Definition

Primary osteoporosis is a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and increased fracture risk. ¹ Primary osteoporosis represents bone mass loss related to aging and loss of gonadal function in women and the aging process in men without any other chronic illness.

Secondary osteoporosis results from a variety of chronic conditions that significantly contribute to bone mineral loss, or from effects of medications and nutritional deficiencies. Causes of secondary osteoporosis are listed in Box 1.

The World Health Organization (WHO) has defined osteoporosis as bone density (BD) that is 2.5 or more standard deviations (SDs) below the young adult mean value (T score < −2.5), and those with BD from 1 to 2.5 SDs below average (T score = −1 to −2.5) are said to have osteopenia. ² Decreased BD imparts an increased risk for bone fracture. Every 1-SD decrease in BD of the spine below the mean increases the risk for a new vertebral fracture by a factor of 2.0 to 2.4. ³

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Prevalence

Osteoporosis is the most common metabolic bone disease in developed countries. Based on the WHO definition, it has been estimated that 54% of postmenopausal white women in the United States have osteopenia and 30% have osteoporosis. Men and nonwhite women at risk add to the number significantly (30 to 54 million affected individuals in the United States).

About 1.3 million osteoporotic fractures occur each year in the United States. Approximately 50% are vertebral fractures, 25% are hip fractures, and 25% are Colles' fractures. ¹ Significant ethnic and geographic differences exist in the prevalence of osteoporosis and osteoporotic fractures. The hip fractures risk is considerably higher in whites than in blacks. Two factors contribute to this difference, higher peak bone mass (highest bone mass achieved by an individual in their lifetime) and slower postmenopausal bone loss in blacks. ⁴

Bone mineral density (BMD) is lower in Asians than in whites. However, when adjusted for body size, most of the difference disappears, suggesting that the lower BMD in Asians is the result of smaller body size.

Decreased BMD and osteoporotic fractures impose a great burden on society and individuals. Wrist fracture incidence starts increasing at about 50 years of age, vertebral fractures in the 60s, and hip fractures in the 70s. An increased mortality rate associated with hip and vertebral fractures may be the worst consequence, but loss of independence and lowered quality of life of patients living with the disease for years might be the greatest burden of osteoporosis. ⁵ Osteoporosis in men is an important health problem, because almost 30% of all hip fractures and up to 20% of symptomatic vertebral fractures occur in men. ⁶

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Pathophysiology

Basic mechanisms responsible for the development of primary osteoporosis are poor bone mass acquisition during growth and development and accelerated bone loss after achieving peak bone mass. Both processes are modulated by environmental and genetic factors.

About two thirds of the fracture risk in postmenopausal women are determined by premenopausal peak bone mass. ⁵ Peak bone mass is higher in blacks than in whites (and Asians), and higher in men than women, resulting in a lower incidence of osteoporosis in these populations.

Approximately 50% of the bone mass accumulates during pubertal development. ⁷ This accumulation is associated with an increase in sex hormone levels and is almost completed when bone end plates close. There is only minimal accumulation of the bone minerals during the next 5 to 15 years (skeletal consolidation), resulting in peak bone mass during the third decade of life.

The main factor influencing peak bone mass is genotype. Studies in twins and mother-daughter pairs have suggested that 40% to 80% of variability in bone mineral mass is determined by genetic factors. None of the proposed genetic markers has been found in most patients with osteoporosis. At this time, knowledge about the genetics of osteoporosis is insufficient to affect patient management.

In contrast to peak bone mass, rate of bone loss in individuals is mostly determined by environmental factors (nutritional, behavioral, medications) in males and females. However, genetic factors also play an important role, mostly acting on estrogen status.

Factors Affecting Rate of Bone Loss

Nutritional Factors

Nutritional factors include dietary calcium intake, vitamin D status, and protein and calorie intake. Other nutrients and trace minerals are also implicated but are less certainly associated with the development of osteoporosis. These include phosphorus, vitamins C and K, copper, zinc, and manganese.

