Osteoporosis, Osteomalacia, and Metabolic Bone Disease

Definition

Osteoporosis is defined as a “systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.” This definition emphasizes the important role of unmeasured ultrastructural abnormalities that contribute to the clinical endpoint of fracture. The incidence of hip fracture increases between the ages of 50 and 90 years seven times more than predicted on the basis of decline in bone density alone. In persons over 75 years of age, nonskeletal risk factors such as gait impairment and falls are significant factors for fracture risk.

Diagnosis of Osteoporosis

A painful fracture is the most obvious clinical consequence of osteoporosis, but as many as 70% of osteoporotic spine fractures are asymptomatic. Although a clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture, which is a fracture sustained from a force equivalent to a fall from a standing height, in the absence of bone mineral density (BMD) measurement, low bone mass is recognized as a more sensitive diagnostic parameter in the absence of symptoms. Low bone mass is also a strong predictor of future fracture risk. The World Health Organization (WHO) has defined osteoporosis and osteopenia on the basis of BMD ( Table 52.1 ). A T-score is defined as the number of standard deviations above or below the average BMD for healthy young Caucasian female reference. For men, the WHO and International Society for Clinical Densitometry (ISCD) also recommend the use of the female reference database for T-score determination. However, this presents controversy because clinical trials for osteoporosis treatment recruited subjects based on T-scores calculated from a healthy young male reference database, and therefore application of the recommendations may vary. The Z-score is defined as the number of standard deviations above or below the average BMD for an age-, ethnicity-, and sex-matched reference. Osteoporosis is diagnosed in postmenopausal women and men 50 years or older when the T-score is −2.5 or less at the lumbar spine, total hip, femoral neck, or one-third radius. Severe osteoporosis is defined as a T-score of −2.5 or less in the presence of one or more fragility fractures. Z-scores are used to assess bone mineral status in premenopausal women and men younger than 50 years of age. A low Z-score (< −2.0) represents a bone density that is below the expected range for age and suggests that secondary causes of bone loss may be present. ^, The WHO thresholds were chosen on the basis of fracture risk in postmenopausal Caucasian women. Similar diagnostic threshold values for men are less well defined. However, several studies have demonstrated that the relative fracture risk for every standard deviation decrement of BMD is similar between men and women. The ISCD advises that the WHO criteria for osteoporosis not be used in premenopausal women or men under 50 years old because the fracture risk is not the same in younger men and women.

Several technologies are available to measure bone mass, including forearm single-photon absorptiometry, spine and hip dual-photon absorptiometry, and quantitative ultrasound of the calcaneus. Although multiple studies have shown that these various measurement techniques may predict osteoporotic risk, the gold standard remains dual-energy x-ray absorptiometry (DXA) of the hip and spine for the diagnosis of osteoporosis. ^, DXA is considered the gold standard because it has been shown to be precise (1%‒2%) and to have acceptable accuracy and good reproducibility. It is also the most extensively validated test for fracture outcomes. ^, Other advantages of DXA include relatively low radiation exposure, wide availability, and the capacity to measure bone density at multiple skeletal sites. The ISCD recommends obtaining BMD measurements of the spine and hip. Numerous studies have shown that BMD measured at the femur (neck or total hip) is the best for predicting hip fracture risk. ^{, ,} Spinal BMD is the optimum for monitoring response to treatment. The risk of hip fracture is increased 2.6 times for each standard deviation decrease at the femoral neck, and the fracture risk gradient at other sites is increased approximately 1.5 times for every standard deviation decrease. ^, Longitudinal BMD measurements should be performed on the same machine at the same institution, owing to variability of BMD assessments among machines and among institutions’ imaging techniques.

Newer generations of DXA scanners permit the acquisition of information in addition to BMD values of central skeletal sites. Vertebral fracture assessment (VFA) is a densitometric spine imaging process that acquires a lateral spine image during a DXA scan and allows detection of vertebral fractures. Vertebral fracture diagnosis is based on the Genant semiquantitative method that assesses grade and severity similar to interpretation of standard radiological approaches. A majority of vertebral fractures are asymptomatic; therefore, the ISCD recommends lateral spine x-rays/VFA when the T-score is less than –1.0 and one or more of the following is applicable: age over 70 years in women or over 80 years in men, reported height loss of greater than 4 cm, self-reported vertebral fracture that is undocumented, or history of glucocorticoid therapy of 5 mg or more of prednisone or equivalent daily for 3 or more months. The trabecular bone score (TBS) is a texture index derived from standard lumbar spine DXA images that provides information that is related to bone microarchitecture independent of BMD and is relatively unaffected by degenerative changes in the lumbar spine. Low TBS is associated with history of fracture and incidence of new fractures. It can be used to enhance fracture risk determination—adjusting the fracture risk assessment tool (FRAX)–probability of fracture—and may have greatest utility for those individuals with BMD values that lie close to thresholds for intervention.

