Osteoporosis: the need for comprehensive treatment guidelines

CLINICAL THERAPEUTICSVVOL. 18, NO. 1, 1996

Osteoporosis: The Need for Comprehensive Treatment Guidelines Thomas A. Abbott III, PhD,‘j2 Bryan J. Lawrence, PharmD,2 and Stanley Walluch, MD3 ‘Rutgers University Newark, New Jersey, 2Sandoz Pharmaceuticals Corporation, East Hanovel; New Jersey, and 3New York University School of Medicine, New York, New York

ABSTRACT Osteoporosis is a debilitating disease that results in nearly 1.3 million fractures per year in the United States. The cost of treating these fractures has been estimated to be as high as $10 billion per year. These costs are expected to more than double during the next 50 years unless comprehensive programs of prevention and treatment are initiated. Both pharmacologic and nonpharmacologic interventions (eg, diet and exercise) have been shown to have a significant impact on the incidence of osteoporosis, depending on the time of their application. Unfortunately, osteoporosis is often not diagnosed until after fractures have occurred, when it may be too late for treatment to have a major impact. To be most effective, therapy should be started early, before serious bone loss has occurred. Because of its efficacy and relatively low acquisition cost, long-term

0149-2918/96/$3.50

hormone replacement therapy (HRT) is considered first-line pharmacologic therapy for the prevention of osteoporosis. However, for various reasons, less than 25% of US women who might benefit from HRT are receiving it. Aside from HRT, the only other products approved by the US Food and Drug Administration for the treatment of osteoporosis are salmon calcitonin and alendronate. Several other agents are under development, including sustained-release fluoride and other products in the bisphosphonate class. The development and adoption of early detection programs and treatment guidelines are crucial to help ease the economic burden of osteoporosis. These guidelines should incorporate preventive measures such as diet and exercise, risk assessment through proper screening programs, and the appropriate use of pharmaceutical products. The purpose of this paper is to discuss relevant economic issues associ-

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ated with osteoporosis and discuss the need for a management algorithm that could be used to more efficiently prevent and treat this disease. We conclude that further modeling is needed to determine which programs and treatments are most cost-effective within each at-risk subgroup. As clinicians better understand the need for preventive care and the advantages of the various pharmacologic therapies, patients with osteoporosis will receive higher-quality and more efficient medical care.

INTRODUCTION Osteoporosis is estimated to afflict at least 25% of postmenopausal white women in the Western world, or approximately 15 to 20 million American women.‘-3 A consensus development conference statement defined osteoporosis as “a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.“4 Osteoporosis manifests itself clinically with fractures primarily of the proximal femur (hip), vertebral bodies, distal forearm, proximal humerus, and ribs.5 Each year, nearly 1.3 million fractures in the United States are attributable to osteoporosis, including approximately 250,000 hip, 250,000 wrist, and 500,000 vertebral fractures.2~3~G8 The cost of treating these fractures is estimated to be as high as $10 billion per year9 Fractures of the proximal femur, or hip, have a serious impact on the quality and length of patient lives. After adjusting for age, the excess mortality rate due to the complications of hip fracture is approximately 20% during the first year.6s,‘0-13 In addition, more than half of patients who

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were living at home at the time of fracture require assistance thereafter with basic activities of daily living.6~8~10~‘2 Although less severe, fractures of the wrist, vertebrae, and other parts of the skeleton also pose a significant burden to both the patient and society. In patients with osteoporosis, vertebral and rib fractures can occur spontaneously or from trauma as mild as coughing. Although many vertebral fractures go unreported and may cause only short-term minor pain that can be adequately treated with analgesics and bed rest,‘4,‘5 collapsed vertebrae never recover their original size and shape. As a result, multiple fractures eventually lead to shortened stature, kyphotic posture, and distorted body habitus, and may lead to chronic, disabling back pain6 Most importantly, the personal and social costs of osteoporosis are expected to rise as the population in the United States continues to age. I6 The already huge cost of treating osteoporotic fractures can be expected to more than double during the next 50 years unless comprehensive programs of prevention and treatment are initiated. l6 Because current therapies primarily slow the rate of bone loss and permit replacement of only a small portion of the lost bone mass,8 it is already too late to avert many of the costs anticipated over the next 15 to 20 years.17*18Nevertheless, pain and disability, as well as some of the excess mortality of future hip fractures, can be alleviated by present-day therapy. Hormone replacement therapy (HRT) is used primarily to treat menopausal symptoms but is also first-line pharmacologic therapy for the prevention of osteoporosis when used long term. However, less than 25% of US women who might benefit from such long-term therapy are receiving it8*19 Until recently, the only other product ap-

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proved for treatment of osteoporosis in the United States was injectable salmon calcitonin. A nasal spray formulation of salmon calcitonin, already in use in many other countries, has recently received approval from the US Food and Drug Administration (FDA). In addition, alendronate, an orally administered product in the bisphosphonate class, also recently received FDA approval. Other bisphosphonates are being researched and a sustained-release formulation of fluoride is presently under FDA review. The purpose of this paper is to outline the impact of osteoporosis on society and to suggest the need for developing comprehensive treatment guidelines, which can use available products as well as products on the horizon to further enhance prevention and treatment. We believe that with these new products, it is time to review the way osteoporosis is treated in the United States. More immediately, we specifically examine the role of salmon calcitonin nasal spray in treating the population of postmenopausal women who are unable or unwilling to use HRT for the prevention of osteoporosis. The first section of this paper outlines relevant pathogenetic, clinical, epidemiologic, and economic aspects of osteoporosis. Section two presents current treatment alternatives and outlines the appropriate role of salmon calcitonin in the prevention and treatment of osteoporosis. In the third section, there is an evaluation of the current state of systems research in osteoporosis and the need to develop comprehensive treatment guidelines. The discussion provides an outline of continuing research on models assessing the social and economic impacts of osteoporosis and its treatment, and their use to guide rational decision making in this area.

