CHAPTER 14
OSTEOPOROSIS
Carolyn Becker, M.D.
Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and greater susceptibility to fracture. The clinical manifestations of osteoporosis relate mainly to its associated fractures. Many diagnostic and therapeutic options have become available over the last 10 years. Osteoporosis should no longer be thought of as an inevitable consequence of aging, but as a condition to be prevented or treated.
Burden of Suffering
There are 1.5 million osteoporosis-related fractures each year in the United States: 300,000 hip, 700,000 spine, 250,000 wrist, and 250,000 others. Osteoporotic fractures occur with minimal trauma, usually a fall from standing height or less. They increase in frequency with age and have a higher incidence in women than men. A 50 year-old white woman has a 40 percent risk of fracture by age 80. The lifetime risk of a hip fracture is 15 percent in white women, eight percent in black women, and six percent in white men. Hip fractures are associated with a 15 to 25 percent reduction in expected survival in the first year, and are frequently associated with loss of independence in those who do survive. Men have a higher mortality rate than women within the first year after a hip fracture. Fifty percent of women who sustain a hip fracture never return to their previous lifestyle. Vertebral fractures lead to chronic pain and deformity known as kyphosis or the "dowager’s hump." Fractures of the wrist, ankle, knee, pelvis, and proximal humerus can also lead to significant disability. Overall, osteoporosis accounts for $14 billion in direct medical costs each year in the U.S. As the population ages, the incidence of fractures and their associated cost will increase dramatically.
Pathophysiology
Peak bone mass is achieved in early adulthood and is influenced by genetic heritage, adequate nutrition, normal sex steroid levels, and physical activity. Once peak bone mass is achieved, bone remodeling (or bone turnover) occurs throughout life in an orderly fashion, with osteoclastic bone resorption followed by osteoblastic new bone formation, a process called "coupling." When bone resorption outstrips bone formation, as occurs in early menopause, osteoporosis can result. The structure of bone is weakened by loss of trabecular plates and bones become fragile and much more likely to fracture with low impact trauma. Similarly, if the rate of bone resorption is normal but bone formation is severely depressed, as is the case in patients on glucocorticoids, severe osteoporosis can also occur. The recent discovery of a new family of cytokines, known as "RANK-ligand/osteoprotegerin" that appear to regulate "coupling" has greatly increased our understanding of bone remodeling and may ultimately lead to novel therapeutic interventions.
Risk Factors
Bone mass or bone mineral density (BMD) is the major predictor of future fracture risk. The balance of osteoclastic bone resorption and osteoblastic bone formation favors formation until around age 35, when bone density is at its peak. Both men and women then begin to lose bone at a slow rate of 0.3 to 0.5 percent per year beginning in the fourth decade. At menopause, some women experience accelerated bone loss at rates of up to three to five percent per year for five to seven years. Subsequently, the rate slows to one percent per year but loss continues throughout life.
In both men and women, the age-associated decrease in BMD leads to an increase in fracture risk. Every five years, the incidence of hip fracture doubles, from 4/1000 (age 70 to 74), to 9/1000 (age 75 to 79), to 17/1000 (age 80 to 84). Similarly, the risk of fracture approximately doubles for each standard deviation below the mean in BMD. In addition to low BMD, other significant risk factors for osteoporotic fracture were identified in the Study of Osteoporotic Fractures as listed in Table 1:
Table 1: Risk Factors for Osteoporotic Fracture
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Nonmodifiable |
Modifiable |
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The four items in boldface were independent risk factors for hip fracture in this study.
Of these risk factors, the single most important predictor of fracture is the history of a prior low trauma fracture. In particular, a vertebral fracture is highly predictive of both additional vertebral fractures as well as nonvertebral fractures. Additional risk factors for osteoporotic fractures include history of hyperthyroidism, anticonvulsant use, and higher caffeine intake.
Secondary causes of osteoporosis can usually be ruled out by a careful history, physical exam, and a few simple laboratory studies. Such causes include multiple myeloma and other hematologic malignancies, hypogonadism, malabsorption, hyperparathyroidism, vitamin D deficiency, hypercalciuria, alcoholism, and chronic liver disease. Medications such as glucocorticoids, anticonvulsants (particularly phenytoin and phenobarbital), excess thyroid hormone, and prolonged heparin are also associated with osteoporosis. Of these, exposure to chronic glucocorticoids represents the most important secondary cause of osteoporosis, affecting both men and women. While men and African American women have higher peak bone mass and a lower risk of osteoporosis, osteoporotic fractures do occur in these groups, especially with advanced age and other risk factors.
