A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone

Abstract

Context: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment.

Objective: To determine the efficacy of alendronate for treatment of FD.

Design: Two-year randomized, double-blind, placebo-controlled trial.

Setting: Clinical research center.

Patients: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age.

Interventions: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg.

Main outcome measures: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing.

Results: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups.

Conclusions: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters.

Trial registration: ClinicalTrials.gov NCT00001728.

Figures

Figure 1.

Study flow diagram. 1, Shortly after starting alendronate, an adult subject with an undisclosed history of reflux developed an esophageal stricture, and a pediatric subject developed nausea and vomiting. Both were taken off study drug. 2, An adult subject voluntarily withdrew. 3, An adult subject voluntarily withdrew and was placed on open-label bisphosphonates. 4, A pediatric subject was taken off study drug after developing diarrhea and a 10 pound weight loss.

Figure 2.

Effects of alendronate on bone turnover markers. A, Subjects in the alendronate group had a sustained decrease in the bone resorption marker urine NTX-telopeptides over the study period, which was significantly different from the placebo group. Time points that were statistically different are marked with an asterisk (*). B, There was no significant change in serum osteocalcin, a bone formation marker, in either group. Error bars represent 1 standard error and the hatched rectangles indicate the periods during which study drug or placebo were administered.

Figure 3.

Effect of alendronate on areal BMD of normal and FD bone. A, aBMD was measured by dual-energy x-ray absorptiometry in the lumbar/sacral (L/S) spine of all subjects who did not have FD at the standard L/S sites as determined by bone scan. Differences between groups were measured as percent change from baseline for each individual. Adults are represented by black-filled bars (alendronate n = 6, placebo n = 12), children by open bars (alendronate n = 5, placebo n = 2), and combined adults and children by gray bars (alendronate = 11, placebo n = 14). There was a statistically significant effect of alendronate on bone density at 24 months on the combined group of adults and children (P = .006). When adults and children were analyzed separately, there was a significant difference in treated children (P = .01), however the changes in adults did not reach statistical significance (P = .13). B, Effect of alendronate on aBMD of FD lesions. Areal BMD was measured at sentinel sites of FD as defined in the Methods. Differences between groups were measured as percent change from baseline for each individual. Adults are represented by black-filled bars (alendronate n = 12, placebo n = 5), children by open bars (alendronate n = 9, placebo n = 3), and combined adults and children by gray bars (alendronate n = 19, placebo n = 8). There was a statistically significant effect of alendronate on the combined group of adults and children (P = .0009). When children were analyzed separately the change in aBMD was significant (P = .001), however there was no significant change detected in a subanalysis including only adults (P = .25).

Figure 4.

Representative radiographs. The left upper panels show images of the proximal femur from a 10-year-old boy in the alendronate group at baseline (A) and 24 months (B). Note lucent lesions consistent with fibrous dysplasia (FD) (arrowheads), which do not improve over the course of treatment. The radiographs in the left lower panels are from a 6-year-old boy in the placebo group at baseline (C) and after 24 months of treatment (D), which show mild progression of cortical thinning. The right upper panels show images from a 12-year-old girl in the alendronate treated group with diffuse tibial involvement at baseline (E) and 24 months (F). The images exhibit typical features of FD including radiolucency, cortical thinning, and deformity, with no evidence of improvement over the treatment course. The right lower panels (G and H) show similar views of the right tibia and fibula from a 17-year-old boy in the placebo group, which likewise did not change significantly over 24 months.

Figure 5.

Effect of alendronate on bone pain. There was no significant change in mean bone pain score in either the alendronate or the placebo groups over the study period, as assessed by the Wisconsin Brief Pain Questionnaire (21). Error bars represent 1 standard deviation and the hatched rectangles indicate the periods during which study drug or placebo were administered.