Definition

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk for fracture. Bone strength primarily reflects the integration of bone density and bone quality. Bone quality refers to factors such as microarchitectural changes, bone turnover, collagen structure, damage accumulation (e.g., microfractures), and degree of mineralization [1].

Osteoporosis can also be defined according to the World Health Organization criteria on the basis of bone mineral density and bone mineral content measurements (see section on diagnostic studies).

Osteoporosis is the most common metabolic bone disease. The National Osteoporosis Foundation estimates that at least 10 million Americans have osteoporosis and another 34 million have decreased bone mass, putting them at increased risk for osteoporosis and fractures. Of the 10 million, 8 million are women and 2 million are men. Annually in the United States, more than 1.5 million fractures attributable to osteoporosis occur, including approximately 750,000 vertebral, 300,000 hip, and 250,000 wrist fractures. The annual cost of caring for osteoporosis-related fractures in the United States is in excess of $16 billion. In addition, there is a 15% to 25% excess mortality within the first year after a hip fracture. In recent years, the hip fracture rate has been reported to be declining [2].

Symptoms

Osteoporosis is a silent disease until a fracture occurs. Pain and deformity are usually present at the site of fracture. Vertebral fractures often occur with little trauma, such as coughing, lifting, or bending over. Acute back pain may be related to a vertebral compression fracture, with pain localized to the fracture site or in a radicular distribution. New back pain or chronic back pain in a patient with osteoporosis and prior vertebral fractures may be related to new fractures, muscle spasm, or other causes.

With vertebral fractures, even if they are asymptomatic, there may be a gradual loss of height and the development of a kyphosis. Breathing may be difficult, and early satiety and bloating—a sensation of fullness and dyspepsia—may develop because of less room in the abdominal cavity.

Physical Examination

In evaluating patients with osteoporosis, it is important to diagnose treatable and reversible causes and to assess the risk factors for development of osteoporosis and osteoporotic fractures. Table 140.1 lists common causes of osteoporosis. Table 140.2 lists risk factors for osteoporosis.

The physical examination focuses on findings suggestive of secondary causes of osteoporosis (e.g., hyperthyroidism and Cushing syndrome). One should also examine areas previously involved with fractures (e.g., back, hip, and wrist) to assess for deformity and limitation of function. A baseline measurement of height should be obtained and reevaluated at subsequent visits. Localized vertebral tenderness may be present from fracture, paravertebral muscle spasm, or exaggerated thoracic kyphosis. The findings of the neurologic examination looking for any deficits due to vertebral fracture are usually normal.

Functional Limitations

Functional limitations are related to the type of fracture and its long-term consequences. With vertebral fractures, the functional limitation may initially be related to the acute pain and inability to move. The chronic limitations may be related to loss of height, chronic back pain, difficulty in moving, abdominal distention, and difficulty in breathing.

The functional limitations after a hip fracture are related to the decreased functional mobility, often the need for long-term use of assistive devices, the lack of independence, and the long-term need for assistive care. An assistive device will be needed permanently for ambulation by 50% of people with a hip fracture, and two thirds will lose some of their ability to perform ordinary daily activities.

Wrist fractures usually heal completely, but some people have chronic pain, deformity, and functional limitations.

Diagnostic Studies

Bone density measurements are the standard for assessment of risk, diagnosis, and long-term management of patients with osteoporosis. Bone density measurement is often essential to make management decisions. Available techniques include single-photon absorptiometry, dual-energy x-ray absorptiometry, quantitative computed tomography, and quantitative ultrasonography. Dual-energy x-ray absorptiometry, although it is not as sensitive as quantitative computed tomography for detection of early trabecular bone loss, is the method of choice for measurement of bone mineral density because of its good precision, low radiation dose, and fast examination time.

Bone mineral density testing should be based on an individual’s fracture risk profile and skeletal health assessment. It should be performed only if the results will influence a treatment decision.

