CHAPTER  251  OSTEOPOROSIS 1577

251 OSTEOPOROSISCLIFFORD ROSEN

DEFINITIONOsteoporosis is a disorder characterized by enhanced skeletal fragility as a result of reduced bone quantity and quality. The clinical symptoms of this disease may include back pain, height loss, and a history of fractures. Bone mineral density (BMD), which can be determined by several techniques, is often markedly reduced in osteoporotic patients with fractures. The World Health Organization (WHO) defines osteoporosis as a condition in which a BMD is less than −2.5 standard deviations (SD) below peak bone mass (i.e., a T-score measured as the units of SD below the normative mean of a 35-year-old woman). However, several large observational studies have shown that osteoporotic fractures can occur across a wide spectrum of BMDs. These events are likely related to altered bone quality, as a result of microarchitec-tural changes in the trabecular and cortical skeleton. Qualitative determi-nants of osteoporotic fractures include trabecular perforations, microcracks, mineralization defects, changes in bone size, and rapid bone turnover (Fig. 251-1). Unfortunately, most of these qualitative changes in the skeleton cannot be captured by clinical measurements, even though they strongly influence overall fracture risk. Recently, introduction of extreme high-resolu-tion computed tomography (CT) and more refined quantitative CT mea-surements have allowed investigators to measure trabecular size, number, and shape accurately, although to date fracture prediction is not markedly enhanced with these new tools. Hence, although low BMD defines osteopo-rosis, this diagnosis should not be excluded in susceptible individuals, par-ticularly those with a history of a low-impact fracture. Finally, although the WHO defined osteopenia as a condition with a T-score between −1.0 and −2.5, and therefore places a given individual at a greater risk for fracture, the clinical significance of this term remains nebulous. Introduction of the FRAX

CHAPTER  251  OSTEOPOROSIS1578

Internet tool, which weighs clinical risk factors with BMD of the hip, may provide greater insight into the long-term fracture risk in individuals with low bone mass. In sum, low BMD is a strong risk factor for subsequent frac-tures, but there is no threshold BMD above or below which fractures occur. Other risk factors, such as a previous fracture history, age greater than 65 years, a strong family history, and recent significant weight loss must be considered.

EPIDEMIOLOGYBy the age of 50 years, the lifetime risk of developing a fracture resulting from osteoporosis in a white woman is nearly 40%, similar to that for coronary heart disease; in men, the corresponding figure is 13%. In the United States, approximately 350,000 hip fractures, close to 1 million vertebral fractures, and 200,000 wrist fractures occur every year. In addition, other fragility-related fractures, particularly those of the pelvis and humerus, are significant causes of morbidity in elderly persons. The incidence of osteoporotic frac-tures increases markedly with age. In women, this increase is seen after the age of 45 years and is mainly the result of forearm fractures. After the age of 65 years, the incidence of hip fractures rises exponentially. In men, the inci-dence of fragility-related fractures increases after the age of 75 years, and in both sexes the hip is the most common fracture site after the age of 85 years. The incidence of vertebral fractures in both men and women is less well documented because many such patients are asymptomatic. Clinical verte-bral fractures increase dramatically with age in men, whereas a more linear age-related increase is noted in women. This age-related increase in fracture prevalence is independent of the change in BMD and almost certainly relates to qualitative changes in trabecular and cortical bone. Hence, age alone is an independent risk factor for fracture.

Marked geographic variations in the incidence of osteoporotic fractures are reported. This characteristic may partly be explained by racial differences in skeletal size; osteoporosis is most common in Asian and white populations and is less frequent in African and American blacks. In many parts of the world, evidence indicates that osteoporotic fractures have increased consider-ably, even allowing for aging of the population. However, a recent report in Canadian individuals demonstrated that in the past 10 years, there has been a decline in hip fractures. Notwithstanding, greater life expectancy alone is expected to increase the number of hip fractures over the next 50 years.

Ethnic and gender differences play a major role in the epidemiology of fractures. Men have higher bone density than women, and African Americans have significantly greater BMD during their adult life than whites, both in the cortical and trabecular compartments. These differences are related in part to the effects of body composition, including muscle strength, body fat distribu-tion, and bone size. Hence, significantly fewer fractures occur in African Americans than in Asians or whites, particularly whites of European descent. However, the role of fat mass relative to BMD has recently undergone reex-amination. Clearly, low body mass index (<20) is associated with low BMD and a greater risk for fracture. This in part is due to lower peripheral conver-sion of testosterone to estrogen and less insulation during impact. On the other hand, the relationship of bone mass to increased fat mass (BMI > 30) is less clear-cut. Increased subcutaneous fat positively affects cortical bone area, but several recent reports suggest that visceral fat may have a negative impact on bone mass and may be associated with a higher fracture risk.

Although often considered protective, it is now established that obesity does not prevent fractures and in some circumstances may increase risk.

BIOLOGYBone RemodelingEven though trauma is the principal cause of fracture, factors that alter the quality or quantity of bone predispose an individual to osteoporotic fractures. Thus, an understanding of bone remodeling is essential for deter-mining how bone mass can be altered by heritable and environmental influ-ences. Briefly, skeletal remodeling preserves serum calcium and bone strength in adults through remodeling or basic multicellular units. Bone remod-eling begins with bone dissolution or resorption and ends with new bone formation, leaving no net change in bone mass. In adulthood, each remodel-ing unit is balanced—resorption equals formation—and lasts between 90 and 130 days. Remodeling preserves bone mass, ensures a ready source of calcium for bodily function, and maintains bone strength through changes in architecture. However, remodeling units can become imbalanced, and over several cycles, this scenario can result in significant bone loss. These imbalances are a result of greater bone resorption relative to bone formation and can be traced to changes in systemic hormones, environmental factors, and mechanical loading.

Peak Bone MassAcquisition of peak bone mass occurs between 12 and 15 years of age but is highly dependent on gender (i.e., girls reach peak earlier than boys) and type of bone (i.e., trabecular versus cortical). During this time, there is a rapid increase in bone mass as a result of growth and modeling of the skeleton, which favors formation over resorption. Pubertal surges of gonadal steroids and growth hormone are critical to propel this increase in bone mass with adolescence. Longitudinal studies suggest that several factors regulate peak bone density, including dietary intake of specific nutrients, physical activity, and most importantly, genetic determinants (Table 251-1). The latter view was established in several ways in both humans and animal models. Daugh-ters of mothers with severe osteoporosis have low BMD. Monozygotic twins have much greater concordance in bone mass than dizygotic pairs, and inbred strains of mice differ significantly in peak BMD. However, despite intense efforts over the past decade to identify the heritable determinants of bone mass, minimal progress has been made. Polymorphic differences in the most promising candidate genes, including the vitamin D and estrogen receptors, insulin-like growth factor-I (IGF-I), parathyroid hormone (PTH), collagen A1a, Lrp5, and others are associated with bone mass. But these genetic deter-minants individually contribute only 1 to 3% to the variance in BMD. It is likely, although not yet proved, that nucleotide polymorphisms in multiple genes contribute more to bone mass than changes in single genes.

Bone FormationInvestigators have uncovered two new pathways in the osteoblast that are genetically regulated and affect the rate of bone formation: (1) the Wnt/Lrp5/β-catenin signaling system, and (2) the lipoxygenase pathways. In the former, activating mutations of the low-density lipoprotein receptor–related protein 5 (LRP5) leads to high bone mass, whereas inactivating mutations lead to the osteoporosis pseudoganglioma syndrome, a condition related to low bone mass in children. The canonical LRP5 signaling pathway is stimu-lated by Wnt ligands and leads directly to greater osteoblast proliferation and differentiation. In the latter system, two critical enzymes determine when and how stromal cells enter into either the fat or bone lineage: 12,15-lipoxygenase (12 LO or Alox 12,15) produces prostaglandins and other endogenous

FIGURE 251-1.  Microcomputed tomography images of trabecular bone from the ver-tebrae  of  an  osteoporotic  individual  (left)  and  a  healthy  age-matched  normal  woman (right). 

TABLE 251-1  FACTORS THAT MAY AFFECT PEAK BONE MASS

GenderRaceGenetic factorsGonadal steroidsGrowth hormoneTiming of pubertyCalcium intakeExercise

CHAPTER  251  OSTEOPOROSIS 1579

ligands that bind to the nuclear receptor peroxisome proliferator activator receptor-γ (PPARG) and stimulate adipocyte differentiation; 5′LO, or Alox 5, generates leukotrienes that can also activate PPARG through generation of prostaglandin J2. Polymorphisms in these two genes in mice and humans have been associated with differences in peak bone mass. Twin studies have shown that the genetic regulation of peak bone mass can be modified by both hormonal and environmental factors. In particular, adequate and timely secretion of sex steroids, balanced nutrient intake, and physical activity can optimize peak BMD even in people with a genetic predisposition to low bone mass. It is likely that disturbances in peak bone acquisition contribute to osteoporosis later in life. For example, men with constitutionally delayed puberty have lower BMD in their 30s and 40s than do men who went through puberty at the appropriate age. Women with anorexia nervosa during their teen years have significantly lower BMD at the time of menopause than do healthy adolescents who do not develop amenorrhea. Women with delayed menarche also have lower BMD in adulthood than do women with a normal timing of menses onset. One area of controversy relates to whether childhood fractures are a sign of subsequent osteoporosis. At least two studies have shown that adolescent radial fractures are associated with lower area bone density and reduced cortical bone size compared with findings in children who do not have fractures. These determinants could predispose children to fractures with relatively low impact and may provide some indication of future risk, although more studies are needed. Interestingly, obesity in chil-dren is a risk factor for future radial fractures.

