We are in the midst of an osteoporosis revolution. As in most revolutions, powerful and opposing forces are at work, and no one can be sure what the outcome will be. One set of forces comes from the recognition of the costs of osteoporosis to society and an improved understanding of the disorder. A potential opposing force comes from pressure for cost containment within the health care system. Although current research has led to more effective diagnosis, prevention, and treatment of osteoporosis, the new approaches are expensive. Thus, these forces seem to be mutually incompatible. We may, however, be able to reduce the costs of these new approaches sufficiently to satisfy policymakers and substantially reduce the long-term costs of health care [1-3]. The goal is to prevent the enormous increase in the incidence of osteoporotic fractures that will probably occur as the U.S. population ages [4]: It is estimated that the annual cost of hip fracture in the United States may exceed $240 billion 50 years from now [5].
Clinicians must keep an eye on the battlefields of this revolution. I report on conditions on five fronts: the role of genetics in determining bone mass and loss, the role of local factors in pathogenesis, the appropriate use of bone mass measurements, the present and future role of biochemical markers of bone turnover, and the advantages and disadvantages of current and future approaches to prevention and therapy.
Increasing evidence shows that not only peak bone mass but also skeletal structure and metabolic activity are genetically determined [6-8]. The incidence of osteoporotic fractures differs greatly among racial and ethnic groups [9]. Recent evidence suggests that specific genes may determine bone mass, bone turnover, and bone loss [7, 10-12]. Although the studies of Eisman [13] have focused attention on the role of vitamin D-receptor alleles in determining bone mass, not all studies have confirmed these findings [14]. Moreover, it appears unlikely that a single gene will contribute more than a small percentage of the variation in a multifactorial disease such as osteoporosis [6]. With rapid progress being made in methods in molecular genetics, several genes that predispose a person to the development of osteoporosis might be identified; this discovery might then lead to genetic screening and early intervention in high-risk persons.
Although we have identified many risk factors for osteoporosis and for fractures, we still cannot determine why some persons show a marked reduction in bone mass and are prone to multiple fractures, whereas other persons with similar risk factors do not have these characteristics. The pathogenesis of the severe progressive vertebral crush fracture syndrome, which occurs in a small proportion of postmenopausal women and, occasionally, in younger women and in men, is unknown. Abnormalities in the production of or response to local factors that regulate bone remodeling will probably be found in these patients [15]. Various cytokines and related substances, including interleukin-1, tumor necrosis factor-
, interleukin-6, and prostaglandin E2, have been implicated as causes of bone loss after oophorectomy or orchidectomy in animal models [16-18]. Data on the role of local cytokine production in the response to estrogen withdrawal and in osteoporosis in humans are conflicting and limited [19-21].
Osteoporosis requires both increased resorption and a defect in bone formation. During adolescence, a high rate of bone resorption is associated with an increase in bone mass because the rate of bone formation is even higher than the rate of resorption. The rate of bone formation may also increase in older persons with osteoporosis, but this increase cannot adequately replace the bone lost by resorption. This may be because of a defect in the production of local or systemic growth factors. Insulin-like growth factor and transforming growth factor-ß have been implicated, but again, the data are limited and conflicting [22, 23].
The campaign to identify the role of local factors in the pathogenesis of osteoporosis has just begun. Skeletal tissue probably contains many stimulators and inhibitors of bone formation and resorption that can interact not only with each other but also with systemic hormones. The long-range goal is to identify specific pathogenetic factors in individual patients, which might then lead to more effective diagnosis and treatment.
In the past, a diagnosis of osteoporosis was made when a fracture occurred (which is too late) or when the radiologist thought the bones "looked thin" (which is too inaccurate). A new, more appropriate approach is to measure bone density and attempt to deal with the problem early. Bone mineral density is a continuous measure of risk for fracture, just as serum lipid levels and blood pressure are continuous measures of certain cardiovascular risks. Indeed, low bone density predicts fracture better than elevated cholesterol levels predict myocardial infarction. This approach has led to the redefinition of 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" [24]. To make this definition more useful, the World Health Organization (WHO) has recommended that osteoporosis be diagnosed when bone mineral density is at least 2.5 SDs below the mean for young adults [25]. A range of ± 1.0 SD is defined as "normal," and a range between –1.0 and –2.5 SD is defined as "low bone mass" or "osteopenia." These definitions are based on epidemiologic data relating fracture incidence to bone mass [26]. The value for young adults rather than that for age-matched controls is used because a large proportion of older persons are, in fact, osteoporotic.