OSTEOPOROSIS BACKGROUND Pathogenesis The human skeleton consists of two types of bone tissue: cortical bone and trabecular bone. Cortical bone is the dense, compact bone found primarily in the long shafts of the arms and legs. Although it comprises approximately 80% of bone volume, it makes up only 30% of the surface area.20 Trabecular, or spongy bone, is honeycombed in appearance and is filled with bone marrow. Trabecular bone is found primarily in the vertebrae, pelvis, ribs, and the ends of long bones such as the upper femora. Trabecular bone represents approximately 20% of the bone mass. At specific sites, most notably the vertebrae and distal forearm, trabecular bone can be as high as 60% to 70% of the bone mass.21 In part because of its greater surface area per unit volume, trabecular bone is approximately five times more metabolically active than cortical bone and hence more susceptible to the effects of osteoporosis.6 Bone remodeling, the continual process of gradual removal and replacement of whole volumes of defunct bone, plays an important role in the development of osteoporosis. Under normal circumstances, this process maintains the biomechanical competence of the skeleton by replacing bone that has accumulated fatigue damage.22 In addition, bone remodeling plays a role in mineral homeostasis and the maintenance of normal serum calcium levels.20T22 In osteoporosis, the bone remodeling process is out of balance, resulting in bone 10~s.~ The process of bone remodeling is conducted by bone remodeling units and consists of two sequential stages- resorption

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and formation. During resorption, osteoclasts are attracted to bone surfaces in need of replacement and gradually excavate a pit, or cavity, on the surface of the bone. During the subsequent process of bone formation, osteoblasts replace the osteoclasts and gradually fill in these cavities with new bone.9 In most instances, there is a tight quantitative coupling between bone resorption and formation,23,24 which results in the maintenance of a steady state of bone mass. However, in older patients, and especially in patients at risk for developing osteoporosis, these opposing actions are not in balance. As a result, a variable decline in bone mass and integrity occurs during the second halfcentury of life. Overall bone mass undergoes phasic changes during life. From conception until epiphyseal closure, bone formation exceeds resorption, and there is a steady increase in bone mass and volume.22 Peak bone mass is generally reached between the ages of 25 and 35 years, with men attaining 20% to 30% more bone mass than women. A few years after peak bone mass is achieved, osteoblastic activity begins to slow, osteoclastic activity increases, and age-related bone loss begins.9 In men, the average rate of overall bone loss is about 0.3% per year; in women, the average loss is more rapid-about 1.5% per year due to an accelerated period of bone loss for approximately 5 to 10 years after menopause.22 This increased rate of bone loss after menopause results from heightened osteoclastic activity secondary to loss of estrogen secretion by the ovaries. Because of its greater surface area, the loss is relatively greater in trabecular bone than cortical bone. As a result of both age-related and menopause-related bone loss, overall bone

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mineral density (BMD) falls significantly during adulthood. Riggs et a121found that the BMD of the femoral neck decreased approximately 60% in women and 40% in men between the ages of 20 and 90 years, whereas BMD of the lumbar spine fell by approximately 40% in women but only 10% in men. The expected decline in normal subjects has led to controversy over the definition of osteoporosis. Some have argued that osteoporosis should be defined as anyone with unexpected low bone mass,25,26 whereas others insist on evidence of more severe loss of structural integrity as indicated by fractures after minimal trauma.2 Ross et a12’ have essentially ended this debate by dividing the general population into three risk groups: normal persons, persons with prefracture osteoporosis, and persons with postfracture osteoporosis. Persons with prefracture osteoporosis have BMD levels and prospective fracture risks closely matching values of patients with established osteoporosis, although they have not yet experienced a fracture. Thus most researchers currently define osteoporosis as excessively low bone mass. There remains an undefined group of patients with intermediate BMD levels between levels of normal persons and persons with prefracture osteoporosis; prospective studies have not yet determined how many of these patients will pass into the prefracture or postfracture groups over time. The development of osteoporosis is a result of two factors: peak bone mass at maturity and the rate of age-related bone loss during later life. A patient may begin with lower-than-normal peak bone mass and as a result of normal age-related bone loss become osteoporotic. Alternatively, a patient with normal peak bone mass may become osteoporotic because of an ab-

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normally high rate of later bone loss.** Among patients with a high rate of bone loss there are two alternative causes-excessive osteoclastic activity or diminished osteoblastic activity. Some authors, notably Riggs and Melton, divide osteoporosis into two types depending on the presumed source of the imbalance in bone remodeling.9~29-3 * Type I osteoporosis results from an increase in osteoclastic activity and occurs mainly in postmenopausal women aged 50 to 65 years. 29 In Type I osteoporosis, the increased osteoclastic activity results in cavities that are much deeper than normal, and may perforate the bony trabeculae. Subsequently, osteoblasts cannot attach to the perforated trabeculae, leading to a loss of supporting bony structure9 above and beyond the degree of bone loss. Type I osteoporosis leads to an early loss in the structural integrity of trabecular bone, which can result in fractures in sites containing significant amounts of trabecular bone, such as the vertebrae and distal radius. In Type II osteoporosis, osteoblastic activity is primarily depressed, resulting in a thinning of both trabecular and cortical bone mass as the osteoblasts only partially refill the cavities created during bone resorption. 9*29This results in a gradual weakening of skeletal structure with fractures developing at sites containing substantial amounts of both cortical and trabecular bone, such as the proximal femur. Type II osteoporosis is found primarily in men and women older than 75 years of age. However, biochemical bone markers of bone remodeling indicate that many older patients have osteoporosis that is due to both Type I and Type II osteoporosis mechanisms. Key risk factors for developing osteoporosis include sex (predominantly women),

