Mayo Clin Proc. 2006;81:662-672
CONCISE REVIEW FOR CLINICIANS
Diagnosis, Screening, Prevention, and Treatment of Osteoporosis
From the Division of General Internal Medicine (K.F.M.) and Division of Endocrinology, Diabetes, Metabolism, and Nutrition (B.L.C.), Mayo Clinic College of Medicine, Rochester, Minn.
Osteoporosis is the most common bone disease in humans and affects both men and women. The clinical and public health implications of the disease are substantial because of the mortality, morbidity, and cost of medical care associated with osteoporotic fractures. Osteoporosis is diagnosed on the basis of a low-impact or fragility fracture or low bone mineral density, which was best assessed by central dual-energy x-ray absorptiometry. Both nonpharmacological therapy (calcium and vitamin D supplementation, weight-bearing exercise, and fall prevention) and pharmacological treatments (antiresorptive and anabolic agents) may be helpful in the prevention and treatment of osteoporosis. Therefore, clinicians need to be vigilant in instituting primary prevention measures for those at high risk for osteoporosis and in instituting treatment for patients diagnosed as having the disease either by screening or a history of fracture. This article provides an overview of the diagnosis, screening, prevention, and treatment of osteoporosis.
Mayo Clin Proc. 2006;81(5):662-672
Osteoporosis is the most common bone disease in humans and affects both men and women, usually during or beyond the seventh decade of life. Among US women older than 50 years, 13% to18% meet current diagnostic criteria for osteoporosis, and an additional 37% to 50% meet criteria for osteopenia. For men of the same age, 3% to 6% meet criteria for osteoporosis, and 28% to 47% meet criteria for osteopenia.1 Osteoporosis has clinical and public health implications because of the mortality, morbidity, and cost of medical care associated with osteoporotic fractures. Elderly persons constitute the fastest-growing age group in the world, and the annual number of osteoporotic fractures is predicted to increase considerably with the continued aging of this population in future decades. In the United States, about 1.5 million fractures are attributed to osteoporosis each year. Of this total, approximately half are vertebral fractures and one fifth each are hip, wrist, and other fractures,2 Although therapy that can reduce the risk of osteoporotic fractures is available, osteoporosis often remains undiagnosed until a fracture occurs. In addition, patients with osteoporosis-related fractures often are not evaluated or treated for osteoporosis and sustain additional fractures. Therefore, clinicians need to be vigilant in instituting primary prevention measures for those at high risk for osteoporosis and in instituting treatment for patients diagnosed with the disease either by screening or a history of fracture. This article provides an overview of the diagnosis, screening, prevention, and treatment of osteoporosis.
Osteoporosis is a chronic, progressive disease characterized by low bone mass, microarchitectural bone deterioration, and decreased bone strength that lead to increased bone fragility and a consequent increase in fracture risk.3 Osteoporosis may be classified as either primary or secondary. Primary osteoporosis is bone loss associated with the aging process in both women and men and with the loss of gonadal function in men. In primary osteoporosis, the rate of activation of skeletal bone remodeling units is normal, but the filling of bone resorption pits is incomplete. Secondary osteoporosis is bone loss caused by a variety of chronic medical conditions, medications, and nutritional deficiencies. In most types of secondary osteoporosis, the rate of activation of skeletal bone remodeling units is increased at least initially, such that an increased proportion of the skeleton is undergoing remodeling at any one time. Some common secondary causes of osteoporosis and disease processes associated with the disorder are outlined in Table 1.
Before 1994, the diagnosis of osteoporosis required evidence of a fragility fracture. In 1994, the World Health Organization established operational definitions of osteoporosis and osteopenia in postmenopausal white women based on bone mineral density (BMD) (Table 2) to help researchers and clinicians classify degrees of bone loss. Expert opinion, based on literature review, suggests that the current World Health Organization definition of osteoporosis in postmenopausal white women can be applied to men as well.5 In current clinical practice, osteoporosis is diagnosed on the basis of either a health outcome (low-impact or fragility fracture) or an intermediate outcome (low BMD). A low-impact fracture is one that occurs after a fall from standing height or less; a fragility fracture occurs spontaneously or with no trauma (cough, sneeze, sudden movement).