It has been shown that increasing dietary intake of milk during adolescence improves bone mineral acquisition. Low calcium intake during childhood increases fracture risk later in life. ⁸ Calcium intake is also positively correlated with bone mineral mass at all ages, and supplementation may reduce rate of bone loss and decrease fracture incidence in calcium-deficient older adults.

Optimal calcium intake varies among age groups and is population specific. A typical U.S. diet is rich in sodium and protein, both of which increase urinary calcium excretion and thus increases dietary calcium requirements (see later, “Treatment”).

Vitamin D is essential for bone mineral metabolism through its role in calcium absorption and osteoclastic resorption. Vitamin D supplementation reduces the rate of all fractures in older adults who are deficient in this vitamin.

Protein and caloric malnutrition predisposes to falls and diminishes soft tissue cover (e.g., fat and muscle) over bony prominences. Protein intake is a major determinant of outcome after hip fracture, and the serum albumin level is the single best predictor of survival in these patients. Eating disorders affect BMD in a profound manner. The body weight history of women with anorexia nervosa is the most important predictor for the development of osteoporosis.

Behavioral Factors

Behavioral factors important in the pathogenesis of osteoporosis include physical activity, smoking, and alcohol consumption. Bone mass is higher in top level athletes—at the collegiate and professional levels—than in nonathletes. This is particularly pronounced in athletes engaging in strength training. Mechanical loading increases bone mass. The relation between load and bone density is curvilinear and more pronounced at low load levels; this is best seen as bone loss during immobilization. In completely immobilized patients, bone mass loss may be up to 40% in 1 year. Conversely, active people who further increase their levels of physical activity may expect only modest losses in bone mineral mass. This may explain relatively modest improvements in BMD (1% to 3% in the lumbar spine) seen in exercise trials using endurance or strength training. ⁹

Chronic alcohol abuse has been associated with decreased BMD in the femoral neck and lumbar spine and is commonly listed as a risk factor for osteoporosis. The prevalence of osteoporosis in alcoholics has been estimated at 28% to 52%. ¹⁰ It is likely that other nutritional deficiencies associated with chronic alcohol abuse play an important role in osteoporosis development in alcoholics. In addition, smoking is often associated with alcoholism and is an independent risk factor for low bone mass.

Optimal bone metabolism is a result of hormonal, nutritional, and mechanical harmony. A deficit in one area is usually impossible to overcome by improvements in others.

Medications

Several medications show a clear association with osteoporosis (see Box 1). Glucocorticoids are the most important of these and cause loss of mostly trabecular bone. Consequently, fractures occur most commonly in the vertebrae, ribs, and ends of long bones. Bone loss occurs rapidly and may be as high as 20% to 40% during the first year of steroid use. The incidence of osteoporotic fractures in patients taking corticosteroids for longer than 6 months has been estimated to be 30% to 50%. A steroid dosage detrimental to BMD in most people appears to be more than 7.5 mg of prednisone daily, but a risk for fracture may be seen with even lower dosages. ¹²

Endocrine regulation of bone mass is a factor related to bone metabolism that deserves separate consideration. Estrogen is essential for reaching peak bone mass and for maintenance of bone mass in women and men. Estrogen deficiency is considered a principal cause of postmenopausal osteoporosis, causing uncoupling of bone formation from resorption and thus accelerating bone loss. ¹³ It may also play an important role in male osteoporosis. Risk factors for low bone mineral density are summarized in Table 1.

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Signs and symptoms

The clinical expression of osteoporosis is a skeletal fracture. Vertebral fracture is the most common type of fracture associated with osteoporosis. Up to two thirds of vertebral fractures are asymptomatic and diagnosed as incidental findings on x-rays taken for other reasons.

