Osteoporosis is defined as a reduction in bone mass [or bone mineral density (BMD)] or the presence of fragility fracture. It is defined operationally as a bone density that falls 2.5 SD below the mean for a young normal individual (a T-score of <–2.5). Those with a T-score of <1.0 (osteopenia) have low bone density and are at increased risk for osteoporosis. The most common sites for osteoporosis-related fractures are the vertebrae, hip, and distal radius.
Osteoporosis is a common condition in the elderly; women are at particularly high risk. In the United States, 8 million women and 2 million men have osteoporosis; an additional 18 million have osteopenia. The annual incidence of osteoporosis-related fractures is at least 1.5 million; almost half of them are vertebral crush fractures, followed in frequency by hip and wrist fractures. Hip fractures are associated with significant morbidity (thromboembolism) and a 5–20% mortality within a year.
Low bone density may result from low peak bone mass or increased bone loss. Risk factors for an osteoporotic fracture are listed in Table 188-1, and diseases associated with osteoporosis are listed in Table 188-2. Certain drugs, primarily glucocorticoids, cyclosporine, cytotoxic drugs, thiazolidinediones, anticonvulsants, aluminum, heparin, excessive levothyroxine, GnRH agonists, and aromatase inhibitors also have detrimental effects on the skeleton.
TABLE 188-1 RISK FACTORS FOR OSTEOPOROSIS FRACTURE
TABLE 188-2 DISEASES ASSOCIATED WITH AN INCREASED RISK OF GENERALIZED OSTEOPOROSIS IN ADULTS
Pts with multiple vertebral crush fractures may have height loss, kyphosis, and secondary pain from altered biomechanics of the back. Thoracic fractures can be associated with restrictive lung disease, whereas lumbar fractures are sometimes associated with abdominal symptoms or nerve compression leading to sciatica. Dual-energy x-ray absorptiometry (DEXA) has become the standard for measuring bone density. The U.S. Preventive Health Services Task Force recommends that women age 65 and older be screened routinely for osteoporosis, and screening should begin at age 60 for women with increased risk. Criteria approved for Medicare reimbursement of bone mass measurement are summarized in Table 188-3. A general laboratory evaluation includes complete blood count, serum and 24-h urine calcium, 25(OH)D level, and renal and hepatic function tests. Further testing is based on clinical suspicion and may include thyroid-stimulating hormone (TSH), urinary free cortisol, parathyroid hormone (PTH), serum and urine electrophoresis, and testosterone levels (in men). Tissue transglutaminase Ab testing may identify asymptomatic celiac disease. Markers of bone resorption (e.g., urine cross-linked N-telopeptide) may be helpful in detecting an early response to antiresorptive therapy if measured prior to and 4–6 months after initiating therapy.
TABLE 188-3 FDA-APPROVED INDICATIONS FOR BMD TESTSa
Treatment involves the management of acute fractures, modifying risk factors, and treating any underlying disorders that lead to reduced bone mass. Treatment decisions are based on an individual’s risk factors, but active treatment is generally recommended if the T-score is ≤2.5. Risk factor reduction is a key part of management; smoking cessation and reduced alcohol intake should be encouraged; offending drugs should be discontinued or doses minimized (e.g., glucocorticoids), an exercise program should be instituted, and fall prevention strategies should be put in place. Oral calcium (1–1.5 g/d of elemental calcium in divided doses) and vitamin D (400–800 IU/d) should be initiated in all pts with osteoporosis. Adequate vitamin D status should be verified by measuring serum 25(OH)D, the value of which should be at least 75 nmol/L (30 ng/mL). Some pts may require higher vitamin D supplements than those recommended above. Moderate sun exposure also generates vitamin D, although recommending outdoor exposure is controversial because of concerns about skin cancer. Bisphosphonates (alendronate, 70 mg PO weekly; risedronate, 35 mg PO weekly; ibandronate, 150 mg PO monthly or 3 mg IV every 3 mo; zoledronic acid, 5 mg IV annually) inhibit bone resorption, augment bone density, and decrease fracture rates. Oral bisphosphonates are poorly absorbed and should be taken in the morning on an empty stomach with 0.25 L (8 oz) of tap water. Long-term bisphosphonate treatment may be associated with atypical femur fractures; a tentative recommendation is to limit therapy to 5 years. Osteonecrosis of the jaw is a rare complication of bisphospho-nate treatment mainly seen with high-dose IV zoledronic acid or pamidronate administered in cancer pts. Estrogen decreases the rate of bone reabsorption, but therapy should be carefully weighed in the context of increased risks of cardiovascular disease and breast cancer. Raloxifene (60 mg/d PO), a selective estrogen receptor modulator (SERM), is an alternative antiresorptive agent that can be used in lieu of estrogen. It increases bone density and decreases total and LDL cholesterol without stimulating endometrial hyperplasia, although it may precipitate hot flashes. A new antiresorptive agent is denosumab, a monoclonal antibody against RANKL, an osteoclast differentiation factor. It is approved for pts at high risk for fracture and is given as an injection twice a year (60 mg SC every 6 months). Clinical experience with denosumab is still limited.