PATHOBIOLOGYAdult BMD is determined both by the acquisition of peak bone mass during adolescence and by the degree of subsequent bone loss over a lifetime (Fig. 251-2). These two processes are regulated at the level of the bone remodeling unit, which is composed of bone-forming osteoblasts, bone-resorbing osteo-clasts, and deeply imbedded cortical osteocytes capable of sensing gravita-tional forces. The remodeling sequence is tightly orchestrated at several levels by the interaction of genetic, environmental, and hormonal factors (Chapter 250). Even small changes in bone formation or bone resorption can result in bone loss or impairment in the capacity to acquire peak bone mass during adolescence. Although an osteoporotic fracture inevitably occurs as a result of trauma—major or minor—to a bone with reduced bone quantity or quality, a strong inverse relationship exists between BMD and fractures. Hence, changes in remodeling that lead to lower bone mass are major factors in determining the overall risk for osteoporosis.

Bone loss occurs when the bone remodeling unit is uncoupled such that bone resorption exceeds formation. The timing of bone loss is a critical deter-minant of future fracture risk. For example, rapid bone loss in elderly persons is rarely recouped and leaves these individuals at very high risk for fracture independent of BMD. Conversely, accelerated bone turnover over a short period (such as that related to transient glucocorticoid excess in childhood or adolescence) may be reversible. Once the inciting event (i.e., pituitary tumor) has been removed or the treatments have stopped, fracture risk returns to baseline, and BMD can be restored. However, bone loss can also be incessant, particularly in postmenopausal women, in whom estrogen

deprivation results in markedly increased osteoclastic activity and high- turnover remodeling. Although the basic multicellular unit is tightly coupled, rapid bone resorption over a prolonged period results in an imbalance because formation cannot be maintained at the same accelerated rate as resorption. During the first few years of menopause (and possibly during the latter phases of premenopause), as estrogen levels decline, trabecular bone loss occurs first. This is followed by cortical thinning. Both conditions are a result of a mismatch between resorption and formation. Surprisingly, during adult bone loss, periosteal expansion occurs in an attempt to preserve bone strength.

In menopause, bone loss averages about 1% per year, but in a few women, loss of spine BMD can be as great as 5% per year. At present, it is impossible to identify those women prospectively. Moreover, premature menopause, chemotherapeutically induced ovarian dysfunction, and amenorrhea related to heavy exercise result in even higher rates of bone resorption that cannot be matched by any increase in bone formation. However, tremendous het-erogeneity exists in the response to estrogen deprivation among postmeno-pausal women. A few women during their first few years of menopause may lose bone at a rate of 2 to 4% per year. Even among “fast losers,” this decline slows over time. Estrogen replacement prevents postmenopausal bone loss even among fast losers, although the popularity of this type of prevention has waned in the years following publication of the Women’s Health Initiative (WHI).

Bone Loss in Elderly PersonsLater in life, particularly in the eighth and ninth decades, bone loss can accelerate dramatically. Several potential mechanisms are responsible for this change. First and foremost, elderly individuals generally have reduced vitamin D and calcium intake, as well as less sun exposure. This, combined with a reduced capacity to generate pre-vitamin D in the skin, results in sec-ondary hyperparathyroidism and enhanced bone resorption. Remarkably, more than 50% of women who are older than 70 years and who live in north-ern latitudes have insufficient or deficient levels of vitamin D (i.e., serum 25-hydroxyvitamin D < 20 ng/mL). Other factors also play a role in the accelerated bone turnover of senescence. Increasing levels of homocysteine may enhance bone resorption or may alter the nature of reactive oxygen species within the skeletal milieu. Inflammatory cytokines such as interleu-kin-6 (IL-6) and tumor necrosis factor (TNF) also increase with age and can stimulate bone turnover.

The uncoupling of the bone remodeling unit in an older person may be associated with a defect in bone formation because both osteoblast number and function decline with age. These changes may be related to low levels of circulating or skeletal IGF-I or to other trophic factors that either enhance osteoblast survival or stimulate stromal cell recruitment. Alterations in lineage allocation among stromal cells can lead to increased marrow adipo-genesis at the expense of osteoblast differentiation. The process of fatty infil-tration of the bone marrow, particularly in the vertebrae of older individuals, is due in part to an age-related increase in activation of PPARG, a nuclear receptor and transcription factor essential for adipocyte differentiation. Drugs may also enhance PPARG activation, and these include the thiazoli-dinediones (e.g., rosiglitazone and pioglitazone) and glucocorticoids. Inter-estingly, PPARG activation may also stimulate new osteoclast development resulting in a marked uncoupling between resorption and formation. Thus, as a result of impaired osteoblast function, the remodeling deficit becomes more pronounced, particularly in the setting of greater bone resorption. Irre-spective of the cause of bone loss with aging, estrogen and other antiresorp-tive therapies are effective in inhibiting bone resorption and in resetting the bone remodeling units, so the two processes are now coupled.

Classification of OsteoporosisEarlier work proposed two types of osteoporosis, based on age of onset: type I, or postmenopausal, osteoporosis, caused by estrogen deprivation around the time of menopause; and type II osteoporosis, related to high turnover from calcium and vitamin D insufficiency. However, it is clear that this type of classification is outdated and has little clinical purpose. Many younger postmenopausal women can have vitamin D deficiency, and elderly individu-als may suffer just as much from bone loss as a result of progressive estrogen insufficiency as younger women. Similarly, even though wrist fractures are more common, as are vertebral fractures, in younger, healthy postmenopausal women, these fractures are very characteristic of any type of osteoporosis, and they represent skeletal failure related to impaired bone quantity or quality, or both, irrespective of age.

10 20 30 40 50 60 70 80

Age (yr)

Bon

e m

iner

al d

ensi

ty

MenWomen

Fracturethreshold

Menopause

FIGURE 251-2.  Cortical bone mineral density versus age in men and women. Women have lower peak cortical bone density than men and experience a period of rapid bone loss at menopause, thus reaching the fracture threshold (the level of bone density at which the risk of developing osteoporotic fractures begins to increase) earlier than men. 

CHAPTER  251  OSTEOPOROSIS1580

Molecular and Cellular Mechanisms of Normal RemodelingTo understand the pathophysiologic mechanisms of bone loss more fully, it is necessary to define the key molecular and cellular events that occur during normal adult remodeling. Mesenchymal stromal cells (MSCs), or osteoblast precursor cells, undergo a series of differentiation stages that culminate in a mature osteoblast capable of laying down matrix and secreting growth factors. These cells, as noted previously, are multipotent, and under the influence of various factors, they may become adipocytes, muscle cells, chondrocytes, or osteoblasts. The ultimate fate of the stromal cells is a critical determinant of normal remodeling. During MSC differentiation, stromal cells release a series of cytokines that target osteoclast progenitors, resulting in the differ-entiation of multinucleated cells from the macrophage lineage. Once these cells become osteoclasts, they have the capacity to cause bone resorption by secreting hydrogen ions and enzymes that dissolve the bone matrix. Within the matrix are several key trophic factors, activated by bone dissolution; as these enter the skeletal milieu, cells of the osteoblast lineage are pushed into differentiation. In this manner, bone resorption is coupled to bone formation.

Several cytokines, including IL-1, IL-6, TNF, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG), a soluble decoy receptor for RANKL, are secreted by preosteoblasts during their differentia-tion. RANKL is expressed on the surface of the osteoblast precursors, and its receptor RANK is the receptor for RANKL on the surface of the osteoclast, a convenient match that actually permits cell-cell interaction (Fig. 251-3). Binding of RANKL to RANK in the presence of permissive levels of another cytokine, macrophage colony-stimulating factor, stimulates the differentia-tion of osteoclasts into mature bone resorbing cells. In contrast, OPG, a cir-culating protein also produced by stromal cells, can bind to RANKL and can prevent its occupation of RANK, thereby reducing osteoclastogenesis.

PATHOGENESISCellular and Molecular Mechanisms of Bone LossOsteoporosis results from an imbalance in bone remodeling. Changes in bone turnover can be due to a number of factors that target both osteoblasts and osteoclasts and result in greater resorption than formation. For example, declining estrogen levels during menopause or after oophorectomy result in an upregulation of all the stromal cytokines, particularly RANKL. Con-versely, OPG secretion is suppressed. This scenario results in greater osteo-clastogenesis and accelerated bone resorption. Because bone formation is coupled to resorption, the entire remodeling unit is activated. Bone resorp-tion is a rapid process, taking about 2 weeks for the osteoclasts to attach and resorb matrix. Formation is much more deliberate, meaning that with the release of soluble cytokines, an imbalance in remodeling immediately occurs, and this favors bone resorption. Eventually, this imbalance leads to increased breakdown of collagen and matrix and an inability to match this loss with increased formation. Estrogen administration can prevent bone loss by enhancing OPG production as well as by suppressing RANKL expression. Other systemic and local factors can cause imbalanced remodeling. High levels of PTH for long periods can stimulate RANKL expression and cause bone loss. Glucocorticoid excess from exogenous steroids or Cushing’s disease also stimulates RANKL production, but in addition shifts stromal cell differentiation away from the osteoblast lineage and toward adipogenesis.

