Common side effects (Table 2) can often be addressed by altering dosages, specific products, or regimens. The risk for breast cancer increases with duration of treatment and with combination HRT, compared with estrogen-only preparations.42,45,46 Combination HRT products are, however, essential for endometrial protection in women who have a uterus. The WHI reported an increase in breast cancer cases of 1 in 1250 women per year during an average 5-year follow-up.42 An increased risk for venous thromboembolism of 1 in 555 women per year was also observed with HRT use. Both the Heart and Estrogen/Progestin Study47 and the WHI studies found that venous thromboembolism occurred more frequently in the first 2 years of HRT use. An increased risk of myocardial infarction in the first 2 years of use was also noted among women with coronary heart disease47 and those without heart disease (1 in 1429 women per year).42 A small increase in stroke risk has also been documented.42,48-50 Contraindications to estrogen use include active thromboembolism, estrogen-related cancers, and liver disease.
Bisphosphonates
Two bisphosphonates, alendronate and risedronate, are approved in the United States for both prevention and treatment of postmenopausal osteoporosis. Clinical trials have demonstrated that both rapidly reduce the risk for symptomatic fractures in women with previous fracture and osteoporosis.37,51,52 The extent of fracture reduction is significant: Recent studies have shown that, over 3 years, the number of patients who would need to be treated with risedronate to prevent a vertebral fracture is 15, with alendronate, 34.53,54 Prevention of fractures among women without a prior vertebral fracture is less well established. No published data demonstrate that one bisphosphonate is more effective than another at preventing clinical fractures. A bisphosphonate is, therefore, the drug of choice for severe osteoporosis.
Bisphosphonates are generally well tolerated.55,56 However, postmarketing surveillance has demonstrated esophagitis and esophageal ulcer associated with alendronate.55 A pooled analysis of trials of risedronate found no increase in upper gastrointestinal (GI) adverse events even in patients with history of peptic ulcers, heartburn, and esophagitis, or among those taking nonsteroidal anti-inflammatory drugs, including aspirin.57
Oral bisphosphonates are not well absorbed (less than 1% of each dose).55,56 Therefore, to maximize absorption and to decrease the likelihood of adverse GI effects, the manufacturers of both bisphosphonates recommend that patients take the medication with a full glass of water, remain upright (sitting or standing) for at least 30 minutes following the dose, and not recline until food is consumed. Both bisphosphonates should be used with caution in patients with active GI disorders. Bisphosphonates are eliminated via the kidney and are not recommended for patients with a creatinine clearance below 30 mL/min.
Selective estrogen receptor modulators (SERMs)
Raloxifene is currently the only selective estrogen receptor modulator approved in the United States for prevention and treatment of osteoporosis. It has been shown to significantly decrease new vertebral fractures in women with a previous history of fracture and osteoporosis.58 The magnitude of fracture reduction is similar to that of bisphosphonates, although improvement in BMD is less marked.59 Raloxifene may confer other benefits. It has been shown to reduce the risk of breast cancer60,61 except in women with low estradiol levels,60 and may reduce the risk of myocardial infarction in women at high risk.60 Raloxifene does not increase the risk for endometrial cancer.60
Hot flashes and leg cramps are relatively common side effects of raloxifene.60 The observed risk of venous thromboembolism, 1 in 465 women per year during 3 years of treatment, is similar to that observed with HRT.60 Raloxifene is teratogenic and should not be used in premenopausal women.
Salmon calcitonin
Salmon calcitonin has demonstrated an analgesic effect for osteoporotic fracture.63,64 A large trial of salmon calcitonin at dosages of 100, 200, and 400 IU/day versus placebo found that salmon calcitonin at 200 IU/day decreased new vertebral fractures among women with a previous osteoporotic vertebral fracture based on radiographic assessment.65 No benefit was observed at the 100 and 400 IU/day dosages. The effect of calcitonin on clinical (symptomatic) fractures has not been reported. Calcitonin is approved for use in treatment, but not prevention, of osteoporosis.
Nasal calcitonin can cause minor rhinitis symptoms.30 Saline nasal solution may be useful to prevent or resolve irritation and dryness. Administration using alternate nostrils helps minimize local side effects. Unopened bottles (14 doses) must be stored in the refrigerator. Open bottles are stable at room temperature for up to 30 days.
Monitoring therapy
The value of serial densitometry to monitor the therapy of individual patients has not been established by randomized trials comparing different monitoring intervals or monitoring versus no monitoring.10,66 One important limitation is the relative imprecision of BMD testing: it takes almost a year to detect a 3% change in BMD.10 Disconcerting decreases in BMD scores are seen in yearly testing and may be offset by larger increases later, without a change in therapy. In studies of alendronate and raloxifene, disproportionately large fracture reductions cannot be explained by improvement in BMD alone.66,68 Bone densitometry is therefore not recommended until the patient has been treated for 2 years, and is of uncertain value beyond that point.