Although multiple technologies are available for measurement of BMD, central dual-energy x-ray absorptiometry (DXA) of the hip (femoral neck or total hip) is the gold standard for diagnosing osteopenia or osteoporosis.5,6 However, many experts, including the International Society for Clinical Densitometry, recommend using the lowest central DXA T score of posteroanterior lumbar spine, femoral neck, or total hip (or the 33% distal radius of the nondominant forearm, if measured) to make the diagnosis.7 Dual-energy x-ray absorptiometric measurements of BMD at other sites (including the trochanter, Ward triangle, lateral lumbar spine, other forearm regions, heel, or total body) or with other technologies (calcaneal ultrasonography, peripheral DXA, quantitative computed tomography, single- or dual-photon radionuclide absorptiometry, or magnetic resonance imaging) may be useful for assessing risk of fracture, but they are not recommended for use in diagnosing osteoporosis.6,7 If DXA measurements at different sites are considerably disparate, most clinicians would use the lowest BMD measurement.
Dual-energy x-ray absorptiometric measurement of bone density is noninvasive, accurate, reproducible, and predictive of short- and long-term fracture risk. The results are reported as a density measurement in gm/cm2, in addition to T and Z scores. T scores represent the number of SDs from the mean bone density values in normal sex-matched young adults. The T score is used to make a diagnosis of normal bone density, osteoporosis, or osteopenia in postmenopausal women and in men age 50 years and older. Z scores represent the number of SDs from the normal mean value for age- and sex-matched control subjects. A Z score of 1.0 or lower (many experts suggest using a Z score of 2.0 or lower) may suggest the presence of a secondary cause of osteoporosis, although no definitive data support this hypothesis. Z scores are used preferentially to assess bone loss in premenopausal females and in men younger than age 50 years. A Z score of 2.0 or lower is defined as below the expected range for age; a Z score above 2.0 is within the expected range for age.7
ROLE OF SCREENING
Osteoporosis is a disease in which screening of asymptomatic individuals may be beneficial because it has a long preclinical course before the onset of fracture and because of the availability of both a reliable test to establish the diagnosis and treatments that have been shown to reduce the risk of fractures. General consensus exists regarding the recommendation that osteoporosis screening with BMD measurements should be individualized, but how this individualized approach to screening should be achieved remains controversial.
Many national and organizational guidelines and systematic reviews have attempted to outline clinical criteria for screening individuals for osteoporosis. Disagreement among the published guidelines reflects, at least in part, variances in expert opinion and gaps in the available evidence to support these recommendations. Most guidelines recommend using risk factor assessment to help select patients for bone density testing, but because of inadequate data, no consensus exists about which risk factors are most important to consider. Several groups have suggested guidelines for BMD testing in postmenopausal women, the population group for which the most evidence is available.
In the United States, a commonly accepted guideline is that of the National Osteoporosis Foundation (NOF)8 (Table 3). However, use of this guideline may result in more frequent testing because the risk factors listed are so common in this population. The US Preventive Services Task Force has also made recommendations regarding osteoporosis screening in postmenopausal women9 (Table 4). These guidelines are conservative and formulated from evidence-based literature review. Unfortunately, they may not be useful clinically because they do not clearly address which postmenopausal women who are younger than 65 years should be tested and do not recommend screening any postmenopausal women younger than age 60 for any reason, even though women between menopause and age 60 experience rapid early postmenopausal bone loss.
Although the NOF and US Preventive Services Task Force guidelines provide recommendations for postmenopausal women, they offer no recommendations for premenopausal women or for men. The Institute for Clinical Systems Improvement (ICSI) guidelines provide a reasonable (evidence- and expert opinionbased) summary of who should be screened according to pretest probability of fracture based on risk factors.4 These guidelines may help clinicians determine which patients should undergo BMD testing. The ICSI guidelines incorporate the NOF recommendations in addition to recommendations for men and both premenopausal and postmenopausal women. Measurement of BMD is recommended for patients at high risk for future fractures, as outlined in Table 5.
