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423 Osteoporosis

supplementation is sometimes needed for weeks to a month or two until bone defects are filled (which, of course, is of therapeutic benefit in the skeleton), making it possible to discontinue parenteral calcium and/or reduce the amount. Differential Diagnosis  Care must be taken to ensure that true hypocalcemia is present; in addition, acute transient hypocalcemia can be a manifestation of a variety of severe, acute illnesses, as discussed above. Chronic hypocalcemia, however, can usually be ascribed to a few disorders associated with absent or ineffective PTH. Important clinical criteria include the duration of the illness, signs or symptoms of asso­ ciated disorders, and the presence of features that suggest a hereditary abnormality. A nutritional history can be helpful in recognizing a low intake of vitamin D and calcium in the elderly, and a history of exces­ sive alcohol intake may suggest magnesium deficiency. Differential Diagnosis  Inherited hypoparathyroidism and PHP are lifelong illnesses, usually (but not always) appearing by adolescence; hence, a recent onset of hypocalcemia in an adult is more likely due to nutritional deficiencies, CKD, or intestinal disorders that result in defi­ cient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathy­ roidism. A history of seizure disorder raises the issue of anticonvulsive medication. Developmental defects may point to the diagnosis of PHP1A. Rickets and a variety of neuromuscular syndromes and defor­ mities may indicate ineffective vitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency. A pattern of low calcium with high phosphorus in the absence of renal failure or massive tissue destruction almost invariably means hypoparathyroidism or PHP. A low calcium and low phosphorus pat­ tern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clear­ ance). The relative ineffectiveness of PTH in calcium homeostasis in

vitamin D deficiency, anticonvulsant therapy, gastrointestinal disor­ ders, and hereditary defects in vitamin D metabolism leads to second­ ary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia. Acknowledgment The authors are grateful to John T. Potts, Jr., for his contributions to this chapter over many previous editions of Harrison’s. ■ ■FURTHER READING Bastepe M, Jüppner H: Pseudohypoparathyroidism, Albright’s heredi­ tary osteodystrophy, and progressive osseous heteroplasia: Disorders caused by inactivating GNAS mutations, in Endocrinology, 8th ed, in Endocrinology, JL Jameson, LJ DeGroot (eds). Philadelphia, W.B. Saunders Company, 2023; pp 974–991. Bilezikian JP et al: Evaluation and management of primary hyper­ parathyroidism: Summary statement and guidelines from the Fifth International Workshop. J Bone Miner Res 37:2293, 2022. Thakker RV et al: Regulation of calcium homeostasis and Genetic disorders that affect calcium metabolism, in DeGroot’s Endocrinology, 8th ed, RP Robertson (eds). Philadelphia, Elsevier 2023. Peter R. Ebeling

Osteoporosis Osteoporosis, a condition characterized by decreased bone strength and fragility fractures, is most common among postmenopausal women, but 30% of fragility fractures occur in men. Other underlying diseases can result in secondary osteoporosis. The clinical manifestations of

osteoporosis are primarily vertebral, nonvertebral, and hip fractures. Osteoporosis affects >10 million individuals in the United States, but only a minority are currently diagnosed and treated.

DEFINITION Osteoporosis is defined as a reduction in the strength of bone that leads to skeletal fragility and fractures. Despite bone mineral density being used to define osteoporosis, other important factors such as micro­ architectural deterioration and misalignment of bone components also contribute. Thus, relying solely on the measure of bone mineral density may underestimate bone fragility. The World Health Organiza­ tion (WHO) operationally defined osteoporosis as a bone density that falls 2.5 standard deviations (SDs) or more below the mean for young healthy adults (age 30 years) of the same sex and race—also referred to as a T-score of –2.5. Postmenopausal women in the lower end of the young normal range (a T-score <–1.0 to –2.5) are defined as having low bone density or osteopenia, a risk factor for developing osteoporosis. Despite a lower fracture risk in this group, >50% of fractures among postmenopausal women, including hip fractures, occur in individu­ als with osteopenia because the size of that population is much larger than the group defined as having osteoporosis by bone density T-score. This has led to a greater emphasis on absolute fracture risk, incorpo­ rating age, sex, and other major clinical risk factors with or without bone mineral density (BMD) to calculate the 10-year risk of hip or major osteoporotic fractures. The calculation of absolute fracture risk with tools such as FRAX® or the Garvan Fracture Risk Calculator has allowed the development of intervention thresholds for osteoporosis treatment that may be country specific and may differ from diagnostic thresholds (e.g., T-score <–2.5). Osteoporosis CHAPTER 423 Fragility fractures are defined as fractures in adults occurring fol­ lowing a fall from standing height or less, but exclude finger, toes, face, and skull fractures. However, recent studies also indicate traumatic fractures should also be regarded as indicative of underlying skeletal fragility and require further evaluation. EPIDEMIOLOGY In the United States, as many as 10.8 million women and 2.5 million men have osteoporosis (BMD T-score <–2.5 at lumbar spine, total hip, or femoral neck). This does not include additional people who pres­ ent with an osteoporosis-related fracture but with osteopenia (T-score <–1.0 to –2.5). It is estimated that 2 million osteoporosis-related fractures occur each year in the United States at a cost of $19 billion, a problem that will increase as the population ages. Globally, hip fractures are increasing and are associated with high costs. The fail­ ure to identify the first fragility fracture and intervene is estimated to cost $6 billion to Medicare alone for secondary fractures. Another 40 million Americans have osteopenia that potentially puts them at increased of fracture and of developing osteoporosis. Although osteo­ porosis is mostly age-related, some individuals appear more at risk. In women, the rapid loss of ovarian function during the perimenopause (on average around age 50 years) precipitates rapid bone loss over the next 5–7 years such that most women will have osteoporosis by age 70–80 years. As the population is aging, the number of individuals with osteoporosis and fractures is rising. As many fragility fractures due to osteoporosis occur in individuals with osteopenia, identification of those individuals with a high absolute fracture risk and their evaluation and treatment are important. Most fractures, especially those of the hip and vertebrae, show exponential increases with advancing age (Fig. 423-1). Lifetime osteo­ porotic fracture risk for a Caucasian woman who reaches the age of

50 years is ~50%, while the corresponding risk for a 50-year-old man is ~25%. Recent data suggest that fractures, including hip fractures, are increasing despite age-related fracture rates decreasing. This may be related to the aging of the population globally or to failure to evaluate and treat patients with a high absolute fracture risk. About 300,000 hip fractures occur each year in the United States, almost all requiring hospital admission and surgical intervention. The lifetime probability that a 50-year-old white individual will have a hip fracture is 14% for women and 5% for men; the risk for African

Women

Hip Incidence/100,000 person-year Vertebrae

PART 12 Endocrinology and Metabolism

Colles’ 35–39 Age group, year FIGURE 423-1  Epidemiology of vertebral, hip, and Colles’ fractures with age. (Reproduced with permission from C Cooper, LJ Melton 3rd: Epidemiology of osteoporosis. Trends Endocrinol Metab 3:224, 1992.) Americans is about half of those rates, and the risk for Asians and non­ black Hispanics appears to be like that for Caucasians. Hip fractures are associated with a high incidence of mortality and morbidity, with 20–25% of patients dying in the year following the injury, with higher mortality rates among males and African Americans. Hip fracture rates and mortality also demonstrate high global variability. About 30% of survivors require long-term care (at least temporarily), and many never regain the independence that they had prior to the fracture. This sequela is the one most feared by patients. There are ~500,000 symptomatic vertebral fractures per year in the United States, but >1,000,000 vertebral fractures may occur annually since only one-third are recognized clinically. The vast majority are clinically “silent” vertebral fractures identified incidentally during spinal radiography (Fig. 423-2) or may be suggested by significant height loss (>4 cm). However, even asymptomatic vertebral fractures are a major sign of skeletal fragility and increase the risk for subse­ quent fracture. Vertebral fractures, like other fragility fractures, are also associated with long-term morbidity and an increase in mortality. The occurrence of the first fracture greatly increases the risk of further fractures, especially in the first year. The consequence is height loss, FIGURE 423-2  Lateral spine x-ray showing severe osteopenia and a severe wedgetype deformity (severe anterior compression).

Other risk factors Menopause Aging Increased bone loss Low peak bone mass Low bone density Propensity to fall Poor bone quality Fractures FIGURE 423-3  Factors leading to osteoporotic fractures. kyphosis, and secondary pain and discomfort related to altered spinal biomechanics. Thoracic fractures can be associated with restrictive lung disease, whereas lumbar fractures are associated with abdominal symptoms including distention, early satiety, and constipation. ≥85 Approximately 400,000 wrist fractures occur in the United States each year. Fractures of other bones (including ~150,000 pelvic frac­ tures and >100,000 proximal humerus fractures) also occur due to osteoporosis. The threshold for fracture is reduced in osteoporotic bone (Fig. 423-3) due to increased skeletal fragility. Traumatic frac­ tures are also increased in patients at risk of osteoporosis. Fewer than 20% of patients with a fracture are currently either investigated for osteoporosis or started on treatment within 6 months. A number of clinical risk factors for fracture exist; the common ones are sum­ marized in Table 423-1. Prior fragility fractures, a family history of hip fracture, low body mass index, cigarette smoking, and exces­ sive alcohol consumption are all independent predictors. Chronic inflammatory diseases, such as rheumatoid arthritis, increase the risk of osteoporosis, as do diseases associated with malabsorption (e.g., celiac disease) and male hypogonadism. Chronic diseases that increase the risk of falling or frailty, including dementia, Parkinson’s disease, and multiple sclerosis, also increase fracture risk (Table 423-1). Many other risk factors for osteoporosis have been described including glucocorticoids, aromatase inhibitors, androgen deprivation therapy, air pollution, triclosan, bariatric surgery, diabetes mellitus, cerebrovascular accidents, dementia (including Alzheimer’s), the death of a spouse, depression and its treatment with selective serotonin reup­ take inhibitors (SSRIs), and proton pump inhibitors, to name a few. Increasing frailty with age is a potent risk factor for fracture, as is sensory inattention (e.g., walking while looking at mobile phone). Globally, fragility fractures are more common among women than men, presumably due to a lower peak bone mass as well as rapid post­ menopausal bone loss in women. However, this sex difference in bone density and hip fracture incidence is not apparent in all countries, pos­ sibly due to genetics, physical activity levels, or diet. Fragility fractures increase the risk for future fractures (Table 423-1). Vertebral fractures increase the risk of other vertebral fractures as well TABLE 423-1  Risk Factors for Osteoporosis Fracture NONMODIFIABLE POTENTIALLY MODIFIABLE Personal history of fracture as an adult History of fracture in first-degree relative Female gender Advanced age White race Dementia Current cigarette smoking Estrogen deficiency   Early menopause (<45 years) or bilateral ovariectomy   Prolonged premenstrual amenorrhea (>1 year) Poor nutrition especially low calcium and vitamin D intake Alcoholism Impaired eyesight despite adequate correction Recurrent falls Inadequate physical activity Poor health/frailty

as fractures of the peripheral skeleton such as the hip and wrist. Wrist fractures also increase the risk of vertebral and hip fractures. Among individuals aged >50 years, any fracture (except those of the fingers, toes, face, and skull) should be considered as fragility fractures. Any fracture in a woman aged >50 years or a man aged >60 years should trigger investigations for osteoporosis. However, this does not occur in the majority as postfracture care is fragmented. Recent attempts to coordinate care using fracture liaison services to guide patients with fragility fractures through health care systems and ensure their investigation and initiate treatment for osteoporosis have been shown to improve outcomes but may be difficult to implement in countries without single-payor systems or closed health care systems. The risk for future fracture after a first fracture is exponentially increased in the first 12–24 months, leading to the concept of immi­ nent fracture risk. A recent large Medicare database study indicated that almost 20% of women will have a second fracture within 2 years after the first. Risk diminishes to less than half of that rate in the sub­ sequent 3 years but remains persistently elevated after a vertebral or hip fracture. PATHOPHYSIOLOGY ■ ■BONE REMODELING A low peak bone mass may underlie the development of osteoporo­ sis due to hormonal, genetic, or nutritional influences. Age-related changes in bone remodeling as well as extrinsic and intrinsic factors may then be superimposed. Consequently, an appreciation of bone remodeling is fundamental to developing an understanding of both the pathophysiology of bone loss (Chap. 421) and mechanisms of phar­ macologic intervention. During growth, the skeleton increases in size by linear growth and by apposition of new bone tissue on the cortical periosteum (Fig. 423-4). The latter process is called modeling, a process that also allows the long bones to adapt in shape to the stresses placed on them. Increased sex hormone production at puberty is required for skeletal maturation, with peak bone mass being achieved by early adulthood. Recent data suggest delayed puberty may be associated with low bone peak mass that persists into adulthood in both sexes. Sexual dimorphism in skeletal size occurs after puberty with larger bones in males, although true bone mineral density remains similar in both sexes. Nutrition and exercise also play an important role in growth, although genetic factors primarily determine peak bone mass. Numerous genes control skeletal growth, peak bone mass, and body size, as well as skeletal structure and density. Heritability estimates of 50–80% for bone mineral density and size have been derived from twin studies. Though peak bone mass is often lower among individuals with a family history of osteoporosis, association studies of candidate genes (vitamin D receptors; type I collagen, estrogen receptors [ERs], and interleukin 6 [IL-6]; and insulin-like growth factor I [IGF-I]) and bone mass, bone turnover, and fracture prevalence have been inconsistent. There is no panel of genetic markers that can be used to diagnose osteo­ porosis. Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass. Families with high bone mass and lacking age-related bone loss have been shown to have an activating mutation in LRP5, low-density lipoprotein receptor–related protein 5. Conversely, an inactivating mutation results in osteoporosis-pseudogli­ oma syndrome, and LRP5 signaling is important in controlling bone for­ mation. Genome-wide scans for low bone mass suggest multiple genes are involved, many of which are also implicated in control of body size. In adults, bone remodeling, not modeling, is the principal metabolic skeletal process. Bone remodeling has two critical functions: (1) to repair bone microdamage to maintain skeletal strength and (2) to supply calcium from the skeleton when required to maintain serum calcium. Remodeling may be activated by bone microdamage due to excessive or accumulated mechanical stress. Acute demands for calcium involve osteoclast-mediated resorption as well as calcium transport by osteocytes. Chronic demands for calcium can result in secondary hyperparathyroidism, increased bone remodeling, and bone loss. Bone remodeling occurs through the well-coordinated activity of osteocytes, osteoblasts, and osteoclasts. Osteocytes are the terminal-differentiated

Preosteoclast BMU A Preosteoblast Osteoporosis CHAPTER 423 Osteoclast B Osteoblasts Osteoid C D E F FIGURE 423-4  Mechanism of bone remodeling. The basic molecular unit (BMU) moves along the trabecular surface at a rate of ~10 μm/d. The figure depicts remodeling over ~120 days. A. Origination of BMU-lining cells contracts to expose collagen and attract preosteoclasts. B. Osteoclasts fuse into multinucleated cells that resorb a cavity. Mononuclear cells continue resorption, and preosteoblasts are stimulated to proliferate. C. Osteoblasts align at bottom of cavity and start forming osteoid (black). D. Osteoblasts continue formation and mineralization. Previous osteoid starts to mineralize (horizontal lines). E. Osteoblasts begin to flatten.

