Alan Ona Malabanan Osteoporosis is characterized by increased bone fragility and increased susceptibility to fracture. This increased bone fragility results from decreases in bone mass and deterioration of bone microarchitecture that occur as the result of estrogen deficiency and aging. A variety of diseases, such as rheumatoid arthritis, and medications, such as glucocorticoids, may contribute to bone loss. Osteoporosis is the most common metabolic bone disease; more than 10 million Americans are affected, and an additional 33.6 million have low bone mass and are at high risk for development of the disease. An important responsibility of the primary care provider is the prevention, detection, and treatment of osteoporosis.1 Osteoporosis is also defined by the World Health Organization (WHO) as a bone mineral density (BMD) of 2.5 standard deviations (SDs) or less below the young normal mean (i.e., T-score ≤−2.5). The International Society for Clinical Densitometry (ISCD) has recommended that this definition be applied only to postmenopausal women and men older than 50 years.2 In the absence of osteoporotic fracture, this densitometric definition is the most clinically relevant, but it should not be used as the sole criterion for treatment decision. Much as elevated cholesterol concentration is one risk factor for heart attack, osteoporosis is but one risk factor for osteoporotic fracture. There is no definitive BMD threshold at which osteoporotic fractures occur, only an increasing likelihood of fracture with decreasing BMD. Other risk factors, such as increasing age, family history of hip fracture, current cigarette smoking, prior osteoporotic fracture, glucocorticoid use, rheumatoid arthritis, and excessive alcohol intake, have an impact on this fracture likelihood independent of the BMD. The National Osteoporosis Foundation guidelines recommend the use of the WHO Fracture Risk Assessment Tool (FRAX) score to guide treatment in patients who have densitometric osteopenia but are at high absolute risk for fracture.1 In addition to providing a supportive and protective framework for the body, bone serves as a large calcium reservoir. Calcium is necessary for proper neural, musculoskeletal, and cardiac function. Normal bone remodeling allows both access to the calcium reservoir and replacement or repair of old and damaged bone. Bone remodeling has two main phases: bone resorption and bone formation. Bone resorption, which releases calcium into the circulation, is the removal of damaged or old bone by osteoclasts, cells derived from macrophages and monocytes. This process is rapid and occurs in a matter of days to weeks. Osteoblasts, in response to parathyroid hormone (PTH) and other cytokines, secrete RANK (receptor activator of nuclear factor κB) ligand and monocyte colony-stimulating factor, which cause monocytes and macrophages to differentiate into osteoclasts and to proliferate. Osteoclasts produce powerful degradative enzymes, such as cathepsin K, to break down bone, releasing calcium, phosphorus, and type I collagen cross-linked products into the circulation. Bone formation occurs when osteoblasts lay down osteoid, an organic matrix composed of type I collagen and other proteins. Bone formation, occurring during months, is a slow process. It is estimated that the skeleton is completely replaced during approximately 4 years. Osteoblasts are also responsible for mineralization of the bone, depositing calcium and phosphorus into the osteoid. This process depends on the presence of adequate amounts of calcium and phosphorus and alkaline phosphatase activity. Poor bone mineralization leads to osteomalacia, a painful softening of the bone. Normally, bone resorption and bone formation proceed at equal rates. In osteoporosis, however, the rate of bone resorption exceeds that of bone formation, producing a net loss of bone. This uncoupling of bone resorption and bone formation is a consequence of estrogen deficiency and is most pronounced in the first 5 to 10 years after menopause. Glucocorticoid use is the most common cause of secondary osteoporosis. It causes osteoblast death, prolongs the life of osteoclasts, decreases levels of estrogen and testosterone, increases the metabolism of vitamin D, and decreases the intestinal absorption of calcium, although the evidence supporting a strong role for PTH and hypogonadism in