InternalMed_Harrison

InternalMed_Harrison. Biochemical markers of bone turnover may: Predict risk of fracture independently of bone density. Predict extent of fracture risk reduction when repeated after 3–6 months of treatment with FDA-approved therapies. Predict magnitude of BMD increases with FDA-approved therapies. Predict rapidity of bone loss. Help determine adequacy of patient compliance and persistence with osteoporosis therapy. • Help determine duration of “drug holiday” (data are quite limited to support this use, but studies are under way). Abbreviations: BMD, bone mineral density; FDA, U.S. Food and Drug Administration. Source: Adapted from the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and Treatment of Osteoporosis. © National Osteoporosis Foundation.


InternalMed_Harrison

InternalMed_Harrison. Biochemical markers of bone resorption may help in the prediction of fracture risk, independently of bone density, particularly in older individuals. In women ≥65 years, when bone density results are greater than the usual treatment thresholds noted above, a high level of bone resorption should prompt consideration of treatment. The primary use of biochemical markers is for monitoring the response to treatment. With the introduction of antiresorptive therapeutic agents, bone remodeling declines rapidly, with the fall in resorption occurring earlier than the fall in formation. Inhibition of bone resorption is maximal within 3 months or so. Thus, measurement of bone resorption (C-telopeptide [CTX] is the preferred marker) before initiating therapy and 3–6 months after starting therapy provides an earlier estimate of patient response than does bone densitometry. A decline in resorptive markers can be ascertained after treatment with potent antiresorptive agents such as bisphosphonates,


InternalMed_Harrison

InternalMed_Harrison. an earlier estimate of patient response than does bone densitometry. A decline in resorptive markers can be ascertained after treatment with potent antiresorptive agents such as bisphosphonates, denosumab, or standard-dose estrogen; this effect is less marked after treatment with weaker agents such as raloxifene or intranasal calcitonin. A biochemical marker response to therapy is particularly useful for asymptomatic patients and may help ensure long-term adherence to treatment. Bone turnover markers are also useful in monitoring the effects of osteoanabolic agents such as 1-34hPTH, or teriparatide, which rapidly increases bone formation (P1NP is preferred, but osteocalcin is a reasonable alternative) and later bone resorption. The recent suggestion of “drug holidays” (see below) has created another use for biochemical markers, allowing evaluation of the off effect of drugs such as bisphosphonates.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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,


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 trans-cutaneous nerve stimulation, may be beneficial in some patients. Pain also occurs in the neck region, not as a result of compression


InternalMed_Harrison

InternalMed_Harrison. of discomfort. Various physical modalities, such as US and trans-cutaneous 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 425-7). 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 FIGURE 425-7 FRAX calculation tool. When the answers to the indicated questions are filled in, the calculator can be used to assess the 10-year probability of fracture. The calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk adjust for various ethnic groups.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 425-5. 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 Estimated Adequate Daily Life Stage Group Calcium Intake, mg/d Note: Pregnancy and lactation needs are the same as for nonpregnant women (e.g., 1300 mg/d for adolescents/young adults and 1000 mg/d for ≥19 years). Source: Adapted from the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board. Institute of Medicine. Washington, DC, 1997, National Academy Press. STEP 1: Estimate calcium intake from calcium-rich foods


InternalMed_Harrison

InternalMed_Harrison. STEP 1: Estimate calcium intake from calcium-rich foods Estimated # of calcium/ Product Servings/d serving, in mg Calcium in mg Milk (8 oz.) __________ × 300 = __________ Yogurt (6 oz.) __________ × 300 = __________ Cheese (1 oz. or 1 cubic in.) __________ × 200 = __________ Fortified foods or juices __________ × 80 to 1000 = __________ STEP 2: Total from above + 250 mg for nondairy sources = total dietary calcium TOTAL Calcium, in mg = __________ Source: Adapted from SM Krane, MF Holick, Chap. 355, in Harrison’s Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998.


InternalMed_Harrison

InternalMed_Harrison. Source: Adapted from SM Krane, MF Holick, Chap. 355, in Harrison’s Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998. 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 425-6) and calculators are available at NOF.org or NYSOPEP.org.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. vitamin d Vitamin D is synthesized in skin under the influence of heat and ultraviolet light (Chap. 423). 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 2497 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 2498 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 413). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 425-8). 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


InternalMed_Harrison

InternalMed_Harrison. in light of absolute risk (Fig. 425-8). 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.


InternalMed_Harrison

InternalMed_Harrison. 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 Number of casesin 10,000 women/year


InternalMed_Harrison

InternalMed_Harrison. Number of casesin 10,000 women/year FIGURE 425-8 Effects of hormone therapy on event rates: green, placebo; purple, estrogen and progestin. CHD, coronary heart disease; VTE, venous thromboembolic events. (Adapted from Women’s Health Initiative. WHI HRT Update. Available at http://www.nhlbi.nih.gov/health/ women/upd2002.htm.) 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 425-5). 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 post-menopausal women, limiting its use for breast cancer prevention in women at low or moderate risk.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 400e), 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.


InternalMed_Harrison

InternalMed_Harrison. Bisphosphonates Alendronate, risedronate, ibandronate, and zoledronic acid are approved for the prevention and treatment of post-menopausal 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.


