Osteoporosis is epidemic in the United States, affecting more than 23 million persons,¹ mostly women. The incidence of osteoporosis increases greatly with age, and this disease has become a major public health problem among the elderly. Classically, osteoporosis has been defined as a fracture syndrome or a radiographic abnormality; however, advances in bone density measurement now allow diagnosis of osteopenia (low bone mass) and osteoporosis before subjective radiographic changes or the occurrence of fracture. Thus, our awareness of osteoporosis and its prevention and treatment has been acutely enhanced.

Osteoporosis is characterized by low bone mass and microarchitectural deterioration of the skeleton leading to enhanced skeletal fragility and a subsequent increase in fracture risk,² which can occur even in the absence of trauma. The skeleton consists of two bone types: cortical, or compact, bone provides 80% of total skeletal mass; trabecular, or spongy, bone, the bone of the vertebral bodies, constitutes about 20% of total bone mass. Bone tissue is subject to continuous turnover just as are most tissues in the body. This process, termed bone remodeling, involves osteoclast-mediated bone resorption and osteoblast-mediated bone formation. High rates of bone turnover are associated with low bone mass in women, regardless of menopausal status.³ Bone remodeling occurs on skeletal surfaces. In contrast to bone mass, which is predominantly cortical bone, skeletal surfaces are predominantly (about 80%) cancellous bone. This high surface-to-mass (volume) ratio of cancellous bone makes skeletal sites that are rich in trabecular bone more susceptible to diseases resulting from remodeling disorders. Thus, vertebral bodies and the ends of long tubular bones, such as the proximal femur, are especially vulnerable to fracture. Spinal compression fractures occur in 25% of white women older than 60 years and are associated with acute and chronic pain, loss of height, and postural deformities. The average untreated postmenopausal white woman can expect to shrink 2.5 inches as a result of these fractures.

Because bone mass is greater in the femoral neck than in the spine, osteoporotic fractures of the femur occur later in life, usually between 70 and 75 years of age. The incidence of hip fractures increases from 0.3 per 1000 to 20 per 1000 from age 45 to 85 years, with 20% of all white women sustaining such a fracture by 90 years of age. Of these, 15% die within 3 months from complications of the fracture, including pulmonary edema, myocardial infarction, and pulmonary embolism. Another 25% of these women suffer significant morbidity and in some cases permanent disability. Hip fractures alone occur in about 250,000 women per year in the United States and are associated with a mortality of 40,000 annually and a cost of $8.7 billion.⁴

Risk factors for osteoporosis include low bone mass at the onset of menopause, white or Asian race, slender build, early onset of menopause, history of estrogen-deficient menstrual disorders, a positive family history for osteoporosis, glucocorticoid therapy, and nulliparity. Avoidable factors contributing to osteoporosis include sedentary lifestyle, inadequate dietary calcium intake, cigarette smoking, excessive caffeine or alcohol intake, and estrogen deficiency. Factors suggested to be protective against osteoporosis include obesity, multiparity, and possibly the use of oral contraceptives for more than 1 year. African American women have both a higher bone mass and a lower incidence and prevalence of osteoporotic fractures than do white women in the United States.

Bone remodeling is regulated by local, humoral, metabolic, nutritional, and mechanical factors; it is not surprising that many disease states can result in osteoporosis. Osteoporosis caused by other disease states, such as excess cortisol in Cushing's disease, is termed secondary osteoporosis. The more common form of osteoporosis, postmenopausal osteoporosis, has been clearly demonstrated to result directly from estrogen deficiency but has been termed a primary osteoporosis. The other major primary osteoporosis, senile or involutional osteoporosis, results from age-related bone loss that is universal in humans, the pathogenesis of which is uncertain.

More than 80% of osteoporosis cases occur among postmenopausal and aging populations. Fracture risk at any age is determined primarily by bone density, which is dependent on the peak bone mass achieved at maturity and the subsequent rate of bone loss. Bone density peaks at about 25 years of age in the hip and at about 35 years of age in the spine.⁵ After 40 years of age, resorption begins to exceed formation by about 0.5% per year. At menopause, there is an acceleration of bone loss, with up to 5% of trabecular bone and 1% to 1.5% of total bone mass lost per year after menopause. This accelerated loss continues for 10 to 15 years, after which the rate of bone loss diminishes but continues as an aging-related loss.⁶ The accelerated loss experienced at menopause is termed type I osteoporosis and is typified by loss of trabecular bone resulting in vertebral fractures, whereas type II osteoporosis is best exemplified by hip fractures that occur in both older men and women (Table 1). Thus, in simple terms, type I osteoporosis is estrogen dependent, and type II osteoporosis is age related. Clearly, the presence of type I disease predisposes patients to type II.

TABLE 1. Types of Osteoporosis

  Primary Osteoporosis

  Postmenopausal (type I)
  Senile (type II)

The most common and most serious secondary from of osteoporosis is corticosteroid induced. Usually, this form is associated with therapeutic use of glucocorticoids, but it can be the presenting sign of endogenous Cushing's syndrome.⁷ Women experience an increased incidence of corticosteroidinduced osteoporosis because of their higher incidence of autoimmune diseases, which may require corticosteroid therapy, coupled with their lower peak bone masses.