Prevention
Maximizing peak bone mass during childhood and adolescence and minimizing bone loss during and after menopause would help prevent much of the osteoporosis that we see today. Approximately 40 percent of peak bone mass is accrued around the time of menarche for girls and a few years later for boys. As a public health policy, all children, adolescents, and adults should be encouraged to get adequate calcium, vitamin D, and regular weight-bearing exercise. Walking, jogging, dancing, and low-impact aerobics represent excellent weight-bearing exercises. Swimming and biking are less beneficial in terms of the skeleton. Other general recommendations include smoking cessation, good general nutrition, and, in the elderly, fall prevention strategies. These may include provision of good lighting, sturdy shoes, unobstructed hallways in the home, appropriate walking aids, physical therapy, and hip padding. One percent of the 30 million falls in the U.S. every year result in hip fracture, and ninety percent of all hip fractures are due to a fall. Elderly patients with a slow or wide-based gait, ataxia, or weakness in the hip and knee extensors have a greatly increased risk of falling. Inability to rise out of a chair without pushing up with the arms or difficulty getting up on an exam table are signs of a patient at high risk for falling. Exercises such as tai chi may be helpful in some cases. For others, use of hip protectors worn over the trochanters may reduce the risk of hip fracture by 50-60 percent.
Screening
Screening tests for osteoporosis are grossly underutilized in clinical practice. Although there have been no randomized clinical trials of the effectiveness of screening for osteoporosis, BMD testing accurately predicts fracture risk and this risk can be modified once diagnosed. The USPS Task Force recommends that women aged 65 and older be routinely screened for osteoporosis, and that women with risk factors for osteoporotic fracture be screened starting at age 60. Osteoporosis experts also recommend routine screening for all individuals over age 50 who sustain low-trauma fractures, and all those initiating or continuing on glucocorticoid therapy for more than three months.
Plain x-rays are not useful for screening for osteoporosis as they reveal osteopenia only after 30 to 50 percent of bone mass has been lost. Fortunately, the dual energy x-ray absorptiometry (DEXA) scan is precise, accurate, painless, relatively fast, and involves minimal radiation exposure. Another device, the quantitative computerized tomography (QCT) is less popular due to greater radiation exposure.
Table 2: Recommendations for BMD testing
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Women |
Men |
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The World Health Organization has defined osteoporosis and osteopenia using BMD measurements. On most DEXA scans, the patient is scanned at several sites: the distal radius, femoral neck, total hip, and lumbar spine. The results are reported in bone mineral density (in gm/cm2) in comparison with age and sex-matched controls (Z-score) and in comparison with controls at "peak bone mass" or young adults (T-score). Normal bone mass is defined as a T-score within one standard deviation (SD) of the young adult mean. Osteopenia is defined as a T-score between one and 2.4 SD below the young adult mean, and osteoporosis is defined as a T-score of 2.5 SD or more below the young adult mean. Severe osteoporosis is defined as osteoporosis on BMD coupled with a history of a fragility fracture. A Z-score value more than two SD below age-matched controls is strongly suggestive of a secondary cause for osteoporosis and warrants a thorough evaluation.
Repeat BMD measurements may be useful for monitoring response to therapy or determining an individual’s rate of bone loss. Generally, BMD should not be repeated more frequently than once every one to two years. Exceptions to this include patients initiating glucocorticoids in whom bone loss can be very rapid, and, perhaps, monitoring of patients on parathyroid hormone (see below). Another means of assessing patients is by measuring biochemical markers of bone turnover. These include markers of bone formation (serum bone-specific alkaline phosphatase and osteocalcin) and markers of bone resorption (urinary excretion of collagen cross-linked N-telopeptide, C-telopeptide, hydroxyproline, or deoxypyridinioline). These markers are less precise than repeat BMD measurements in determining response to therapy but can be useful indicators of medication adherence and efficacy. There is some evidence that elevated markers of bone resorption may predict increased risk of fracture independently of BMD.
