect BMD include glucocorticoids, excess thyroid supplement, anticonvulsants, methotrexate, cyclosporine, and heparin. In older adults, glucocorticoids and thyroid hormone are used quite commonly; accordingly, clinicians should consider the effects these medications may have on the already increased risk of fracture when prescribing them for older adults.
Glucocorticoids result in bone loss primarily through the direct suppression of bone formation, although they also further reduce sex hormone levels and cause secondary hyperparathyroidism through their effects on intestinal calcium absorption. The prevalence of vertebral fractures in persons taking glucocorticoids for 1 year is estimated to be 11%. The rate of trabecular bone loss is dose dependent and generally occurs in the first 6 months of therapy. Although inhaled corticosteroids have not been as well studied, high doses of high-potency inhaled steroids may also result in bone loss. The best strategy for older persons who require long-term glucocorticoid therapy is to maximize bone health by a variety of interventions. It is important to use the lowest possible dose of glucocorticoids, to assure adequate calcium and vitamin D intake (see the treatment section, below). Further, alendronateOL, risedronate, and intermittent etidronateOL have been shown to successfully prevent bone loss that is due to glucocorticoid therapy when they are initiated at the same time as the steroids (see the treatment section, below).
BMD, or bone mass measurement, is the best predictor of fracture. The relative risk of fracture is 10 times greater in women in the lowest quartile of BMD than in women whose BMD is in the highest quartile.
Bone density of the hip, spine, wrist, or calcaneus may be measured by a variety of techniques. The preferred method of BMD measurement is dual-energy radiographic absorptiometry (DXA). BMD of the hip, anterior-posterior spine, lateral spine, and wrist can be measured with this technology. There are several other methods of measuring BMD, including quantitative computed tomography, ultrasonography of the calcaneus, single radiographic absorptiometry of the calcaneus, and radiographic absorptiometry. Quantitative DXA is the best predictor of hip fracture and is equal to the wrist in predicting fractures at other sites; the relative risk of fracture for each one–standard deviation decrease in BMD is 2.6. In the Study of Osteoporotic Fractures, heel ultrasonography was found to be slightly worse that DXA of the hip in predicting hip fracture in women 65 years and older. In a large study (> 200,000) of postmenopausal women aged 50 years and over, baseline T scores were for the heel (ultrasound or single radiographic absorptiometry), forearm (DXA), and finger (DXA). After 1 year of follow-up, women with T scores less than −2.5 by any measure had an adjusted relative risk for all fractures of 2.74 (confidence interval [CI], 2.4 to 3.1). These measures were not compared with DXA of the hip, and information on performance by age group or risk factors was not provided.
The National Osteoporosis Foundation, in conjunction with numerous specialty organizations including the U.S. Preventive Services Task Force, recommends BMD testing for all women aged 65 years and over, regardless of risk-factor status; there are no data to determine the frequency of screening or the age to stop screening for osteoporosis in women. For women between 60 and 64 years of age, the presence of additional risk factors, particularly low body weight and no estrogen replacement therapy, makes their risk of osteoporosis and fracture comparable to that of women over 65 years. Indications for BMD testing are listed in Table 29.3. Interpretation of BMD involves evaluating the quality of the DXA as well as the T scores. As previously stated, osteoporosis is defined as 2.5 or more standard deviations below the young adult mean (also known as the T score). The BMD of the individual patient is compared with that of young women (25 to 35 years of age) who are considered to be at or near peak bone mass. For every standard deviation below the young adult mean (or decrease in 1 unit T score), fracture risk at the spine and hip approximately doubles. For example, if a woman has a T score of −2, her risk of fracture is four times that of a woman with normal bone density (controlled for height and weight). When evaluating the spine BMD over time, several considerations are important. Vertebral or arterial or lymph node calcification or any scoliosis may falsely increase BMD of the posteroanterior spine DXA. Thus, a woman with osteoporosis of the spine may have a DXA T score that is higher than −2.5. Usually, one can see these changes on the DXA report if the picture of the scan is included in the report. It is important to evaluate BMD of lumbar vertebrae 1–4 when making a decision about therapeutic intervention. Because these changes in and around the spine are common in older adults, hip BMD tends to be the more reliable site for estimating fracture risk. Another important issue when using DXA over time is the measurement variability. The DXA equipment is stable over time, but regular testing will allow detection of any drift. More importantly, one needs to be assured that patient positioning is consistent over time. With the founding of the International Society of Clinical Densitometry, standardized training courses are now available for technicians and also for physicians interpreting the results. The cost for DXA testing is between $200 and $300, and Medicare and Medicaid will cover the cost if indications for its use (eg, estrogen deficiency) are met.