Most clinical guidelines recommend screening for osteoporosis at age 65 years for healthy women and at age 70 years for healthy men. The ISCD recommends screening women younger than 65 years and men younger than 70 years if they have risk factors for low bone density. Another indication for screening is radiographic evidence of osteopenia or vertebral fracture. In addition, DXA screening is recommended for people who have diseases associated with bone loss, such as rheumatoid arthritis, as well as people initiating treatment or currently being treated with corticosteroid therapy for greater than 3 months with a dose of 5 mg or more of prednisone or equivalent daily ( Box 52.1 ). Current evidence does not support routine screening of all perimenopausal women, as its value in directing preventive therapy against future fractures has not been established.

Bone turnover markers (BTMs) reflecting bone formation and resorptive activity are not recommended for routine diagnostic purposes, as they have not been found to predict bone mass or fracture risk. Indices of bone formation include bone-specific alkaline phosphatase (ALP), N-terminal propeptide of type 1 collagen (P1NP), and osteocalcin. Markers for resorption include serum and urine levels of type 1 collagen C- and N-telopeptides (CTX, NTX). Although not reliable diagnostically, they have been found to be helpful in clinical trials for understanding the mechanism of bone loss. A fracture may result in elevation of BTM for 6 to 9 months. Bone turnover markers may also be helpful for monitoring response to therapy and adherence to treatment.

Evaluation of patients with osteoporosis should include a thorough history and physical examination, as most of the secondary causes of osteoporosis can be excluded. A minimum screening laboratory profile should be considered for patients who have been diagnosed with osteoporosis ( Table 52.2 ). This is particularly important in men and premenopausal women, as approximately 50% will have an identifiable secondary cause. The more common identifiable causes of osteoporosis include hypogonadism, glucocorticoid usage, gastrointestinal disease, vitamin D deficiency, and anticonvulsant therapy. As mentioned previously, patients with an abnormally low Z-score should also be studied more aggressively for secondary causes. Initial general screening should include a complete blood count, complete chemistry profile with ALP, serum calcium, serum 25 hydroxy-vitamin D, phosphorus, thyroid-stimulating hormone (TSH), testosterone in men, and 24-hour urine for calcium and creatinine. Tannenbaum and colleagues looked at the yield of laboratory testing to identify secondary causes of osteoporosis in otherwise healthy women. Their findings suggest that a basic screen of serum calcium, serum parathyroid hormone (PTH), and 24-hour urinary calcium excretion in all patients, and serum TSH in patients on thyroid replacement, provides a high diagnostic yield (86% in their study) at a low cost (mean cost of $75/patient). Additional studies should be obtained selectively on the basis of risk factors and results of preliminary studies ( Table 52.3 ). Some examples include PTH and 1,25-dihydroxyvitamin D in setting of hypercalcemia or hypercalciuria, celiac testing if there is evidence of malabsorption, serum and urine protein electrophoresis if there is concern for multiple myeloma, anemia, and unexplained weight loss, and 24-hour urinary free cortisol measurement if there are signs of Cushing syndrome.

Prevalence and Costs

The prevalence of osteoporosis increases with age in both men and women. It is estimated that 10.2 million Americans older than 50 years of age have osteoporosis and 43 million have low bone mass. This number is expected to increase to more than 14 million people in 2020. Although osteoporosis is commonly conceived of as a disease of women, more than 20% of people with osteoporosis or low BMD in the United States are men. The clinical consequence of osteoporosis is fracture. The 2004 U.S. Surgeon General’s Report on Bone Health and Osteoporosis concluded that osteoporosis results in approximately 1.5 million fragility fractures annually. The worldwide incidence rate of hip and vertebral fractures varies widely based on country of origin, but ranges from less than 100 to 600 per 100,000 people to less than 100 to 1400 per 100,000 people, respectively. ^, Vertebral compression fractures are the most common, accounting for approximately 700,000 fractures per year. More than 50% of women and 30% of men will experience a vertebral compression in their lifetime. As many as 20% of people who suffer from a vertebral fragility fracture will experience another within 1 year.

Beyond the personal suffering and functional impact, the economic burden to society of osteoporosis is considerable. The estimated cost of caring for the greater than 2 million osteoporotic fractures in 2005 was estimated to be $17 billion. These figures are expected to increase by 50% by 2025, when the annual fracture incidence will surpass 3 million, and costs will exceed $25 billion.

