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Osteoporosis

Chapter 423 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Osteoporosis is defined as a reduction in bone strength leading to skeletal fragility and fractures.
  2. WHO defines osteoporosis as a bone density 2.5 standard deviations (SDs) or more below the mean for young healthy adults (T-score ≤ –2.5).
  3. Fragility fractures are defined as fractures in adults occurring following a fall from standing height or less, excluding finger, toes, face, and skull fractures.
  4. Lifetime osteoporotic fracture risk for a Caucasian woman reaching age 50 is ~50%; for a 50-year-old man is ~25%.
  5. Approximately 20% of women will have a second fracture within 2 years after the first fracture.
  6. Recommended daily calcium intake is 1000–1200 mg; intakes <400 mg are detrimental to the skeleton.
  7. Optimal serum 25(OH)D for skeletal health is >75 nmol/L (30 ng/mL).
  8. Estrogen deficiency increases RANKL production and reduces osteoprotegerin production, increasing osteoclast formation.
  9. Glucocorticoids are the most common cause of medication-induced osteoporosis.
  10. Prior fragility fractures, family history of hip fracture, low BMI, smoking, and excessive alcohol are independent predictors.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Effects of teriparatide (TPT) on the following: A
2 🖼 Figure Effects of various bisphosphonates on fracturs
3 🖼 Figure hip, respectively, after 10 years of denosumab treatment
4 🖼 Figure Mechanism of bone remodeling
5 🖼 Figure new devices are being developed that may circumvent these prob- lems and...
6 🖼 Figure Colles’ 35–39 ≥85 Age group, year FIGURE 423-3 Factors leading to osteoporotic...
7 🖼 Figure Hormonal control of bone resorption
8 🖼 Figure FRAX calculation tool
9 🖼 Figure and increased risk of venous thrombosis and stroke, similar in magnitude to...
10 🖼 Figure bone density, mostly of the spine, which is a particular problem in...
11 🖼 Figure benefit for teriparatide against vertebral fractures (Fig

1. DEFINITION & OVERVIEW

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

1.1 Definition

📖 Harrison's defines this as:

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 microarchitectural deterioration and misalignment of bone components also contribute. Thus, relying solely on the measure of bone mineral density may underestimate bone fragility.

1.2 WHO Criteria

The World Health Organization (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 50% of fractures among postmenopausal women, including hip fractures, occur in individuals with osteopenia because the size of that population is much larger than the group defined as having osteoporosis by bone density T-score.

1.3 Fragility Fractures

Fragility fractures are defined as fractures in adults occurring following 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.

2. 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 present 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.

2.1 Fracture Statistics

Globally, hip fractures are increasing and are associated with high costs. The failure 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 risk of fracture and of developing osteoporosis. Although osteoporosis 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.

2.2 Fracture Incidence by Age

Most fractures, especially those of the hip and vertebrae, show exponential increases with advancing age. Lifetime osteoporotic 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.

2.3 Mortality and Morbidity

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 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 subsequent fracture.

2.4 Risk Factors

The common clinical risk factors for fracture are summarized in Table 423-1. Prior fragility fractures, a family history of hip fracture, low body mass index, cigarette smoking, and excessive 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. 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 reuptake 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 postmenopausal bone loss in women. However, this sex difference in bone density and hip fracture incidence is not apparent in all countries, possibly due to genetics, physical activity levels, or diet.

Table 1 — TABLE 423-1 Risk Factors for Osteoporosis Fracture

NONMODIFIABLE POTENTIALLY MODIFIABLE
Personal history of fracture as an adult Current cigarette smoking
History of fracture in first-degree relative Estrogen deficiency
Female gender Early menopause (<45 years) or bilateral ovariectomy
Advanced age Prolonged premenstrual amenorrhea (>1 year)
White race (>1 year) Poor nutrition especially low calcium and vitamin D intake
Dementia Alcoholism
Impaired eyesight despite adequate correction
Recurrent falls
Inadequate physical activity
Poor health/frailty

3. ETIOLOGY & PATHOPHYSIOLOGY

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. A low peak bone mass may underlie the development of osteoporosis due to hormonal, genetic, or nutritional influences. Age-related changes in bone remodeling as well as extrinsic and intrinsic factors may then be superimposed.

3.1 Bone Remodeling

During growth, the skeleton increases in size by linear growth and by apposition of new bone tissue on the cortical periosteum. 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 osteoporosis. 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-pseudoglioma syndrome, and LRP5 signaling is important in controlling bone formation. Genome-wide scans for low bone mass suggest multiple genes are involved, many of which are also implicated in control of body size.

3.2 Remodeling Mechanisms

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 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 damaged 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 hormone (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 primarily 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.

