Osteoporosis: Diagnosis and Managements _ _____________________________________________________
Oral bisphosphonates are generally well-tolerated; however, complaints of upper gastrointestinal side effects (e.g., dyspepsia, reflux) are common in adults [20; 73]. When side effects occur and threaten to interfere with therapy, evaluate the patient’s ability to comply with dosing instructions (e.g., take on empty stomach with 8 ounces water, remain upright 30 to 60 minutes) [20; 73]. If esophagitis/gastritis associated with alendronate is suspected, discontinue therapy for four to six weeks. Some patients may benefit from a change to risedronate; however, studies have found similar gastrointestinal tolerability between risedronate and alendronate [89; 90]. Intravenous bisphosphonates may be used in patients who are unable to tolerate oral preparations. IV zoledronic acid (preferred) is administered once every year (for treatment) or once every two years (for prevention); ibandronate is administered once every three months [73; 91]. Results after three years of therapy with oral bisphosphonates vary across studies. Generally, femoral neck and spine BMD have increased by 1.5% to 6% and 5.5% to 6.5%, respectively, and vertebral/femoral neck fracture risk has been reduced by 40% to 60%, a significant difference from trial placebo groups [92]. A 2017 meta-analysis of 24 studies was conducted to evaluate the efficacy of bisphosphonates in preventing fracture in patients with osteoporosis. The analysis included 21,335 patients assigned to a bisphosphonate group and 17,862 patients assigned to a placebo group [93]. The overall rate of osteoporotic fracture was 5.9% in the bisphosphonate group and 9.9% in the placebo group. The rate of vertebral fracture was 5.9% in the bisphosphonate and 10.3% in the placebo group. The rate of nonvertebral fracture was 6.9% in the bisphosphonate group and 9.6% in the placebo group [93]. The best long-term (5 to 10 years) data come from the use of alendronate [94; 95; 96]. There is no consensus on the optimal duration of bisphosphonate treatment [97; 98]. Generally, it is considered reasonable to discontinue treatment (“drug holiday”), after five years of oral therapy or three years of IV therapy, in low-risk women with stable BMD and no previous history of vertebral/ femoral fracture [49; 99]. Most experts favor continuing therapy for high-risk patients (i.e., previous fracture, elderly/frail). The duration of drug holiday is a matter for clinical judgment and individual patient considerations, determined in part by annual BMD monitoring and the patient’s level of activity and fracture risk [49; 100]. Alendronate, a second-generation bisphosphonate, has been shown to be most effective for patients with T-scores less than -2.5 or for patients with previous vertebral fracture. Alendronate has demonstrated the ability to reduce the incidence of wrist, hip, and spinal fractures by 50% over a three- year period in women with a prior fracture of the spine [20]. In the Fracture Intervention Trial (FIT), a large alendronate study, women with osteoporosis and vertebral fracture showed a significant decrease in vertebral and hip fractures [101]. A follow-up trial to FIT, the Fracture Intervention Trial Long-
Term Extension (FLEX), showed that when compared with women who stopped alendronate after an average of five years, women who continued alendronate maintained a higher BMD and greater reduction of bone turnover. The risk for vertebral fracture between the two groups was relatively the same. While results indicated that women with very high risk of clinical vertebral fractures may benefit by continuing alendronate beyond five years, study results indicated that more data are needed on the effect of continuation versus discontinuation of alendronate before an optimal length of treatment can be recommended [94; 97]. One study sought to predict fracture risk among participants in the FLEX trial by looking only at those assigned to the placebo group [96]. Hip and spine DXA and two biochemical markers of bone turnover were measured when placebo was begun (FLEX baseline) and again after one and three years of follow-up. During five years of placebo, 22% of women in the placebo group experienced one or more symptomatic fractures and 19% had fractures after one year. Age and hip BMD at discontinuation predicted clinical fractures during the subsequent five years [96]. In both the FIT and follow-up FLEX trials, women were encouraged to take 500 mg/day of calcium and 250 IU/day of vitamin D in addition to the alendronate. One study suggests that the success of alendronate therapy may depend on the vitamin D status of patients [102]. Alendronate dosing is 5 mg/day for osteoporosis prevention and 10 mg/day for treatment [73; 103]. It is also available in a 35-mg and a 70-mg once-weekly oral dose that may be better for patient compliance due to its easier dosing. As stated, bisphosphonate medications should be taken on an empty stomach with a full glass of water. The most common side effects of alendronate are gastrointestinal, including esophagitis and gastric ulcer. Muscular and skeletal pains have also been reported. As stated, to prevent the gastrointestinal effects, the patient is urged to sit upright for at least 30 minutes after taking the medication [73]. Proton pump inhibitors and other acid reducing agents do not appear to prevent the gastrointestinal side effects of the bisphosphonates [103]. Of note, the effects of alendronate on bone density after discontinuation of hormone replacement therapy have yielded promising, if mixed, results. For example, in a published randomized controlled trial, women who had been diagnosed as having low BMD and had recently stopped hormone replacement therapy were randomized to either 10 mg of alendronate or placebo. At the end of the one-year trial, treatment with alendronate had demonstrated a 2.3% mean increase in spine BMD versus a mean loss of 3.2% in the placebo group. There was also greater total body and hip BMD preservation as well as decreased bone turnover with the use of alendronate as compared to placebo [104]. A separate trial, designed to evaluate the combined use of alendronate and estrogen, indicated that combination therapy produced somewhat larger increases in BMD than either agent alone and was well tolerated [105]. A trial designed to determine the rate
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