F. Osteoblasts turn into lining cells; bone remodeling at initial surface (left of drawing) is now complete, but BMU is still advancing (to the right). (Reproduced with permission from SM Ott, in JP Bilezikian, LG Raisz, GA Rodan: Principles of Bone Biology, vol. 18. San Diego, CA: Academic Press; 1996.) cells derived from osteoblasts after incorporation into newly formed bone tissue. Osteoblasts derive from mesenchymal cell lineage and osteoclasts from monocyte/macrophage lineage. Remodeling sites are discrete units with osteoclasts initiating the process by removal of dam­ aged bone tissue and osteoblasts synthesizing new organic bone that becomes gradually mineralized. Bone remodeling is regulated by multiple hormones, including estrogens (in both sexes), androgens, vitamin D, and parathyroid hor­ mone (PTH), as well as locally produced bone-derived growth factors, such as IGF-I, transforming growth factor β (TGF-β), PTH-related peptide (PTHrP), interleukins (ILs), prostaglandins, and members of the tumor necrosis factor (TNF) superfamily. These factors primar­ ily modulate the rate at which new remodeling sites are activated, a process that results initially in bone resorption by osteoclasts, followed by a period of repair during which new bone tissue is synthesized by osteoblasts (Chap. 421). The cytokine responsible for communication

CFU-GM OPG Activated T lymphocytes Activated synovial fibroblasts RANKL RANK M-CSF Preosteoclast Activated dendritic cells PART 12 Endocrinology and Metabolism T Multinucleated osteoclast Bone Osteoblasts or bone marrow stromal cells Activated osteoclast Proresorptive and calciotropic factors 1,25(OH)2 vitamin D3. PTH, PTHrP, PGE2, IL-1, IL-6, TNF, prolactin, corticosteroids, oncostatin M, LIF A FIGURE 423-5  Hormonal control of bone resorption. A. Proresorptive and calciotropic factors. B. Anabolic and antiosteoclastic factors. RANKL expression is induced in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation, activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. CFU-GM, colony-forming units, granulocyte macrophage; IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; OPG-L, osteoprotegerin ligand; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor-κB; TGF-β, transforming growth factor β; TNF, tumor necrosis factor; TPO, thrombospondin. (Reproduced with permission from WJ Boyle et al: Osteoclast differentiation and activation. Nature 423:337, 2003.) between the osteoblasts, other marrow cells, and osteoclasts is recep­ tor activator of nuclear factor-κB (RANK) ligand (RANKL). RANKL, a member of the TNF family, is secreted by osteocytes, osteoblasts, and certain immune cells. The osteoclast receptor for this protein is referred to as RANK. Activation of RANK by RANKL is a final common path in osteoclast development and activation. A humoral decoy for RANKL, also secreted by osteoblasts, is referred to as osteoprotegerin (Fig. 423-5). Modulation of osteoclast recruitment and activity appears to be related to the interplay among these three factors (RANKL, RANK, and osteoprotegerin). Additional influences include nutrition (particularly calcium intake) and physical activity level. RANKL production is in part regulated by the canonical Wnt signaling pathway. Wnt activation through mechanical loading or by hormonal or cytokine factors stimulates bone formation by increasing formation and activity of osteoblasts and decreases RANKL secretion, which inhibits osteoclast formation and activity. Sclerostin, also an osteocyte protein, is a major inhibitor of Wnt activation and bone formation. Its secretion is inhibited by weight-bearing physical activity and PTH. Both the RANKL and Wnt pathways have become major targets for osteoporosis treatment (see below). In young adults, bone remodeling is balanced with resorbed bone being replaced by an equal amount of new bone. Thus, the mass of the skeleton remains constant after peak bone mass is achieved. However, after age 30–45 years, bone resorption exceeds formation, resulting in bone loss. This imbalance may begin at different ages, varies at differ­ ent skeletal sites, and becomes exaggerated in women due to estrogen deficiency. Bone loss can be due to an increase in osteoclastic activity and/or a decrease in osteoblastic activity. In addition, an increase in remodeling activation frequency, and thus the number of remodeling sites, can magnify small imbalances seen at the individual remodeling unit. Increased bone remodeling can result in permanent bone loss and disrupted skeletal microarchitecture, with an imbalance between resorption and formation within each cycle. In trabecular bone, if the osteoclasts penetrate trabeculae, rapid bone loss ensues and cancel­ lous connectivity is reduced. A higher number of remodeling sites

M-CSF T Apoptotic osteoclast Anabolic or antiresorptive factors Estrogens, calcitonin, BMP 2/4, TGF-β, TPO, IL-17, PDGF, calcium B increases the likelihood of this event. In cortical bone, increased activation of bone remodeling creates more porous bone. The effect of this increased cortical porosity on cortical bone strength may be modest if the overall diameter of the bone is not changed. However, decreased apposition of new bone on the periosteal surface coupled with increased endocortical resorption of bone decreases the biome­ chanical strength of long bones. Even a slight exaggeration in normal bone loss increases the risk of osteoporosis-related fractures because of microarchitectural changes, and osteoporosis is largely a disease of dis­ ordered skeletal microarchitecture. Currently the predominant clinical tool (dual-energy x-ray absorptiometry [DXA]) measures bone mass rather than bone microarchitecture. Several additional tools are avail­ able to estimate bone microarchitecture (including the trabecular bone score [TBS], a noninvasive addition to spinal DXA measurements, and high-resolution peripheral quantitative computerized tomography [HR-pQCT], which has limited availability). ■ ■CALCIUM NUTRITION Peak bone mass may be impaired by inadequate dietary calcium intake during growth among other nutritional factors (calories, protein, and other minerals), leading to increased risk of osteoporosis later in life. During the adult phase of life, insufficient calcium intake contributes to secondary hyperparathyroidism and an increase in bone remodel­ ing rate. PTH stimulates the 1-alpha hydroxylation of vitamin D in the kidney, leading to increased levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] and enhanced gastrointestinal calcium absorption. PTH also reduces renal calcium loss. Although these are appropriate com­ pensatory homeostatic responses for improving calcium economy, the long-term effects are detrimental to the skeleton because the increased remodeling rates and the ongoing imbalance between resorption and formation at remodeling sites combine to accelerate bone loss. Total daily calcium intakes <400 mg are detrimental to the skeleton, and intakes in the range of 600–800 mg, which is about the average intake among adults in the United States, are also probably suboptimal. The recommended daily required intake of 1000–1200 mg for adults

accommodates population heterogeneity in controlling calcium bal­ ance. Such intakes should preferentially come from dietary sources, with supplements used only when dietary intakes fall short and cannot be modified easily. The supplement should be enough to bring total intake to ~1200 mg/d. Recent studies have suggested that there may be differences in safety based on calcium source so that increasing dietary calcium is preferred; higher intakes from supplement sources appear to result in a greater risk of renal stones and perhaps cardiovascular events (although the literature is inconsistent and controversial); how­ ever, supplement doses below about 700 mg/d have not been associated with cardiovascular events. Increasing calcium intake above this level does not have any benefit. Increasing calcium intake by itself will not prevent bone loss due to other factors (e.g., postmenopausal status) ■ ■VITAMIN D (See also Chap. 421) Severe vitamin D deficiency causes rickets in children and osteomalacia in adults. However, vitamin D insufficiency (circulating levels of 25-hydroxyvitamin D [25(OH)D] that may be inadequate [<75 nmol/L or 30 ng/mL] but above the level that results in rickets) may be more prevalent than previously thought, particularly among individuals at increased risk such as the elderly; those living in northern or southern latitudes; and individuals with poor nutrition, obesity, malabsorption, or chronic liver or renal disease. Dark-skinned individuals are also at high risk of vitamin D in the insufficiency range or lower, but African Americans have a low risk of osteoporosis, with better calcium homeostasis than Caucasians. Although there is considerable controversy about overall optimal health targets for serum 25(OH)D, there is evidence that for optimal skeletal health, serum 25(OH)D should be >75 nmol/L (30 ng/mL). To achieve this level for most adults requires limited skin exposure to sunlight (estimated to be exposure of face and arms for at least one-half hour each day) or an intake of at least 800–1000 units/d, or even higher in individuals with risk factors (as above), particularly obesity. Vitamin D insufficiency leads to compensatory secondary hyper­ parathyroidism and is an important risk factor for osteoporosis and fractures. Some studies have shown that >50% of inpatients on a general medical service exhibit biochemical features of vitamin D defi­ ciency, including increased levels of PTH and alkaline phosphatase and lower levels of ionized calcium. Among those living in northern and southern latitudes, vitamin D levels decline during the winter months without supplementation due to insufficient ultraviolet B radiation. This is associated with seasonal bone loss, reflecting increased bone turnover. Even among healthy ambulatory individuals, mild vitamin D deficiency is increasing in prevalence. In part, this is due to decreased exposure to sunlight. Treatment with vitamin D can return levels to normal (>75 nmol/L [30 ng/mL]) and prevent the associated increase in bone remodeling, bone loss, and fractures. Reduced falls and frac­ ture rates also have been documented among individuals in northern latitudes who have greater vitamin D intake and have higher 25(OH)D levels (though one study suggested an increased fall risk with 25[OH] D levels >70 ng/mL or >175 nmol/L). Although vitamin D levels are suspected to affect risk and/or severity of other diseases, including can­ cers (colorectal, prostate, and breast), autoimmune diseases, multiple sclerosis, and cardiovascular disease, most controlled clinical trials have not confirmed these effects. However, vitamin D does prevent progression of prediabetes to diabetes in those with vitamin D defi­ ciency (25[OH]D levels <12 ng/mL or <30 nmol/L). Treating vitamin D–sufficient individuals with vitamin D does not reduce fractures. For most adults, supplements of 1000–2000 IU/d are adequate and safe. ■ ■ESTROGEN STATUS Estrogen deficiency causes bone loss by two distinct but interrelated mechanisms: (1) activation of new bone remodeling sites and (2) ini­ tiation or exacerbation of an imbalance between bone formation and resorption, in favor of the latter. The change in activation frequency causes a transient bone loss until a new steady state between resorp­ tion and formation is achieved. This commences in the perimenopause prior to cessation of periods. This remodeling imbalance results in a permanent decrement in mass. In addition, the increase in remodeling

sites in the skeleton alone increases the probability of trabecular per­ foration, eliminating the template on which new bone can be formed and accelerating bone loss. The consequence is degraded skeletal microarchitecture, particularly affecting trabecular bone, so that at any given bone density, the risk of a fracture is greater in those who have experienced rapid bone loss than in those who have not. The addition of the TBS to spinal DXA measurements is an attempt to indirectly capture these microarchitectural changes, while HR-pQCT scans mea­ sure these directly.

The most common cause of estrogen deficiency is the menopause, which occurs on average at age 51 years (Chap. 407). Thus, with cur­ rent life expectancy, an average woman will spend ~35 years without an ovarian estrogen supply. Breast cancer treatment with either bilateral ovariectomies and/or aromatase inhibitors is an increasingly common cause of even more severe estrogen deficiency. The mechanism by which estrogen deficiency causes bone loss is summarized in Fig. 423-5. Bone marrow cells (macrophages, monocytes, osteoclast precursors, mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express both ERs (α and β). Loss of estrogen increases RANKL production but also reduces osteoprotegerin production, increasing osteoclast forma­ tion and recruitment. Estrogen also may play a role in determining the life span of bone cells by controlling their rate of apoptosis. Thus, in situations of estrogen deprivation, the life span of osteoblasts may be decreased, whereas the longevity and activity of osteoclasts are increased. The rate and duration of bone loss after menopause are het­ erogeneous and unpredictable. Once surfaces are lost from trabecular bone, the rate of bone loss declines. In cortical bone, loss is slower but may continue for longer. Osteoporosis CHAPTER 423 Since remodeling is initiated at the surface of bone, it follows that trabecular bone—which has a considerably larger surface area (80% of the total) than cortical bone—will be affected preferentially by estro­ gen deficiency. Fractures occur earliest at sites where trabecular bone contributes most to bone strength; consequently, vertebral fractures are the most common early skeletal consequence of estrogen deficiency. In males, estrogen may have an important role in regulation of bone remodeling. In an experiment in which males were rendered estrogen and androgen deficient, restoring estrogen supply reduced remodeling rate more than restoring androgen. ■ ■PHYSICAL ACTIVITY Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss. Concordantly, athletes have higher bone mass than non­ athletes. These increases in skeletal mass are most marked when the stimulus begins during growth in the years before puberty at the time of skeletal modeling and can result in a higher peak bone mass in both sexes. Adults are less able to increase bone mass after restoration of physical activity. Epidemiologic data support the beneficial effects on the skeleton of chronic high levels of physical activity. Fracture risk is lower in rural communities and in countries where physical activity is maintained into old age. However, when exercise is initiated during adult life, the effects of progressive resistance training on the skeleton are modest, with increases in spine and hip bone mass of 2–4% in short-term randomized trials of <2 years’ duration. Muscle strength is also increased, while balance and functional exercises combined also reduce falls by about 25%. A Cochrane review showed balance and functional exercises reduced the number of people who experienced one or more fall-related fractures. Continuing physical activity into the later years may also slow cognitive decline, another major reason for including exercise programs for the aging population. ■ ■CHRONIC DISEASES Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis (Table 423-2). Mechanisms that contribute to bone loss are unique for each disease and typically result from mul­ tiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodeling or bone quality. In most, but not all circumstances, the primary diagnosis is made before osteo­ porosis presents clinically. Both type 1 and type 2 diabetes mellitus are associated with an increased fracture risk, with increased risk at higher