How often should screening BMD testing be repeated? The US Preventive Services Task Force addressed this issue and reported no evidence for or against repeated screening.10 However, estimations can be made based on the age-specific prevalence of osteoporosis and the precision of the bone density test used. In clinical practice, BMD is often measured at 2- to 3-year intervals for recently postmenopausal women because this age group has a higher rate of bone loss, at 5-year intervals for younger postmenopausal women after the immediate postmenopausal bone loss has stabilized, and at 2- to 5-year intervals for older women. No data support an appropriate age at which to stop screening.
Clinical guidelines help guide practice but should not replace clinical judgment and patient preferences. The final decision about when and how often to perform BMD testing is ultimately at the discretion of the physician and the patient.
LABORATORY TESTING FOR SECONDARY CAUSES
Among men, 30% to 60% of osteoporosis cases are associated with secondary causes (most commonly hypogonadism, glucocorticoid use, and alcoholism); among perimenopausal women, more than 50% of cases are associated with secondary causes (most commonly hypoestrogenemia, glucocorticoid use, thyroid hormone excess, and anticonvulsant therapy). The prevalence of secondary conditions is thought to be lower in postmenopausal women, but the actual proportion is unknown.10
General consensus exists among osteoporosis specialists that a minimum screening laboratory profile should be considered for all patients who are diagnosed as having osteoporosis. However, no consensus exists regarding which tests should be done. Many experts have also suggested that patients who have osteoporosis and a Z score of less than 1.0 (some suggest using a Z score of less than 2.0) should have more extensive laboratory screening for secondary causes of osteoporosis. A diagnosis of osteoporosis in men should also prompt a thorough work-up for secondary causes regardless of their Z score because about half will have an identifiable cause for the bone loss. The ICSI guidelines provide recommendations regarding laboratory testing in patients with newly diagnosed osteoporosis4 (Table 6).
The cost-effectiveness of testing for secondary causes of osteoporosis is unknown because cost-effectiveness analyses have yet to be performed. In a chart review study, Tannenbaum et al11 examined this issue in perimenopausal and postmenopausal women and found that a testing strategy consisting of 24-hour urinary calcium, serum calcium, and serum parathyroid hormone determinations in all women and serum thyrotropin measurements in women receiving thyroid replacement therapy would be sufficient to diagnose secondary causes of osteoporosis in 86% of women; adding 25-hydroxyvitamin D would diagnose secondary causes in up to 98%. However, this study was observational and small. More recently, in a secondary analysis of data collected as part of the Fracture Intervention Trial that included 15,316 postmenopausal women, Jamal et al12 reported that the prevalence of abnormal test results in postmenopausal women with and without osteoporosis was similar, with the exception of low thyrotropin. These authors concluded that routine laboratory testing (other than thyrotropin measurements) in otherwise healthy women with osteoporosis was not useful.
Clearly, more research is needed in this area, especially in premenopausal and perimenopausal women and in men because the prevalence of secondary causes of osteoporosis in these groups is high. Until more cost-effectiveness data are available, it is reasonable to follow the strategy outlined in the ICSI guidelines (Table 6) for premenopausal or perimenopausal women, for postmenopausal women with comorbidities, and for men. For otherwise healthy postmenopausal women who have no clinical history or physical examination finding suggestive of a secondary cause of osteoporosis, it may be reasonable to only obtain a serum thyrotropin level.
Importantly, the aforementioned recommendations should be used only to direct testing for individuals who are asymptomatic or do not have clinical evidence of secondary osteoporosis on history and physical examination. If a specific secondary cause of osteoporosis is suspected on the basis of the history and physical examination findings, further directed testing is indicated.