BMD testing may also be used to establish the diagnosis and severity of osteoporosis in men, and it should be considered for men with low-trauma fractures, radiographic criteria consistent with low bone mass, or diseases known to place a person at risk for osteoporosis. Data relating BMD to fracture risk are derived from studies of women, but data suggest that similar associations may be valid for men. Data from several studies indicate that patients with hip fractures are often not evaluated and treated for osteoporosis. It is important to consider the diagnosis of osteoporosis in any older person with a fracture, and evaluation is indicated if treatment would be considered for the individual patient.
Serum and urine biochemical markers can estimate the rate of bone turnover (remodeling) and may provide additional information to assist the clinician. A number of markers have been developed that reflect collagen breakdown (or bone resorption) and bone formation. Several markers have been associated with increased hip fracture risk, decreased bone density, and bone loss in older adults. In addition, markers of bone resorption and formation decrease in response to antiresorptive treatment. The use of markers in clinical practice, however, is controversial because of the substantial overlap of marker values in women with high and low bone density or rate of bone loss. Further, few studies have compared the response of a particular marker (or combination of markers) and bone density with therapy in order to determine the magnitude of decrease of a biochemical marker necessary to prevent bone loss or, more importantly, fracture. Two markers of bone resorption, deoxypyridinoline cross-links and cross-linked N-telopeptides of type I collagen, and one formation marker, bone alkaline phosphatase, may be used in clinical practice to provide an early assessment of treatment efficacy. A decrease from baseline levels in the level of these markers after 3 to 6 months of therapy would indicate successful treatment.
Exercise is an important component of osteoporosis treatment and prevention, although exercise alone is not adequate to prevent the rapid bone loss associated with estrogen deficiency in early menopause. Among exercisers in the Rancho Bernardo cohort, those who reported strenuous or moderate exercise had higher BMD at the hip than did those who reported mild or less-than-mild exercise. Similar associations were seen for lifelong regular exercisers and hip BMD. In a randomized study of women ≥ 10 years postmenopausal, the group receiving calcium supplementation plus exercise had less bone loss at the hip than did those assigned to calcium alone. Further, the effectiveness of high-intensity strength training in maintaining femoral neck BMD as well as in improving muscle mass, strength, and balance in postmenopausal women has been demonstrated, suggesting that resistance training would be useful to help maintain BMD and to reduce the risk of falls among older adults.
Marked decrease in physical activity or immobilization results in a decline in bone mass; accordingly, it is important to encourage older adults to be as active as possible. Weight-bearing exercise, such as walking, can be recommended for all adults. Older persons should be encouraged to start slowly and gradually increase both the number of days as well as the time spent walking each day. (See Physical Activity.)
Calcium and vitamin D are required for bone health at all ages. In order to maintain a positive calcium balance, the current recommendations for calcium intake for postmenopausal women and men aged 65 years and older is at least 1200 mg per day of elemental calcium. The amount of vitamin D required is between 400 and 800 IU per day. In older adults, regardless of climate or exposure to sunlight, a daily supplement of ≥ 400 IU per day of vitamin D is recommended because skin changes that occur with aging result in less efficient use of ultraviolet light by the skin to synthesize vitamin-D precursors. Calcium plus vitamin D at different doses have been shown to increase or maintain bone density in postmenopausal women and to prevent hip as well as all nonvertebral fractures in older adults. The dietary intake of calcium for postmenopausal women in the United States averages 500 to 700 mg per day; thus, most American women require calcium supplementation to ensure adequate intake. (See Table 29.4 for information on the calcium contained in selected foods.)