TABLE 423-2  Diseases Associated with an Increased Risk of Generalized Osteoporosis in Adults Hypogonadal states Turner’s syndrome Klinefelter’s syndrome Anorexia nervosa Hypothalamic amenorrhea Hyperprolactinemia Other primary or secondary hypogonadal states Endocrine disorders Cushing’s syndrome Hyperparathyroidism Thyrotoxicosis Diabetes mellitus (both type 1 and 2) Acromegaly Adrenal insufficiency Nutritional and gastrointestinal disorders Malnutrition Parenteral nutrition Malabsorption syndromes Gastrectomy Severe liver disease, especially biliary cirrhosis Pernicious anemia Rheumatologic disorders Rheumatoid arthritis Ankylosing spondylitis Hematologic disorders/malignancy Multiple myeloma Lymphoma and leukemia Malignancy-associated parathyroid hormone–related peptide (PTHrP) production Mastocytosis Hemophilia Thalassemia Selected inherited disorders Osteogenesis imperfecta Marfan’s syndrome Hemochromatosis Hypophosphatasia Glycogen storage diseases Homocystinuria Ehlers-Danlos syndrome Porphyria Menkes’ syndrome Epidermolysis bullosa Other disorders Immobilization Chronic obstructive pulmonary disease Pregnancy and lactation Scoliosis Multiple sclerosis Sarcoidosis Amyloidosis PART 12 Endocrinology and Metabolism bone density than in the nondiabetic population. This is due to differ­ ences in collagen cross-linking in bone tissue due to accumulation of advanced glycation end products, making it more brittle than normal, a predilection for conversion of precursors to adipose cells rather than osteoblasts, and the sequelae of diabetes that increase the risk of falls and injury. Severe bone loss occurs in quadriplegic and paraplegic individuals below the level of the injury. The combination of loss of muscle func­ tion and innervation of both muscle and bone contributes to failure to recover mobility, which leads to a high fracture risk in those attempting to pursue athletic activities despite their primary diagnosis (e.g., wheel­ chair athletes). Bone loss also follows a stroke and is again dependent on the severity of the paralysis. The risk of fracture can be predicted by the FRAX (Fracture Risk Assessment) score and seems highest in the first year after stroke. The increasing prevalence of transgender and gender nonconforming individuals has prompted a guideline for evalu­ ation of bone density in that population by the International Society of Clinical Densitometry published in 2019. ■ ■MEDICATIONS Many medications used in clinical practice have potentially detrimen­ tal effects on the skeleton (Table 423-3). Glucocorticoids are the most TABLE 423-3  Drugs Associated with an Increased Risk of Generalized Osteoporosis in Adults Glucocorticoids Excessive thyroxine Cyclosporine Aluminum Cytotoxic drugs Gonadotropin-releasing hormone agonists Anticonvulsants Heparin Aromatase inhibitors Selective serotonin reuptake inhibitors Lithium Protein pump inhibitors Thiazolidinediones Androgen deprivation therapies

common cause of medication-induced osteoporosis. It is often not possible to determine the extent to which osteoporosis is related to glucocorticoid treatment or to other factors, as the effects of medica­ tion are superimposed on the effects of the primary disease, which may be associated with bone loss (e.g., rheumatoid arthritis). Excessive doses of thyroid hormone can accelerate bone remodeling and result in bone loss. Other medications have less detrimental effects on the skeleton than pharmacologic doses of glucocorticoids. Anticonvulsants are thought to increase the risk of osteoporosis, although many affected individuals have concomitant insufficiency of 1,25(OH)2D, as some anticonvul­ sants induce the cytochrome P450 system and vitamin D metabolism. Patients undergoing transplantation are at high risk for rapid bone loss and fracture not only from glucocorticoids but also from treatment with other immunosuppressants such as cyclosporine and tacrolimus (FK506). In addition, these patients often have preexisting metabolic abnormalities such as hepatic or renal failure predisposing to bone loss. Long-term use of proton pump inhibitors and selective serotonin reuptake inhibitors has been shown to be associated with a higher risk of fracture in observational studies. Given their frequent long-term use, their skeletal effects are important from a public health perspective and for individual fracture risk. Aromatase inhibitors, which potently block the aromatase enzyme that converts androgens and other adrenal precursors to estrogen, reduce circulating postmenopausal estrogen levels severely. These agents, used to treat breast cancer, also cause declines in bone density and rapidly increase fracture risk. Androgen deprivation therapy, used to treat men with prostate cancer, also results in rapid bone loss and increased fracture risk. The diabetes medications, thiazolidinediones and insulin, also increase the risk of fracture; however, metformin and glucagon-like peptide-1 receptor agonists decrease risk. It is difficult in some cases to separate the risk accrued by the underlying disease from that attributable to the medication. For example, both depression and diabetes are risk factors for fracture by themselves. ■ ■SMOKING Smoking produces detrimental effects on bone mass mediated directly by toxic effects on osteoblasts or indirectly by modifying estrogen metabolism. On average, cigarette smokers reach menopause 1–2 years earlier than the general population. Cigarette smoking also results in intercurrent respiratory and other illnesses, frailty, decreased exercise, poor nutrition, and the need for additional medications (e.g., glucocor­ ticoids for lung disease) that can all increase fracture risk. ■ ■OTHER POTENTIAL FACTORS In the past few years, many potential risk factors for fracture have been identified. These include excessive alcohol intake and other drugs of abuse, pollution, use of triclosan, chronic obstructive pulmonary disease, excess vitamin B, and hormonal therapies utilized among the transgender population. DIAGNOSIS ■ ■MEASUREMENT OF BONE MASS Several noninvasive techniques are available for estimating skeletal mass or BMD. They include DXA, quantitative computed tomography (QCT), peripheral QCT, HR-pQCT, and ultrasound. DXA is a highly accurate x-ray technique that has become the standard for measuring bone density. Though it can be used for measurement in any skeletal site, clinical determinations usually are made of the lumbar spine and hip. DXA also can be used to measure the radius, total body bone mass, and body composition (lean mass, fat mass). Two x-ray ener­ gies are used to estimate mineralized tissue, allowing for correction for attenuation through soft tissue. The mineral content is divided by bone area, which partially corrects for body and bone size. However, this correction is only partial since DXA is a two-dimensional scan­ ning technique and cannot estimate the depth of the bone. Thus, small slim people tend to have lower than average BMD, a feature that is important in interpreting BMD measurements. Bone spurs, which are common in osteoarthritis (spinal spondylosis), tend to falsely increase

Z- and T-scores

BMD score

–1 –2 T-Score = –2.5 –3 Z-Score = –1

Age FIGURE 423-6  Relationship between Z-scores and T-scores in a 60-year-old woman. BMD, bone mineral density; SD, standard deviation. bone density, mostly of the spine, which is a particular problem in mea­ suring spine BMD in older individuals. Because DXA measurement devices are provided by different manufacturers, the output varies in absolute terms. Absolute bone density results are related to “normal” values by using T-scores (a T-score of 1 equals 1 SD), which compare individual results to those in a young adult population (age 30 years) matched for race and sex. The mean value is given a score of zero and the range is +2.5 to –2.5 (i.e., 2.5 SDs above or below the mean). Z-scores (also SDs) compare individual results to those of an age- and sex-matched reference population. Thus, a 60-year-old woman with a Z-score of –1 (1 SD below mean for age) has a T-score of –2.5 (2.5 SDs below mean for a young adult population) (Fig. 423-6). A T-score ≤–2.5 in the lumbar spine, femoral neck, or total hip has been defined as osteoporosis, whereas a T-score of –1.0 to –2.5 has been defined as low bone density or osteopenia. Although the outputs from different instruments and, more importantly, different manufacturers correlate well, different machines used over time may show changes in BMD that may be attributed to biological changes or simply the result of differences between machines. This is particularly true with measure­ ments of the femoral neck. Consequently, it is recommended that serial measurements be performed on the same machine and preferably by the same technician. As noted above, since >50% of fractures occur in individuals with osteopenia (e.g., a T-score between –1.0 and –2.5), it is important to consider absolute fracture risk in addition to BMD. The most com­ monly used absolute fracture risk assessment tool is FRAX, which includes age, sex, height, weight, fracture history, hip fracture in a parent, glucocorticoid use, rheumatoid arthritis, and other secondary causes, with or without bone density of the femoral neck. The pro­ gram calculates the estimated risk over a 10-year time frame for major osteoporosis-related fractures (clinical spine, hip, wrist, and proximal humerus) and for hip fracture. Computed tomography (CT) can also be used to measure the spine and hip but is rarely used clinically, in part because the radiation exposure and cost are both much higher than with DXA. HR-pQCT measures cortical and trabecular bone variables in the forearm or tibia and provides information on skeletal microarchitecture noninvasively. Magnetic resonance imaging (MRI) can also be used to obtain some architectural information on the forearm and perhaps the hip but is primarily a research tool. Ultrasound can be used to measure bone mass by calculating the attenuation of the signal as it passes through bone or the speed with which it traverses the bone. Although the ultrasound technique was purported to assess properties of bone other than mass (e.g., quality), this has not been confirmed. Because of its relatively low cost and mobility, ultrasound bone density measurement is amenable for use as a screening tool. All these techniques for measuring BMD have been approved by the U.S. Food and Drug Administration (FDA) based on their capacity to predict fracture risk. The total hip is the preferred site of measure­ ment, since it allows the best prediction of hip fracture risk. When hip measurements are performed by DXA, the spine is usually measured at the same time. In younger individuals such as perimenopausal or early

TABLE 423-4  Indications for Bone Mineral Density Testing • Women aged ≥65 and men aged ≥70; regardless of clinical risk factors • Younger postmenopausal women, women in the menopausal transition, and men aged from 50 to 69 with clinical risk factors for fracture • Adults who have a fracture at or after age 50 • Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids at a daily dose >5 mg prednisone or equivalent for >3 months associated with low bone mass or bone loss +1 SD –1 SD

Osteoporosis CHAPTER 423 postmenopausal women, spine measurements may be more sensitive. When the spine or hip is not measurable due to severe degenerative spine disease or scoliosis, or prior spine or hip surgery, wrist BMD is often measured. ■ ■INDICATIONS FOR BONE MASS MEASUREMENT Several clinical guidelines have been developed for the use of bone den­ sitometry in clinical practice (Table 423-4). The National Osteoporosis Foundation (NOF) guidelines recommend bone mass measurements in postmenopausal women who have one or more risk factors for osteo­ porosis in addition to age, sex, and estrogen deficiency. The guidelines further recommend that bone mass measurement be considered in all women by age 65, a position ratified by the U.S. Preventive Health Services Task Force. In males, the use of bone density determination is not recommended until the age of 70 years in the absence of multiple risk factors or the occurrence of a fragility fracture. The FRAX score incorporates clinical risk factors (age, prior frac­ ture, family history of hip fracture, low body weight, tobacco use, excessive alcohol use, glucocorticoid use, and rheumatoid arthritis) with or without BMD to assess the 10-year fracture probabilities for major osteoporotic (hip, clinical spine, wrist, or humerus) and hip fractures. Fracture risk probability calculators are available as part of the report from all DXA machines and available online (https://www

.sheffield.ac.uk/FRAX/) (Fig. 423-7). In the United States, cost-effective treatment thresholds occur if the 10-year major osteoporotic fracture risk from FRAX is ≥20% and/or the 10-year risk of hip fracture is ≥3%. FRAX is an imperfect tool, as it does not include any assessment of fall risk, and secondary causes are excluded when BMD is entered. It also does not account for glucocorticoid dose or diabetes. Most importantly, it does not increase the absolute fracture risk conferred by a recent fracture versus the lesser risk conferred by a more remote fracture. Moreover, there is no mandate for vertebral fracture diagnosis and no additional fracture probability estimated for patients who have had multiple fragility fractures. Many of these deficiencies are likely to be corrected in the next version of FRAX (FRAX Plus and FRAX 2.0). ■ ■VERTEBRAL IMAGING DXA equipment can also be used to obtain lateral images of the tho­ racic and lumbar spine, a technique called vertebral fracture assess­ ment (VFA). While not as definitive as a radiograph, it is an excellent screening tool for vertebral abnormality in both women and men. It is an important assessment as the majority of vertebral fractures are asymptomatic (70%). Furthermore, VFA can detect vertebral abnor­ malities causing height loss or back pain that may be indicative of an undiagnosed vertebral fracture. Because most vertebral fractures are asymptomatic, the diagnosis of vertebral fracture is rarely made when they first occur. However, ver­ tebral fractures, whether symptomatic or asymptomatic, are associated with the same clinical sequelae, so it is critical they are identified. Ver­ tebral fracture prevalence in the United States based on the National Health and Nutrition Evaluation Studies (NHANES) population appears to be 20% in the 1980s, when the strictest criteria for diagnosis are utilized. It is recommended that women aged 65 years or older and men aged 70 years or older undergo vertebral imaging if there is a T-score is ≤–1.5 at the spine, hip, or femoral neck. Vertebral imaging is also recommended for women by the age of 70 years and men by the age of 80 years if a T-score is <–1.0. For younger individuals, vertebral imaging is recommended for those with a fragility fracture, height loss, or glucocorticoid use. (See Table 423-5.)

PART 12 Endocrinology and Metabolism FIGURE 423-7  FRAX calculation tool. When the answers to the indicated questions are filled in, the calculator can be used to assess the 10-year probability of fracture.

The calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk adjust for various ethnic groups. APPROACH TO THE PATIENT Osteoporosis The development of osteoporosis is a gradual process occurring under a variety of genetic and environmental influences throughout life. Just prior to and at the time of puberty are important times to affect accrual of peak bone mass while the perimenopause and menopause in women are important times to reduce bone loss. Rec­ ognition of these influences allows intervention at several points, although the type of intervention depends on a careful evaluation of each individual patient. TABLE 423-5  Indications for Vertebral Testing Consider vertebral imaging tests for the following individualsa • All women aged ≥70 and all men aged ≥80 if bone mineral density (BMD) T-score at the spine, total hip, or femoral neck is <1.0 • Women aged from 65 to 69 and men aged from 70 to 79 if BMD T-score at the spine, total hip, or femoral neck is <1.5 • Postmenopausal women and men aged ≥50 with specific risk factors: • Low-trauma fracture during adulthood (aged ≥50) • Historical height loss of ≥1.5 in. (4 cm)b • Prospective height loss of ≥0.8 in. (2 cm)c • Recent or ongoing long-term glucocorticoid treatment aIf bone density testing is not available, vertebral imaging may be considered based on age alone. bCurrent height compared to peak height during childhood. cCumulative height loss measured during interval medical assessment.

The menopausal transition affects all women by their late 50s and represents an opportunity to initiate a discussion about bone loss, the role of estrogen loss, and other clinical risk factors. Assessment of fracture risk with FRAX (with or without bone density) provides a 10-year estimate of hip and major osteoporosis-related fracture risk and opens the discussion about preventive steps including, if required, the use of medication. If risk is low, then nutrition and resistance training exercise are the focus. If menopausal symp­ toms are prominent and estrogen intervention is needed, then the added protection against bone loss and fragility fractures should be emphasized. Among older women with a fracture, an evaluation of skeletal status including bone density testing should proceed. In this case, any fracture, whether traumatic or not, should trigger this assess­ ment. Although osteoporosis is associated with a risk of fragility fracture, individuals with osteoporosis are also more likely to experience traumatic fractures, and such individuals should not be excluded from osteoporosis evaluation simply because of the level of trauma. This concept, while obvious and evidence-based, still needs emphasis with individual patients, physicians, and payors. Patients who present with hip or spine fractures by definition have osteoporosis and will require treatment for both the fracture itself and the underlying skeletal disorder. Other long bone frac­ tures (e.g., distal radius) are triggers for evaluation of the skeleton upon which treatment decisions can be based. In all individuals presenting with a fracture as a result of a fall, fall prevention strategies including balance exercises are an impor­ tant adjunct to other lifestyle and nutritional interventions.

ROUTINE LABORATORY EVALUATION There is no established algorithm for the evaluation of women or men who present with osteoporosis. A general evaluation that includes complete blood count, serum and 24-h urine calcium, and renal and liver function tests is useful for identifying selected secondary causes of low bone mass, particularly for those with frac­ tures or unexpectedly low Z-scores. An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum calcium level may reflect malnutrition or a malabsorption disease, such as celiac disease. In the presence of hypercalcemia, a serum PTH level differentiates between hyperparathyroidism (PTH↑) and malignancy (PTH↓), and a high PTHrP level can help document the presence of humoral hypercalcemia of malignancy (Chap. 422). A low urine calcium (<50 mg/24 h) suggests malnutri­ tion, or malabsorption; a high urine calcium (>300 mg/24 h) during normal calcium intake (excluding calcium supplements for at least a week before the urine collection) is indicative of hypercalciuria. Hypercalciuria occurs primarily in three situations: (1) a renal cal­ cium leak; more common in males with osteoporosis; (2) absorptive hypercalciuria, which can be idiopathic or associated with increased 1,25(OH)2D in granulomatous disease; or (3) hematologic malig­ nancies or conditions associated with excessive bone turnover such as Paget’s disease, hyperparathyroidism, hyperthyroidism, and iron chelation therapy (desferoxamine) for thalassemia. Renal hypercal­ ciuria is treated with thiazide diuretics, which lower urine calcium and help improve calcium economy. In this setting, thiazides alone can improve bone mass and possibly reduce risk of fracture. They might also reduce renal stone risk. Individuals who have fragility fractures or bone density in the osteoporotic range should have a measurement of serum 25(OH) D level since serum 25(OH)D levels <30 ng/mL (vitamin D insuf­ ficiency) are common, particularly in older adults. Hyperthy­ roidism should be evaluated by measuring thyroid-stimulating hormone (TSH). When there is clinical suspicion of Cushing’s syndrome, 24-h urinary free cortisol levels or a fasting serum cortisol should be measured after taking 1 mg dexamethasone at midnight. When bowel disease, malabsorption, or malnutrition is suspected, serum albumin, cholesterol, and a complete blood count should be checked. Asymptomatic malabsorption may be heralded by anemia (macrocytic—vitamin B12 or folate deficiency; microcytic—iron deficiency) or low serum cholesterol or urinary calcium levels. If these or other features suggest malabsorption, further evaluation is required. Asymptomatic celiac disease with selective malabsorp­ tion is being found with increasing frequency; the diagnosis can be made by testing for transglutaminase IgA antibodies but may require confirmation by endoscopic biopsy. A trial of a gluten-free diet can also be confirmatory (Chap. 336). When osteoporosis is found associated with symptoms of rash, multiple allergies, diar­ rhea, or flushing, mastocytosis should be considered and excluded by using 24-h urine histamine collection or serum tryptase. Myeloma can masquerade as generalized osteoporosis, although it more commonly presents with bone pain and characteristic “punched-out” lesions on radiography. Serum and urine electro­ phoresis and/or evaluation for serum free light chains in serum are required to exclude this diagnosis. More commonly, a monoclo­ nal gammopathy of undetermined significance (MGUS) is found, and the patient is subsequently monitored to ensure that this is not an incipient myeloma. MGUS itself may be associated with an increased risk of osteoporosis. A bone marrow biopsy may be required to rule out myeloma (in patients with equivocal electro­ phoretic results) and can be used to exclude mastocytosis, leukemia, and other marrow infiltrative disorders, such as Gaucher’s disease. Testosterone levels should be checked in men with osteoporosis. An important cause of fracture among the aging population is diabetes, both type 1 and type 2. Patients with diabetes appear, at any given bone density, to be at higher risk of fracture than non­ diabetics. The reasons include the effects on muscle and nerve that

increase the risk of falls, but it can also be due to an underlying skeletal fragility as part of the metabolic consequences of diabetes with deposition of advanced glycation end products in bone. BONE BIOPSY Double tetracycline labeling of the skeleton allows determination of the rate of remodeling as well as evaluation for other metabolic bone diseases. However, the current use of BMD, in combina­ tion with hormonal evaluation and biochemical markers of bone remodeling, has largely replaced the clinical use of bone biopsy, although it remains an important tool in the diagnosis of chronic kidney disease–mineral bone disease (CKD-MBD), in evaluating the mechanism of action of osteoporosis pharmacology and in clinical research. Osteoporosis CHAPTER 423 BIOCHEMICAL MARKERS Several biochemical tests are available that provide an index of the overall rate of bone remodeling (Table 423-6). Biochemical mark­ ers usually are characterized as those related primarily to bone formation or bone resorption. These tests measure the overall state of bone remodeling at a single point in time. Clinical use of these tests has been hampered by biologic variability (in part related to circadian rhythm and food consumption) as well as analytic vari­ ability, although the latter has improved. For the most part, remodeling markers do not predict rates of bone loss well enough in individuals to make accurate assessment of potential future changes in bone density. However, they do provide adjunct information that assists in both evaluation of the patient and in assessment of treatment response. Markers of bone resorption may help in the prediction of fracture risk, indepen­ dently of bone density, particularly in older individuals. In women ≥65 years, when bone density results are greater than the usual treatment thresholds noted above, a high level of bone resorption should prompt consideration of treatment. However, the primary use of biochemical markers is for monitoring treatment response. With the introduction of antiresorptive drugs, bone remodeling declines rapidly, with the fall in resorption occurring earlier than the fall in formation. Inhibition of bone resorption is maximal within 3 months or so. Thus, measurement of bone resorption (serum C-terminal telopeptide measured in a fasting specimen at 9 A.M. is the preferred marker) before initiating therapy and 3–6 months after starting therapy provides an earlier estimate of patient response than does bone densitometry. A decline in bone resorption markers can be ascertained after treatment with bisphos­ phonates, denosumab, or estrogen; this effect is less marked after treatment with weaker agents such as raloxifene or calcitonin. Bone turnover markers are also useful in monitoring the effects of ana­ bolic drugs [hPTH(1–34) or teriparatide or romosozumab], which both rapidly increases bone formation (P1NP is the most sensi­ tive, but osteocalcin is also a very good bone remodeling marker), while teriparatide increases bone resorption and romosozumab decreases bone resorption. The recent suggestion of “drug holi­ days” (see below) has opened another use for biochemical markers, allowing evaluation of the offset of effect of drugs such as oral and intravenous bisphosphonates. Drug holidays should be avoided for denosumab or anabolic drugs because of a more rapid offset effect observed with these drugs. TABLE 423-6  Biochemical Markers of Bone Metabolism in Clinical Use Bone formation   Serum bone-specific alkaline phosphatase   Serum osteocalcin   Serum propeptide of type I procollagen Bone resorption   Urine and serum cross-linked N-telopeptide   Urine and serum cross-linked C-telopeptide

TREATMENT Osteoporosis MANAGEMENT OF PATIENTS WITH FRACTURES Treatment of a patient with osteoporosis frequently involves man­ agement of acute fractures as well as treatment of the underly­ ing disease. Hip fractures almost always require surgical repair. Depending on the location and severity of the fracture, condition of the neighboring joint, and general status of the patient, procedures may include open reduction and internal fixation with pins and plates, hemiarthroplasties, and total arthroplasties. These surgical procedures are followed by intense rehabilitation to return patients to their prefracture functional level. Long bone fractures often require either external or internal fixation. Other fractures (e.g., vertebral, rib, and pelvic fractures) can often be managed with sup­ portive care, requiring no specific orthopedic treatment. PART 12 Endocrinology and Metabolism Only ~30% of vertebral compression fractures present with sudden-onset back pain. For acutely symptomatic fractures, treat­ ment with analgesics is required, including nonsteroidal antiinflammatory agents and/or acetaminophen, sometimes with the addition of a narcotic agent. (A few small, randomized clinical trials suggest that calcitonin may reduce pain related to acute vertebral compression fracture). Vertebral augmentation with the percutane­ ous injection of artificial cement (polymethylmethacrylate) into the vertebral body (vertebroplasty or kyphoplasty) may offer significant pain relief in a subset of patients with continuing pain; however, systematic reviews of controlled trials of both procedures have provided doubt about their efficacy. Furthermore, risks include acute extravasation of cement outside of the vertebral body with neurologic impairment and possibly an increased risk of vertebral fracture in adjacent vertebrae due to increased rigidity of the treated vertebral body. Short periods of bed rest may be helpful for pain management, but in general, early mobilization is recommended as it helps prevent further bone loss associated with immobilization. Occasionally, use of a soft elastic-style back brace may facilitate earlier mobilization. Muscle spasms often occur with acute com­ pression fractures and can be treated with muscle relaxants and heat treatments. Severe pain usually resolves within 6–10 weeks. More chronic severe pain might suggest the possibility of multiple myeloma or other underlying bone conditions. Vertebral fractures cause height loss because of the loss of verte­ bral body height during compression of the vertebral body. These fractures can produce a kyphosis, particularly when wedge shaped, or just loss of thoracic height. Chronic pain following vertebral fracture is probably not bony in origin; instead, it is related to abnormal strain on muscles, ligaments, and tendons and to second­ ary facet-joint arthritis associated with alterations in thoracic and/ or abdominal shape. Chronic pain may also be the result of ribs sitting right on top of the iliac crest bones, particularly in patients who have had multiple vertebral compression fractures. Chronic pain is difficult to treat effectively and may require analgesics, sometimes including narcotic analgesics with the attendant risk of addiction. Frequent intermittent rest in a supine or semireclin­ ing position is often required to allow the soft tissues, which are under tension, to relax. Back and core-strengthening exercises may be beneficial. Heat treatments help relax muscles and reduce the muscular component of discomfort. Various physical modalities, such as ultrasound and transcutaneous nerve stimulation, may be beneficial in some patients. Pain also occurs in the neck region, not as a result of compression fractures (which almost never occur in the cervical spine as a result of osteoporosis) but because of chronic strain associated with trying to elevate the head in a person with a significant thoracic kyphosis. Multiple vertebral fractures often are associated with often neglected psychological symptoms. Changes in body configuration and back pain can lead to marked loss of self-image and a secondary depression. Altered balance, precipitated by the kyphosis and the anterior movement of the body’s center of gravity, leads to a fear of

falling, a consequent tendency to remain indoors, and the onset of social isolation. These symptoms sometimes can be alleviated by family support and/or psychotherapy. Medication may be necessary when depressive features are present. A MISSED OPPORTUNITY Multiple studies show most patients presenting with fractures after age 50 years (even fractures traditionally linked to osteoporosis) are not screened or treated for osteoporosis. Only <25% of fracture patients receive follow-up care. Recently, several studies have dem­ onstrated the effectiveness of a relatively simple and inexpensive program that reduces the risk of subsequent fractures. In the Kaiser system, it is estimated that a 20% decline in hip fracture occurrence was seen with the introduction of a fracture liaison service. This approach has also been successful in other non-U.S. health systems, including the United Kingdom and New Zealand. This involves a health care professional (usually a nurse or physician’s assistant) whose job is to educate patients and coordinate evaluation and osteoporosis treatment as patients move through the emergency room, inpatient care in an acute care hospital, rehabilitation hos­ pital care, and/or orthopedic practice to outpatient management. If the Kaiser experience can be repeated, there would not only be significant savings of health care dollars but also a dramatic drop in hip fracture incidence and a marked improvement in morbidity and mortality among the aging population. Initiatives to obtain Medicare funding for fracture liaison services in the United States are continuing but have not yet been successful. MANAGEMENT OF THE UNDERLYING DISEASE Risk Factor Reduction  After risk assessment, patients should be thoroughly educated to reduce the impact of modifiable risk fac­ tors associated with bone loss and falling. Medications should be reviewed to ensure that all are necessary and taken at the lowest required dose. Glucocorticoid medication, if present, should be evaluated to determine that it is truly indicated and is being given in doses as low as possible. For those on thyroid hormone replace­ ment, TSH testing should be performed to determine that an excessive dose is not being used, as iatrogenic thyrotoxicosis can be associated with increased bone loss. In patients who smoke, efforts should be made to facilitate smoking cessation. Reducing risk fac­ tors for falling also includes alcohol abuse treatment and a review of the medical regimen for any drugs that might be associated with orthostatic hypotension and/or sedation, including hypnotics, anti­ psychotics, and anxiolytics. If nocturia occurs, the frequency should be reduced, if possible (e.g., by decreasing or modifying diuretic use), as arising in the middle of sleep is a common precipitant of a fall. Patients should be instructed about environmental safety, such as eliminating exposed wires, curtain strings, slippery rugs, and mobile tables. Avoiding stocking feet on wood floors, checking carpet condition (particularly on stairs), and providing good light in paths to bathrooms and outside the home are important preven­ tive measures. Treatment for impaired vision is recommended, particularly a problem with depth perception, which is specifically associated with increased falling risk. Patients with neurologic impairment (e.g., stroke, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis) are particularly at risk of falling and require specialized supervision and care. In patients with risk factors for falls, especially those who live alone or spend significant time alone, medical alert systems should be prescribed. Nutritional Recommendations  •  Calcium  A large body of data indicates that less than optimal calcium intake results in bone loss. Consequently, an adequate intake suppresses bone turnover. Recom­ mended intakes from an Institute of Medicine report are shown in Table 423-7. The NHANES have consistently documented that aver­ age calcium intakes fall considerably short of these recommendations. The preferred source of calcium is diet, but many patients require calcium supplementation to bring intake to ~1000 mg/d. Calcium supplement doses of ≤600 mg/d are likely to be safe. Best sources of