Treatment
The decision to initiate treatment for osteoporosis is dependent upon a number of factors such as age, risk for falls, previous fractures, and BMD value. As noted above, primary preventive measures for all individuals should include adequate calcium, vitamin D, exercise, and avoidance of excess alcohol or tobacco use. Beyond that, high-risk groups should also be considered for pharmacologic therapies that have been shown in clinical trials to significantly reduce the risk of fractures. This evidence will be reviewed below.
Calcium and Vitamin D are critical for preventing calcium deficiency, calcium malabsorption, secondary hyperparathyroidism and excessive bone loss. In children, adolescents, and young adults, calcium and vitamin D are critical for attainment of peak bone mass. In early menopause, supplemental calcium and vitamin D can slow the rate of bone loss but not prevent it. In elderly patients, however, these nutrients have been shown in clinical trials to reduce hip and other nonvertebral fractures. Recommended daily doses for elemental calcium include 1300 mg for young adolescents, 1000 mg for premenopausal women and men, and 1200-1500 mg for postmenopausal women. Recommended daily doses of Vitamin D include 400-600 IU for those less than age 70 and 600-800 IU daily for those over age 70. Food sources of calcium include milk, yogurt, cheese, calcium-fortified orange juice and certain green vegetables, but most people are unable to achieve optimal intake through diet alone. Vitamin D may be obtained from fortified milk and certain foods but most of it is produced in our skin by exposure to sunlight. Thus, individuals who are homebound or institutionalized and those who live in northern climates may suffer from profound vitamin D deficiency.
Calcium supplements vary in the amount of elemental calcium and in the efficacy of absorption. Calcium carbonate (Tums, Oscal, Caltrate, Viactiv) consists of 40 percent calcium but must be taken with food for optimal absorption. Calcium citrate (Citracal) has 24 percent calcium but may be taken with or without food and is better absorbed by elderly patients. Both forms of calcium should be given in divided doses, with no more than 500-600 mg calcium given at one time. Both forms can cause gas and constipation though side effects are somewhat less with calcium citrate. Calcium supplements that also contain magnesium may help alleviate constipation. Vitamin D is needed to promote calcium absorption and avoid osteomalacia (inability to mineralize bone matrix). Vitamin D supplements are available in standard multivitamins that contain 400 IU or may be found as part of the calcium supplement itself. Activated forms of vitamin D, such as calcitriol (Rocaltrol) are appropriate for patients with renal failure but otherwise should be avoided due to high cost and potential for hypercalcemia.
Hormone replacement therapy (HRT) has clearly been shown to prevent postmenopausal bone loss due to estrogen deficiency and to increase BMD at the spine and hip. Estrogen reduces cytokines such as interleukin-6 that cause an increase in bone resorption while it stimulates osteoprotegerin that reduces bone resorption. Thus, markers of bone turnover decrease in women who take estrogen. Epidemiologic studies have shown that 5 years of HRT is associated with a 50 to 60 percent reduction in hip fractures. However, there has been only one small randomized clinical trial showing a decrease in vertebral fractures with HRT and no large, prospective clinical trials demonstrating a decrease in nonvertebral fractures. A recent meta-analysis concluded that HRT appears to reduce nonvertebral fractures by 35 to 50 percent if initiated before age 60 but no other conclusions about anti-fracture efficacy could be derived from the existing data. Hopefully, the ongoing Women’s Health Initiative will help resolve this issue. In the meantime, HRT is FDA-approved only for the prevention but not the treatment of established osteoporosis. For many women, concerns about postmenopausal symptoms, uterine bleeding, and fears of thrombophlebitis, uterine, and breast cancer will outweigh skeletal considerations. Decisions regarding use of HRT in postmenopausal women are complex and discussed in Chapter 11.
Raloxifene (Evista) was the first SERM (Selective Estrogen Receptor Modulator) introduced for the prevention and treatment of postmenopausal osteoporosis. SERMS have high affinity for estrogen receptors but their effects vary according to the target tissue. Thus, raloxifene acts as an estrogen "antagonist" at the breast and endometrium but as an estrogen "agonist" at the skeleton and heart. In a large randomized clinical trial, (the Multiple Outcomes of Raloxifene Evaluation or MORE Trial), raloxifene 60 mg daily significantly reduced the incidence of new vertebral fractures by 30 percent in women with preexisting vertebral fractures and by 50 percent in women without preexisting fractures. However, the MORE study has not shown any benefit of raloxifene therapy on the risk of nonvertebral or hip fractures, despite maintenance of bone density at the hip. In fairness, though, the study was not powered to assess nonvertebral fracture risk.
