Improve Fracture Healing Research Articles

Focused high-energy extracorporeal shockwaves as supplemental treatment in a rabbit model of fracture-related infection.

Focused high-energy extracorporeal shockwave therapy (fhESWT) is used to improve fracture healing in cases of nonunion. In addition, it has been shown to have direct antibacterial effects. We evaluated fhESWT as an adjunct to conventional treatment in a clinically relevant rabbit model of fracture-related infection (FRI). A humeral osteotomy in 31 rabbits was fixed with a seven-hole locking compression plate. FRI was established with a clinical Staphylococcus aureus isolate. After 2 weeks, a revision surgery was performed with debridement, irrigation, and implant retention. Rabbits then received: no further treatment (controls); shockwaves (4000 impulses with 23 kV at days 2 and 6 after revision); systemic antibiotics (rifampin and nafcillin); or the combination of antibiotics and shockwaves. Treatments were applied over 1 week. Blood cultures were taken before and after shockwave sessions. After another week without treatment, rabbits were euthanized and quantitative bacteriology was performed on implants and tissues to determine infection burden. Indicator organs (brain, heart, liver, lungs, kidneys, and spleen) were cultured to assess possible bacteremia. All the rabbits were infected at revision surgery as determined by the bacteriological culture of debrided materials. fhESWT in combination with antibiotic treatment lowered the bacterial burden 100-fold compared with antibiotic treatment alone in all samples (P = .38). This effect was most prevalent for the implant sample (P = .08). No significant effect was seen for fhESWT alone compared with untreated controls. No signs of bacteremia occurred in blood cultures and organs. fhESWT appears safe and could be a helpful adjunct to conventional treatment in certain difficult-to-treat FRIs.

CircRNA AFF4 promotes osteoblast cells proliferation and inhibits apoptosis via the Mir-7223-5p/PIK3R1 axis.

Fracture healing is a complex process involving various cell types, cytokines, and mRNAs. Here, we report the roles of the circRNA AFF4/miR-7223-5p/PIK3R1 axis during fracture healing. We found that increased expression of PIK3R1 during fracture healing is directly associated with augmented proliferation and decreased apoptosis of MC3T3-E1 cells. Furthermore, miR-7223-5p targeted PI3KR1 and inhibited MC3T3-E1 proliferation while promoting apoptosis. CircRNA AFF4 acted as a sponge of miR-7223-5p, thereby promoting MC3T3-E1 cell proliferation and inhibiting apoptosis. Local injection of circRNA AFF4 into femoral fracture sites promoted fracture healing in vivo while the injection of miR-7223-5p delayed healing. These findings suggest that CircRNA AFF4 promotes fracture healing by targeting the miR-7223-5p/PIK3R1 axis, and suggests miR-7223-5p, CircRNA AFF4, and the miR-7223-5p/PIK3R1 axis are potential therapeutic targets for improving fracture healing.

CLINICAL APPLICATION OF BONE MORPHOGENETIC PROTEIN ON FRACTURE HEALING PROCESS

Delayed union or non-union often occurs in bone healing fracture process. The clinical application of Bone Morphogenetic Proteins (BMPs) has helped an increasing number of patients achieve bone regeneration in clinical area lacking simple solutions for difficult bone healing situations. Many researches has proved that BMPs improved fracture healing regeneration. In this review article, introduction and current clinical issues are summarized on efficacy and function of BMPs. Currently, rhBMP-2 and rhBMP-7 have shown clinical significance but other subfamily members of BMPs still lacked of evidence.