TABLE 423-7  Adequate Calcium Intake ESTIMATED ADEQUATE DAILY CALCIUM INTAKE, mg/d LIFE STAGE GROUP Young children (1–3 years)

Older children (4–8 years)

Adolescents and young adults (9–18 years)

Men and women (19–50 years)

Men and women (51 years and older)

Note: Pregnancy and lactation needs are the same as for nonpregnant women (e.g., 1300 mg/d for adolescents/young adults and 1000 mg/d for those ≥19 years old). Source: Data from Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: The National Academies Press; 1997. calcium include dairy products (milk, yogurt, and cheese), nondairy milks (almond, rice, soy), nuts, and fortified foods such as certain cereals, waffles, snacks, juices, and crackers. Some of these fortified foods contain as much calcium per serving as milk. Various veg­ etables and fruits, such as kale, broccoli, and dried figs, contain rea­ sonably high calcium content, although some of it may not be fully bioavailable. Calcium intake calculators are available at NOF.org or NYSOPEP.org and will give a rough idea of total calcium intake. If calcium supplements are required, they should be taken in doses sufficient to bring total intake to the required level (~1000 mg/d). Doses of supplements should be ≤600 mg per single dose, as the calcium absorption fraction decreases at higher doses. Calcium supplements should be calculated on the basis of the elemental calcium content of the supplement, not the weight of the calcium salt (Table 423-8). Calcium supplements contain­ ing carbonate are best taken with food since they require acid for solubility. Calcium citrate supplements can be taken at any time, although taking calcium supplements in the evening may reduce nocturnal increases in PTH. Several controlled clinical trials of calcium, mostly with accom­ panying vitamin D, have confirmed reductions in clinical fractures, including fractures of the hip (~20–30% risk reduction), particu­ larly in elderly individuals who are likely to be dietarily deficient. The majority of recent studies of pharmacologic agents have been conducted in the context of calcium replacement (± vitamin D). Thus, it is standard practice to ensure an adequate calcium and vitamin D intake in patients with osteoporosis whether they are receiving additional pharmacologic therapy or not. A systematic review confirmed a greater BMD response to antiresorptive therapy when calcium intake was adequate. Although side effects from supplemental calcium are minimal (eructation and constipation mostly with carbonate salts), indi­ viduals with a history of kidney stones should have a 24-h urine calcium determination before starting increased calcium to avoid exacerbating hypercalciuria. A recent analysis of published data has suggested that high intakes of calcium from supplements are associated with an increase in the risk of renal stones, calcification in arteries, and potentially an increased risk of heart disease and stroke. This is controversial, with recent meta-analyses showing no TABLE 423-8  Elemental Calcium Content of Various Oral

Calcium Preparations CALCIUM PREPARATION ELEMENTAL CALCIUM CONTENT Calcium citrate 60 mg/300 mg Calcium lactate 80 mg/600 mg Calcium gluconate 40 mg/500 mg Calcium carbonate 400 mg/g Calcium carbonate + 5 μg vitamin D2 (OsCal 250) 250 mg/tablet Calcium carbonate (Tums 500) 500 mg/tablet Source: Adapted from SM Krane, MF Holick, in Harrison’s Principles of Internal Medicine, 14th ed. New York, NY: McGraw Hill; 1998.

effect of calcium supplements on cardiovascular events. Daily doses of <700 mg appear safe. However, since high calcium intakes also increase the risk of renal stones and confer no extra benefit to the skeleton, the recommendation that total intakes should be between 1000 and 1500 mg/d seems reasonable.

Vitamin D  Diet alone is inadequate to maintain vitamin D suf­ ficiency (serum 25[OH]D consistently >75 μmol/L [30 ng/mL]). Vitamin D is synthesized from a precursor in the skin under the influence of heat and ultraviolet light (Chap. 421). Production is blocked by sunscreen and sun avoidance. However, large segments of the population do not obtain sufficient vitamin D from either skin production or dietary sources. Since vitamin D supplemen­ tation at doses that would achieve these serum levels is safe and inexpensive, the National Academy of Medicine recommends daily intakes of 200 IU for adults <50 years of age, 400 IU for those 50–70 years, and 600 IU for those >70 years (based on obtaining a serum level of 20 ng/mL, lower than the level recommended by most other guidelines). Multivitamin tablets usually contain 400 IU, and many calcium supplements also contain vitamin D. Some data suggest that higher doses (≥1000 IU) may be required, particularly in the obese, elderly, and chronically ill. A daily intake of up to 4000 IU/d is safe. For those with osteoporosis or those at risk, 1000–2000 IU/d can usually maintain serum 25(OH)D above 30 ng/mL. Recent large randomized controlled trials show vitamin D supplementation by itself at doses equivalent to 2000 IU/d does not appear to reduce fracture risk in older individuals with normal baseline vitamin D levels. However, the combination of adequate calcium intake and vitamin D does decrease fracture risk in those with vitamin D deficiency, particularly the institutionalized elderly population. Although low vitamin D levels appear associated with more serious outcomes in response to COVID-19, trials of vitamin D supplementation have been inconsistent and largely negative. Osteoporosis CHAPTER 423 Other Nutrients  Other nutrients such as salt, high animal protein intakes, and caffeine may have modest effects on calcium excretion or absorption. Adequate vitamin K status is required for optimal carboxylation of osteocalcin. States in which vitamin K nutrition or metabolism is impaired, such as with long-term war­ farin therapy, have been associated with reduced bone mass. How­ ever, a recent trial showed no benefit of vitamin K2 on BMD when added to calcium and vitamin D supplementation. Research concerning cola-based soda beverage intake is controversial but suggests a possible link to reduced bone mass through factors that appear independent of caffeine. Magnesium is abundant in foods, and magnesium deficiency is quite rare in the absence of a serious chronic disease. Magnesium supplementation may be warranted in patients with inflammatory bowel disease, celiac disease, chemotherapy, severe diarrhea, mal­ nutrition, or alcoholism. Dietary phytoestrogens, which are derived primarily from soy products and legumes (e.g., garbanzo beans [chickpeas] and lentils), exert some estrogenic activity but are insuf­ ficiently potent to justify their use in place of a pharmacologic agent in the treatment of osteoporosis. Patients with hip fractures are often frail and relatively malnour­ ished. Some data suggest an improved outcome in such patients when they are provided calorie and protein supplementation. Excessive protein intake can increase renal calcium excretion, but this can be corrected by an adequate calcium intake. Exercise  Exercise in young individuals prior to and at the time of puberty increases the likelihood that they will attain the maximal genetically determined peak bone mass. Meta-analyses of studies performed in postmenopausal women indicate that progressive high-intensity resistance training results in small gains in bone mass of 3–4%. However, this beneficial effect wanes if exercise is discon­ tinued. Most of the studies are relatively short term, and a more substantial effect on bone mass is likely if exercise is continued over a long period. Exercise also has beneficial effects on neuromuscu­ lar function, and it improves coordination, balance, and strength,

thereby reducing the risk of falling. A walking program is a practical way to start. Other activities such as dancing, racquet sports, crosscountry skiing, and progressive high-intensity resistance training are also recommended, depending on the patient’s personal prefer­ ence and general condition. Even women who cannot walk benefit from swimming or water exercises, not so much for the effects on bone, which are quite minimal, but because of effects on muscle. Exercise habits should be consistent, optimally at least three times a week. For most patients, participation in exercise regimens that the patient enjoys is recommended in order to improve adherence. We also emphasize the importance of making exercise a social activity, again to improve adherence. Many individuals experience a fear of falling that can lead to social isolation and depression. Group exer­ cise can help to alleviate this problem by providing a sense of social connectivity among participants.

PART 12 Endocrinology and Metabolism Tai chi is a traditional Chinese martial art that utilizes a series of gentle, flowing movements to promote and maintain flexibil­ ity, balance, endurance, proprioception, and strength. It involves constant movement through all three spatial dimensions. As a three-dimensional exercise, tai chi may be incorporated as part of balance training program for individuals with osteoporosis. Tai chi is generally considered a safe activity. The evidence for fall preven­ tion in tai chi has been evaluated in randomized controlled trials, and systematic reviews indicate tai chi can significantly reduce the risk of falls in older adults, particularly when it is practiced with increased frequency. It is recommended that individuals with osteoporosis or osteo­ porotic vertebral fractures participate in exercise programs that involve both high-intensity progressive resistance and balance training. Slow, controlled movements are recommended in order to avoid injuries. Exercise modifications and avoidance of certain postures (such as spinal flexion) may be advised. Caution should be taken to avoid activities that can lead to potential fractures, such as performing activities on slippery surfaces, or twisting or bending the spine quickly while transitioning between different positions. Precautions should be taken to avoid injury when exercising with loads and performing exercises that challenge balance. For individ­ uals with osteoporosis who have a high risk for fracture, vertebral fractures, sedentary lifestyle, or comorbid conditions that impact exercise tolerance, consultation with physical therapists to learn safe exercise programs is recommended. PHARMACOLOGIC TREATMENT OF OSTEOPOROSIS Several international osteoporosis management guidelines have been published. They recommend patients with fractures of the hip and spine should be evaluated for treatment. Patients with minimal trauma fractures in the setting of a BMD in the osteopenia or osteo­ porosis range should be treated with pharmacologic agents. Most guidelines also suggest that patients be considered for treatment when BMD T-score is ≤–2.5, a level consistent with the diagnosis of osteoporosis. Treatment should also be considered in postmeno­ pausal women with a minimal trauma fracture or multiple risk factors even if BMD is not in the osteoporosis range. Treatment thresholds depend on cost-effectiveness analyses but, in the United States, are a >20% 10-year major fracture probability and >3% 10-year hip fracture probability. It must be emphasized, however, that as with other diseases, risk assessment is an inexact science when applied to the individual. As a result, patients often accept fracture risks that are higher than the physician might like out of concern for the usually considerably lower but better publicized risks of adverse events of drugs. Pharmacologic therapies for osteoporosis are either antiresorp­ tive or anabolic. The antiresorptive agents include medications that have broad effects such as hormone/estrogen therapy and selective estrogen receptor modulators (SERMS) as well as specific agents for osteoporosis treatment (bisphosphonates, denosumab, and cal­ citonin). The anabolic agents are teriparatide, abaloparatide, and romosozumab. Denosumab allows bone formation to continue, and thus, there is an increase in bone density beyond that occurring

with agents that inhibit resorption directly leading to a reduction in bone formation like bisphosphonates. Antiresorptive Agents  •  Estrogens  A large body of clinical trial data indicates that various types of estrogens (conjugated equine estrogens, estradiol, estrone, esterified estrogens, ethinyl estradiol, and mestranol) reduce bone turnover, prevent bone loss, and induce small increases in bone mass of the spine, hip, and total body. The effects of estrogen are seen in women with natural or surgical menopause and in late postmenopausal women with or without established osteoporosis. Estrogens are efficacious when administered orally, transdermally, or by subcutaneous implant. For both oral and transdermal routes of administration, combined estrogen/progestin preparations are now available in many coun­ tries, obviating the problem of taking two tablets or using a patch and oral progestin. For oral estrogens, the standard recommended doses have been 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine estrogens, and 5 μg/d for ethinyl estradiol. For transdermal estro­ gen, the commonly used dose supplies 50 μg of estradiol per day, but a lower dose may be appropriate for some individuals. Doseresponse data for conjugated equine estrogens indicate that lower doses (0.3 and 0.45 mg/d) are also effective. Doses even lower have also been shown to slow bone loss. Fracture Data  Epidemiologic databases indicate that women who take estrogen replacement have a 50% reduction, on average, of osteoporosis-related fractures, including hip fractures. The ben­ eficial effect of estrogen is greatest among those who start replace­ ment early and continue the treatment; the benefit declines after discontinuation to the extent that there is no residual protective effect against fracture by 10 years after discontinuation. The first clinical trial evaluating fractures as secondary outcomes, the Heart and Estrogen-Progestin Replacement Study (HERS) trial, showed no effect of hormone therapy on hip or other clinical fractures in women with established coronary artery disease. These data made the results of the Women’s Health Initiative (WHI) exceedingly important (Chap. 395). The estrogen-progestin arm of the WHI in

