Treatment of Postmenopausal Osteoporosis Richard Eastell, M.D.

Osteoporosis affects an estimated 75 million people in Europe, the United States, and Japan.1 It is a preventable and treatable condition, yet many people with osteoporosis remain unrecognized and untreated. The purpose of this review is to consider the evidence that treatments for postmenopausal osteoporosis are effective and safe. Definition of Osteoporosis Definitions of osteoporosis have usually been conceptual and therefore difficult to apply to individual patients. For example, a Consensus Development Conference defined osteoporosis as "a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture." 1 A Working Group of the World Health Organization has operationally defined osteoporosis as a bone mineral density (T score) that is 2.5 SD below the mean peak value in young adults. 2 This definition is useful as an entry criterion for a clinical trial or as a tool to study the epidemiology of osteoporosis, but it has limitations in clinical practice. It raises a risk factor for fracture to the status of a diagnostic criterion, ignores the importance of other determinants of bone strength, 3 ignores the higher risk of fracture associated with a certain level of bone mineral density in older women, and does not specify the technique by which or the site at which bone mineral density should be measured. Bone mineral density can also be compared with the mean value in normal subjects of the same age and sex (z score). A z score below -1 at either the lumbar spine or the proximal femur would indicate a value in the lowest 25 percent of the reference range, a value at which the risk of fracture is approximately doubled. A z score below -2 would indicate a value in the lowest 2.5 percent of the reference range, a level associated with a considerably larger increase in the risk of fracture. Risk Factors A number of risk factors for osteoporosis have been identified (Table 1). Bone loss can be slowed or even reversed if risk factors such as physical inactivity, low dietary calcium intake, and primary hyperparathyroidism are identified and reversed. A report from the National Osteoporosis Foundation concluded that the following factors were useful in identifying women at risk for fracture: low body weight (<58 kg), current smoking, first-degree relative with low-trauma fracture, and personal history of low-trauma fracture. 4 These risk factors are common and easy to ascertain. Diagnostic Evaluation Bone mineral density should be measured in women with strong risk factors for osteoporosis (Table 1). It should also be measured in those with osteoporosis-related fractures (fracture of the wrist, spine, proximal femur, or humerus after mild or moderate trauma) and those with osteopenia or spinal deformities noted on spinal radiographs. Several techniques are available for the measurement of bone mineral density (Table 2). Among them the most useful in clinical practice is dual-energy x-ray absorptiometry. With this technique, measurement of the density of the proximal femur is the most useful for predicting fractures, and measurement of lumbar-spine density is the most useful for monitoring therapy (Figure 1). Figure 1. Bone Mineral Density at the Lumbar Spine and Femoral Neck in Postmenopausal Women with Osteoporosis Treated with Alendronate for Three Years.

Alendronate (10 mg per day) resulted in a greater increase in bone mineral density in the lumbar spine than in the femoral neck. The values shown are means SD. The shaded area represents the changes that can occur as a result of measurement error (the smallest change that is significant is 5 percent for the lumbar spine and 8 percent for the femoral neck). After one year, more than half the women taking alendronate had responded to therapy, as defined by a change above the shaded area, according to measurements at the lumbar spine. In contrast, after three years, fewer than half of these patients had responded to therapy according to measurements at the femoral neck. Reprinted from Eastell,5 with the permission of the publisher. Bone density can be useful in making the diagnosis of osteoporosis and in decisions about starting therapy. A T score lower than -2.5, especially in the presence of the risk factors listed above, indicates the need for treatment to prevent fractures. 4 A T score lower than -1 within five years after menopause or a z score lower than -1 at the lumbar spine or proximal femur at any age indicates the need to prevent further bone loss. 6 A bone-mineraldensity value at any site below the reference range (a z score lower than -2) indicates accelerated bone loss, and further studies to identify a major risk factor (Table 1) are indicated. Biochemical markers of bone turnover reflect bone formation or bone resorption (Table 3). These markers show large changes early in the course of treatment. 