TREATMENT Osteoporosis MANAGEMENT OF PATIENTS WITH FRACTURES
Treatment of a patient with osteoporosis frequently involves management of acute fractures as well as treatment of the underlying disease. Hip fractures almost always require surgical repair if the patient is to become ambulatory again. Depending on the location and severity of the fracture, condition of the neighboring joint, and general status of the patient, procedures may include open reduction and internal fixation with pins and plates, hemiarthroplasties, and total arthroplasties. These surgical procedures are followed by intense rehabilitation in an attempt to return patients to their prefracture functional level. Long bone fractures (e.g., wrist) often require either external or internal fixation. Other fractures (e.g., vertebral, rib, and pelvic fractures) usually are managed with supportive care, requiring no specific orthopedic treatment.
Only ~25–30% of vertebral compression fractures present with sudden-onset back pain. For acutely symptomatic fractures, treatment with analgesics is required, including nonsteroidal anti-inflammatory agents and/or acetaminophen, sometimes with the addition of a narcotic agent (codeine or oxycodone). A few small, randomized clinical trials suggest that calcitonin may reduce pain related to acute vertebral compression fracture. Percutaneous injection of artificial cement (polymethylmethacrylate) into the vertebral body (vertebroplasty or kyphoplasty) may offer significant immediate pain relief in patients with severe pain from acute or subacute vertebral fractures. Safety concerns include extravasation of cement with neurologic sequelae and increased risk of fracture in neighboring vertebrae due to mechanical rigidity of the treated bone. Exactly which patients are the optimal candidates for this procedure remains unknown. Short periods of bed rest may be helpful for pain management, but in general, early mobilization is recommended because it helps prevent further bone loss associated with immobilization. Occasionally, use of a soft elastic-style brace may facilitate earlier mobilization. Muscle spasms often occur with acute compression fractures and can be treated with muscle relaxants and heat treatments.
Severe pain usually resolves within 6–10 weeks. More chronic severe pain might suggest the possibility of multiple myeloma or underlying metastatic disease. Chronic pain following vertebral fracture is probably not bony in origin; instead, it is related to abnormal strain on muscles, ligaments, and tendons and to secondary facet-joint arthritis associated with alterations in thoracic and/or abdominal shape. Chronic pain is difficult to treat effectively and may require analgesics, sometimes including narcotic analgesics. Frequent intermittent rest in a supine or semireclining position is often required to allow the soft tissues, which are under tension, to relax. Back-strengthening exercises (paraspinal) may be beneficial. Heat treatments help relax muscles and reduce the muscular component of discomfort. Various physical modalities, such as US and transcutaneous nerve stimulation, may be beneficial in some patients. Pain also occurs in the neck region, not as a result of compression fractures (which almost never occur in the cervical spine as a result of osteoporosis) but because of chronic strain associated with trying to elevate the head in a person with a significant thoracic kyphosis.
Multiple vertebral fractures often are associated with psychological symptoms; this is not always appreciated. The changes in body configuration and back pain can lead to marked loss of self-image and a secondary depression. Altered balance, precipitated by the kyphosis and the anterior movement of the body’s center of gravity, leads to a fear of falling, a consequent tendency to remain indoors, and the onset of social isolation. These symptoms sometimes can be alleviated by family support and/or psychotherapy. Medication may be necessary when depressive features are present. Multiple thoracic vertebral fractures may be associated with restrictive lung disease symptoms and increased pulmonary infections. Multiple lumbar vertebral fractures are often associated with abdominal pain, constipation, protuberance, and early satiety. Multiple vertebral fractures are associated with greater age-specific mortality.
Multiple studies show that the majority of patients presenting in adulthood with fractures are not evaluated or treated for osteoporosis. Estimates suggest only about 20% of fracture patients receive follow-up care. Patients who sustain acute fractures are at dramatically elevated risk for more fractures, particularly within the first several years, and pharmacologic intervention can reduce that risk substantially. Recently, several studies have demonstrated the effectiveness of a relatively simple and inexpensive program that reduces the risk of subsequent fractures. In the Kaiser system, it is estimated that a 20% decline in hip fracture occurrence was seen with the introduction of what is called a fracture liaison service. This typically involves a health care professional (usually a nurse) whose job is to coordinate follow-up care and education of fracture patients. If the Kaiser experience can be repeated, there would be significant savings of health care dollars, as well as a dramatic drop in hip fracture incidence and a marked improvement in morbidity and mortality among the aging population. MANAGEMENT OF THE UNDERLYING DISEASE
Patients presenting with typical osteoporosis-related fractures (certainly hip and spine) can be assumed to have osteoporosis and can be treated appropriately. Patients with osteoporosis by BMD are handled in a similar fashion. Other fracture patients and those with reduced bone mass can be classified according to their future risk of fracture and treated if that risk is sufficiently high. It must be emphasized, however, that risk assessment is an inexact science when applied to individual patients. Fractures are chance occurrences that can happen to anyone. Patients often do not understand the relative benefits of medications, compared to the perceived risks of the medications themselves. Risk Factor Reduction
Several tools exist for risk assessment. The most commonly available is the FRAX tool, developed by a working party for the WHO, and available as part of the report from many DXA machines. It is also available online (http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) (Fig. 35-7). In the United States, it has been estimated that it is cost-effective to treat a patient if the 10-year major fracture risk (including hip, clinical spine, proximal humerus, and tibia) from FRAX is ≥20% and/or the 10-year risk of hip fracture is ≥3%. FRAX is an imperfect tool because it does not include any assessment of fall risk and secondary causes are excluded when BMD is entered. Moreover, it does not include any term for multiple fractures or recent versus remote fracture. Nonetheless, it is useful as an educational tool for patients.