NONPHARMACOLOGICAL THERAPY FOR PREVENTION AND TREATMENT OF BONE LOSS
Calcium and Vitamin D
Calcium absorption normally decreases with advancing age. In addition, aging is associated with decreasing serum 1,25-dihydroxyvitamin D levels, less sun exposure, and reduced skin capacity for vitamin D production. Supplementation of calcium and vitamin D should be considered in all elderly patients if dietary intake and sun exposure are inadequate to meet recommended targets.
Calcium supplementation may prevent bone loss or even mildly increase BMD,13,14 and some data suggest that it may minimally reduce fracture risk.15 However, for patients with osteoporosis, calcium supplementation should be used as an adjunct to other pharmacological interventions rather than as monotherapy. The National Institutes of Health consensus conference guidelines16 suggest that women should optimize their elemental calcium intake to 1000 mg/d until menopause and increase it to 1500 mg/d thereafter. Men should optimize their elemental calcium intake to 1000 mg/d until age 65, then increase it to 1500 mg/d.
The preferred source of calcium is foods such as dairy products. Some dietary sources of calcium include yogurt (400 mg per cup), milk (300 mg per cup), calcium-enriched orange juice (300 mg per cup), cheese (150-180 mg/oz), and canned salmon with bones (180 mg per 3 oz). Calcium supplements are an alternative means by which optimal calcium intake can be reached in those who cannot meet this need by diet alone. Numerous calcium supplements are available in a variety of salts that can be used to supplement dietary calcium intake. The most commonly used calcium supplements are calcium carbonate or calcium citrate. Factors to consider in selecting an agent include absorption, convenience, and cost. Calcium absorption is generally maximal at individual doses of 500 mg of elemental calcium. Calcium carbonate contains 40% elemental calcium, requires stomach acid for digestion and absorption, and is the least expensive option. It should be taken with meals in doses of no more than 500 mg of elemental calcium at a time. Calcium citrate contains 21% elemental calcium, does not require stomach acid for digestion, and is more bioavailable but is more expensive than calcium carbonate. Calcium citrate can be taken with or without food in doses of no more than 500 mg of elemental calcium at a time. Calcium citrate is the preferred calcium supplement for patients who are hypochlorhydric or achlorhydric (including those taking gastric acidinhibiting drugs) and for patients with a history of kidney stones. The most common adverse effects of all calcium supplements are constipation, bloating, and gas; however, these adverse effects may be less frequent with calcium citrate. Patients taking medications whose absorption may be impaired by calcium (ie, levothyroxine, fluoroquinolones, angiotensin-converting enzyme inhibitors) should also be advised to avoid taking calcium supplements within several hours of taking these medications.
Vitamin D supplementation may prevent bone loss or mildly increase BMD17 and modestly reduces vertebral and nonvertebral fracture risk in vitamin Ddeficient individuals.15,18 A recent meta-analysis concluded that oral vitamin D supplementation of 700 to 800 IU/d appears to reduce the risk of hip and nonvertebral fractures in ambulatory or institutionalized elderly persons, whereas a dose of 400 IU/d was insufficient for fracture prevention.19 Sufficient vitamin D intake is necessary to maintain circulating serum levels of 1,25-dihydroxyvitamin D adequate to stimulate calcium absorption; therefore, a combination supplement containing both calcium and vitamin D is preferred if dietary intake is inadequate. Dietary sources of vitamin D include vitamin Dfortified milk or orange juice (400 IU per quart) and cereals (40-50 IU per serving), egg yolks, saltwater fish, and liver. Some calcium supplements and most multivitamin tablets also contain vitamin D. An intake of 400 to 600 IU of vitamin D per day is recommended by the National Academy of Sciences for all adults older than age 50. The NOF recommends 800 IU/d for those at risk of deficiency, such as elderly, chronically ill, housebound, or institutionalized individuals.
