4. The Low-Intensity Pulsed Ultrasound (LIPUS) Mechanism and the Effect of Teriparatide on Fracture Healing

Low-Intensity Pulsed Ultrasound (LIPUS) provided a mechanical stimulus, and was thought to promote fracture healing by signal transduction through integrin, a cytoskeletal protein. Meanwhile, teriparatide, a drug for osteoporosis treatment, showed efficacy in promoting bone metabolism. This drug also appeared to prevent fractures in patients with serious osteoporosis by improving bone mineral density and bone quality, which in turn resulted from promoting action for bone metabolism. Further, clinical trials and fundamental research reported that teriparatide demonstrated the effect of promoting fracture healing. Mechanical stimulus by LIPUS had a topical effect on fractures; on the other hand, teriparatide (peptide hormone) had both topical and systemic effects. Both LIPUS and teriparatide had the effect of fracture healing, but it was supposed that the characteristics of each effect were different because of the different mechanism of action. Moreover, the combination therapy of LIPUS and teriparatide was expected to produce synergies. We used elderly rats as models for the femoral fracture to examine the effects of LIPUS and teriparatide on promoting fracture healing for treatment delay by aging. We observed the fracture healing process in 40-week-old rats as an elderly model using simple radiographs, and recognized a delay in fracture healing compared with that of 8-week-old rats. As discussed in histomorphology, it was demonstrated that the period of endochondral ossification, from chondrogenesis to teleost cross-linked callus, was prolonged and the fracture healing process was delayed by aging. Next, we treated the elderly fracture models with LIPUS for 20 minutes a day from the first day after the fracture, and compared them with non-treated models. The bone unions of the treated models were observed earlier than those of non-treated models in the simple radiographs. LIPUS shortened the period of endochondral ossification. Further, we gave the elderly fracture models teriparatide subcutaneously 5 μg/kg three times a week from the first day after the fracture. Bone unions of the treated models were observed earlier than those of non-treated models in simple radiographs as well. In micro CT analysis, it was demonstrated that lamellar bone transforming and bone remodeling of the trabecular structure of external callus were especially accelerated. The results of these trials showed that both LIPUS and teriparatide demonstrated the effect of promoting fracture healing, and each had unique characteristics.