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Jane Takagi, Pharm. D. |
Osteoporosis is the most common metabolic bone disease and affects 25 million Americans, of which 80% are women. Postmenopausal women are identified as the group most at risk for osteoporosis; however, it can occur in both men and women with advancing age, or it may be drug-induced. This article will briefly review osteoporosis and comment on the newer drugs available for prevention and treatment.
Bone affected by osteoporosis is described as "porous" and is characterized by low mass and structural deterioration. This leads to bone fragility and an increased susceptibility to fractures.1 Until a fracture occurs, bone loss typically proceeds without symptoms. Fractures may occur at any skeletal site, but are most common at the spine, hip, and wrist. Vertebral (spinal) fractures may cause back pain, loss of height, or deformities such as "dowager's hump." Painful and debilitating hip fractures cause most of the disability and death associated with osteoporosis
The socioeconomic impact of fractures related to osteoporosis includes physical disability, loss of independence, and a tremendous economic cost. Of individuals who experience a hip fracture, 50% will require assistance after leaving the hospital, and 25% will require care in a nursing home. Individuals suffering hip fractures have a 5-20% greater risk of dying within the first year following that injury than others in their age group.2 Estimated national direct expenditures for osteoporosis and related fractures, including the cost of hospitalization, surgery, and nursing home care, are at least $10 billion annually, and the cost continues to rise.2
Diagnosis of osteoporosis often occurs after a fracture. Screening may identify individuals at risk, but at this time screening is not widely available and is not considered cost-effective. Bone mineral density (BMD) is an indirect measure of bone strength and is associated with the likelihood of fracture. BMD can be measured noninvasively by using dual energy X-ray absorptiometry (DEXA). DEXA can measure bone mass at any site in the skeleton with a precision that is within 1-2% of actual bone mass.2 The World Health Organization (WHO) Classification provides a practical definition for osteoporosis based on BMD. Normal BMD is defined as a value within 1 standard deviation (SD) of the average BMD for young normal adults. Low BMD or osteopenia is defined as a value between 1 and 2.5 SD below the young normal average. Osteoporosis is defined as a BMD value 2.5 SD below the young normal average. Severe osteoporosis is a bone density more than 2.5 SD below the average and a history of nonviolent bone fracture.'' Based on this classification, one of nine postmenopausal women (age 60-70) have normal BMD, approximately 30-50% have osteoporosis, and women in the remaining group have osteopenia.1
The clinical consequence of osteoporosis is bone fracture. Osteoporosis is responsible for more than 1.5 million bone fractures annually that are nonviolent in nature.1, 2 The lifetime risk of a clinically evident spine, hip, or wrist fracture is approximately 40%1.'The incidence of bone fracture is low until age 50 and then rises exponentially with advancing age.1 Risk factors for osteoporosis are listed in Table 1. Without a baseline BMD measurement, it is difficult to predict which individuals are at highest risk for osteoporotic fractures.
The maintenance of bone mass is a dynamic process of growth, balance, and gradual decline. With age, bone formation (mediated by bone building cells called osteoblasts) occurs more slowly than bone resorption (mediated by bone removing cells called osteoclasts), resulting in a net loss of bone mass with each cycle.' The risk of osteoporosis is influenced by peak bone mass, rate of bone loss, and microarchitectural deterioration. An individual's peak bone mass is achieved by age 35 and is influenced by genetics, diet, and exercise- Weight-bearing exercise and adequate dietary intake of calcium and vitamin D during the ages ranging from adolescence to 35 years are important for achieving maxima] peak bone mass. Bone mass decreases more rapidly in women than men because they have less bone to begin with; at menopause, loss of estrogen also enhances bone loss. Bone loss related to aging (in both men and women) results from decreased bone formation.3 Microarchitectural deterioration of bone leads to decreased bone density and decreased bone strength
HRT is the current standard and most cost-effective pharmacotherapy for preventing and treating osteoporosis in postmenopausal women. Rapid bone loss of 2-4% per year occurs with menopause due to the reduction in estrogen levels. Although this rapid bone loss levels off after five to ten years, age-related bone loss persists. HRT reduces bone resorption. The exact mechanism is unclear, but the binding of estrogen to receptors on bone appears to reduce both bone turnover and bone loss. This antiresorptive activity is mediated by osteoclasts and may also be influenced by cytokine activity and parathyroid hormone.
HRT typically consists of oral conjugated estrogens 0.625 mg daily or transdermal estradiol 0.05 mg patches applied twice weekly for 25 days, with a progesrin for 10-13 days each month at the end of the cycle.5 A higher dose of estrogen than that required to control menopausal symptoms may be necessary for bone protective effects.
By decreasing the rate of bone loss, estrogen maintains or slightly increases BMD. The magnitude of effect is 1-3% each year in the initial years of therapy after menopause.5 This averages to an overall increase in BMD of 5-10%. HRT reduces the vertebra] fracture risk by approximately 40-50%, and the nonvertebral fracture risk by approximately 25%.5 The bone protective effect is maintained only during the time period that HRT is taken, and bone loss resumes once therapy is discontinued.