glucocorticoid-induced osteoporosis is lacking. This increased bone resorption and decreased bone formation lead to a rapid loss of bone, the majority of which occurs in the first 6 months of glucocorticoid use. In addition, the bone quality is impaired, leading to a rapid increase in relative risk of fracture by as much as 75% within the first 3 months after initiation of glucocorticoids.3 Other drugs, such as chronic opiates, immunosuppressants, anticonvulsants, heparin, excessive thyroid hormone, leuprolide, and cancer chemotherapeutics, lead to similar changes in bone metabolism. Risk factors, both unmodifiable and modifiable, increase the risk of bone loss or osteoporotic fracture. The WHO FRAX model includes the following risk factors: advanced age, female gender, a prior osteoporotic fracture (including morphometric vertebral fracture), femoral neck BMD, low body mass index, oral glucocorticoid use of 5 mg of prednisone or more per day for 3 or more months (ever), rheumatoid arthritis, secondary osteoporosis, parental history of hip fracture, current smoking, and alcohol intake of three or more drinks per day. The National Osteoporosis Foundation recommends use of these risk factors through the WHO FRAX (at www.shef.ac.uk/FRAX) to decide on treatment of densitometric osteopenia in postmenopausal women and men aged 50 years and older. There are many other risk factors not included in FRAX that may play a role in individual assessment of need for bone density testing or osteoporosis therapy (Box 182-1). Unless an osteoporotic fracture is present, osteoporosis is clinically silent. Low BMD in the absence of osteoporotic fracture does not cause pain. If pain is present, the fracture should be confirmed or a secondary cause of the low BMD, such as osteomalacia, ruled out. The sine qua non of osteoporosis is an osteoporotic fracture, a fracture occurring with no or minimum trauma. The presence of a typical osteoporotic fracture in a postmenopausal woman is usually sufficient for the diagnosis of osteoporosis. The typical sites of fractures include the vertebrae, the distal wrist, the proximal femur, and the ribs. Unfortunately, even in the presence of a typical osteoporotic fracture, the diagnosis of osteoporosis is often missed and treatment is never initiated. Osteoporosis occurring in men and premenopausal or perimenopausal women should lead to a consideration of secondary causes of osteoporosis. Severe or established osteoporosis, that is, osteoporosis with fractures, is readily identifiable. The dowager’s hump is a thoracic spine kyphosis that occurs with multiple vertebral compression fractures. Vertebral compression fractures may also lead to scoliosis and height loss. A wall-occiput distance greater than 0 cm and rib-pelvis distance less than 2 fingerbreadths suggest the presence of occult spinal fracture.4 The physical examination in osteoporosis should be directed toward finding signs of secondary osteoporosis. Band keratopathy may suggest a diagnosis of primary hyperparathyroidism. Exophthalmos or lid lag, goiter, tremor, warm moist skin, weight loss, or pretibial myxedema may indicate a diagnosis of hyperthyroidism. Dorsal fat, facial plethora, supraclavicular fat, hypertension, centripetal obesity, proximal muscle weakness, edema, or violaceous abdominal striae may suggest a diagnosis of Cushing syndrome. Gynecomastia, decreased facial or axillary hair, and testicular atrophy may suggest hypogonadism. Blue sclera or dentition as well as joint hypermobility may suggest a diagnosis of osteogenesis imperfecta. Fall risk should be assessed in each patient with osteoporosis. Lower extremity strength, balance, gait, and postural reflexes should be carefully assessed. Poor visual acuity, weak grip strength, difficulty rising from a chair, Romberg sign, excessive body sway, and unsteady gait may all be signs of increased fall risk that may benefit from evaluation by a physical therapist or in a specialty fall clinic. Routine chemistry profiles (serum electrolyte values; fasting serum calcium and phosphorus levels; serum glucose, blood urea nitrogen [BUN], and creatinine concentrations) are usually normal in idiopathic osteoporosis. However, screening laboratory tests may be indicated to exclude underlying pathologic processes suggested by physical examination or presenting symptoms. Serum calcium concentration, PTH level, thyroid-stimulating