A variety of gastrointestinal diseases are associated with osteoporosis and osteomalacia. Subtotal gastrectomy is associated with the development of osteomalacia and osteoporosis in 5% to 10% of cases many years after surgery.⁸ The mechanism may be calcium malabsorption, similar to that which occurs with achlorhydria and old age. Malabsorption associated with sprue and other intestinal diseases is underrecognized as a potential risk factor for osteoporosis. Malnutrition associated with alcoholism and anorexia nervosa likewise may increase the incidence of osteoporosis. Alcohol has additional direct adverse effects on the skeleton and is associated with a pseudo-Cushing's syndrome that includes increased endogenous steroid production. The bone loss of anorexia nervosa is aggravated by the accompanying estrogen deficiency.

Endocrine disorders commonly associated with secondary osteoporosis include hyperthyroidism and iatrogenic hyperthyroidism from overreplacement. Periodic reassessment of the replacement dose is appropriate, especially because a person's daily requirement for thyroid hormone can decrease with age. The incidence of primary hyperparathyroidism may be as high as 1 in 1000. In its mildest form, there may be no symptoms, in which case it is discovered only through routine determinations of serum calcium. In more severe forms, symptoms associated with hypercalcemia or hypercalciuria may lead to its diagnosis. Hypogonadal states are associated with osteoporosis in both genders, and hypogonadism commonly is underdiagnosed in aging men. Clinical conditions resulting in hypogonadism may include anorexia nervosa, hyperprolactinemia, acromegaly, and hypothalamic amenorrhea. Iatrogenic estrogen deficiency, as occurs with gonadotrophin releasing hormone agonist or antagonist therapy, also results in accelerated bone loss, which may not be fully reversible when therapy is discontinued.

Because osteoporosis usually is asymptomatic until the first fracture has occurred, the importance of early diagnosis cannot be overemphasized. Noninvasive studies that allow detection of low bone density in patients without symptoms also allow initiation of therapy and prevention of fractures. Standard radiographs do not provide an early assessment of fracture risk because 25% to 30% of bone must be lost before radiographic changes become apparent. Low bone mass and increased fracture risk can be assessed only by direct measurement of bone mineral density (BMD). Each standard deviation (about 10%) decrement in BMD results in about twice the risk of fracture.⁹ To assist in patient management, the World Health Organization has defined degrees of deficit in BMD with a value between 1 and 2.5 standard deviations below peak adult bone mass as osteopenia or low bone mass and any value more than 2.5 standard deviations below peak adult bone mass as osteoporosis.⁹ The association between decreasing BMD and increasing fracture risk is analogous to the association between increasing serum cholesterol and increasing risk of acute myocardial infarction. The sensitivity of the BMD and fracture association, however, is greater than the cholesterol and acute myocardial infarction relation.¹⁰ Although BMD measured at any site assesses global fracture risk, site-specific measurements provide more reliable site-specific information. For example, each standard deviation decrement in BMD at the proximal femur is associated with a relative risk of hip fracture of 3, whereas the relative risk of hip fracture for every standard deviation decrease in forearm BMD is only 2. Nonetheless, the forearm measurement is clearly better than no measurement at all, and substantially so.

Table 2 lists the several options for direct, noninvasive measurement of BMD at different skeletal sites. All these methods measure BMD with 95% or greater accuracy, and all have been associated with increasing fracture risk as BMD decreases. Dual-energy x-ray absorptiometry employs photons from two energy sources and provides good precision for all sites of osteoporotic fractures. Quantitative computed tomography (CT) for bone density measurements can be performed on most commercial CT systems; however, radiation exposure is higher than with dual-energy x-ray absorptiometry, and measurements of the femur are not available. Volumetric CT allows better visualization of the femur neck as well as improved spinal measurements, but likewise is associated with increased radiation exposure. Single-energy x-ray absorptiometry measures bone density in the calcaneus, which correlates less well with vertebral bone density. Radiographic absorptiometry uses standard radiographic equipment and a calibrated marker to image the phalanges. Radiographs are interpreted using computer technology to determine the BMD. Ultrasonography of the calcaneus and patella has been demonstrated to correlate with vertebral bone density. Most important, each method and site of measurement of bone mass or density has been demonstrated to assess fracture risk, whether or not there is a good statistical correlation with other sites with respect to measured BMD. Magnetic resonance microscopy is under investigation to elucidate trabecular microarchitecture quantitatively. Because it is relatively expensive and time-consuming, it probably will not be useful for primary osteoporosis screening; however, it may be useful for identifying high-risk patients after initial bone densitometry and for research into the pathophysiology of the osteopenic disease process.

TABLE 2. Bone Mineral Density Measurement

False-negative results occur with each method of measuring BMD; that is, some subjects have a normal T score at one site and a low T score at another. This is shown graphically in Figure 1, which is redrawn from the data of Melton and colleagues.¹¹ In this figure, BMD measurement at three sites identifies more subjects with a low T score than any single site measurement. In the study reported, there was no apparent superiority of one site over any other. Alternatively, the clinician can order BMD measurement at other skeletal sites, or simply repeat the measurement using the original method after an interval of 2 years. The risk of fracture during that 2-year interval is small, and if the follow-up measurement is abnormal, intervention can be initiated at that

Indications for Bone Mineral Density Measurement

As shown in Figure 1, in the early postmenopausal years, BMD is normal in more than 80% of women; yet by 80 years of age, more than 50% of women have osteoporosis. Therefore, hormone replacement therapy (HRT) should be offered without reliance on BMD measurement. Women who accept a recommendation to begin HRT after counseling of the benefits and risks probably do not need a BMD measurement, although it has been suggested that women are more likely to agree to HRT if it can be demonstrated that the BMD is low.^12,13,14 The act of measuring BMD may serve to reenforce the serious nature of osteoporosis; those women tested and found to have normal BMD measurements are more likely to agree to HRT than their nontested counterparts.^12,14 BMD measurement should be an integral part of the menopausal evaluation in women who are unwilling to begin HRT after full counseling on its benefits and risks and in women with an absolute or relative contraindication to HRT because there are alternative therapies for bone loss.