After risk assessment, patients should be thoroughly educated to reduce the impact of modifiable risk factors associated with bone loss and falling. All medications that increase risk of falls, bone loss, or fractures should be reviewed to ensure that they are necessary and being used at the lowest required dose. For those on thyroid hormone replacement, TSH testing should be performed to confirm that an excessive dose is not being used, because biochemical and symptomatic thyrotoxicosis can be associated with increased bone loss. In patients who smoke, efforts should be made to facilitate smoking cessation. Reducing risk factors for falling also include alcohol abuse treatment and a review of the medical regimen for any drugs that might be associated with orthostatic hypotension and/or sedation, including hypnotics and anxiolytics. If nocturia occurs, the frequency should be reduced, if possible (e.g., by decreasing or modifying diuretic use), because arising in the middle of sleep is a common precipitant of a fall. Patients should be instructed about environmental safety with regard to eliminating exposed wires, curtain strings, slippery rugs, and mobile tables. Avoiding stocking feet on wood floors, checking carpet condition (particularly on stairs), and providing good light in paths to bathrooms and outside the home are important preventive measures. Treatment for impaired vision is recommended, particularly a problem with depth perception, which is specifically associated with increased falling risk. Elderly patients with neurologic impairment (e.g., stroke, Parkinson’s disease, Alzheimer’s disease) are particularly at risk of falling and require specialized supervision and care. Nutritional Recommendations Calcium
A large body of data indicates that optimal calcium intake reduces bone loss and suppresses bone turnover. Recommended intakes from an Institute of Medicine report are shown in Table 35-5.
The National Health and Nutrition Examination Surveys (NHANES) have consistently documented that average calcium intakes fall considerably short of these recommendations. Food sources of calcium are dairy products (milk, yogurt, and cheese) and fortified foods such as certain cereals, waffles, snacks, juices, and crackers. Some of these fortified foods contain as much calcium per serving as milk. Green leafy vegetables and nuts, particularly almonds, are also sources of calcium, although their bioavailability may be lower than with dairy products. Calcium intake from the diet can also be assessed (Table 35-6) and calculators are available at NOF.org or NYSOPEP.org.
If a calcium supplement is required, it should be taken in doses sufficient to supplement dietary intake to bring total intake to the required level (1000–1200 mg/d). Doses of supplements should be ≤600 mg at a time, because the calcium absorption fraction decreases at higher doses. Calcium supplements should be calculated on the basis of the elemental calcium content of the supplement, not the weight of the calcium salt. Calcium supplements containing carbonate are best taken with food because they require acid for solubility. Calcium citrate supplements can be taken at any time. To confirm bioavailability, calcium supplements can be placed in distilled vinegar. They should dissolve within 30 min.
Several controlled clinical trials of calcium, mostly plus vitamin D, have confirmed reductions in clinical fractures, including fractures of the hip (~20–30% risk reduction). All recent studies of pharmacologic agents have been conducted in the context of calcium replacement (± vitamin D). Thus, it is standard practice to ensure an adequate calcium and vitamin D intake in patients with osteoporosis whether they are receiving additional pharmacologic therapy or not. A systematic review confirmed a greater BMD response to antiresorptive therapy when calcium intake was adequate.
