Prevention and Management of Osteoporosis
David M. Slovik
Osteoporosis is a major health problem that predisposes to incapacitating fractures and increased morbidity and mortality. It affects an estimated 10 million persons in the United States (8 million women and 2 million men); another 34 million persons have reduced bone mass and are also at increased risk for fractures. The problem is most prevalent among postmenopausal women, but it is also becoming an issue for older men as life expectancy increases (lifetime osteoporotic fracture risk in men, 15%). In the United States, more than 250,000 hip fractures occur annually, most in persons older than the age of 65 years. Osteoporotic vertebral fractures are manifested by back pain, loss of height, decreased ambulation, and decreased quality of life. An estimated 750,000 vertebral fractures occur annually and are present in 5% to 10% of women by age 60 years and in 40% by age 80 years. Current annual expenditures for hip fractures alone are in excess of $15 billion. Morbidity and mortality can be substantial, with 15% to 25% of women and 30% to 40% of men needing long-term nursing home care or dying as a consequence of osteoporotic hip fracture.
The pathophysiologic mechanisms for postmenopausal osteoporosis are imperfectly understood, but the means to ensure maximal skeletal growth and strength, prevent and treat bone loss, and noninvasively evaluate bone mass are available. The primary care physician has a central role in the evaluation and management of this common and important condition.
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16)
Pathophysiology
Osteoporosis is defined as a skeletal disorder characterized by impaired bone strength that predisposes to an increased risk of fracture. Bone strength is a composite of bone density and bone quality. Bone mineral density (BMD; defined as mass of bone per unit area or volume) receives most of the attention because it is measurable and important. Because the strength of a bone is proportional to its density, the mechanical support of the skeleton is affected as bone mass declines. Bone quality is also very important to bone strength and is determined by such factors as bone architecture, turnover, microdamage, collagen structure, trabecular connectivity, fatigue damage, and mineralization, which are all much harder to measure.
The World Health Organization established an operational definition for osteoporosis based on BMD. The T-score compares an individual’s BMD with the mean value for young normal individuals expressed in standard deviations (SD), and a Z score compares the values to age- and sex-matched individuals. In terms of BMD, osteoporosis is defined as a T-score that is 2.5 or more SD below the mean for a healthy young white woman (T-score of -2.5 or less). Osteopenia (originally a radiologic term to indicate a reduced amount of bone mineralization), also known as low bone mass, is defined in BMD terms as a T-score between -1.0 and -2.5. Normal bone density is a T-score of -1 or above.
Osteoporosis can occur not only from bone loss but also from failure earlier in life to make sufficient bone, resulting in a lower peak bone density at skeletal maturity. Osteoporosis is labeled as primary when it is due to the aging process and secondary when it is a consequence of an underlying medical condition or drug (Table 164-1). The principal mechanism of age-related disease is increased bone resorption/reduced new bone formation. Secondary osteoporosis is often a consequence of medications (e.g., glucocorticoid therapy, excessive thyroid hormone, aromatase inhibitors, androgen deprivation therapy) or conditions such as malabsorption (e.g., celiac disease), which impair the absorption and deposition of calcium and phosphorus. The latter may also cause osteomalacia, a condition with inadequate mineralization, as compared to osteoporosis, which has a normal ratio of mineral to matrix, just less of it.
TABLE 164-1 Important Causes of Osteoporosis | ||||||||||||||||||||
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Increased Osteoclastic Bone Resorption and Reduced New Bone Formation
The resorption and formation of bone is a continuous process throughout life. Under steady-state physiologic circumstances, the rates of these processes are equal and coupled, with bone damage repaired and bone mass retained. Cytokines in bone and skeletal growth factors may act synergistically and serve as mediators of bone formation and resorption.
With estrogen deficiency, there is an increase in boneresorbing cytokines (e.g., interleukin-1 and tumor necrosis factor and RANK ligand, an important factor in osteoclastogenesis). Estrogen deficiency may also reduce bone formation directly through estrogen receptors on osteoblasts—the cells that synthesize bone matrix proteins. Estrogen deficiency also reduces the local production of growth factors such as insulinlike growth factor and transforming growth factor.