The dosing, relative costs, and special considerations for the medications used to prevent and treat osteoporosis are provided in Table 29.5.
Alendronate has been approved for osteoporosis prevention (women) and treatment (men and women). Women with osteoporosis who were treated with alendronate and compared with women on placebo were found to have increased bone density of the spine and hip, as well as decreased vertebral fracture rate. The Fracture Intervention Trial examined the effect of alendronate on postmenopausal women with severe osteoporosis, with or without vertebral fracture at baseline. Regardless of the presence of vertebral fractures at baseline, alendronate was found to decrease the vertebral fracture rate. In addition, alendronate resulted in a 50% reduction in hip fractures. A study in women aged 60 to 85 years indicated that an even lower dose of alendronate might be effective in older women. Further, data indicate that once-weekly dosing with alendronate (70 mg) is as effective in increasing spine BMD over 1 year as is daily dosing (10 mg) in postmenopausal women with osteoporosis (age range 42 to 95 years). Alendronate has also been approved for the prevention of osteoporosis in early postmenopausal women. The daily dose for prevention is lower—5 mg—than that given for the treatment of osteoporosis—10 mg. If treatment with alendronate alone is not effective (bone loss of > 4% or fracture within 3 months of initiation), combining raloxifene or estrogen replacement therapy with alendronate, which has an additive effect on bone density, may be indicated. In women with lesser degrees of osteoporosis, alendronate has not been shown to prevent hip fracture. Alendronate has now been approved to treat osteoporosis in men and in glucocorticoid-induced osteoporosis. The optimal duration of treatment with bisphosphonates is unclear; however, one study indicated that the greatest increase in vertebral bone mass occurred during the first 5 years of treatment, and benefit was maintained for 10 years without undue risk.
The major adverse effects of alendronate are gastrointestinal, including abdominal pain, dyspepsia, esophagitis, nausea, vomiting, and diarrhea. Musculoskeletal pain may also occur. Esophagitis, particularly erosive esophagitis, may be seen most commonly in patients who do not take the medication properly. The absorption of oral bisphosphonates is very poor; thus, it is extremely important to provide specific and detailed instructions for patients receiving any bisphosphonate therapy (Table 29.6).
Risedronate, another bisphosphonate, has been approved for osteoporosis prevention and treatment (women only). In a 3-year study of postmenopausal women with ≥ 1 vertebral fracture at baseline, the cumulative incidence of new vertebral fractures was reduced by 41% (95% CI, 18% to 58%) in the group receiving risedronate (5 mg per day) rather than placebo. In addition, the incidence of nonvertebral fractures also decreased by 39% (95% CI, 6% to 61%) in the treatment group. BMD of the hip and spine increased significantly in the risedronate group. In the same study, 2.5 mg per day of risedronate was found to be ineffective and was discontinued after the first year of the study. Withdrawals because of side effects and any upper gastrointestinal adverse events were similar in the risedronate and placebo groups. In older women (70 to 79 years) with osteoporosis, risedronate was found to decrease the risk of hip fracture by 40% in comparison with placebo (all participants received adequate calcium and vitamin D) with a relative risk of 0.6 (95% CI, 0.4 to 0.9). In women at least 80 years of age, risedronate was not found to significantly reduce hip fracture incidence; however, these women were selected primarily on the basis of clinical risk factors rather than BMD criteria. This study demonstrates that even in older women, BMD measurement and assessment of previous vertebral fractures are needed to identify those for whom the treatment will be the most effective.
Etidronate was shown to increase spinal bone mass and decrease vertebral fractures in two studies in the early 1990s, and a 5-year follow-up study demonstrated continued benefit. Etidronate was given intermittently—400 mg per day orally for 14 days, and then stopped for 2.5 months—in these studies because continuous high doses can impair mineralization and produce osteomalacia. However, etidronate is not approved for use in treating osteoporosis because the data supporting fracture reduction were not sufficient. A separate study indicated a role for etidronate in preventing bone loss in patients who require long-term glucocorticoids.