Biochemical Markers of Bone Remodeling

Bone is lost when resorption exceeds formation; these processes can be assessed by a number of biochemical studies (Table 3). Because of individual variability, the relation between any of these markers and BMD is poor, although statistically significant, and these biochemical tests are inadequate to diagnose low BMD. The markers, however, are useful in determining the efficacious dose of HRT both at initiation of therapy and at follow-up. A favorable biochemical response (i.e., values on treatment are within the premenopausal reference interval) after 3 months of HRT indicates adequate skeletal effect at a specific dose. Conversely, if the biochemical response is suboptimal, an increased dose is indicated. Changes in the biochemical markers can be identified 4 to 12 weeks after initiating therapy.¹⁵ This approach can be particularly helpful when initiating HRT in older women who are more removed from menopause and more concerned about short-term side effects because a lower dose may yield optimal skeletal protection. When the HRT dose is effective for bone mass preservation, each of the markers should be within the premenopausal reference interval after 3 months of therapy. Measurement of biochemical markers is also useful in evaluation of patients already using HRT. A low BMD measurement in a woman with biochemical markers in the premenopausal range is more likely to reflect that the BMD was low before initiation of HRT and less likely to indicate that her current dosage is ineffective. In these patients, increased doses of estrogen or additional therapy with an antiresorptive drug (discussed later) are unlikely to provide further benefit.

TABLE 3. Biochemical Markers of Bone Remodeling

The urine-based markers of resorption respond earlier than the serum-based markers of formation (4 weeks versus 12 weeks), and this makes them the preferred investigation in some clinical circumstances. Decreased urinary cross-linked N-telopeptide of type I collagen (NTx) was seen after only 2 weeks of HRT. Eighty-eight percent of women who experience at least a 30% decrease in NTx from baseline to 6 months had the same or better BMD measurements compared to 57% of those women who had less than a 30% decrease.¹⁶ The disadvantage of the resorption markers is that they are subject to diurnal variation, and an early morning (first or second void) specimen is required. This may require a special trip to the clinic to deliver the specimen. The serum-based markers of bone formation are not affected by diurnal variation; therefore, unless follow-up is required after just 4 weeks of HRT rather than after 3 months, formation markers may be preferable. Two studies^15,17 have clearly demonstrated the clinical utility of these markers in patients who are candidates for estrogen replacement therapy (ERT). In cases in which markers of bone turnover were lowest, there was minimal further loss of bone when only calcium supplementation was given, and only minimal gain in BMD on ERT. At the other end of the spectrum, women with the highest rates of remodeling assessed by these markers lost substantial bone when only calcium was provided and gained significant bone on ERT.

Osteoporosis is more effectively prevented than treated. The primary goal of prevention is to achieve as high a peak bone mass as genetically possible and to reduce the rate of bone loss (in aging). Peak bone mass is to a great extent genetically determined. Optimizing peak bone mass can be accomplished only with proper nutrition, sufficient weight-bearing activity, and minimization of risk factors (e.g., smoking, excessive alcohol use, immobilization). The average calcium intake in the United States is below the recommended daily requirement, and physician-directed education during childhood and adolescence may encourage improved calcium intake with resultant increased bone density and protection against osteoporosis in later life. Adults require 1000 mg/day of elemental calcium, and adults older than 65 years require about 1500 mg. Although adequate calcium intake and exercise are critical for building bone, they are inadequate for prevention of bone loss in estrogen-deficient states.

The addition of vitamin D or its active metabolite has little impact on osteoporosis fracture rates, except in people deficient in vitamin D. Elderly people in nursing homes are frequently deficient in vitamin D, and it is recommended that people older than 70 years should add 800 U of vitamin D to calcium supplementation. Significant reduction in the rate of hip fracture was noted in several randomized prospective trials in which elderly women received supplementation of calcium and vitamin D.^18,19 Although exposure to the sun usually provides adequate vitamin D, in northern climates and in people wearing occlusive clothing, deficiency of vitamin D may occur. For these people, the recommended daily dietary allowance of vitamin D is 400 U/day.²⁰

Hormone Replacement Therapy

ESTROGEN.

The metabolism of calcium changes dramatically when estrogen production declines in women. There is evidence for an increase in activation frequency of new bone remodeling units and an increase in remodeling imbalance. The remodeling imbalance results from increased osteoclastic activity, possibly coupled with impairment of osteoblastic activity. ERT maintains BMD in postmenopausal women by increasing calcium absorption, interfering with parathyroid hormone action, and influencing various cytokines and local growth factors, resulting in inhibition of bone resorption.²¹ Because unopposed ERT results in an increased incidence of endometrial hyperplasia and carcinoma in women with intact uteri, estrogen almost always is administered in conjunction with progestogen. The term HRT is used when discussing combined estrogen and progestogen therapy. Progestogen does not counteract the beneficial influence of estrogen on bone metabolism. Whether progestogen offers any independent benefit on BMD is controversial and is discussed later.