5 Because the markers vary from day to day, several measurements should be made before and during treatment for these to be useful in monitoring treatment response. Several drugs will cause an increase in bone mineral density, which is best monitored at the lumbar spine (Figure 1). However, the bone mineral density of the lumbar spine cannot be measured in all women, because of lack of access to densitometry services, fractures, or degenerative changes in the lumbar spine. Among these women, measurements of biochemical markers may be useful in determining the response to treatment. Pathophysiology of Osteoporosis Bone mineral density in a patient is related to bone mass at maturity (peak bone mass) and subsequent bone loss. Bone is remodeled throughout life, and the rate of remodeling is increased in older adults. The rate of resorption exceeds the rate of formation in older adults, 7,8 resulting in too little bone, or osteoporosis. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, with bone resorption always being followed by bone formation, a phenomenon referred to as coupling. The sequence is similar in cortical and cancellous bone.9 The process of resorption of bone, followed by synthesis of bone matrix and its subsequent mineralization, takes up to eight months. If the processes of bone resorption and bone formation are not matched, there is remodeling imbalance. Such an imbalance would be magnified if the rate of initiation of new cycles of bone remodeling were to increase. Most of the drugs used to treat osteoporosis act by decreasing bone resorption9 and are referred to as antiresorptive drugs. They include estrogens, bisphosphonates, and calcitonin. The name is misleading: because the processes of bone resorption and bone formation are coupled, these drugs decrease the rates of both processes. When an antiresorptive drug is given, the rate of bone resorption decreases within weeks and the rate of bone formation decreases within months. This difference in timing results from the time sequence of the bone-remodeling cycle. At any time, some bone will have been resorbed and not yet replaced, which is referred to as the remodeling space. It is increased in postmenopausal osteoporosis. Antiresorptive therapy decreases the rate of initiation of new remodeling cycles, resulting in fewer remodeling sites and a decrease in the remodeling space. The filling in of the remodeling space accounts for the increase in bone mineral density of 5 to 10 percent that occurs in postmenopausal women given antiresorptive therapy. This process usually takes two to three years, after which bone density changes very little (Figure 2).

Figure 2. Effect of Therapy on Lumbar-Spine Bone Mineral Density in Postmenopausal Women with Osteoporosis. Therapy that stimulates bone formation results in continued increases in bone mineral density beyond two years (broken line). This increase does not always translate to an increase in bone strength. Antiresorptive therapy results in an increase in bone mineral density, followed by a plateau (dotted line). The increase may persist beyond two years with the use of estrogen 10,11 or bisphosphonates,12 perhaps as a result of a prolonged period of secondary mineralization or of positive remodeling imbalance. Administration of placebo may be associated with bone loss (solid line). However, in many trials there was no statistically significant bone loss. The absence of bone loss may be a result of the supplemental calcium therapy and recommended lifestyle measures, or it may be due to artifacts or to drift in bone-mineraldensity measurements. Adapted from Parfitt,13 with the permission of the publisher Some drugs used to treat osteoporosis act by increasing bone formation. They include fluoride and intermittent parathyroid hormone. The newly formed bone either overfills resorption cavities or is laid down on surfaces not previously resorbed. Drugs that stimulate bone formation result in annual rates of increase in bone mineral density similar to those resulting from antiresorptive therapies, but the increase continues beyond two years (Figure 2). Hormones and drugs affect different regions of the skeleton by differing amounts. For example, estrogen deficiency and glucocorticoid therapy14 result primarily in cancellous-bone loss, whereas parathyroid hormone excess15 results primarily in cortical-bone loss. These differences may be due to different effects on cortical and cancellous bone, on bones subjected to weight-bearing and those subjected to nonweight-bearing stresses, or on bones containing red marrow and those containing yellow marrow. Evaluation of Drug Efficacy The response to a drug is usually evaluated by serial measurements of bone mineral density. As noted above, antiresorptive drugs result in a 5 to 10 percent increase in the bone mineral density of the lumbar spine in two years in women with postmenopausal osteoporosis. This