16,000 postmenopausal healthy women not selected based on low bone mass indicated that hormone therapy reduces the risk of hip and clinical spine fracture by 34% and that of all clinical fractures by 24%. A few smaller clinical trials have evaluated spine fracture occur­ rence as an outcome with estrogen therapy. They have consistently shown that estrogen treatment reduces vertebral fracture incidence. The WHI has provided a vast amount of data on the multisys­ temic effects of hormone therapy. Although earlier observational studies suggested that estrogen replacement might reduce heart disease, the WHI showed that combined estrogen-progestin treat­ ment increased risk of fatal and nonfatal myocardial infarction by ~29%, confirming data from the HERS study. Other important relative risks included a 40% increase in stroke, a 100% increase in venous thromboembolic disease, and a 26% increase in risk of breast cancer. Subsequent analyses have confirmed the increased risk of stroke and, in a substudy, showed a twofold increase in dementia. Benefits other than the fracture reductions noted above included a 37% reduction in the risk of colon cancer. These relative risks must be interpreted in light of absolute risk (Fig. 423-8). For example, out of 10,000 women treated with estrogen-progestin for 1 year, there will be 8 excess heart attacks, 8 excess breast cancers, 18 excess venous thromboembolic events, 5 fewer hip fractures, 44 fewer clinical fractures, and 6 fewer colorectal cancers. These numbers must be multiplied by the number of years of hormone treatment. There was no effect of combined hormone treatment on the risk of uterine cancer or total mortality. It is important to note that these WHI findings apply specifically to hormone treatment in the form of conjugated equine estrogen plus medroxyprogesterone acetate. The relative benefits and risks of unopposed estrogen in women who had hysterectomies vary somewhat. They still show benefits against fracture occurrence

Risks Benefits Neutral

Additional events

in 10,000 women/year

Number of cases

Reduced events

CHD Stroke Deaths Breast cancer VTE Hip fracture Endometrial cancer Colorectal cancer FIGURE 423-8  Effects of hormone therapy on event rates: green, placebo; purple, estrogen and progestin. CHD, coronary heart disease; VTE, venous thromboembolic events. (Adapted from Women’s Health Initiative. WHI HRT Update.) and increased risk of venous thrombosis and stroke, similar in magnitude to the risks for combined hormone therapy. In contrast, though, the estrogen-only arm of WHI indicated no increased risk of heart attack and a decreased risk of breast cancer. The data suggest that at least some of the detrimental effects of combined therapy are related to the progestin component. In addition, there is the possibility, suggested by primate data, that the risk accrues mainly to women who have some years of estrogen deficiency before initiating treatment. Therefore, the benefit/risk ratio of hormone therapy is improved if it is commenced before the age of

60 years or within 10 years of menopause. Nonetheless, there has been marked reluctance among women for estrogen therapy/ hormone therapy, and the U.S. Preventive Services Task Force has specifically suggested that estrogen therapy/hormone therapy not be used for disease prevention. Mode of Action  Two subtypes of ERs, α and β, have been identified in bone and other tissues. Cells of monocyte lineage express both ERα and ERβ, as do osteoblasts. Estrogen-mediated effects vary with the receptor type. Using ER knockout mouse models, elimination of ERα produces a modest reduction in bone mass, whereas mutation of ERβ has less of an effect on bone. A man with a homozygous mutation of ERα had markedly decreased bone density as well as abnormalities in epiphyseal closure, con­ firming the important role of ERα in bone biology. The mecha­ nism of estrogen action in bone is an area of active investigation

(Fig. 423-5). Although data are conflicting, estrogens may inhibit osteoclasts directly. However, most estrogen (and androgen) effects on bone resorption are mediated indirectly through paracrine fac­ tors produced by osteoblasts. These actions include (1) increasing the inhibitor of RANK-L, osteoprotegerin, production by osteo­ blasts, (2) increasing IGF-I and TGF-β, and (3) suppressing IL-1 (α and β), IL-6, TNF-α, and osteocalcin synthesis. These indirect estrogen actions primarily decrease bone resorption. Progestins  In women with a uterus, daily progestin or cyclical progestins at least 12 days per month are prescribed in combination with estrogens to reduce the risk of uterine cancer. Medroxypro­ gesterone acetate and norethindrone acetate blunt the high-density lipoprotein response to estrogen, but micronized progesterone does not. Neither medroxyprogesterone acetate nor micronized pro­ gesterone appears to have an independent effect on bone; at lower doses of estrogen, norethindrone acetate may have an additive ben­ efit. In breast tissue, progestins may account for the increased risk of breast cancer with combination treatment. SERMs  Two SERMs are used currently in postmenopausal women: raloxifene, which is approved by the FDA for the preven­ tion and treatment of osteoporosis as well as the prevention of breast cancer, and tamoxifen, which is approved for the prevention and treatment of breast cancer. A third SERM, bazedoxifene, is marketed in combination with conjugated estrogen for treatment of

menopausal symptoms and prevention of bone loss. Bazedoxifene protects the uterus and breast from effects of estrogen and makes the use of progestin unnecessary.

Tamoxifen reduces bone turnover and bone loss in postmeno­ pausal women compared with placebo groups. These findings support the concept that tamoxifen acts as an estrogenic agent in bone. There are limited data on the effect of tamoxifen on fracture risk, but the Breast Cancer Prevention study indicated a possible reduction in clinical vertebral, hip, and Colles’ fractures. Tamoxifen is not FDA approved for prevention or treatment of osteoporosis. The major benefit of tamoxifen is on breast cancer occurrence and recurrence in women with ER-positive tumors. The breast can­ cer prevention trial indicated that tamoxifen administration over 4–5 years reduced the incidence of new invasive and noninvasive breast cancer by ~45% in women at increased risk of breast cancer. The incidence of ER-positive breast cancers was reduced by 65%. Tamoxifen increases the risk of uterine cancer in postmenopausal women, limiting its use for breast cancer prevention in women at low or moderate risk. Osteoporosis CHAPTER 423 Raloxifene (60 mg/d) has effects on bone turnover and bone mass that are very similar to those of tamoxifen, indicating that this agent is also estrogenic on the skeleton. The effect of raloxifene on bone density (+1.4–2.8% vs. placebo in the spine, hip, and total body) is somewhat less than that seen with standard doses of estrogens. Raloxifene reduces the occurrence of vertebral fracture by 30–50%, depending on the population; however, there are no data confirm­ ing that raloxifene can reduce the risk of nonvertebral fractures after 8 years of observation. Raloxifene, like tamoxifen and estrogen, has effects on other organ systems. The most beneficial effect appears to be a reduction in invasive breast cancer (mainly decreased ER-positive) occurrence of ~65% in women who take raloxifene compared with placebo. In a head-to-head study, raloxifene was as effective as tamoxifen in preventing breast cancer in high-risk women, and raloxifene is FDA approved for this indication. In a further study, raloxifene had no effect on heart disease in women with increased risk for this outcome. In contrast to tamoxifen, raloxifene is not associated with an increase in the risk of uterine cancer or benign uterine disease. Raloxifene increases the occurrence of hot flashes but reduces serum total and low-density lipoprotein cholesterol, lipoprotein(a), and fibrinogen. Raloxifene, with its positive effects on breast cancer and vertebral fractures, has become a useful agent for the treatment of the younger asymptomatic postmenopausal woman. In some women, a recurrence of menopausal symptoms may occur. Usually this is evanescent but occasionally is sufficiently impactful on daily life and sleep that the drug must be withdrawn. Raloxifene increases the risk of deep-vein thrombosis and may increase the risk of death from stroke among older women. Consequently, it is not usually recommended for women over age 70 years. MODE OF ACTION OF SERMS All SERMs bind to the ER, but each agent produces a unique recep­ tor-drug conformation. As a result, specific coactivator proteins or co-repressor proteins are bound to the receptor (Chap. 389), result­ ing in differential effects on gene transcription that vary depending on other transcription factors present in the cell. Another aspect of selectivity is the affinity of each SERM for the different ERα and ERβ subtypes, which are expressed differentially in various tissues. These tissue-selective effects of SERMs offer the possibility of tailoring estrogen therapy to best meet the needs and risk factor profile of an individual patient. Bisphosphonates  Bisphosphonates have become the mainstay of osteoporosis treatment globally, in part related to cost as they have become generic. Alendronate, risedronate, ibandronate, and zole­ dronic acid are approved for the prevention and treatment of post­ menopausal osteoporosis. Alendronate, risedronate, and zoledronic acid are also approved for the treatment of glucocorticoid-induced osteoporosis, and risedronate and zoledronic acid are approved for prevention of glucocorticoid-induced osteoporosis. Alendronate,

risedronate, and zoledronic acid are also approved for treatment of osteoporosis in men.

Alendronate decreases bone turnover and increases bone mass by up to 8 and 6% versus placebo in the spine and hip, respectively. Multiple trials have evaluated its effect on fracture occurrence. The Fracture Intervention Trial provided evidence in >2000 women with prevalent vertebral fractures that daily alendronate treatment (5 mg/d for 2 years and 10 mg/d for 9 months afterward) reduces vertebral fracture risk by ~50%, multiple vertebral fractures by up to 90%, and hip fractures by up to 50%. Several subsequent trials have confirmed these findings (Fig. 423-9). For example, in a study of >1900 women with low bone mass treated with alendronate

(10 mg/d) versus placebo, the incidence of all nonvertebral fractures was reduced by ~47% after only 1 year. In the United States, the 70-mg weekly dose is approved for treatment of osteoporosis and the dose of 35 mg per week is approved for prevention, with those doses showing equivalence to daily dosing based on bone turnover and bone mass response. PART 12 Endocrinology and Metabolism Consequently, once-weekly therapy generally is preferred because of lower incidence of gastrointestinal side effects, ease of adminis­ tration, and improved persistence with therapy. Alendronate should be taken with a full glass of water before breakfast after an over­ night fast, as bisphosphonates are poorly absorbed. Because of the potential for esophageal irritation, alendronate is contraindicated in patients who have stricture, achalasia, or inadequate emptying of the esophagus. It is recommended that patients remain upright (standing or sitting) for at least 30 min after taking the medication to avoid esophageal irritation and that food and fluids (other than water) be avoided for the same duration. In clinical trials, overall gastrointestinal symptomatology was no different with alendronate than with placebo, but in practice, all oral bisphosphonates have been associated with esophageal irritation and inflammation. Risedronate also reduces bone turnover and increases bone mass. Controlled clinical trials have demonstrated 40–50% reduction in vertebral fracture risk over 3 years, accompanied by a 40% reduc­ tion in clinical nonspine fractures. The only clinical trial specifically designed to evaluate hip fracture outcome (HIP) indicated that risedronate reduced hip fracture risk in women in their seventies with confirmed osteoporosis by 40%. In contrast, risedronate was not effective at reducing hip fracture occurrence in older women (80+ years) without proven osteoporosis. Studies have shown that 35 mg of risedronate administered once weekly is therapeutically equivalent to 5 mg/d. The instructions for oral administration noted for alendronate apply to all three oral bisphosphonates. There is also a preparation of risedronate with an enteric coating (35 mg) that can be taken after breakfast. Risedronate is the only bisphos­ phonate that has this dosing flexibility. Ibandronate is the third amino-bisphosphonate approved in the United States. Ibandronate (2.5 mg/d) has been shown in clinical trials to reduce vertebral fracture risk by ~40% but with no overall effect on nonvertebral fractures. In a post hoc analysis of subjects with a femoral neck T-score of ≤–3, ibandronate reduced the risk of nonvertebral fractures by ~60%. In clinical trials, ibandronate doses of 150 mg per month PO or 3 mg every 3 months IV had greater effects on turnover and bone mass than did 2.5 mg/d. Patients should take oral ibandronate in the same way as other bisphospho­ nates but with 1 h elapsing before other food or drink (other than plain water). Zoledronic acid is a potent bisphosphonate with a unique admin­ istration regimen (5 mg by 30-min IV infusion at most annually). Zoledronic acid data confirm that it is highly effective in fracture risk reduction. In a study of >7000 women followed for 3 years, zoledronic acid (5 mg IV annually) reduced the risk of vertebral fractures by 70%, nonvertebral fractures by 25%, and hip fractures by 40%. These results were associated with less height loss and disability. In the treated population, there was an increased risk of almost 25% of an acute phase response (APR) in patients with no prior bisphosphonate exposure (fever, myalgias, headache, malaise), but effects were short-lived (2–3 days). A recent study shows the

APR can be eliminated by the administration of dexamethasone

(4 mg) for 3 days commencing 90 min before the infusion. Although there was also an increased risk of atrial fibrillation in this trial, detailed evaluation of all bisphosphonates has failed to confirm a risk of atrial fibrillation. Zoledronic acid has also been studied in a placebo-controlled trial of older women and men within 3 months of an acute hip fracture. The risk of recurrent fracture was reduced by 35%, and there was a 28% reduction in mortality that was asso­ ciated with a reduction in infections and cardiovascular events. In older postmenopausal women with osteopenia, the risk of non­ vertebral, vertebral, or clinical fragility fractures was significantly lower in women with osteopenia who received zoledronate every 18 months for 6 years than in women who received placebo. In an extension study of the women who had received zoledronic acid infusions for 6 years, the risk of nonvertebral fractures remained low for up to 3.5 years after the last dose but increased after that time. This suggests less frequent dosing may be required after an initial course of three or four zoledronic acid infusions. Common Bisphosphonate Adverse Events  All bisphospho­ nates have been associated with some musculoskeletal and joint pains of unclear etiology, which are occasionally severe. There is poten­ tial for renal toxicity, particularly in women with stage 3 chronic kidney disease (CKD), and bisphosphonates are contraindicated in those with an estimated glomerular filtration rate <30–35 mL/min.