Study protocol: design and rationale for an exploratory phase II randomized controlled trial to determine optimal vitamin D3 supplementation strategies for acute fracture healing

BackgroundObservational studies have found that 75% of healthy adult fracture patients (ages 18–50) have serum 25-hydroxyvitamin D (25(OH)D) levels < 30 ng/mL. Although lower serum 25(OH)D levels have yet to be correlated to fracture healing complications or poor fracture outcomes, many orthopedic surgeons are routinely prescribing vitamin D supplements to improve fracture healing in healthy non-osteoporotic patients. To address this gap in the literature, we propose a phase II exploratory randomized controlled trial comparing three vitamin D3 dosing regimens for early surrogate treatment response.MethodsWe will conduct a 4-arm blinded exploratory phase II trial in 96 adults aged 18–50 years with a closed or low-grade open (Gustilo type I or II) tibial or femoral shaft fracture. Eligible patients will be randomized in equal allocation ratio of 1:1:1:1 to one of the treatment groups: (1) 150,000 IU loading dose vitamin D3 plus daily dose placebo; (2) loading dose placebo plus 4000 IU vitamin D3 per day, (3) loading dose placebo plus 600 IU vitamin D3 per day, or (4) loading dose placebo plus daily dose placebo. The primary outcome is fracture healing, assessed as follows: (1) clinical fracture healing measured using the Function IndeX for Trauma, (2) radiographic fracture healing measured using the Radiographic Union Score for Tibial fractures, and (3) biological fracture healing measured using serum levels of cross-linked C-terminal telopeptides of type I collagen and amino-terminal procollagen propeptides of collagen type I. The main secondary outcome will be assessed by measuring serum 25(OH)D levels. All outcome analyses will be exploratory and adhere to the intention-to-treat principle. Per-protocol sensitivity analyses will also be conducted.DiscussionStudy results will be disseminated through a publication in an academic journal and presentations at orthopedic conferences. Study results will inform dose selection for a large definitive randomized controlled trial and provide preliminary clinical data on which dose may improve acute fracture healing outcomes in healthy adult patients (18–50 years) at 3 months.Trial registrationVita-Shock (A Blinded Exploratory Randomized Controlled Trial to Determine Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing) was registered at ClinicalTrials.gov (identifier NCT02786498) prior to enrollment of participants.

Mg2+ in β-TCP/Mg-Zn composite enhances the differentiation of human bone marrow stromal cells into osteoblasts through MAPK-regulated Runx2/Osx.

Inducing the osteogenic differentiation from bone marrow stromal cells (BMSCs) might be a potent strategy for treating bone loss and nonunion during fracture and improving fracture healing. Among several signaling pathways involved, mitogen-activated protein kinases (MAPKs) have been reported to play a critical role. Magnesium (Mg)-based alloys, including Mg-Zn alloy, have been used clinically as implants in the musculoskeletal field and could promote BMSC osteogenic differentiation. However, the underlying mechanisms remain unclear. In this study, we produced Mg-Zn alloy consists of Mg and low concentrations of Zn, calcium carbonate, and β-tricalcium phosphate (β-TCP; manifesting process not shown), prepared Mg, Zn, and Mg-Zn extracts, and investigated the specific effects of these extracts on human BMSC (hBMSC) osteogenic differentiation and MAPK signaling. Mg extracts and Mg-Zn extracts could significantly promote the osteogenic differentiation of hBMSCs as manifested as increased alkaline phosphatase levels, enhanced calcium nodules formation, and increased messenger RNA expression and protein levels of osteogenesis markers, including BMPs, Col-I, Runx2, and Osx; in the meantime, Mg culture medium (CM) and Mg-Zn CM both significantly enhanced the activation of MAPK signaling in hBMSCs. By adding ERK1/2 signaling, p38 signaling, or JNK signaling inhibitor to Mg-Zn CM, or conducting p38 MAPK silence in hBMSCs, we revealed that these extracts might promote hBMSC osteogenic differentiation via p38 MAPK signaling and MAPK-regulated Runx2/Osx. In conclusion, Mg2+ in β-TCP/Mg-Zn extract promotes the osteogenic differentiation of hBMSCs via MAPK-regulated Runx2/Osx interaction.