Fractures usually occur during routine daily activities, such as bending of the body, coughing, or lifting and are most common in lumbar spine and lower thoracic vertebrae. If the fracture is above the T7 level, a diagnosis other than osteoporosis should be considered. Fracture occurrence may be accompanied by acute onset of pain, which may disappear or become chronic dull back pain. Multiple fractures may lead to significant height loss and the development of thoracic kyphosis (Dowager's hump). Patients notice abdominal protuberance, a change in the way clothes fit, and loss of waist. This is caused by loss of the vertical dimensions of abdominal cavity because of vertebral collapses and shifting of abdominal content anteriorly. Restrictive respiratory problems are seen because of diminished volume of the thoracic cage and poor expansion with breathing. Hip fractures are commonly seen in osteoporotic individuals, affecting about 15% of women and 5% of men older than 80 years. These fractures usually occur after falls or other trauma, but subchondral insufficiency fractures of the femoral head have been described. Fractures of the distal radius (Colles' fractures) occur more often in patients with osteoporosis and may be caused by falls on an outstretched hand, but also after minor trauma.

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Diagnosis

History and physical examination are important in screening for secondary causes of osteoporosis, uncovering behavioral risk factors, use of medications, and presence of signs and symptoms of osteoporotic complications. Using risk factors to prescreen patients for further diagnostic procedures has been shown to be inefficient and fails to identify a substantial proportion of patients with osteoporosis.

Laboratory Evaluation

Laboratory evaluation of the patient should be aimed at diagnosing the secondary causes of osteoporosis. The exact tests used depend on the specific clinical situation (Table 2). In some cases, assessment of bone turnover may yield useful information and guide management decisions.

Biochemical Markers of Bone Metabolism

During bone synthesis, osteoblasts make collagen (predominantly type I) and other noncollagenous proteins that may be measured in serum and urine. In addition, during bone resorption by osteoclasts, collagen breakdown products are released in the circulation and excreted in urine, where they can be measured and used to assess the dynamic status of bone metabolism. These tests are noninvasive, widely available and inexpensive. They may indicate changes in bone metabolism much faster than measurements of BMD and can be repeated frequently. However, these tests are relatively new and their role in patient treatment is still being defined (Box 2).

Markers of Bone Formation

Terminal portions of type I procollagen are cleaved off during collagen assembly. Their serum concentration may be used as a measure of bone formation. Several assays measure these carboxy terminal or amino terminal peptides in serum. However, other tissues also produce type I collagen, particularly skin, and current assays cannot distinguish among peptides of different origins.

Osteocalcin is a small noncollagenous protein of osteoblastic origin that circulates in several forms. Assays detecting intact molecules or large amino terminal fragments (residues 1-43) have been shown to be reliable bone formation markers.

Bone-specific alkaline phosphatase is produced by osteoblasts and is essential for proper mineralization of the skeleton. Newer assays using specific antibodies against bone-specific alkaline phosphatase have been developed and show a cross-reactivity with alkaline phosphatase of other origin (liver) of 10% to 20%.

Markers of Bone Resorption

During bone resorption, type I collagen degradation products are released into the circulation and excreted via the kidneys. These promise to be the most useful bone mineral metabolism markers. Collagen fibrils in the bone are bound together covalently by cross-links. These are derivatives of 3-hydroxypyridinium and bridge several collagen molecules that stabilize the collagen superstructure. There are two forms, pyridinoline cross-links (more abundant) and deoxypyridinoline cross-links (more bone-specific). Cross-links are released into circulation free or peptide-bound and are excreted into the urine. Both forms are measured by immunoassays in urine, but the gold standard remains high-performance liquid chromatography (HPLC).

Hydroxyproline and hydroxylysine are amino acids formed inside the osteoblasts during the post-translational processing of collagen. When bone is degraded, these are released into the circulation, metabolized by the liver, and excreted in the urine, where they can be measured by HPLC. Hydroxyproline is not bone specific but is also produced in the skin. Accurate hydroxyproline measurements require a collagen-free diet, because dietary collagen interferes with measurement. In contrast, hydroxylysine measurements are not influenced by dietary factors. The main disadvantage of these measurements is lack of a convenient immunoassay and the need for HPLC.