Hypocalcemia can occur. Two potential side effects have been associated with bisphospho­ nate use. The first is medication-related osteonecrosis of the jaw (MRONJ). MRONJ usually follows a dental procedure in which bone is exposed (dental extractions and implants). It is presumed that the exposed bone becomes infected and dies. MRONJ is more common among cancer patients receiving high doses of bisphos­ phonates for skeletal metastases. It is rare among persons with osteoporosis on usual doses of bisphosphonates. Additional risk factors for MRONJ are poor dental hygiene, diabetes, and gluco­ corticoids. Oral antibiotic rinses and oral systemic antibiotics may be useful to prevent this rare adverse event if risk is perceived to be particularly high. In addition, any invasive dental procedures should be performed prior to commencement of bisphosphonate therapy. Because bisphosphonates have a long skeletal half-life, it is unlikely that withholding therapy prior to an invasive procedure will reduce MRONJ risk; however, this is often recommended by dentists and faciomaxillary surgeons. Teriparatide treatment for 2 months has been shown to reduce bone lesions associated with MRONJ versus placebo. The second side effect is called atypical femoral fracture. These are stress fractures occurring in the subtrochanteric femoral region or across the femoral shaft distal to the lesser trochanter. They are often preceded by pain in the lateral thigh or groin that can be present for weeks, months, or even years before the fracture. The fractures occur following either no or trivial trauma, are predomi­ nantly horizontal with a medial beak, and are noncomminuted. An American Society for Bone and Mineral Research Task Force described the major and minor criteria for these fractures, which are related to duration of bisphosphonate therapy and increase after 5–7 years of treatment, but only after 3 years of exposure in Asian patients. The overall risk appears quite low, especially when compared with the number of hip fractures prevented by these therapies, but they often require surgical fixation and show delayed healing. The risk is also increased with Asian ethnicity, rheumatoid arthritis, glucocorticoids, proton pump inhibitors, and SSRIs. In some cases (10–30%), there is no bisphosphonate exposure, and in some of these cases, there may be an underlying rare monogenetic bone disease such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemic rickets, X-linked osteoporosis, or pyc­ nodysostosis. Other genetic risk factors for atypical femur fractures have been identified in families with bisphosphonate-associated atypical femur fractures. If the fractures are found early, when there is evidence of periosteal stress reaction or stress fracture, prior to the occurrence of overt fracture, surgical intervention may be

Risedronate pooled, post hoc Alendronate pooled, post hoc

PLB PLB ALN RIS

Percent of patients 45%↓*

A Months Months Months Months Alendronate pooled, post hoc Risedronate pooled, post hoc

PLB ALN 27%↓* Percent of patients

Months B Months Cumulative incidence of hip fractures over 3 years

Cumulative incidence (%)

Placebo (n = 3861) Zolendronate (n = 3875)

Time to first hip fracture (months) C FIGURE 423-9  Effects of various bisphosphonates on fracturs. A. Clinical vertebral fractures. B. Nonvertebral fractures. C. Hip fractures. Plb, placebo; RRR, relative risk reduction. (Data from DM Black et al: J Clin Endocrinol Metab 85:4238, 2000; C Roux et al: Curr Med Res Opin 4:433, 2004; CH Chesnut et al: J Bone Miner Res 19: 1241, 2004; DM Black et al: N Engl J Med 356:1809, 2007; JT Harrington et al: Calcif Tissue Int 74:129, 2003.)

Vertebral fractures Ibandronate preplanned Zoledronate preplanned

PLB IBAN PLB ZOL

49↓* Osteoporosis CHAPTER 423 77%↓*

69%↓* ?

Nonvertebral fractures Zoledronate preplanned

PLB PLB RIS ZOL

25%↓* 59%↓* ?

Months Hip fractures RRR 41%

required. The evidence that teriparatide can help heal the fracture and preclude the need for surgical repair from case series is mixed, and published trial data are not available. When patients initiate bisphosphonates, they should be informed that if they develop thigh or groin pain, they should inform their health care profes­ sional. Routine x-rays will sometimes detect cortical thickening or even a stress fracture, but MRI or technetium bone scans are more sensitive. The presence of an abnormality requires, at minimum, a period of modified weight-bearing and may need prophylactic rodding of the femur. It is important to realize that these may often be bilateral (~50% of the time), and when an abnormality is found, the other femur should be checked. It is unknown whether patients who have these atypical femur fractures can ever receive antiresorp­ tive therapies again in the future, but it seems prudent to avoid their use for most of these individuals.

PART 12 Endocrinology and Metabolism Mode of Action  Bisphosphonates are structurally related to pyrophosphates, compounds that are incorporated into bone matrix. Bisphosphonates are taken up at sites of active bone remodeling and specifically impair osteoclast function and reduce osteoclast number, in part by inducing apoptosis. Recent evidence suggests that the nitrogen-containing bisphosphonates also inhibit protein prenyl­ ation, one of the end products in the mevalonic acid pathway, by inhibiting the enzyme farnesyl pyrophosphate synthase. This effect disrupts intracellular protein trafficking and ultimately may lead to apoptosis. Some bisphosphonates have very long retention in the skeleton and may exert long-term effects via recirculation of bisphos­ phonates retained in bone when bone remodeling recurs at that site. Calcitonin  Calcitonin is a polypeptide hormone produced in the thyroid gland (Chap. 422). Its physiologic role is unclear as no skeletal disease has been described in association with calcitonin deficiency or excess. Calcitonin preparations are approved by the FDA for Paget’s disease, hypercalcemia, and osteoporosis in women

5 years past menopause. Injectable calcitonin produces small increments in bone mass of the lumbar spine. However, difficulty of administration and frequent reactions, including nausea and facial flushing, make gen­ eral use limited. A nasal spray containing calcitonin (200 IU/d) is available for treatment of osteoporosis in postmenopausal women. One study suggests that nasal calcitonin produces small increments in bone mass and a small reduction in new vertebral fractures in calcitonin-treated patients (at one dose) versus those on calcium alone. There has been no proven effectiveness against nonvertebral fractures. Calcitonin is not indicated for prevention of osteoporosis and is not sufficiently potent to prevent bone loss in early post­ menopausal women. Calcitonin might have an analgesic effect on bone pain, both in the subcutaneous and possibly in the nasal form. Concerns have been raised about an increase in the incidence of cancer associated with calcitonin use. Initially, the cancer noted was of the prostate, but an analysis of all data suggested a more general increase in cancer risk. In Europe, the European Medicines Agency has removed the osteoporosis indication, and an FDA Advisory Committee has voted for a similar change in the United States. Mode of Action  Calcitonin suppresses osteoclast activity by direct action on the osteoclast calcitonin receptor. Osteoclasts exposed to calcitonin cannot maintain their active ruffled border, which normally maintains close contact with underlying bone. Denosumab  Denosumab is a human monoclonal antibody that inhibits RANKL, a potent stimulus of osteoclast activity. It is administered twice yearly by subcutaneous injection. In a random­ ized controlled trial in postmenopausal women with osteoporosis, it has been shown to increase BMD at the spine, hip, and forearm and reduce vertebral, hip, and nonvertebral fractures over a 3-year period by 68, 40, and 20%, respectively (Fig. 423-10). Unlike bisphosphonates in which BMD plateaus after 4–5 years of treat­ ment, bone density continues to increase as long as denosumab treatment is continued. In a long-term extension of the pivotal fracture trial, BMD increased by 21.7 and 9.2% at the spine and

A New vertebral fracture Placebo Denosumab RR, 0.32 p <0.001 RR, 0.39 p <0.001 RR, 0.22 p <0.001 RR, 0.35 p <0.001

Crude incidence (%)

0–36 0–12

12–24 12–36 Month B Time to first nonvertebral fracture

Placebo

Cumulative incidence (%) Cumulative incidence (%)

Denosumab

Month

No. at risk Placebo Denosumab

C Time to first hip fracture 1.4 Placebo 1.2 1.0 0.8 0.6 Denosumab 0.4 0.2 0.0

Month

No. at risk Placebo Denosumab

FIGURE 423-10  Effects of denosumab on the following: A. new vertebral fractures; and B. and C. times to nonvertebral and hip fracture. RR, relative risk. (From SR Cummings et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756, 2009. Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) hip, respectively, after 10 years of denosumab treatment. Over the 10 years, fracture rates also remained at least as low as those seen with denosumab during the active placebo-controlled portion of the trial. Other clinical trials indicate ability to increase bone mass in postmenopausal women with osteopenia and in postmenopausal women with breast cancer treated with aromatase inhibitors. In the oncology literature, denosumab reduces the risk of fractures in women on aromatase inhibitors. In a study of men with prostate cancer treated with androgen deprivation therapy, denosumab increased bone mass and reduced vertebral fracture incidence over 3 years. An analysis of five placebo-controlled studies has also

suggested reduced risk of falls in patients with osteoporosis treated with denosumab. Denosumab was approved by the FDA in 2010 for the treatment of postmenopausal women who have a high risk for osteoporotic fractures, including those with a history of fracture or multiple risk factors for fracture, and those who have failed or are intolerant to other osteoporosis therapy. Denosumab is also approved for the treatment of osteoporosis in men at high risk for fracture, women with breast cancer on aromatase inhibitors, and men with prostate cancer on androgen deprivation treatment. Denosumab may increase the risk of MRONJ and atypical femur fractures similarly to bisphosphonates. Estimated incidence is 5/10,000 patient-years for MRONJ and 1/10,000 patient-years for atypical femur fractures. Denosumab can cause hypersensitivity reactions, hypocalcemia, and skin reactions including dermatitis, rash, and eczema. Early concerns about an imbalance in infections with denosumab have largely been allayed. Severe hypocalcemia may occur in patients with CKD and an estimated glomerular filtration rate <30 mL/min, particularly in those on hemodialysis. Serum calcium levels should be monitored if denosumab is used in such patients, and active vitamin D analogues and calcium may be required for its treatment. Unlike bisphosphonates, when denosumab is discontinued, there is a rebound increase in bone turnover and an acceleration of bone loss. This likely reflects the maturation of accumulated osteoclast precursors (osteomorphs) in bone marrow when the drug was administered that then coalesce to become mature bone resorbing cells once denosumab is withdrawn. Other mechanisms involv­ ing reduced osteoprotegerin levels and osteocytes may also be involved. The consequences of this rebound increase in remodelingassociated bone loss are trabecular perforation and a rapid increase in the risk of fracture, particularly vertebral fracture, with a specific increase in multiple vertebral fractures. In patients who need to stop denosumab or in patients in whom BMD and fracture risk reduc­ tion goals have been met, temporary use of bisphosphonate treat­ ment may prevent the rebound increase in remodeling and rapid bone loss. In clinical practice, a single infusion of zoledronic acid at the time of the missed denosumab dose seems to maintain BMD for 1–2 years but may need to be repeated after 3 months, or more often, if bone turnover markers remain elevated. Oral bisphospho­ nates can also be used for 12–24 months to maintain bone density. In both cases, the required duration of bisphosphonate use to eliminate the rebound effect is not clear and may vary considerably among patients so bone density should continue to be monitored. Mode of Action  Denosumab is a fully human monoclonal anti­ body to RANKL, the final common effector of osteoclast formation, activity, and survival. Denosumab binds to RANKL, inhibiting its ability to initiate formation of mature osteoclasts from osteoclast precursors and to bring mature osteoclasts to the bone surface and initiate bone resorption. Denosumab also plays a role in reducing osteoclast survival. Through these actions on the osteoclast, deno­ sumab induces a potent and rapid antiresorptive action, as assessed biochemically and histomorphometrically. Anabolic Agents  •  Parathyroid Hormone  Endogenous PTH is an 84-amino-acid peptide that is largely responsible for calcium homeostasis (Chap. 422). Although chronic elevation of PTH, as occurs in hyperparathyroidism, is associated with bone loss (par­ ticularly at cortical bone sites such as the femoral neck and radius), PTH also can exert anabolic effects on bone if administered inter­ mittently. Consistent with this, some observational studies have indicated that mild endogenous hyperparathyroidism is associated with maintenance of trabecular bone mass but loss of cortical bone. Based on these findings, early small-scale observational stud­ ies showed that PTH analogues could augment trabecular BMD. Subsequent controlled clinical trials have confirmed that PTH can increase bone mass and reduce fracture incidence. The first random­ ized controlled trial in postmenopausal women showed that PTH (1–34) (teriparatide), when superimposed on ongoing estrogen

therapy, produced substantial increments in bone mass (13% over a 3-year period compared with estrogen alone) and reduced the risk of vertebral compression fractures. In the pivotal study (median,

19 months’ duration), 20 μg PTH (1–34) daily by subcutaneous injection (with no additional therapy) reduced vertebral fractures by 65% and nonvertebral fractures by 53% (Fig. 423-11). Teriparatide produces rapid and robust increases in bone formation and then bone remodeling overall, resulting in substantial increases in bone mass and improvements in microarchitecture, including cancel­ lous connectivity and cortical width. The BMD effects, particularly in the hip, are lower when patients switch from bisphosphonates to teriparatide, possibly in proportion to the potency of the anti­ resorptive agent. The hip BMD effect is particularly impaired and may result in transient bone loss, when patients switch from

Osteoporosis CHAPTER 423 Effect of teriparatide on the risk of new vertebral fractures

more new vertebral fractures Number of women with 1 or

Risk reduction

Relative: 65% Absolute: 9.3% Relative: 69% Absolute: 9.9% % of women

Placebo (n = 448) TPTD20 (n = 444) TPTD40 (n = 434) A Effect of teriparatide on the risk of nonvertebral fragility fractures

nonvertebral fragility fractures Risk reduction

Number of women with Relative: 53% Absolute: 2.9% Relative: 54% Absolute: 3.0%

% of women

Placebo (n = 544) TPTD20 (n = 541) TPTD40 (n = 552) B Effect of teriparatide on the risk of nonvertebral fragility fractures (time to first fracture)

% of women** *p <0.05 vs. placebo Placebo

TPTD20 TPTD40 * *

C Months since randomization FIGURE 423-11  Effects of teriparatide (TPT) on the following: A. new vertebral fractures; and B. and C. nonvertebral fragility fractures. (A and B are data from RM Neer et al: Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med May 344:1434, 2001. C From New England Journal of Medicine RM Neer et al: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis, 344:1434-1441. Copyright © 2001 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

denosumab to teriparatide. In patients on denosumab who need teriparatide treatment, there may be a role for combination therapy. In previously untreated women, teriparatide is administered as monotherapy and followed by a potent antiresorptive agent such as denosumab or an oral or intravenous bisphosphonate. Combi­ nation therapy is generally avoided because of cost and potential inhibition of the anabolic activity of teriparatide. Comparison with Antiresorptive Therapy  In women with painful acute osteoporotic vertebral fractures, teriparatide reduced subsequent vertebral fractures by ~50% compared with risedronate. There was no difference in nonvertebral fracture outcome between the two medications. A study comparing teriparatide with risedro­ nate in patients with prevalent vertebral fractures showed significant benefit for teriparatide against vertebral fractures (Fig. 423-12) and clinical fractures with a trend for a benefit of teriparatide against nonvertebral fractures.