3.3 RANKL/OPG Pathway

The cytokine responsible for communication between the osteoblasts, other marrow cells, and osteoclasts is receptor 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. 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.

3.4 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 remodeling 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)D] and enhanced gastrointestinal calcium absorption. PTH also reduces renal calcium loss. Although these are appropriate compensatory 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 balance. 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); however, 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).

3.5 Vitamin D

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 (30 ng/mL). 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 estrogen 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.

3.6 Estrogen Status

Estrogen deficiency causes bone loss by two distinct but interrelated mechanisms: (1) activation of new bone remodeling sites and (2) initiation 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 resorption and formation is achieved. This commences in the perimenopause but prior to cessation of periods. This remodeling imbalance results in a permanent decrement in mass. In addition, the 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 cancellous connectivity is reduced. A higher number of remodeling sites in the skeleton alone increases the probability of trabecular perforation, 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 measure these directly. The most common cause of estrogen deficiency is the menopause, which occurs on average at age 51 years. Thus, with current 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 formation 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 heterogeneous 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.

3.7 Physical Activity

Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss. Concordantly, athletes have higher bone mass than nonathletes. 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 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.

3.8 Chronic Diseases

Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis. Mechanisms that contribute to bone loss are unique for each disease and typically result from multiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodeling or bone quality. In most, not all circumstances, the primary diagnosis is made before osteoporosis presents clinically. Both type 1 and type 2 diabetes mellitus are associated with an increased fracture risk, with increased risk at higher bone density than in the nondiabetic population. This is due to differences 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 function 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., wheelchair 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 evaluation of bone density in that population by the International Society of Clinical Densitometry published in 2019.

Table 2 — TABLE 423-2 Diseases Associated with an Increased Risk of Generalized Osteoporosis in Adults

Hypogonadal states Endocrine disorders Nutritional and gastrointestinal disorders Rheumatologic disorders Hematologic disorders/malignancy Selected inherited disorders Other disorders
Turner's syndrome Cushing's syndrome Malnutrition Rheumatoid arthritis Multiple myeloma Osteogenesis imperfecta Immobilization
Klinefelter's syndrome Hyperparathyroidism Parenteral nutrition Ankylosing spondylitis Lymphoma and leukemia Marfan's syndrome Chronic obstructive pulmonary disease
Anorexia nervosa Thyrotoxicosis Malabsorption syndromes Scoliosis Malignancy-associated parathyroid hormone–related peptide (PTHrP) production Hypophosphatasia Pregnancy and lactation
Hypothalamic amenorrhea Diabetes mellitus (both type 1 and 2) Gastrectomy Amyloidosis Mastocytosis Glycogen storage diseases Sarcoidosis
Hyperprolactinemia Acromegaly Severe liver disease, especially biliary cirrhosis Multiple sclerosis Hemophilia Homocystinuria Ehlers-Danlos syndrome
Other primary or secondary hypogonadal states Adrenal insufficiency Pernicious anemia Sarcoidosis Thalassemia Menkes' syndrome Epidermolysis bullosa
Porphyria Thalassemia Porphyria

3.9 Medications

Many medications used in clinical practice have potentially detrimental effects on the skeleton. Glucocorticoids are the most 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 medication 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)D, as some anticonvulsants induce the cytochrome P450 system and 2 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. 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.

Table 3 — TABLE 423-3 Drugs Associated with an Increased Risk of Generalized Osteoporosis in Adults

Drug Class Specific Agents
Glucocorticoids Excessive thyroxine
Cyclosporine Aluminum
Cytotoxic drugs Gonadotropin-releasing hormone agonists
Anticonvulsants Heparin
Aromatase inhibitors Lithium
Selective serotonin reuptake inhibitors Protein pump inhibitors
Thiazolidinediones
Androgen deprivation therapies

4. CLINICAL FEATURES

The clinical manifestations of a hip fracture are most common among postmenopausal women, but 30% of fragility fractures occur in men. Other underlying diseases can result in secondary osteoporosis. The threshold for fracture is reduced in osteoporotic bone due to increased skeletal fragility. Traumatic fractures 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 summarized in Table 423-1. Prior fragility fractures, a family history of hip fracture, low body mass index, cigarette smoking, and excessive 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. 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 reuptake 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 postmenopausal bone loss in women. However, this sex difference in bone density and hip fracture incidence is not apparent in all countries, possibly due to genetics, physical activity levels, or diet.

4.1 Vertebral Fractures

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 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 subsequent 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, 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.

4.2 Wrist and Other Fractures

Approximately 400,000 wrist fractures occur in the United States each year. Fractures of other bones (including ~150,000 pelvic fractures and >100,000 proximal humerus fractures) also occur due to osteoporosis. The threshold for fracture is reduced in osteoporotic bone due to increased skeletal fragility. Traumatic fractures 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. 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.

