Fracture healing in osteoporotic bone
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.
Section snippets
Mechanical sensitivity in estrogen deficiency-induced osteoporotic fracture (type I) and the role of estrogen receptors
A number of reports revealed the differences of mechano-biology between osteoporotic and normal bones [12] and osteoporotic fracture healing was impaired in both early [13] and late phases with decrease in callus cross-sectional area, bone mineral density (BMD) and mechanical properties [14]. The mechanism of impaired osteoporotic fracture healing is multi-factorial and some reports indicated that low sensitivity of osteoblasts to mechanical signals [15], [16], reduced angiogenesis [17], [18],
The effect of aging on osteoporotic fracture healing (type II)
Our current understanding of the effects of aging on fracture repair comes from work in animal models. Although the sequence of fracture healing has been aptly described, less is known about the age-related changes to each step. Previous animal studies have described dysregulation of key processes, such as mesenchymal cell differentiation, inflammatory cell activity, and local revascularization [30], [31], [32], [33], [34], [35]. While these findings are derived from rodent models, the same
Future of osteoporotic fracture research – small animal model for metaphyseal fracture healing
Although the above observations nicely summarize the animal studies and filled in some of our current knowledge gaps in our understanding of osteoporotic fractures related to type I and type II osteoporosis, one phenomenon of osteoporosis is that it is mainly manifested by the microarchitectural deterioration of trabecular bone at the distal radius, proximal humerus and proximal femur [71], [72]. This is one of the main reasons why osteoporotic fractures most frequently occur at these
Conclusion
As the world aging population continues to escalate and the prevalence of osteoporotic fracture is projected to increase substantially, the healing process and outcome of fractures in osteoporotic bone caused by postmenopausal estrogen deficiency (type I) or aging (type II) have been extensively studied in the past decade. The well-orchestrated healing process in osteoporotic bone seems to be having one or few of the instruments playing slightly out-of-tune. The expression of estrogen receptor
Conflict of interest
The authors have no conflict of interest.
Acknowledgements
The part “Future of Osteoporotic Fracture Research – Small Animal Model for Metaphyseal Fracture Healing” was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB-TRR 79.
The part “Mechanical Sensitivity in Estrogen Deficiency-induced Osteoporotic Fracture (Type I) and the Role of Estrogen Receptors” was supported by the National Natural Science Foundation of China (NSFC) (Reference: A.03.15.02401).
References (88)
- et al.
Molecular aspects of healing in stabilized and non-stabilized fractures
J Orthop Res
(2001) - et al.
A model for intramembranous ossification during fracture healing
J Orthop Res
(2002) - et al.
Osteoporosis influences the early period of fracture healing in a rat osteoporotic model
Bone
(2001) - et al.
Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet
J Steroid Biochem Mol Biol
(1999) - et al.
Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF beta-release in response to cyclic strain
J Biomech
(1995) - et al.
The effect of donor age on the sensitivity of osteoblasts to the proliferative effects of TGF(beta) and 1,25(OH(2)) vitamin D(3)
Life Sci
(2002) - et al.
Stimulated angiogenesis for fracture healing augmented by low-magnitude, high-frequency vibration in a rat model-evaluation of pulsed-wave doppler, 3-D power Doppler ultrasonography and micro-CT microangiography
Ultrasound Med Biol
(2012) - et al.
Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells
Bone
(2003) - et al.
Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading
Bone
(2003) - et al.
Low-magnitude high-frequency vibration treatment augments fracture healing in ovariectomy-induced osteoporotic bone
Bone
(2010)
A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction
J Biol Chem
Cellular basis for age-related changes in fracture repair
J Orthop Res
Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats
J Orthop Res
MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes
Cell
MMP9 regulates the cellular response to inflammation after skeletal injury
Bone
The role of oxygen during fracture healing
Bone
The angiogenic response to skeletal injury is preserved in the elderly
J Orthop Res
Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing
Bone
Effect of repeated irrigation and debridement on fracture healing in an animal model
J Orthop Res
Intra-articular fibrous tissue formation following ankle fracture: the significance of arthroscopic debridement of fibrous tissue
Arthroscopy
From mechanotransduction to extracellular matrix gene expression in fibroblasts
Biochim Biophy Acta
The mechanical strength of bone in different rat models of experimental osteoporosis
Bone
Epidemiology of osteoporosis
Trends Endocrinol Metab
Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling
J Surg Res
Development of a locking femur nail for mice
J Biomech
A new metaphyseal bone defect model in osteoporotic rats to study biomaterials for the enhancement of bone healing in osteoporotic fractures
Acta Biomater
Differences of bone healing in metaphyseal defect fractures between osteoporotic and physiological bone in rats
Injury
The cell and molecular biology of fracture healing
Clin Orthop Relat Res
Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis
J Dent Res
Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation
J Cell Biochem
The Multifaceted Role of the Vasculature in Endochondral Fracture Repair
Front Endocrinol
An aging nation: the older population in the United States
Proc. Economics and Statistics Administration, US Dept. of Comm.
Estimating the risk of nonunion following nonoperative treatment of a clavicular fracture
J Bone Joint Surg Am
Management of odontoid fractures in the elderly
Eur Spine J
Risk of mortality following clinical fractures
Osteoporos Int
Rate of mortality for elderly patients after fracture of the hip in the 1980’s
J Bone Joint Surg Am
Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone
Osteoporos Int
Age-dependent impairment of angiogenesis
Circulation
Pathogenesis of age-related osteoporosis: impaired mechano-responsiveness of bone is not the culprit
PLoS One
Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones
J Orthop Res
Ovariectomy sensitizes rat cortical bone to whole-body vibration
Calcif Tissue Int
Evidence for cell-specific changes with age in expression of oestrogen receptor (ER) alpha and beta in bone fractures from men and women
J Pathol
Callus formation is related to the expression ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic fracture healing
Arch Orthop Trauma Surg
Restoration of estrogen receptor expression for osteoporotic fracture healing by low-magnitude high-frequency vibration therapy
Annual Meeting of the Orthopaedic Research Society
Cited by (144)
The impact of osteoporosis and diabetes on fracture healing under different loading conditions
2024, Computer Methods and Programs in BiomedicineFracture healing research: Recent insights
2023, Bone Reports