Although side effects from supplemental calcium are minimal (eructation and constipation mostly with carbonate salts), individuals with a history of kidney stones should have a 24-h urine calcium determination before starting increased calcium to avoid significant hypercalciuria. Many studies confirm a small but significant increase in the risk of renal stones with calcium supplements, but not dietary calcium. A recent analysis of published data has suggested that high intakes of calcium from supplements are associated with an increase in the risk of heart disease. This is an evolving story with additional studies that confirm or refute this finding. Because high calcium supplement intakes increase the risk of renal stones and confer no extra benefit to the skeleton, the recommendation that total intakes should be between 1000 and 1200 mg/d is reasonable. Vitamin D
Vitamin D is synthesized in skin under the influence of heat and ultraviolet light (Chap. 32). However, large segments of the population do not obtain sufficient vitamin D to maintain what is now considered an adequate supply [serum 25(OH)D consistently >75 μmol/L (30 ng/mL)]. Because vitamin D supplementation at doses that would achieve these serum levels is safe and inexpensive, the Institute of Medicine (based on obtaining a serum level of 20 ng/mL) recommends daily intakes of 200 IU for adults <50 years of age, 400 IU for those 50–70 years, and 600 IU for those >70 years. Multivitamin tablets usually contain 400 IU, and many calcium supplements also contain vitamin D. Some data suggest that higher doses (≥1000 IU) may be required in the elderly and chronically ill. The Institute of Medicine report suggests that it is safe to take up to 4000 IU/d. For those with osteoporosis or those at risk of osteoporosis, 1000–2000 IU/d can usually maintain serum 25(OH)D above 30 ng/mL. Other Nutrients
Other nutrients such as salt, high animal protein intakes, and caffeine may have modest effects on calcium excretion or absorption. Adequate vitamin K status is required for optimal carboxylation of osteocalcin. States in which vitamin K nutrition or metabolism is impaired, such as with long-term warfarin therapy, have been associated with reduced bone mass. Research concerning cola intake is controversial but suggests a possible link to reduced bone mass through factors that are independent of caffeine. Although dark green leafy vegetables such as spinach and kale contain a fair amount of calcium, the high oxalate content reduces absorption of this calcium (but does not inhibit absorption of calcium from other food eaten simultaneously).
Magnesium is abundant in foods, and magnesium deficiency is quite rare in the absence of a serious chronic disease. Magnesium supplementation may be warranted in patients with inflammatory bowel disease, celiac disease, chemotherapy, severe diarrhea, malnutrition, or alcoholism. Dietary phytoestrogens, which are derived primarily from soy products and legumes (e.g., garbanzo beans [chickpeas] and lentils), exert some estrogenic activity but are insufficiently potent to justify their use in place of a pharmacologic agent in the treatment of osteoporosis.
Patients with hip fractures are often frail and relatively malnourished. Some data suggest an improved outcome in such patients when they are provided calorie and protein supplementation. Excessive protein intake can increase renal calcium excretion, but this can be corrected by an adequate calcium intake. Exercise
Exercise in young individuals increases the likelihood that they will attain the maximal genetically determined peak bone mass. Meta-analyses of studies performed in postmenopausal women indicate that weight-bearing exercise helps prevent bone loss but does not appear to result in substantial gain of bone mass. This beneficial effect wanes if exercise is discontinued. Most of the studies are short term, and a more substantial effect on bone mass is likely if exercise is continued over a long period. Exercise also has beneficial effects on neuromuscular function, and it improves coordination, balance, and strength, thereby reducing the risk of falling. A walking program is a practical way to start. Other activities, such as dancing, racquet sports, cross-country skiing, and use of gym equipment, are also recommended, depending on the patient’s personal preference and general condition. Even women who cannot walk benefit from swimming or water exercises, not so much for the effects on bone, which are quite minimal, but because of effects on muscle. Exercise habits should be consistent, optimally at least three times a week. PHARMACOLOGIC THERAPIES
Before the mid-1990s, estrogen treatment, either by itself or in concert with a progestin, was the primary therapeutic agent for prevention or treatment of osteoporosis. There are now a number of new medications approved for osteoporosis and more under development. Some are agents that specifically treat osteoporosis (bisphosphonates, calcitonin, denosumab, and teriparatide [1-34hPTH]); others, such as selective estrogen response modulators (SERMs) and, most recently, an estrogen/SERM combination medication, have broader effects. The availability of these drugs allows therapy to be tailored to the needs of an individual patient. Estrogens
A large body of clinical trial data indicates that various types of estrogens (conjugated equine estrogens, estradiol, estrone, esterified estrogens, ethinyl estradiol, and mestranol) reduce bone turnover, prevent bone loss, and induce small increases in bone mass of the spine, hip, and total body. The effects of estrogen are seen in women with natural or surgical menopause and in late postmenopausal women with or without established osteoporosis. Estrogens are efficacious when administered orally or transdermally. For both oral and transdermal routes of administration, combined estrogen/progestin preparations are now available in many countries, obviating the problem of taking two tablets or using a patch and oral progestin. Dose of Estrogen
For oral estrogens, the standard recommended doses have been 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine estrogens, and 5 μg/d for ethinyl estradiol. For transdermal estrogen, the commonly used dose supplies 50 μg estradiol per day, but a lower dose may be appropriate for some individuals. Dose-response data for conjugated equine estrogens indicate that lower doses (0.3 and 0.45 mg/d) are effective. Doses even lower have been associated with bone mass protection. Fracture Data
Epidemiologic databases indicate that women who take estrogen replacement have a 50% reduction, on average, of osteoporotic fractures, including hip fractures. The beneficial effect of estrogen is greatest among those who start replacement early and continue the treatment; the benefit declines after discontinuation to the extent that there is no residual protective effect against fracture by 10 years after discontinuation. The first clinical trial evaluating fractures as secondary outcomes, the Heart and Estrogen-Progestin Replacement Study (HERS) trial, showed no effect of hormone therapy on hip or other clinical fractures in women with established coronary artery disease. These data made the results of the Women’s Health Initiative (WHI) exceedingly important (Chap. 16). The estrogen-progestin arm of the WHI in >16,000 postmenopausal healthy women indicated that hormone therapy reduces the risk of hip and clinical spine fracture by 34% and reduces the risk of all clinical fractures by 24%. There was similar antifracture efficacy seen with estrogen alone in women who had had a hysterectomy.