change is associated with a decrease in the fracture rate of approximately 50 percent. In prospective studies of the relation between bone mineral density and risk of fracture, the risk of fracture approximately doubled for each decrease of 1 SD in bone mineral density (Figure 3).16,19 The benefit of antiresorptive therapy in reducing the risk of fracture is greater than expected from the change in bone mineral density.12,18 Figure 3. Relation between Lumbar-Spine Bone Mineral Density and Rate of Vertebral Fracture. For every decrease of 1 SD in lumbar-spine bone mineral density, the rate of vertebral fracture approximately doubled.16 The effect of sodium fluoride on lumbar-spine bone mineral density according to the same densitometer was an increase of 31 percent, with a 17 percent decrease in vertebral fractures (P not significant). 17 The effect of transdermal estradiol on lumbar-spine bone mineral density according to a different densitometer (but with a correction factor) was an increase of 5 percent, with a decrease in vertebral fractures of 61 percent. 18 Alendronate therapy resulted in an increase in bone mineral density of 9 percent and a decrease in vertebral fractures of 48 percent.12 Sodium fluoride had a smaller effect on fractures than was expected from the change in bone mineral density, and estrogen and alendronate had a greater effect than expected. Bone turnover is another determinant of the risk of fracture. 20 High bone turnover is associated with a greater rate of bone loss.21 It may be a risk factor for fracture that is independent of bone mineral density,22 possibly because of the increased number of bone-remodeling sites that can buckle.23 Bone strength may be determined by factors other than bone mineral density and bone

turnover.3 Sodium fluoride therapy results in large increases in bone mineral density, but the effect on fracture rates is small (Figure 3).17 Fluoride is incorporated into the hydroxyapatite crystals of bone, thus weakening the bone.24 Because the aim of treatment is to prevent fractures, fractures are the key end point of any clinical trial of therapy for osteoporosis. 25 The diagnosis of nonvertebral fractures is straightforward. The diagnosis of vertebral fractures is difficult, because they may be painless,26 and other vertebral deformities may mimic fractures. There is now strong evidence that a number of drugs prevent further fractures in postmenopausal women with osteoporosis. This evidence, based on randomized, controlled trials, cohort studies, and cross-sectional studies, is reviewed below. Current Therapies Estrogen-Replacement Therapy Information about the effect of estrogen-replacement therapy on rates of vertebral fracture in postmenopausal women is limited (Table 4). In a one-year study of transdermal estrogen therapy in 75 postmenopausal women with osteoporosis, the relative risk of vertebral fractures was 0.39 in the treatment group as compared with the placebo group. 18 There was also an increase in the bone mineral density of the lumbar spine of 5.1 percent and a decrease in bone turnover, as assessed by biochemical markers and bone histomorphometry. In a primary-prevention study of 100 women who underwent bilateral oophorectomy and who were treated with mestranol or placebo for 6 to 12 years, there was no bone loss from the radius and the metacarpal bones in the group receiving estrogen during the first 8 years, with slow bone loss thereafter. Spinal radiographs at the end of the study also revealed fewer wedge deformities of the vertebrae in this group.27 Additional evidence that estrogen-replacement therapy prevents fractures comes from prospective cohort studies.48,49,50 For example, in the Study of Osteoporotic Fractures, 51 the relative risk of nonspinal fracture was 0.66 in postmenopausal women currently taking estrogen as compared with those not taking estrogen. The beneficial effect of estrogen-replacement therapy was more marked in women who began therapy within five years after menopause, and it was unaffected by age18,51,52,53 or concomitant progestin therapy.10,51 Concurrent smoking may48 or may not51 attenuate the benefits of estrogen-replacement therapy. Whether bone loss is accelerated after estrogenreplacement therapy is discontinued is controversial.54,55,56,57 Other beneficial effects and side effects of estrogen are listed in Table 5. These will not be discussed here, except to say that they all contribute importantly to the decision whether to choose estrogen as therapy for osteoporosis in a postmenopausal woman. Bisphosphonates Bisphosphonates are stable analogues of pyrophosphate. They are poorly absorbed from the intestine (absorption, less than 10 percent)64 and must not be taken with food. They are deposited in bone at sites of mineralization and in the resorption lacunae or are eliminated by the kidneys. The exact mode of action is uncertain, but their net effect is on osteoclasts or their precursors, with a resultant increase in cell death and therefore a decrease in bone resorption. 65 Bisphosphonate therapy results in increased bone mineral density and a decreased fracture rate. Several compounds of this family have been evaluated for the prevention of bone loss (clodronate, pamidronate, tiludronate, risedronate, and ibandronate). Data on fractures are available for etidronate and alendronate (Table 4). Etidronate given continuously at high doses can result in impaired mineralization, which can be avoided by low-dose intermittent therapy.66 Therefore the drug is usually given at a dose of 400 mg