Skeletal mass is usually maximal by age 35 years and declines in women after age 40 years and in men after age 50 years, when the rate of new bone formation does not equal the rate of bone resorption. With the onset of estrogen deficiency, osteoclastic bone resorption increases. The rate of decline in skeletal mass is most rapid in women within 2 to 3 years of menopause. The greatest and earliest loss occurs in trabecular bone in the thoracic and lumbar vertebrae, sites where future fracture is likely. Later in life, new bone formation is impaired.
Inadequate Deposition of Calcium and Phosphorus (Osteomalacia)
Osteomalacia is defined as the inadequate deposition of calcium and phosphorus in bone tissue matrix. It is found in 10% to 15% of patients with hip fracture and is often a result of vitamin D deficiency. Fractional intestinal absorption of calcium in elderly persons is decreased. This decline in intestinal calcium absorption appears in part to be caused by a decrease in the formation of 1,25-dihydroxyvitamin D, which is the active form of vitamin D. Vitamin D deficiency is very common especially in homebound elderly persons, who are unlikely to eat dairy products or go out in the sun. Forty to fifty percent of patients presenting with a hip fracture have been found to be vitamin D deficient. Other causes include impaired vitamin D metabolism, malabsorption, systemic acidosis, and phosphate depletion.
Risk Factors
The strongest measurable determinant of risk is the BMD, which can be measured directly (see later discussion and Chapter 144). The risk for osteoporotic fracture increases twofold to fourfold for every SD of reduction in BMD. However, the BMD is not the only determinant of bone fragility and is an imperfect predictor of fracture risk in a given individual. A prior history of fracture is probably the strongest indicator of bone fragility and future fracture risk; self-reported humped back has a positive likelihood ratio of 3.0, also making it predictive. Meta-analytic study finds several physical findings predictive of osteoporosis, including weight less than 51 kg (positive likelihood ratio [LR], 7.3), distance from the back of the head to the wall on standing upright greater than 0 cm (LR, 4.6), less than two fingerbreadths between the lowest palpable rib and the pelvic brim (LR, 3.8), and tooth count less than 20 (LR, 3.4).
Although attention to other risk factors is essential to estimating the probability of osteoporosis and risk for fracture, the predictive value of most clinical risk factors is not great because they do not account for all contributing factors. Those factors that seem to confer the greatest risk include advanced age, low body weight and body mass index, maternal history of fracture, and current smoking, but the strength of these associations is only moderate. Physical inactivity can lead to decreased bone mass, as can intense exercise that results in amenorrhea. A poor lifetime intake of calcium is a weak risk factor.
Conversely, increased bone mass correlates strongly with increased weight and strength. In general, the loading or mechanical forces on bone are potent stimuli to osteoblastic activity and new bone formation. Height and increased age at the onset of menopause are also moderate predictors of increased bone mass. An increase in current calcium intake has only a minor effect on bone mass.
Medical conditions causing secondary disease range from endocrine disorders, gastrointestinal (GI) diseases, and chronic systemic illnesses to nutritional deficiencies and drugs (see Table 164-1) and are prominent in men and perimenopausal women. In men and perimenopausal women, secondary causes account for nearly 50% of cases. Hypogonadism (including that associated with the treatment of prostate disease), glucocorticosteroid use, and alcoholism are the most common causes in men; in perimenopausal women, they are excesses in the intake of steroids, thyroid hormone, and anticonvulsants, as well as of aromatase inhibitors used to treat breast cancer.
Drugs are an important cause; in addition to glucocorticosteroids and excess thyroid hormone replacement, recent reports suggest an increase in fragility fracture with proton pump inhibitors, selective serotonin reuptake inhibitors, and thioglitazones. Osteoporosis can be a major problem in persons who have undergone organ transplantation due to immobilization, steroid and cyclosporine therapy, and the underlying disease for which the transplant was performed.