Raloxifene has also demonstrated some very intriguing non-skeletal effects. After 4 years, raloxifene-treated women in the MORE trial have shown a 72 percent reduction in the risk of estrogen-receptor-positive, invasive breast cancer compared to placebo-treated women. Most recently, raloxifene was also shown to significantly decrease the risk of cardiovascular events in a subset of women who entered the MORE trial with increased cardiovascular risk factors. Raloxifene is known to have favorable effects on the lipid profile and C-reactive protein. But definitive evidence of benefit in reducing cardiovascular disease and breast cancer still awaits results from ongoing clinical trials (RUTH and STAR trials, respectively). Side effects of raloxifene include hot flashes, leg cramps, and venous thromboembolism.
Calcitonin is a bone-specific, antiresorptive agent that is approved for the treatment of vertebral osteoporosis in women who are five years or more post-menopause. It works by interfering with osteoclastic bone resorption. Calcitonin may be given as a subcutaneous injection or as a daily nasal spray (Miacalcin). In the Prevent Recurrence of Osteoporotic Fractures (PROOF) study, the 200 IU dose of nasal calcitonin increased BMD at the spine and significantly reduced new vertebral fractures by 33% after five years. However, it did not prevent bone loss from the hip and had no effect on hip or other nonvertebral fractures. In some patients, calcitonin may provide a mild, temporary analgesic effect following a painful vertebral fracture. Though well-tolerated and safe, calcitonin is generally considered to be a second- or third-line agent for patients with spinal osteoporosis.
Bisphosphonates are pyrophosphate analogs that bind to hydroxyapatite (bone tissue containing calcium and phosphorus) throughout the skeleton and are "ingested" by bone-resorbing osteoclasts. Once ingested, the nitrogen-containing bisphosphonates disrupt the cytoskeleton of the osteoclast, leading to premature apoptosis or "cellular death" of these cells. Thus, the bisphosphonates are powerful inhibitors of osteoclastic bone resorption. Currently, two oral bisphosphonates are approved for the prevention and treatment of osteoporosis: alendronate (Fosamax) and risedronate (Actonel). In the three year Fracture Intervention Trial (FIT-1), alendronate reduced new vertebral fractures by 47 percent, hip fractures by 51 percent, and forearm fractures by 48 percent in women with osteoporosis who already had at least one vertebral fracture. In the FIT-2 trial which looked at women without a prevalent vertebral fracture, alendronate significantly reduced vertebral, all clinical, and hip fractures only in patients with T-scores £ -2.5. Overall, alendronate resulted in an 11.4 percent increase in spinal BMD compared to placebo after 7.6 years of treatment, and it reduced markers of bone resorption by 70 percent. Alendronate is also approved for treatment of male osteoporosis and glucocorticoid-induced osteoporosis. The major side effects from alendronate are related to the upper gastrointestinal tract with abdominal pain, nausea, dyspepsia and heartburn occurring most often. Erosive esophagitis and gastritis have been described with the drug, though serious complications are quite rare. Due to poor absorption, alendronate must be taken first thing in the morning on a totally empty stomach with 6-8 ounces of water. Patients are advised not to lie down or eat for at least 30-60 minutes after the dose. Recently, a weekly 70 mg pill has been introduced as an alternative to the daily 10 mg tablet. Though there are no fracture data using the 70 mg pill, the effects on BMD have been indistinguishable from the daily 10 mg dose. It is hoped that the easier dosing regimen will lead to better compliance and perhaps better tolerability.
Risedronate was the second oral bisphosphonate approved for the prevention and treatment of postmenopausal osteoporosis as well as for glucocorticoid-induced osteoporosis. Like alendronate, treatment with risedronate results in significant reductions in vertebral and nonvertebral fractures in postmenopausal women. Moreover, over three years, it leads to significant increases in spinal and hip BMD and reduces markers of bone turnover. Interestingly, in a group of elderly women with marked osteoporosis at the hip (T-score <-4 or <-3 plus 1 or more other risk factors), risedronate led to a significant 40 percent reduction in hip fracture. However, in another group of elderly women (age > 80) who did not necessarily have osteoporosis, risedronate was not associated with a significant decrease in hip fracture. These results suggest that bisphosphonates have their greatest anti-fracture efficacy in patients with the most severe osteoporosis and that measurement of BMD is critical in deciding whom to treat with these drugs.
