Most women gain about 2 percent to 4 percent in bone mineral density (BMD) when they are first placed on alendronate therapy. The rare patient who loses bone in the first year of treatment may be biologically unresponsive to the drug; if she is, she will continue to lose BMD in the second. If, however, measurement variations are responsible for findings of bone loss, BMD should be regained with continued treatment. The concept of “regression to the mean” predicts that “outliers” who have an unusual response to treatment are likely to respond more typically if treatment is continued. This concept was tested by reviewing data from two randomized, double-blind, placebo-controlled trials: the Fracture Intervention Trial (FIT), performed in 11 U.S. clinical research centers, and the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial, conducted at 180 centers in the United States and other countries. In the FIT, 2634 postmenopausal women with low BMD were assigned to receive 5 mg daily of alendronate sodium, and their BMD was monitored for 2 years. A calcium supplement and cholecalciferol also were given when needed. In the MORE trial, 3954 postmenopausal women with osteoporosis received 60 or 120 mg daily of raloxifene and underwent 2 years of monitoring.
Women complying with alendronate therapy gained an average of 2.2 percent BMD in the total hip and 4.5 percent in the spine. An additional 0.9 percent and 1.7 percent, respectively, were gained in the second year of treatment. Women who lost BMD at the hip initially usually gained BMD in the second year, and those losing the most initially were the most likely to gain later (Fig. 1). In contrast, women gaining more than 8 percent in BMD in the first year lost 1 percent on average in the second year of alendronate therapy. Similar changes were noted in spinal BMD, and the changes at both sites also were observed in placebo recipients. Women on placebo who lost more than 4 percent of BMD at the hip initially gained an average of 4.8 percent in the second year. In the raloxifene trial, women losing BMD in the femoral neck in the first year usually gained density in the following year. As in the alendronate study, women gaining more than 8 percent BMD in the first year lost 2.8 percent on average in the second year on raloxifene. These findings suggest that osteoporotic women who lose BMD when placed on an antiresorptive drug will generally go on to gain BMD if treatment is continued, in accord with the principle of regression to the mean.