Clinical Presentation
The progressive decline in skeletal mass (which may approach 50%) may become clinically manifest when a fracture is sustained spontaneously or after minimal trauma. Fractures most commonly occur in the thoracic and lumbar vertebrae, hip, wrist, humerus, and pelvis. The clinical course and frequency of fractures in individual patients cannot be predicted; however, the development of one vertebral fracture increases the risk of another by fivefold, and two or more vertebral fractures increase the risk by 12-fold within 1 year. Loss of teeth is a less-appreciated manifestation of reduced bone density, but, by correlating with reduction in quality of mandibular alveolar bone, correlates with the risk of osteoporosis. A loss of height and the development of kyphosis may indicate vertebral compression fracture, although intervertebral disk space narrowing may be part of the reason for the height loss.
Radiographically, the bones may appear osteopenic, indicative of a nearly 30% loss in bone mass. The characteristic x-ray appearance of the osteoporotic spine is loss of horizontal vertebral trabeculae, accentuating the end plates and producing biconcave “codfish” vertebrae. A vertebral compression fracture may be noted, manifested by a loss in vertebral height. Grade 1 fractures are defined as a 20% to 24% loss; grade 2, a 25% to 39% loss; and grade 3, a loss greater than 40%. Pseudofractures, generally occurring in weight-bearing long bones, for example, femur, are pathognomonic for osteomalacia.
The laboratory features of postmenopausal osteoporosis include normal serum levels of calcium, phosphate, 25-hydroxyvitamin D, parathyroid hormone (PTH), and alkaline phosphatase, although the alkaline phosphatase may be elevated in the context of a healing fracture and the 25-hydroxy-vitamin D level may be low in the setting of inadequate vitamin D intake or absorption. In the setting of vitamin D deficiency, there may be low or low-normal serum levels of calcium and phosphate and elevated PTH levels. Persons with an underlying pathologic state causing osteoporosis manifest laboratory evidence of the condition (e.g., low thyrotropin [TSH] in hyperthyroidism, low testosterone in male hypogonadism, elevated cortisol in Cushing syndrome, and inappropriately elevated PTH in the setting of an elevated calcium, characteristic of primary hyperparathyroidism).
History and Physical Examination
A detailed review of historical features predictive of osteoporosis is essential, especially for identifying preexisting disease and determining the need for bone density screening. One should inquire into loss of height, loss of teeth, prior fracture, smoking, inactivity, calcium and vitamin D intake, and maternal history of osteoporosis or fracture. A review of medications is essential, including steroids; hormonal treatment for thyroid, prostate disease, and breast cancer; and anticonvulsants. Self-report of significant loss of height and a humped back (dorsal kyphosis, dowager hump) is suggestive of having sustained silent vertebral compression fractures.
A few key observations made during the physical examination can supplement the historical assessment. These include (a) measuring height and comparing it to the patient’s recollection of height as a young adult, (b) counting teeth, (c) having the patient stand with the back against the wall and measuring the distance from the wall to the occiput, and (d) standing behind the patient, noting how many fingerbreadths occupy the space between the inferior rib margin and the superior surface of the pelvic brim. Loss in height of 1½ to 2 inches, a tooth count less than 20, a wall-occiput distance of greater than 0 cm, and a rib-pelvis distance of two or fewer fingerbreadths significantly increase the pretest probability of osteoporotic disease and indicate the need for bone density determination.
Measurement of Bone Mineral Density
Because bone density is the principal determinant of fracture risk, its measurement is often essential to management decisions, but the test should be ordered only if the results will affect clinical decision making. If it is already apparent from history or physical examination that the patient has had an osteoporotic fracture, then bone mineral testing may be superfluous although still helpful in monitoring patients on therapy. Although guidelines for screening are emerging (see Chapter 144), clinical judgment remains important for determining who should be tested in evaluation for suspected disease.
Dual-energy x-ray absorptiometry (DXA, DEXA) is considered to be the technique of choice, representing the best combination of sensitivity, technical simplicity, reproducibility, cost, and minimization of radiation exposure. The test is safe, acceptable to patients, and predictive of osteoporotic fracture risk. Its use helps assess response to therapy. Current guidelines recommend that all women of normal risk be tested at age 65 years and that women deemed at higher risk be tested earlier (see Chapter 144).