Collagen molecules are cross-linked in specific places along the molecule, regions known as amino terminal and carboxy terminal telopeptides. Several assays have been developed for the measurement of these telopeptides in the circulation and urine. Tartrate-resistant acid phosphatase, originating in bone, and bone sialoprotein are other markers of bone resorption that are occasionally used.

Clinical use of the bone metabolism markers measured in the urine has been limited by the need to collect 24-hour urine samples or correct results for creatinine levels. Serum markers are free of these problems, but there are marked circadian variations in serum levels, so the timing of the blood sample collection may be important.

Long-term variability of bone metabolism markers in clinically stable individuals has been 20% to 30% for urinary measurements and 10% to 15% for serum measurements. Consequently, large changes in the levels of bone metabolism markers are required for them to be of clinical significance. After initiation of successful antiresorptive therapy, there is a marked decrease in levels of bone resorption markers in 4 to 6 weeks and bone formation markers in 2 to 3 months. ¹⁴ These levels should remain reduced for the duration of therapy.

Bone Density Measurements

The diagnosis of clinically apparent osteoporosis is made from the history of fractures or radiologic evidence of fractures, but the diagnosis of asymptomatic early osteoporosis requires measurement of the BMD. The American Association of Clinical Endocrinologists has provided indications for BMD determination:

1. Perimenopausal or postmenopausal women willing to accept therapeutic or preventive interventions if osteoporosis is diagnosed
2. Individuals whose x-ray findings suggest osteoporosis
3. Individuals starting or receiving long-term glucocorticoid therapy if therapeutic or preventive intervention is acceptable
4. Individuals with symptomatic primary hyperparathyroid-ism or other nutritional conditions detrimental to bone health, when evidence of bone mineral loss would result in parathyroidectomy
5. Individuals treated for osteoporosis to monitor their response to therapy
6. All women older than 40 years with history of fracture
7. All women older than 65 years

Indications for BMD measurement in men are less clear but should include the following:

1. All men 70 years of age or older
2. Hypogonadism
3. Presence of chronic disease adversely affecting bone health
4. Use of medications detrimental to bone health
5. Techniques of measurement include quantitative ultrasound (US) measuring the speed of sound and attenuation of the ultrasonic beam in the bone. Results of these measurements correlate with bone density and strength ¹⁵ and can predict hip fracture.

Further confirmation of these findings may make US techniques an attractive alternative to dual energy x-ray absorptiometry (DEXA) because of lower cost, portability, and lack of radiation exposure. Ultrasound measurements are limited to peripheral bone (usually calcaneus) and are very precise (coefficient of variation lower than 1%). These properties make quantitative US an attractive screening test for osteoporosis. Currently, ultrasound results suggestive of osteoporosis should be confirmed by DEXA, which is widely accepted as a standard technique for BMD measurements. The x-ray tube produces two distinct radiation energies and thus allows simultaneous measurements of two tissue types (bone and soft tissue, or lean tissue and fat tissue). This method may also be used as a precise instrument for body composition analysis.

The standard DEXA measurement consists of spine and hip imaging in anteroposterior projections. Spinal measurements in lateral projection are possible but are not standardized. Interpretation of spinal DEXA measurements in older adults may be difficult because of common arthritic changes. In those younger than 65 years, these changes are seen infrequently and measurements are more reliable. The hip area is rarely affected by such difficulties and some physicians have recommended using it at all ages. ¹⁶ Approximately 15% of patients have high bone density at one site and low bone density at another. Thus, measurements at multiple sites are desirable. Measurements of total body bone mineral content and density are also possible with DEXA; these are useful for assessment of bone mineral accumulation during growth and development and for body composition analysis.