Bone mineral density testing should be considered on the basis of the National Osteoporosis Foundation guidelines, as follows [3]:

• Women age 65 and older and men age 70 and older, regardless of clinical risk factors

• Younger postmenopausal women and men age 50-69 about whom you have concern based on their clinical risk factor profile

• Adults who have a fracture after age 50

• Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose of 5 mg or more for > 3 months) associated with low bone mass or bone loss

• Anyone being considered for pharmacologic therapy for osteoporosis

• Anyone being treated for osteoporosis, to monitor treatment effect

• Anyone not receiving therapy in whom evidence of bone loss would lead to treatment

• Postmenopausal women discontinuing estrogen

Bone mineral density is reported by T and Z scores (Table 140.3). The T score compares an individual’s bone mineral density with the mean value for young normal individuals expressed as a standard deviation (SD); the Z score compares the values to age- and sex-matched adults.

• Normal: a T score value for bone mineral density or bone mineral content that is not more than 1 SD below the young adult mean value.

• Low bone mass (osteopenia): a T score value for bone mineral density or bone mineral content that lies between1.0 and 2.5 SDs below the young adult mean value.

• Osteoporosis: a T score value for bone mineral density or bone mineral content that is 2.5 SDs or more below the young adult mean value.

The lower the T score, the higher the risk for subsequent fractures. However, the score will not predict who will fracture because other factors come into play (e.g., fall velocity, type of fall, direction of fall, and protective padding). A low Z score may suggest excessive bone loss due to secondary causes of osteoporosis.

Specific laboratory tests are obtained to help in the differential diagnosis of osteoporosis and to rule out osteomalacia. The general laboratory tests include a complete blood count, chemistry profile including calcium and phosphorus, liver and kidney tests, serum and urine protein electrophoresis, and thyroid-stimulating hormone concentration. A 24-hour collection of urine for calcium and creatinine measurement is also helpful. Because of the high prevalence of vitamin D deficiency in the adult population, especially elderly individuals, a serum 25-hydroxyvitamin D level should be obtained. A parathyroid hormone level should be determined in suspected cases of primary or secondary hyperparathyroidism. Blood and urine test results are usually normal in uncomplicated cases of osteoporosis. After a fracture, the alkaline phosphatase activity may be elevated. Biochemical markers of bone turnover, including urine N-telopeptide and serum C-telopeptide, may be helpful in selective patients to assess for bone turnover and whether someone is responding to treatment.

The initial approach to the prevention and treatment of osteoporosis involves nonpharmacologic interventions and, in appropriate patients, the use of various pharmacologic agents (Table 140.4). Prevention and treatment guidelines are presented in Tables 140.5 and 140.6.

Calcium

Adequate calcium is important for all age groups. Epidemiologic studies suggest that long-standing dietary calcium deficiency can result in lower bone mass. The average dietary calcium intake in postmenopausal women is less than 600 mg/day. Several studies have shown that calcium supplementation along with vitamin D, especially in the elderly, may slow bone loss and reduce vertebral and nonvertebral fracture rates [5]. A total calcium intake of 1200 to 1300 mg/day is recommended for postmenopausal women [6]. This can be achieved primarily by consumption of foods that have a high calcium content, such as milk and dairy products and calcium-fortified foods, especially yogurt. Calcium supplementation is often required, especially in elderly individuals. Calcium carbonate supplements have the highest calcium content but may cause abdominal discomfort with bloating and constipation and are better absorbed when they are taken with foods. Calcium citrate preparations are generally better absorbed and are not dependent on gastric acid.

Vitamin D

Vitamin D insufficiency and deficiency are common in postmenopausal women, especially in those who have sustained a hip fracture and those who are chronically ill, housebound, institutionalized, and poorly nourished [6,7]. Vitamin D improves muscle strength and balance and reduces the risk of falling. There may also be other unproven nonskeletal beneficial effects. A dose of 800 to 1000 IU/day (from supplements, multivitamins, and other sources) should be administered to prevent vitamin D deficiency. Some need higher amounts. Many calcium supplements now contain vitamin D. Maintaining a serum 25-hydroxyvitamin D level of more than 30 ng/mL (70 nmol/L) is suggested by many experts, although the Institute of Medicine suggests levels above 20 ng/mL.