race (predominantly white or Oriental), slight build, and being postmenopausal. Other risk factors include early estrogen deficiency in younger women, calcium deimmobilization, ficiency, alcoholism, smoking, and corticosteroid use.*q5 However, hereditary factors probably account for 50% to 70% of the bone loss and underlie osteoporotic fractures. Therefore, even with risk factors identified, it is difficult to predict which patients will develop osteoporotic fractures without measuring BMD levels directly.25 Fortunately, over the past decade several noninvasive methods have been developed to measure bone mineral content and BMD. These methods include: single-photon absorptiometry, dual-energy photon absorptiometry, dualenergy x-ray absorptiometry (DXA), and quantitative computed tomography. These methods offer a safe and relatively easy way to determine which individuals are at risk for developing osteoporosis and subsequent fractures.32 DXA is considered the method of choice because it is relatively inexpensive, involves low radiation exposure, and can accurately measure the bone mineral content and BMD of the lumbar spine, upper femur, and wrist, which are the areas most commonly fractured in osteoporosis.

Fracture Incidence Declining bone mass from either Type I or Type II osteoporosis is a major risk factor for fractures. *s Epidemiologically, Type I osteoporotic fractures increase in frequency in women during the postmenopausal period, when the cumulative impact of estrogen deficiency is most pronounced.29 Fractures of the distal radius are the most commonly treated fractures among white women in the United States

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and northern Europe until age 75 years, when they are surpassed by hip fractures.6 Women at age 50 years are estimated to have a lifetime risk of a distal radial fracture of 15%.6*‘2 The incidence rate rises from 100 per 100,000 person-years from ages 35 to 40 years, to 700 per 100,000 person-years from ages 55 to 60 years, and then stabilizes at that level.t2 In contrast, distal radial fractures in men start at a much lower rate and climb to a peak of 100 per 100,000 person-years by age 55 years and thereafter remain constaint Comparable data on the incidence of vertebral fractures are not available, partially because some vertebral fractures produce minimal symptoms or go untreated for other reasons. There are also problems in defining vertebral fractures33 because the vertebral deformity produced can be subtle and not distinguishable from vertebral deformity due to other causes. The prevalence of vertebral fractures can be assessed through retrospective radiologic studies, but definition problems still remain. One study among 70-year-old Danish women estimated the prevalence of vertebral fractures to be 20%; a US study I2 found that one third of women older than 65 years in Rochester, Minnesota, had one or more vertebral fractures if all the possible clinical and radiologic manifestations that could be applicable were included. From these cross-sectional data, one can estimate an incidence rate of vertebral fractures of 500 per 100,000 person-years between the ages of 50 and 54 years, rising to 3000 per 100,000 person-years for women older than 85 years. 33 Thus vertebral fractures are even more common than distal radial fractures, although they occur under less dramatic circumstances and may go undiagnosed and/or untreated.

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Type II osteoporosis generally manifests itself in fractures at sites that contain both trabecular and cortical bone, such as the proximal femur, proximal humerus, and pelvis. 29These fractures generally occur later in life. For example, the incidence of fractures of the proximal femur in women increases exponentially from 10 per 100,000 person-years from ages 35 to 40 years to a peak rate of 3300 per 100,000 person-years at age 85 years and beyond. The incidence in men is similar at ages 35 to 40 years (10 per 100,000 person-years), but the peak rate is much lower at age 85 years, with only 1800 per 100,000 person-years.12 After adjusting for differences in life expectancy, the overall lifetime risk of a hip fracture is 15% in women, and only 5% in men.12 Given the severity of hip fractures, they represent a major public health problem for the elderly. Moreover, because of the exponential increase in the rate of hip fractures with age, doubling every 5 or 6 years, even a small increase in bone mass or a slight slowing of the rate of bone loss could delay the onset of hip fractures significantly and thus substantially reduce the personal and social costs of osteoporosis.9g34 Although rib fractures are also a problem in managing patients with osteoporotic fractures, the literature provides limited documentation as to their specific economic and clinical impact.

Social costs Incidence and prevalence data for osteoporotic fractures tell only part of the social and economic cost of osteoporosis. The remainder of these costs are captured by the morbidity and mortality associated with fractures in the elderly. In this regard, hip fractures are the most serious,

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but distal radial and vertebral fractures contribute significantly to the deterioration of health among the elderly. Hip Fractures In 1991 there were 300,000 hip fractures in the United States, with the majority of these fractures (94%) occurring in people older than 50 years.35 Although not all fractures are the direct result of osteoporosis, it is considered a major contributing factor in the majority of them.35 The Office of Technology Assessment (OTA) estimated the average expenditure per hip fracture patient older than 50 years to be $19,300.00, with the aggregate health care cost for all hip fractures totaling $5.4 billion. 35 In 1984, Holbrook et aP6 estimated the total cost of acute plus long-term care for osteoporotic hip fractures at $7.3 billion. The economic cost of treating hip fractures is only a small part of the overall cost to society. MillerlO found that only 50% of hip fracture patients returned to preinjury ambulatory levels, 25% died within the first year from related complications, and 25% needed a wheelchair or other assistance with basic activities of daily living. By 1990, the average l-year mortality rate for hip fracture patients had fallen by only a few percentage points, and still remained 10% to 20% above normal.35 In addition, the OTA report found that 40% of hip fracture patients were discharged from the hospital to a nursing home, and one third of these (representing 15% of all hip fracture patients) were still in the nursing home at the end of 1 year, whereas the remaining two thirds had either died or returned home. Regarding longer term outcomes, Riggsz3 reports one half of hip fracture survivors are unable to walk unassisted, and 25% are confined to a long-term care facility.