Calcium and Vitamin D Involvement in the Fragility Fracture of the Pelvis

The fragility fracture is the widest spread of the bone diseases, in elderly. It particularly affects the vertebrae, the femur, the proximal humerus, the distal radius, the pelvis, thus preventing the patient�s free movement. The most debilitating of all these fractures is the fragility fracture of the pelvis. This type of fracture raises supplementary problems compared to the other fractures due to the difficulties of diagnosis, surgical approach and to the longer recovery period. Choosing the right treatment for FFP is difficult due to health and comorbidities in elderly patients. Both conservative and surgical therapy involve equally large risks: prolonged immobilization or surgical risks. Therefore, pharmacological therapy is an alternative to surgery. Bisphosphonates prove their utility in the fracture-healing outcome, but the influence of calcium and vitamin D were overlooked. The aim of our study was to evaluate the role of calcium and vitamin D in the healing process of patients with pelvic fragility fracture in osteoporotic patients with and without calcium and vitamin D supplementation. Our study shows that calcium and vitamin D exert a positive influence on the healing process of the fragility fractures and strongly emphasizes the need to educate patients to comply with the prescription to supplement calcium and vitamin D in order to improve fracture healing and prevent additional fractures.

Calcium and Vitamin D Involvement in the Fragility Fracture of the Pelvis

The fragility fracture is the widest spread of the bone diseases, in elderly. It particularly affects the vertebrae, the femur, the proximal humerus, the distal radius, the pelvis, thus preventing the patient’s free movement. The most debilitating of all these fractures is the fragility fracture of the pelvis. This type of fracture raises supplementary problems compared to the other fractures due to the difficulties of diagnosis, surgical approach and to the longer recovery period. Choosing the right treatment for FFP is difficult due to health and comorbidities in elderly patients. Both conservative and surgical therapy involve equally large risks: prolonged immobilization or surgical risks. Therefore, pharmacological therapy is an alternative to surgery. Bisphosphonates prove their utility in the fracture-healing outcome, but the influence of calcium and vitamin D were overlooked. The aim of our study was to evaluate the role of calcium and vitamin D in the healing process of patients with pelvic fragility fracture in osteoporotic patients with and without calcium and vitamin D supplementation. Our study shows that calcium and vitamin D exert a positive influence on the healing process of the fragility fractures and strongly emphasizes the need to educate patients to comply with the prescription to supplement calcium and vitamin D in order to improve fracture healing and prevent additional fractures. Keywords: osteoporosis, fragility fracture, pelvis, calcium, vitamin D

AGE-RELATED CHANGES TO MACROPHAGES AFFECT FRACTURE HEALING

Fracture healing follows a strict temporal sequence characterized by an initial inflammatory phase. Perturbation of the inflammatory phase may be responsible for the poorer fracture healing outcomes in older adults. Herein, we examine age-related changes to the macrophage during fracture healing. Macrophages regulate inflammation through pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Anti-inflammatory activity is promoted via activation of triggering receptor expressed on myeloid cells 2 (TREM2). Tibia fractures were made in old (24 months) and young (3 months) mice. Immune cells from the fracture callus were analyzed via RNAseq and FACS, and fracture healing was evaluated histologically. Old mice demonstrated significantly delayed fracture healing compared to young (p<0.05). The quantity of infiltrating macrophages into the fracture callus was similar in young and old mice. However, 1222 genes were significantly differentially regulated (FDR<0.1) in callus macrophages from old mice compared to young, and old macrophages demonstrated a more pro-inflammatory phenotype. TREM2 expression was increased in macrophages after fracture in both groups but was significantly less in old mice compared to young via RNAseq and FACS (FDR<0.1, p<0.05). TREM2-/- mice demonstrated increased pro-inflammatory cytokine expression within the callus with resulting significant delays in fracture healing compared to age-matched controls (p<0.05). Inhibition of macrophage infiltration into the fracture callus significantly improved fracture healing in old mice compared to age-matched controls. Age-related changes to macrophages, including increased pro-inflammatory cytokine expression and dysregulated TREM2 expression, may explain fracture healing deficits observed in older adults. Therapeutically targeting macrophages may improve management of fractures in older adults.

MicroRNA-186 improves fracture healing through activating the bone morphogenetic protein signalling pathway by inhibiting SMAD6 in a mouse model of femoral fracture: An animal study.