A few smaller clinical trials have evaluated spine fracture occurrence as an outcome with estrogen therapy. They have consistently shown that estrogen treatment reduces the incidence of vertebral compression fracture.
The WHI has provided a vast amount of data on the multisystemic effects of hormone therapy. Although earlier observational studies suggested that estrogen replacement might reduce heart disease, the WHI showed that combined estrogen-progestin treatment increased risk of fatal and nonfatal myocardial infarction by ~29%, confirming data from the HERS study. Other important relative risks included a 40% increase in stroke, a 100% increase in venous thromboembolic disease, and a 26% increase in risk of breast cancer. Subsequent analyses have confirmed the increased risk of stroke and, in a substudy, showed a twofold increase in dementia. Benefits other than the fracture reductions noted above included a 37% reduction in the risk of colon cancer. These relative risks have to be interpreted in light of absolute risk (Fig. 35-8). For example, out of 10,000 women treated with estrogen-progestin for 1 year, there will be 8 excess heart attacks, 8 excess breast cancers, 18 excess venous thromboembolic events, 5 fewer hip fractures, 44 fewer clinical fractures, and 6 fewer colorectal cancers. These numbers must be multiplied by years of hormone treatment. There was no effect of hormone treatment on the risk of uterine cancer or total mortality.
It is important to note that these WHI findings apply specifically to hormone treatment in the form of conjugated equine estrogen plus medroxyprogesterone acetate. The relative benefits and risks of unopposed estrogen in women who had hysterectomies vary somewhat. They still show benefits against fracture occurrence and increased risk of venous thrombosis and stroke, similar in magnitude to the risks for combined hormone therapy. In contrast, though, the estrogen-only arm of WHI indicated no increased risk of heart attack or breast cancer. The data suggest that at least some of the detrimental effects of combined therapy are related to the progestin component. In addition, there is the possibility, suggested by primate data, that the risk accrues mainly to women who have some years of estrogen deficiency before initiating treatment. (The average woman in the WHI was more than 10 years from the last menstrual period). Nonetheless, there is reluctance among women to use estrogen/hormone therapy, and the U.S. Preventive Services Task Force has specifically suggested that estrogen/hormone therapy not be used for disease prevention. Mode of Action
Two subtypes of ERs, α and β, have been identified in bone and other tissues. Cells of monocyte lineage express both ERα and ERβ, as do osteoblasts. Estrogen-mediated effects vary with the receptor type. Using ER knockout mouse models, elimination of ERα produces a modest reduction in bone mass, whereas mutation of ERβ has less of an effect on bone. A male patient with a homozygous mutation of ERα had markedly decreased bone density as well as abnormalities in epiphyseal closure, confirming the important role of ERα in bone biology. The mechanism of estrogen action in bone is an area of active investigation (Fig. 35-5). Although data are conflicting, estrogens may inhibit osteoclasts directly. However, the majority of estrogen (and androgen) effects on bone resorption are mediated through paracrine factors produced by osteoblasts and osteocytes. These actions include decreasing RANKL production and increasing OPG production by osteoblasts. Progestins
In women with a uterus, daily progestin or cyclical progestins at least 12 days per month are prescribed in combination with estrogens to reduce the risk of uterine cancer. Medroxyprogesterone acetate and norethindrone acetate blunt the high-density lipoprotein response to estrogen, but micronized progesterone does not. Neither medroxyprogesterone acetate nor micronized progesterone appears to have an independent effect on bone; at lower doses of estrogen, norethindrone acetate may have an additive benefit. On breast tissue, progestins may increase the risk of breast cancer. SERMs
Two SERMs are used currently in postmenopausal women: raloxifene, which is approved for the prevention and treatment of osteoporosis as well as the prevention of breast cancer, and tamoxifen, which is approved for the prevention and treatment of breast cancer. A third SERM, bazedoxifene, has been complexed with conjugated estrogen, creating a tissue selective estrogen complex (TSEC). This agent has been approved for prevention of osteoporosis.
Tamoxifen reduces bone turnover and bone loss in postmenopausal women compared with placebo groups. These findings support the concept that tamoxifen acts as an estrogenic agent in bone. There are limited data on the effect of tamoxifen on fracture risk, but the Breast Cancer Prevention Study indicated a possible reduction in clinical vertebral, hip, and Colles’ fractures. The major benefit of tamoxifen is on breast cancer occurrence. The breast cancer prevention trial indicated that tamoxifen administration over 4–5 years reduced the incidence of new invasive and noninvasive breast cancer by ~45% in women at increased risk of breast cancer. The incidence of ER-positive breast cancers was reduced by 65%. Tamoxifen increases the risk of uterine cancer and increases risk of venous thrombosis, cataracts, and possibly stroke in postmenopausal women, limiting its use for breast cancer prevention in women at low or moderate risk.