When the WHO definition is used, it is possible to make a diagnosis and initiate therapy before fractures occur. However, this approach has created several problems. Because bone density is a continuous measure of risk for fracture, the chosen cutoffs are obviously arbitrary. (The same problem exists for measurement of blood pressure and cholesterol levels.) Moreover, the epidemiologic data on which the diagnosis is based were largely derived from postmenopausal white women and may not apply to other populations. The incidence of osteoporotic fractures in men is increasing as their life expectancy increases, and the incidence of hip fractures worldwide is predicted to increase enormously in nonwhite populations. Finally, the most widely used measurement method, dual-energy x-ray absorptiometry of the lumbar spine and proximal femur, is expensive and not universally available. Femur measurements are important both because they are good predictors of hip fracture and because values obtained from the spine are often falsely high in older persons with osteoarthritis [27, 28]. Densitometry is currently recommended for high-risk populations, but, as already pointed out, the usual risk factors are not reliable in identifying the population with low bone density. We can meet these challenges in several ways. The cost of densitometry of the spine and femur could be reduced, and the availability of this service could be increased. Alternatively, simpler measurements, such as those of forearm bone density or those made with ultrasonography, could be used for more widespread screening [29]. We do not yet know which is the most cost-effective strategy.
If bone densitometry is in its adolescence, then the use of new biochemical markers to assess the skeleton is in its infancy [30]. Earlier markers, such as the total alkaline phosphatase level and urinary hydroxyproline or calcium levels, were of limited value. New measures of bone resorption (such as collagen crosslinks) and of bone formation (such as levels of bone-specific alkaline phosphatase and osteocalcin) are better indicators of bone turnover. Several of these assays are now available for clinical use. It was initially hoped that the assays would be diagnostic tools that would indicate a risk for fracture similar to that provided by measurements of bone density. In population studies, high bone turnover is associated with lower bone mass, more rapid bone loss, and an increased propensity for fracture [30-33]. However, the variation is too great for diagnostic use in individual patients. Markers of bone resorption can currently be used to assess the response to a new antiresorptive therapy sooner than a response in bone density can be detected [34, 35]. This field is developing rapidly, and assays to determine bone turnover will probably be refined and made less expensive so that they will become cost-effective tests in the treatment of osteoporosis.
The battle to achieve optimal prevention and therapy in osteoporosis is well under way. The newest weapons are alendronate (a bisphosphonate) and a nasal spray form of calcitonin, both of which were recently approved by the Food and Drug Administration and are already widely used [36, 37]. In addition, the importance of calcium and vitamin D intake has been sufficiently documented; these substances must be part of any preventive regimen [38]. However, no trials directly compare the efficacy of the new antiresorptive agents with estrogen, which has been the mainstay of antiresorptive therapy [39]. Moreover, we do not yet know whether combination therapy with a new antiresorptive agent and estrogen is effective.
Alendronate is a potent antiresorptive bisphosphonate that has been shown in clinical trials to increase bone mass and decrease the rate of vertebral fractures [36]. The recommended course is 10 mg/d for 3 years. One drawback of all bisphosphonates, including alendronate, is that they are poorly absorbed orally and must be taken long before or after any food or other medication. No unexpected long-term side effects have been reported to date, but alendronate has been used for only a few years. Current data indicate that alendronate is appropriate therapy for postmenopausal women with established osteoporosis who cannot or will not take estrogen. At present, alendronate is indicated for patients not receiving estrogens who have had vertebral crush fractures associated with low bone mass. Although no direct comparisons have been done, the effects of alendronate on bone mass in the lumbar spine and the proximal femur appear to be at least the same as those of estrogen and probably greater than those of calcitonin. Studies to determine the effectiveness of alendronate in glucocorticoid-induced osteoporosis and in men are currently in progress.