Arguments can be made for either initiating therapy at menopause or delaying HRT until age 60.4 Beginning HRT (or unopposed estrogen if the individual has had a hysterectomy) just after menopause and up to five years later is convenient and effective in reducing the rapid bone loss related to menopause. Women who are at increased risk for osteoporosis (see Table I) should consider beginning HRT when menopause occurs. To achieve the maximal bone benefit and reduction of fracture risk, HRT must be taken for at least 7-10 years, and perhaps indefinitely.5 However, the symptoms of menopause (e.g., hot flashes) generally resolve within a few years, and after this point, compliance with HRT is usually poor.
| Table 1: Risk Factors for Osteoporosis |
|---|
| • Estrogen deficiency |
| • History of fracture after age 50 |
| • Advancing age |
| • Diet low in calcium, vitamin D |
| • Physical inactivity, bedridden |
| • Thin and or small frame |
| • Family history |
| • Smoking history |
| • Corticosteroid use |
The greatest risk for bone fracture is advancing age (75-80 years). One in six women will suffer a hip fracture in her lifetime.4 Fortunately, even if a woman delays HRT until age 65-70, it is still beneficial for reducing the risk of hip fracture. HRT still has a positive effect, but it is not as significant (in terms of increased BMD) as when therapy is started earlier in the postmenopausal period.
The controversy surrounding acceptance of HRT is related to cancer risk. The risk of endometrial cancer is increased in women with an intact uterus who take unopposed estrogen. The increased risk of endometrial cancer can be prevented with concomitant use of progesrins for 10-13 days a month.5 The effect of HRT on breast cancer risk is controversial and unclear. There is a slightly increased risk for developing breast cancer among individuals who have received HRT compared to individuals who have never taken estrogens.
If a woman is undecided or reluctant to begin HRT, she should consider her menopausal symptoms, coronary heart disease risk, and history of, or risk of, breast cancer. In general, the risk of hip fracture is equal to the combined risk of developing breast, uterine, and ovarian cancer. In an individual who is intolerant of HRT, consider her age (>50-60 years), number of risk factors for osteoporosis and BMD (hip). If the individual has a low BMD and risk factors for osteoporosis, an alternative therapy (discussed below) may be offered.
Raloxifene has just been FDA-approved for prevention of osteoporosis in postmenopausal women. Raloxifene is a selective estrogen receptor modulator (SERM). SERMs selectively stimulate bone and cardiovascular tissue but not breast and uterine tissue. Thus, one benefits from the positive estrogen effects on bone (inhibit bone resorption) and cardiovascular (lipid profile) system without the serious estrogen-related adverse effects (cancer risk) and eliminates the need for concomitant progestins use in women with a uterus. The recommended dose of raloxifene is 60 mg daily.
Alendronate is a new, potent bisphosphonate which inhibits osteoclast-mediated bone resorption by binding to bone.6, 7 Alendronate was FDA-approved in October 1995 for the treatment of osteoporosis in postmenopausal women and has been marketed as the first nonhormonal therapy for osteoporosis. It serves as an alternative for individuals who cannot tolerate estrogens.
Bisphosphonates can inhibit both bone resorption and bone mineralization. Eridronate is a nonselective, less potent bisphosphonate that must be administered cyclically to avoid mineralization defects and osteomalacia.6 The effects of eridronate on bone mass are most pronounced in the first 6-12 months of therapy, then are progressively less evident in the second and third years of use. Alendronate decreases bone loss by selectively increasing BMD in a dose-dependent manner. Unlike eridronate, the doses ofalendronate used to increase BMD do not impair bone mineralization.
The recommended dose of alendronate for the treatment of osteoporosis is 10 mg daily. The patient should take it on an empty stomach with a full glass of plain water (avoiding coffee, juices, carbonated drinks) in the morning to maximize absorption. Due to its potential for causing esophageal irritation, the patient must stay upright (not lie down) for at least 30 minutes after taking a dose. Calcium supplements, antacids, and food can decrease alendronate absorption. The administration of alendronate should be separated from mat of other medications and food by at least 60 minutes.
Alendronate is well tolerated. The most frequently reported adverse effects are gastrointestinal in nature and include abdominal pain, nausea, upset stomach, constipation, diarrhea, and flatulence. Infrequently, musculoskeletal pain and headache have been reported.