Distal Radial Fractures The economic and social costs of fractures of the distal radius are difficult to estimate because they are rarely fatal and cause much less disability than hip fractures6 Only 20% of these fractures require hospitalization, and the majority of patients receive minimal rehabilitation services.37 In a classic 1980 cost-benefit analysis of estrogen, Weinstein3* estimated the treatment cost then to be $250.00 per patient, based on the assumption that most of these fractures are handled on an outpatient basis. In 1987, Melton and Riggs12 estimated the aggregate medical care cost to be about $140 million each year, implying an estimated cost of about $500.00 per fracture. The treatment cost today, including cases that require fixation procedures for complicated fractures, is even higher. The social costs of distal radial fractures, however, could be substantially higher because of lost productivity. Among white women, the median age of distal radial fracture patients is 66 years,39 and it is reasonable to assume that 30% to 40% of these women were working at the time of injury. The social costs from missed work and reduced productivity may exceed the direct medical costs discussed above. Additional research is needed to identify and estimate these costs if a proper assessment of social costs is to be made. Vertebral Fractures The economic and social costs of vertebral fractures are even more difficult to document because they are not always dramatic in onset. Vertebral fractures vary widely in anatomic and clinical severity, ranging from wedge fractures (in which the anterior side of the vertebrae is re-

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duced in height), to compression (in which the middle portion of the vertebrae is reduced in height), to crush fractures (complete collapse). The treatment for vertebral fractures ranges from reduced activity at home and over-the-counter analgesics, to several weeks of complete bed rest in the hospital, the use of narcotics to block pain, and a slow resumption of ambulation over several months. 14,24 In a sample of 203 Japanese women, Ross et a140 found that the occurrence of new vertebral fractures, as determined by radiographic examination, increased the frequency and severity of previously present back pain or caused new acute back pain. Moreover, “the pain frequency index increased approximately 3-fold, relative to pre-fracture levels. At the end of follow-up (mean = 3.5 years), the index was still two times greater than baseline.“40 The National Osteoporosis Foundation Scientific Advisory Board4’ reported that vertebral fractures were three times as frequent as hip fractures among women older than 50 years, and although many go untreated, vertebral fractures account for 160,000 physician office visits and more than 5 million restricted activity days each year. In addition to the episodic costs of treatment and disability from new fractures, vertebral fractures also have a cumulative effect on patient quality of life. Although a single fracture may result in only temporary inconvenience and transient back pain, multiple fractures over time result in kyphotic posture, chronic back pain, loss of independence, and disability, all of which diminish quality of life in later years. 6,40,42-45 Finally, because most vertebral crush fractures tend to occur at an earlier age than hip fractures, there are indirect costs

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associated with lost productivity. In most cases of vertebral fracture, patients and their informal caregivers during the acute episode are temporarily out of the labor force. Thus, although difficult to measure and quantify, there are important indirect costs associated with vertebral fractures.

Future Cost Implications Unless comprehensive programs to prevent and treat osteoporosis are adopted soon, the economic and social costs of osteoporosis are expected to rise as the population in the United States continues to age. Cummings et all6 estimate that the number of hip fractures could rise to 5 12,000 per annum by the year 2040, with an associated cost of nearly $16 billion, at today’s cost of treatment. In addition, there is evidence from European studies indicating that the age-adjusted incidence of fractures is on the rise.& Although there is no similar evidence for the United States, one must cautiously interpret the results of Cummings et al in light of the trends observed elsewhere. Moreover, because current treatments only slow the rate of bone loss and replace only a small fraction of lost bone mass, it is already too late to prevent costs from rising over the next 15 to 20 years.i8 Nevertheless, more comprehensive attention to treatment options must start now.

TREATMENT

OPTIONS

Because of the high personal and social costs associated with the treatment of osteoporotic fractures, the prevention of osteoporosis is seen as the most costeffective way to address this growing public health problem. 9,1s,47 Given the progressive nature of the disease, there are

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two ways to prevent, or at least delay, the onset of osteoporosis: (1) increase peak bone mass; and (2) prevent or slow the rate of bone loss in later life.2,5*28Moreover, because of the exponential increase in the risk of osteoporosis-related fractures as patients lose bone mass, a decrease in the rate of bone loss, a small increase in bone mass, or a delay in the evolution of osteoporosis could be very important.9,34 Brody et a134 suggest that “if it were possible to manipulate bone metabolism and postpone the onset of hip fractures by five to six years among these women, we would reduce the occurrence of hip fractures by about 50 percent.” Advocacy of diet (including adequate calcium intake), exercise, and avoidance of negative lifestyle factors such as smoking and excessive alcohol and caffeine use are the keys to increasing peak bone mass in the general population. These comprise the first line of defense and must be emphasized early in life. The second line of defense for treating or preventing osteoporosis is to slow the rate of bone loss after peak mass has been achieved. In addition to diet, exercise, and lifestyle modification, pharmaceutical treatments have been shown to be effective in preventing or decreasing the rate of postmenopausal bone loss. Currently, estrogens, salmon calcitonin, and alendronate are approved for use in the treatment or prevention of osteoporosis. These drugs slow the rate of bone loss primarily by inhibiting bone resorption9 although there is some evidence that calcitonin may stimulate osteoblastic activity as well. All three agents can result in a small gain in BMD levels.48 In theory, a third approach would be to stimulate bone formation and thereby rebuild lost bone mass effectively. Unfortunately, this ap-

proach has not been successfully incorporated into an approved therapy, although sustained-release fluoride has recently been submitted to the FDA for evaluation. Thus, because current treatments primarily slow the rate of bone loss and do not rebuild substantial amounts of bone mass, it is imperative that they be started early, preferably before serious bone loss has occurred.8*‘7

