Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Abstract

Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/β‐catenin signaling, and recombinant FGF‐2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:213–223, 2017.

Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture

“…Fracture healing is usually a robust process that restores a broken bone's original strength and geometry . Several endogenous factors are involved in orchestrating the multi‐step process leading to successful fracture healing, including parathyroid hormone‐related protein (PTHrP) . Throughout much of the fracture healing cascade, numerous mesenchymal cell types increase their expression of PTHrP, including osteoblasts engaged in intramembranous ossification and chondrocytes involved in endochondral ossification .…”

“…PTH1R, the receptor for PTHrP and PTH, is also highly expressed by osteoblasts and chondrocytes during fracture healing, and PTH1R mediates the anabolic responses to locally‐upregulated PTHrP expression. The genetic ablation of PTHrP or PTH impairs long bone fracture healing in mice, and the systemic delivery of recombinant or synthetic forms of PTHrP and other PTH1R ligands, including full‐length PTH(1–84) and its active amino‐terminal fragment PTH(1–34), promotes fracture healing in animals . Systemically‐administered PTH(1–34) has also been shown to favorably influence some aspects of fracture healing in humans …”

“…Among patients with open long bone fractures, as many as 25% may develop delayed union or nonunion, which can cause major loss of productivity, decreased quality of life, and extensive health care utilization . Despite clear unmet clinical needs, no pharmacological agents are currently approved for the acceleration of fracture healing or for the treatment of delayed or nonunion fractures . Recombinant human bone morphogenetic protein‐2 (rhBMP‐2) mixed with an absorbable collagen sponge (ACS) is indicated for the acute treatment of tibial shaft fractures, but this combination “device” product is associated with several safety issues and is only indicated for the treatment of tibial fractures that have accessible fracture lines .…”

Applied Induced Pluripotent Stem Cells in Combination With Biomaterials in Bone Tissue Engineering

“…Small lesions bone itself heals, but when the repair mechanism was not able to reconstruct the bone, to the great cause injury, or other causes, including infections, bone grafts should be used. Bone grafting means that the bone from elsewhere and taken to the injury linked [Gómez‐Barrena et al, ; Kostenuik and Mirza, ]. Preferably, the bone of the patient's one's body (like the hip bone) is prepared as bone, says autologous bone.…”

Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach

“…Adjuvants to these treatments, such as bone morphogenetic proteins, platelet-rich plasma, and low-intensity pulsed ultrasound, have been employed to promote local biology [6, 7]. …”