InternalMed_Harrison

InternalMed_Harrison. 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 2499 by up to 50%. Several subsequent trials have confirmed these findings (Fig. 425-9). 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. 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 Alendronate Risedronate Ibandronate Zoledronate pooled, post hoc pooled, post hoc preplanned preplanned Percent of patients


InternalMed_Harrison

InternalMed_Harrison. Alendronate Risedronate Ibandronate Zoledronate pooled, post hoc pooled, post hoc preplanned preplanned Percent of patients Alendronate pooled, post hoc Risedronate pooled, post hoc Zoledronate preplanned * * 0 12 24 36 0 5 10 15 Percent of patients PLB ALN 27%˜* * * ** * ** * * * PLB RIS 0 0 12 24 36 5 10 15 59%˜* 0 0 12 24 36 5 10 15 PLB ZOL 25%˜* ? Cumulative incidence of hip fractures over 3 years Time to first hip fracture (months)


InternalMed_Harrison

InternalMed_Harrison. FIGURE 425-9 Effects of various bisphosphonates on clinical vertebral fractures (A), nonvertebral fractures (B), and hip fractures (C). PLB, placebo; RRR, relative risk reduction. (After DM Black et al: J Clin Endocrinol Metab 85:4118, 2000; C Roux et al: Curr Med Res Opin 4:433, 2004; CH Chesnut et al: J Bone Miner Res 19:1241, 2004; DM Black et al: N Engl J Med 356:1809, 2007; JT Harrington et al: Calcif Tissue Int 74:129, 2003.) not permanent reduction in renal function was seen in comparison fractures was reduced significantly by about 35%, and there was to placebo. Detailed evaluation of all bisphosphonates failed to a trend toward reduced risk of a second hip fracture (effect size confirm that these agents increased the risk of atrial fibrillation. similar to that seen above). There was also a reduction in mortality Zoledronic acid is the only osteoporosis agent that has been stud-of about 30% that was not completely accounted for the reduced ied in the elderly with a prior hip


InternalMed_Harrison

InternalMed_Harrison. was also a reduction in mortality Zoledronic acid is the only osteoporosis agent that has been stud-of about 30% that was not completely accounted for the reduced ied in the elderly with a prior hip fracture. The risk of all clinical hip fracture risk.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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. 425-10). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. FIGURE 425-10 An atypical femur fracture (AFF) of the femoral diaphysis. A. Note the transverse fracture line in the lateral cortex that becomes oblique as it progresses medially across the femur (white arrow). B. On radiograph obtained immediately after intramedullary rod placement, a small area of periosteal thickening of the lateral cortex is visible (white arrow). C. On radiograph obtained at 6 weeks, note callus formation of the fracture site (white arrow). D. On radiograph obtained at 3 months, there is a mature callus that has failed to bridge the cortical gap (white arrow). Note the localized periosteal and/or endosteal thickening of the lateral cortex at the fracture site (white arrow). (From E Shane et al: J Bone Min Res 29:1-23, 2014. Courtesy of Fergus McKiernan.) acid pathway, by inhibiting the enzyme farnesyl pyrophosphate 2501 synthase. This effect disrupts intracellular protein trafficking and ultimately may lead to apoptosis. Some bisphosphonates have very long


InternalMed_Harrison

InternalMed_Harrison. by inhibiting the enzyme farnesyl pyrophosphate 2501 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.


InternalMed_Harrison

InternalMed_Harrison. Calcitonin Calcitonin is a polypeptide hormone produced by the thyroid gland (Chap. 424). 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.


InternalMed_Harrison

InternalMed_Harrison. 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 calcitonintreated 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 425-11). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. Effect of teriparatide on the risk of new vertebral fractures


InternalMed_Harrison

InternalMed_Harrison. Effect of teriparatide on the risk of new vertebral fractures Relative: Relative: 10 65% 69% Absolute: Absolute: 40 9.3% 9.9% Number of women with 1 or % of women % of women Effect of teriparatide on the risk of nonvertebral fragility fractures Relative: 53% Absolute: 2.9% Relative: 54% Absolute: 3.0% Risk reduction Placebo TPTD20 TPTD40 30 14 14 Number of women with


InternalMed_Harrison

InternalMed_Harrison. Relative: 53% Absolute: 2.9% Relative: 54% Absolute: 3.0% Risk reduction Placebo TPTD20 TPTD40 30 14 14 Number of women with Effect of teriparatide on the risk of nonvertebral fragility fractures (time to first fracture) *P <0.05 vs. placebo PlaceboTPTD20 TPTD40 * * % of women** tures (A) and nonvertebral fragility fractures (B and C). (After RM Neer et al: N Engl J Med 344:1434, 2001.) 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.


InternalMed_Harrison

InternalMed_Harrison. 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 FIGURE 425-11 Effects of denosumab on new vertebral fractures (A) and times to nonvertebral and hip fracture (B and C). RR, relative risk. (After SR Cummings et al: N Engl J Med 361:756, 2009.) If denosumab is stopped, bone will be lost rapidly if another agent is not used.