Exercise and Calcium Intake Exercise and calcium intake (diet and/or supplementation) are believed to be important determinants in achieving peak bone mass. Several cross-sectional and longitudinal studies have shown a direct relationship between weight-bearing exercise or physical fitness and bone mass.49-s2 Repetitive stress loading tends to increase bone density at the site of the stress, whereas low levels of physical activity lead to a reduction in bone density. For example, complete bed rest produces a negative calcium balance within a few days and a detectable reduction in bone density within a few weeks.53 Several studies54-56 have evaluated the relationship between calcium intake and peak bone mass. Although results vary, it is generally accepted that proper calcium intake contributes to peak bone mass, especially when started relatively early.5’ Because peak bone mass is achieved between the ages of 25 and 35 years, it is suggested that both exercise and proper calcium intake be encouraged at a much earlier age.54,55 For example, Murphy et a153 demonstrated a consistent upward trend in BMD levels with increasing historical milk consumption, with the strongest association being between hip bone mass and milk consumption before age 25

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years. Thus nutritional and exercise programs should be started early and continued through at least midlife.

Postmenopausal Estrogen Therapy Postmenopausal estrogen therapy (with or without concomitant progestogen), also known as HRT, relieves vasomotor and urogenital symptoms of menopause, has cardioprotective features, prevents postmenopausal loss of bone mineral content, and reduces the incidence of later hip, radial, and vertebral fractures.57 Although HRT therapy initiated at the time of menopause clearly prevents bone loss and decreases fractures, the use of estrogen in established osteoporosis is less effective because estrogens can replace only a small fraction of the lost bone mass.58 Although the benefits of HRT are well established, many physicians in the United States have been reluctant to prescribe HRT for the prevention of osteoporosis, and many women will not accept long-term HRT. Notelovitz59 attributes much of this reluctance to two main factors. First, despite incurring postmenopausal bone loss, up to 75% of all postmenopausal women will not develop clinical osteoporosis. Thus, without screening, the clinical indication is not present for the majority of women. Second, there has been a lack of public education about the benefits of HRT, whereas potential adverse effects have received much visibility in the media, causing substantial patient concerns about beginning or continuing estrogen therapy.59 The decision to undertake HRT is complex and involves balancing the beneficial effects of HRT against the unknown risks of breast cancer, the discomfort of menstrual bleeding and other possible gynecologic symptoms, and the cost of follow-up care.a2

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Furthermore, although HRT is appropriate first-line therapy for osteoporosis prophylaxis and treatment, there is a significant portion of the population who cannot or will not use HRT due to contraindications, noncompliance, or a perception of increased risk of breast cancer, both by the patient and the physician.63”5 Reginster et alI9 have suggested that alternatives to HRT must be developed to prevent osteoporosis in women who do not want or will not benefit from HRT after menopause. In 1990, less than 25% of the postmenopausal population in Europe and the United States were effectively protected against osteoporosis by HRT.‘9.57,66 Thus the remainder of this paper addresses the appropriate role of calcitonin and other new products for the prevention and treatment of osteoporosis.

Calcitonin Therapy Internationally, several forms of calcitonin are available for therapeutic administration including human, salmon, porcine, and eel. Salmon calcitonin, the most potent of these forms,67 has been approved in the United States in an injectable form since 1984 for the treatment of osteoporosis. Its use has been limited by the need for injections and by annoying side effects in some patients during initiation. Recently, an intranasal formulation of salmon calcitonin, which avoids these problems, was approved by the FDA. Intranasal and suppository forms of salmon calcitonin have been available in Europe, Hong Kong, Mexico, and other parts of the world since the mid- 1980s. Many studies have consistently shown that salmon calcitonin is both safe and effective in the treatment of osteoporotic women. McDermott and Kidd68 identified

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27 published studies on the effects of calcitonin on osteoporosis, using bone mass measurements as a surrogate for the disease. In general, they found that injectable calcitonin inhibited osteoclastic activity (bone resorption) and had little negative effect on, or even stimulated,4s osteoblastic activity (bone formation). As a result, the studies have consistently found a significant increase (from baseline) in bone mass over the first 12 to 16 months of therapy. However, with injectable salmon calcitonin, some patients may develop tolerance to treatment, and after about 12 to 16 months, the rate of increase of bone mass plateaus or diminishes. Nevertheless, a net gain compared with baseline prevails. Moreover, there is evidence of a decreased vertebral fracture rate over this relatively short period.48 Calcitonin has also been found to have independent analgesic properties. McDermott and Kidd68 reviewed 38 studies that evaluated the impact of calcitonin on pain. All but 2 studies reported significant analgesic effects in the majority of patients after 1 to 4 weeks. This analgesic property makes calcitonin a viable alternative for treating patients with acute vertebral fracture because the inactivity associated with confined bed rest for severe pain increases morbidity and worsens the osteoporosis. Calcitonin also decreases chronic back pain in osteoporotic patients with multiple vertebral fractures, although this analgesic effect sets in gradually over several months of continued treatment.68*69 The most common side effects associated with injectable salmon calcitonin include nausea, vomiting, and flushing; these side effects, which usually occur with initiation of treatment, are the most frequent reason that patients discontinue therapy. 7o Many physicians are not aware