Measurement of forearm BMD or ultrasound of the heel provides an inexpensive approach, which might be suitable for mass screening; however, separate DXA studies of the hip and spine provide the best assessments of risk for a given patient because the degree of osteoporotic change may be site specific (see Chapter 144). Hip fracture risk is best determined by BMD measurements at the hip sites.
The DXA study expresses bone density in terms of the number of SD from the mean for normal young adults of the same sex (T-score) and as the number of SD from the mean for persons of the same sex and age (Z score). The World Health Organization diagnostic criterion for osteoporosis is a T-score of -2.5 or lower. Osteopenia or low bone mass is defined as a T-score between -1.0 and -2.5. Normal bone density is a T-score of -1.0 or higher. The finding of a Z score less than -1.5 suggests a secondary cause of osteoporosis. The risk for osteoporotic fracture increases 1.6 to 2.6 times for every SD of reduction in BMD.
Workup for Osteomalacia and Other Causes of Osteopenia
Hip fracture and incidentally encountered osteopenia on radiologic study should raise concern about osteomalacia. Clinical manifestations of osteomalacia include muscle and joint aches, muscle weakness, and balance disturbances. Having a high index of suspicion for osteomalacia and other causes of osteopenia is essential because they are often treatable. DXA study can be obtained. As noted, the finding on DXA determination of a Z score of less than -1.5 suggests a secondary cause of osteopenia and should prompt a workup for this. Plain films should be reviewed with the radiologist for pseudofractures (pathognomonic of osteomalacia). A bone biopsy can provide definitive diagnosis of osteomalacia but is usually reserved for patients undergoing orthopedic procedures.
The determination of fasting levels of serum calcium and phosphate can help in detecting common causes of osteomalacia, as can a 25-hydroxy-vitamin D level. Hypophosphatemia may indicate a renal phosphate wasting disorder as the cause of osteomalacia. A low serum calcium may be seen in vitamin D deficiency. Low serum levels of 25-hydroxy-vitamin D are characteristic of vitamin D deficiency or insufficiency.
Other etiologies of osteoporosis that need to be considered include hyperthyroidism (see Chapter 103), hyperparathyroidism (see Chapter 96), anorexia nervosa (see Chapter 234), hyperprolactinemia (see Chapter 100), malignancy (e.g., myeloma, lymphoma; see Chapter 84), disease of the GI tract (e.g., inflammatory bowel disease, chronic liver disease; see Chapters 71 and 73), rheumatoid diseases (see Chapter 156), and medications (e.g., steroids, anticonvulsants, lithium, vitamin A supplements, tamoxifen, gonadotropin-releasing hormone agonists, aromatase inhibitors, and androgen deprivation therapy).
Laboratory workup should be tailored to those conditions suggested by pertinent history and physical examination findings. In the absence of clinical clues, one might consider screening for secondary disease by ordering a complete blood count, serum calcium, phosphorus, 25-hydroxy-vitamin D, parathyroid hormone (PTH), thyrotropin (TSH), serum protein electrophoresis, tissue transglutaminase (screen for celiac disease), and a 24-hour urine collection for calcium and creatinine measurement.
PRINCIPLES OF THERAPY
The best candidates for prevention and therapeutic intervention include patients with major clinical risk factors (e.g., maternal history of fracture, current smoker, small frame, lack of exercise, low-calcium intake), a T-score on DXA bone scanning indicative either of osteopenia (between -1.0 and -2.5) or of osteoporosis (-2.5 or lower), clinical evidence of fracture, or radiographic evidence of osteopenia. The National Osteoporosis Foundation suggests pharmacologic intervention if (a) T-score at any site is -2.5 or lower, (b) osteoporotic fracture has occurred, or (c) using the Fracture Risk Assessment Tool (FRAX), there is a 10-year probability of sustaining any osteoporotic fracture of 20% or hip fracture of 3.0%. Even persons at no increased risk can benefit from such primary preventive measures as regular exercise and ensuring adequate dietary intake of calcium and vitamin D.