InternalMed_Harrison

InternalMed_Harrison. Parathyroid Hormone Endogenous PTH is an 84-amino-acid peptide that is largely responsible for calcium homeostasis (Chap. 424). 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. 425-12). Treatment is administered as 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.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 425-13 Effect of parathyroid hormone (PTH) treatment on bone microarchitecture. Paired biopsy specimens from a 64-year-old woman before (A) and after (B) treatment with PTH. (From DW Dempster et al: J Bone Miner Res 16:1846, 2001.) 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. 425-13).


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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, 2503 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Osteoporotic fractures are a well-characterized consequence of the hypercortisolism associated with Cushing’s syndrome. However, the therapeutic use of glucocorticoids is by far the most common form of glucocorticoid-induced osteoporosis. Glucocorticoids are used widely in the treatment of a variety of disorders, including chronic lung disorders, rheumatoid arthritis and other connective tissue diseases, inflammatory bowel disease, and after transplantation. Osteoporosis and related fractures are serious side effects of chronic glucocorticoid therapy. Because the effects of glucocorticoids on the skeleton are often superimposed on the consequences of aging and menopause, it is not surprising that women and the elderly are most frequently affected. The skeletal response to steroids is remarkably heterogeneous, however, and even young, growing individuals treated with glucocorticoids can present with fractures.


InternalMed_Harrison

InternalMed_Harrison. The risk of fractures depends on the dose and duration of glucocorticoid therapy, although recent data suggest that there may be no completely safe dose. Bone loss is more rapid during the early months of treatment, and trabecular bone is affected more severely than cortical bone. As a result, fractures have been shown to increase within 3 months of steroid treatment. There is an increase in fracture risk in both the axial skeleton and the appendicular skeleton, including risk of hip fracture. Bone loss can occur with any route of steroid administration, including high-dose inhaled glucocorticoids and intraarticular 2504 injections. Alternate-day delivery does not appear to ameliorate the skeletal effects of glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. Glucocorticoids increase bone loss by multiple mechanisms, including (1) inhibition of osteoblast function and an increase in osteoblast apoptosis, resulting in impaired synthesis of new bone; (2) stimulation of bone resorption, probably as a secondary effect; (3) impairment of the absorption of calcium across the intestine, probably by a vitamin D–independent effect; (4) increase of urinary calcium loss and perhaps induction of some degree of secondary hyperparathyroidism; (5) reduction of adrenal androgens and suppression of ovarian and testicular secretion of estrogens and androgens; and (6) induction of glucocorticoid myopathy, which may exacerbate effects on skeletal and calcium homeostasis as well as increase the risk of falls.


InternalMed_Harrison

InternalMed_Harrison. Because of the prevalence of glucocorticoid-induced bone loss, it is important to evaluate the status of the skeleton in all patients starting or already receiving long-term glucocorticoid therapy. Modifiable risk factors should be identified, including those for falls. Examination should include testing of height and muscle strength. Laboratory evaluation should include an assessment of 24-h urinary calcium. All patients on long-term (>3 months) glucocorticoids should have measurement of bone mass at both the spine and the hip using DXA. If only one skeletal site can be measured, it is best to assess the spine in individuals <60 years and the hip in those >60 years.


InternalMed_Harrison

InternalMed_Harrison. Bone loss caused by glucocorticoids can be prevented and the risk of fractures significantly reduced. Strategies must include using the lowest dose of glucocorticoid for disease management. Topical and inhaled routes of administration are preferred, where appropriate. Risk factor reduction is important, including smoking cessation, limitation of alcohol consumption, and participation in weight-bearing exercise, when appropriate. All patients should receive an adequate calcium and vitamin D intake from the diet or from supplements. Several bisphosphonates (alendronate, risedronate, and zoledronic acid) have been demonstrated in large clinical trials to reduce the risk of vertebral fractures in patients being treated with glucocorticoids, as well as improve bone mass in spine and hip. Teriparatide also improves bone mass and reduces fracture risk in glucocorticoid-treated osteoporosis compared to an active comparator (alendronate).


InternalMed_Harrison

InternalMed_Harrison. Paget’s Disease and Other Dysplasias of Bone Murray J. Favus, Tamara J. Vokes PAGET’S DISEASE OF BONE Paget’s disease is a localized bone-remodeling disorder that affects 426e widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation, resulting in a structurally disorganized mosaic of woven and lamellar bone. Pagetic bone is expanded, less compact, and more vascular; thus, it is more susceptible to deformities and fractures. Although most patients are asymptomatic, symptoms resulting directly from bony involvement (bone pain, secondary arthritis, fractures) or secondarily from the expansion of bone causing compression of surrounding neural tissue are not uncommon. Epidemiology There is a marked geographic variation in the frequency of Paget’s disease, with high prevalence in Western


InternalMed_Harrison

InternalMed_Harrison. Epidemiology There is a marked geographic variation in the frequency of Paget’s disease, with high prevalence in Western Europe (Great Britain, France, and Germany, but not Switzerland or Scandinavia) and among those who have immigrated to Australia, New Zealand, South Africa, and North and South America. The disease is rare in native populations of the Americas, Africa, Asia, and the Middle East; when it does occur, the affected subjects usually have evidence of European ancestry, supporting the migration theory. For unclear reasons, the prevalence and severity of Paget’s disease are decreasing, and the age of diagnosis is increasing.