Weight-bearing exercise appears to be effective in maintaining or increasing bone density at the lumbar spine and hip in postmenopausal women, but currently, no evidence suggests that it decreases fractures.20 Recommendations include weight-bearing exercise in the form of walking, mild- to moderate-impact aerobics, and resistance exercises as tolerated. Regular exercise also increases muscle mass and strength, improves balance and coordination, and has been shown to reduce the risk of falls by about 25% in frail elderly persons.21
Randomized clinical trials have supported the value of assessing risk factors for falls in elderly patients and making appropriate interventions for those at high risk.22 Risk factors include visual impairment, cognitive impairment, poor balance or gait, neuromuscular and musculoskeletal disabilities, muscle weakness, postural hypotension, multiple medications, and environmental hazards. Interventions for modifiable risk factors should include physical therapy to improve strength and balance, gait aids if needed, prevention or treatment of hypotension, and avoidance of medications that may potentially alter mental status or gait stability. Elimination of environmental hazards in the home is also helpful in preventing falls. This includes recommending shoes with nonskid soles, placing nonslip mats under area rugs, removing any nonessential throw rugs in the home or clutter on the floors, and installing grab bars in the tub, shower, and toilet areas, sturdy stairway railings, and night-lights. In a recent meta-analysis, vitamin D supplementation was reported to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%.23
PHARMACOLOGICAL INTERVENTIONS FOR PREVENTION AND TREATMENT OF BONE LOSS
Treatment thresholds for osteoporosis are not the same as diagnostic thresholds, although some experts have recommended that they should be. In the United States, most experts agree on the treatment thresholds outlined by the NOF,24 which recommends that the following individuals be considered for pharmacological intervention: (1) patients with a BMD T score below 2.0, (2) patients with a BMD T score below 1.5 if additional risk factors are present (previous fracture as an adult, history of fragility fracture in a first-degree relative, body weight <57 kg, current smoking, use of oral corticosteroid therapy for >3 months), and (3) any patient with a previous vertebral or hip fracture.
Pharmacological interventions with Food and Drug Administration (FDA) approval for treatment of osteoporosis should be recommended first. These include the oral bisphosphonates (alendronate, risedronate, and ibandronate), raloxifene, nasal calcitonin, and teriparatide. The FDA has withdrawn approval of estrogen or hormone therapy for treatment of osteoporosis but has continued approval of their use for osteoporosis prevention in selected postmenopausal women.
The primary goal of pharmacological therapy in patients with osteoporosis is to reduce the risk of future fracture, not just increase bone density. Currently, the pharmacological agents available for treatment of osteoporosis fall into 1 of 2 categories: antiresorptive agents or anabolic agents. All the currently available drugs except teriparatide are antiresorptive agents. These agents reduce bone resorption more than promote bone formation and thereby suppress bone turnover and loss, whereas anabolic agents stimulate bone formation more than reduce bone resorption. Table 7 summarizes the currently available FDA-approved medications for the prevention and/or treatment of osteoporosis.
No head-to-head clinical trials have compared the fracture efficacy of the antiresorptive agents, and only a few head-to-head clinical trials have compared the bone density effects of these agents. Most studies with fracture end points have involved postmenopausal women. In short-term clinical trials, alendronate increased BMD more than did raloxifene or calcitonin and produced a slightly greater increase than risedronate. Evidence from the current literature suggests that the antiresorptive therapies (including bisphosphonates, raloxifene, calcitonin, and estrogen) reduce vertebral fracture risk by 30% to 50%. Hip fracture reduction has been shown consistently with only some of the oral bisphosphonates (alendronate and risedronate) and with hormone therapy.25 However, because the efficacy of the oral bisphosphonates in reducing hip fracture risk has been shown in osteoporotic patients or subgroups of osteoporotic patients in these trials, many experts suggest that oral bisphosphonates be considered as first-line therapy for patients with established osteoporosis (those with T scores lower than 2.5 and prevalent vertebral fractures).
