Testosterone Delivered with a Scaffold Is as Effective as Bone Morphologic Protein-2 in Promoting the Repair of Critical-Size Segmental Defect of Femoral Bone in Mice

Abstract

Loss of large bone segments due to fracture resulting from trauma or tumor removal is a common clinical problem. The goal of this study was to evaluate the use of scaffolds containing testosterone, bone morphogenetic protein-2 (BMP-2), or a combination of both for treatment of critical-size segmental bone defects in mice. A 2.5-mm wide osteotomy was created on the left femur of wildtype and androgen receptor knockout (ARKO) mice. Testosterone, BMP-2, or both were delivered locally using a scaffold that bridged the fracture. Results of X-ray imaging showed that in both wildtype and ARKO mice, BMP-2 treatment induced callus formation within 14 days after initiation of the treatment. Testosterone treatment also induced callus formation within 14 days in wildtype but not in ARKO mice. Micro-computed tomography and histological examinations revealed that testosterone treatment caused similar degrees of callus formation as BMP-2 treatment in wildtype mice, but had no such effect in ARKO mice, suggesting that the androgen receptor is required for testosterone to initiate fracture healing. These results demonstrate that testosterone is as effective as BMP-2 in promoting the healing of critical-size segmental defects and that combination therapy with testosterone and BMP-2 is superior to single therapy. Results of this study may provide a foundation to develop a cost effective and efficient therapeutic modality for treatment of bone fractures with segmental defects.

Effect of Selective Androgen Receptor Modulator Enobosarm on Bone Healing in a Rat Model for Aged Male Osteoporosis

“…Testosterone has been shown to have a direct, positive effect on bone healing by inducing callus formation and improving the biomechanical stability of fractured bone [ 30 , 31 ]. As testosterone is aromatized to estrogen, it not only acts on bone directly via ARs but also indirectly via estrogen receptors (ERs) [ 9 , 32 ].…”

Construction of Radial Defect Models in Rabbits to Determine the Critical Size Defects

“…Small animal models could avoid the demerits of large animals, especially for large sample sizes, so they are considered to be more suitable for fundamental research problems and screening experiments [ 35 ]. For example, CSD in the femur of Wistar rats is 5 mm [ 35 ], in the femur of C57BL/7 mice is 2.5mm [ 36 ], while in an adult guinea pig, the CSD (diameter) within the calvaria is 8mm [ 37 ], and in dogs the CSD of the ulnar is 2.0 cm [ 38 ]. In recent years, the CSD of radial bone defects in New Zealand white rabbits were largely applied to tissue engineering research.…”

Determining the critical size of a rabbit rib segmental bone defect model

“…The experimental animal’s age, weight, gender, and defect type all affected the rate of bone union [ 10 ]. For example, CSD in Wistar rats femur is 5 mm [ 11 ], in C57BL/7 mice femur is 2.5 mm [ 12 ], while, the CSD (diameter) in an adult guinea pig within the calvaria is 8 mm [ 13 ], and the CSD in dogs ulna is 2.0 cm [ 14 ]. The rabbit rib defect used in this study was younger and likely had a stronger regenerative potential than did the other defect type used in their study.…”