InternalMed_Harrison

InternalMed_Harrison. The prevalence is greater in males and increases with age. Autopsy series reveal Paget’s disease in about 3% of those over age 40. Prevalence of positive skeletal radiographs in patients over age 55 is 2.5% for men and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per 100,000 person-years in men and women, respectively. Etiology The etiology of Paget’s disease of bone remains unknown, but evidence supports both genetic and viral etiologies. A positive family history is found in 15–25% of patients and, when present, raises the prevalence of the disease sevento tenfold among first-degree relatives.


InternalMed_Harrison

InternalMed_Harrison. A clear genetic basis has been established for several rare familial bone disorders that clinically and radiographically resemble Paget’s disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin (Fig. 426e-1), causes juvenile Paget’s disease, also known as familial idiopathic hyperphosphatasia, a disorder characterized by uncontrolled osteoclastic differentiation and resorption. Familial patterns of disease in several large kindred are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget’s disease are associated with mutations in TNFRSF11A gene, which encodes RANK (receptor activator of nuclear factor-κB), a member of the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 426e-1). Finally, mutations in the gene for valosin-containing protein cause a rare


InternalMed_Harrison

InternalMed_Harrison. nuclear factor-κB), a member of the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 426e-1). Finally, mutations in the gene for valosin-containing protein cause a rare syndrome with autosomal dominant inheritance and variable penetrance known as inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD). The role of genetic factors is less clear in the more common form of late-onset Paget’s disease. Although a few families with mutations in the gene encoding RANK have been reported, the most common mutations identified in familial and sporadic cases of Paget’s disease have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in the C-terminal ubiquitin-binding domain. The p62 protein is involved in nuclear factor κB (NF-κB) signaling and regulates osteoclastic differentiation. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may


InternalMed_Harrison

InternalMed_Harrison. and regulates osteoclastic differentiation. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may influence clinical expression of the disease.


InternalMed_Harrison

InternalMed_Harrison. Mesenchymal cell Collagen osteocalcin Osteoclast Osteoclast precursor Osteoblasts Osteoblasts IGF-1 IGF-2 OPG M-CSF IL-1, IL-6 c-fms + RANK L RANK


InternalMed_Harrison

InternalMed_Harrison. FIGurE 426e-1 Diagram illustrating factors that promote differentiation and function of osteoclasts and osteoblasts and the role of the RANK pathway. Stromal bone marrow (mesenchymal) cells and differentiated osteoblasts produce multiple growth factors and cytokines, including macrophage colony-stimulating factor (M-CSF), to modulate osteoclastogenesis. RANKL (receptor activator of nuclear factor-κB ligand) is produced by osteoblast progenitors and mature osteoblasts and can bind to a soluble decoy receptor known as OPG (osteoprotegerin) to inhibit RANKL action. Alternatively, a cell-cell interaction between osteoblast and osteoclast progenitors allows RANKL to bind to its membrane-bound receptor, RANK, thereby stimulating osteoclast differentiation and function. RANK binds intracellular proteins called TRAFs (tumor necrosis factor receptor–associated factors) that mediate receptor signaling through transcription factors such as NF-κB. M-CSF binds to its receptor, c-fms, which is the


InternalMed_Harrison

InternalMed_Harrison. proteins called TRAFs (tumor necrosis factor receptor–associated factors) that mediate receptor signaling through transcription factors such as NF-κB. M-CSF binds to its receptor, c-fms, which is the cellular homologue of the fms oncogene. See text for the potential role of these pathways in disorders of osteoclast function such as Paget’s disease and osteopetrosis. IL, interleukin; IGF, insulin-like growth factor.


InternalMed_Harrison

InternalMed_Harrison. Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget’s disease, including (1) the presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts and (2) viral mRNA in precursor and mature osteoclasts. The viral etiology is further supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus nucleocapsid or matrix genes. However, the viral etiology has been questioned by the inability to culture a live virus from pagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget’s disease.


InternalMed_Harrison

InternalMed_Harrison. Pathophysiology The principal abnormality in Paget’s disease is the increased number and activity of osteoclasts. Pagetic osteoclasts are large, increased 10to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 μg/d (normal is 1 μg/d). Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)2D3; (2) osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; (3) marrow stromal cells from pagetic lesions have increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget’s disease and is overexpressed in


InternalMed_Harrison

InternalMed_Harrison. increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget’s disease and is overexpressed in pagetic osteoclasts; (5) expression of the protooncogene c-fos, which increases osteoclastic activity, is increased; and


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 426e Paget’s Disease and Other Dysplasias of Bone (6) the antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed. Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is high, and bone mass is normal or increased, not reduced, unless there is concomitant deficiency of calcium and/or vitamin D.