that these early side effects do not constitute significant organ toxicity, can often be counteracted, and usually diminish with continued treatment. Unfortunately, although calcitonin offers many advantages as a treatment alternative to HRT, the injectable formulation has not gained widespread use in the US market. Salmon calcitonin nasal spray overcomes many of the problems associated with the injectable formulation. Its route of administration is more acceptable to patients, which can lead to increased compliance. Also, almost none of the systemic side effects observed with the injectable form occur in patients treated with the Most importantly, innasal spray. 18,66,70,71 tranasal salmon calcitonin has been shown to be effective at halting bone loss. Recent studies show that patients treated with nasal calcitonin and calcium gain 2% to 3% in BMD compared with patients treated with calcium alone,66*72 and compared with their baseline measurements.73 A subanalysis of a randomized, parallelgroup, 2-year study comparing salmon calcitonin nasal spray (200 III/d) versus placebo revealed that 31 (76%) of 41 patients in the calcitonin arm responded to treatment, with an increase in vertebral BMD from baseline.74 In contrast, only 37% of patients receiving placebo had a similar result (P c 0.001). The relative risk of bone loss for patients receiving salmon calcitonin nasal spray was 0.19 (95% confidence interval, 0.07 to 0.50). There is also prospective evidence showing that intranasal calcitonin reduces the incidence of vertebral fractures.75 Other comparisons have been conducted showing that intranasal calcitonin is as effective as injectable calcitonin76 and estrogen. 77 Finally, intranasal salmon calcitonin has been shown to have strong

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analgesic properties,69 thus providing a safe, effective alternative to HRT in instances where estrogen is either contraindicated or unacceptable. Recently published results of long-term studies in postmenopausal women show that the beneficial effects of calcitonin nasal spray can delay bone loss for up to 5 years.19~78

Bisphosphonates Until the recent approval of alendronate, bisphosphonates were approved in the United States only to treat Paget’s disease and malignant hypercalcemia. Bisphosphonates are carbon-substituted analogs of pyrophosphate, an endogenous physiologic inhibitor of bone mineralization. They act by binding to the hydroxyapatite crystals of bone and are thus retained in the bone for a prolonged period. During the process of bone resorption, the bisphosphonates are released locally and taken up by the osteoclasts, thereby inhibiting the osteoclasts’ ability to resorb bone.9 The oral absorption of bisphosphonates is only 1% to 5% of the total dose administered. This absorption is reduced even further with the presence of food or calcium, which can bind and inactivate the drug in the gut.79-81 Etidronate has been studied in various disorders of mineral metabolism and is approved in the United States for the treatment of Paget’s disease, ectopic calcification, and hypercalcemia.82 In studies evaluating the use of etidronate in osteoporosis, the drug has been shown to be superior to placebo in increasing bone densityss@ and possibly decreasing fractures.83 Alendronate, recently approved by the FDA, has also been shown to be effective in clinical trials for the treatment of postmenopausal osteoporosis.85-87 A recent

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study by Liberman et alg8 showed a decrease in biochemical markers of bone resorption and an increase in BMD compared with placebo. Mean increases in BMD over a 36-month period, compared with placebo, were 8.8% in the spine, 5.9% in the femoral neck, 7.8% in the trochanter, and 2.5% in the total body (P c 0.001 for all comparisons).88 Prevention of postmenopausal bone loss has also been noted.89 These quantitative effects on BMD are accompanied by decreased fracture rates.90q9’

Experimental

Therapies

Pharmaceutical research continues on a number of fronts in the search for treatments to prevent or delay the onset of osteoporotic fractures. Products currently under investigation include other bisphosphonates, sustained-release fluoride, calcitriol, and several others. Fluoride Fluoride has been approved for the treatment of osteoporosis in eight European countries but is not in wide use in the United States. It affects osteoporosis by stimulating the osteoblast precursors that form new bone on existing trabecular surfaces.24 Treatment with fluoride clearly increases bone density in the spine, but questions remain about its impact on cortical bone. Fluoride becomes incorporated into the bone matrix and results in an abnormal structure; the effect of this abnormal structure on bone fragility is not clear9* Sodium fluoride can cause gastrointestinal irritation and bleeding, and a lower extremity pain syndrome that may be due to stress fractures.24 Recently, the use of a slow-release preparation of sodium fluoride in combination with calcium sup-

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plementation was noted to have beneficial effects on both spinal and femoral neck BMD, without promoting appendicular fractures or gastric ulceration.93s94 Calcitriol Calcitriol is the most active of the vitamin D metabolites and acts to increase calcium absorption, as well as stimulate osteoblasts.9 In some studies, calcitriol treatment has been shown to increase calcium balance and decrease the rate of new vertebral fractures,95,96 although its mechanisms of action are uncertain. Cal&i01 is currently available in Japan and several Asian and European countries. In the United States, it is indicated only for the control of hypocalcemia, and it appears to have a very narrow therapeutic window. The wide discrepancy in reports of efficacy in various countries may relate to ethnic differences in vitamin D receptor gene polymorphisms.97 Other Experimental Agents In addition to the aforementioned agents, several other agents are being examined for their effects on the skeleton.24 Tamoxifen, an estrogen antagonist, has effects on bone similar to estrogen but causes excessive uterine endometrial stimulation. A new estrogen antagonist, raloxifene, appears to have similar effects to estrogen on bone without stimulating either the endometrium or breast. Newer analogs are also being prepared for clinical investigation. The degree of cardioprotection offered by the estrogen antagonists is unclear. In recent years, the anabolic steroids have largely been abandoned because of androgenic side effects, but probably should be reexamined, as they may directly stimulate bone formation. Amino-terminal fragments of parathyroid hormone are anabolic for trabecular