hormone (TSH) level in those receiving thyroid hormone, and 24-hour urine calcium excretion may be the most cost-effective workup for identification of secondary causes of osteoporosis among postmenopausal women, although a study has suggested that TSH level alone is sufficient in the majority of postmenopausal women.5,6 Vitamin D deficiency is common among women with osteoporosis.7 Guidelines from the Institute of Medicine have supported a serum 25-hydroxyvitamin D level of 20 ng/mL as the threshold for vitamin D sufficiency for the general population,8 although the Endocrine Society guidelines support a threshold of 30 ng/mL for individual patients without a history of sarcoidosis, who are susceptible to a vitamin D toxicity, with hypercalciuria and hypercalcemia.9 The National Osteoporosis Foundation recommends intake of 800 to 1000 IU of vitamin D supplementation daily. A variety of regimens for vitamin D correction are available, but the greatest success in achieving a 25-hydroxyvitamin D level of 20 ng/mL appears to be linked to a total intake of at least 600,000 IU (i.e., 50,000 IU of vitamin D2 three times weekly for 4 weeks).10 A regimen of 50,000 IU of vitamin D2 every other week appears to be safe and effective with up to 6 years of therapy.11 There have been concerns that annual high-dose vitamin D regimens may increase the risk of falls among women.12 Biochemical markers are urine and blood tests that measure breakdown products of bone and collagen. A biochemical marker is an indirect measurement of bone turnover (i.e., bone resorption and formation). Bone resorption markers (N-telopeptides and C-telopeptides CTX) are used to evaluate osteoclast activity, and bone formation markers (bone-specific alkaline phosphatase, osteocalcin, procollagen I extension peptides) are used to evaluate osteoblast activity. High levels imply increased bone turnover. At this time, the role of bone markers in primary care is unclear, although specialists may use them. Bone resorption markers help identify response to antiresorptive drug treatment. Six-month intervals are the usual frequency for testing of bone markers. Plain radiographs are useful primarily in confirming the presence of fracture. They are insensitive to decreases in bone mass. In the absence of fracture, the definitive method for diagnosis of osteoporosis is bone densitometry, by dual energy x-ray absorptiometry, of the hip and posteroanterior lumbar spine. The wrist may be used in very obese patients, uninterpretable hip and spine scans, and primary hyperparathyroidism. Indications for bone densitometry are listed in Box 182-2. Bone density assessment of other sites, such as the finger, wrist, and ankle, and the use of other technologies, such as ultrasonography, are useful in diagnosis of osteoporosis and predicting fracture risk (particularly in adults older than 65 years) but may not be as useful in ruling out osteoporosis. Vertebral fracture assessment, which may be obtained from some bone density services, offers information similar to that of thoracic and lumbar spine radiography, with much less radiation exposure. The presence of a vertebral compression fracture, which may be asymptomatic, in the setting of osteopenia is sufficient for the clinical diagnosis of osteoporosis, particularly in the absence of or with minimal trauma. The ISCD recommends this testing when the T-score is below −1.0 and one or more of the following is present: women age 70 years or older; or men age 80 years or older; historical height loss of greater than Bone densitometry provides three pertinent numbers. The first is the actual area density in grams per centimeters squared. This density is then compared with the reference database for young normal adults and age-matched adults. This comparison results in a T-score and a Z-score, respectively. The T-score is used in diagnosis of osteopenia (T score <−1.0 and >−2.5) and osteoporosis (≤−2.5). The Z-score is ignored unless it is less than −2.0 or the patient is a premenopausal woman or man younger than 50 years, and then it is preferentially used. Only bone densitometry of the posteroanterior lumbar spine and hip is recommended for monitoring of osteoporosis treatment efficacy, and it is generally performed at 1- to 2-year intervals, depending on the precision of the scan. In general, a 5% density change is considered significant