The selective estrogen receptor modulators are agents that act as estrogen agonists in bone and heart but act as estrogen antagonists in breast and uterine tissue. These medications have the potential to prevent osteoporosis or cardiovascular disease without the increased risk of breast or uterine cancer. Tamoxifen, an agent used to treat breast cancer, has beneficial effects on bone, as reported in several studies, but it also has stimulatory effects on the uterus. Thus, tamoxifen is not indicated for osteoporosis treatment or prevention.
Raloxifene has been approved for the treatment and prevention of osteoporosis in postmenopausal women. Comparison of raloxifene with placebo in postmenopausal women with osteoporosis found that raloxifene decreases bone turnover and maintains hip and total body bone density. There were no differences between groups in breast abnormalities or endometrial thickness. Most importantly, data demonstrate that raloxifene (60 mg per day) reduces incident vertebral fractures by about 60%, despite only modest increases in bone density. In this study raloxifene was not found to significantly reduce nonvertebral, hip, or wrist fractures. Reported adverse effects with raloxifene include flu-like symptoms, hot flushes, leg cramps, and peripheral edema.
Another important finding with raloxifene was a reduction in breast cancer risk in women who participated in the Multiple Outcomes of Raloxifene Trial. When women receiving raloxifene were compared with women receiving placebo, the relative risk for women receiving raloxifene of developing breast cancer was found to be 0.24 (95% CI, 0.13 to 0.44). In the same study, raloxifene was not found to increase the risk of endometrial cancer but was found to increase the risk of venous thromboembolic disease. In other studies, raloxifene was found to decrease total and low-density lipoprotein cholesterol and lipoprotein (a) levels without affecting high-density lipoprotein cholesterol or triglyceride levels. Thus, in clinical trials to date, raloxifene appears to be beneficial to several organ systems, although further study is required with regard to cardiovascular diseases and breast cancer prevention.
Calcitonin is a hormonal inhibitor of bone resorption that is approved for the treatment of osteoporosis in women. It is available as a subcutaneous injection and as a nasal spray. The nasal spray has fewer reported side effects and greater patient acceptance, but it may be less effective. Calcitonin has been shown to increase bone density in the spine and reduce vertebral fractures. In epidemiologic studies, calcitonin has been shown to reduce the incidence of hip fractures, although in clinical trials, hip bone density has not been found to increase. Results of a 5-year study demonstrated that the incidence of vertebral fractures in women receiving 200 IU per day of nasal spray calcitonin was lower than that of women on placebo. The reduction in hip fracture incidence was not statistically significant in the group receiving calcitonin in comparison with the placebo group. Doses of 100 and 400 IU per day were studied as well, but they did not reduce incidence of vertebral fractures. In the same study, BMD changes at 3 years and changes in markers of bone turnover in the treatment and placebo groups were found not to be significantly different. Although there are no direct comparisons, calcitonin appears to be less effective than other antiresorptive drugs. There is some evidence that calcitonin produces an analgesic effect in some women with painful vertebral compression fractures.