Several randomized, double-blinded, placebo-controlled trials have evaluated the safety and efficacy of alendronate in postmenopausal osteopororic women.7-10 Alendronate prevents bone loss and increases BMD in a magnitude similar to that reported with HRT (5-10%) and restores bone turnover to rates similar to those in normal premenopausal women.''" Alendronate reduces the risk of vertebral, fractures by approximately 40-50% and that of nonvertebral fractures by 20-30%.7-9
BMD changes appear more closely related to the daily dose than to the cumulative dose, as seen when individuals given 10 mg daily for the treatment period are compared to individuals given high dose alendronate (20 mg-40 mg) for three months followed by low dose alendronate (5 mg).7 In one trial, the increase in BMD during the first year of treatment persisted during the subsequent year, suggesting that the effects ofalendronate are sustained following discontinuation. This is in contrast to the prompt decreases in BMD that are seen with the discontinuation of estrogen and calcitonin therapy.7 The cumulative long-term effects of alendronate are unknown and are currently being evaluated
This large, randomized and controlled trial, was designed to evaluate the effect of alendronate on the frequencies of vertebral and nonvertebral fractures in postmenopausal women with low bone mass.10 Women were divided into two groups based on presence or absence of an existing vertebral fracture at time of recruitment. Black et al. have reported early findings from the group of women with an existing vertebral fracture at the rime of recruitment. This group represented those at highest risk for subsequent fractures and was divided into a treatment (alendronate) and placebo group. The women in the treated group received alendronate 5 mg daily for 24 months and 10 mg daily thereafter. Preliminary findings showed such significant reduction in fracture risk that the investigators closed this arm of the trial so that women in the placebo group may benefit from alendronate as well. As with other alendronate studies, BMD measurements increased at the spine, hip, and other skeletal sites. Follow-up radiographs showed that the risks of new vertebral, hip, and wrist fractures were reduced by 47%, 51%, and 41%, respectively.
Clearly, alendronate is a promising antiresorptive agent that is indicated for treatment and prevention of osteoporosis.
Calcitonin is a hormone secreted from the parafollicular cells of the thyroid gland. It plays a regulatory role in calcium and phosphorus homeostasis and acts directly on osteoclasts to inhibit bone resorption. Calcitonin has been used in diseases of calcium metabolism characterized by increased bone turnover, including osteoporosis and Paget's disease. Salmon-calcitonin is a synthetic polypeptide that has similar activity to mammalian calcitonin, but is more potent and has a longer duration of action.
Intranasal salmon-calcitonin is a new dosage form that is FDA-approved for the treatment of postmenopausal osteoporosis. Until recently, calcitonin was available only for subcutaneous or intramuscular injection. The intranasal formulation provides similar efficacy to that of injectable calcitonin in the prevention of bone loss. It is a more acceptable alternative for women who are unable to tolerate injectable calcitonin, HRT, or alendronate.
Intranasal calcitonin is dosed as one spray per day (which delivers 200 IU of calcitonin). Most adverse effects of the intranasal formulation are local (mild rhinitis, or runny nose). Nasal irritation can be avoided by alternating nostrils each day. Treatment failure may occur in patients with allergic rhinitis. Calcitonin therapy is contraindicated in patients with hypocalcemia.
In a randomized, double-blind, placebo-controlled trial, Overgaard et al. showed that nasal calcitonin provides a dose-dependent increase in spinal BMD (3%), and a reduction in vertebral fracture risk by two-thirds in elderly women (68-72 years old) with osteoporosis. 11 In addition, calcitonin provides a potent analgesic effect in individuals who have osteoporosis with the presence of a fracture. The mechanism for this analgesic effect is unclear.12
Fluoride decreases bone resorption, and unlike other antiresorptive agents, stimulates osteoblast proliferation to increase bone formation. However, fluoride use is controversial; there are concerns regarding both its efficacy and its risks. Histological studies show that new bone formed in response to fluoride may be poor in quality, have increased fragility, and an increased risk of fracture.13 If fluoride is taken without high dose calcium supplementation, substantial calcium content can be lost from the skeleton. A four-year study of postmenopausal women with osteoporosis and vertebral fractures by Riggs et al. demonstrated that sodium fluoride in daily doses of 75 mg increased spinal BMD but also decreased bone strength.14 Presently, fluoride is not FDA-approved for use in osteoporosis due to the above stated concerns despite its wide use in Europe.
Adverse effects, which are primarily gastrointestinal, are common. Nausea, vomiting, upset stomach, and gastrointestinal bleeding have all been reported. With immediate release products, lower extremity pain involving the feet, ankles, and legs has been reported. It is not clear if these effects are related to fluoride or result from stress fractures. Long-acting or slow release products may decrease the gastrointestinal effects.
Osteoporosis is a disease that is best managed with preventive measures. Maximizing peak bone mass with weight-bearing exercise and adequate intake of calcium and vitamin D are key preventive measures, whether drug therapy to prevent bone loss is initiated or not. Questions which must still be answered include who should have bone mineral density screening, and what is the optimum age for beginning drug therapy?
There are not sufficient data to show that treating everyone for fracture prevention is cost-effective; however, individuals with low bone mineral density and a history of bone fracture are at the highest risk for future fractures and should be treated. HRT remains the standard therapy for prevention and treatment of postmenopausal osteoporosis. Other promising alternatives include alendronate and intranasal calcitonin, and raloxifene. In the future, measures to assess drug efficacy may include periodic BMD measurements as these procedures become more affordable and widely available.