Immobilization suppresses bone formation and enhances bone resorption. Aging in general leads to a reduction in several osteoblastic trophic factors such as IGF-I, as well as increased PPARG activation, and these changes can impair the rate of new bone formation.

Secondary Causes of Bone Loss in the AdultAlthough most cases of osteoporosis can be labeled idiopathic and result from the cellular and molecular processes that are related to estrogen depriva-tion and aging, it is important to exclude secondary causes, primarily because these disorders are sometimes reversible with resolution of the underlying disease (Table 251-2). Hypogonadism of any cause, in either men or women, is probably the most frequent secondary cause of osteoporosis, particularly in younger patients. Anorexia nervosa, hypothalamic amenorrhea, hyperpro-lactinemia, and exercise-induced amenorrhea lead to early and rapid bone loss that can result in subsequent osteoporotic fractures if these conditions are sustained over a prolonged period. In male patients, primary or secondary hypogonadism results in low peak bone mass and can cause significant bone loss during middle life. Hormonal disorders that interfere with the normal hypothalamic gonadal axis, such as hypercortisolemia, also lead to reduced bone mass. Glucocorticoid excess dampens gonadotropin-releasing hormone signaling, thereby lowering estrogen or androgen levels and enhancing bone resorption; these changes are accompanied by alterations in osteoblast recruitment and function, increased marrow adiposity, reduced IGF-I signal-ing, and impaired calcium absorption. As the remodeling unit is uncoupled, bone loss occurs rapidly, and fractures are a frequent component of this syndrome. Other endocrine disorders are associated with low bone mass or high bone turnover (see Table 251-2). These include severe hyperthyroidism, primary hyperparathyroidism, and growth hormone deficiency. In primary hyperparathyroidism, bone loss is principally confined to cortical bone sites and is reversible with surgical removal of the tumor.

Other systemic diseases can cause osteoporosis (see Table 251-2). Patients with hepatobiliary disorders often have osteoporosis or osteomalacia, or both, resulting from impaired absorption of vitamin D and secondary hyper-parathyroidism. Gluten enteropathy is one of the most common heritable diseases, and patients frequently present in adult life with low bone mass (Chapter 252). These patients often have low 25-hydroxyvitamin D levels and markedly increased PTH concentrations with modest elevations in total alkaline phosphatase. The definitive diagnosis is made by small bowel biopsy, although tissue transglutaminase levels can be very helpful when screening individuals with low bone mass. Patients with systemic disorders such as lupus erythematosus (Chapter 274), scleroderma (Chapter 275), rheuma-toid arthritis (Chapter 272), and mixed connective tissue disease may also present with low bone mass independent of whether they have been treated with glucocorticoids. This form of secondary osteoporosis most likely results from a combination of immobility, malabsorption, and the release of inflam-matory cytokines both locally and systemically as well as the use of other medications that may be detrimental to the skeleton, such as heparin, ethanol, cyclosporine, tacrolimus, and anticonvulsant agents. Chronic alcohol inges-tion (Chapter 32) may be particularly detrimental to the skeleton because it can suppress osteoblast function, increase stromal cell differentiation into adipocytes, and enhance bone resorption. Many patients who suffer from chronic alcoholism are hypogonadal (either primary or secondary) and fre-quently have low vitamin D levels. Male patients with hypercalciuria or

Proliferation Differentiation Survivaland fusion

OPG

Cell-bound RANKL

Soluble RANKL

RANK

M-CSF

c-fms

Activation Apoptosis

1 2 3 4 5

IL-1IL-6

TNF-α

IL-1IL-6

TNF-α

+ +++

− − +− + +− −

FIGURE 251-3.  Regulation of osteoclast development by receptor activator of  nuclear  factor-κB  ligand  (RANKL),  receptor  activator  of  nuclear  factor-κB (RANK), and osteoprotegerin (OPG). c-fms = receptor for M-CSF; IL = interleukin; M-CSF = macrophage colony-stimulating factor; TNF-α = tumor necrosis factor-α. (From  Hofbaurer  LC,  Heufelder  AE.  The  role  of  receptor  activator  of  nuclear factor-κ ligand and osteoprotegerin in the pathogenesis and treatment of meta-bolic bone diseases. J Clin Endocrinol Metab. 2000;85:2355-2363.)

CHAPTER  251  OSTEOPOROSIS 1581

kidney stones are also at risk for low bone mass and osteoporotic fractures. The pathogenesis of this relationship is not entirely clear, but secondary hyperparathyroidism in patients with hypercalciuria leads to enhanced bone resorption and gradual bone loss. Finally, drug-induced bone loss is a major cause of secondary osteoporosis. Besides glucocorticoids, chronic heparin therapy, some anticonvulsants, the thiazolidinediones, and some second-generation antipsychotics can cause osteoporosis. Recently, use of second-generation selective serotonin reuptake inhibitors (SSRIs) and proton pump inhibitors has been linked to both bone loss and osteoporotic fractures in older women and men. If confirmed in prospective trials, these agents may become the most common cause of secondary osteoporosis.

MalignancyMetastatic neoplasms to the skeleton can sometimes manifest as an osteopo-rotic fracture or as a lytic lesion of uncertain significance. Usually, these lesions are atypical in location (e.g., midshaft of long bones, or pelvis), and the underlying disease frequently is obvious. Less commonly confused with

osteoporosis are osteoblastic lesions of vertebrae or long bones. However, primary hematopoietic and lymphoproliferative disorders are often insidious and can be associated with low bone mass and fractures. Multiple myeloma (Chapter 193) is the most common hematologic malignancy related to osteo-porosis because patients with this disease often have diffuse osteopenia, occa-sionally with classic osteoporotic fractures of the spine or long bones. Unlike other metastatic processes to bone, multiple myeloma is associated with very high rates of bone resorption but no change or suppression in bone forma-tion. This situation can lead to rapid bone loss. Plasma cells release cytokines, particularly TNF-α, IL-1, and IL-6, that stimulate osteoclastogenesis. Simul-taneously, these cells produce Dickopf I and III, soluble factors that block the Wnt/LRP5/β-catenin canonical network. Hence patients have dramatic uncoupling of bone remodeling, rapid bone loss, and fractures. Debate is ongoing about the relationship of osteoporosis to monoclonal gammopathies of uncertain significance (MGUS), although osteopenia is often reported in these patients. Other secondary causes of osteoporosis are noted in Table 251-2.

CLINICAL MANIFESTATIONSAlthough osteoporosis is often considered a silent disease, its presentation has changed dramatically in the past two decades. Previously, fractures of the vertebrae, with or without height loss, were the most frequent presenting complaints. Until recently, hip fractures in elderly patients, which can be a late manifestation of osteoporosis, were frequently considered traumatic but not metabolic. Similarly, wrist fractures in early postmenopausal women are a sentinel indication of underlying osteoporosis. They were treated in the past by orthopedic surgeons without regard for any underlying skeletal pathologic processes. However, these patterns began to change in the early 21st century, particularly with the availability of dual-energy x-ray absorptiometry (DXA), the method of choice for measuring BMD. Now, the most frequent present-ing complaint to a provider regarding osteoporosis is a low BMD measure-ment, done either routinely or for screening purposes. Because bone mass is only one of several risk factors for osteoporosis, other clinical manifestations of this disease must be considered. Loss of more than 2 inches in height is a reasonable surrogate of previous vertebral fractures. A clinical history of wrist or ankle fractures is another indication of underlying osteoporosis and may be the first manifestation of the disease in younger postmenopausal women. Compression fracture of the spine with minimal stress is another presenting complaint of osteoporosis. Such fractures cause significant midlumbar and lower thoracic back pain that may radiate to the flanks or anteriorly. Sharp, knifelike back pain after an acute injury is disabling, frequently requires nar-cotics, and often subsides over a period of weeks to months unless a new fracture intervenes. Patients have an approximately 20% likelihood of a new vertebral fracture in the first year after a spinal fracture. In addition, some patients have chronic back pain as a result of one or more vertebral fractures. Low bone mass in and of itself does not result in back pain, and other diag-noses should be considered in that situation. Cervical lordosis and dorsal kyphosis are the classic manifestations of “dowager’s hump” but are less fre-quently seen in young women. Hip fractures resulting in femoral neck, tro-chanteric, or cervical injuries generally occur following a fall. The direction and height of the fall are critical elements in determining the type of hip fracture, the ensuing surgery, and disability. Hip fractures can be extremely catabolic, both because of the trauma and because of the resultant major surgery. These factors, combined with underlying illnesses, enhance the mor-tality of hip fractures in older individuals to approximately 20% in the first year alone.