InternalMed_Harrison

InternalMed_Harrison. The characteristic feature of Paget’s disease is increased bone resorption accompanied by accelerated bone formation. An initial osteolytic phase involves prominent bone resorption and marked hypervascularization. Radiographically, this manifests as an advancing lytic wedge, or “blade of grass” lesion. The second phase is a period of very active bone formation and resorption that replaces normal lamellar bone with haphazard (woven) bone. Fibrous connective tissue may replace normal bone marrow. In the final sclerotic phase, bone resorption declines progressively and leads to a hard, dense, less vascular pagetic or mosaic bone, which represents the so-called burned-out phase of Paget’s disease. All three phases may be present at the same time at different skeletal sites.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations Diagnosis is often made in asymptomatic patients because they have elevated ALP levels on routine blood chemistry testing or an abnormality on a skeletal radiograph obtained for another indication. The skeletal sites most commonly involved are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases with an early presentation often have numerous active sites of skeletal involvement.


InternalMed_Harrison

InternalMed_Harrison. The most common presenting symptom is pain, which may result from increased bony vascularity, expanding lytic lesions, fractures, bowing, or other deformities. Bowing of the femur or tibia causes gait abnormalities and abnormal mechanical stresses with secondary osteoarthritis of the hip or knee joints. Long bone bowing also causes extremity pain by stretching the muscles attached to the bone softened by the pagetic process. Back pain results from enlarged pagetic vertebrae, vertebral compression fractures, spinal stenosis, degenerative changes of the joints, and altered body mechanics with kyphosis and forward tilt of the upper back. Rarely, spinal cord compression may result from bone enlargement or from the vascular steal syndrome. Skull involvement may cause headaches, symmetric or asymmetric enlargement of the parietal or frontal bones (frontal bossing), and increased head size. Cranial expansion may narrow cranial foramens and cause neurologic complications including hearing


InternalMed_Harrison

InternalMed_Harrison. asymmetric enlargement of the parietal or frontal bones (frontal bossing), and increased head size. Cranial expansion may narrow cranial foramens and cause neurologic complications including hearing loss from cochlear nerve damage from temporal bone involvement, cranial nerve palsies, and softening of the base of the skull (platybasia) with the risk of brainstem compression. Pagetic involvement of the facial bones may cause facial deformity; loss of teeth and other dental conditions; and, rarely, airway compression.


InternalMed_Harrison

InternalMed_Harrison. Fractures are serious complications of Paget’s disease and usually occur in long bones at areas of active or advancing lytic lesions. Common fracture sites are the femoral shaft and subtrochanteric regions. Neoplasms arising from pagetic bone are rare (<0.5%). The incidence of sarcoma appears to be decreasing, possibly because of earlier, more effective treatment with potent antiresorptive agents. The majority of tumors are osteosarcomas, which usually present with new pain in a long-standing pagetic lesion. Osteoclast-rich benign giant cell tumors may arise in areas adjacent to pagetic bone, and they respond to glucocorticoid therapy.


InternalMed_Harrison

InternalMed_Harrison. Cardiovascular complications may occur in patients with involvement of large (15–35%) portions of the skeleton and a high degree of disease activity (ALP four times above normal). The extensive arteriovenous shunting and marked increases in blood flow through the vascular pagetic bone lead to a high-output state and cardiac enlargement. However, high-output heart failure is relatively rare and usually develops in patients with concomitant cardiac pathology. In addition, calcific aortic stenosis and diffuse vascular calcifications have been associated with Paget’s disease.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis The diagnosis may be suggested on clinical examination by the presence of an enlarged skull with frontal bossing, bowing of an extremity, or short stature with simian posturing. An extremity with an area of warmth and tenderness to palpation may suggest an underlying pagetic lesion. Other findings include bony deformity of the pelvis, skull, spine, and extremities; arthritic involvement of the joints adjacent to lesions; and leg-length discrepancy resulting from deformities of the long bones.


InternalMed_Harrison

InternalMed_Harrison. Paget’s disease is usually diagnosed from radiologic and biochemical abnormalities. Radiographic findings typical of Paget’s disease include enlargement or expansion of an entire bone or area of a long bone, cortical thickening, coarsening of trabecular markings, and typical lytic and sclerotic changes. Skull radiographs (Fig. 426e-2) reveal regions of “cotton wool,” or osteoporosis circumscripta, thickening of diploic areas, and enlargement and sclerosis of a portion or all of one or more skull bones. Vertebral cortical thickening of the superior and inferior end plates creates a “picture frame” vertebra. Diffuse radiodense enlargement of a vertebra is referred to as “ivory vertebra.” Pelvic radiographs may demonstrate disruption or fusion of the sacroiliac joints; porotic and radiodense lesions of the ilium with whorls of coarse trabeculation; thickened and sclerotic iliopectineal line (brim sign); and softening with protrusio acetabuli, with axial migration of the hips and


InternalMed_Harrison

InternalMed_Harrison. lesions of the ilium with whorls of coarse trabeculation; thickened and sclerotic iliopectineal line (brim sign); and softening with protrusio acetabuli, with axial migration of the hips and functional flexion contracture. Radiographs of long bones reveal bowing deformity and typical pagetic changes of cortical thickening and expansion and areas of lucency and sclerosis (Fig. 426e-3). Radionuclide 99mTc bone scans are less specific but are more sensitive than standard radiographs for identifying sites of active skeletal lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) studies are not necessary in most cases,