ObjectivesMicroRNAs (miRNAs) have been reported as key regulators of bone formation, signalling, and repair. Fracture healing is a proliferative physiological process where the body facilitates the repair of a bone fracture. The aim of our study was to explore the effects of microRNA-186 (miR-186) on fracture healing through the bone morphogenetic protein (BMP) signalling pathway by binding to Smad family member 6 (SMAD6) in a mouse model of femoral fracture.MethodsMicroarray analysis was adopted to identify the regulatory miR of SMAD6. 3D micro-CT was performed to assess the bone volume (BV), bone volume fraction (BVF, BV/TV), and bone mineral density (BMD), followed by a biomechanical test for maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. The positive expression of SMAD6 in fracture tissues was measured. Moreover, the miR-186 level, messenger RNA (mRNA) level, and protein levels of SMAD6, BMP-2, and BMP-7 were examined.ResultsMicroRNA-186 was predicted to regulate SMAD6. Furthermore, SMAD6 was verified as a target gene of miR-186. Overexpressed miR-186 and SMAD6 silencing resulted in increased callus formation, BMD and BV/TV, as well as maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. In addition, the mRNA and protein levels of SMAD6 were decreased, while BMP-2 and BMP-7 levels were elevated in response to upregulated miR-186 and SMAD6 silencing.ConclusionIn conclusion, the study indicated that miR-186 could activate the BMP signalling pathway to promote fracture healing by inhibiting SMAD6 in a mouse model of femoral fracture.Cite this article: Bone Joint Res 2019;8:550–562.

Inhibition of MicroRNA-9 Improves Fracture Healing by Modulating the Bone Morphogenetic Protein-7 Pathway

We evaluated the effect of microRNA (miR)-9 inhibition on fracture healing in a rat model of femoral fracture. The rats were divided into sham, negative control and miR-9 inhibitor groups. The miR-9 inhibitor group received 30 pmol/mL inhibitor intrathecally for 8 consecutive weeks following surgery-induced femoral fracture. The effect of miR-9 inhibition on fracture healing was estimated by determining the bone mineral density (BMD) and by performing X-ray analysis of the fractured bone. The serum levels of markers of bone formation were estimated by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, and western blotting and immunohistochemical analysis were performed to assess the effect of miR-9 inhibition on fracture healing. The BMD at the fracture site was significantly higher in the miR-9 inhibitor group than in the negative control group. Inhibition of miR-9 blocked the fracture gap and resulted in new callus formation at the fracture site. The serum levels of osteocalcin and bone GLA protein were increased and that of alkaline phosphatase was decreased by inhibition of miR-9 compared to levels in the negative control. However, inhibition of miR-9 significantly increased the mRNA levels of runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 7 (BMP-7) in the bone tissue at the fracture site compared to the negative control group; this result was confirmed by western blotting. In conclusion, ­miR-9 inhibition enhanced fracture healing by modulating the BMP-7/Runx2 signalling pathway in a rat model of femoral fracture.

Delayed Presentation of Seymour Fractures: A Single Institution Experience and Management Recommendations.

Background: Seymour fractures in children are prone to complications without prompt and appropriate treatment. This study investigated outcomes of Seymour fractures with delayed presentations; specifically, if deep infection predisposed to operative treatment, if antibiotic administration improved fracture healing, and if oral clindamycin had fewer treatment failures than oral cephalexin. Methods: A single-institution retrospective cohort study was performed of patients with delayed Seymour fracture presentations (defined as greater than 24 hours post-injury) between 2009 and 2017. Data collected included demographics, time to presentation, infection on presentation, operative treatment, antibiotic use and duration, fracture union, and complications. Statistical testing used logistic regression and Fisher's exact test, with results reported as P-values (P), odds ratios (ORs), and 95% confidence intervals (CIs). Results: There were 73 patients with delayed Seymour fracture presentations, with mean age of 11.1 years (standard deviation: 2.9), with 56 (77%) males, and median time to presentation of 7 days (interquartile range: 3-17). Deep infection on presentation was a risk factor for operative intervention (OR = 34.4, P = .0001, CI, 5.5-217.2). Antibiotic administration protected against the development of a nonunion or delayed union (OR = 0.11, P = .008, CI, 0.021-0.57). Time to antibiotics did not protect against nonunion or delayed union (OR = 0.77, P = .306, CI, 0.37-1.3). Clindamycin had fewer treatment failures than cephalexin (P = .039). Conclusions: Deep infection is a risk factor for operative treatment of Seymour fractures with delayed presentations. Clindamycin is a better antibiotic choice for Seymour fractures that present in delayed fashion.