and not caused by measurement statistical variation, but each bone density service should determine its least significant change, as recommended by the ISCD.2 Some disease states, such as chronic glucocorticoid therapy and paraplegia, may lead to more rapid bone density changes. In these cases, assessment of bone density every 6 months to 1 year may be justified. Osteoporosis is classified as primary or secondary. Primary osteoporosis includes bone loss arising from menopausal estrogen deficiency or aging. Secondary osteoporosis results from an acquired or inherited disease that interferes with bone remodeling or increases bone turnover. Postmenopausal osteoporosis should be distinguished from secondary causes of osteoporosis (Box 182-3). Secondary causes of osteoporosis may be reversible. Suspicion of secondary causes of osteoporosis should be high in premenopausal and perimenopausal women, men, those with bone density Z-scores of less than −2.0, and those with bone pain in the absence of fracture. The presence of a fragility fracture in the absence of low bone density should raise the concern of localized bone destruction, as with metastatic disease or plasmacytoma. Thoracic spine fractures caused by metastasis are more likely when they involve vertebrae above T7. Less common metabolic bone diseases, such as Paget disease and osteopetrosis, also may lead to pathologic fractures, despite normal or even high bone density. Further testing, which can include computed tomography (CT) scanning, magnetic resonance imaging (MRI), nuclear medicine bone scanning, or even tetracycline-labeled bone biopsy, may be indicated. Much of the bone loss of osteoporosis is irreversible, and prevention should be the major focus of health care providers. Ideally, efforts at preventing osteoporosis should begin before puberty and should consist of adequate calcium and vitamin D intake, adequate weight-bearing exercise, and maintenance of normal body weight. Avoidance of cigarette smoking and excessive alcohol intake should be stressed. These preventive efforts are also recommended in adults and in those in whom osteoporosis has already developed. The National Osteoporosis Foundation recommends 1000 to 1200 mg of elemental calcium (3 to 4 cups of milk) daily and 800 to 1000 IU of vitamin D daily. Orange juice with calcium has roughly the same content as milk. Those who are unable to obtain their calcium from the diet may have to use calcium supplements, such as calcium carbonate and calcium citrate.1 Vitamin D, although it is synthesized from sunlight exposure and available in some foods, may need supplementation for vitamin D sufficiency to be achieved.13 In 2011, the Institute of Medicine updated its recommended daily allowance (RDA) for calcium and vitamin D (Table 182-1), targeting a serum 25-hydroxyvitamin D level of 20 ng/mL (50 nmol/L). The RDA of calcium for all adults aged 19 to 50 years is 1000 mg daily; for men 51 to 70 years, 1000 mg daily; and for men older than 70 years as well as women aged 51 years and older, 1200 mg daily. The RDA for vitamin D for adults aged 19 to 70 years is 600 IU daily and for those older than 70 years, 800 IU daily.8 The Endocrine Society has supported these guidelines but recognizes that some patients may need at least 1500 to 2000 IU daily to maintain their 25-hydroxyvitamin D levels above 30 ng/mL; obese patients, those with malabsorption, and those taking medications affecting the metabolism of vitamin D require 3000 to 6000 IU daily. Sarcoidosis patients may need less.9 Studies have raised concerns about an increased risk of cardiovascular events in women taking calcium or calcium–vitamin D supplements.14,15 In the end, there has to be a balance between good bone health and good cardiovascular health, and patient-provider discussions will need to consider this to avoid extremes of too little calcium and vitamin D as well as too much.
Metabolic Bone Disease
Osteoporosis and Paget Disease of Bone
Osteoporosis
Definition and Epidemiology
Pathophysiology
Risk Factors
Clinical Presentation
Physical Examination
Diagnostics
inches; self-reported but undocumented prior vertebral fracture; and glucocorticoids therapy equivalent to 5 mg of prednisone or more or the equivalent per day for 3 months or longer.2
Differential Diagnosis
Management
Metabolic Bone Disease: Osteoporosis and Paget Disease of Bone
Chapter 182