Pathophysiology

Peak bone mass is achieved by about age 30 years in both sexes. Differences in peak bone mass account for some of the variation in osteoporosis risk between men and women, as well as between racial and ethnic groups. For example, African-American women have higher bone densities than non-Hispanic women at all ages and are at lower risk for fractures of the spine and hip. Because achievement of genetically determined peak bone mass occurs primarily before the age of 20 years, osteoporosis in later life may, in part, be regarded as a pediatric disease with geriatric consequences. Calcium intake during childhood and adolescence is positively associated with bone mass in the fourth decade of life.

Age-related bone loss begins in the fourth decade and continues throughout life in men and women. By the eighth or ninth decade of life, women have lost approximately 35% of their cortical bone mass and 50% of their trabecular bone mass. Men lose about 30% of their trabecular bone and 20% of their cortical bone during their lifetimes. Menopause in women is associated with a period of accelerated loss of trabecular bone in the first 2 years that persists for about 10 years. Thereafter, bone loss from trabecular and cortical sites continues at a slower rate, similar to that of men. Skeletal sites that are predominantly trabecular in composition, including vertebral bodies and distal forearm bones, are therefore at greatest risk for osteoporosis at any earlier timepoint. Rates of Colles and vertebral fractures in women rise sharply after menopause.

The major cause of primary age-related osteoporosis in both men and women is loss of gonadal function. In young adults, skeletal remodeling is an ongoing process with closely coupled bone resorption and formation. In estrogen-deficient women, there is an imbalance between bone formation and resorption, resulting in net bone loss. Estrogen has multiple effects on both osteoclast and osteoblast function. Estrogen suppresses osteoclast development by suppressing receptor activator of nuclear factor κB ligand (RANKL) production, as well as regulating production of osteolytic cytokines, including interleukin-1, interleukin-6, tumor necrosis factor–α, and prostaglandins. ^, Estrogen plays a role in bone formation by stimulating production of growth factors by osteoblasts. The principal risk factors for primary osteoporosis in women are related to estrogen deficiency: postmenopausal status; nulliparity; late menarche; early menopause (before age 45 years), whether natural or surgically- or medically-induced; and secondary amenorrhea related to exercise or eating disorders. As in women, estrogen plays a critical role in maintaining bone density in men, and serum estradiol levels are more predictive of bone density in men than androgen levels. Although androgens are important determinants of muscle mass in males, serum estradiol levels are more predictive of bone density. Peripheral aromatization of androgens to estrogen is important in maintaining estradiol levels above the threshold required to maintain skeletal homeostasis.

In older men and women, other factors contribute to age-related bone loss, including physiological hyperparathyroidism, vitamin D deficiency, and secretion of various bone-resorbing cytokines. ^{, ,} Studies suggest a remarkably high level of vitamin D deficiency among older adults. In one study, more than 50% of older North American women currently treated for osteoporosis were found to have suboptimal vitamin D levels. In the patients with fractures or falls, the prevalence of vitamin D deficiency exceeds 90%. In most studies of older adults, the prevalence of low serum vitamin D levels is unrelated to gender, race, latitude, or global location.

Risk Assessment

In addition to the changes in bone density related to decline in gonadal function in both men and women, multiple lifestyle factors, medical disorders, and drugs may exacerbate or accelerate “age-related” bone loss ( Box 52.2 ). Approximately 50% of men with osteoporosis have underlying “secondary” causes, and as many as one-third of women with osteoporosis are found to have other conditions beyond estrogen deficiency. ^, In men with osteoporosis, the most common secondary causes are hypogonadism, glucocorticoid use, and alcoholism. In women, secondary causes are more common in perimenopausal women and include glucocorticoid use, thyroid hormone excess, and anticonvulsant treatment.

Measurements of BMD alone are insensitive as predictors of risk of clinical fragility fractures. Incorporating assessment of clinical risk factors for bone loss and fracture risk into predictive models for fragility fracture, with or without BMD measurement, greatly enhances the assessment of fracture risk in both men and women. The WHO has developed the FRAX tool, which incorporates multiple risk factors, including body mass index, personal history of previous fracture, history of parental hip fracture, current smoking, history of long-term glucocorticoid use, rheumatoid arthritis, and daily consumption of three or more units of alcohol. The tool also includes the presence or absence of other secondary causes of osteoporosis, including hypogonadism, inflammatory bowel disease, prolonged immobility, organ transplantation, type 1 diabetes, and thyroid disorders. FRAX is available to clinicians online ( www.shef.ac.uk/FRAX ) and provides estimates of the 10-year probability of hip fracture and major osteoporotic fracture.