A program should be established that combines nonpharmacologic interventions along with pharmacologic intervention when appropriate (Table 164-2). Combining diet, exercise, and pharmacologic measures can reduce the risk of osteoporotic fracture in high-risk persons. Primary prevention is more effective than treating established disease, but both require attention. Outcomes are maximized by careful patient selection and the design of a treatment program customized to the patient’s fracture risk, overall medical condition, lifestyle, and preferences.
Current treatment options include dietary calcium and vitamin D supplementation, weight-bearing and strengthening exercise, bisphosphonates, selective estrogen receptor modulators, calcitonin, PTH, and denosumab. Estrogen, although beneficial to bone, should primarily be used to treat menopausal symptoms (see Chapter 118).
Current treatment options include dietary calcium and vitamin D supplementation, weight-bearing and strengthening exercise, bisphosphonates, selective estrogen receptor modulators, calcitonin, PTH, and denosumab. Estrogen, although beneficial to bone, should primarily be used to treat menopausal symptoms (see Chapter 118).
TABLE 164-2 Basic Therapeutic Options for Prevention and Treatment of Osteoporosis | |||||||||||||||||||||||||||||||||
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Exercise, Diet, and Calcium and Vitamin D Supplementation (8,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33)
Exercise
An important component of the preventive therapy of osteoporosis is ensuring the maximal development of skeletal mass. The amount of bone accumulated in childhood and premenopausal women may be critical to the appearance of osteoporosis later in life, as evidenced by the low incidence of osteoporosis in African American women (and in men), who have a greater skeletal mass than do White women. Exercise and physical activity have been shown to increase skeletal mass and increase total body calcium. Physical activity, in conjunction with dietary supplementation of calcium and vitamin D daily, offers the best hope for increasing skeletal mass during skeletal growth. However, exercise programs so intensive as to induce amenorrhea and estrogen deficiency (e.g., competitive marathon running) and excessive weight loss (e.g., anorexia nervosa) may lead to osteoporosis.
In postmenopausal women, regular weight-bearing and strengthening exercise (e.g., walking, low-impact aerobics, weight lifting, tennis) three times per week can help retard bone mineral loss (down to 0.5% of the baseline value per year), especially when combined with calcium and vitamin D supplementation. A more ambitious program of formal exercise training (e.g., 50 minutes of walking and jogging three times per week) in combination with calcium and vitamin D supplementation may have even more pronounced effects (e.g., increase in lumbar bone mineral content). Care must be taken to ensure that the exercise program in older women is safe and does not subject the patient to an increased risk for falls or other injuries.
The efficacy of a program of exercise combined with calcium and vitamin D supplementation suggests that it should be the core of every treatment program, whether for prophylaxis or treatment of osteoporosis.
Dietary Calcium and Calcium Supplements
For women over age 50, the recommended daily calcium is 1,200 mg (diet plus supplements). This can help preserve trabecular and cortical bone mass. Although calcium supplementation does not prevent bone loss to the degree that other therapies do, it does represent an essential component of all osteoporosis treatment programs. Its use for primary prevention of osteoporosis remains a subject of debate, as exemplified by U.S. Preventive Services Task Force statements that find the evidence inconclusive.
Calcium can be considered a weak antiresorptive agent. Its effect on bone loss probably falls between those of estrogen and placebo. Its effect in slowing bone loss is more pronounced in late menopause compared to early menopause. The inadequate dietary calcium intake of many postmenopausal women (about 600 mg/d) and the declining fractional absorption of calcium associated with aging make it important to ensure a total intake of 1,200 to 1,500 mg/d in elderly patients, especially as they age. Serious complications such as renal stones or hypercalcemia are uncommon with a daily intake of elemental calcium in this range.
Dietary calcium is readily available, more nutritious, and better absorbed than calcium tablets, and it is less likely to cause kidney stones (possibly by inhibiting oxalate absorption). A cup of milk provides approximately 300 mg of calcium, an 8-oz serving of low-fat yogurt provides 300 to 350 mg, a 1-oz serving of cheddar cheese provides 200 mg, and a ½ cup of broccoli provides 36 mg. However, the amount of calcium varies so much in foods and supplements that it is important to check the food label to determine the amount that one is taking.