Raloxifene (60 mg/d) has effects on bone turnover and bone mass that are very similar to those of tamoxifen, indicating that this agent is also estrogenic on the skeleton. The effect of raloxifene on bone density (+1.4–2.8% vs placebo in the spine, hip, and total body) is somewhat less than that seen with standard doses of estrogens. Raloxifene reduces the occurrence of vertebral fracture by 30–50%, depending on the population; however, there are no data confirming that raloxifene can reduce the risk of nonvertebral fractures over 8 years of observation.
Raloxifene, like tamoxifen and estrogen, has effects in other organ systems. The most beneficial effect appears to be a reduction in invasive breast cancer (mainly decreased ER-positive) occurrence of ~65% in women who take raloxifene compared to placebo. In a head-to-head study, raloxifene was as effective as tamoxifen in preventing breast cancer in high-risk women, and raloxifene is now FDA approved for this indication. In a further study, raloxifene had no effect on heart disease in women with increased risk for this outcome. In contrast to tamoxifen, raloxifene is not associated with an increase in the risk of uterine cancer or benign uterine disease. Raloxifene increases the occurrence of hot flashes but reduces serum total and low-density lipoprotein cholesterol, lipoprotein(a), and fibrinogen. Raloxifene, with positive effects on breast cancer and vertebral fractures, has become a useful agent for the treatment of the younger asymptomatic postmenopausal woman. In some women, a recurrence of menopausal hot flashes may occur. Usually this is evanescent, but occasionally, it is sufficiently impactful on daily life and sleep that the drug must be withdrawn. Raloxifene increases the risk of deep vein thrombosis and may increase the risk of death from stroke among older women. Consequently, it is not usually recommended for women over 70 years of age.
The main advantage of the bazedoxifene/conjugated estrogen compound is that the bazedoxifene protects uterine tissue from the effects of estrogen and makes it possible to avoid taking a progestin, while using an estrogen primarily for control of menopausal symptoms. The TSEC prevents bone loss somewhat more potently than raloxifene alone and appears safe for the breast. Mode of Action of Serms
All SERMs bind to the ER, but each agent produces a unique receptor-drug conformation. As a result, specific co-activator or co-repressor proteins are bound to the receptor (Chap. 2), resulting in differential effects on gene transcription that vary depending on other transcription factors present in the cell. Another aspect of selectivity is the affinity of each SERM for the different ERα and ERβ subtypes, which are expressed differentially in various tissues. These tissue-selective effects of SERMs offer the possibility of tailoring estrogen therapy to best meet the needs and risk factor profile of an individual patient. Bisphosphonates
Alendronate, risedronate, ibandronate, and zoledronic acid are approved for the prevention and treatment of postmenopausal osteoporosis. Alendronate, risedronate, and zoledronic acid are also approved for the treatment of steroid-induced osteoporosis, and risedronate and zoledronic acid are approved for prevention of steroid-induced osteoporosis. Alendronate, risedronate, and zoledronic acid are approved for treatment of osteoporosis in men.
Alendronate has been shown to decrease bone turnover and increase bone mass in the spine by up to 8% versus placebo and by 6% versus placebo in the hip. Multiple trials have evaluated its effect on fracture occurrence. The Fracture Intervention Trial provided evidence in >2000 women with prevalent vertebral fractures that daily alendronate treatment (5 mg/d for 2 years and 10 mg/d for 9 months afterward) reduces vertebral fracture risk by about 50%, multiple vertebral fractures by up to 90%, and hip fractures by up to 50%. Several subsequent trials have confirmed these findings (Fig. 35-9). For example, in a study of >1900 women with low bone mass treated with alendronate (10 mg/d) versus placebo, the incidence of all nonvertebral fractures was reduced by ~47% after only 1 year. In the United States, the 10-mg dose is approved for treatment of osteoporosis and 5 mg/d is used for prevention.
Trials comparing once-weekly alendronate, 70 mg, with daily 10-mg dosing have shown equivalence with regard to bone mass and bone turnover responses. Consequently, once-weekly therapy generally is preferred because of the low incidence of gastrointestinal side effects and ease of administration. Alendronate should be given with a full glass of water before breakfast, because bisphosphonates are poorly absorbed. Because of the potential for esophageal irritation, alendronate is contraindicated in patients who have stricture or inadequate emptying of the esophagus. It is recommended that patients remain upright for at least 30 min after taking the medication to avoid esophageal irritation. Cases of esophagitis, esophageal ulcer, and esophageal stricture have been described, but the incidence appears to be low. In clinical trials, overall gastrointestinal symptomatology was no different with alendronate than with placebo. Alendronate is also available in a preparation that contains vitamin D.