Estrogen replacement therapy (ERT) is an option for osteoporosis prevention (approved by the Food and Drug Administration; indication withdrawn as a treatment); however, it is not recommended as a first-line choice. In case-control and cohort studies, ERT has been found to be associated with a 30% to 70% reduction in hip fracture incidence. Multiple studies have demonstrated that postmenopausal estrogen use prevents bone loss at the hip and spine when initiated within 10 years of menopause. However, in a cross-sectional study, BMD in women who initiated hormone replacement therapy (HRT) after age 60 years was found not to be significantly different from women who initiated HRT within 2 years of menopause. In the Postmenopausal Estrogen/Progestin Intervention trial, older women, women with low initial BMD, and women who had not previously used HRT were found to gain more bone than did young women, women with higher baseline BMD, and those who had previously used HRT. Decreased incident vertebral fractures were seen in a small study of postmenopausal women using a transdermal estradiol preparation. Recent prospective data from the Women’s Health Initiative (WHI) also demonstrated that postmenopausal women who took hormone replacement therapy for approximately 7 years had a decreased hip fracture risk; however, the dose and preparation of hormone therapy used also increased the risk of breast cancer, heart disease, stroke, and deep-vein thrombosis. Given the WHI findings, recent U.S. Preventive Services Task Force guidelines advise against the routine use of estrogen plus progesterone for the prevention of chronic conditions in postmenopausal women. The estrogen-only arm of WHI was also stopped 1 year ahead of schedule and demonstrated an increased risk of stroke but not of coronary heart disease or breast cancer. Estrogen alone decreased hip fracture risk (relative risk 0.61 [95% CI, 0.41 to 0.91]). Previously, HRT was recommended for prevention of osteoporosis; however, given the results of the WHI and the availability of other effective medications for osteoporosis prevention and treatment, the Food and Drug Administration changed its indication for estrogen and estrogen-progestin products. “When these products are being prescribed solely for the prevention of postmenopausal osteoporosis, approved non-estrogen treatments should be carefully considered. Estrogens and combined estrogen-progestin products should only be considered for women with significant risk of osteoporosis that outweighs the risks of the drug.”
Other data suggest that lower-than-usual doses of estrogen, when given with adequate calcium and vitamin D, are effective in reducing bone turnover and bone loss in older women. In a randomized controlled study, women treated with 0.3 mg per day of conjugated equine estrogen plus 2.5 mg per day of medroxyprogesterone acetate were found to gain spine and hip BMD, whereas women treated with placebo showed no change. A more recent study compared 0.25 mg per day of 17β-estradiol with placebo and determined that this dose increases BMD at all sites and decreases bone turnover in older women, with minimal side effects. The effect of lower-dose estrogen on fracture incidence and other health outcomes is unknown at this time.
See also the section on hormone replacement therapy in Endocrine and Metabolic Disorders.
PTH (teriparatide), although leading to increased bone resorption when continuously elevated, can increase bone mass, trabecular connectivity, and mechanical strength when administered intermittently. PTH is approved for the treatment of osteoporosis in men and women. It has been shown to increase spinal BMD in osteoporotic men and women. In a 3-year randomized study of postmenopausal women with osteoporosis, the group receiving estrogen plus intermittent PTH was found to have continuous increase in spinal bone mass over the study period, as well as decreased vertebral fracture rate. Bone mass of the hip and total body also increased significantly in the estrogen-plus-PTH group, in comparison with the group on estrogen alone. Recent studies have also demonstrated the effectiveness of PTH in reducing vertebral and nonvertebral fractures in postmenopausal women. In men with primary or hypogonadal osteoporosis, PTH also increased BMD at all sites. The combination of alendronate and PTH does have a synergistic effect on bone; in fact, it appears that alendronate attenuates the anabolic effect of PTH in both men and women. PTH, which is given subcutaneously, is approved for men and women who are at risk for osteoporotic fracture and who are unable to tolerate other approved agents. PTH was found to increase the incidence of osteosarcomas in male and female rats; the relevance of these findings to humans is unknown. PTH should not be used as a first-line therapy for osteoporosis.
Other bisphosphonates currently under investigation for the treatment and prevention of osteoporosis include pamidronate, zoledronate, and tiludronate. New selective estrogen receptor modulators are also being tested for use in osteoporosis treatment.
Zoledronate has been shown to decrease bone turnover and increase BMD of the hip and spine, in comparison with placebo, in doses given one, two, or four times per year. All women in this study were postmenopausal with spine BMD T score ≤ −2 at baseline. The change in bone turnover parameters and bone density were similar in magnitude to those achieved with oral bisphosphonates that have already been approved for prevention and treatment of osteoporosis.