PART 12 Endocrinology and Metabolism Side effects of teriparatide are generally mild and can include muscle pain, weakness, dizziness, headache, and nausea. These tend to remit with continuing treatment but may be mitigated by giving injections at night. Rodents given prolonged treatment with PTH in high doses (3–60 times the human dose) developed osteogenic sarcomas after ~18 months of treatment. Rare cases of osteosarcoma have been described in patients treated with teriparatide consistent with the background incidence of osteosarcoma in adults. Long-term surveillance studies of a high proportion of patients diagnosed with osteosarcoma as adults in both the United States and Scandinavia reveal no prior exposure to teriparatide in any of the cases. Teriparatide use may be limited by cost and its mode of admin­ istration (daily subcutaneous injection). Alternative modes of delivery have been investigated, but none have proven successful. Because of the rodent osteosarcoma data and the maximum dura­ tion of teriparatide in the pivotal trial of 2 years, the FDA previously limited teriparatide treatment to 2 years in a lifetime. However, registry data confirming no increased risk of osteogenic sarcoma in humans treated with teriparatide have allowed the FDA to drop this restriction on duration of use. As a result, consideration may be given to using intermittent courses of teriparatide therapy. In many other countries, however, teriparatide use is still restricted to 2 years in a lifetime. Mode of Action  Exogenously administered PTH appears to have direct actions on osteoblast activity, with biochemical and his­ tomorphometric evidence of de novo bone formation within a week or two in response to teriparatide. There is subsequently resorption. Incidence of new vertebral fractures First clinical fracture

64/533 Relative risk: 0.44 (95% Cl: 0.29–0.68) p<0.0001 Hazard ratio: 0.48 (95% Cl: 0.32–0.74) p=0.0009 Teriparatide Risedronate Patients with new vertebral fractures (%)

Relative risk: 0.52 (95% Cl: 0.30–0.91) p=0.019

35/585 28/516

18/574

A FIGURE 423-12  Effect of parathyroid hormone (PTH) treatment on vertebral fracture incidence at 12 and 24 months (A) and clinical fractures (B) compared with risedronate. (Reproduced with permission from D Kendler et al: Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO):

A multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 391:230, 2018.)

A B FIGURE 423-13  Effect of parathyroid hormone (PTH) treatment on bone microarchitecture. Paired biopsy specimens from a 64-year-old woman before (A) and after (B) treatment with PTH. (Reproduced with permission from DW Dempster et al: Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: A paired biopsy study. J Bone Miner Res 16:1846, 2001.) Subsequently, teriparatide primarily activates remodeling-based bone formation, favoring bone formation over bone resorption. Teriparatide given by daily injection stimulates osteoblast recruit­ ment and activity through activation of Wnt signaling. Teriparatide produces a true increase in bone tissue and an apparent restoration of bone microarchitecture (Fig. 423-13). Abaloparatide  Abaloparatide is a synthetic analogue of human PTHrP, which has significant homology to PTH and binds the PTH type 1 receptor. Abaloparatide and teriparatide exert different bind­ ing affinities to the two different receptor conformations, R0 and RG. Compared with teriparatide, abaloparatide binds with similar high affinity to the RG conformation but with much lesser affinity to the R0 conformation. These differences appear to result in a simi­ lar bone formation stimulus but lesser bone resorption stimulus, and abaloparatide was specifically chosen for development among many PTH and PTHrP analogues for what appeared to be an opti­ mized anabolic profile. In the phase 3 Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) study, 2463 postmenopausal women with osteoporosis were randomized to blinded daily subcutaneous aba­ loparatide versus placebo or open-label teriparatide. At 18 months, spine BMD increase was similar with abaloparatide and teriparatide (11.2% with abaloparatide and 10.5% with teriparatide); in the total hip, BMD increments were slightly larger with abaloparatide

Risedronate

Cumulative incidence (%)

Teriparatide

Number at risk Teriparatide Risedronate

B

Osteoporosis CHAPTER 423 (4.2 vs 3.3%). New vertebral fracture incidence was reduced by 86% with abaloparatide and 80% with teriparatide compared with placebo (both p <.001). The hazard ratio for abaloparatide versus teriparatide was not quoted. Nonvertebral fractures were reduced by 43% with abaloparatide (p = .05) and by 28% with teriparatide (not significant; p = .22). The ACTIVE study was extended, with 92% of eligible participants from the abaloparatide and placebo arms transitioned to open-label alendronate for a total treatment period of 24 months of alendronate. Both vertebral and nonvertebral fractures were less common in the group who transitioned from abaloparatide to alendronate, suggesting that the fracture benefit of abaloparatide can be maintained with antiresorptive treatment. Romosozumab  Romosozumab is a humanized antibody that blocks the osteocyte production of sclerostin, resulting in a unique action, with an increase in bone formation and decrease in bone resorption. In the pivotal trial (FRAME), 7180 postmenopausal women with osteoporosis were randomized to receive blinded monthly subcutaneous romosozumab (210 mg) or placebo for 1 year followed by transition to open-label subcutaneous deno­ sumab (60 mg) every 6 months for an additional year. BMD increased by over 13% in the spine and almost 7% in the hip in 1 year with romosozumab. At 1 year, the incidence of new vertebral fractures in the romosozumab group was significantly reduced by 73% compared with placebo. Clinical fracture risk (nonvertebral fractures and clinical vertebral fractures combined) was signifi­ cantly reduced by 36%. Nonvertebral fractures were also reduced, but the difference just missed statistical significance perhaps due to geographical differences; in the high-enrolling Latin American region, there was no significant reduction in nonvertebral fractures, probably due to a very low background incidence in that region. In the rest of the world, nonvertebral fractures were significantly reduced by >40%. During the second year of the FRAME study, both groups transitioned to denosumab. Over 24 months, women who had received romosozumab during the first 12 months and then denosumab had 75% fewer new vertebral fractures than those who had received placebo for a year followed by denosumab. There were also nearly significant trends toward reduced clinical and nonvertebral fractures in the romosozumab/denosumab group. Compared with baseline, BMD increased by 17.6% in the spine and 8.8% in the total hip in the romosozumab/denosumab group. Safety and tolerability of the two drugs were similar, with a slightly higher incidence of injection site reactions in the denosumab group. There was no increase of cardiovascular events in patients treated with romosozumab. The FRAME extension study where all participants received continued denosumab for an additional year (2 years in total) showed significant decreases in vertebral, clinical, and non­ vertebral fractures with a trend for hip fracture reduction. Comparison with Antiresorptive Therapy  The ARCH trial of very-high-risk patients, all of whom have prevalent vertebral fractures, compared romosozumab with alendronate for 1 year, followed by transition to, or continuation of, alendronate for at least 2 additional years. This study showed increases in bone den­ sity that were comparable with the FRAME study and significant reductions in vertebral, nonvertebral, clinical, and hip fractures compared with alendronate (Fig. 423-14). In this study, there was an increase in cardiovascular adverse events in patients treated with romosozumab, prompting a warning on the label and avoidance of this medication in patients with a past history of acute myocardial infarction or stroke. Comparison with Other Anabolic Therapy  No studies have compared romosozumab with other anabolic drugs with frac­ tures as the primary outcome. One study compared the effects of romosozumab with teriparatide in postmenopausal women with osteoporosis who had been previously treated with bisphospho­ nates, including 12 months of alendronate immediately prior to the study. Effects of both anabolic drugs on BMD were attenuated by prior bisphosphonate therapy, but the increases in spine, total hip, and femoral neck BMD were greater with romosozumab than with teriparatide. Increases in cortical bone mineral content and bone strength at the hip were also greater with romosozumab than with teriparatide. Sequence of Therapy  Because teriparatide and romosozumab have greater efficacy at reducing vertebral and clinical fractures, and vertebral, clinical, nonvertebral, and hip fractures, respectively, compared with bisphosphonates, they are now being considered as first-line therapy for patients with severe osteoporosis. Increases in BMD also occur more rapidly and to a greater extent with ana­ bolic drugs than with antiresorptive drugs, although the relative risk reduction for vertebral fractures is similar for zoledronic acid, denosumab, teriparatide, and romosozumab at about 70%. When their use is second-line following antiresorptive drugs, improve­ ments in BMD are attenuated, particularly following denosumab therapy. In response to these clinical data, initiatives have been made to identify patients at very high risk for fracture who would derive the most benefit from these greater improvements in BMD and more rapid reductions in fracture risk. Both U.S. and inter­ national guidelines have therefore focused on defining a group of individuals at very high fracture risk who could be selected for ana­ bolic therapy as first-line treatment. The definitions vary between these guidelines, but the criteria showing the most agreement are a recent fracture within the last 12–24 months, multiple fragility fractures (two or more), fractures while on antiresorptive therapy, or high absolute fracture risk (FRAX-derived 10-year risks of >4.5% or >30% for hip and major osteoporotic fractures, respectively). There has also been a focus on a goal-directed approach to long-term management of fracture risk. This helps ensure the most appropriate initial treatment and treatment sequence is selected for individual patients. Importantly, the selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and/or imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the likelihood that a BMD treatment target can be attained relatively rapidly and needs to consider differences in fracture risk reduction and BMD increases with anabolic versus antiresorptive therapy. In conclusion, for those patients with a very high and/or imminent fracture risk, the ideal treatment sequence would be anabolic followed by anti­ resorptive therapy. However, reimbursement considerations may limit the implementation of this approach. OTHER PHARMACOLOGIC AGENTS NOT APPROVED IN THE UNITED STATES Testosterone has been used to treat osteoporosis associated with low testosterone levels in men. There are data that indicate that testos­ terone can increase bone density, but there are no data indicating reductions in fractures. In fact, a recent large study showed fracture incidence was numerically higher among men who received tes­ tosterone than among those who received placebo. Since there are many other effects of testosterone, especially in older men (includ­ ing prostate hypertrophy), decisions to use it for treatment of osteoporosis must take these multisystemic effects into account. In hypogonadal men with a high or very high fracture risk, anti-osteo­ porosis therapy should be used in addition to testosterone therapy. Sodium fluoride was tested in two large parallel clinical trials in the late 1980s. Although BMD increased substantially, the increase was in part due to fluoride incorporation in the hydroxyapatite crystal. Fracture risk was not reduced and, in fact, was increased in nonvertebral sites. Therefore, fluoride is no longer considered a viable option for osteoporosis treatment. Several small studies of growth hormone, alone or in combina­ tion with other agents, have not shown consistent or substantial positive effects on bone mass. NONPHARMACOLOGIC APPROACHES Protective pads worn around the outer thigh, which cover the trochanteric region of the hip, can prevent hip fractures in elderly residents in nursing homes. They are only effective when worn, and their use is limited largely by issues of compliance and comfort, but

Incidence of new vertebral fracture 12 Months

Patients (%) Risk ratio, 0.63 P=0.003 6.3 (128/2047) 4.0 (82/2046)

PART 12 Endocrinology and Metabolism

Alendronate Romosozumab A First clinical fracture in time-to-event analysis

P<0.001 Cumulative incidence (%) Alendronate→ Alendronate

Romosozumab→ Alendronate Alendronate

Romosozumab

Month

No. at Risk Alendronate 2047 1868 1743 Romosozumab 2046 1865 1770 Alendronate→ 1645 1564 1066 680 325 108 alendronate Romosozumab→ 1683 1615 1103 705 347 109 alendronate B C FIGURE 423-14  Effect of romosozumab versus alendronate for 12 months followed by alendronate on vertebral, clinical, and nonvertebral fracture incidence. (From The New England Journal of Medicine, Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis, KG Saag et al: 377:1417. Copyright @2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) new devices are being developed that may circumvent these problems and provide adjunctive treatments. Kyphoplasty and vertebroplasty are nonpharmacologic approaches for the treatment of painful vertebral fractures. The overall data do not support routine surgical intervention for painful vertebral fractures since, while this can reduce pain, there is concern about long-term vertebral fracture risk. Vertebral augmentation should be avoided in patients with vertebral fractures associated with denosumab discontinuation as it can increase the risk of adjacent vertebral fractures in this setting. TREATMENT MONITORING There are currently no well-accepted guidelines for monitoring treatment of osteoporosis. Because most osteoporosis treatments produce small or moderate bone mass increments on average, it is reasonable to consider BMD as a monitoring tool. Changes must exceed ~3% in the spine and 6% in the hip to be considered significant in any individual. The total hip is the preferred site due to larger surface area and greater reproducibility. Medication-induced increments may require several years to produce changes of this magnitude. Consequently, it can be argued that BMD should be repeated at intervals of every 2 years. Only significant BMD reductions (>~3% or ~6% at the spine and or hip, respectively) should prompt a change in therapy, as it is expected that some individuals will not show responses greater than the detection limits of the current measurement techniques.

24 Months Risk ratio, 0.52 P<0.001

11.9 (243/2047)

6.2 (127/2046)

Alendronate→ Alendronate Romosozumab→ Alendronate First nonvertebral fracture in time-to-event analysis

P=0.04 Cumulative incidence (%) Alendronate→ Alendronate

Romosozumab→ Alendronate Alendronate

Romosozumab

Month

No. at Risk Alendronate 2047 1873 1755 Romosozumab 2046 1867 1776 Alendronate→ 1661 1590 1097 697 330 110 alendronate Romosozumab→ 1693 1627 1114 714 350 109 alendronate Biochemical markers of bone turnover can help in treatment monitoring, with significant changes seen within 3 months of initiating treatment with approved medications and the possible benefit of improving adherence. It remains unclear which endpoint is most useful. If bone turnover markers are used, a determination should be made before therapy is started and repeated ≥3–4 months after therapy is initiated. In general, a change in bone turnover markers must be 30–40% lower than the baseline, or in the lower part of the standardized premenopausal range, to be significant because of the biologic and analytic variability in these tests. Because markers change more rapidly than bone density, they are often early signs of treatment effect. Currently collagen C-telopeptide (CTX) measured on a fasting serum sample in the morning is the preferred marker of bone resorption, and the propeptide of type 1 collagen (P1NP) is the preferred marker for bone formation. GLUCOCORTICOID-INDUCED OSTEOPOROSIS Osteoporotic fractures are a well-characterized consequence of the hypercortisolism associated with Cushing’s syndrome. However, the therapeutic use of glucocorticoids is by far the most common form of glucocorticoid-induced osteoporosis (GCIOP). Glucocorticoids are used widely in the treatment of a variety of disorders, including chronic lung disorders, rheumatoid arthritis and other connective tissue diseases, and inflammatory bowel disease, and after transplantation.