In addition to preservation of bone mass, estrogen use is associated with a reduced prevalence of osteoporotic fractures.^{22,23,24,25,26,27} In one study, women taking HRT had less than half the fractures of the placebo group, with the most apparent decline seen after 5 years of therapy or longer.²⁶ The preservation of bone mass and reduction in fracture incidence are less clearcut for the proximal femur than for the forearm or spine; some studies suggest that higher doses may be needed to obtain similar responses at the hip.²⁶ Women initiating therapy within 2 years of the onset of menopause have optimal reduction in fracture risk,²⁸ but the Rancho Bernardo Study demonstrated nearly equivalent results in women currently taking HRT who initiated therapy after 60 years of age.²⁹ This also supports the concept that maximal increases in BMD occur during the first few years of ERT, then show a trend toward stabilization or slow decline.^27,30

There is considerable uncertainty about the optimal duration of HRT from a skeletal perspective. As little as 2 years of HRT reduced fracture risk in one study²²; in other studies, 7 to 10 years were necessary to reduce risk. In the Rancho Bernardo cohort, past users had low BMD measurements, even when estrogen was taken for the same duration as current users, although the more recent the estrogen use in past users, the higher the BMD.²⁹ Almost every study has suggested that estrogen therapy taken only at the time of menopause preserves bone during use but may not preserve bone density late in life^31,32 or protect against osteoporotic fractures.^22,23,32,33 The concept that continued HRT remains effective at advanced ages is supported by Cauley and associates,²⁸ who reported that the risk for wrist fractures was reduced by 61% among current users but by only 19% among previous users of estrogen. Estrogen use between the ages of 65 and 74 years has been documented to protect against fractures,²² and increased bone density has been reported in estrogen users up to the age of 80 years.³⁴ The response appears to be greatest among women who are farthest from menopause and who have the lowest pretreatment bone mass.^35,36,37 Lufkin and colleagues²⁴ reported that estrogen therapy improved BMD by about 5% during the first year of therapy and reduced the rate of new fractures even in women with existing osteoporotic fractures. It is estimated that initiation of estrogen in women as old as 70 years could reduce the risk of fracture by about one third.³⁸ As seen with estrogen use for prevention of osteoporosis, estrogen use in women with established osteoporosis has a greater effect on the BMD of the lumbar spine than on that of the hip.

Data are accumulating that support delaying the initiation of ERT and HRT until the patient is 60 to 65 years of age, at least with specific respect to skeletal protection. That the therapy works in this age group is well established, and the former dictum that therapy is effective only during the first 5 to 7 years after menopause, when bone remodeling rates are highest, is no longer valid. Because of the poor long-term compliance generally reported for ERT and HRT and the influence of knowledge of BMD on patients' decisions to commence therapy for skeletal protection, there is merit in starting therapy this late in life. Additionally, the evidence linking ERT and HRT to an increased likelihood of breast cancer generally has not demonstrated any increase inside 15 years of therapy. In great part, the timing of ERT or HRT is a function of symptoms at menopause and identified risk from cardiovascular, skeletal, and neurologic disease. Analysis has offered guidelines for estimating this risk in groups of patients and possibly in individual patients. We do not yet encourage this approach of delaying therapy because it relates only to the skeleton and may minimize many of the important benefits of ERT and HRT.

Data concerning the skeletal response to stopping HRT also are controversial, with one study indicating that bone loss accelerates³⁹ and another suggesting that bone loss is not accelerated.⁴⁰ These two studies differed in important aspects, which probably minimizes the differences in their conclusions. One study initiated HRT at the time of bilateral oophorectomy with a more abrupt decrease in estrogen levels; the other included only women with natural menopause, 1 to 3 years after their last menstrual period. It is most likely that cessation of HRT restores the rate of bone loss to that occurring at the time therapy was initiated. Because it is well established that this rate of loss declines naturally with increasing time after menopause, the earlier HRT is started, the more rapid the anticipated loss when therapy is stopped. Because of its potential cardiovascular benefits as well as its role in the prevention of osteoporosis, HRT usually should be offered at the onset of menopause and continued indefinitely.

The minimal dose of estrogen required to preserve bone mass has been researched intensively. Multiple retrospective, cross-sectional, and prospective studies have demonstrated that the minimal effective dose for maintenance of axial and peripheral bone mass in 80% of women is equivalent to 0.625 mg conjugated equine estrogens (CEE).⁴¹ Other investigators have reported less than a 5% nonresponder rate at this dosage.⁴² Several recent studies have suggested that lower doses of estrogen preparations may be protective when administered with calcium, but in some cases, the rate of nonresponders was as high as 50%.⁴³ Transdermal administration of 50 μg of estradiol twice a week is as effective on bone density as 0.625 mg of oral conjugated estrogens during 1 year, whereas transdermal administration of 100 μg combined with a progestin both increased bone density and reduced the fracture rate in older women with established osteoporosis.⁴⁴ Serum estrogen levels in women taking 100 μg of transdermal estradiol, however, were about twice the levels of most other postmenopausal regimens. Although transdermal or oral routes of administration are equally effective at maintaining bone density, 12% of women on both regimens may continue to lose bone at the hip. Not all types of estrogen or estrogen preparations are equipotent in preserving bone mass (Table 4). We have been able to find only one reference suggesting that estrone has bone-sparing potential,⁴⁵ and estriol has no apparent role in skeletal protection in postmenopausal women.⁴⁶ The most effective approach is to provide sufficient estrogen to ensure that the rates of bone remodeling assessed biochemically remain within the premenopausal range. Although intellectually less than ideal, this can be accomplished in most women by a single measurement of a biochemical marker after 3 months of therapy, with dose adjustment if needed. Again, these remarks refer only to skeletal protection and are untested in other areas that benefit from ERT or HRT.