The use of fluoride to treat osteoporosis is appealing because fluoride results in a large increase in spine bone density; however, the increase in BMD has not been found to be consistently associated with a decrease in vertebral fractures. In fact, in one study, the group receiving fluoride therapy was found to have a higher rate of appendicular fractures. Slow-release fluoride therapy has been found to be associated with an increase in spine BMD, as well as decreased incidence of vertebral fractures. Further studies are required before slow-release fluoride can be recommended for the treatment of osteoporosis.
The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may also affect bone. This class of medication is commonly prescribed for the management of hypercholesterolemia and has been shown to stimulate bone formation in animals. Preliminary epidemiologic data suggest that the use of statins is associated with decreased incidence of fracture. However, recent data from the WHI Observational Study indicated that neither fracture risk nor BMD is altered by statin use.
Strontium ranelate increases bone formation and decreases bone resorption in animals. A randomized, placebo-controlled study in postmenopausal women with osteoporosis (at least one vertebral fracture plus lumbar spine T score < −2.5) at baseline demonstrated that strontium ranelate increases BMD and decreases the incidence of vertebral fractures at the highest dose tested (2 g per day). At this dose, bone alkaline phosphatase increases and urinary excretion of N-telopeptides of type I collagen decreases.
Establishing and maintaining an optimal regimen usually requires considerable discussion with individual patients and is much easier if patients are well informed. The use of educational materials can be quite helpful, as can the efforts of a nurse or other office personnel. Effective prevention and treatment of osteoporosis is possible if the patient and clinician work together in a sustained fashion.
The osteoporosis patient’s adherence to the medication regimen is important. Baseline and follow-up BMD measurements (every 1 to 2 years) are important to assess response to therapy; these measurements may also improve adherence by providing visual information regarding the effectiveness of the therapy. Another way to inform patients about their response to therapy is to measure markers of bone resorption. In particular, adequate estrogen and bisphosphonate therapy will almost certainly decrease the levels of urine or serum markers of bone resorption within 3 to 6 months.
Most vertebral fractures are asymptomatic and are diagnosed by spinal radiographs. Over time, one may notice decreased height, increased kyphosis, or simply the fact that clothes no longer fit the person properly. Many older adults have chronic back pain due to the changes in the spine that occur with vertebral compression. In the case of symptomatic vertebral compression fractures, adequate pain control is essential. The pain usually lasts 2 to 4 weeks and can be quite debilitating. Nonsteroidal anti-inflammatory drugs and calcitonin can be tried; narcotics are commonly required to control the pain. Physical therapy is an important part of osteoporosis treatment programs for the management of acute and chronic pain, as well as for patient education. The physical therapist can provide postural exercises, alternative modalities for pain reduction, and information on changes in body mechanics that may help prevent future fractures. (See also Persistent Pain.) Support groups for patients with osteoporosis are also important. Newer treatments for vertebral fractures involve the injection of bone cement into the collapsed vertebra (vertebroplasty) or use of a balloon tamp into the fractured vertebrae (kyphoplasty). Although these methods have not been studied in randomized controlled studies, case reports suggest that they decrease pain and improve quality of life and function. Long-term benefits and complications have not yet been demonstrated; therefore, further study is required before these procedures are used routinely.
Osteomalacia, an impairment of bone mineralization, is much less common than osteoporosis and can be definitively diagnosed only by bone biopsy. The clinical syndrome associated with osteomalacia consists of pain, myopathy, and fracture. The most common cause of osteomalacia in older adults is vitamin-D deficiency as a result of inadequate intake. In addition, excessive use of phosphate-binding antacids, chronic use of anticonvulsants, chronic kidney failure, hepatobiliary disease, and malabsorption syndromes may also result in osteomalacia. The use of high-dose etidronate and fluoride may cause osteomalacia, albeit rarely. The symptoms of osteomalacia may be subtle, and thus the diagnosis may be delayed. Patients typically complain of diffuse bone pain and tenderness, proximal muscle weakness, and generalized fatigue. A characteristic waddling gait may result from the hip pain and thigh weakness. Laboratory studies typically demonstrate an elevated alkaline phosphatase, low phosphate, low or normal calcium, and low 25(OH)D levels. Plain radiographic films may show osteopenia or characteristic pseudofractures, most commonly seen in the proximal femur.