Osteoporosis can also be diagnosed by a radiologist or a primary care provider from plain radiographs, as shown in Figure 251-4. Most often, patients have an obvious loss of bone mass, resulting in the radiographic term osteopenia, although at that stage BMD by DXA is usually well below −2.5 SD. Radiographs of the spine can demonstrate kyphosis, osteopenia, and com-pression fractures in the thoracic or lumbar vertebrae. For the upper lumbar or lower thoracic areas that are the most vulnerable to injury, compression fractures can frequently be visualized. Collapse of either the anterior or pos-terior elements is often visible on lateral radiographs of the spine; anterior wedging or the so-called codfish deformity results from weakening of the subchondral plates and expansion of the intervertebral discs (see Fig. 251-4). CT scanning of the spine for other reasons will sometimes be able to detect fractures and can be used clinically to measure density. Magnetic resonance imaging (MRI) is now more frequently used as a diagnostic tool; it may demonstrate a compression fracture with or without marrow edema resulting in a bright signal on T1-weighted images. Technetium-99m bone scans are

TABLE 251-2  SECONDARY CAUSES OF OSTEOPOROSISENDOCRINE DISEASESFemale hypogonadism

HyperprolactinemiaHypothalamic amenorrheaAnorexia nervosaPremature and primary ovarian failure

Male hypogonadismPrimary gonadal failure (e.g., Klinefelter’s syndrome)Secondary gonadal failure (e.g., idiopathic hypogonadotropic hypogonadism)Delayed puberty

HyperthyroidismHyperparathyroidismHypercortisolismGrowth hormone deficiencyVitamin D deficiencyIdiopathic hypercalciuriaDiabetes mellitus

GASTROINTESTINAL DISEASESSubtotal gastrectomyMalabsorption syndromesChronic obstructive jaundicePrimary biliary cirrhosis and other cirrhosesAlactasia

BONE MARROW DISORDERSMultiple myelomaLymphomaLeukemiaHemolytic anemiasSystemic mastocytosisDisseminated carcinoma

CONNECTIVE TISSUE DISEASESOsteogenesis imperfectaEhlers-Danlos syndromeMarfan syndromeHomocystinuria

DRUGSAlcoholHeparinGlucocorticoidsThyroxineAnticonvulsantsGonadotropin-releasing hormone agonistsCyclosporineTacrolimusChemotherapySelective serotonin reuptake inhibitors (?)ThiazolidinedionesProton pump inhibitors

MISCELLANEOUS CAUSESImmobilizationRheumatoid arthritisRenal tubular acidosis

CHAPTER  251  OSTEOPOROSIS1582

very sensitive to fracture and can be used to detect stress fractures in the pelvis, femur, or tibia. However, because of its high sensitivity, this test is not a useful tool for diagnosis of osteoporosis. In fact, it is rare for the bone scan to be the initial clue to osteoporosis, and in the setting of a positive bone scan, alternative diagnoses, including malignant disease, should be considered.

DIAGNOSISA recent fragility-related fracture of the spine, hip, wrist, ankle, shoulder, or other appendicular sites in postmenopausal women or men should lead to a diagnosis of osteoporosis. However, secondary causes of this condition (as discussed earlier and listed in Table 251-2) should be excluded before therapy is initiated. Similarly, because the WHO has established that a BMD at any site lower than −2.5 SD from the young normal value meets the definition of osteoporosis, a diagnosis can be made from a densitometry report or mea-surement. However, this finding must be interpreted in relation to the patient’s age, ethnicity, fracture history, family background, previous medica-tions, timing of menopause, and other concomitant disorders. Based on the WHO criteria, most providers make the diagnosis of osteoporosis by measur-ing bone density with or without biochemical markers of bone turnover. Recently the introduction of the FRAX Internet tool by WHO has made long-term fracture risk prediction an important and easy tool for the patient and the provider.

Bone DensitometrySeveral techniques are available for measuring areal BMD (i.e., two-dimen-sional measurements expressed as g/cm2) in the axial and appendicular skel-eton. Multiple prospective studies have convincingly shown that a low BMD at virtually any site (i.e., hip, spine, radius, total body, calcaneus) predicts subsequent osteoporotic fractures whether these are in the same area or elsewhere. In general, regardless of the technology, for every 1 SD below a young (i.e., 35-year-old) normal value (i.e., T-score), the risk for future osteo-porotic fractures increases by nearly 50%. However, site-specific measure-ments, for example, spine BMD, usually predict spine fractures better than a hip BMD. Because of the inverse relationship between fracture risk and BMD, a very strong rationale exists for measuring bone mass at least once during the lifetime of every postmenopausal woman.

Dual-Energy X-Ray Absorptiometry Measurements of Bone Mineral DensityTechniques for measuring bone mass include the following: DXA of the spine, hip, radius, or total body; CT of the spine; ultrasound scanning of the calcaneus or wrist; finger DXA; and peripheral quantitative CT of the wrist or tibia. Other experimental techniques that are being tested for evaluating trabecular bone and bone quality include MRI of the calcaneus and radius, virtual MRI using computerized reconstructions of trabecular bone, and

“extreme CT” with high-resolution imaging of the radius. The most popular, least expensive, and most precise tool is DXA. Results from DXA measure-ments are traditionally expressed as either the T-score or the Z-score. The T-score is the number of SDs below or above which the patient’s BMD differs from peak bone density of an individual of the same gender and ethnicity. The Z-score is the number of SDs by which the patient’s bone density differs from that of an individual matched for age, gender, and ethnicity. Not surpris-ingly, there can be disparity in absolute BMD by skeletal site within the same individual. This disparity can be attributed to the relative proportion of tra-becular and cortical bone at a particular site. For example, the vertebra is 85% trabecular bone, whereas the femoral shaft or neck is principally cortical bone. Several studies have shown that nearly one in three subjects has dispa-rate hip and spine T-scores. This finding can be attributed to the differences in skeletal composition; in other words, cortical or outer shell bone is thicker and remodels less frequently, whereas trabecular bone, which is the inner spongiform bone bathed by marrow elements, is metabolically very active. DXA integrates both skeletal compartments as an areal measurement. However, because skeletal sites often differ in composition and function, this disparity is frequently noted. Furthermore, age-related changes in the two skeletal compartments differ, and their genetic determinants may be com-pletely distinct. In general, it is recommended that the lowest BMD measure-ment at any site be used for fracture risk assessment.

The two most common skeletal sites recommended for measuring BMD by DXA are spine and hip. For the spine, both anteroposterior and lateral spine DXAs can be obtained, although most providers use the anteroposte-rior spine, which is both a sensitive indicator of early bone loss and a precise measure. However, anteroposterior spine DXA can often show high bone mass resulting from increases in degenerative arthritis, disc collapse, vertebral fracture, or calcification of the aorta. Hence, in patients who are more than 65 years old, femoral neck and total hip BMD measurements are preferable. Both have good precision, are accurate, and are not complicated by those processes. Either site has strong predictive value for subsequent fractures.

Other Tools for Measuring Bone MassOther means of measuring BMD are available, and each provides T-score equivalents, although these cannot easily be translated across technologies. Quantitative CT scanning of the vertebrae provides a true volumetric measure of bone mass (mg/cm3), can detect early bone loss, is accurate, and is available at many centers. However, its reproducibility is not as good as that of DXA, and T-scores can be quite disparate from DXA measurements. More-over, significantly greater radiation exposure occurs with CT than DXA, and CT requires more time. Ultrasound scanning of peripheral sites has the advantages of portability and ease of operation, and the technique enables the clinician to predict fractures; however, the parameters used to measure sound transmission do not change much with age, or with treatment, thereby making this tool difficult to use for follow-up examination. Peripheral quan-titative CT is expensive but accurate; it has greater radiation exposure but provides information about both cortical and trabecular elements. Fewer data on fracture risk are available with this technique, which is primarily a research tool.

In summary, DXA provides the most accurate and precise tool to assess fracture risk. The DXA measurement, combined with age, history of previous fracture, and family history, gives the clinician the most accurate assessment of osteoporotic risk. For follow-up, BMD measurements by DXA are prefer-able to other technologies because of the low precision error and greater reproducibility.

Risk Assessment Using FRAXSince the introduction of widespread bone density measurements, it has become clear that BMD alone is not sufficient to define overall fracture risk and that consideration of clinical risk factors is essential. Often this is done at the point-of-care using age (>65 years), previous fracture, and family history. However, this combination does provide an estimate of 10-year risk, which clinicians often use to assess other diseases such as myocardial infarc-tion. Hence, the WHO in collaboration with international osteoporosis foun-dations developed a virtual tool, FRAX, that can be used alongside the patient to determine his or her 10-year fracture risk. On any computer, BMD by DXA of the hip is entered into a box along with age, height, gender, country, and responses to queries about family history, use of glucocorticoids or alcohol, previous fracture, and weight loss. A 10-year fracture risk in percent is then calculated for a major osteoporotic fracture (i.e., spine, hip, wrist, and humerus) as well as hip fracture alone. Current guidance suggests that

FIGURE 251-4.  Radiograph  showing  radiolucency,  compression  fractures,  and kyphosis in the spine of a patient with osteoporosis. 