It is important to realize that all these methods measure apparent bone density (g/cm²) calculated as bone mineral content/unit of projected area rather than true volumetric bone density (g/cm³). Quantitative computed tomography (QCT) is the only method able to measure true (volumetric) bone density. This is achieved by comparing the density of the skeletal area on the CT scan with the densities of the standard (a series of tubes filled with different concentrations of calcium solution) included in the field of view of the CT apparatus. The ability to measure BMD of the trabecular bone, on which structural strength mostly depends, may allow for slightly better prediction of vertebral fracture risk than with DEXA. However, QCT is seldom used because of expense, higher radiation dose, and lower reproducibility than DEXA.

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Treatment

General preventive measures against osteoporosis should be emphasized whenever possible and at all ages to optimize bone mass and preserve skeletal integrity. Ensuring adequate dietary calcium intake is one of the mainstays, which is particularly important for children and adolescents. The recommended daily calcium intake is presented in Table 3. Needs may be met via a calcium-rich diet (e.g., milk, dairy products, calcium-fortified fruit juices) or by using calcium supplements. Patients with untreated renal stones or hypercalciuria should only receive calcium supplementation under medical supervision.

Vitamin D supplementation should be prescribed whenever there is suspicion of inadequate intake, particularly in older patients. About 800 IU/day is considered sufficient intake, but tests of serum vitamin D and urinary calcium levels can more accurately determine the necessary amount.

Good general nutrition, with adequate caloric and protein intake, should be promoted. Use of tobacco should be strongly discouraged, as well as excessive use of alcohol. Regular weight-bearing exercise is essential for skeletal development during growth and development and might slow bone loss in older adults. In addition, it promotes agility, flexibility, and strength, possibly preventing falls.

Hormone replacement therapy (HRT) was considered the standard of care for the prevention and treatment of postmenopausal bone loss. Recently, doubts have been raised about the efficacy of HRT for fracture prevention in a population not selected for osteoporosis. The HERS (Heart Estrogen/Progestin Replacement Study) data have shown no evidence of reduction in fracture incidence with HRT in older women. ¹⁷ In addition, data from the FHI (Female Health Initiative) study on the increased risk from HRT therapy regarding the incidence of breast and endometrial cancer, as well as the incidence of stroke, coronary artery disease, and other thrombotic incidents derived, have forced us to rethink its role in osteoporosis therapy. Table 4 lists available preparations for HRT.

Selective estrogen receptor modulators (SERMs) are newer medications that may be free of undesirable effects on reproductive tissues. ¹⁸ Raloxifene is a tissue-selective receptor agonist, possessing both estrogen agonist and antagonist properties. Raloxifene has estrogen-like activity on estrogen receptor in bone and cardiovascular tissue, but not in endometrial and breast tissue. Raloxifene preserves bone density and decreases the serum total cholesterol level. It does not cause endometrial or breast tissue hyperplasia.

In clinical trials, raloxifene has been shown to cause a modest BMD increase in all tested skeletal sites (2.4% in the lumbar spine and 2.0% for the whole body) over 2 years. These changes persisted during the third year, and markers of bone turnover were suppressed to the normal premenopausal range in raloxifene-treated women. The antagonistic effect on breast tissue has a protective effect on the incidence of breast cancer in women treated with raloxifene. There was no increase in endometrial cancer, but increased incidence of thromboembolic disease was observed, comparable with the risk with estrogen. Raloxifene is U.S. Food and Drug Administration (FDA)–approved for osteoporosis prevention and treatment.

