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Reamer Bushardt is Program Director; Jennifer Turner is Graduate Researcher; and David Askins is Professor and Chair; all in the Department of Clinical Services, College of Health Professions, Medical University of South Carolina, Charleston. Kelly Ragucci is Associate Professor, Department of Pharmacy and Clinical Sciences, College of Pharmacy, at the same institution. The authors have indicated no relationships to disclose relating to the content of this article.

A major health problem in the United States, osteoporosis disproportionately affects women. Of the 10 million Americans who already have the disease, 80% are women. An estimated 18 million more Americans have low bone mass, placing them at increased risk for osteoporosis.¹

Background

Bone is constantly being remodeled by osteoblasts, the specialized cells responsible for bone formation, and by osteoclasts, the cells responsible for resorption.² During childhood and adolescence, bone formation exceeds bone destruction, resulting in a steady increase in bone mass in the young adult years. Between the ages of 25 and 35 years, bone reaches maximum density, which correlates with the time of peak bone mineral density (BMD). After this period, osteoclasts are more active, resulting in more bone being removed than is replaced.²

The average postmenopausal woman will lose bone at a rate of about 1% to 3% annually, with the greatest losses during the early postmenopausal years. Following the onset of menopause, some women lose up to 20% of their bone mass within 7 years, increasing their susceptibility to osteoporosis.³ The consequences of low BMD are decreased bone strength and increased fracture risk.⁴

Primary and secondary osteoporosis Primary osteoporosis, the most common form of the disease, is mainly associated with estrogen loss in postmenopausal women. Bone loss at skeletal sites such as the lumbar spine, proximal femur, hip, and forearm is linked to the greatest number of fractures. Secondary osteoporosis has other causes, such as hyperparathyroidism, hyperthyroidism, Cushing’s syndrome, hypercortisolism, hypogonadism, and certain medications. Osteoporosis has also been associated with chronic use of corticosteroids, levothyroxine (at high dosages), anticonvulsants, cancer chemotherapy drugs, heparin, or alcohol.

Fractures Vertebral fractures are more prevalent than hip fractures among patients with osteoporosis, but hip fractures are associated with high rates of morbidity and mortality. After age 50 years, one in two women and one in eight men will sustain an osteoporosis-related fracture.⁵ In the United States, more than 1.5 million osteoporosis-related fractures occur annually: around 46% at the vertebra, 20% at the hip, 16% at the wrist, and 20% at other sites.⁴

Prevalence Although the condition is most common among postmenopausal women, osteoporosis may also affect men, children, and premenopausal women. Numerous risk factors exist^4,6 (see Table 1). The strongest predictors of osteoporosis-related fractures among elderly women are decreased BMD and prior fracture. History of a fracture is associated with triple the risk of a subsequent fracture. One in five postmenopausal women who experience a vertebral fracture will have another within a year.

Osteoporosis is less common in men, probably because they generally have a larger skeleton and later onset bone loss, and they do not experience the rapid bone loss that women do when estrogen production declines. Declining testosterone levels, however, have been associated with osteoporosis in men. Long-term surveillance suggests that men at age 60 years have a 25% chance of suffering an osteoporotic fracture during their lifetimes.⁶

Patient evaluation

The clinician should suspect osteoporosis in postmenopausal women with risk factors, paying careful attention to patients presenting with a recent fracture or a history of fracture following minimal to moderate trauma. Because the majority of vertebral compression fractures are asymptomatic, take into account patient characteristics such as loss of height, change in posture, back pain, and difficulty with or limitations in activities of daily living.⁴ The physical examination should include height measurement, careful spinal assessment for thoracic kyphosis, and further evaluation of other unusual deformities. Spine radiographs are particularly useful for detecting vertebral fractures or deformities.⁴ Laboratory testing is also useful in ruling out secondary causes.

Measuring BMD Dual-energy x-ray absorptiometry (DEXA scanning) is the screening tool of choice to assess bone density and diagnose osteoporosis. DEXA measurements, often of the lumbar spine and proximal femur, are also used to monitor response to treatment.⁵ The World Health Organization defines diagnostic criteria for osteoporosis using T-scores to express BMD in standard deviations relative to the normal adult mean (see Table 2). The National Osteoporosis Foundation (NOF) recommends BMD testing for all women older than 65 years and for younger women when the results could influence a treatment decision, such as in patients already receiving drug treatment for osteoporosis or those receiving a medication associated with the development of bone disease.⁶

Screening for men Experts have recommended formal screening for all men at high risk for osteoporosis-related fracture. Risk factors include a history of nontraumatic fracture, radiographic evidence of osteopenia, long-term corticosteroid use, hyperparathyroidism, hypogonadism, use of other medications associated with osteoporosis, or a gait disorder. Formal screening includes diagnostic measures such as DEXA scanning of the hip and spine, heel ultrasonography, or quantitative CT.^7,8