Exercise

There is increasing evidence that weight-bearing and strength training exercises are beneficial to bone in helping achieve peak bone mass and preserving bone later in life [8]. Bone adapts to physical and mechanical loads placed on it by altering its mass and strength. This occurs either by the direct impact from the weight-bearing activity or by the action of muscle attached to bone. Exercising can also help strengthen back muscles, improve balance, lessen the likelihood of falling, and give one a sense of well-being [9]. Back extension exercises and abdominal strengthening exercises are helpful. However, acute stresses to the back, such as trunk flexion, side-bending, high impact, and heavy weights, should be avoided to lessen the likelihood of injury and fracture. A proper exercise program should be established. Older postmenopausal women and even the frail elderly can tolerate and potentially show improvements in muscle strength and bone mineral density in response to strength training and resistive exercise programs.

Smoking Cessation

A 5% to 10% reduction in bone density has been seen in women who smoked one pack per day in adulthood. Therefore, it is recommended that physicians aggressively pursue smoking cessation in their treatment plans.

Fall Prevention

Many factors can lead to falls, including poor vision, frailty, medication (especially narcotic pain medications, hypotensive agents, and psychotropic drugs), and balance disturbances [10]. Each area needs to be assessed appropriately. Prevention measures include keeping rooms free from clutter and having good lighting. Advise patients to wear supportive shoes, to be aware of thresholds, and to avoid slippery floors; rugs should be tacked down. Grab bars are useful in the bathroom. A portable telephone and a personal alarm activator are helpful, and someone should check on the individual regularly.

Guidelines for Treatment

The guidelines for treatment of postmenopausal women based on National Osteoporosis Foundation recommendations are as follows:

• Hip or spine fracture

• T score − 2.5 or below at the spine, femoral neck, or total hip

• T score between − 1.0 and − 2.5 and high 10-year fracture risk by the U.S.-adapted World Health Organization Fracture Risk Assessment Calculator (FRAX). Treat if 10-year risk is 3% or more for hip fractures or 20% or more for major osteoporosis-related fractures [11].

Hormone Replacement Therapy

Hormone replacement therapy can be used in the short-term management of postmenopausal women with symptoms of estrogen deficiency, including hot flashes, memory deficits, urinary frequency, and vaginal dryness. Long-term hormone replacement therapy can slow bone loss and lower the incidence of fractures [12]. In the Women’s Health Initiative (WHI) study with estrogen and progestin, there was a 34% reduction in vertebral and hip fractures. However, there was an increase in breast cancer, coronary heart disease, stroke, and thromboembolic disease [13]. The mean age of patients in the WHI was 63 years. A recent reanalysis from the WHI showed no increase in coronary heart disease risk in women when hormone replacement therapy was started within 10 years of the onset of menopause [14]. Significant controversy still exists about the results of the WHI. Estrogen is approved for the prevention of osteoporosis but not for treatment. The major reason to use hormone replacement therapy is to treat menopausal symptoms. The lowest dose of estrogen and progesterone should be used to effectively relieve these symptoms. Women who have had a hysterectomy should be given estrogen alone. A progestin should be added to the estrogen regimen if the uterus is still present.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators are synthetic compounds that have both estrogen-antagonistic and estrogen-agonistic properties. Raloxifene (Evista) is approved by the Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis at an oral dose of 60 mg daily. Raloxifene is also approved for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer. Raloxifene reduces new vertebral fractures by 40% to 50% but not the risk of nonspine fractures [15]. Raloxifene acts as an antiestrogen on breast tissue and reduces the risk of invasive breast cancer similar to the reduction by tamoxifen. It does not produce uterine hypertrophy and does not significantly affect the risk of coronary heart disease. Raloxifene has no beneficial effects on menopausal symptoms and may increase hot flashes and the risk of deep venous thrombosis.

Bisphosphonates

The bisphosphonates are a group of compounds related chemically to pyrophosphate. They are characterized by a P-C-P structure. Changes in the side chains affect the binding and potency of the bisphosphonates. They are potent inhibitors of osteoclastic bone resorption.

Alendronate (Fosamax) was the first approved by the FDA in 1995 for the prevention and treatment of postmenopausal osteoporosis. Alendronate is also approved for the treatment of glucocorticoid-induced osteoporosis [15] and osteoporosis in men. In postmenopausal women, the dose for prevention is 5 mg/day or 35 mg once weekly; the dose for treatment is 10 mg/day or 70 mg once weekly. Alendronate significantly increases bone mineral density at various sites. In addition, there is a significant decrease in the incidence of vertebral, hip, and wrist fractures as well as painful vertebral fractures, hospitalization days, and other measurements of functional impairment [16].