Bisphosphonates

Bisphosphonates are medications that inhibit bone resorption and have minimal side effects (Table 5). The bisphosphonates are widely used for the prevention and treatment of osteoporosis. After administration, they attach to the bony surfaces and are released during the remodeling process to prevent osteoclast-mediated bone resorption. ¹⁹ Alendronate was the first bisphosphonate approved for the treatment and prevention of osteoporosis. It increases BMD in the spine, femoral neck, and greater trochanter area and, at 10 mg/day, decreases the risk of vertebral and nonvertebral fractures in postmenopausal women, ²⁰ even if they already had a vertebral fracture or were older than 75 years. Alendronate is used for osteoporosis treatment (70 mg weekly or 10 mg daily orally) and prevention (35 mg weekly or 5 mg daily orally), ²¹ and is also used for steroid-induced osteoporosis. The incidence of upper gastrointestinal (GI) problems in patients receiving alendronate in clinical trials was no different than with placebo, but pill-induced esophagitis and ulcer can occur. These may be severe enough to warrant hospitalization and may lead to esophageal stricture. Because of these complications, alendronate should not be given to patients with active upper GI disease and should be stopped if patients develop any symptoms of esophagitis. Alendronate should be taken on an empty stomach with water (240 mL) while standing or sitting to facilitate passage of the pill from the esophagus to the stomach. Patients should remain upright for 30 minutes after taking the pill and should not eat anything, which can help improve absorption of the drug and prevent reflux.

Risedronate is safe and effective in preventing bone loss caused by corticosteroids and can be given to postmenopausal women with normal bone density. ²² A daily 5-mg dose or weekly 35-mg dose is taken in the same way as alendronate. It appears that the GI side effects of risedronate may be less severe than with alendronate, as demonstrated by a lower incidence of gastric ulcers (4.1% vs. 13.2%) in an endoscopic study after 2 weeks of therapy. Risedronate is FDA-approved for the prevention and treatment of steroid-induced osteoporosis. It increases spinal and hip density and prevents vertebral and hip fractures.

Etidronate is given cyclically (usually 400 mg/day for 2 weeks every 15 weeks) and has demonstrated effectiveness for the treatment of vertebral osteoporosis and reducing vertebral fractures in postmenopausal women ²³ and for patients taking glucocorticoids. It is approved in Canada and Europe, but not in the United States, for the treatment of osteoporosis.

Pamidronate is approved by the FDA to treat hypercalcemia of malignancy and Paget's disease. It has been used off-label to treat postmenopausal ²⁴ and corticosteroid-induced osteoporosis, and to prevent postmenopausal osteoporosis. In most cases, it is administered intravenously, with an initial dose of 90 mg and then 30 mg every 3 months, over 1 to 4 hours. It is given to patients who are intolerant to oral drugs.

Ibandronate has been approved for the treatment of postmenopausal osteoporosis. It is taken orally in a once-monthly 150-mg dose or given IV, 3 mg once every 3 months.

Clodronate, tiludronate, and zoledronate are currently not approved for use in osteoporosis.

Other Pharmacologic Agents

Calcitonin is used in injection form (subcutaneously and intramuscularly) and as an intranasal spray. Injections (50 to 10 IU daily or every other day) are shown to increase BMD in the spine and reduce vertebral fracture better than calcium alone. The metered nasal spray has replaced the injectable form. It stabilizes bones, prevents loss, and decreases the incidence of vertebral fractures (by less than 20%). Calcitonin is shown to have a significant analgesic effect on bone pain by an unknown mechanism ²⁵ and may reduce the pain of vertebral fracture.

The anabolic agent teriparatide (human recombinant parathyroid hormone [PTH] 1-34) increases bone density more than antiresorptive therapies, about twice as much. It is given as a daily subcutaneous injection, at 20 μg/dose. This results in a short-lasting peak of serum PTH concentration that far exceeds the normal level and stimulation of bone formation, whereas bone resorption is not significantly increased, as is seen with continuous infusion or in patients with primary hyperparathyroidism. Teriparatide therapy increases the bone density of the spine after only 3 months, ²⁶ whereas hip BMD increases after 6 to 12 months. ²⁷ The increase is first seen in trabecular bone, but cortical bone stays stable or even decreases slightly (1% to 2%) in the first year of therapy and then starts to increase.