InternalMed_Harrison

InternalMed_Harrison. FIGurE 426e-2 A 48-year-old woman with Paget’s disease of the skull. Left. Lateral radiograph showing areas of both bone resorption and sclerosis. Right. 99mTc HDP bone scan with anterior, posterior, and lateral views of the skull showing diffuse isotope uptake by the frontal, parietal, occipital, and petrous bones. FIGurE 426e-3 Radiograph of a 73-year-old man with Paget’s disease of the right proximal femur. Note the coarsening of the trabecular pattern with marked cortical thickening and narrowing of the joint space consistent with osteoarthritis secondary to pagetic deformity of the right femur. CT may be useful for the assessment of possible fracture, and MRI is necessary to assess the possibility of sarcoma, giant cell tumor, or metastatic disease in pagetic bone. Definitive diagnosis of malignancy often requires bone biopsy.


InternalMed_Harrison

InternalMed_Harrison. Biochemical evaluation is useful in the diagnosis and management of Paget’s disease. The marked increase in bone turnover can be monitored using biochemical markers of bone formation and resorption. The parallel rise in markers of bone formation and resorption confirms the coupling of bone formation and resorption in Paget’s disease. The degree of bone marker elevation reflects the extent and severity of the disease. Patients with the highest elevation of ALP (10 × the upper limit of normal) typically have involvement of the skull and at least one other skeletal site. Lower values suggest less extensive involvement or a quiescent phase of the disease. For most patients, serum total ALP remains the test of choice both for diagnosis and assessing response to therapy. Occasionally, a symptomatic patient with evidence of progression at a single site may have a normal total ALP level but increased bone-specific ALP. For unclear reasons, serum osteocalcin, another marker of bone formation,


InternalMed_Harrison

InternalMed_Harrison. patient with evidence of progression at a single site may have a normal total ALP level but increased bone-specific ALP. For unclear reasons, serum osteocalcin, another marker of bone formation, is not always elevated and is not recommended for use in diagnosis or management of Paget’s disease. Bone resorption markers (serum or urine N-telopeptide or C-telopeptide measured in the blood or urine) are also elevated in active Paget’s disease and decrease more rapidly in response to therapy than does ALP.


InternalMed_Harrison

InternalMed_Harrison. Serum calcium and phosphate levels are normal in Paget’s disease. Immobilization of a patient with active Paget’s disease may rarely cause hypercalcemia and hypercalciuria and increase the risk for nephrolithiasis. However, the discovery of hypercalcemia, even in the presence of immobilization, should prompt a search for another cause of hypercalcemia. In contrast, hypocalcemia or mild secondary hyperparathyroidism may develop in Paget’s patients with very active bone formation and insufficient calcium and vitamin D intake, particularly during bisphosphonate therapy when bone resorption is rapidly suppressed and active bone formation continues. Therefore, adequate calcium and vitamin D intake should be instituted prior to administration of bisphosphonates.


InternalMed_Harrison

InternalMed_Harrison. The development of effective and potent pharmacologic agents (Table 426e-1) has changed the treatment philosophy from treating only symptomatic patients to treating asymptomatic patients who are at risk for complications. Pharmacologic therapy is indicated in


InternalMed_Harrison

InternalMed_Harrison. Dose and Mode Name of Delivery Normalization of ALP the following circumstances: to control symptoms caused by metabolically active Paget’s disease such as bone pain, fracture, headache, pain from pagetic radiculopathy or arthropathy, or neurologic complications; to decrease local blood flow and minimize operative blood loss in patients who need surgery at an active pagetic site; to reduce hypercalciuria that may occur during immobilization; and to decrease the risk of complications when disease activity is high (elevated ALP) and when the site of involvement involves weight-bearing bones, areas adjacent to major joints, vertebral bodies, and the skull. Whether or not early therapy prevents late complications remains to be determined. A randomized study of over 1200 patients from the United Kingdom showed no difference in bone pain, fracture rates, quality of life, and hearing loss between patients who received pharmacologic therapy to control symptoms (bone pain) and those receiving


InternalMed_Harrison

InternalMed_Harrison. Kingdom showed no difference in bone pain, fracture rates, quality of life, and hearing loss between patients who received pharmacologic therapy to control symptoms (bone pain) and those receiving bisphosphonates to normalize serum ALP. However, the most potent agent (zoledronic acid) was not used, and the duration of observation (mean of 3 years with a range of 2 to 5 years) may not be long enough to assess the impact of treatment on long-term outcomes. It seems likely that the restoration of normal bone architecture following suppression of pagetic activity will prevent further deformities and complications.


InternalMed_Harrison

InternalMed_Harrison. Agents approved for treatment of Paget’s disease suppress the very high rates of bone resorption and secondarily decrease the high rates of bone formation (Table 426e-1). As a result of decreasing bone turnover, pagetic structural patterns, including areas of poorly mineralized woven bone, are replaced by more normal cancellous or lamellar bone. Reduced bone turnover can be documented by a decline in serum ALP and urine or serum resorption markers (N-telopeptide, C-telopeptide).