Risedronate (Actonel) is approved by the FDA for the prevention and treatment of postmenopausal osteoporosis with an oral dose of 5 mg daily, 35 mg weekly, or 150 mg monthly. Studies have shown an increase in bone mineral density at various sites along with a decrease in vertebral and nonvertebral fractures [17]. Risedronate is also approved for the prevention and treatment of glucocorticoid-induced osteoporosis and osteoporosis in men.

Ibandronate (Boniva) is approved by the FDA for the prevention and treatment of postmenopausal osteoporosis. The oral dose is either 2.5 mg daily or 150 mg monthly. An intravenous preparation is also available for the treatment of postmenopausal osteoporosis in a dose of 3 mg intravenously every 3 months. Studies have shown an increase in bone density and a reduction in vertebral fractures [18].

The bisphosphonates are poorly absorbed and must be given on an empty stomach to maximize their absorption. Alendronate and risedronate must be taken at least 30 minutes (ibandronate, 60 minutes) before the first food, beverage, or medication with a full glass of plain water, and patients should not lie down for at least 30 minutes (ibandronate, 60 minutes) to avoid the potential upper gastrointestinal side effects, especially of esophagitis. Patients with a history of reflux should not be given these medications.

Zoledronic acid (Reclast) is approved by the FDA for the treatment of postmenopausal osteoporosis, osteoporosis in men, and glucocorticoid-induced osteoporosis and after surgical repair of hip fracture,. It is administered as a once-yearly infusion of 5 mg, administered usually during 15 to 20 minutes. It significantly reduces spine, hip, and nonhip fractures and increases bone density [19].

The major side effects with the intravenous bisphosphonates are the acute phase symptoms, including fever, muscle and joint pains, influenza-like symptoms, and headache. These usually last for no more than 24 to 72 hours. These symptoms have been reported in 32% of patients with the first infusion, in 7% after the second yearly infusion, and in 3% after the third infusion of zoledronic acid. Very uncommon but serious adverse complications from long-term use of the bisphosphonates include osteonecrosis of the jaw [20] and atypical femur fractures [21]. Osteonecrosis of the jaw has been reported primarily in cancer patients who receive bisphosphonates for skeletal metastases at a dose much higher than the dose given for osteoporosis.

Calcitonin

Synthetic salmon calcitonin given parenterally by injection and nasal spray (Miacalcin, Fortical) is approved for the treatment of postmenopausal osteoporosis. The injectable calcitonin is given as 100 units daily subcutaneously or intramuscularly. The nasal spray of calcitonin is approved in a dose of 200 units (one spray) daily. A reduction in new vertebral fractures but not in hip or nonvertebral fractures has been reported [22]. Occasional nasal irritation or headache may be seen with the nasal spray.

Parathyroid Hormone

As long ago as the late 1920s, there was evidence that parathyroid extract, administered in an intermittent once-a-day injection, stimulated osteoblast activity in animal models. This is in contrast to bone loss seen with chronic elevations in parathyroid hormone in primary hyperparathyroidism. After human parathyroid hormone was sequenced in the early 1970s, clinical studies with use of the 1-34 amino-terminal fragment started. Early results in osteoporosis trials showed increases in bone accretion, calcium balance, and trabecular bone volume with normal skeletal architecture. In the multicenter trial of recombinant human parathyroid hormone 1-34 fragment (teriparatide), 20 µg administered subcutaneously daily produced an increase in vertebral and hip bone density and a 55% reduction in vertebral fracture risk [23]. Teriparatide (Forteo) is generally well tolerated and is self-administered for up to 2 years by use of a 31-gauge needle and a prefilled syringe with a 28-day supply of medication. It is currently the only anabolic agent available (in contrast to the antiresorptive agents) and is approved for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. It is also approved for treatment of osteoporosis in men and glucocorticoid-induced osteoporosis. In rats given teriparatide in doses up to 60 times the exposure in humans, there was an increase in osteosarcoma, which was dose and duration dependent. Thus, teriparatide should not be administered to patients who have an increased baseline risk for osteosarcoma, including patients with Paget disease of bone, those with unexplained elevated alkaline phosphatase, and those who have received prior external beam or implant radiation therapy involving the skeleton.

