Promethazine Downregulates Wnt/ß-Catenin Signaling and Increases the Biomechanical Forces of the Injured Achilles Tendon in the Early Stage of Healing.

BACKGROUND: Wnt/ß-catenin signaling suppresses the differentiation of cultured tenocytes, but its roles in tendon repair remain mostly elusive. No chemical compounds are currently available to treat tendon injury. HYPOTHESIS: We hypothesized that the inhibition of Wnt/ß-catenin signaling would accelerate tendon healing. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon-derived cells (TDCs) were isolated from rat Achilles tendons. The right Achilles tendon was injured via a dermal punch, while the left tendon was sham operated. A Wnt/ß-catenin inhibitor, IWR-1, and an antihistamine agent, promethazine (PH), were locally and intramuscularly injected, respectively, for 2 weeks after surgery. The healing tendons were histologically and biomechanically evaluated. RESULTS: The amount of ß-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/ß-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased ß-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/ß-catenin signaling in human chondrosarcoma cells, we examined the effects of antihistamines on TDCs. We found that a first-generation antihistamine agent, PH, increased the expression of the tendon marker genes Mkx and Tnmd in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased ß-catenin in healing tendons and increased the peak force and stiffness of the healing tendons on postoperative week 2. On postoperative week 8, however, the biomechanical properties of vehicle-treated tendons became similar to those of PH-treated tendons. CONCLUSION: IWR-1 and PH suppressed Wnt/ß-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them. CLINICAL RELEVANCE: PH is a candidate repositioned drug that potentially accelerates tendon repair.

Subtrochanteric fracture in a patient receiving zoledronic acid therapy for metastatic breast cancer.

A 61-year-old woman presented with acute pain of the right thigh after falling on a public street. She had been diagnosed with metastatic breast cancer and bisphosphonate therapy along with zoledronic acid. Radiographs demonstrated transverse subtrochanteric femoral fracture with thickening of the lateral cortex and spike of the medial cortex at the site of fracture. The contralateral femur showed thickening of the lateral cortex at the same site. This type of stress fracture is related to severe suppression of bone turnover (SSBT) under bisphosphonate therapy. Our patient had been receiving zoledronic acid therapy for 3.6 years, and the radiographic findings were typical of stress fracture associated with bisphosphonate. Therefore, the facture in our patient was considered related to SSBT under zoledronic acid therapy. Zoledronic acid is administered to patients with osteoporosis or complications due to cancer such as hypercalcemia of malignancy. Recently stress fractures associated with zoledronic acid therapy for osteoporosis have attracted attention. However, there are few reports of fracture associated with zoledronic acid therapy for cancer. Doses of zoledronic acid recommended for cancer patients are much greater than those for patients with osteoporosis. Clinicians treating such cancer patients need to cautiously manage stress fractures as a complication of zoledronic acid therapy.