Risedronate also reduces bone turnover and increases bone mass. Controlled clinical trials have demonstrated 40–50% reduction in vertebral fracture risk over 3 years, accompanied by a 40% reduction in clinical nonspine fractures. The only clinical trial specifically designed to evaluate hip fracture outcome (HIP) indicated that risedronate reduced hip fracture risk in women in their seventies with confirmed osteoporosis by 40%. In contrast, risedronate was not effective at reducing hip fracture occurrence in older women (80+ years) without proven osteoporosis. Studies have shown that 35 mg of risedronate administered once weekly is therapeutically equivalent to 5 mg/d and that 150 mg once monthly is therapeutically equivalent to 35 mg once weekly. Patients should take risedronate with a full glass of plain water to facilitate delivery to the stomach and should not lie down for 30 min after taking the drug. The incidence of gastrointestinal side effects in trials with risedronate was similar to that of placebo. A new preparation, which allows risedronate to be taken with food, was recently approved.
Etidronate was the first bisphosphonate to be approved, initially for use in Paget’s disease and hypercalcemia. This agent has also been used in osteoporosis trials of smaller magnitude than those performed for alendronate and risedronate but is not approved by the FDA for treatment of osteoporosis. Etidronate probably has some efficacy against vertebral fracture when given as an intermittent cyclical regimen (2 weeks on, 2.5 months off). Its effectiveness against nonvertebral fractures has not been studied.
Ibandronate is the third amino-bisphosphonate approved in the United States. Ibandronate (2.5 mg/d) has been shown in clinical trials to reduce vertebral fracture risk by ~40% but with no overall effect on nonvertebral fractures. In a post hoc analysis of subjects with a femoral neck T-score of –3 or below, ibandronate reduced the risk of nonvertebral fractures by ~60%. In clinical trials, ibandronate doses of 150 mg/month PO or 3 mg every 3 months IV had greater effects on turnover and bone mass than did 2.5 mg/d. Patients should take oral ibandronate in the same way as other bisphosphonates, but with 1 h elapsing before other food or drink (other than plain water).
Zoledronic acid is a potent bisphosphonate with a unique administration regimen (5 mg by slow IV infusion annually). The data confirm that it is highly effective in fracture risk reduction. In a study of >7000 women followed for 3 years, zoledronic acid (three annual infusions) reduced the risk of vertebral fractures by 70%, nonvertebral fractures by 25%, and hip fractures by 40%. These results were associated with less height loss and disability. In the treated population, there was an increased risk of transient postdose symptoms (acute-phase reaction) manifested by fever, arthralgia, myalgias, and headache. The symptoms usually last less than 48 h. An increased risk of atrial fibrillation and transient but not permanent reduction in renal function was seen in comparison to placebo. Detailed evaluation of all bisphosphonates failed to confirm that these agents increased the risk of atrial fibrillation. Zoledronic acid is the only osteoporosis agent that has been studied in the elderly with a prior hip fracture. The risk of all clinical fractures was reduced significantly by about 35%, and there was a trend toward reduced risk of a second hip fracture (effect size similar to that seen above). There was also a reduction in mortality of about 30% that was not completely accounted for the reduced hip fracture risk.
Recently there has been concern about two potential side effects associated with bisphosphonate use. The first is osteonecrosis of the jaw (ONJ). ONJ usually follows a dental procedure in which bone is exposed (extractions or dental implants). It is presumed that the exposed bone becomes infected and dies. It is not uncommon among cancer victims with multiple myeloma or patients receiving high doses of bisphosphonates for skeletal metastases, but is rare among persons with osteoporosis on usual doses of bisphosphonates. The second side effect is called atypical femur fracture. These are unusual fractures that occur distal to the lesser trochanter and anywhere along the femoral shaft. They are often preceded by pain in the lateral thigh or groin that can be present for weeks or months before the fracture. The fractures occur with trivial trauma, sometimes completely spontaneously, and are primarily transverse, with a medial break when complete and minimally comminuted. A localized periosteal reaction, consistent with a stress fracture, is often seen in the lateral cortex (Fig. 35-10). The overall risk is low (suggested to be about one-one hundredth to one-tenth that of hip fracture) but appears to increase in incidence with long-term use of bisphosphonates. Although the fractures may be bisphosphonate related in many individuals, they clearly occur in patients with no prior bisphosphonate exposure. When complete, they require surgical fixation and may be difficult to heal. Anabolic medication may accelerate healing of these fractures in some patients, and surgery can sometimes be avoided. Patients initiating bisphosphonates need to be warned that if they develop thigh or groin pain they must notify their physician. Routine x-rays will sometimes pick up cortical thickening or even a stress fracture, but more commonly MRI or technetium bone scan is required. The presence of an abnormality requires at minimum a period of modified weight bearing and may need prophylactic rodding of the femur. It is important to realize that these fractures may be bilateral, and when an abnormality is found, the other femur should be investigated. Mode of Action
Bisphosphonates are structurally related to pyrophosphates, compounds that are incorporated into bone matrix. Bisphosphonates specifically impair osteoclast function and reduce osteoclast number, in part by inducing apoptosis. Recent evidence suggests that the nitrogen-containing bisphosphonates also inhibit protein prenylation, one of the end products in the mevalonic acid pathway, by inhibiting the enzyme farnesyl pyrophosphate synthase. This effect disrupts intracellular protein trafficking and ultimately may lead to apoptosis. Some bisphosphonates have very long retention in the skeleton and may exert long-term effects. The consequences of this, if any, are unknown. Calcitonin
Calcitonin is a polypeptide hormone produced by the thyroid gland (Chap. 34). Its physiologic role is unclear because no skeletal disease has been described in association with calcitonin deficiency or excess. Calcitonin preparations are approved by the FDA for Paget’s disease, hypercalcemia, and osteoporosis in women >5 years past menopause. Concerns have been raised about an increase in the incidence of cancer associated with calcitonin use. Initially, the cancer noted was of the prostate, but an analysis of all data suggested a more general increase in cancer risk. In Europe, the European Medicines Agency (EMA) has removed the osteoporosis indication, and an FDA Advisory Committee has voted for a similar change in the United States.
