Introduction: Goal of study to demonstrate that treatment with low-intensity pulsed ultrasound [LIPUS] results in greater increases in bone density and greater reductions in bone gap area as compared to sham control in tibia fractures with delayed union (no progression of healing for at least four months).

Methods: Two primary effectiveness variables, change of bone density and gap area during treatment, were selected as surrogates for bone healing. Abbreviated treatment period was maximum that sham treatment could be administered ethically. Both variables measured by blinded central reviewers from CT-scans taken before/after termination of treatment. All adverse events recorded, evaluated. Treatment duration was 16wks. Patients instructed to apply device once daily for 20 minutes. Control devices were visually identical but did not transmit ultrasound waves. Neither patients nor physicians could recognize shams.

Results: 101 patients enrolled (51 LIPUS, 50 sham), mean age 42.6 (active) versus 45.1 years (sham). Based on log-transformed data, mean improvement in bone density was 1.34 (90% CI 1.14 to 1.57) times greater for patients randomized to LIPUS compared to sham (p=0.002). A mean reduction in bone gap area also favored LIPUS treatment (p=0.014).

Conclusion: Double-blind, intent-to-treat analyses demonstrated statistically significant superior effectiveness for LIPUS device compared to sham in terms of both endpoints over 16wks of treatment. Estimated increase in bone density among patients randomized to LIPUS treatment was 34% greater than among patients randomized to sham. A significantly greater mean reduction in bone gap area after LIPUS treatment was also shown. Evaluation of adverse events showed that ultrasound therapy is safe.