per day for 2 weeks, followed by 500 mg of supplemental calcium per day for 11 weeks. This regimen resulted in an increase in bone mineral density of 4 to 8 percent in the lumbar spine and of 2 percent in the femoral neck in three years, as well as a decrease in the vertebral-fracture rate (Table 4).28,29,67 Alendronate is given at a dose of 10 mg per day for the treatment of osteoporosis in postmenopausal women. Alendronate resulted in an increase in bone mineral density of 8.8 percent in the lumbar spine and of 5.9 percent in the femoral neck in three years.12 This increase in bone mineral density was matched by a decrease in biochemical markers of bone turnover, with the markers of bone resorption decreasing maximally at two months and the markers of bone formation decreasing maximally at six months. The change in markers of bone resorption at three months appears to predict the response in terms of bone mineral density at two years.68 Alendronate therapy also resulted in a 48 percent decrease in the proportion of women with new fractures and prevented height loss.12 In a report from a two-year prevention study, 5 mg of alendronate per day had less effect on bone mineral density than estrogen-replacement therapy but resulted in fewer adverse events.69 Among the 2027 women with vertebral fractures in the Fracture Intervention Trial30 who were treated with 5 mg of alendronate daily for two years, with a subsequent increase to 10 mg per day for the final nine months of the study, the rate of new vertebral fractures (including those that were apparent clinically) decreased by 47 percent as compared with the rate in the placebo group. There were similar decreases in the frequency of hip and wrist fractures but not of other fractures. Alendronate has been associated with esophagitis, including erosive esophagitis.70 The symptoms of esophagitis usually begin within one month after therapy is started. To minimize the risk of esophagitis and increase drug absorption, the patient should take alendronate with a glass of water while upright at least 30 minutes before breakfast. Upper gastrointestinal problems, such as achalasia and esophageal stricture, are absolute contraindications to alendronate therapy, and gastroesophageal reflux disease is a relative contraindication. Bone turnover increases to the previous level in six to nine months in women who take alendronate for six months and then stop.71 In contrast, among women treated with pamidronate for six years,72 bone mineral density did not decrease during the first two years after therapy was discontinued. The optimal duration of bisphosphonate therapy is not known. Calcium and Vitamin D Elderly women adapt poorly to a low-calcium diet, and those who live at far northern or southern latitudes or who avoid sunlight may become deficient in vitamin D. In a study of 3270 institutionalized women in France who were treated with calcium (1200 mg per day) and vitamin D (800 IU per day) for three years, the risk of hip fractures was 30 percent lower than the risk in the placebo group.36 This therapy also resulted in a reversal of secondary hyperparathyroidism and an increase in the bone mineral density of the femoral neck. Care must be taken in generalizing the results of these studies. In another study of 2578 women of a similar age in the Netherlands who were treated with vitamin D (400 IU per day) or placebo for three and a half years (but no supplemental calcium), the rate of hip fracture in the two groups was similar.38 The likely explanations for the differences between these two studies 36,38 include differences in the women (the French women had lower dietary calcium intakes, were more frail, and had lower serum 25-hydroxyvitamin D concentrations), in the dose of vitamin D, and in the coadministration of calcium. It may be that calcium and vitamin D are effective only in housebound elderly women. In a more recent study of 389 men and women over the age of 63 years who were treated with calcium (500 mg per day) and vitamin D (700 IU per day) in the United States, the rate of