bone but catabolic for cortical bone. Lowdose, intermittent injection programs appear to minimize this adverse effect and when coadministered with vitamin D analogs, can significantly increase trabecular bone. Research continues regarding the optimal program and whether a noninjection route of administration is feasible. Similarly, both growth hormone and its product, insulin-like growth factor-l (somatomedin), are highly anabolic for bone and are being actively evaluated to determine optimal programs for their administration, as well as strategies to increase their concentrations in bone indirectly. Other cytokine-like growth factors, such as a series of bone morphogenetic proteins and a number of osteolytic cytokine antagonists, are also being studied. Several other treatment areas are also being explored. Among inorganic agents, magnesium, strontium, manganese, and zeolite (a silicon-aluminum complex) may hold some promise. Physical modalities including ultrasound, electromagnetic emanations, and mechanical stimuli are also potential agents to prevent or combat osteoporosis.

SUMMARY To date, the FDA has approved only HRT, salmon calcitonin, and alendronate for the treatment of osteoporosis. HRT is considered first-line therapy, and because of its additional cardioprotective benefits, some clinicians believe that most postmenopausal women should receive HRT. Unfortunately, many American women do not want to take estrogens, and most physicians do not regularly recommend estrogens for their postmenopausal patients. Although the reasons vary, the most common negative responses are: (1) patient reluctance; (2) concern about the risk

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of breast and endometrial cancer; and (3) estrogen contraindications9* Moreover, to prevent bone loss, a prolonged duration of treatment is needed.* As a result, less than 25% of the postmenopausal population is adequately protected against bone loss by HRT.*T’~ Until recently, calcitonin was available only in the injectable form in the United States, which has limited its use. With the recent approval of salmon calcitonin nasal spray and oral alendronate, nonestrogenic products are now available that may provide an acceptable long-term option for the treatment of osteoporosis.

COMPREHENSIVE TREATMENT GUIDELINES Osteoporosis is a major public health problem throughout the world. Older persons are the most rapidly growing demographic group in the United States and are the most susceptible to the excess morbidity and mortality associated with osteoporosis-related fractures. As the population continues to age, the costs to society will continue to rise, unless programs are adopted that prevent or delay the onset of osteoporosis. Ross et all7 have observed “current medical practice for preventing osteoporotic fractures is both haphazard and ineffective.” It is time for the medical community to seriously address the effects of osteoporosis, and not look on it as a natural part of the aging process. There is nothing “natural” about broken bones, chronic back pain, kyphotic posture, or living in a wheelchair. To be most effective, preventive measures should be started before peak bone mass is attained, and current pharmaceutical therapies should be started before serious bone loss has occurred. Unfortu-

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nately, osteoporosis is often diagnosed only after a fracture occurs, and it is then often too late for existing therapies to have a major impact on the course of the disease. Thus developing programs for the early detection and prevention is essential for controlling future social and economic costs of osteoporosis. Unfortunately, because of a lack of continuity of care in the United States, no group has the financial incentive to undertake prevention programs for younger women when the benefits are not realized until the women reach their 6Os, 70s and 80s. Insurance plans and managed-care programs primarily cover pre-Medicare age patients and also have considerable turnover in their enrollees. They see no cost avoidance by adopting preventive programs. Nevertheless, early detection programs must be developed within broad guidelines incorporating medically appropriate prevention and treatment programs for osteoporosis. Such guidelines, developed under the auspices of the National Osteoporosis Foundation, the Agency for Health Care Policy and Research, or other interested groups, would take clinicians, both within and independent of managed-care programs, through a series of steps designed to help control the disease and ensure that treatment options are utilized efficiently. Defining good clinical practice is essential to overcoming the inertia in clinical practice and the financial disincentives for managed-care programs to both prevent and treat osteoporosis. The treatment guidelines should lay out a step-care approach to patients at risk for developing osteoporosis. The figure outlines one possible example of a treatment algorithm. Step 1: All women beginning as early as their teens should include proper diet

T.A. ABBOTT III ET AL.

Step 1

I

Diet, physical conditioning, and lifestyle changes (calcium supplementation

if necessary)

I Menopausal

Step 2

women

BMD screening

1. Diet, exercise, and lifestyle changes

1. Diet, exercise, and lifestyle changes

1. Diet, physical conditioning, and lifestyle changes

2. No drug treatment

2. Periodic monitoring of BMD

2. Drug therapy -Hormone replacement therapy -Salmon calcitonin nasal spray -Alendronate 3. Periodic monitoring of BMD

Figure.