Calcium supplements are abundant. The two most common are the calcium carbonate and calcium citrate preparations. The carbonate salt is the least costly and has the highest amount of elemental calcium. Chewable preparations are well absorbed, albeit a bit more expensive. Splitting the daily supplement dose facilitates absorption and minimizes GI upset. A reasonable supplemental dose of calcium is in the range of 500 to 1,000 mg/d but will also depend on the amount of calcium from food sources. Larger doses, particularly in conjunction with vitamin D, may predispose the patient to hypercalcemia and hypercalciuric renal stone disease. Calcium carbonate supplements require gastric acid for absorption and thus are poorly absorbed in patients on proton pump inhibitor therapy. Taking it with meals increases absorption. Calcium carbonate is 40% elemental calcium. Thus, a preparation that contains 1,250 mg of calcium carbonate has 500 mg of elemental calcium. Calcium carbonate preparations may cause abdominal discomfort with bloating and constipation. Calcium citrate preparations were developed out of concern about the solubility and gut absorption of calcium carbonate. The citrate preparations are more expensive, but better tolerated and better absorbed, being less dependent on gastric acid for absorption. Also, citrate preparations are preferred if there is concurrent use of a proton pump inhibitor, which lowers gastric acid production. Calcium citrate is 21% elemental calcium; 1,000 mg of calcium citrate has approximately 21% elemental calcium, and, although less calcium than the carbonate, its better absorption makes up for the difference.
Cost can be an issue, given the need for long-term use. The least expensive sources of calcium carbonate supplementation are the antacid TUMS (200 to 500 mg/tablet) and generic preparations (500 to 600 mg/tablet). There are also other calcium preparations available (especially from health food stores); they are often much more expensive and of no proven advantage.
Vitamin D
The principal effect of vitamin D is on the gut absorption of calcium; it also directly affects osteoblasts and osteoclasts and exerts a positive effect on muscle, which reduces sway and translates into a 22% reduced risk of falls in the elderly (see later discussion). Recent evidence also suggests but has yet to prove positive effects in such areas as immune regulation and cancer risk; effect on cardiovascular risk has also been of interest (see Chapters 18 and 31).
When vitamin D is taken together with calcium, reductions in fracture rates of 30% to 70% have been documented although this is quite variable. The benefit appears greatest in vitamin D-deficient institutionalized and home-bound elderly persons,
but it is also evident among those who are living independently in the community. When vitamin D supplementation is given in conjunction with calcium to otherwise healthy persons older than the age of 65 years with a low calcium intake, the BMD improves significantly, and the risk for nonvertebral osteoporotic fracture is reduced. Daily recommended dose requirements for vitamin D have been raised to a range of 800 to 1,000 IU by the National Osteoporosis Foundation; the Institute of Medicine guidelines recommend a vitamin D3 intake of 600 IU for women aged 51 to 70 and 800 IU for those over 70. Randomized trial finds 600 to 800 IU/d achieves a therapeutic serum level in most postmenopausal women.
but it is also evident among those who are living independently in the community. When vitamin D supplementation is given in conjunction with calcium to otherwise healthy persons older than the age of 65 years with a low calcium intake, the BMD improves significantly, and the risk for nonvertebral osteoporotic fracture is reduced. Daily recommended dose requirements for vitamin D have been raised to a range of 800 to 1,000 IU by the National Osteoporosis Foundation; the Institute of Medicine guidelines recommend a vitamin D3 intake of 600 IU for women aged 51 to 70 and 800 IU for those over 70. Randomized trial finds 600 to 800 IU/d achieves a therapeutic serum level in most postmenopausal women.
