The role of intermittent PTH administration in conjunction with allogenic stem cell treatment to stimulate fracture healing

Abstract

Aims A growing number of fractures progress to delayed or nonunion, causing significant morbidity and socioeconomic impact. Localized delivery of stem cells and subcutaneous parathyroid hormone (PTH) has been shown individually to accelerate bony regeneration. This study aimed to combine the therapies with the aim of upregulating fracture healing. Methods A 1.5 mm femoral osteotomy (delayed union model) was created in 48 female juvenile Wistar rats, aged six to nine months, and stabilized using an external fixator. At day 0, animals were treated with intrafracture injections of 1 × 106 cells/kg bone marrow mesenchymal stem cells (MSCs) suspended in fibrin, daily subcutaneous injections of high (100 μg/kg) or low (25 μg/kg) dose PTH 1-34, or a combination of PTH and MSCs. A group with an empty gap served as a control. Five weeks post-surgery, the femur was excised for radiological, histomorphometric, micro-CT, and mechanical analysis. Results Combination therapy treatment led to increased callus formation compared to controls. In the high-dose combination group there was significantly greater mineralized tissue volume and trabecular parameters compared to controls (p = 0.039). This translated to significantly improved stiffness (and ultimate load to failure (p = 0.049). The high-dose combination therapy group had the most significant improvement in mean modified Radiographic Union Score for Tibia fractures (RUST) compared to controls (13.8 (SD 1.3) vs 5.8 (SD 0.5)). All groups demonstrated significant increases in the radiological scores – RUST and Allen score – histologically compared to controls. Conclusion We demonstrate the beneficial effect of localized MSC injections on fracture healing combined with low- or high-dose teriparatide, with efficacy dependent on PTH dose. Cite this article: Bone Joint Res 2021;10(10):659–667.

Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis

“…miRNAs play pivotal roles in the different stages of osteogenesis and fracture healing. 29 , 37 , 38 BMSCs are the basic cell unit of embryonic bone formation. These cells have been widely used in regenerative medicine because of their unique capabilities of self-renewal and multilineage differentiation.…”

Stem Cells and Their Derivatives: An Implication for the Regeneration of Nonunion Fractures

“…The published data emphasize local administration of MSCs in conjunction with systemic PTH as a therapy deserving of further investigation; the data given support the efficacy of combining both techniques. Furthermore, additional research on the underlying mechanistic mechanisms is required 12 .…”

Overview of Physical and Pharmacological Therapy in Enhancing Bone Regeneration Formation During Distraction Osteogenesis

“…A growing number of delayed or nonunion of fractures emerge. Osagie-Clouard et al used external fixator to establish a delayed union model and testified the favorable effect of localized MSC injections on fracture healing combined with low- or high-dose teriparatide, with efficacy dependent on PTH dose ( Osagie-Clouard et al, 2021 ). Wagner et al enrolled sixteen patients to undergo a clinical study, and concluded that teriparatide treatment during the consolidation period might double the mineralization rate of the regeneration.…”