nonvertebral fractures was decreased.37 This decrease was surprising, because the increases in the bone mineral density of the lumbar spine (0.9 percent), femoral neck (1.2 percent), and total body (1.2 percent) were small. The major differences between this study and the Dutch study were the lower base-line dietary intake of calcium and the higher serum 25-hydroxyvitamin D concentrations in the U.S. patients. In another study vitamin D given annually by intramuscular injection resulted in a decrease in nonvertebral fractures (Table 4).34 Calcium alone may be partially effective in preventing bone loss, especially in older women and those with a low calcium intake (Table 4).73 In a study of 86 women treated with 1000 mg of calcium per day or placebo for four years, there was a sustained reduction in the loss of total-body bone mineral density in the calcium group; there was also a reduction in the loss of lumbar-spine and proximal-femur bone mineral density, with most of the difference occurring during the first year of calcium supplementation.39 There was a borderline reduction in the rate of symptomatic fractures in the calcium group as compared with the placebo group. In another study of women who were over 60 years old and consumed less than 1000 mg of calcium per day, a calcium supplement of 1200 mg per day prevented bone loss from the forearm over a period of four years.40 There was a 59 percent reduction in the rate of vertebral fracture in the women who had vertebral fractures at base line. The active metabolite of vitamin D, calcitriol, and the related alfacalcidol (1-hydroxyvitamin D) increase calcium absorption and may have direct effects on bone cells. They may reduce the rate of fracture.31,32,33,74 In a study of 622 postmenopausal women with vertebral fractures treated with calcitriol or calcium for three years, calcitriol resulted in no change in the rate of vertebral fractures, whereas calcium increased the rate of vertebral fractures.35 Bone mineral density was not measured. Calcitonin Calcitonin is a 32-amino-acid peptide that is normally produced by the thyroid C cells and results in decreased bone resorption. Osteoclasts have calcitonin receptors, and calcitonin rapidly inhibits the action of osteoclasts. Salmon or human calcitonin is given by subcutaneous or intramuscular injection at doses of up to 100 IU daily (Table 4). Calcitonin therapy results in an increase in bone mineral density, and in one unblinded study it resulted in a decrease in the rate of vertebral fracture.42 Calcitonin is less effective at preventing cortical-bone loss than cancellous-bone loss in postmenopausal women.75 It is expensive, must be given by injection, and can cause nausea, flushing, and diarrhea. Some patients become resistant to its action with long-term use, perhaps as a result of the development of neutralizing antibodies.76 The development of intranasal salmon calcitonin may make calcitonin therapy more acceptable. At least 200 IU per day must be given to have an effect on bone mineral density. Intranasal calcitonin is not effective in preventing bone loss in early postmenopausal women.77,78,79 In older women it decreased the vertebral-fracture rate,41 but the number of fractures was small. The spray has few side effects (nasal discomfort, nausea, and facial flushing) and, like subcutaneous calcitonin, it has an analgesic effect.80 Suppositories of calcitonin are only weakly effective and are poorly tolerated.81,82 Fluoride Sodium fluoride stimulates bone formation by unknown mechanisms. In one study of 202 women with osteoporosis who were treated with sodium fluoride, lumbar-spine bone mineral density increased by 8 percent per year during all four years of the trial (Table 4). 17 There was substantial bone loss from the forearm, indicating redistribution of bone mineral from cortical to cancellous bone. Biochemical markers of bone formation increase in fluoride-treated women, but markers of

bone resorption do not. The large increase in bone mineral density would be expected to be associated with a large decrease in the fracture rate (Figure 3). In most studies the effect on fracture was small,17,43,45 but in one study there was a significant reduction in the rate of vertebral fracture (relative risk, 0.3).46 The dose of fluoride was smaller than in the earlier studies, and it was given intermittently as slow-release sodium fluoride. The Fluoride and Vertebral Osteoporosis Study was a randomized, placebo-controlled, two-year trial of sodium fluoride (50 mg per day) and monofluorophosphate (two doses) in 354 women with osteoporosis.44 Fluoride therapy, as compared with placebo, had a large effect on bone mineral density in the lumbar spine (increase, 10.8 percent vs. 2.4 percent), but no effect on the rate of vertebral fracture. Thus, even at relatively low doses, fluoride had little beneficial effect on fracture rates. Sodium fluoride causes gastric irritation, which can be reduced if the drug is given along with a calcium supplement. It also causes stress fractures, the so-called lower-extremity pain syndrome.17,44 Future Treatments Raloxifene Raloxifene has mixed estrogen-agonist and estrogen-antagonist activity and is referred to as a selective estrogen-receptor modulator.83 In a two-year study in postmenopausal women, raloxifene therapy resulted in a decrease in bone resorption 84 and an increase in bone mineral density in the lumbar spine (2.4 percent), total hip (2.4 percent), and total body (2.0 percent). 