_______________________________________________________ Osteoporosis: Diagnosis and Management
of bone loss when therapy with alendronate, estrogen, or both agents was discontinued revealed accelerated bone loss after withdrawal of estrogen therapy, but not after withdrawal of alendronate or combination therapy [106]. One randomized, placebo-controlled trial compared BMD and bone turnover changes after therapy withdrawal in postmenopausal women treated with alendronate or estrogen/progestin [107]. Of the 1,609 women at the start of the trial, one-third were switched from alendronate to placebo after the second year and one-third after the fourth year (while all remained blinded to treatment assignment). Women taking estrogen/progestin in years 1 to 4 were followed off therapy in years 5 and 6. BMD decreased steadily in the placebo group during all six years, whereas spine and hip BMD increased during the first four years in groups receiving both alendronate and estrogen/progestin. BMD decreased during years 5 and 6 in the group previously treated with alendronate for four years. In comparison, large BMD decreases were observed at the spine and hip among women who received estrogen/progestin for four years [107]. Risedronate is another agent that is effective for osteoporosis. A three-year trial of risedronate on patients with pre-existing vertebral fracture demonstrated a significant reduction in both vertebral and nonvertebral fractures [108]. It reduced the incidence of fractures of the spine by 41% to 49% and other fractures by 36% in patients with prior spinal fractures [20]. The recommended dose of risedronate is 5 mg/day, or a 35 mg weekly dose for both treatment and prevention [20; 73]. The 35 mg dose of risedronate should be taken weekly with 1250 mg of calcium carbonate taken daily on the intervening six days. Reported side effects include headache, nausea, arthralgias, asthenia, abdominal pain, and other gastrointestinal problems [73]. A two-year study of risedronate given at a dose of 150 mg once a month to women with postmenopausal osteoporosis found similar efficacy and safety compared with risedronate 5 mg daily [109]. The mean percent changes in BMD at the hip and in biochemical markers of bone turnover were similar, as were adverse events. Ibandronate also has been added to the FDA-approved list for the prevention and treatment of postmenopausal osteoporosis. The medication has been shown to reduce the incidence of spinal fractures by approximately 50% over a three-year period. It may be taken in tablet form, 150-mg tablet once a month, or intravenously, 3 mg every three months [73]. The side effects are similar to those of the other bisphosphonate medications [20; 73]. Denosumab Denosumab is a human monoclonal antibody being studied for its effects on bone metastases, rheumatoid arthritis, and multiple myeloma [110; 111]. In 2011, the FDA approved denosumab for treatment of osteoporosis in postmenopausal women who are at high risk of fracture [73; 112; 113]. Denosumab acts by binding to and inhibiting receptor activator of nuclear factor kappaB ligand (RANKL). RANKL controls the differentiation, proliferation, and survival of osteoclasts.
Inhibition of RANKL provides a lengthened period of absorption, inhibition of bone resorption, and higher BMD [20; 73; 114]. Dosing of denosumab is 60 mg subcutaneous injection every six months. Several studies evaluating the efficacy of denosumab in the prevention and treatment of postmenopausal osteoporosis have been completed. In the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial, use of denosumab resulted in a reduced risk for vertebral, nonvertebral, and hip fractures in women with osteoporosis [115]. The trial involved 7,868 postmenopausal women with T-scores between -2.5 and -4 who were randomly assigned to receive placebo or a subcutaneous injection of 60 mg denosumab every 6 months for 36 months. Results demonstrated a 68% decrease in new vertebral fracture in the treatment group as compared to the placebo group (2.3% versus 7.2%) [115]. Significant reductions in hip and nonvertebral fractures were also noted. The authors reported no increases in adverse effects (e.g., cancer, delayed healing, osteonecrosis of the jaw, injection site reactions) associated with use of denosumab. While results of one meta-analysis also found a decreased risk of nonvertebral fracture with use of denosumab in postmenopausal women with osteoporosis or low BMD, the study did find a significantly increased risk of serious adverse event related to infection [116]. A 12-month study compared the effects on BMD and bone turnover on patients with osteoporosis who were suboptimally adherent to bisphosphonates (and at higher risk for fracture) who were transitioned to denosumab or monthly oral bisphosphonate (ibandronate or risedronate) [117]. A total of 1,703 women were randomized to either denosumab 60 mg subcutaneously every six months or oral bisphosphonate 150 mg monthly. In both the overall and higher-risk populations, denosumab was associated with greater gains in BMD at 12 months than oral bisphosphonate at the total hip, femoral neck, and lumbar spine. Adverse events were generally similar between the two treatment groups [117]. Long-term use of denosumab is associated with a significant (48%) reduction in risk of all upper limb fractures and a 43%, 43%, and 58% reduction, respectively, in risk of forearm, wrist, and humerus fractures at seven years [118; 119]. Calcitonin Calcitonin is a hormone normally produced by the parafollicular cells of the thyroid gland. Recombinant salmon calcitonin is approved by the FDA for the treatment and prevention of osteoporosis in women who have been postmenopausal for at least five years; it has not been recommended as a first-line treatment [20; 35]. In the proper dosages, it is an inhibitor of bone resorption [20; 23]. Calcitonin may be administered by intranasal spray or by a subcutaneous injection of 100 IU/day. Intranasal use has been shown to decrease vertebral fractures in patients with pre-existing fractures, but only at 200 IU/day, not at 100 IU or 400 IU/day [20; 21; 23]. Oral and inhaled forms of calcitonin are under development [23].
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