Osteoporosis prevention and treatment

Strategies to prevent osteoporosis should be initiated early in life. Calcium increases spine BMD and reduces the risk of vertebral and nonvertebral fractures,⁹ and vitamin D is necessary for calcium absorption and homeostasis. The NOF recommends at least 1,200 mg of elemental calcium and 400 to 800 IU of vitamin D daily for all women older than 50 years.⁶ Although exercise is beneficial at all ages, resistance training and weight-bearing exercises started early in life are likely most beneficial.⁹ Estrogen supplementation helps stabilize bone remodeling.² Several oral and transdermal hormone therapy products have received FDA approval for osteoporosis prevention; however, this article focuses on non-estrogen therapies. The goals of pharmacotherapy for osteoporosis comprise both prevention and treatment. Each agent or class of agents has unique characteristics and selective indications (see Table 3).

Bisphosphonates inhibit bone resorption without directly suppressing bone formation, resulting in increased bone mass and mineralization.¹⁰ Oral agents include alendronate, risedronate, and ibandronate. Bisphosphonates are generally well tolerated; adverse effects are usually mild and may include abdominal and musculoskeletal pain and, less frequently, nausea, dyspepsia, constipation, diarrhea, and flatulence. Because these agents may cause local irritation of the upper GI mucosa, leading to esophagitis, esophageal ulcers, esophageal erosions, and esophageal strictures, patients should be instructed to follow prescribing directions carefully. Contraindications include delayed esophageal emptying, inability to stand or sit upright for 30 to 60 minutes, and hypocalcemia. This class of drugs is not recommended for patients with a creatinine clearance less than 35 mL/min. Unless contraindicated, bisphosphonates are generally considered first-line options for osteoporosis prevention and treatment.

Raloxifene is a selective estrogen receptor modulator, a class of agents that has a high affinity for estrogen receptors and may exhibit agonistic or antagonistic estrogen effects.² Common adverse effects noted in clinical trials include hot flashes and leg cramps. Use of raloxifene together with hormone replacement therapy has not been studied and is not currently recommended. Raloxifene is associated with increased risk of thromboembolic events; therefore it is contraindicated in sedentary or pregnant patients and in those with current or past deep vein thrombosis or pulmonary embolism.¹¹ Patients should be asked about tobacco use, which has been linked to increased risk of thromboembolic events. Raloxifene should be discontinued for 72 hours before, and withheld during, any period of prolonged immobilization; it may be resumed once the patient is fully ambulatory. Raloxifene can increase hot flashes and the risk of thromboembolism, and less is known about its effects on fracture risk compared with bisphosphonates and calcitonin, so raloxifene is often used only when other agents are not tolerated.

Calcitonin, a hormone produced by the thyroid gland, inhibits bone resorption through binding to osteoclast receptors. Salmon calcitonin, a nasal spray, is the most potent and commonly used preparation.² Instruct patients to follow prescribing directions carefully. The few side effects include nausea, flushing, and nasal symptoms (rhinitis, epistaxis, and nasal discomfort), which may be minimized by administering the drug at least 4 to 5 hours after a meal. Contraindications include clinical allergy to calcitonin and hypersensitivity to salmon protein or gelatin diluents. Based on fracture data comparison, calcitonin is typically considered a second-line therapy and is used when bisphosphonates are inappropriate.

Teriparatide, a form of parathyroid hormone, is the first agent that stimulates new bone formation by increasing the number and action of osteoblasts.¹² This agent is administered subcutaneously in the thigh or abdominal wall. The drug must be refrigerated at 36°F to 46°F (2.2°C to 7.8°C) and each injection pen can be used for up to 28 days after the first injection, so patients must be educated on the use and storage of the device. Adverse reactions include hypertension, syncope, angina, and dizziness. Teriparatide caused a dose- and duration-dependent increase in the incidence of osteosarcoma in rats, and a black box warning appears in the package insert stating that the drug should be avoided in patients at increased risk of osteosarcoma, including those with Paget’s disease, unexplained elevation of alkaline phosphatase levels, open epiphyses, and prior radiation involving the skeleton.¹³ Because of its cost and formulation, teriparatide is generally used only when other standard therapies have failed.

Discussion

The two most important factors to consider when evaluating the clinical efficacy of a drug used to prevent or treat osteoporosis are BMD measurements and fracture prevention rates. BMD, a surrogate marker, is considered a disease-oriented outcome and is most helpful in the initial period of study for a pharmacologic agent. Pharmacologic agents that have demonstrated reductions in fracture rates are preferable to agents that have shown improvement only in surrogate markers of osteoporosis.

It is important to distinguish patients who derive the greatest benefit from pharmacologic therapy from those who can benefit from nutritional and exercise therapies alone. Clinical study results that can be used to calculate the absolute risk reduction and the number needed to treat (NNT) to prevent fracture can help estimate the anticipated impact of therapy. The NNT and drug costs can be used to gauge the pharmacoeconomic impact of therapies. Note that in all the studies discussed here, patients also received calcium and vitamin D.