The adequacy of vitamin D intake and absorption can be assessed by measuring a 25-hydroxy-vitamin D level (a measure of body vitamin D stores). Measurement of 25-hydroxy-vitamin D is expensive, but worthwhile for a baseline in osteoporotic women; repeat testing is unnecessary since repletion is usually sufficient, unless there is concern about compliance or malabsorption. The Institute of Medicine suggests that a level of 20 ng/mL would be adequate for primary prevention of fractures in the population, but many experts feel this level is too low and recommend aiming for a target serum level of greater than 30 ng/mL, especially in osteoporotic women—at lower levels, PTH secretion increases.
A generic combination preparation also containing calcium carbonate provides an inexpensive and practical approach to vitamin D supplementation. Drinking 8 oz/d of vitamin D-fortified low-fat or skim milk is a more nutritious option. If the diet is already sufficient in calcium, one can recommend a plain vitamin D3 supplement containing 600 to 2,000 IU daily, depending on the presence and degree of any vitamin D deficiency.
Bisphosphonates (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 and 59)
These synthetic carbon phosphate compounds bind avidly to pyrophosphate in bone and inhibit bone resorption by osteoclasts. Bisphosphonate therapy has risen to first-line status with the advent of multiple oral and intravenous preparations (alendronate, risedronate, ibandronate, zoledronic acid) that provide enhanced efficacy, reasonable safety, and once-weekly or monthly oral bisphosphonates or quarterly or yearly intravenous bisphosphonates.
Efficacy
Long-term continuous oral therapy is both safe and effective. Significant increases in BMD are achieved, and risks of vertebral and nonvertebral fractures are markedly decreased. Alendronate and risedronate have been shown to reduce the risks of osteoporotic fracture in the spine and hip by 40% to 60%. Oral ibandronate reduces the risk of spinal fractures to a similar degree. Effects on bone density appear to be cumulative. A 10-year course of full-dose therapy with alendronate increases mean bone density by about 6% in the femoral neck and nearly 15% in the lumbar spine. Similar increases are achieved with risedronate, although equivalent long-term data are not yet available. Alendronate and risedronate have also demonstrated efficacy in the prevention of bone loss and fracture associated with corticosteroid use and male osteoporosis.
Benefits are greatest when full doses are used in the setting of low bone density or prior osteoporotic fracture, but lowdose therapy in persons without established osteoporosis also provides effective primary prophylaxis against osteoporosis due to menopause and glucocorticosteroid use. A unique feature of bisphosphonate therapy is a measurable residual effect lasting for years after the cessation of treatment, which is believed to be a consequence of bisphosphonate deposition and tight bonding to bone mineral. A report comparing the fracture incidence and bone density at 10 years in patients on alendronate for either 5 or 10 years found that patients who stopped after 5 years had similar fracture rates at 10 years (except for clinical vertebral fractures) when compared to those on it for 10 years. Compared to the cessation of estrogen therapy, bisphosphonate withdrawal results in a much slower loss of bone.
The intravenous bisphosphonate preparations have shown improvements in BMD in postmenopausal women comparable to those of the oral medications. Once-yearly zoledronic acid reduced spine fractures by 70% and hip fractures by 41%.
Adverse Effects and Safety
Adverse effects are an important consideration because chronic use is required. The major concerns that have emerged are upper GI mucosal injury, osteonecrosis of the jaw (ONJ), atypical femur fractures, musculoskeletal pain syndrome, and atrial fibrillation.
Upper Gastrointestinal Mucosal Injury.
Although no increase in the risk of upper GI complications has been found in randomized, long-term trials comparing alendronate, risedronate, or ibandronate with placebo, postmarketing surveillance generated reports of mucosal erosions and bleeding in the esophagus, apparently related to instances in which pills failed to clear the esophagus and a chemical esophagitis resulted. These findings are seen more commonly in patients with a history of reflux. The risk of serious GI complications is low, but care is needed in patient selection and instruction (see later discussion). Oral bisphosphonates should be used with caution in patients with upper GI problems (e.g., reflux). They should not be given to patients with Barrett esophagus, esophageal varices, or to those who have abnormalities that delay transit of the tablet (e.g., achalasia, stricture). Concurrent use of a proton pump inhibitor is prescribed by some clinicians to minimize GI side effects. Another option is to go to one of the intravenous bisphosphonates, which bypasses the GI tract.
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