Bisphosphonates block bone resorption by inhibiting osteoclast activity and are currently the most potent oral antiresorptive agents available for prevention or treatment of osteoporosis. Only 3 bisphosphonates are currently FDA-approved for osteoporosis treatment and prevention: alendronate, risedronate, and ibandronate. The recommended doses and FDA indications for use are summarized in Table 7. Intravenous bisphosphonates, including pamidronate and zoledronic acid, are not FDA-approved for prevention or treatment of osteoporosis but are occasionally used off-label for patients who cannot tolerate oral bisphosphonates. Strong clinical trial evidence supports the use of alendronate, risedronate, and ibandronate for preventing fractures in women with postmenopausal osteoporosis or osteopenia.26,27 These agents have been shown to reduce vertebral and hip fractures by 50% to 60% in postmenopausal women.28-30 Clinical trial evidence also supports the use of alendronate for preventing fractures in men with osteoporosis.31
For all oral bisphosphonates, patients should be instructed to take each tablet with 6 to 8 ounces of plain water first thing in the morning and at least 30 minutes before ingesting the first meal, beverage, or medication of the day. Patients should not recline for at least 30 minutes (60 minutes with ibandronate) to reduce the potential for esophageal injury. If symptoms of esophageal disease (difficult or painful swallowing, retrosternal pain, new or worsening heartburn) or severe musculoskeletal pain develops, discontinuation may be appropriate. Rarely, patients may develop jaw osteonecrosis or eye inflammation with oral or intravenous bisphosphonates. However, if one oral bisphosphonate is not tolerated, occasionally an alternative oral bisphosphonate is. Oral bisphosphonates are contraindicated in patients with hypocalcemia, hypersensitivity to bisphosphonates, renal insufficiency (creatinine clearance <30-35 mL/min), or esophageal irritation or stricture. Oral bisphosphonates should be used cautiously in patients who have difficulty swallowing or severe gastroesophageal reflux and those who have undergone gastric bypass or are receiving long-term anticoagulant therapy.
Raloxifene is a selective estrogen receptor modulator that is approved for both the prevention and the treatment of postmenopausal osteoporosis at a dose of 60 mg/d. It has been shown to decrease vertebral fractures by about 50%, but because of inadequately powered trials, no evidence is currently available on hip fracture reduction.26,32
Raloxifene selectively interacts with estrogen receptors, exerting an estrogen agonist effect in some areas (bone and lipid metabolism) while acting as an estrogen antagonist in others (breast and uterus). Because of this selective effect on estrogen receptors, raloxifene potentially has the added benefits of breast cancer risk reduction and cardiovascular disease prevention, although this has not yet been shown definitively in clinical trials. Raloxifene decreases total and low-density lipoprotein cholesterol but has no effect on high-density lipoprotein cholesterol. Common adverse effects include increased risk of venous thromboembolism and increased vasomotor symptoms. Raloxifene is contraindicated in patients with a history of venous thromboembolic events and should not be recommended for premenopausal women or women concurrently using estrogen replacement therapy. Although clinical trial evidence suggests that raloxifene may reduce breast cancer risk, its use in breast cancer patients is not recommended at this time.
Salmon calcitonin nasal spray is FDA-approved for the treatment of osteoporosis at a dose of 200 IU in alternating nostrils each day. It inhibits bone resorption by osteoclasts, thereby preventing bone loss and vertebral fractures, but it has not been shown to reduce nonvertebral or hip fractures.33,34 This drug may also decrease the pain associated with acute or subacute vertebral fractures. There are no contraindications to calcitonin use other than hypersensitivity to the drug; common adverse effects include nasal symptoms and rhinitis in about 12% of patients. Because of the availability of other medications that have better efficacy in fracture reduction, calcitonin is not considered first-line treatment for osteoporosis.