Combination therapy trials have shown an additive effect of estrogen with etidronate and alendronate ²⁸ on BMD. The effect is modest and there are no data showing a further decrease in fracture rate on combination therapy. The use of combination therapy may be justified in patients who continue to lose bone mass on monotherapy. Combining anabolic therapy with recombinant human PTH (rhPTH) and antiresorptive therapy with bisphosphonate alendronate have shown diminished BMD gains in men when compared with rhPTH alone. ²⁹

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Outcomes

Studies have shown that estrogen reduces the vertebral fracture rate by 50% or more in women taking it for 7 to 10 years. ³⁰ Women older than 75 years may still experience senile bone loss and the efficacy of estrogen may be lower in this age group. Meta-analyses have suggested a relative fracture risk of 0.7 in estrogen users versus nonusers.

Raloxifene has demonstrated the ability to reduce vertebral fracture risk in postmenopausal women with osteoporosis, regardless of the presence of prevalent vertebral fracture, reducing the risk to 0.45 if there was no evidence of prevalent fracture and to 0.70 if prevalent fracture was present.

Alendronate is effective in reducing the incidence of new vertebral fractures in patients with or without prevalent vertebral fracture (48%), as well as hip fractures (51%) and wrist fractures (48%). In the Fracture Intervention Trial (FIT), ³¹ therapy with alendronate was associated with a reduction of bedridden days and days of decreased activity, suggesting a beneficial effect on the quality of life.

Risedronate has been shown to reduce vertebral fractures by 41% and 49%, respectively, in patients with and without prevalent vertebral fractures. ³² These studies also demonstrated a reduction in nonvertebral fractures by 33% to 39%. A significant reduction in the incidence of hip fractures has been noted. A significant effect on fracture risk is seen after only 1 year of risedronate treatment. ³³

Nasal spray calcitonin has shown a small reduction in the incidence of vertebral fractures (less than 20%), but no fracture reduction in the hip. ³⁴

Therapy with hPTH-(1-34) for 18 months in osteoporotic postmenopausal women who had at least one previous vertebral fracture reduced the risk of new vertebral fractures by 65%, severe vertebral fractures by 90%, and nonvertebral fracture fragility fractures by 54%. ³⁵

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Clinical guidelines for primary care physicians

We propose the following guidelines for testing and treatment of patients with suspected or established osteoporosis. The following measures are recommended for average-risk patients:

• Take a careful history to determine osteoporosis risk factors (see Table 1) and falls in each patient.
• Educate patients about osteoporosis and the importance of prevention and treatment.
• Instruct about adequate nutrient intake, especially calcium, vitamin D, and protein.
• Emphasize the benefits of regular physical activity.
• Educate about the detrimental effects of alcohol and tobacco abuse.
• Establish patient willingness to accept preventive measures and medications for osteoporosis.

Patients perceived to be at higher risk include the following:

• Individuals with a history of hip or vertebral fracture in a first-degree relative
• Individuals with low body weight (less than 127 pounds in females)
• All women between ages 20 and 55 years with a history of fracture not caused by significant trauma
• Patients with a history of falling
• Patients with medical conditions that cause secondary osteoporosis (see Box 1)
• Patients taking medications detrimental to bone health (see Box 1)
• Women 65 years old and older
• Men 70 years and older

The evaluation should consist of laboratory testing and BMD measurements:

• Levels of serum calcium, phosphorus, 25-hydroxyvitamin D, alkaline phosphatase, liver enzymes, and total protein and albumin, and indices of renal function
• 24-hour urinary calcium excretion
• Tests aimed at secondary causes of osteoporosis in patients with clinical suspicion of these conditions (see Table 2)
• BMD measurement of nondominant hip and anteroposterior scan of the spine using DEXA at a facility where the patient will be able to have subsequent BMD measurements performed (to ensure use of the same DEXA machine)

Patients suspected of having osteoporosis based on quantitative US should have the diagnosis confirmed by DEXA.

Based on the results of the evaluation, patients should be advised about preventive measures against osteoporosis and falling, offered treatment, or referred to an osteoporosis specialist. Preventive measures consist of adequate nutrition (calcium, vitamin D, protein), regular physical exercise, cessation of smoking, and fall prevention (adequate lighting, hand rails, anchored rugs, adequate shoes). Prevention only, without further intervention, should be implemented by patients with a normal BMD at all measured sites (T score no less than −1), a BMD T score between −1 and −2.5 at any site and without risk factors, taking medications that may increase their propensity to fall, or not willing to accept any other form of treatment.