Osteomalacia is managed by treating the underlying cause. If vitamin-D deficiency is diagnosed, repletion can be accomplished with oral vitamin D, 1000 IU per day. Hypophosphatemia is corrected by the use of neutral phosphate salts, 500 mg four times daily. Patients on long-term anticonvulsant therapy may be supplemented with 400 to 800 IU of vitamin D daily. Osteomalacia due to hepatobiliary disease or chronic kidney failure is managed with supplemental 25(OH)D and 1,25(OH)2D, respectively.
■ Bauer DC, Ettinger B, Nevitt MC, et al. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med. 2001; 134(7):561–568.
This study evaluated the association between low levels of thyroid-stimulating hormone (TSH) and fracture in older women in case-cohort sampling from the Study of Osteoporotic Fractures (postmenopausal women > 65 years). Baseline calcaneal bone mineral density was measured, lateral spine films taken, and serum collected in all participants. Baseline serum samples were randomly selected from women with hip fracture (N = 148) and women with incident vertebral fracture (N = 149), and 398 women were randomly selected from the original cohort to be controls. TSH levels were then measured on archived serum in the case-cohort sample. The risk for hip and vertebral fractures was found to be higher in women with low TSH (≤ 0.1 mIU/L) after adjustment for age, history of previous hyperthyroidism, self-rated health, and use of estrogen and thyroid hormone. Previous history of hyperthyroidism, but not use of thyroid hormone itself, was associated with a higher risk of hip fracture. The authors concluded that women aged 65 years and older with low TSH levels are at increased risk for hip and vertebral fractures.
■ Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA. 2003; 290(13):1729–1738.
This is a randomized controlled trial of more than 16,000 women with an intact uterus aged 50 to 79 years. They were assigned either to placebo or to conjugated equine estrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg. The main outcome measure was confirmed osteoporotic fractures; bone mineral density (BMD) was measured in a subset of women. The study also evaluated a global index, which summarizes the risk and benefits of therapy, across tertiles of fracture risk. Estrogen plus progestin reduced hip fracture risk by 33% (hazard ratio: 0.67 [0.47 to 0.96 unadjusted and 0.41 to 1.10 adjusted]). The reduction in incident hip fracture was greater in women who took more that 1200 mg calcium per day. The risk of hip fracture was similarly reduced with estrogen-progestin therapy across age, smoking, falls, previous fracture history, past use of hormone replacement therapy, years since menopause, and summary fracture-risk score. BMD of the spine and hip was found to increase over time in the women receiving estrogen-progestin therapy, in comparison with placebo. Using the global index, the researchers found no evidence of a net benefit to estrogen-progestin, even in women at high risk of fracture. The authors conclude that although estrogen-progestin decreases hip fracture risk and increases BMD measurements, the overall risk-benefit ratio does not support the use of hormone therapy except in women with vasomotor symptoms.
■ Finklestein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate or both in men with osteoporosis. N Engl J Med. 2003;349(13):1216–1226.
This study examined the effect on bone of combining alendronate, an antiresorptive agent, with parathyroid hormone (PTH), an agent that increases both bone resorption and bone formation. Men (46 to 85 years) were randomly assigned to receive alendronate (10 mg per day), PTH (40 μg per day), or both. Bone mineral density (BMD) of the spine was the primary outcome; hip, radius, and total body BMD were also measured. Overall, PTH alone was found to increase spine (posterior-anterior and lateral) and femoral neck BMD and trabecular bone mineral density (measured by quantitative computed tomography) more than combination therapy or alendronate monotherapy. Total hip BMD was found to increase in the group receiving PTH in comparison with the alendronate group, and radial shaft BMD was found to increase slightly in the alendronate and combination group but to decrease slightly in the PTH group. In addition, serum alkaline phosphatase, a marker of bone formation, increased in the group receiving PTH alone in comparison with the other groups. The authors concluded that alendronate impairs the ability of PTH to stimulate new bone formation and to increase BMD of the spine and hip. This study suggests that the anabolic effects of PTH are dependent on the ability of PTH to stimulate bone resorption.
■ McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med. 2001;344(5):333–340.
This study examined the effect of risedronate on hip fractures in two groups of older women: women aged 70 to 79 years with osteoporosis and women aged 80 and older with at least one nonskeletal risk factor for hip fracture or low femoral neck bone mass. Women in each age group were randomly assigned to receive risedronate (2.5 or 5.0 mg) or placebo. The primary endpoint was hip fracture incidence over 3 years. Overall, risedronate was found to decrease the incidence of hip fractures (relative risk 0.7 [0.6 to 0.9]). In the group with osteoporosis (70 to 79 years), the relative risk was 0.6 (0.4 to 0.9) but in the group selected in the basis of risk factors, hip fracture risk did not decrease with treatment in comparison with placebo. The adverse-event profile was similar in the treatment and placebo groups. The authors concluded that risedronate can reduce hip fractures in older women with osteoporosis but not in older women selected on risk factors other than low bone mass. These data demonstrate the importance of bone mineral density measurement in identifying older women who will benefit from pharmacologic treatment.
■ Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000;343(9):604–610.
A 2-year double-blind, placebo-controlled trial of 10 mg of alendronate daily was carried out in 241 men with osteoporosis who were aged 31 to 87. Men with secondary causes of osteoporosis except for low serum testosterone were excluded from the study; 36% of the men studied had a low testosterone level. After 2 years, men in the alendronate group showed a 7.1% increase in bone density at the lumbar spine, but those in the placebo group showed a 1.8% increase. Comparison also showed significant increases in bone marrow density of the hip, trochanter, and femoral neck in the experimental group over the placebo group. On follow-up radiographs, 7.1% of the men in the placebo group were found to have sustained a vertebral fracture, whereas 0.8% in the alendronate group had a fracture (number needed to treat to prevent one fracture = 16). These results are comparable to the effects of alendronate observed in women and in persons with glucocorticoid-induced osteoporosis.
■ Prestwood KM, Kenny AM, Kleppinger A, et al. Ultralow-dose micronized 17β-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003:290(8):1042–1048.
This was 3-year placebo-controlled study examining the effect of 17β-estradiol on bone density and bone metabolism in older women (mean age 75 years). Older women were randomly assigned to receive 17β-estradiol (0.25 mg) or placebo daily; all women received for 1300 mg of elemental calcium plus 1000 IU of vitamin D per day. Women with an intact uterus received micronized progesterone 100 mg per day for 2 weeks every 6 months. This dose of estrogen significantly increased bone mineral density at the hip, spine, total body, and wrist in comparison with placebo. Bone alkaline phosphatase and N-telopeptides of type I collagen, markers of bone turnover, were found to significantly decrease in the treatment group in comparison with placebo. The adverse-event profiles of the two groups were similar. The authors concluded that ultralow-dose estrogen is beneficial to bone with minimal adverse effects and recommended a study to determine the effect of ultralow-dose estrogen on fractures.
■ Van Schoor NM, Smit JH, Twisk JWR, et al. Prevention of hip fractures by external hip protectors: a randomized controlled trial. JAMA. 2003;289(15):1957–1962.
This is a randomized controlled study to determine the effectiveness of hip protectors in preventing hip fracture in a group of persons at high risk for hip fracture. All persons were older than 70 years and had low bone density (as determined by broadband ultrasound measurement of the calcaneus) or a high risk for falling, or both. The primary outcome was time to first hip fracture, determined by using survival analysis. The overall incidence of hip fracture in the control group was 7%. Overall, there was no significant difference between the intervention and the control group with regard to time to first hip fracture. Eighteen hip fractures occurred in the hip protector group and 20 in the control group; the fracture rate was 5/100 in both groups. The authors concluded that hip protectors are not effective in preventing hip fractures in a high-risk population, possibly because adherence was good during the day but not at night.
Karen M. Prestwood, MD