Fracture healing in osteoporotic bone

Abstract

As the world population rises, osteoporotic fracture is an emerging global threat to the well-being of elderly patients. The process of fracture healing by intramembranous ossification or/and endochondral ossification involve many well-orchestrated events including the signaling, recruitment and differentiation of mesenchymal stem cells (MSCs) during the early phase; formation of a hard callus and extracellular matrix, angiogenesis and revascularization during the mid-phase; and finally callus remodeling at the late phase of fracture healing.

Through clinical and animal research, many of these factors are shown to be impaired in osteoporotic bone. Animal studies related to post-menopausal estrogen deficient osteoporosis (type I) have shown healing to be prolonged with decreased levels of MSCs and decreased levels of angiogenesis. Moreover, the expression of estrogen receptor (ER) was shown to be delayed in ovariectomy-induced osteoporotic fracture. This might be related to the observed difference in mechanical sensitivity between normal and osteoporotic bones, which requires further experiments to elucidate.

In mice fracture models related to senile osteoporosis (type II), it was observed that chondrocyte and osteoblast differentiation were impaired; and that transplantation of juvenile bone marrow would result in enhanced callus formation. Other factors related to angiogenesis and vasculogenesis have also been noted to be impaired in aged models, affecting the degradation of cartilaginous matrixes and vascular invasion; the result is changes in matrix composition and growth factors concentrations that ultimately impairs healing during age-related osteoporosis. Most osteoporotic related fractures occur at metaphyseal sites clinically, and reports have indicated that differences exist between diaphyseal and metaphyseal fractures. An animal model that satisfies three main criteria (metaphyseal region, plate fixation, osteoporosis) is suggested for future research for more comprehensive understanding of the impairment in osteoporotic fractures. Therefore, a metaphyseal fracture or osteotomy that achieves complete discontinuity fixed with metal implants is suggested on ovariectomized aged rodent models.

Introduction

Bone tissues demonstrate a remarkable ability to regenerate following fracture injury, recovering from structural failure and lost physiological function [1]. The cascade of events following traumatic bone injury is well-documented in both stabilized and non-stabilized fractures. The former primarily heal via intramembranous ossification in which bone regenerates directly from mesenchymal cells, while the latter primarily heal via endochondral ossification in which bone regenerates through a cartilage intermediate [1], [2], [3], [4], [5]. Both events begin with the formation of a hematoma between the damaged bone ends and surrounding soft tissues. Inflammatory cells are recruited by local chemokines to debride the wound, which allows for the migration of mesenchymal stem cells. In stabilized fractures, these cells differentiate directly into osteoblasts and form trabecular bone [5]. In non-stabilized fractures, these cells alter their fate and differentiate into granulation and cartilage tissues [1]. A predominantly cartilaginous soft fracture callus develops and stabilizes the injury site. Then, a hard fracture callus develops through vascularization and mineralization of the extracellular matrix, which yield trabecular bone. Once trabecular bone is generated in both ossification processes, a series of bone depositions and resorptions by osteoblasts and osteoclasts, respectively, reform lamellar bone.

Despite the fine degree of orchestration during fracture healing, the process may be impaired. Currently, 10–15% of the approximately 15 million fractures that occur annually result in poor or unresolved healing [6]. As the aging population is expected to double by 2050 [7] and the occurrence of osteoporotic fractures rise in the near future, impairment in osteoporotic fracture healing is becoming an emerging public health concern. Moreover, it has previously been reported that the risk of non-union increases with age [8], [9]; and that osteoporotic fracture is associated high morbidity, mortality rate [10], [11] and increased healthcare costs.

As the pathophysiology of both post-menopausal estrogen deficiency (type I) and senile (type II) account for the major causes of osteoporosis and subsequently osteoporotic fractures, this paper is intended to review our current understanding on fracture healing in osteoporotic bone in both types and to discuss a number of key determining factors that are impaired during osteoporotic fracture healing. These factors include the recruitment, proliferation and differentiation of progenitor cells; the revascularization of callus; and also the role of mechanical sensitivity in the healing osteoporotic bone. These factors are of high potential as therapeutic targets in future research. Some experiences in animal studies on diaphyseal osteoporotic fracture are summarized in this paper; nonetheless, a general direction of future development in metaphyseal osteoporotic fracture model is suggested in order to improve our research work in terms of clinical relevance and translational applicability.