An example of an osteoporosis

treatment algorithm. BMD = bone mineral density.

and appropriate exercise in their daily living. An additional option is to include calcium supplementation for women who will not accept adequate amounts of dairy products and other sources of calcium in their daily diet. The justification for Step 1 is that these advocacies are beneficial in preventing osteoporosis, can be achieved at very little cost, and have few adverse side effects. Other dietary needs for this population should include reducing excessive acid ash diets (cola drink, very high protein intake, etc.) and ensuring an adequate vit-

amin D intake. At the same time, prudent lifestyle changes should be promoted, including avoidance of cigarette smoking or of excessive alcohol or caffeine. Step 2: Screen women for low BMD at the time of menopause using DXA measurements of the lumbar spine and upper femur. Although other risk factors such as race, age at menopause, body build, lifestyle, and family history could be incorporated into a checklist to prescreen women, this is probably unnecessary. Such risk factors have limited power to

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predict BMD,25 and the cost of DXA screening is acceptable and not labor intensive. OTA estimates the actual cost of BMD screening at $100.00 per patient.99 BMD screening is painless and offers little risk to the patient. The initial screening data can divide the population into several risk groups, corresponding to high risk (needing immediate treatment), medium risk (requiring periodic monitoring of BMD), and low risk (requiring no further treatment or monitoring). Step 3 (high-risk group): Include guidelines outlining pharmaceutical treatment in individual patients. HRT is probably the first-line pharmaceutical agent for most patients because it is effective for osteoporosis at a relatively low cost and provides additional cardiovascular benefits. The results of bone mineral densitometry have been shown to have a positive effect on patient willingness to begin longterm HRT.toO One could therefore anticipate greater acceptance of HRT under such a comprehensive program. Unfortunately, even after receiving the results of BMD screening, many women will not be willing or able to take estrogens. As a result, many women will discontinue HRT before the desired goals are achieved. In these instances, the guidelines should incorporate additional pharmaceutical agents that can prevent, delay, or ameliorate the onset of osteoporosis, including salmon calcitonin nasal spray and alendronate. Reinforcement of the importance of proper diet, physical conditioning, and appropriate lifestyle changes should also be reiterated to patients beginning drug therapy. Other recommendations should include periodic BMD measurements to determine whether there is ongoing bone loss, and appropriate follow-up of drug

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therapy. The details of drug therapy followup are beyond the scope of this paper. Step 4 (medium-risk group): Follow-up of the medium-risk group should include continuation of proper diet, exercise, and appropriate lifestyle changes, as well as periodic BMD measurements to determine whether there is ongoing bone loss. Step 5 (low-risk group): Continuation of proper diet, exercise, and appropriate lifestyle changes should again be reiterated. Periodic BMD screening will be less frequently indicated than in the high-risk and medium-risk groups, but may be needed in some patients during extended follow-up. Without the development of comprehensive guidelines for osteoporosis prevention and treatment, many health care providers and payers may be resistant to starting long-term programs, even in patients at high risk, because the benefits of treatment are not realized for many years. As the United States moves into a disease management environment, the adoption of comprehensive clinical guidelines will be made on the basis of economic analyses. In recent years, there has been considerable debate regarding the costs and effectiveness of widespread BMD screening programs.8,17,25,41,42,47.101-104 Mu& of this debate has centered on whether the use of bone mineral densitometry alters a woman’s decision to begin long-term HRT, which has historically been viewed as the only viable treatment. Because decisions about HRT are usually made on bases other than the prevention of osteoporosis, several authors42,101*102 have concluded that there is no benefit in conducting broad-based screening programs. With new treatment modalities available and others on the horizon, health care providers and society need to reexamine

T.A. ABBOTT

the

III ET AL.

economics of BMD screening and osteoporosis prevention. Women now have alternatives to HRT that may make them more amenable to long-term treatment. Thus existing analyses of screening need to be extended to examine the costs and benefits of salmon calcitonin nasal spray, alendronate, and of experimental therapies as they undergo FDA approval to determine their appropriateness for individual patients. Moreover, many prior studies have focused only on the impact of hip fracture, whereas the societal costs of distal radial and vertebral fractures are also substantial and should be included in the analyses. Considerable research remains to be done to support the development and implementation of comprehensive diagnosis, prevention, and treatment programs for osteoporosis. Because of the length of time between menopause and the maximum incidence of hip fractures during the seventh and eighth decades of life, it is not feasible to conduct randomized clinical trials to determine the effects of alternative treatments. Thus careful modeling of the disease and the impact of treatment is the only way to assess the costs and benefits of alternative treatment programs. These models necessarily make assumptions about the relationship between long-term treatment, BMD levels, and the risk of osteoporotic fractures. However, when properly developed and analyzed, these models can provide results of sufficient scientific validity on which to base public policy and individual patient treatment decisions. For example, smoking has never been shown to cause cancer in humans in a randomized clinical trial, yet there is sufficient evidence to conclude that smoking causes cancer. Likewise, HRT has never been shown to reduce the risk of coronary heart disease or hip fracture, or increase

the risk of endometrial or breast cancer in randomized prospective clinical trials, yet there is sufficient evidence to build these outcomes into the cost-benefit assessment of long-term HRT. In developing this review of existing literature on the impact and treatment of osteoporosis, the paucity of information on the social, economic, and quality-oflife effects of vertebral, distal radial, and rib fractures became blatantly apparent. The inclusion of health-related quality-oflife instruments specifically for use in osteoporosis treatment trials,43,105*‘06and the development of methods to measure the benefits of treatment, will greatly enhance the design of models to assess strategies for preventing and combating osteoporosis. Increased awareness of the clinical, economic, and social impacts of osteoporosis, use of comprehensive screening programs, and the development of new therapies and improved dosage forms that increase patient compliance will all contribute to optimizing treatment in patients at risk for developing the disease. To maximize the potential public health benefits, guidelines also need to be developed to determine how, and for whom, each of these alternatives is cost-effective. Efforts are currently under way to develop models to address these issues. Address correspondence to: Lawrence, PharmD, Assistant Pharmacoeconomics, Sandoz ceuticals Corporation, 59 Route Hanover, NJ 07936-1080.

Bryan J. Director, Pharma10, East

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