4.3 Fracture Risk Progression

The risk for future fracture after a first fracture is exponentially increased in the first 12–24 months, leading to the concept of imminent 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 subsequent 3 years but remains persistently elevated after a vertebral or hip fracture. Vertebral fractures increase the risk of other vertebral fractures as well 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.

5. 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 associated 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 excessive alcohol intake may suggest magnesium deficiency. 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 deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathyroidism. 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 deformities 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 pattern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clearance). The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders, and hereditary defects in vitamin D metabolism leads to secondary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia.

6. INVESTIGATIONS & DIAGNOSIS

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 energies 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 scanning 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 bone density, mostly of the spine, which is a particular problem in measuring 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 in a population of the same age, sex, and race.

6.1 Diagnostic Criteria

📖 Harrison's defines this as:

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 microarchitectural 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 Organization (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 50% of fractures among postmenopausal women, including hip fractures, occur in individuals 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, incorporating 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).

6.2 Imaging Findings

Fragility fractures are defined as fractures in adults occurring following 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. The vast majority are clinically "silent" vertebral fractures identified incidentally during spinal radiography 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 subsequent 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, 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.

7. MANAGEMENT & TREATMENT

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. 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); however, 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). 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 fracture 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 cancers (colorectal, prostate, and breast), autoimmune diseases, multiple sclerosis, and cardiovascular disease, most controlled clinical trials also have not confirmed these effects. However, vitamin D does prevent progression of prediabetes to diabetes in those with vitamin D deficiency (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.

7.1 Calcium Supplementation

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 balance. Such intakes should preferentially come from dietary sources, for 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.

7.2 Vitamin D Supplementation

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. 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. For most adults, supplements of 1000–2000 IU/d are adequate and safe.

7.3 Fracture Liaison Services

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.

8. PROGNOSIS & COMPLICATIONS

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. 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 risk for future fracture after a first fracture is exponentially increased in the first 12–24 months, leading to the concept of imminent 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 subsequent 3 years but remains persistently elevated after a vertebral or hip fracture. Vertebral fractures increase the risk of other vertebral fractures as well 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.

8.1 Mortality

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.

8.2 Secondary Fractures

The failure to identify the first fragility fracture and intervene is estimated to cost $6 billion to Medicare alone for secondary fractures. The occurrence of the first fracture greatly increases the risk of further fractures, especially in the first year. The risk for future fracture after a first fracture is exponentially increased in the first 12–24 months, leading to the concept of imminent 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 subsequent 3 years but remains persistently elevated after a vertebral or hip fracture.

9. SPECIAL CONSIDERATIONS

The increasing prevalence of transgender and gender nonconforming individuals has prompted a guideline for evaluation of bone density in that population by the International Society of Clinical Densitometry published in 2019. The most common cause of estrogen deficiency is the menopause, which occurs on average at age 51 years. Thus, with current 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. 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.

9.1 Transgender Population

The increasing prevalence of transgender and gender nonconforming individuals has prompted a guideline for evaluation of bone density in that population by the International Society of Clinical Densitometry published in 2019.

9.2 Medication Risks

Many medications used in clinical practice have potentially detrimental effects on the skeleton. Glucocorticoids are the most 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 medication 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)D, as some anticonvulsants induce the cytochrome P450 system and 2 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. 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.

Table 4 — TABLE 423-3 Drugs Associated with an Increased Risk of Generalized Osteoporosis in Adults

Drug Class Specific Agents
Glucocorticoids Excessive thyroxine
Cyclosporine Aluminum
Cytotoxic drugs Gonadotropin-releasing hormone agonists
Anticonvulsants Heparin
Aromatase inhibitors Lithium
Selective serotonin reuptake inhibitors Protein pump inhibitors
Thiazolidinediones
Androgen deprivation therapies

10. KEY PEARLS & CLINICAL TRAPS

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 associated 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 excessive alcohol intake may suggest magnesium deficiency. 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 deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathyroidism. 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 deformities 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 pattern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clearance). The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders, and hereditary defects in vitamin D metabolism leads to secondary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia.

WHAT EXCLUDES THE DIAGNOSIS

Fragility fractures are defined as fractures in adults occurring following 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.

10.1 Exclusion Criteria

Fragility fractures are defined as fractures in adults occurring following a fall from standing height or less, but exclude finger, toes, face, and skull fractures.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Effects of teriparatide (TPT) on the following: A

Caption: 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.) — Figure 423-1: Epidemiology of vertebral, hip, and Colles' fractures with age, showing exponential increases with advancing age.