TABLE 4. Dose Estrogen Required to Prevent Bone Loss

The role of repeat BMD measurements in women on HRT is uncertain. Some investigators believe that the potential for nonresponders at the standard dose justifies routine BMD measurement before initiation of HRT and within 2 years after its commencement. Also, studies indicate that compliance is improved with positive feedback in terms of the BMD response, and this may justify repeat measurements in selected patients but clearly not in most women. In women in whom BMD measurement has been an integral part of the initial decision not to begin HRT and in those with established osteopenia or osteoporosis, follow-up measurement after an interval of 2 years is appropriate.

In practical terms, there are abundant data that HRT containing at least 0.625 mg/day of CEE or the equivalent should be instituted as soon as possible after the last menstrual period and continued for at least 10 years. Because some studies could demonstrate no reduction in fracture use in previous estrogen users even after 10 years of therapy,²⁸ estrogen should be initiated soon after the menopause and continued indefinitely. There is little need to measure BMD before therapy, but a case could be made for measurement of a biochemical marker of resorption or formation after 3 months of HRT to ensure that remodeling has been suppressed to the premenopausal rate.

A major factor in ensuring efficacy of any medication is the side effects, perceived or real, associated with the medication. The use of estrogen in HRT regimens is a particularly good example. Market research data indicate that up to one third of women do not fill their prescriptions for estrogen and that less than 40% of women who begin therapy continue it after 1 year.⁴⁷ The reasons generally fall into two categories: the occurrence of vaginal bleeding and the fear of cancer.

Vaginal bleeding commonly is cited as a problem when therapy is used in asymptomatic women, especially in women more removed from menopause. This can often be avoided by providing continuous combined therapy in which the progestin is administered daily with the estrogen. Although some spotting and irregular bleeding is not uncommon during the first 6 months of therapy, about 90% of women are amenorrheic by 1 year after commencement of therapy. Studies support the safety of this regimen when used for 3 to 5 years.³⁵ Longer-term data are not yet available, and unexplained bleeding requires further evaluation.

The second most commonly cited concern is fear of cancer, particularly uterine and breast cancer. Because data suggest that sequential progestin therapy returns the level of risk of endometrial malignancy at least to that expected in the untreated postmenopausal population,⁴⁸ providing accurate information regarding the protective effect of progestin usually reassures the patient. A more difficult issue is the concern about breast cancer. The main problem is that the data are far from clear. Metaanalyses of the published studies offer no conclusive data on the risk or safety of estrogen, and only randomized prospective studies can conclusively answer this question. If hormone therapy increases the risk of breast cancer, the magnitude of that increase is less than that of other established risk factors, and no studies have shown an increase in mortality from breast cancer in estrogen-treated women. A forthright discussion of the issues usually allows most women to balance the benefits with the risks of therapy. Other nuisance side effects, such as water retention, bloating, and nausea, usually respond to use of another estrogen and progestin preparation.

PROGESTIN.

It is controversial whether the addition of progestin modifies the skeletal response to estrogen, in part because the different types of progestin have different qualities and because their effects on bone and calcium metabolism must be studied separately. Only a few studies have been published on the individual effects of progestin on the postmenopausal calcium metabolism. Medroxyprogesterone acetate (MPA) given cyclically (10 mg/day or 20 mg/day for 12 or 15 days each month) or continuously (2.5 mg/day) with CEE did not increase spinal BMD over that seen with CEE alone^35,49; even at high doses, MPA failed to reduce trabecular bone loss.⁵⁰ MPA may be more effective in women with established osteoporosis; use of a combination of estrogen and MPA (5 mg MPA and 0.625 mg of conjugated estrogens daily) was associated with a 65% increase in spinal BMD measurements over those observed in osteoporotic women treated with unopposed estrogen.⁵¹ Norethindrone acetate, however, is associated with a greater dose-dependent increase in spinal BMD measurements than that seen with ethinyl estradiol alone, even in the absence of established osteoporosis.⁵² Norethisterone likewise increased bone mineral content when administered alone for 2 years,⁵³ as did gestronol hexanoate.⁵⁴ Because it lacks the cardioprotective features associated with estrogen compounds, progestin rarely is indicated alone for the prevention or treatment of osteoporosis. However, because of the increased incidence of endometrial carcinoma in women taking unopposed estrogen, progestin should be routinely used in women with intact uteri.

ANDROGEN.