CHAPTER  251  OSTEOPOROSIS 1583

high-risk individuals are those with a 10-year risk of more than 3% for hip fracture and 20% for major osteoporotic fracture.

The FRAX tool has been widely praised, and its use has increased signifi-cantly since its introduction in 2007. Its strengths lie in the point-of-care nature of performing risk assessment, the country-specific assessment (e.g., United States vs. England vs. France), the recent revisions that incorporate new data sets providing more up-to-date fracture incidences for the United States, and ease of use. Concerns persist about several limitations, including that only hip BMD can be entered for fracture risk; FRAX should not be used in patients already receiving treatment; and in some populations, risk is over-estimated, particularly in the younger postmenopausal female. Notwith-standing, fracture risk evaluation provides a reliable estimate for both the patient and provider and is preferred over a single BMD measurement to establish risk.

Biomarkers: Biochemical Markers of Bone TurnoverNewer methods of measuring bone breakdown and synthesis products have been developed since the mid-1980s. Previously, urinary calcium and hydroxyproline were the two urinary markers used to assess bone resorption; both were nonspecific, and their precision was poor. Subsequently, serum and urine biochemical markers have been perfected and tested in large clini-cal trials and are now available for clinical use. Markers of bone resorption mediated by osteoclasts include urinary pyridinoline and deoxypyridinoline as well as urine cross-links of the C- and N-terminal peptides of type I col-lagen. The latter can be measured either in urine or in serum. Markers of osteoblast-mediated bone formation include bone-specific alkaline phospha-tase, osteocalcin, type I procollagen amino-terminal propeptide, and type I procollagen carboxy-terminal propeptide. Increases in markers of formation or resorption, or both, imply accelerated remodeling. For example, immedi-ately after estrogen production ceases, markers of bone formation and bone resorption increase significantly. Similarly, later in life, and during states of secondary hyperparathyroidism, these markers can be extremely elevated. In addition, antiresorptive drugs such as estrogen or the bisphosphonates sig-nificantly lower urinary and circulating concentrations of these markers. Both longitudinal and cross-sectional studies have demonstrated that high turn-over markers predict fracture in elderly women. These markers are indepen-dent of BMD and imply that accelerated bone turnover itself is a risk for fracture. Such indices of bone turnover provide a current estimate of the state of the skeleton, whereas bone density measurements are stoichiometric and reflect all the events leading up to the measurement.

In addition its potential for defining risk for fracture, several groups have shown that suppression in turnover markers with bisphosphonates or estro-gens can predict fracture risk reduction in older postmenopausal women. Notwithstanding, the use of markers in clinical practice has been disappoint-ing for several reasons. First, the variability in individual measurements, par-ticularly for urine studies, is quite high. Therefore, even a single measurement has significant measurement error; follow-up to assess change from baseline is often even more confusing because of the variability issue. Second, most women have turnover marker values within the normal range, making inter-pretation difficult. Third, the number of older women with high bone turn-over has probably been overestimated, particularly in the early postmenopausal period. These issues have limited enthusiasm for a single blood or urine test to help determine risk and assist in management once therapy has com-menced. Occasionally, these tests can be helpful: in the young woman who undergoes premature menopause resulting from chemotherapy, for example, knowledge not just of the BMD but also of the rate of bone turnover could help in managing her condition with either aggressive antiresorptive therapy or a more measured approach using calcium and vitamin D. It is not recom-mended that these markers be used routinely to assess compliance with anti-resorptive therapies.

Diagnostic EvaluationThe diagnosis of osteoporosis is usually made by bone mass measurements and a history of previous osteoporotic fractures. Secondary causes of osteo-porosis must be excluded, and follow-up is required to ensure that the disease is not rapidly progressive. Routine profiles for renal and thyroid function are indicated. A serum 25-hydroxyvitamin D measurement in an older individ-ual, particularly in northern latitudes, is recommended because deficiencies can be corrected with vitamin D supplementation. At present, DXA, com-bined with fracture risk assessment such as performed in the FRAX model, represents the best tool for assessing overall fracture risk and determining the course of therapy. Biochemical markers may be helpful in some cases.

Treatment PlanA comprehensive management plan for osteoporosis includes diagnosing 

those at highest risk, excluding secondary causes of  low BMD, and selecting appropriate treatment. Decision making should also take into account several caveats. First, osteoporosis therapy can reduce fracture risk by as much as 50%, but some women will continue to have fractures despite treatment. Identify-ing those women at greatest risk for progressive disease is mandatory. Second, lifestyle and pharmacologic interventions are lifetime commitments such that cost,  compliance,  and  safety  must  be  factored  into  therapeutic  decisions. Studies suggest  that even with weekly or monthly bisphosphonate therapy, more than 40% of individuals treated will not continue therapy beyond 1 year. Third, it is not uncommon for women with T-scores higher than −2.5 to have fractures. In fact, in the National Osteoporosis Risk Assessment cohort of more than 140,000 postmenopausal women in the United States, almost one third of  the  women  who  had  fractures  also  had  BMD  scores  in  the “osteopenic” range. Thus, treatment decisions should not be based solely on BMD.

Therapy  for  postmenopausal  osteoporosis  is  framed  in  terms  of  primary prevention when it  is prescribed for those at risk who do not have low bone mass (T-score < −2.5) or fractures or in terms of treatment for those with estab-lished disease, including previous osteoporotic fractures or markedly reduced BMD, or both. Thus, selection of an appropriate treatment regimen depends on  whether  the  therapy  is  designed  principally  to  prevent  bone  loss  or  to reduce  the  likelihood  of  a  new  spine  or  nonvertebral  fracture  in  high-risk individuals.

General MeasuresDietCalcium

Calcium  supplementation  should  be  an  adjunct  to  drug  treatments  for women  with  established  osteoporosis  and  must  be  part  of  any  prevention strategy  to  ameliorate  bone  loss  independent  of  other  treatment  choices. Increased  calcium  intake  reduces  the  secondary  hyperparathyroidism  often seen  with  advancing  age  and  can  enhance  mineralization  of  newly  formed bone.  Evidence  that  calcium  and  vitamin  D  together  or  individually  reduce fracture  risk  in  the  osteoporotic  individual  remains  somewhat  controversial. However, a recent meta-analysis of calcium and vitamin D intervention trials demonstrated  a  consistent  albeit  small  increase  in  BMD  and  a  reduction  in nonvertebral  fractures  when  at  least  1200 mg  of  calcium  is  combined  with more than 400 units of vitamin D. Calcium supplementation alone has not been shown to reduce the incidence of nonvertebral fractures in high-risk women. A very large calcium intervention trial from WHI did not demonstrate hip frac-ture  reduction  with  1000 mg  of  daily  calcium  supplements  and  400 IU  of vitamin  D  for  all  postmenopausal  women.  However,  for  those  older  than  60 years, the risk reduction was statistically significant. 1  Interestingly, calcium supplementation  in  this  cohort  was  associated  with  a  17%  greater  risk  for kidney stones. This may have been due to the  finding that baseline calcium intake in these women averaged 1100 mg per day. New Institute of Medicine (IOM) guidelines recommend 1200 mg per day of calcium in women over age 70  and  800 IU  of  vitamin  D  per  day  in  that  same  age  group.  Certainly,  with intakes greater than 2000 mg per day, the risk for nephrocalcinosis increases.

Vitamin DVitamin  D  is  essential  for  skeletal  maintenance  and  for  enhancement  of 

calcium absorption. Insufficiency of this vitamin is a growing problem; as many as two thirds of all patients who have hip fractures are classified as vitamin D deficient (Chapter 252). However, the results from randomized trials are con-flicted. Elderly people in chronic care living situations are particularly vulner-able to vitamin D deficiency and may benefit from supplementation. One large randomized placebo-controlled trial (RPCT) demonstrated a 33% reduction in hip fractures for nursing home residents who received calcium and vitamin D compared with those receiving placebo. 2  In another trial, high-dose intermit-tent  vitamin  D  reduced  nonvertebral  fractures  by  nearly  one  third  among ambulatory  elderly  persons. 3   In  older  New  England  men  and  women,  the combination of calcium citrate and 700 IU of vitamin D was shown to lessen by one third the risk for nonvertebral fractures. 4  However, in a large popula-tion-based study with calcium and vitamin D, supplementation had no effect on nonvertebral fractures, 5  although compliance and assessment of vitamin D  levels were not sufficiently well documented to exclude an effect. Several recent meta-analyses suggest  that 800 IU per day of vitamin D  is needed to have  fracture  efficacy.  Besides  the  potentially  positive  effects  of  vitamin  D supplementation on the skeleton, particularly in older women, vitamin D may also  enhance  muscle  strength  and  has  been  shown  to  reduce  the  risk  for falling. Therefore, for most individuals with osteoporosis, 800 IU/day of vitamin D is sufficient to maintain adequate levels of 25-hydroxyvitamin D. However, in those patients with low bone mass and insufficient or deficient 25-hydroxyvi-tamin D  levels  (i.e., <20 ng/mL), administration of 50,000 IU of ergocalciferol (vitamin  D2)  or  cholecalciferol  (vitamin  D3)  given  once  weekly  is  a  safe  and effective way to restore vitamin D levels to the normal range. Upper limits of 

TREATMENT

CHAPTER  251  OSTEOPOROSIS1584

vitamin  D  supplementation  are  currently  being  reviewed  to  determine whether there is toxicity at higher doses.