The role of hormone therapy in the prevention and treatment of osteoporosis remains controversial. The US National Institutes of Healthfunded Womens Health Initiative trial showed that estrogen alone,35 or in combination with progesterone,36 decreased bone turnover, bone loss, and fractures. Combination hormone therapy is associated with a mildly increased absolute risk of serious adverse events, including coronary heart disease, stroke, venous thromboembolism, and breast cancer36; estrogen therapy alone also has been shown to be associated with an increased risk of stroke and venous thromboembolism but does not appear to be associated with an increase in coronary heart disease or invasive breast cancer.35 In the United States, hormone therapy is approved only for the prevention, not treatment, of osteoporosis. The revised FDA guidelines recommend that approved nonestrogen products be considered for prevention of osteoporosis; however, if hormone therapy is used, it is recommended in doses as low as possible for as short a time as possible. Nevertheless, some experts believe that estrogen therapy is still the first-line therapy for osteoporosis prevention in younger women with surgical menopause who have no contraindications to its use. In addition, some experts advocate the short-term use (5-7 years) of combination hormone therapy in the immediate postmenopausal years for the prevention of osteoporosis (and often for the treatment of hot flashes) in women who have no contraindications to its use.
Recombinant human parathyroid hormone analogues are potent bone anabolic agents that increase bone turnover (formation more than resorption). Teriparatide is the first anabolic drug approved for treatment of osteoporosis. It is FDA-approved for the treatment of osteoporosis in postmenopausal patients with severe bone loss who are at high risk for fracture37 and for the treatment of hypogonadal or primary osteoporosis in men at high risk for fracture.38 This drug increases bone density, thereby reducing vertebral fractures by 65% and nonvertebral fractures by 53%. The reduction in vertebral fracture risk continues for at least 18 months after therapy is discontinued.39 Teriparatide may potentially be used in combination or in sequence with antiresorptive agents but is not yet approved for such use (see Combination Therapy section).
Teriparatide is given as a once-daily 20-¼g subcutaneous injection for a maximum duration of 2 years. Adverse effects include light-headedness, dizziness, nausea, arthralgias, leg cramps, and occasionally a postinjection increase in serum calcium level. The risk of postinjection hypercalcemia is insufficient to warrant monitoring of serum calcium levels during treatment. A black box warning indicates that teriparatide produced an increased incidence of osteosarcoma in rats and that it should not be used in patients with a history of bone malignancy, Paget disease of bone, unexplained hypercalcemia, or skeletal radiation exposure or those younger than 18 years. Its use is best reserved for men or postmenopausal women with severe bone loss and preexisting osteoporotic fractures. Teriparatide should also be considered for individuals at high risk for fractures (T scores less than 3.5), even in the absence of preexisting fracture. In addition, teriparatide is an alternative for patients who are unable to tolerate oral bisphosphonates.
To date, no studies of combination therapy have had sufficient power to assess its effects on fracture outcomes. However, risedronate and alendronate, as well as calcitonin, have been shown to have an additive effect of increasing BMD when combined with hormone replacement therapy.40 Teriparatide used in combination with alendronate has been reported to be less effective in increasing bone density than teriparatide alone in postmenopausal women41 and in men.38 Combination treatment with raloxifene and teriparatide may enhance the bone-forming effects of teriparatide in postmenopausal women,42 and previous treatment with raloxifene does not blunt the expected teriparatide-induced BMD increases when these agents are used in sequence.43 However, previous treatment with alendronate does prevent the expected teriparatide-induced BMD increase, particularly in the first 6 months.43 For now, combination therapy is reserved for patients who have severe osteoporosis and should be initiated and monitored by a bone specialist.
FOLLOW-UP TESTING AFTER PHARMACOLOGICAL INTERVENTION
The need for routine follow-up BMD testing to monitor the effect of pharmacological intervention is still controversial. Serial measurements of BMD or markers of bone turnover are potentially useful methods to monitor response to therapy.