Androgen deficiency at menopause also may affect bone metabolism. Both androgen and estrogen receptors have been found in bone cells from both sexes, and positive correlations between bone mass and androgen levels have been observed in premenopausal and postmenopausal women. There are some data that, unlike estrogen therapy, androgens may stimulate bone formation.⁵⁵ Although androgenic hormones generally are not used as single-agent therapy in women because of the potential for hirsutism as well as adverse cardiovascular effects, they may potentiate the effects of estrogen on BMD, particularly because HRT actually may reduce endogenous androgen production by reducing the high levels of luteinizing hormone and follicle-stimulating hormone that can stimulate androgen production by the climacteric ovary. Anabolic androgenic hormones, such as nandrolone decanoate, have been demonstrated to increase bone mass in postmenopausal women alone^56,57 and in combination with estrogen.⁵⁸ Combination therapy of CEE with methyltestosterone demonstrated not only decreases in bone resorption markers but also increases in serum markers of bone formation, whereas CEE resulted only in reduction of the bone formation markers.⁵⁹ These findings are in agreement with the greater increase in BMD of the spine and hip observed in women taking a CEE and methyltestosterone combination therapy than that seen in women taking CEE alone.⁶⁰ Thus, in patients with established osteoporosis, combined androgen and estrogen therapy may be indicated until other therapies that stimulate bone formation become available.

Tibolone, a synthetic C-19 steroid with weak estrogenic, progestational, and androgenic properties, has been studied as an alternative to standard HRT. At doses of 1.25 mg/day and 2.5 mg/day, tibolone appears to be effective in increasing BMD and improving biochemical markers in postmenopausal women for prevention^61,62 and treatment⁶³ of osteoporosis. One of the benefits of tibolone therapy is improvement of climacteric symptoms, seemingly without adverse effects on the endometrium or breasts.⁶⁴ Anabolic steroids, such as stanozolol, are effective in preserving bone mass in postmenopausal women,⁶⁵ but the optimal dose has not been defined, and is unclear whether this optimal dose is sufficiently free of unwanted androgenic side effects. Early studies of ipriflavone demonstrated maintenance of bone density at the spine as well as reduction in back pain in women with established osteoporosis, but bone mineral content of the hip was not significantly different in patients taking ipriflavone.⁶⁶ One study has suggested a synergistic effect of ipriflavone in increasing forearm bone density when administered with a subtherapeutic dose (0.3 mg) of conjugated equine estrogens for 1 year.⁶⁷ Similar results were obtained with a combination regimen of ipriflavone (600 mg/day) and estriol (1 mg/day).⁶⁸

Selective Estrogen Receptor Modulators

Although HRT is the regimen of choice for most women, other preventive and therapeutic options are available for women who cannot or will not take estrogen. Tamoxifen is a viable alternative to HRT as adjuvant therapy for breast cancer. Tamoxifen acts as an estrogen agonist on bone; increased lumbar BMD was demonstrated after 2 years of tamoxifen therapy,^69,70,71 but the magnitude of increase was less than that typically observed with estrogen. This suggests that the degree of protection is not equivalent to that of estrogen, although long-term studies have yet to be completed. Because tamoxifen is associated with increased incidence of endometrial hyperplasia and carcinoma, there is little enthusiasm for its use for skeletal protection in circumstances other than breast cancer. Often, its use is limited to 5 years, which presents a major problem for younger women, in whom premature menopause resulted from the chemotherapy for the breast cancer. There is mounting evidence that HRT may be safe in selected women after successful treatment of breast cancer,⁷² but many breast cancer survivors, and their treating physicians, are reluctant to consider hormonal therapy.

Several new antiestrogenic compounds are being developed and tested clinically. These compounds are termed selective estrogen receptor modulators because of their differential effects at various estrogen receptors. The most promising of these agents are droloxifene and raloxifene. Droloxifene has a shorter half-life than tamoxifen and a 10-fold higher binding affinity for the estrogen receptor. It also exhibits lower estrogenic and higher antiestrogenic activity on the immature rat uterus.⁷³ The results of several clinical trials suggest that droloxifene may be a useful treatment for breast cancer. Raloxifene is effective in preventing the development of carcinogen-induced rat mammary tumors, although it is not as potent an antitumor agent as tamoxifen.⁷⁴ In a short-term study, similar effects on markers of bone turnover as well as serum lipids were seen in women treated with raloxifene and estrogen, whereas no proliferative effect on endometrial histology was noted in the raloxifene-treated women.⁷⁵ A 4-month study comparing conjugated estrogens, tamoxifen, raloxifene, and placebo demonstrated reduced bone turnover with short-term positive effects on bone mass in the spine and the femoral neck in all treatment groups.⁷⁶ This suggests that raloxifene may be a suitable alternative to HRT for prevention of osteoporosis. Long-term studies are needed to prove its efficacy in reducing BMD loss and fracture risk as well as its safety with regard to potential adverse effects on the breast, endometrium, and cardiovascular system.

BISPHOSPHONATES.