Injectable calcitonin produces small increments in bone mass of the lumbar spine. However, difficulty of administration and frequent reactions, including nausea and facial flushing, make general use limited. A nasal spray containing calcitonin (200 IU/d) is available for treatment of osteoporosis in postmenopausal women. One study suggests that nasal calcitonin produces small increments in bone mass and a small reduction in new vertebral fractures in calcitonin-treated patients versus those on calcium alone. There has been no proven effectiveness against nonvertebral fractures.
Calcitonin is not indicated for prevention of osteoporosis and is not sufficiently potent to prevent bone loss in early postmenopausal women. Calcitonin might have an analgesic effect on bone pain, both in the subcutaneous and possibly the nasal form. Mode of Action
Calcitonin suppresses osteoclast activity by direct action on the osteoclast calcitonin receptor. Osteoclasts exposed to calcitonin cannot maintain their active ruffled border, which normally maintains close contact with underlying bone. Denosumab
A novel agent that was given twice yearly by SC administration in a randomized controlled trial in postmenopausal women with osteoporosis has been shown to increase BMD in the spine, hip, and forearm and reduce vertebral, hip, and nonvertebral fractures over a 3-year period by 70, 40, and 20%, respectively (Fig. 35-11). Other clinical trials indicate ability to increase bone mass in postmenopausal women with low bone mass (above osteoporosis range) and in postmenopausal women with breast cancer treated with hormonal agents. Furthermore, a study of men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonist therapy indicated the ability of denosumab to improve bone mass and reduce vertebral fracture occurrence. Denosumab was approved by the FDA in 2010 for the treatment of postmenopausal women who have a high risk for osteoporotic fractures, including those with a history of fracture or multiple risk factors for fracture, and those who have failed or are intolerant to other osteoporosis therapy. Denosumab is also approved for the treatment of osteoporosis in men at high risk, men with prostate cancer on GnRH agonist therapy, and women with breast cancer on aromatase inhibitor therapy. Mode of Action
Denosumab is a fully human monoclonal antibody to RANKL, the final common effector of osteoclast formation, activity, and survival. Denosumab binds to RANKL, inhibiting its ability to initiate formation of mature osteoclasts from osteoclast precursors and to bring mature osteoclasts to the bone surface and initiate bone resorption. Denosumab also plays a role in reducing the survival of the osteoclast. Through these actions on the osteoclast, denosumab induces potent antiresorptive action, as assessed biochemically and histomorphometrically, and may contribute to the occurrence of ONJ. Atypical femur fractures have also been noted. Serious adverse reactions include hypocalcemia, skin infections (usually cellulitis of the lower extremity), and dermatologic reactions such as dermatitis, rashes, and eczema. The effects of denosumab are rapidly reversible. If denosumab is stopped, bone will be lost rapidly if another agent is not used. Parathyroid Hormone
Endogenous PTH is an 84-amino-acid peptide that is largely responsible for calcium homeostasis (Chap. 34). Although chronic elevation of PTH, as occurs in hyperparathyroidism, is associated with bone loss (particularly cortical bone), PTH when given exogenously as a daily injection exerts anabolic effects on bone. Teriparatide (1-34hPTH) is approved for the treatment of osteoporosis in both men and women at high risk for fracture. In a pivotal study (median time of treatment, 19 months’ duration), 20 μg of teriparatide daily by SC injection reduced vertebral fractures by 65% and nonvertebral fractures by 45% (Fig. 35-12). Treatment is administered as a single daily injection given for a maximum of 2 years. Teriparatide produces increases in bone mass and mediates architectural improvements in skeletal structure. These effects are lower when patients have been exposed previously to bisphosphonates, possibly in proportion to the potency of the antiresorptive effect. When teriparatide is being considered for treatment-naive patients, it is best administered as monotherapy and followed by an antiresorptive agent such as a bisphosphonate. If teriparatide treatment is not followed by an antiresorptive agent, the bone gained is rapidly lost.