85 It decreases serum low-density lipoprotein cholesterol concentrations but does not stimulate endometrial growth. (Tamoxifen has a similar beneficial effect on bone mineral density, 86 but it can cause endometrial carcinoma.87) The results of studies of bone mineral density need to be supported by fracture studies, but raloxifene and other selective estrogen-receptor modulators under development (droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogenreplacement therapy. Parathyroid Hormone Daily injections of parathyroid hormone stimulate bone formation. It may be given as the intact hormone or as a synthetic fragment. Treatment for up to two years results in increased bone mineral density of the spine, but no change in bone mineral density of the femoral neck, and an increase in biochemical markers of bone formation and resorption.88 Its effects on the fracture rate are not yet known. In 34 women with osteoporosis who were already receiving estrogenreplacement therapy, administration of parathyroid hormone for three years increased the bone mineral density of the lumbar spine (13 percent), femoral neck (3 percent), and total body (8 percent), with a borderline decrease in vertebral deformities.47 Drugs that stimulate the secretion of endogenous parathyroid hormone or mimic its action might also be effective. Other Therapies A number of cytokines and growth factors have potent effects on bone cells. These factors also affect other organs; for example, cytokines modulate the immune system. The challenge will be to target such factors to bone. Other drugs that have been developed for the treatment of osteoporosis include vitamin D analogues, strontium salts (S12911),89 and ipriflavone.90

Therapeutic Choices

The women who are most at risk for fractures should be treated. Among them are women who have already sustained a fracture with minimal or no trauma and those who have low bone mineral density, especially if they also have other risk factors for fracture. Women with osteoporosis often present with acute vertebral fracture. During the acute phase, the pain can usually be managed with analgesic drugs and a lumbar-support corset. If this is ineffective, a short period of bed rest and calcitonin therapy (for its analgesic properties) should be tried. Lifestyle changes should be recommended, including the avoidance of heavy lifting and the encouragement of exercise, such as walking. Falls can be prevented by exercise and the avoidance of sedating drugs.91 In frail elderly women, hip protectors can protect against hip fracture, but compliance with use of the protectors now available is poor.92 Calcium intake should be increased to 1500 mg per day, 93 either with diet or with supplements. Soluble salts of calcium, such as calcium citrate, are better absorbed than insoluble salts, such as calcium carbonate, which need to be taken with meals. The effect on bone resorption is greater if the calcium is taken at bedtime.94 Excess consumption of alcohol should be avoided, and tobacco use eliminated. It is important to select the appropriate treatment for each woman. Estrogen-replacement therapy is the treatment of first choice, because of long-term experience and its other benefits besides the treatment of osteoporosis. The treatment should be given for at least five years, and preferably longer, because the benefits may not persist after treatment is stopped. Compliance is enhanced by a detailed discussion of the risks and benefits of estrogen-replacement therapy (Table 5), by using preparations that do not cause uterine bleeding (continuous combined estrogen and progestin), and by monitoring the response to treatment. A bisphosphonate is an effective alternative to estrogen-replacement therapy. It is particularly useful for women who are concerned about the adverse effects of estrogen therapy. The importance of the timing of administration should be stressed, and the response to treatment should be monitored (Figure 1). There is no evidence that combining estrogen-replacement therapy and bisphosphonates is more effective than either treatment alone. Vitamin D therapy is necessary for housebound patients and is given orally (800 IU per day) or intramuscularly (250,000 IU per year).95 The goals of therapy should be realistic. The effect of these therapies on osteoporosis is to halve the risk of fracture. A new fracture should not be considered a setback, and the woman should be encouraged to continue therapy.