Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-Induced Osteoporosis: A Randomized, Double-Blind, Phase 3 Trial

Abstract

Context Glucocorticoids (GC) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. Objective To determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). Patients, Design and Setting Children 5-17 years of age with GIO were enrolled in this multi-national randomized, double-blind, placebo-controlled phase 3 trial (ClinicaTrials.gov NCT 00799266). Interventions and Main Outcome Measures Eligible children were randomized 1:1 to six monthly IV ZA 0.05 mg/kg or IV placebo. The primary endpoint was the change in lumbar spine bone mineral density Z-score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. Results Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures. LSBMDZ increased from −2.13 ± 0.79 to −1.49 ± 1.05 on ZA, compared with −2.38 ± 0.90 to −2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% confidence interval 0.02, 0.81; p=0.04]); when corrected for height Z-score, the least squares means difference in LBMDZ was 0.75 [0.27, 1.22; p=0.004]. Two children on placebo had new low-trauma VF versus none on ZA. Adverse events (AEs) were reported in 15/18 children (83%) on ZA, and in 12/16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths, nor treatment discontinuations due to treatment-emergent AEs. Conclusions LSBMDZ increased significantly on ZA compared with placebo over one year in children with GIO. Most AEs occurred after the first infusion.

Efficacy and safety of bisphosphonates on childhood osteoporosis secondary to chronic illness or its treatment: a meta-analysis

“…Finally, nine RCTs ( n = 429 in total) were included in our meta-analysis. 7 – 15 Of note, we excluded three articles because of no available outcome data 16 – 18 and another one article because of data not consistent with other studies 19 when assessing the full articles. The details of included studies are shown in Table 1 .…”

“…Among the nine included RCTs, six trials 8 – 13 used oral bisphosphonates, and the other three 7 , 14 , 15 trials used IV bisphosphonates. Placebo was used for the control group in two RCTs.…”

“…Placebo was used for the control group in two RCTs. 13 , 15 Calcium or calcium plus vitamin D were used in both control and bisphosphonate groups in eight RCTs. 7 – 12 , 14 , 15 The follow-up duration was 12 months in six RCTs, 8 – 10 , 12 , 13 , 15 3 months in one RCT, 11 18 months in one RCT, 7 and 24 months in the other one RCT.…”

“…Seven included RCTs with a total of 355 individuals that measured the changes in BMD Z-scores of the LS. 7 , 9 , 10 , 12 – 15 Among these included RCTs, three RCTs 7 , 14 , 15 used IV bisphosphonates and four RCTs 9 , 10 , 12 , 13 used oral bisphosphonates. As shown in Figure 4 , the meta-analysis showed that the changes in LS BMD Z -scores in the bisphosphonate groups were higher than those in the control groups (MD = 0.52, 95% CI = 0.23–0.81, p < 0.01, I 2 = 86%).…”

“…Seven included trials reported AEs, and a total of 173 out of 363 patients experienced at least one kind of AE. 7 – 10 , 12 , 14 , 15 Among these included RCTs, four RCTs 8 – 10 , 12 used oral bisphosphonates and the other three RCTs 7 , 14 , 15 used IV bisphosphonates. As shown in Figure 6 , the meta-analysis showed that bisphosphonates did not increase the total AE rate significantly (OR = 1.61, 95% CI: 0.87–2.99, p = 0.13, I 2 = 0%).…”