Risedronate trial The Vertebral Efficacy with Risedronate Therapy (VERT) trial was a randomized, double-blind, placebo-controlled, 3-year multicenter trial of 2,458 ambulatory postmenopausal women. Treatment with 5 mg daily of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41% over 3 years. The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39%.^14,15 These results are summarized in the table “Fracture risk reduction with bisphosphonate therapy” .

Alendronate trial The effect of alendronate on fracture risk reduction was studied in the Fracture Intervention Trial (FIT). This study evaluated a total of 6,459 postmenopausal women in two distinct arms. In the Vertebral Fracture Arm, alendronate was associated with a significant reduction in both the incidence of new vertebral fractures and the incidence of any clinical fracture.¹⁶ In the Clinical Fracture Arm, alendronate significantly reduced the risk of clinical fractures in women with an initial femoral neck T-score of -2.5 or less; it did not significantly alter clinical fracture risk in patients with higher BMD. For the entire study group, the difference in clinical fracture rates with alendronate versus placebo was not statistically significant.¹⁷

Ibandronate trials The Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) included 2,946 postmenopausal women 55 to 80 years old with lumbar spine BMD 2 to 5 standard deviations below the premenopausal mean in at least one vertebra and with 1 to 4 preexisting vertebral fractures.^18,19 Two ibandronate regimens given for the 3-year study significantly reduced the incidence of vertebral fractures compared to placebo, but the number of nonvertebral fractures at 3 years was similar among those treated with ibandronate and with placebo.

The efficacy of extended-interval dosing in the BONE trial supported researching additional extended-interval dosing, as many believe less frequent dosing might decrease adverse effects and improve patient adherence. In the phase 3 noninferiority Monthly Oral Ibandronate in Ladies (MOBILE) study, the safety and tolerability of the 2.5-mg/d ibandronate regimen is compared to three once-monthly regimens in 1,609 postmenopausal women 55 to 80 years old. After 1 year, all monthly regimens were proven noninferior and the 150-mg single monthly dose was deemed superior based on increases in lumbar spine BMD.²⁰

Raloxifene trial In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a multicenter, randomized, blinded, placebo-controlled study, 7,705 women aged 31 to 80 years old were randomized to receive 60 mg/d or 120 mg/d of raloxifene or placebo. Risk of vertebral fracture was significantly reduced in both groups of women taking raloxifene. Results for patients who received placebo or raloxifene 60 mg/d are summarized in the table “Results from the MORE study”. Risk of nonvertebral fracture for both doses of raloxifene versus placebo did not differ significantly.²¹

Calcitonin trial A 5-year, double-blind, randomized, placebo-controlled study was conducted to determine if salmon calcitonin nasal spray reduced the risk of new vertebral fractures in women with osteoporosis. The Prevent Recurrence of Osteoporotic Fractures (PROOF) study included 1,255 postmenopausal women with established osteoporosis. The women were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. The 200-IU dosages significantly reduced the risk of new vertebral fractures by 33% compared with placebo. The reductions in vertebral fractures in the 100-IU and 400-IU groups were not significantly different from placebo. Percentages of nonvertebral fractures were significantly lower in the 100-IU calcitonin group than with placebo but not in the 200- or 400-IU groups. One important limitation of this study is that nearly 60% of patients who were originally enrolled were lost to follow-up.²² (See the table “Results from the PROOF study”.)

Teriparatide trial In the multicenter Fracture Prevention Trial (FPT), 1,637 women received 20 or 40 mcg of teriparatide or placebo subcutaneously. Results showed a significant reduction in both new vertebral fractures and new nonvertebral fractures with teriparatide.¹² (See the table “Effects of teriparatide on fractures”.) Both baseline BMD and BMD change contributed to the prediction of fracture risk. The average increase in BMD in teriparatide-treated patients was 0.09 g/cm², which was similar across baseline BMD values. Increases in BMD due to teriparatide therapy accounted for 30% to 41% of vertebral fracture risk reduction. Additional study is needed to characterize any drug-specific advantages or potential benefits for bone integrity.

Conclusion

Osteoporosis should be considered a disease requiring proper treatment and no longer a natural part of aging. The costs of the disease and its complications exceed $18 billion annually in the United States.²³ A thorough history and physical examination, and possibly additional diagnostic tests, are needed before decisions are made about therapy. Adequate daily intake of both calcium and vitamin D and regular weight-bearing exercise are integral parts of all treatment plans. Because of recent information detailing the risks of exogenous estrogen therapy in postmenopausal women, providers must understand the recent study data and determine whether benefits such as relief of vasomotor symptoms outweigh the risks in each individual patient. Non-estrogen treatments for osteoporosis have gained popularity, and it is important to understand the evidence related to each therapy. The clinician should review the studies and tables in this article, recognizing that similarities and differences in baseline characteristics between the trial participants and the patients we treat is key to making evidence-based, cost-effective decisions about preventing and treating osteoporosis.

Acknowledgment: The authors thank Rebecca Smith for her assistance.

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