InternalMed_Harrison

InternalMed_Harrison. The first clinically useful agent, etidronate, is now rarely used because the doses required to suppress bone resorption may impair mineralization, necessitating that the drug be given for a maximum of 6 months followed by a 6-month drug-free period. The second-generation oral bisphosphonates—tiludronate, alendronate, and risedronate—are more potent than etidronate in controlling bone turnover and, thus, induce a longer remission at a lower dose. The lower doses reduce the risks of impaired mineralization and osteomalacia. Oral bisphosphonates should be taken first thing in the morning on an empty stomach, followed by maintenance of upright posture with no food, drink, or other medications for 30–60 min. The efficacy of different agents, based on their ability to normalize or decrease ALP levels, is summarized in Table 426e-1, although the response rates are not comparable because they are obtained from different studies.


InternalMed_Harrison

InternalMed_Harrison. Intravenous bisphosphonates approved for Paget’s disease include pamidronate and zoledronic acid. Although the recommended dose for pamidronate is 30 mg dissolved in 500 mL of normal saline or dextrose IV over 4 h on 3 consecutive days, a more commonly used simpler regimen is a single infusion of 60–90 mg in patients with mild elevation of serum ALP and multiple 90-mg


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 426e Paget’s Disease and Other Dysplasias of Bone infusions in those with higher levels of ALP. In many patients, particularly those who have severe disease or need rapid normalization of bone turnover (neurologic symptoms, severe bone pain due to a lytic lesion, risk of an impending fracture, or pretreatment prior to elective surgery in an area of active disease), treatment with zoledronic acid is the first choice. It normalizes ALP in about 90% of patients by 6 months, and the therapeutic effect persists for at least 6 more months in most patients. About 10–20% of patients experience a flulike syndrome after the first infusion, which can be partly ameliorated by pretreatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with high bone turnover, vitamin D and calcium should be provided to prevent hypocalcemia and secondary hyperparathyroidism. Remission following treatment with IV bisphosphonates, particularly zoledronic acid, may persist


InternalMed_Harrison

InternalMed_Harrison. vitamin D and calcium should be provided to prevent hypocalcemia and secondary hyperparathyroidism. Remission following treatment with IV bisphosphonates, particularly zoledronic acid, may persist for well over 1 year. Bisphosphonates should not be used in patients with renal insufficiency (glomerular filtration rate <35 mL/min).


InternalMed_Harrison

InternalMed_Harrison. The subcutaneous injectable form of salmon calcitonin is approved for the treatment of Paget’s disease. The common side effects of calcitonin therapy are nausea and facial flushing. Secondary resistance after prolonged use may be due to either the formation of anticalcitonin antibodies or downregulation of osteoclastic cell–surface calcitonin receptors. The lower potency and injectable mode of delivery make this agent a less attractive treatment option that should be reserved for patients who either do not tolerate bisphosphonates or have a contraindication to their use. In early reports, denosumab, an antibody to RANKL, has shown promise but has not been approved for this indication.


InternalMed_Harrison

InternalMed_Harrison. Osteopetrosis refers to a group of disorders caused by severe impairment of osteoclast-mediated bone resorption. Other terms that are often used include marble bone disease, which captures the solid x-ray appearance of the involved skeleton, and Albers-Schonberg disease, which refers to the milder, adult form of osteopetrosis also known as autosomal dominant osteopetrosis type II. The major types of osteopetrosis include malignant (severe, infantile, autosomal recessive) osteopetrosis and benign (adult, autosomal dominant) osteopetrosis types I and II. A rare autosomal recessive intermediate form has a more benign prognosis. Autosomal recessive carbonic anhydrase (CA) II deficiency produces osteopetrosis of intermediate severity associated with renal tubular acidosis and cerebral calcification.


InternalMed_Harrison

InternalMed_Harrison. Etiology and Genetics Naturally occurring and gene-knockout animal models with phenotypes similar to those of the human disorders have been used to explore the genetic basis of osteopetrosis. The primary defect in osteopetrosis is the loss of osteoclastic bone resorption and preservation of normal osteoblastic bone formation. Osteoprotegerin (OPG) is a soluble decoy receptor that binds osteoblast-derived RANK ligand, which mediates osteoclast differentiation and activation (Fig. 426e-1). Transgenic mice that overexpress OPG develop osteopetrosis, presumably by blocking RANK ligand. Mice deficient in RANK lack osteoclasts and develop severe osteopetrosis.


InternalMed_Harrison

InternalMed_Harrison. Recessive mutations of CA II prevent osteoclasts from generating an acid environment in the clear zone between its ruffled border and the adjacent mineral surface. Absence of CA II, therefore, impairs osteoclastic bone resorption. Other forms of human disease have less clear genetic defects. About one-half of the patients with malignant infantile osteopetrosis have a mutation in the TCIRG1 gene encoding the osteoclast-specific subunit of the vacuolar proton pump, which mediates the acidification of the interface between bone mineral and the osteoclast ruffled border. Mutations in the CICN7 chloride channel gene cause autosomal dominant osteopetrosis type II.