Figure 2

Effects of various bisphosphonates on fracturs

Caption: FIGURE 423-9 Effects of various bisphosphonates on fracturs. A. Clinical vertebral reduction. (Data from DM Black et al: J Clin Endocrinol Metab 85:4238, 2000; C Roux et al: DM Black et al: N Engl J Med 356:1809, 2007; JT Harrington et al: Calcif Tissue Int 74:129, — Figure 423-2: Lateral spine x-ray showing severe osteopenia and a severe wedge-type deformity (severe anterior compression).

Figure 3

hip, respectively, after 10 years of denosumab treatment

Caption: 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 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.) — Figure 423-3: Factors leading to osteoporotic fractures, illustrating the threshold for fracture reduced in osteoporotic bone.

Figure 4

Mechanism of bone remodeling

Caption: FIGURE 423-4 Mechanism of bone remodeling. The basic molecular unit (BMU) of 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.) — Figure 423-4: Mechanism of bone remodeling, depicting the basic molecular unit (BMU) moving along the trabecular surface over ~120 days.

Figure 5

new devices are being developed that may circumvent these prob-...

Caption: new devices are being developed that may circumvent these prob- lems 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 FIGURE 423-14 Effect of romosozumab versus alendronate for 12 months followed by England Journal of Medicine, Romosozumab or Alendronate for Fracture Prevention in Medical Society. Reprinted with permission from Massachusetts Medical Society.) — Figure 423-5: Hormonal control of bone resorption, showing proresorptive factors (RANKL) and anabolic/antiosteoclastic factors (OPG).

Figure 6

Colles’ 35–39 ≥85 Age group, year FIGURE 423-3 Factors leading...

Caption: Colles’ 35–39 ≥85 Age group, year 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. Approximately 400,000 wrist fractures occur in the United States each year. Fractures of other bones (including ~150,000 pelvic frac- FIGURE 423-1 Epidemiology of vertebral, hip, and Colles’ fractures with age. tures and >100,000 proximal humerus fractures) also occur due to (Reproduced with permission from C Cooper, LJ Melton 3rd: Epidemiology of — Figure showing Dual-Energy X-ray Absorptiometry (DXA) measurement sites, typically lumbar spine and hip.

Figure 7

Hormonal control of bone resorption

Caption: FIGURE 423-5 Hormonal control of bone resorption. A. Proresorptive and calciotropic in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating prostaglandin E; PTH, parathyroid hormone; RANKL, receptor activator of nuclear 2 thrombospondin. (Reproduced with permission from WJ Boyle et al: Osteoclast 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, of — Figure illustrating Calcium homeostasis and the role of PTH and Vitamin D in gastrointestinal absorption and renal retention.

Figure 8

FRAX calculation tool

Caption: FIGURE 423-7 FRAX calculation tool. When the answers to the indicated questions are The calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) — Figure depicting the mechanism of estrogen deficiency on bone cells, showing increased RANKL and decreased osteoprotegerin.

Figure 9

and increased risk of venous thrombosis and stroke, similar in...

Caption: 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 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.) — Figure showing Vertebral fracture types, including wedge-type and biconcave (codfish) deformities.

Figure 10

bone density, mostly of the spine, which is a particular...

Caption: 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 FIGURE 423-6 Relationship between Z-scores and T-scores in a 60-year-old woman. BMD, bone mineral density; SD, standard deviation. — Figure representing Fracture Risk Assessment (FRAX) score calculation components.

Figure 11

benefit for teriparatide against vertebral fractures (Fig

Caption: benefit for teriparatide against vertebral fractures (Fig. 423-12) and FIGURE 423-13 Effect of parathyroid hormone (PTH) treatment on bone clinical fractures with a trend for a benefit of teriparatide against microarchitecture. Paired biopsy specimens from a 64-year-old woman before (A) and after (B) treatment with PTH. (Reproduced with permission from DW Dempster nonvertebral fractures. et al: Effects of daily treatment with parathyroid hormone on bone microarchitecture Side effects of teriparatide are generally mild and can include and turnover in patients with osteoporosis: A paired biopsy study. J Bone Miner Res muscle pain, weakness, dizziness, headache, and nausea. These tend 16:1846, 2001.) to remit with continuing treatment but may be mitigated by giving injections at night. Rodents given prolonged treatment with PTH Subsequently, teriparatide primarily activates remodeling-based in high doses (3–60 times the human dose) developed osteogenic bone formation, favoring bone formation over bone resorption. sarcomas after ~18 months of treatment. Rare cases of osteosarcoma Teriparatide given by daily injection stimulates osteoblast recruit- — Figure showing Bone histology comparing trabecular and cortical bone architecture and remodeling sites.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.