_______________________________________________________ Osteoporosis: Diagnosis and Management
recommended against routine use of unopposed estrogen in patients who have undergone a hysterectomy [77]. Hormone replacement therapy has been implicated in increased risk of breast cancer, stroke, venous thromboembolism, cholecystitis, and possibly coronary heart disease. Unopposed estrogen also has been shown to increase the risk of endometrial cancer. The WHI, HERS, and HERS II studies helped form an argument against hormone therapy in postmenopausal women, and given the other effective treatments for osteoporosis, treatment with hormones is not recommended [77]. While the WHI study findings have been useful, it should be noted that concerns have arisen in response to their conclusions. Specifically, the high average age of the study population (63.3 years of age) and use of only one type of medication and dosage have been the source of much criticism. It is necessary to remember that the use of hormone therapy should be individualized to the patient’s needs and medical history. Hormone replacement therapy may be beneficial short- term for a small subset of women with severe fracture risk [23]. The AACE has suggested that hormone replacement could be acceptable for treatment of osteoporosis under the following circumstances, after obtaining informed consent, discussing the risks and benefits of replacement, and with strict follow-up [36]: • Women with significant menopausal symptoms who are at risk for osteoporosis • Women with significant osteoporosis who are unable to tolerate alternative therapies When used to treat menopausal symptoms, estrogen should be used at the lowest necessary dosage and for the shortest possible time [49]. Because research is ongoing in this area,
Interestingly, some data have suggested that raloxifene may reduce coronary events and strokes in women at high risk for cardiovascular events and lower cholesterol levels, similar to statins [79]. Additional research is being conducted with respect to these outcomes [82]. Tibolone is an estrogen-like agent that has been used for decades in Europe to reduce menopausal symptoms and possibly prevent bone loss. Although there is some evidence of an increased risk of stroke, it does not appear to stimulate breast or uterine tissue and has been suggested for use in the treatment of vasomotor symptoms and prevention of osteoporosis [83]. However, it is not currently approved by the FDA for use in the United States [73]. Another SERM, bazedoxifene, was approved for the treatment of osteoporosis by the European Medicines Agency in 2009 [84]. One randomized, controlled trial of postmenopausal women with osteoporosis compared 20 mg or 40 mg of bazedoxifene with 60 mg raloxifene or placebo [85]. After 36 months, the incidence of new vertebral fractures was significantly lower in all treatment groups compared to placebo. Bazedoxifene also improved BMD and reduced bone marker levels. FDA approval of bazedoxifene was granted in 2013 [73; 86]. Bisphosphonates Bisphosphonates act to decrease resorption by causing apoptosis and decreased function of osteoclasts. Several medications or drug combinations have been approved by the FDA for the prevention and treatment of osteoporosis, including alendronate, alendronate plus D (alendronate and cholecalciferol), ibandronate, risedronate, risedronate with a calcium supplement, and zoledronic acid [20]. These agents may also be effective in reversing the effects of steroid-induced osteoporosis [73; 87]. The FDA also has approved the use of other bisphosphonates, including etidronate disodium, pamidronate, and tiludronate; however, they have not been approved for use in osteoporosis [73; 88].
recommendations may evolve or change. Selective Estrogen Receptor Modulators
SERMs are designed to mimic the beneficial effects of estrogen on bone, the heart, and the central nervous system, while at the same time minimizing the adverse effects on the breast and the uterus [23]. For example, raloxifene is an estrogen receptor modulator that acts as an estrogen agonist for bone and the lipoproteins, but an antagonist at the breast and uterus. It was the first SERM approved for the prevention and treatment of osteoporosis in postmenopausal women and has been shown to increase BMD, structurally recover bone, and decrease the risk of vertebral fractures [78; 79]. It is contraindicated in patients with a history of clotting disorders, such as venous thromboembolism. Side effects include leg cramps, arthralgias, rhinitis, headaches, and hot flashes [73; 79]. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a multicenter, randomized, double-blind, placebo- controlled study that followed 7,705 postmenopausal women for three years. The MORE trial demonstrated a decreased risk of invasive breast cancer by 76% as well as increased bone density in the spine and femoral neck and significantly reduced risk of vertebral (but not hip) fractures [80; 81].
According to the Institute for Clinical Systems Improvement,
bisphosphonates should be considered (unless contraindicated) for reduction of fracture risk (both vertebral and non- vertebral) in men and postmenopausal
women with osteoporosis. (https://www.icsi.org/wp-content/uploads/2019/ 01/Osteo.pdf. Last accessed October 15, 2024.) Strength of Recommendation/Level of Evidence : Strong recommendation, high-quality evidence
For severe osteoporosis, bisphosphonates are the best treatment option, with beneficial effects typically seen within a year. Note that bisphosphonates should be used with caution in patients with severe renal impairment [20; 73].
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