Vitamin D analogues have been used in the treatment of osteoporosis since the  early  1980s.  However,  this  remains  a  controversial  area.  High  doses  of 1,25-dihydroxyvitamin  D  increase  bone  mass,  but  many  patients  develop hypercalciuria  or  hypercalcemia,  or  both.  At  doses  of  0.5 µg/day,  calcitriol reduced the rate of both vertebral and nonvertebral fractures, and it increased bone density in a very small trial. Other studies have found little benefit with a  narrow  therapeutic  window,  particularly  in  relation  to  renal  function  and hypercalcemia. Currently, vitamin D analogues are not recommended for the routine treatment of osteoporosis. A subset of patients with renal insufficiency (chronic kidney disease > 3) and high PTH levels may benefit from supplemen-tation with calcitriol.

Physical ActivityBedrest  or  immobility,  particularly  in  elderly  persons,  can  result  in  rapid 

bone loss. Moreover, the number of falls increases with age, and the number of  falls  that  result  in  fractures  also  rises.  A  meta-analysis  by  the  Cochrane Review  Group  demonstrated  that  muscle  strengthening,  balance  retraining, home hazard assessment, withdrawal of psychotropic medications, and use of a multidisciplinary risk factor assessment program are beneficial in protecting against  falls.  An  additional  approach  is  to  reduce  loads  applied  to  the  hip during a fall by padding. Hip protectors have been shown to reduce the risk for hip fractures in at least one population, although compliance is generally poor. A more recent study failed to demonstrate the efficacy of these devices in older women in an assisted living facility. Regular physical activity, including aerobic,  weight-bearing,  and  resistance  exercises,  is  effective  in  increasing spine BMD and in strengthening muscle mass in postmenopausal women, but no  large-scale  studies  have  established  whether  these  interventions  reduce fracture risk.

LifestyleOther interventions, including smoking cessation and reduction of alcohol 

intake, should be considered within the framework of an individual’s preven-tive health strategy. However, studies to date have been inconclusive in respect to understanding how changes in these lifestyles affect overall fracture risk.

Medical TherapyAbundant evidence indicates that an aggressive intervention program can 

be successful in reducing fracture risk and in improving quality of life among postmenopausal  women  with  preexisting  osteoporosis.  Several  pharmaco-logic options are available, and these can be classified by their mechanism of action. The two major classes of osteoporosis drugs are (1) antiresorptives (i.e., agents that block bone resorption by inhibiting osteoclasts), and (2) anabolics (i.e., drugs that stimulate bone formation by primarily acting on osteoblasts).

Antiresorptive AgentsAntiresorptives  inhibit bone resorption by suppressing osteoclast activity. 

Slowing the remodeling cycle allows bone formation to catch up to resorption, thereby  enhancing  matrix  mineralization  and  stabilizing  trabecular  microar-chitecture. The antiresorptives increase BMD and reduce fracture risk, but their efficacy varies.

EstrogenEstrogen  replacement  therapy  was  long  considered  the  cornerstone  of 

therapy  for  postmenopausal  women  with  osteoporosis.  It  works  by  slowing bone  resorption  through  inhibition  of  cytokine  signaling  including  RANKL from  the  osteoblast  to  the  osteoclast,  thereby  increasing  BMD.  Estrogen replacement inhibits both cortical and trabecular bone loss, and BMD gener-ally increases by 3 to 5% after 3 years. 6  There does not appear to be an addi-tive effect from progesterone on bone mass in women also receiving estrogen. Conversely, progesterone is a necessary part of hormone replacement therapy in women with a uterus because it prevents the development of endometrial hyperplasia and carcinoma.  In  the WHI, estrogen and progesterone  lowered hip  fracture  risk  by  one  third. 7   Low-dose  conjugated  estrogens  (0.3  or 0.45 mg/day)  and  ultralow-dose  estradiol  increase  BMD  and  have  been approved for  the prevention of bone  loss, but antifracture efficacy  for  these preparations has not been established. Discontinuation of estrogen results in measurable bone loss (3 to 5% in the first year), although whether that trans-lates into a greater fracture risk is not clear.

Significant concern has been expressed about the nonskeletal risks associ-ated with long-term estrogen and estrogen in combination with progesterone (Chapter 248). Particularly troublesome is the increased risk for breast cancer with the long-term use of estrogen and progesterone. In the WHI, there was a 26% increase in risk for invasive breast cancer over a 5.2-year period of follow-up. 7   Hence,  estrogen  replacement  is  contraindicated  in  any  woman  with  a history  of  breast  cancer;  yearly  mammograms  are  indicated  in  all  women receiving hormone replacement therapy. Previous case-control and retrospec-tive studies suggested that estrogen could reduce the risk for coronary artery disease; however, in the WHI, the risk for myocardial infarction or death from coronary  artery  disease  was  29%  higher  in  women  receiving  combination therapy. 7  Thromboembolic disease is also increased more than three-fold by 

hormone  replacement  therapy. 7   Hence,  the  use  of  estrogen  or  estrogen  in combination with progestins for the prevention or treatment of osteoporosis has fallen dramatically. Moreover, the availability of newer and effective anti-resorptive drugs  for  the  treatment of osteoporosis has  lessened enthusiasm for primary hormonal therapy in osteoporotic women.

Selective Estrogen Receptor ModulatorsSelective  estrogen  receptor  modulators  such  as  tamoxifen  and  raloxifene 

also inhibit bone resorption by blocking cytokine release from the osteoblast. Both have been shown to reduce bone loss in postmenopausal women with breast  cancer,  but  only  raloxifene  is  approved  by  the  U.S.  Food  and  Drug Administration (FDA) for the prevention and treatment of osteoporosis.

Both these agents block the actions of estrogen on the breast but act like an estrogen agonist in bone; tamoxifen, but not raloxifene, has estrogen ago-nistic properties on the uterus and is associated with a greater risk for endo-metrial carcinoma with long-term use. Both agents have been associated with a  reduction  in  new  cases  of  breast  cancer  when  they  are  administered  as prophylaxis for high-risk patients. 8  Low-density lipoprotein cholesterol levels are also reduced in patients receiving these selective estrogen receptor modu-lators. Raloxifene increases spine BMD slightly (as does tamoxifen) and lowers the risk for vertebral fracture by 40%, although it has no effect on nonvertebral fracture  risk. 9   Hot  flashes,  leg  cramps,  and  a  greater  risk  for  deep  venous thrombosis can occur with raloxifene therapy. The recommended dose of ral-oxifene is 60 mg once daily.

Tissue  selectivity  with  these  selective  estrogen  receptor  modulators  and others being investigated is a subject of great scientific interest. Raloxifene and estrogen  both  bind  to  the  same  region  of  the  estrogen  receptor,  but  they induce  different  conformational  changes  in  that  receptor.  Coactivating  and co-repressing proteins are recruited to the receptor-ligand complex, and it is thought  that  these  transcription  factors  ultimately  determine  the  activity  of the  nuclear  complex.  Because  recruitment  also  depends  on  location,  it  is highly likely that significant tissue selectivity exists for these partners. Newer agents have been designed to facilitate particular complexes and rearrange-ments within the nucleus; these are being studied at both the preclinical and the clinical levels.

BisphosphonatesThe  bisphosphonates  are  the  most  widely  prescribed  antiresorptives  and 

are often considered first-line therapy for the treatment of severe postmeno-pausal osteoporosis. These drugs are carbon-substituted analogues of pyro-phosphate  that  bind  tightly  to  hydroxyapatite  crystals.  It  is  thought  these agents directly  suppress  resorption by  inhibiting osteoclast attachment and enhancing  programmed  cell  death.  The  first-generation  bisphosphonates include etidronate and clodronate. Neither  is approved  for  the  treatment of osteoporosis, although etidronate is widely used “off label” and in Europe. The dose of etidronate is 400 mg/day for 2 weeks every 3 months. The drug has few gastrointestinal side effects, and vertebral fracture risk reduction is significant with  this  agent.  Alendronate  and  risedronate,  two  second-generation  nitro-gen-containing bisphosphonates, are effective in suppressing bone resorption and increasing BMD. In postmenopausal women with established osteoporo-sis, alendronate and risedronate reduced vertebral, hip, and nonvertebral frac-tures by nearly 50%, particularly during the first year of treatment. 10,11  Like other antiresorptive drugs, increases in BMD with alendronate or risedronate account for a small fraction of their antifracture efficacy. Hence, follow-up DXA measurements may significantly underestimate fracture risk reduction. Recent clinical  trials have shown that  these drugs can be safely administered  for at least 7 years without adversely affecting bone strength. Moreover, discontinu-ation of alendronate after 5 years results in minimal bone loss over the ensuing 5 years. Both drugs have excellent safety profiles, although erosive esophagitis is  a  serious  complication  of  all  nitrogen-containing  bisphosphonates.  Once-weekly  administration  of  alendronate  has  been  shown  to  reduce  the  preva-lence  of  drug-induced  esophagitis,  and  currently  both  bisphosphonates  are marketed as once-weekly treatments. Recently, the FDA approved the use of once-monthly risedronate (150 mg) for the treatment of osteoporosis.