Medical treatment available to primary care physicians includes alendronate, risedronate, raloxifene, and calcitonin, in addition to the preventive measures. Candidates for treatment include the following:

1. Patients with a BMD T score less than −2.5
2. Patients with BMD T-scores less than −1.5 and the presence of one or more risk factors for osteoporosis
3. Patients with demonstrated bone loss, despite adequate prevention measures
4. Patients with a low-trauma bone fracture and BMD T score less than −1.0

Osteoporosis specialists should be consulted for further management of patients with the following:

1. Unusually severe osteoporosis (BMD T score less than −3.0)
2. Osteoporosis at a young age (premenopausal women or men younger than 60 years)
3. Fractures despite a normal or low-normal BMD
4. Transplanted organs
5. Secondary causes of osteoporosis
6. No response to treatment (fractures or continuing bone loss while on therapy)
7. Inability to tolerate FDA-approved treatment

Patients evaluated for osteoporosis should be re-evaluated yearly to assess adherence to recommended prevention and therapeutic measures and to detect any new signs or symptoms suggestive of osteoporotic complications. These patients should have serial BMD measurements performed on the same DEXA machine, with the following caveats:

1. Individuals with an unusually high BMD may not need further measurements.
2. Individuals with normal BMD may have repeated measurements in intervals of 3 to 5 years.
3. Patients implementing a osteoporosis prevention program and with a borderline BMD (T score between −1 and −2.5) should have BMD measurements in intervals of 1 to 2 years until the BMD is stabilized, and then at 2- to 3-year intervals.
4. Patients treated for established osteoporosis should have BMD measurements yearly until a stable BMD is demonstrated, and every 2 years after that.

Summary

• Osteoporosis is a condition characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and increased fracture risk.
• Osteoporosis is the most common metabolic bone disease.
• Low bone mass may be caused by other bone disorders; it is diagnosed based on clinical features and laboratory evaluation.
• Dual x-ray densitometry of the bone is the gold standard for assessment of the severity of osteoporosis.
• The most common mode of treatment is the use of bisphosphonate medications (antiresorptive therapy) in association with adequate calcium and vitamin D intake.

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Suggested Readings

• Cummings SR, Black D. Bone mass measurements and risk of fracture in Caucasian women: A review of findings from prospective studies. Am J Med. 98: 1995; 24S-28S.
• Heaney RP. Pathophysiology of osteoporosis. Endocrin Metabol Clin North Am. 27: 1998; 255-265.
• Kanis JA, Melton LJ , Christiansen C. The diagnosis of osteoporosis. J Bone Miner Res. 9: 1994; 1137-1141.
• Libanati CR, Baylink DJ. Prevention and treatment of glucocorticoid-induced osteoporosis. A pathogenetic perspective. Chest.. 102: 1992; 1426-1435.
• Liberman UA, Weiss SR , Broll J. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 333: 1995; 1437-1443.
• Mortensen L, Charles P , Bekker PJ. Risedronate increases bone mass in an early postmenopausal population: Two-year of treatment plus one year of follow-up. J Clin Endocrinol Metab. 83: 1998; 396-402.
• Neer RM, Arnaud CD , Zancehtta JR. Effect of parathyroid hormone (1-34) on fracture and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 344: 2001; 1434-1441.
• Pande I, Francis RM. Osteoporosis in men. Best Pract Res Clin Rheumatol. 15: 2001; 415-427.
• Rodan GA, Fleisch HA. Bisphosphonates: Mechanism of action. J Clin Invest. 97: 1996; 2692-2696.
• Sambrook P, Birmingham J , Kelly P. Prevention of corticosteroid osteoporosis: A comparison of calcium, calcitriol and calcitonin. N Engl J Med. 328: 1993; 1747-1752.