Side effects of teriparatide are generally mild and can include leg cramps, muscle pain, weakness, dizziness, headache, and nausea. Rodents given prolonged treatment with PTH in relatively high doses developed osteogenic sarcomas. Long-term surveillance studies suggest no association between 2 years of teriparatide administration and osteosarcoma risk in humans.
PTH use may be limited by its mode of administration; alternative modes of delivery are being investigated. The optimal frequency of administration also remains to be established, and it is possible that PTH might be effective when used intermittently. Cost also may be a limiting factor. In some settings, the effect of PTH might be enhanced by combination with an antiresorptive agent. This might be particularly important in patients who have been treated previously with bisphosphonate medications. Mode of Action
Exogenously administered PTH appears to have direct actions on osteoblast activity, with biochemical and histomorphometric evidence of de novo bone formation early in response to PTH, before activation of bone resorption. Subsequently, PTH activates bone remodeling but still appears to favor bone formation over bone resorption. PTH stimulates Wnt signaling, IGF-I, and collagen production and appears to increase osteoblast number by stimulating replication, enhancing osteoblast recruitment, and inhibiting apoptosis. Unlike all other treatments, PTH produces a true increase in bone tissue and an apparent restoration of bone microarchitecture (Fig. 35-13). Fluoride
Fluoride has been available for many years and is a potent stimulator of osteoprogenitor cells when studied in vitro. It has been used in multiple osteoporosis studies with conflicting results, in part because of the use of varying doses and preparations. Despite increments in bone mass of up to 10%, there are no consistent effects of fluoride on vertebral or nonvertebral fracture; the latter may actually increase when high doses of fluoride are used. Fluoride remains an experimental agent despite its long history and multiple studies. Strontium Ranelate
Strontium ranelate is approved in several European countries for the treatment of osteoporosis. It increases bone mass throughout the skeleton; in clinical trials, the drug reduced the risk of vertebral fractures by 37% and that of nonvertebral fractures by 14%. It appears to be modestly antiresorptive while at the same time not causing as much of a decrease in bone formation (measured biochemically). Strontium is incorporated into hydroxyapatite, replacing calcium, a feature that might explain some of its fracture benefits. Small increased risks of venous thrombosis, sometimes severe dermatologic reactions, seizures, and abnormal cognition have been seen and require further study. An increase in risk of cardiovascular disease has also been associated with use of strontium, such that the EMA has restricted its use at present. Other Potential Anabolic Agents
Several small studies of growth hormone (GH), alone or in combination with other agents, have not shown consistent or substantial positive effects on skeletal mass. Many of these studies have been relatively short term, and the effects of GH, growth hormone–releasing hormone, and the IGFs are still under investigation. Anabolic steroids, mostly derivatives of testosterone, act primarily as antiresorptive agents to reduce bone turnover but also may stimulate osteoblastic activity. Effects on bone mass remain unclear but appear weak in general, and use is limited by masculinizing side effects. Several observational studies suggested that the statin drugs, used to treat hypercholesterolemia, may be associated with increased bone mass and reduced fractures, but conclusions from clinical trials have been largely negative. Early studies with sclerostin antibodies, which inhibit sclerostin, activate Wnt, and might be highly anabolic to bone, are under development. Odanacatib is a mixed antiresorptive, partial bone formation stimulator that is currently in the late stages of development. NONPHARMACOLOGIC APPROACHES
In some early studies, protective pads worn around the outer thigh, which cover the trochanteric region of the hip, were able to prevent hip fractures in elderly residents in nursing homes. Randomized controlled trials of hip protectors have been unable to confirm these early findings. Therefore, the efficacy of hip protectors remains controversial at this time.
Kyphoplasty and vertebroplasty are also useful nonpharmacologic approaches for the treatment of painful vertebral fractures. However, no long-term data are available. TREATMENT MONITORING
There are currently no well-accepted guidelines for monitoring treatment of osteoporosis. Because most osteoporosis treatments produce small or moderate bone mass increments on average, it is reasonable to consider BMD as a monitoring tool. Changes must exceed ~4% in the spine and 6% in the hip to be considered significant in any individual. The hip is the preferred site due to larger surface area and greater reproducibility. Medication-induced increments may require several years to produce changes of this magnitude (if they do at all). Consequently, it can be argued that BMD should be repeated at intervals >2 years. Only significant BMD reductions should prompt a change in medical regimen, because it is expected that many individuals will not show responses greater than the detection limits of the current measurement techniques.
Biochemical markers of bone turnover may prove useful for treatment monitoring, but little hard evidence currently supports this concept; it remains unclear which endpoint is most useful. If bone turnover markers are used, a determination should be made before therapy is started and repeated ≥4 months after therapy is initiated. In general, a change in bone turnover markers must be 30–40% lower than the baseline to be significant because of the biologic and technical variability in these tests. A positive change in biochemical markers and/or bone density can be useful to help patients adhere to treatment regimens.