Injectable calcitonin has been available for almost 30 years, but its use has been limited because of inconvenience and side effects. No unexpected late side effects have been reported, which may justify a trial of calcitonin in younger patients. Because of its analgesic effects, calcitonin is recommended for patients with painful vertebral fractures [39]. Nasal calcitonin is easy to administer and can prevent bone loss [37], but its long-term efficacy in decreasing the rate of fractures has not been adequately evaluated.
One concern about the osteoporosis revolution is that new agents and approaches may lead to an unwarranted reduction in the use of estrogen. In postmenopausal women, hormone replacement therapy with estrogen is highly effective in preventing bone loss and reducing the incidence of fractures. Unopposed estrogen therapy can increase the risk for endometrial cancer, but this can be prevented by adding progestin. A large proportion of postmenopausal women do not use estrogen, in part because of the frequency of side effects (including breast tenderness and menstrual bleeding) and in part because of fear of an increased risk for breast cancer [40]. However, estrogen therapy reduces the incidence of both osteoporotic fractures and cardiovascular disease; it may, therefore, have a much greater positive effect on health [41]. Evidence also exists to show that estrogen is effective in older women who are many years past menopause [35, 42].
The large prospective trials done by the Women's Health Initiative will give us more data about the costs and benefits of hormone replacement therapy. Meanwhile, another approach is being developed. Antiestrogens, such as tamoxifen, raloxifene, and droloxifene, can have beneficial effects on bone and might reduce the incidence of breast cancer [43-45]. The effects of these drugs on cardiovascular disease and on the uterus are less well established. Trials with raloxifene and droloxifene are under way and may provide an exciting new approach to prevention of osteoporosis in postmenopausal women.
Even if antiresorptive agents can increase bone mass and decrease the rate of fractures, agents that stimulate bone formation, such as fluoride, are likely to provide additional benefits in established osteoporosis. However, two prospective clinical trials using high doses of sodium fluoride showed that, despite a progressive increase in bone mass, the incidence of vertebral fractures did not decrease [46]. In a recent small prospective study, Pak and colleagues [47] showed that low-dose sodium fluoride given with calcium citrate on an intermittent schedule (12 months on, 2 months off) increased bone mass and decreased vertebral fractures. If further data support this beneficial effect, this form of fluoride therapy might be useful in treating osteoporosis. One unresolved issue is the possibility that the rate of appendicular fractures, particularly hip fractures, will increase with fluoride therapy. Other potential anabolic agents, such as parathyroid hormone, are being evaluated [48]. Androgens, which may be anabolic for bone, were found to reverse the inhibitory effects of estrogen on biochemical markers of bone formation [49], but their side effects may preclude their extensive use in postmenopausal women.
The osteoporosis revolution is far from over. Indeed, many battles have not yet begun. We have little information on how to diagnose, prevent, or treat osteoporosis in men; yet, as our population ages, this will become an increasing problem. Some forms of secondary osteoporosis, particularly glucocorticoid-induced osteoporosis, are poorly understood and refractory to treatment. Although antiresorptive agents may slow bone loss in glucocorticoid-induced osteoporosis [50-52], the major pathogenetic mechanism is probably decreased bone formation.
It may be possible to make osteoporosis largely a disease of the past, but this will require not only the resolution of scientific issues but a better evaluation of costs compared with benefits [53]. Indeed, health care policy planners might well ask, Why all the fuss? Unlike heart disease and cancer, osteoporosis is not fatal, but it does carry a cost to individual persons and to society, not only in terms of health care costs but also in terms of lost productivity and reduced quality of life. The health care costs of osteoporosis will increase dramatically worldwide as the aging population expands. Although we are still uncertain about the best times and methods of intervention to prevent this increase [54-56], we now have effective methods for diagnosis, prevention, and treatment of this disorder. Primary care physicians must learn about these methods and keep a close eye on the ever-changing course of the osteoporosis revolution.
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