Two new bisphosphonates have been approved by the U.S. FDA and have reached the market in the past 5 years: ibandronate and zoledronate. Ibandro-nate is given in a single monthly dose of 150 mg or intravenously (3 mg) every 3 months.  It  suppresses bone  resorption and  reduces  the  rate of  spine  frac-tures,  but  its  efficacy  in  nonspine  fractures  is  somewhat  less  than  that  of alendronate or residronate. 12,13  Compliance with the once-monthly regimen is higher than the weekly dosing, although long-term data are not encourag-ing. Zoledronate is also approved for the prevention and treatment of osteo-porosis. 14  It is administered as a single intravenous infusion over 15 minutes (5 mg)  once  yearly.  Large  randomized  controlled  trials  have  unequivocally established its antifracture efficacy for hip, spine, and other nonspine fractures. Recently, the FDA approved the use of zoledronate for prevention of osteopo-rosis by administration of the drug once every 2 years. Both newer bisphos-phonates can cause first-dose side effects, including joint pain, stiffness, and low-grade fevers. These do not persist with recurrent administration. However, the  FDA  has  cautioned  that  zoledronic  acid  should  be  administered  over  1 hour rather than 15 minutes to lessen any risk, albeit small, of renal damage. 

CHAPTER  251  OSTEOPOROSIS 1585

GLUCOCORTICOID-INDUCED OSTEOPOROSISThe most common secondary cause of osteoporosis is glucocorticoid induced. This is often a result of pharmacologic doses of steroids used to treat inflammatory or autoimmune disorders. Generally, it is considered that glu-cocorticoids (Chapter 34) have a dose-dependent effect on the skeleton, such that longer duration and higher doses of steroids are most likely to cause bone loss and fractures. However, there clearly are subsets of individuals who are more or less sensitive to the skeletal effects of high doses of glucocorti-coids. As a general clinical rule, those individuals with a cushingoid appear-ance and fat redistribution almost always have low bone mass or fractures, or both.

The effects of glucocorticoids on the skeleton are multifaceted and are particularly devastating because these agents cause uncoupling in the remod-eling unit. Besides the indirect suppressive effects of glucocorticoids on the hypothalamic-gonadal axis, and inhibition of calcium absorption in the gut, high doses of steroids can stimulate osteoclastogenesis, increase RANKL production, and decrease OPG. This situation results in higher rates of bone resorption. Additionally, glucocorticoids also have a strong negative effect on bone formation by suppressing expression of IGF-I in bone cells and by shift-ing marrow stromal cells into the fat lineage and away from the osteoblast differentiation pathway. It is presumed that just as fat redistribution syn-drome in the supraclavicular and mediastinal area is a clinical hallmark of Cushing’s syndrome, enhanced adiposity in the bone marrow is a character-istic feature, almost certainly as a function of increased stromal cell differen-tiation into adipocytes. Bone strength is markedly compromised by the uncoupling in remodeling, and bone loss can be rapid over a short time period, particularly with high doses of glucocorticoids. Although there is no true dose-dependent effect on bone resorption, it is thought that prednisone doses as low as 5 mg/day may increase fracture risk. Indeed, in this syn-drome, baseline BMD is not predictive of fractures and can often be normal even in the presence of ongoing resorption and recurrent fractures. Trabecu-lar bone suffers the most in this syndrome, and spine DXA is the most sensi-tive indicator of bone loss. Markers of bone turnover are not helpful in the management of these patients.

Therapy for steroid-induced bone loss centers on treating the underlying disease or reducing the dose of glucocorticoids to the lowest possible regimen, or both. Barring that, several interventions have been shown to retard bone loss and prevent fractures. Adequate calcium and vitamin D intake is critical for every patient receiving glucocorticoids. However, these measures alone are not sufficient. Three bisphosphonates have been shown to have efficacy in glucocorticoid-induced osteoporosis—etidronate, alen-dronate, 20  and risedronate—and they are now considered the standard of care for this disease. These drugs are administered either weekly or cyclically to prevent bone loss and to reduce the risk for fractures. Some anecdotal data support the use of gonadal steroids in this condition, but clearly the bisphos-phonates are superior. In a randomized trial, synthetic PTH (teriparatide, 20 mg daily subcutaneously for 18 months) significantly increased hip and spine bone mass density and reduced new vertebral fractures (from 7.2 to 3.4%), but not other fractures, compared with alendronate. 21  More studies are needed to establish its long-term efficacy in this disease, particularly

Intravenous zoledronic acid is also approved for the treatment of hypercalce-mia  of  malignancy  (Chapter  186)  and  multiple  myeloma,  and  as  palliative therapy for metastatic disease.

Other bisphosphonates are available for off-label use or are being studied for the treatment of osteoporosis. Intravenous pamidronate has been available since  the  mid-1990s  for  the  treatment  of  Paget’s  disease  (Chapter  255)  and malignant hypercalcemia (Chapter 186). It is currently also used to treat osteo-porotic women who cannot tolerate oral bisphosphonates, although it has not been  formally  approved  by  the  FDA  for  this  indication,  and  its  antifracture efficacy  has  not  been  established. The  dose  ranges  from  30  to  90 mg  given every  3  to  9  months.  Acute  and  delayed-type  hypersensitivity  reactions  can occur with this drug, and its use is contraindicated in patients who are vitamin D deficient because it can precipitously drop serum calcium.

In regard to the bisphosphonates, two rare side effects have been reported. Osteonecrosis of the jaw is a devastating condition associated with mandibu-lar destruction following dental  intervention (Chapter 256).  It has been seen in patients  taking bisphosphonates, particularly  those  receiving  intravenous therapy  who  also  have  associated  conditions  such  as  multiple  myeloma  or metastatic breast cancer. Its true prevalence is unknown but is likely about 1 in 250,000 cases, and it is rare in women and men treated for osteoporosis who are  otherwise  healthy.  Nevertheless,  caution  must  be  exercised  in  recom-mending dental surgery to patients taking a bisphosphonate. Subtrochanteric fracture is the other condition that may be associated with long-term bisphos-phonate use. These midshaft  fractures usually occur  in middle-aged women taking an oral bisphosphonate for several years,  frequently accompanied by treatment  with  glucocorticoids  or  use  of  an  additional  antiresorptive  agent. The  patient  typically  complains  of  leg  pain  before  the  fracture,  and  cortical thickening  is  noted  in  the  subtrochanteric  region  on  radiograph  before  the fracture.  The  true  prevalence  of  this  is  unknown,  but  it  is  likely  extremely uncommon, and the etiology is thought to be related to oversuppression of bone  turnover.  Treatment  does  not  differ  from  any  surgical  management, although discontinuation of the bisphosphonate is recommended.

CalcitoninCalcitonin is a 32–amino acid peptide normally produced by the thyroid C 

cells. Osteoclasts have calcitonin receptors, and calcitonin can rapidly inhibit bone  resorption.  Salmon  calcitonin  is  more  potent  than  human  and  is  the preferred  treatment  choice.  Nasal  and  subcutaneous  calcitonin  are  both approved  for  the  treatment  of  postmenopausal  osteoporosis.  However,  the evidence  favoring  a  strong  effect  from  this  hormone  on  either  bone  loss  or fracture efficacy is lacking. In an RPCT of women with postmenopausal osteo-porosis, 200 IU/day of nasal calcitonin reduced vertebral fracture incidence by one third. 15  However, methodologic flaws in that trial have limited enthusi-asm  for  this  agent  as  a  primary  treatment  for  osteoporosis.  In  at  least  one placebo-controlled  study,  nasal  calcitonin  reduced  the  pain  associated  with new spine fractures. The recommended dose of nasal calcitonin is 200 IU/day, and that of subcutaneous calcitonin is 100 IU/day. Side effects are uncommon with intranasal calcitonin and include nasal stuffiness and flushing. With sub-cutaneous administration, nausea is not infrequent.

Strontium RanelateStrontium ranelate is orally administered and stimulates calcium uptake in 

bone  while  it  inhibits  bone  resorption.  It  is  thought  to  have  some  anabolic activity, although the precise mechanism of action in the skeleton, where it is incorporated, is not known. In an RPCT of postmenopausal women with estab-lished  disease,  daily  strontium  reduced  the  risk  for  vertebral  fractures  by 40%. 16  However, a statistically significant effect on nonvertebral fractures was limited to a small subset of women in a post hoc analysis. This drug is approved by European regulatory agencies but not by the FDA.

Anabolic AgentsA new class of antiosteoporosis drugs was introduced in 2002. These are the 

so-called  anabolics,  agents  that  stimulate  bone  formation  more  than  bone resorption.  As  such,  these  agents  enhance  bone  remodeling  and  contrast sharply with the antiresorptives, which slow bone turnover. PTH1-34 (teripara-tide) was the first of this class of drugs to be approved by the FDA.