Denosumab

Denosumab (Prolia) is a human monoclonal antibody directed against RANKL, a cytokine mediator responsible for accelerating osteoclast formation. It is approved for the treatment of postmenopausal osteoporosis at high risk for fractures and osteoporosis in men. The dose is 60 mg subcutaneously every 6 months. Reductions in spine, hip, and nonspine fractures are seen, and there is an increase in bone density. Side effects include a small increase in serious infection, such as skin infections. It is not affected by renal function and can be given to patients with reduced renal function [24].

Rehabilitation

Rehabilitation efforts in osteoporosis should commence long before a fracture. Either a physical or occupational therapist can be involved in assessing the patient’s home to make sure it is safe and to decrease the risk of falls. Specialized equipment, such as grab bars for the bathroom and hand-held reachers for high cupboards, can be very helpful. It is important to educate patients about keeping the floors clear of clutter and throw rugs. Small pets also can be a hazard underfoot.

Therapists can assess whether the patient would be safer ambulating with an assistive device (e.g., cane or walker) in the home and community. It is important for all assistive devices to be appropriately prescribed and fitted for the patient.

Finally, therapists can instruct patients about how to exercise to improve strength, flexibility, and balance. All of these activities can help prevent falls, and weight-bearing strengthening exercises may also improve bone density.

In patients with a hip fracture or other disabling fracture, a multidisciplinary coordinated team approach involving the physician, therapists, and other rehabilitation specialists (e.g., nurse, social worker) is necessary for the patient to regain maximal function and to lead a productive life. The initial rehabilitation program also involves pain control, bowel and bladder care, and maintenance of skin integrity. The therapists, in addition to working on a program involving bed mobility, transfers, gait activities, safety precautions, and activities of daily living, must be cognizant of the medical problems in each patient. After an acute rehabilitation stay, some patients may need an additional stay in a transitional setting on their way to eventually going home or else require long-term placement. For those able to go home, the team needs to teach the patient a home exercise program, to order appropriate equipment, and to arrange for continued therapy, either at home or in an outpatient setting.

Back Braces

Back braces may be helpful, especially in the short term, to get patients out of bed and ambulatory so they can participate in activities. Back braces, however, can be very uncomfortable and often are not tolerated. Long-term use should be discouraged unless it helps the patient in functional activities and with control of pain.

Procedures

Other than surgery for fracture repair, procedures are generally not needed in the management of osteoporosis. Two procedures—vertebroplasty and kyphoplasty—are available to stabilize vertebral fractures and to alleviate pain.

Surgery

The preferred treatment of hip fracture and some other fractures is surgical repair and stabilization.

Potential Disease Complications

As bone density decreases, the risk for sustaining a fracture increases. Osteoporosis is asymptomatic until a fracture occurs. Thereafter, all complications are related to the problems from these fractures, to the surgery (if it is required), and to the recuperative period and eventually to the loss of function and independence.

After vertebral fractures, acute pain may limit mobility. Bed rest and narcotic analgesics may be necessary. Severe constipation and urinary retention may ensue. Chronically, patients may suffer from severe back pain and have respiratory problems, abdominal distention, bloating, and constipation. Many patients who wear a back brace complain about the discomfort and difficulty in using it.

Potential Treatment Complications

The complications of treatment can be related either to the surgical repair of the fracture and the recuperative phase or to medications used to prevent or to treat osteoporosis.

Most osteoporotic fractures occur in older patients and result in loss of function and loss of independence and the need for long-term care. Because surgery is required to repair a hip fracture, complications from surgery, anesthesia, bed rest, and pain medications (often narcotics) are common. Pneumonia, phlebitis, urinary tract infection, constipation, and respiratory problems also are frequent.

Complications from drug therapy for osteoporosis include the following: potential increase in breast cancer (estrogen), heart disease (estrogen), clotting and thromboembolic problems (estrogen, raloxifene), and endometrial cancer (in those using only estrogen); hot flashes (raloxifene); upper gastrointestinal symptoms and esophagitis from oral alendronate, risedronate, and ibandronate; fever, muscle and joint aches, and influenza-like symptoms from intravenous ibandronate and zoledronic acid; osteonecrosis of the jaw and atypical femur fractures with long-term bisphosphonates; running nose and headache from calcitonin; and transient mild hypercalcemia with teriparatide and a small increase in infections with denosumab.