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Rodriguez-Merchan, E.C. Bone Healing. Encyclopedia. Available online: (accessed on 15 April 2024).
Rodriguez-Merchan EC. Bone Healing. Encyclopedia. Available at: Accessed April 15, 2024.
Rodriguez-Merchan, Emerito Carlos. "Bone Healing" Encyclopedia, (accessed April 15, 2024).
Rodriguez-Merchan, E.C. (2021, February 22). Bone Healing. In Encyclopedia.
Rodriguez-Merchan, Emerito Carlos. "Bone Healing." Encyclopedia. Web. 22 February, 2021.
Bone Healing

Main methods of biophysical enhancement in treating bone nonunions.

bone fracture healing bone tissue engineering

1. Introduction

It is estimated that between 5% and 10% of bone fractures do not heal properly [1]. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age.

Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect [2]. Several biological enhancement methods have been published so far for managing nonunions (Table 1) [3][4][5].

Table 1. Main methods of biophysical enhancement in treating bone nonunions.

There are, however, no current pharmacological treatments to enable effective bone consolidation. A better understanding of the molecular mechanisms underlying bone healing is therefore essential for developing new treatments to accelerate the process [1].

A biological or mechanical deficiency, a lack of information regarding the host’s comorbidities, and a lack of vascularization can all lead to nonunion. The presence of osteoinductive mediators, osteogenic cells, and an osteoconductive matrix (scaffolding) is paramount for proper unions. An optimal mechanical environment, appropriate vascularization, and treatment of any pre-existing comorbidity are also required for proper unions [4].

2. Factors that Delay Bone Healing

Factors that delay bone healing can be divided into local and systemic. The most important local factors are the following: inadequate bone reduction, unstable bone fixation, bone infection, and radiation. The most important systemic factors are the following: patient age (bone healing is faster in children than in adults), nutrition status (sufficient amount of nutrients and vitamins A, B, C, and D are essential for the healing of broken bones). Smoking has a negative effect on bone healing. Steroids also can slow down the healing process. Systemic diseases such as hyperthyroidism and renal insufficiency delay fracture healing. Genetic diseases such as Marfan syndrome, Ehler–Danlos syndrome, osteogenesis imperfecta are among the factors affecting bone healing.

2.1. Inhibition of Estrogen Receptor Alpha Signalling Delays Bone Regeneration

Wu et al. evaluated the role of the estrogen receptor alpha (ERα) axis in bone consolidation and its possible mechanisms of action, demonstrating that inhibition of the ERα signaling delays bone regeneration. Female Institute of Cancer Research (ICR) mice were bred with a metaphyseal bone defect in the left femur and were administered methyl piperidino pyrazole (MPP), an ERα inhibitor, and bone consolidation was evaluated by microcomputer tomography. ERα placement with alkaline phosphatase (ALP) and ERα translocation into the mitochondria were determined, and the levels of ERα, ERβ, PECAM-1, VEGF, and β-actin were measured. The expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs was quantified. Angiogenesis was measured by immunohistochemistry. After surgery, the bone mass was increased in the bone-defect area in a time-dependent manner. Simultaneously, the ERα levels increased, correlating positively with bone consolidation. The administration of MPP decreased ERα levels and bone consolidation. Regarding the mechanism of action in bone consolidation, osteogenesis was improved; however, MPP attenuated osteoblast maturation. In parallel, the expression levels of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were increased in the injured zone. Treatment with MPP produced significant inhibition of the expression of ALP, Runx2, and osteocalcin genes, decreased translocation from ERα to the mitochondria, and expression of COX-1 and COX-2 genes related to mitochondrial energy production, and decreased levels of PECAM-1 and VEGF in the area of the experimentally created bone defects. The study demonstrated the role of the ERα axis in bone consolidation through the stimulation of energy production, osteoblast maturation, and angiogenesis [6].

2.2. Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity during Fracture Healing

Smoking causes delayed union and/or nonunion of bone fractures. Unfortunately, orthopedic surgeons rarely delay surgery in patients who smoke nor do they suggest methods for patients to quit smoking. It is important to recommend smoking cessation methods such as transdermal patches, chewing gum, lozenges, inhalers, sprays, bupropion, and varenicline during the perioperative period. Smoking cessation in the perioperative period appears to be effective in reducing delayed union and nonunion rates of bone fractures, even if performed up to 4 weeks prior to the surgery [7].