The bisphosphonates share a common P-C-P structure and are analogs of pyrophosphate; they differ in their side chains, imparting differences in potency and skeletal toxicity. Bisphosphonates bind avidly to hydroxyapatite, inhibit osteoclastic bone resorption, and are then buried within the skeleton, where they remain for 10 to 12 years or longer. Bisphosphonates also have the potential to inhibit mineralization of bone in a dose-dependent manner. The ratio of the dose that inhibits resorption to the dose that inhibits mineralization determines the clinical usefulness of one bisphosphonate over another. Nearly all bisphosphonates that have been evaluated have been shown to prevent bone loss effectively. The first-generation bisphosphonate etidronate (Didronel) has been studied in several controlled trials and causes a small increment in bone mass, compatible with reduction in activation frequency, with some reduction in fracture occurrence during the initial 2 years of study.^77,78 Long-term studies with etidronate have been open-label, however, and although they demonstrated its continued effectiveness in increasing BMD and reducing vertebral fracture rate,⁷⁹ verification of these data from placebo-controlled trials is lacking. Concerns about a mineralization defect with longer-term etidronate therapy did not materialize when the drug was administered intermittently (2 weeks on therapy, 12 weeks off),⁸⁰ which was done in the controlled trials. Initial studies indicate that combined HRT and etidronate therapy may result in greater increases in BMD than are seen with either therapy alone, with no evidence of osteomalacia.⁸¹

The second- and third-generation bisphosphonates do not impair bone mineralization at doses that maximally inhibit bone resorption and are not associated with osteomalacia, effects that have been attributed to etidronate. Alendronate sodium (Fosamax), a potent aminobisphosphate, is approved for use in the United States and many other countries for the treatment and prevention of osteoporosis. In women with postmenopausal osteoporosis, alendronate reduced markers of bone remodeling and increased BMD at the spine, hip, and total body, progressively during 3 years of therapy at doses of 5 and 10 mg daily.^82,83,84 In addition, the increased bone mass was associated with a 48% reduction in the proportion of women with new vertebral fractures and with a reduction in the number of new vertebral fractures, the progression of vertebral deformity, and height loss.⁸⁵ Only 8% of women with at least one vertebral fracture at baseline treated with alendronate experienced a subsequent vertebral fracture, compared with 15% of the placebo-treated group. In women with two or more fractures at baseline, the difference was even greater, with 90% fewer subsequent vertebral fractures in alendronate-treated women. Alendronate also reduces nonvertebral fractures,⁸⁶ with about a 50% reduction in the incidence of hip fractures.^85,86 Alendronate has been approved for prevention of osteoporosis. At a dose of 5 mg daily, alendronate resulted in significant increases in BMD of the spine, hip, and total body in women without established osteoporosis.⁸⁷ Thus, alendronate and estrogen currently are the only two drugs approved for both prevention and treatment of osteoporosis.

Clinical use of alendronate occasionally has been associated with esophagitis and upper gastrointestinal symptoms such as abdominal pain and flatulence. No significant differences in the frequencies of such disorders were noted between the alendronate and placebo groups during the Fracture Intervention Trial.⁸⁵ This may have resulted because women with a recent history of active peptic ulcer disease or complications and those taking medication for dyspepsia daily were excluded. Careful use of alendronate and careful attention to dosing instructions may reduce the risk of esophageal irritation. Women using alendronate should be instructed to take the medication with at least 100 mL of water and not to lie down during the next 30 minutes.

Other bisphosphonates, including clodronate, pamidronate, and tiludronate, also are available for clinical use outside the United States. These and others (ibandronate, residronate) are undergoing extensive clinical trial. Individual patient tolerance, cost, and availability are the principal means of selecting one bisphosphonate over another. Pamidronate (Aredia) is available in the United States for the treatment of Paget's disease of bone and acute hypercalcemia. Early trials of an oral preparation of this drug were discontinued because of concerns regarding esophagitis as a complication, although the incidence of esophagitis is lower in other countries where the oral form is available. From a skeletal standpoint, the drug is effective at retarding bone loss, and it may be appropriate in some circumstances to administer this drug intravenously when treating osteoporosis. Ibandronate is being developed as an intermittent (every 3 months) bolus intravenous injection for treatment of osteoporosis. A transdermal bisphosphonate also is being developed. The bisphosphonates as a class of drugs are effective for prevention and therapy for osteoporosis, and there soon will be a plethora of drugs from which to select for individual patient care.

CALCITONIN.

Calcitonin, a polypeptide hormone produced by the parafollicular C cells of the normal human thyroid, inhibits bone resorption in pharmacologic doses, although the precise physiologic role of this hormone in humans is unknown. Synthetic calcitonin from several species (salmon, eel, human) has been extensively studied as a potential therapy for osteoporosis and has been found to be both effective and safe. The salmon hormone appears to be the most potent and is the most widely used. Most of the studies have been conducted in patients with established osteoporosis, but there is little reason to believe that it is not equally effective in preventing early postmenopausal bone loss.⁸⁸ Until recently, this drug was available only in a parenteral (subcutaneous injection) formulation (Calcimar, Miacalcin), limiting its appeal for prophylaxis against bone loss. The recent availability of an intranasal salmon calcitonin spray (Miacalcin nasal spray, 200 U/day) has resulted in the reappraisal of this drug for prevention of early postmenopausal bone loss, and it is a viable alternative to HRT in women who cannot or will not take HRT. Because the only current indication for calcitonin in postmenopausal women is the inhibition of bone loss, use of this drug should be limited to women in whom BMD measurement has demonstrated increased risk of fracture. Overall, the gains in bone mass seen with calcitonin therapy do not appear to be as great as those seen with the bisphosphonates, and the data on antifracture efficacy are less comprehensive.^89,90,91 As noted with other antiresorptive drugs, the women with the lowest baseline bone mass demonstrate the greatest response to calcitonin therapy.⁹⁰ One study⁹² has reported some synergy with respect to increases in BMD when eel calcitonin and HRT were given in combination. Combining calcitonin with the anabolic steroid nandrolone decanoate does not result in further increases in BMC, however; rather, it yields results inferior those seen with either drug used alone.⁹³