In addition to the oral bisphosphonates, two intravenous bisphosphonates are sometimes used in patients with severe osteoporosis when oral bisphosphonates are contraindicated or poorly tolerated. Neither drug is approved for this indication and neither drug has been shown to reduce fractures in clinical trials. Pamidronate (Aredia) is used for treatment of hypercalcemia of malignancy, multiple myeloma, Paget’s disease, and metastatic breast cancer to bone. For osteoporosis, it is given in a dose of 30 mg, 60 mg, or 90 mg intravenously over two hours, every three months and numerous small studies have shown improvements in BMD and reductions in bone turnover. Recently, another intravenous bisphosphonate, zoledronate (Zometa), was reported to show four to five percent increases in spinal BMD and three percent increases in hip BMD after one year when given at various different doses. Unlike pamidronate, zoledronate can be given more rapidly (over 15-30 minutes) and appears to have much greater anti-resorptive efficacy. A single four-mg IV dose resulted in the same increase in BMD and suppression of bone markers as smaller, more frequently administered doses given over the course of a year (0.25 mg, 0.5 mg, or 1 mg q 3 months or 2 mg q 6 months). Side effects include fever, myalgias, renal dysfunction, and potentially, hypocalcemia. A theoretical concern with zoledronate is whether bone turnover may be suppressed so profoundly that normal bone repair mechanisms are affected. Until these drugs are shown to be safe and efficacious in large numbers of patients with osteoporosis, they should be reserved for the rare patients with severe osteoporosis who are unable to take or unable to absorb alternative therapies.
Parathyroid Hormone (Forteo) is scheduled for release soon and will represent the first truly anabolic (bone-building) therapy for patients with osteoporosis. The paradox of parathyroid hormone (PTH) is that when it is continuously high, as in hyperparathyroidism, it is a cause of bone loss and osteoporosis. Yet when administered as a daily or intermittent therapy, PTH results in a net increase in BMD. PTH works by stimulating osteoblastic new bone formation, which is soon followed by osteoclastic bone resorption. Thus, bone turnover actually increases with PTH therapy but formation outstrips resorption and bone mass increases, similar to the situation in children and adolescents. In a large, prospective, randomized, placebo-controlled, double-blind trial, 20 mcg of PTH given by daily subcutaneous injection resulted in marked increases in spinal and hip bone density (10% and 2.5%, respectively), as well as a 65 percent reduction in vertebral fractures, and a 35 percent reduction in nonvertebral fractures in over 1600 postmenopausal women. Side effects included mild hypercalcemia and leg cramps but back pain and height loss were significantly reduced in the women receiving PTH. Other potential uses for PTH include treatment for male osteoporosis and glucocorticoid-induced osteoporosis. Clinical trial data suggest that skeletal gains from PTH persist after discontinuation of the drug, so long as antiresorptive therapy is initiated or continued at that point. Finally, PTH will come with a "black box" warning about an increase risk of osteosarcoma in rats that were given high doses of the drug from birth till death. There are no cases of endogenous or exogenous PTH causing cancer in humans but the drug may be limited to only two years of exposure. Other disadvantages of PTH include the need to administer by SC injection and the anticipated high cost.
Future Treatments under investigation include new SERMS, insulin-like growth factor-1, tibolone (a synthetic hormone modulator with estrogenic, androgenic, and progestin-like actions), osteoprotegerin (OPG), and the statins.
Summary
Primary care physicians should be aware of the high prevalence of osteoporosis in clinical practice. A recently published study that screened over 200,000 postmenopausal women from primary care practices across the U.S. found that nearly 50 percent of the women had low bone density.13 Primary care physicians have a responsibility to screen patients for osteoporosis and to offer effective therapies to those with low bone density and/or high risk of falling. By so doing, we can hopefully slow or reverse the epidemic of osteoporotic fractures in our aging population.