Specific evidence addressing the most efficient use of BMD measurements for monitoring treatment is lacking. Many experts have advocated a role for serial BMD measurements in monitoring the effects of therapy. If follow-up BMD testing is done, the results should be interpreted cautiously. Central DXA, although one of the most precise measurements used in medical practice, is still limited by the calculated precision of the machine and the expertise of the technician performing the test (coefficient of variation is between 1% and 2%, depending on the machine). Follow-up BMD testing should be performed on the same machine, preferably by the same technologist, to achieve the lowest precision error and greatest accuracy in documenting true change. An antiresorptive agent will generally affect trabecular bone (spine) earlier and to a greater degree than cortical bone (hip). Therefore, considerable improvement of BMD at the lumbar spine can be expected earlier than at the hip. Lack of bone-density response at the hip should not be interpreted as treatment failure if the repeat testing is done within 2 years. Stability or an increase in BMD indicates successful therapy.
In normal circumstances, bone is lost from the lumbar spine at a rate of approximately1% per year during late postmenopause. With treatment, bone loss should be notably decreased. However, the DXA machine is not precise enough to detect such small differences in BMD after a short interval. Therefore, a period of at least 2 years is usually needed to ensure that the change in BMD seen on DXA is true change and not just due to random variations in measurement. In general, repeated BMD testing to monitor treatment in a patient with normal rates of bone loss is recommended after a period of 2 to 5 years. An exception to this strategy would be patients who are at high risk for accelerated bone loss (bone lost at a higher rate than usual) such as patients taking corticosteroids or suppressive doses of thyroid hormone, women in early menopause who are not taking hormone replacement therapy, and women who have recently stopped hormone replacement therapy. In such patients, follow-up DXA may be indicated at an earlier interval (6-12 months). Medicare provides coverage for BMD evaluation with central DXA every 2 years to monitor osteoporosis therapy or for screening of patients with risk factors for osteoporosis and includes a provision for BMD testing at an earlier interval when medically necessary. Patients in whom bone density declines considerably during therapy may require further evaluation. This decline may be due to treatment failure, but other considerations include noncompliance, inadequate calcium or vitamin D intake, or a secondary cause of osteoporosis.
Biochemical markers of bone turnover have also been advocated for monitoring response to therapy. Many experts believe that the markers of bone turnover may offer additional value in assessing the effectiveness of drug therapy because the effects of most osteoporosis therapies on bone markers are rapid (3-6 months) compared to BMD, in which 1 to 2 years may be necessary to determine the effect of treatment. Markers of bone turnover typically are separated into those associated with bone formation vs those associated with bone resorption. Markers of bone formation include bone alkaline phosphatase, osteocalcin, and the type I collagen propeptides. Markers of bone resorption include urinary calcium, tartrate-resistant acid phosphatase, bone sialoprotein, type I collagen crosslinked telopeptides, and pyridinium derivatives. Currently, however, the daily and seasonal fluctuations in these markers, in addition to intraindividual variation, have limited their clinical use. Because no single marker is accurate enough to reliably identify nonresponders to treatment and further research is necessary to clarify which markers should be used and when, routine measurement of markers of bone turnover is not recommended for monitoring response to osteoporosis treatment at this time.
Osteoporosis is an important growing public health concern that is underrecognized, undertreated, and largely preventable. Most patients at high risk for fractures do not receive adequate evaluation or treatment for prevention of future fractures. More concerning is that most patients who are diagnosed as having fragility or low-impact fractures are not being evaluated or treated for osteoporosis. In fact, a recent review of the literature concluded that treatment rates for osteoporosis were low across all populations, but men and patients treated by generalists are at an especially high risk of not receiving treatment.44 Many factors likely contribute to these poor statistics and have not been well defined in the literature. Intuitively, however, generalists have a major role in educating patients about osteoporosis, assessing their risk for the disease, facilitating screening, and administering treatment. This concise review provides a straightforward and useful approach to these issues for practicing clinicians.
Questions About Osteoporosis
1. Which one of the following statements regarding calcium supplementation is false?
2. In which one of the following situations would BMD testing not be necessary?
3. Which one of the following statements regarding BMD testing is false?
4. In which one of the following should pharmacological treatment of osteoporosis be recommended based on the NOF guidelines?
5. Which one of the following statements regarding the currently available FDA-approved medications for osteoporosis is true?