There is abundant anecdotal evidence from many physicians, and supporting documentation from some controlled clinical trials,^94,95 that calcitonin has analgesic properties when administered during the acute phase after osteoporotic vertebral fracture. Calcitonin stimulates endorphin synthesis and release,⁹⁶ which is the putative mechanism for its analgesic properties. It remains unclear why this analgesic effect is seen only with acute fracture pain and not in the chronic back pain associated with vertebral fractures. The analgesic effect has not been documented after femoral neck fractures. There is almost three decades of clinical experience with calcitonin (mainly for treatment of Paget's disease), and the long-term safety of this drug is well established. It is easier to take as a nasal spray than alendronate and has an important role for many patients. An abstract reported on the use of an inhaled form of calcitonin,⁹⁷ which should expand the potential for its use.

SODIUM FLUORIDE.

Sodium fluoride has been studied extensively for more than 35 years for the treatment of osteoporosis and is available for this purpose in many countries. As a nonpatentable compound, the larger pharmaceutical companies have been reluctant to invest the time and money needed to complete pharmacologic studies with sodium fluoride, which has hampered the development of this drug for clinical use. Pak and associates^98,99 completed a series of controlled clinical trials with a slow-release preparation of sodium fluoride (Neosten), which almost certainly will have been approved for use by the time this chapter is published. Unlike ERT, the bisphosphonates, and calcitonin, sodium fluoride directly stimulates bone formation rather than inhibiting bone resorption. Accordingly, gains in bone mass are generally greater than those seen with antiresorptive drugs, and the increment appears to be linear and continuous over many years. This is in contrast to the antiresorptive drugs, with which most of the gains in bone mass are seen in the first year of therapy. A particular concern with sodium fluoride is that it accumulates in the skeleton and, when allowed to accumulate to excess, results in a paradoxical decrease in bone strength. This important side effect is dose and duration dependent. The seeming advantage of slow-release preparation is the delayed intestinal absorption, low peak serum levels, and lesser skeletal accumulation than were reported with earlier studies of plain sodium fluoride. Nonetheless, the drug must be administered intermittently, with a 2-month drug-free interval at the end of each year of therapy. As with all therapies that result in bone gain, it is imperative that the patient ingest enough “bone substrate” (calcium) to form properly mineralized bone. This is particularly important for fluoride therapy¹⁰⁰ because osteomalacia has been reported in some patients who do not ingest enough calcium. On the horizon are newer preparations of fluoride, particularly a slow-release preparation of monosodium fluorophosphate, which appears to have a safety and efficacy profile similar to that of the slow-release preparation of sodium fluoride.¹⁰¹

Selection of Therapy and Combination Therapy

Choosing between the antiresorptive drugs (bisphosphonate, calcitonin, estrogen, selective estrogen receptor modulators) that are already or soon to be available remains an individual physician and patient preference. From a cost standpoint, ERT is the most appropriate, particularly given the many nonskeletal benefits of therapy. The bisphosphonates and calcitonin are more expensive than HRT and have no known extraskeletal benefit. In general, their use should be restricted to patients who cannot or will not take ERT yet have a demonstrated need for prevention or treatment of osteoporosis. Use of tamoxifen is restricted to patients with breast cancer for whom it is prescribed independent of any skeletal benefit. In contrast, the selective estrogen receptor modulators under development are targeted for the non—breast cancer patient as potential alternatives to ERT. The ultimate cost of these drugs is unknown but is likely to be substantially greater than ERT. From a side-effect point of view, calcitonin is the preferred selection. This is not to imply that that there are substantial or worrying side effects from bisphosphonates or ERT for most patients. It simply is an acknowledgment that there are few, if any, recognized contraindications to calcitonin therapy, and the drug is extremely well tolerated by most patients using the nasal spray preparation.

The only formation—stimulation agent likely to be available in the immediate future is slow-release sodium fluoride. There is no clear indication of when this drug should be selected over an antiresorptive drug. In theory, antiresorptive drugs should be the treatment of choice for patients with high turnover, and formation—stimulation drugs should be used for those with low turnover. There is evidence that the response to ERT^34,35,36 and calcitonin⁹⁰ is greatest in those with high turnover, but response to bisphosphonates and slow-release sodium fluoride has not been shown to be dependent on turnover.

As more therapeutic options become available, discussions concerning combination therapies always follow. There is limited formal documentation of synergism when more than one antiresorptive therapy is used,^{44,45,53,58,70} although no study has demonstrated a blunting of effect. One study did suggest a blunting of effect of calcitonin when an anabolic progesterone⁹³ was used in combination. Data on combined antiresorptive therapy with slow-release sodium fluoride is not available. Several patients in the slow-release sodium fluoride clinical trials were also on ERT, however, and their response to therapy was indistinguishable from those not on ERT. A number of pharmacoeconomic models can be developed to assist in selecting the most cost-efficient strategy for prevention and treatment of osteoporosis, but until more complete data are available, these are heavily biased by unproven assumptions. Physicians should adopt the same approach to osteoporosis therapy as they do in other circumstances in which multiple options are available: become familiar with one or two alternatives and limit the use of other (possibly equally effective) therapies to patients not responding appropriately to the initial choice.

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