Hao et al. published a study in which they exposed three murine strains (C57BL/6J, 129 × 1/SvJ, and BALB/cJ) to cigarette smoke for 3 months before performing a midshaft transverse femoral osteotomy. Using radiography, microcomputed tomography, and biomechanical tests, the authors evaluated fracture healing 4 weeks after the osteotomy. The radiographic study showed a significant decrease in the fracture healing capacity of 129 × 1/SvJ smoke-exposed mice. The microcomputed tomography results showed a delay in the remodeling of the fracture calluses in all three strains after exposure to cigarette smoke. The biomechanical tests showed a more significant deterioration of functional properties in the 129 × 1/SvJ mice than in the C57BL/6J and BALB/cJ mice after exposure to cigarette smoke. In other words, the 129 × 1/SvJ strain was the most suitable for simulating the smoke-induced deterioration of fracture healing. In the 129 × 1/SvJ mice, the authors investigated the molecular and cellular disorders of fracture healing caused by cigarette smoke using histology, flow cytometry, and multiplex cytokine/chemokine analysis. The histological analysis showed abnormal chondrogenesis due to cigarette smoke exposure. In addition, significant populations of repair cells, including skeletal stem cells and their subsequent progenitors, showed a decrease in post-injury expansion as a result of cigarette smoke exposure. Furthermore, the authors observed a significant increase in pro-inflammatory mediators and immune cell recruitment in fracture hematomas in the mice exposed to smoke. These results show the important cellular and molecular disorders that occur during fracture healing due to smoking, such as abnormal chondrogenesis, aberrant activity of skeletal stem and progenitor cells, and an intense initial inflammatory response [8]. Table 2 shows the main factors that induce and delay bone healing according to recent publications on the molecular mechanisms of bone healing.

Table 2. Factors that induce and delay bone healing according to recent publications on the molecular mechanisms of bone healing.


  1. Valiya Kambrath, A.; Williams, J.N.; Sankar, U. An improved methodology to evaluate cell and molecular signals in the reparative callus during fracture healing. J. Histochem. Cytochem. 2020, 68, 199–208.
  2. Rodriguez-Merchan, E.C.; Gomez-Castresana, F. Internal Fixation of Nonunions. Clin. Orthop. Relat. Res. 2004, 419, 13–20.
  3. Rodriguez-Merchan, E.C.; Forriol, F. Nonunion: General principles and experimental data. Clin. Orthop. Relat. Res. 2004, 419, 4–12.
  4. Galvez-Sirvent, E.; Ibarzabal-Gil, A.; Rodriguez-Merchan, E.C. Treatment options for aseptic tibial diaphyseal nonunion: A review of selected studies. EFORT Open Rev. 2020, 5, 835–844.
  5. Gómez-Barrena, E.; Padilla-Eguiluz, N.; Rosset, P.; Gebhard, F.; Hernigou, P.; Baldini, N.; Rouard, H.; Sensebé, L.; Gonzalo-Daganzo, R.M.; Giordano, R.; et al. Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions. Injury 2020, 51 (Suppl. 1), S63–S73.
  6. Wu, G.J.; Chen, J.T.; Lin, P.I.; Cherng, Y.G.; Yang, S.T.; Chen, R.M. Inhibition of the estrogen receptor alpha signaling delays bone regeneration and alters osteoblast maturation, energy metabolism, and angiogenesis. Life Sci. 2020, 258, 118195.
  7. Rodriguez-Merchan, E.C. The importance of smoking in orthopedic surgery. Hosp. Pract. 2018, 46, 175–182.
  8. Hao, Z.; Li, J.; Li, B.; Alder, K.D.; Cahill, S.V.; Munger, A.M.; Lee, I.; Kwon, H.K.; Back, J.; Xu, S.; et al. Smoking alters inflammation and skeletal stem and progenitor cell activity during fracture healing in different murine strains. J. Bone Miner. Res. 2020.
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