The only available drug that induces bone formation is teriparatide [PTH(1-34)]. It is indicated for treatment of severe osteoporosis and is administered as a daily injection for a maximum of 2 years. Teriparatide therapy must be followed by antiresorptive agent therapy to prevent rapid loss of the newly formed bone.
Defective mineralization of the organic matrix of bone results in osteomalacia. The childhood form of osteomalacia is called rickets. Osteomalacia is caused by inadequate intake or malabsorption of vitamin D (chronic pancreatic insufficiency, gastrectomy, malabsorption) and disorders of vitamin D metabolism (anticonvulsant therapy, chronic renal failure, genetic disorders of vitamin D activation or action). Osteomalacia can also be caused by long-standing hypophosphatemia, which can be due to renal phosphate wasting (e.g., X-linked hypophosphatemic rickets or oncogenic osteomalacia) or excessive use of phosphate binders.
Skeletal deformities may be overlooked until fractures occur after minimal trauma. Symptoms include diffuse skeletal pain and bony tenderness and may be subtle. Proximal muscle weakness is a feature of vitamin D deficiency and may mimic primary muscle disorders. A decrease in bone density is usually associated with loss of trabeculae and thinning of the cortices. Characteristic x-ray findings are radiolucent bands (Looser’s zones or pseudofractures) ranging from a few millimeters to several centimeters in length, usually perpendicular to the surface of the femur, pelvis, and scapula. Changes in serum calcium, phosphorus, 25(OH)D, and 1,25(OH)2D levels vary depending on the cause. The most specific test for vitamin D deficiency in an otherwise healthy individual is a low serum 25(OH)D level. Even modest vitamin D deficiency leads to compensatory secondary hyperparathyroidism characterized by increased levels of PTH and alkaline phosphatase, hyperphosphaturia, and low serum phosphate. With advancing osteomalacia, hypocalcemia may develop due to impaired calcium mobilization from undermineralized bone. 1,25-Dihydroxyvitamin D levels may be preserved, reflecting upregulation of 1α-hydroxylase activity.
In osteomalacia due to vitamin D deficiency [serum 25(OH)D <50 nmol/L (<20 ng/mL)], vitamin D2 (ergocalciferol) is given orally in doses of 50,000 IU weekly for 8 weeks, followed by maintenance therapy with 800 IU daily. Osteomalacia due to malabsorption requires larger doses of vitamin D (up to 50,000 IU/d orally or 250,000 IU IM biannually). In pts taking anticonvulsants or those with disorders of abnormal vitamin D activation, vitamin D should be administered in doses that maintain the serum calcium and 25(OH)D levels in the normal range. Calcitriol (0.25–0.5 μg/d PO) is effective in treating hypocalcemia or osteodystrophy caused by chronic renal failure. Vitamin D deficiency should always be repleted in conjunction with calcium supplementation (1.5–2.0 g of elemental calcium daily). Serum and urinary calcium measurements are efficacious for monitoring resolution of vitamin D deficiency, with a goal 24-h urinary calcium excretion of 100–250 mg/24 h.
For a more detailed discussion, see Bringhurst FR, Demay MB, Krane SM, Kronenberg HM: Bone and Mineral Metabolism in Health and Disease, Chap. 352, p. 3082; and Lindsay R, Cosman F: Osteoporosis, Chap. 354, p. 3120, in HPIM-18.