InternalMed_Harrison

InternalMed_Harrison. Clinical Presentation The incidence of autosomal recessive severe (malignant) osteopetrosis ranges from 1 in 200,000 to 1 in 500,000 live births. As bone and cartilage fail to undergo modeling, paralysis of one or more cranial nerves may occur due to narrowing of the cranial foramens. Failure of skeletal modeling also results in inadequate marrow space, leading to extramedullary hematopoiesis with hypersplenism and pancytopenia. Hypocalcemia due to lack of osteoclastic bone resorption may occur in infants and young children. The untreated infantile disease is fatal, often before age 5.


InternalMed_Harrison

InternalMed_Harrison. Adult (benign) osteopetrosis is an autosomal dominant disease that is usually diagnosed by the discovery of typical skeletal changes in young adults who undergo radiologic evaluation of a fracture. The prevalence is 1 in 100,000 to 1 in 500,000 adults. The course is not always benign, because fractures may be accompanied by loss of vision, deafness, psychomotor delay, mandibular osteomyelitis, and other complications usually associated with the juvenile form. In some kindred, nonpenetrance results in skip generations, while in other families, severely affected children are born into families with benign disease. The milder form of the disease does not usually require treatment.


InternalMed_Harrison

InternalMed_Harrison. radiography Typically, there are generalized symmetric increases in bone mass with thickening of both cortical and trabecular bone. Diaphyses and metaphyses are broadened, and alternating sclerotic and lucent bands may be seen in the iliac crests, at the ends of long bones, and in vertebral bodies. The cranium is usually thickened, particularly at the base of the skull, and the paranasal and mastoid sinuses are underpneumatized. Laboratory Findings The only significant laboratory findings are elevated serum levels of osteoclast-derived tartrate-resistant acid phosphatase (TRAP) and the brain isoenzyme of creatine kinase. Serum calcium may be low in severe disease, and parathyroid hormone and 1,25-dihydroxyvitamin D levels may be elevated in response to hypocalcemia.


InternalMed_Harrison

InternalMed_Harrison. Allogeneic HLA-identical bone marrow transplantation has been successful in some children. Following transplantation, the marrow contains progenitor cells and normally functioning osteoclasts. A cure is most likely when children are transplanted before age 4. Marrow transplantation from nonidentical HLA-matched donors has a much higher failure rate. Limited studies in small numbers of patients have suggested variable benefits following treatment with interferon γ-1β, 1,25-dihydroxyvitamin D (which stimulates osteoclasts directly), methylprednisolone, and a low-calcium/highphosphate diet. Surgical intervention is indicated to decompress optic or auditory nerve compression. Orthopedic management is required for the surgical treatment of fractures and their complications including malunion and postfracture deformity.


InternalMed_Harrison

InternalMed_Harrison. This is an autosomal recessive form of osteosclerosis that is believed to have affected the French impressionist painter Henri de Toulouse-Lautrec. The molecular basis involves mutations in the gene that encodes cathepsin K, a lysosomal metalloproteinase highly expressed in osteoclasts and important for bone-matrix degradation. Osteoclasts are present but do not function normally. Pyknodysostosis is a form of short-limb dwarfism that presents with frequent fractures but usually a normal life span. Clinical features include short stature; kyphoscoliosis and deformities of the chest; high arched palate; proptosis; blue sclerae; dysmorphic features including small face and chin, frontooccipital prominence, pointed beaked nose, large cranium, and obtuse mandibular angle; and small, square hands with hypoplastic nails. Radiographs demonstrate a generalized increase in bone density, but in contrast to osteopetrosis, the long bones are normally shaped. Separated cranial sutures, including


InternalMed_Harrison

InternalMed_Harrison. with hypoplastic nails. Radiographs demonstrate a generalized increase in bone density, but in contrast to osteopetrosis, the long bones are normally shaped. Separated cranial sutures, including the persistent patency of the anterior fontanel, are characteristic of the disorder. There may also be hypoplasia of the sinuses, mandible, distal clavicles, and terminal phalanges. Persistence of deciduous teeth and sclerosis of the calvarium and base of the skull are also common. Histologic evaluation shows normal cortical bone architecture with decreased osteoblastic and osteoclastic activities. Serum chemistries are normal, and unlike osteopetrosis, there is no anemia. There is no known treatment for this condition, and there are no reports of attempted bone marrow transplant.


InternalMed_Harrison

InternalMed_Harrison. Also known as Camurati-Engelmann disease, progressive diaphyseal dysplasia is an autosomal dominant disorder that is characterized radiographically by diaphyseal hyperostosis and a symmetric thickening and increased diameter of the endosteal and periosteal surfaces of the diaphyses of the long bones, particularly the femur and tibia, and, less often, the fibula, radius, and ulna. The genetic defect responsible for the disease has been localized to the area of chromosome 19q13.2 encoding tumor growth factor (TGF) β1. The mutation promotes activation of TGF-β1. The clinical severity is variable. The most common presenting symptoms are pain and tenderness of the involved areas, fatigue, muscle wasting, and gait disturbance. The weakness may be mistaken for muscular dystrophy. Characteristic body habitus includes thin limbs with little muscle mass yet prominent and palpable bones and, when the skull is involved, large head with prominent forehead and proptosis. Patients may also display