The prototypical anabolic drug was sodium fluoride, which saw widespread use in the 1970s and 1980s because of its ability to stimulate new bone forma-tion. However, an RPCT in 1990 established that although there were dramatic increases in BMD, nonvertebral fracture risk actually increased. Unlike sodium fluoride, synthetic PTH (PTH1-34) was approved by the FDA for the treatment of postmenopausal  osteoporosis  because  it  not  only  increases  bone  mass  but also  reduces  fractures.  In  the  largest  RPCT  using  teriparatide  in  postmeno-pausal women with severe osteoporosis, 20 µg/day of PTH, administered sub-cutaneously,  reduced  spinal  and  nonvertebral  fractures  by  more  than  50% while it substantially increased (i.e., 8% per year) lumbar BMD. 17  Similar find-ings were noted in men with osteoporosis who were treated for 11 months. Unfortunately, the PTH trial in postmenopausal women was stopped after 20 months because of concerns related to the development of osteosarcoma in rats  treated  with  high  doses  of  PTH1-34.  However,  retrospective  studies  have found no association between osteosarcoma and primary or secondary hyper-parathyroidism, and only two cases of osteosarcoma in PTH-treated patients 

have  been  reported.  More  recently,  recombinant  human  PTH  (PTH1-84)  has shown  similar  benefits. 18   Currently,  it  is  recommended  that  PTH  therapy should be limited to those individuals with moderate to severe osteoporosis, and then taken only for 2 years.

Despite the appeal of using an anabolic with an antiresorptive, no evidence indicates  that  combinations  of  classes  of  drugs  are  additive  or  synergistic. Unlike the bisphosphonates, discontinuation of PTH can result in bone loss of 3 to 4% in the first year after PTH cessation. This post-treatment effect is pre-vented by adding an antiresorptive drug after PTH is stopped. In general, PTH is well tolerated, although nausea, flushing, hypotension, and mild but asymp-tomatic hypercalcemia (i.e., serum calcium < 11.0 mg/dL) can occur. Cost and compliance have been major limiting factors.

Vertebroplasty/KyphoplastyVertebroplasty (percutaneous injection of cement into a collapsed vertebra 

to  stabilize  it)  and  kyphoplasty  (use  of  a  balloon  to  inflate  the  vertebral  body prior to injection of the cement, in an attempt to restore the height and angle  of  the  vertebral  body)  are  widely  used  to  treat  the  pain  of  vertebral compression fracture. Despite promising results for pain relief compared with standard  care,  benefits  have  not  been  seen  when  compared  with  a  sham procedure. 19 

CHAPTER  251  OSTEOPOROSIS1586

because secondary hyperparathyroidism is a frequent accompaniment of steroid-induced osteoporosis.

FUTURE DIRECTIONSDenosumab, a synthetic RANKL antibody that works like OPG, prevents bone loss in women with severe disease and, in large randomized placebo-controlled trials, reduced hip, spine, and nonspine fractures when adminis-tered as a single subcutaneous injection (60 mg) once every 6 months. This drug is not associated with osteonecrosis of the jaw, but lower extremity cellulitis occurs three times more often with this therapy than with placebo. Currently, denosumab is not approved by the FDA. PTH-related protein (PTHrp), a peptide that is structurally similar to PTH, binds to the same receptor, is responsible for some cases of hypercalcemia of malignancy, and has significant anabolic properties when administered intermittently. It is not approved yet by the FDA for the treatment of osteoporosis.

OSTEOPOROSIS IN MENEPIDEMIOLOGY

Osteoporosis in men is now more frequently recognized. This may stem from greater awareness in respect to the clinical presentation, the role of bone density screening, and a better understanding of the pathogenesis of osteo-porosis, particularly in older men. Thirty percent of all hip and vertebral fractures occur in men, and one in six men in later life will suffer a hip fracture.

CLINICAL MANIFESTATIONSThe clinical presentation is often different from that in women, especially in relation to the time to diagnosis after symptoms begin. Back pain with verte-bral compression is the most common presenting complaint. Bone density measurements are less frequently obtained in men, but they are performed after symptoms occur, a far different situation than in postmenopausal women.

PATHOPHYSIOLOGYSecondary causes of osteoporosis dominate this disease in men. Hypogonad-ism and hypercortisolemia are the major etiologic factors in male osteoporo-sis and must be considered regardless of the phenotypic presentation. However, certain other conditions, including gluten enteropathy, gastric resection or bypass, and ethanol abuse, are more common in men than women with osteoporosis. Hypercalciuria (with or without kidney stones) that is associated with secondary hyperparathyroidism occurs in men and is a frequent cause of low bone mass in young men. In contrast, anorexia in male patients is extremely rare, and the athlete’s triad so characteristic of women runners (i.e., exercise, hypogonadism, and low bone mass) is infrequent, although not unheard of, in men.

Lack of androgens results in a skeletal deficit. Peak bone mass is clearly reduced in androgen-insufficient young male patients whether the condition results from idiopathic hypogonadotropic hypogonadism, Klinefelter’s syn-drome, or constitutional delayed puberty. The use of long-acting gonadotro-pin-releasing hormone analogues that block androgen production and are administered in the treatment of prostate cancer is also associated with sig-nificant bone loss and fractures in later life. Men with primary gonadal failure, hemochromatosis, hyperprolactinemic hypogonadism, and other disorders of the hypothalamus or pituitary often have very low bone mass. Androgens act by directly stimulating bone formation because osteoblasts have androgen receptors. However, testosterone probably also blocks bone resorption and can dampen the release of TNF, IL-6, and IL-1. Not surprisingly, estrogen also plays an important role in the male skeleton. Inhibition of aromatization of testosterone (i.e., aromatase P-450) to estrogen, whether caused by a genetic mutation or drugs, leads to significant bone loss. Investigators have also shown that men with low estradiol levels are at greater risk for osteopo-rosis. Thus, it appears that both estrogen and androgen are necessary for the development and maintenance of the male skeleton.

1. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.

2. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly woman. N Engl J Med. 1992;327:1637-1642.

3. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementa-tion on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469.

4. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337:670-676.

5. Grant AM, Avenell A, Campbell MK, et al, for the RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evalua-tion of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365:1621-1628.

6. Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1996;276:1389-1396.

7. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

8. Cummings S, Eckert S, Krueger K, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281:2189-2197.

9. Ettinger B, Black D, Mitlak B, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA. 1999;282:637-645.

10. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women: Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340.

11. Black D, Cummings S, Karpf D, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet. 1996;348:1535-1541.

12. Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermit-tently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.

13. Felsenberg D, Miller P, Armbrecht G, et al. Oral ibandronate significantly reduces the risk of verte-bral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis. Bone. 2005;37:651-654.

14. Eastell R, Black DM, Boonen S, et al, for the HORIZON Pivotal Fracture Trial. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab. 2009;94:3215-3225.

15. Chesnut CH 3rd, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109:267-276.

16. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.

17. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.

18. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326-339.

19. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.

20. de Nijs RNJ, Jacobs JWG, Lems WF, et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med. 2006;355:675-684.

21. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteopo-rosis. N Engl J Med. 2007;357:2028-2039.

22. Orwoll ES, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000;343:604-610.

SUGGESTED READINGS

Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362:686-696. In a randomized trial of postmenopausal women with osteoporosis, lasofoxifene (0.5 mg per day) decreased the risk of fractures, breast cancer, strokes, and coronary heart disease but increased the risk of venous thromboembolic events.

Donaldson MG, Cawthon PM, Lui LY, et al. Estimates of the proportion of older white men who would be recommended for the pharmacologic treatment by the new U.S. National Osteoporosis Founda-tion guidelines. J Bone Miner Res. 2010;25:1506-1511. Estimates that about 35% of U.S. white men aged 65 years and older and 50% of those aged 75 years and older would be recommended for drug treatment.

Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med. 2010;363:2027-2035. Review.Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommenda-

tions for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62:1515-1526. Consensus guidelines.

Therapies for osteoporosis in male patients center on identifying any under-lying cause and then treating with drugs that are also used in women. Hypo-gonadism  can  be  effectively  treated  with  androgen  replacement,  although caution must be used in elderly men because of the risk for prostate cancer. Hypercalciuria can be diminished by use of hydrochlorothiazide, which may 

TREATMENT

also enhance bone density in men. Alendronate has been shown to prevent bone  loss  and  to  reduce  fractures  in  men  with  idiopathic  osteoporosis  or osteoporosis  resulting  from  androgen  deficiency  states. 22   PTH1-34  has  also been  approved  for  the  treatment  of  male  osteoporosis  because  it  too  can enhance  bone  density  and  prevent  fractures.  In  a  large  randomized  trial  of men  with  limited  prostate  cancer  taking  gonadotropin-releasing  agonists, denosumab reduced fractures and prevented bone loss. This agent, if approved by the FDA, may be the most appropriate therapy for a growing cohort of men receiving aggressive anticancer therapy. Selective androgen receptor modula-tors  are  under  development  and  may  offer  a  new  approach  to  male osteoporosis.

Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010;182:1864-1873. Consensus guidelines.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377:1276-1287. Review.

Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815-1822. In a randomized controlled trial, high-dose vitamin D surprisingly increased the risk of falls and fractures.

U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011;154:356-364. Clinical guidelines recommend screen-ing in women but not clearly in men.

Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16:1-37. Consensus guidelines.