Thrombopoietin: Role in Fracture Healing and Pain

Background and Hypothesis: The megakaryocyte (MK) growth factor, thrombopoietin (TPO), improves bone healing in mice, rats, and pigs. Here we explore the role of MK-secreted platelet-derived growth factor-BB (PDGF–BB) in TPO’s mechanism of improving fracture healing. Interestingly, PDGF has neuroprotective effects, and neuronal PDGF receptors (PDGFRs) are primarily stimulated by PDGF–BB. Additionally, fibroblast growth factor 2 (FGF2) is secreted by osteoblasts (OBs), and MKs stimulate OB proliferation; therefore, MKs may regulate FGF2 expression which also promotes nerve regeneration. Importantly, neuropathic pain caused by fractures can be prevented by neuroprotective therapies. We hypothesize that increases in fracture-related neuropathic pain observed with age are due to reductions in: MK-secreted PDGF-BB and MK-stimulated, OBsecreted FGF2. &#x0D; Experimental Design or Project Methods: Dorsal root ganglia (DRG) and MKs from bone marrow and spleens were isolated from 3-4 month-old (young) and 22-24 month-old (old) mice. MKs were also isolated from E13-15 fetal livers of mice and OBs were isolated from the calvaria of neonatal mice. OBs were cultured alone or in the presence of MKs for 4 days. Real-time PCR was completed to examine the expression of PDGF-BB in MKs, FGF2 in OBs, and PDGFR in DRG.&#x0D; Results: Old MKs exhibit a 63% reduction in PDGF–BB expression and old DRG exhibit a 68% reduction in PDGFR expression. OBs cultured with MKs show a 1.78 fold increase in FGF2 expression.&#x0D; Conclusion and Potential Impact: Decreased expression of PDGF-BB in old MKs and PDGFR in old neurons, as well as increased FGF2 expression in OBs cultured with MKs present possible mechanisms for both the reduction in bone healing and increased fracture pain observed with age. TPO improves bone healing and may potentially reduce neuropathic pain directly by increasing MK secreted PDGF-BB and indirectly through MK PDGF-BB stimulating FGF2 secretion from OBs.

A Reactive Element Approach to Improve Fracture Healing in Metallic Systems

Self-healing materials demonstrate the ability to close fractures and regain mechanical integrity after a catastrophic failure. However, self-healing in metals can be inhibited by the natural tendency for technologically-relevant metallic systems to oxidize on the crack surface. This study seeks to provide a thermodynamically-based mechanism to enhance healing capability at a solid/liquid interface through alloys designed with a reactive element alloying addition possessing a lower free energy of oxide formation than the parent element. In this study, model Sb-Cu and Sb-Zn systems enable comparisons between mechanistic behaviors based only on thermodynamic reactivity. Mechanical and microstructural investigation demonstrated that the more reactive alloying addition resulted in more effective bonding through increasing bond area and load-bearing capacity of the system. The improved bonding was attributed to improved wetting and reduction of the passivating surface oxide across an interface. The work has potential to advance self-healing capabilities in metallic systems through more appropriate alloy selection to enable improved healing.

Pharmacologic targeting of \u03b2-catenin improves fracture healing in old mice

β-catenin protein needs to be precisely regulated for effective fracture repair. The pace of fracture healing slows with age, associated with a transient increase in β-catenin during the initial phase of the repair process. Here we examined the ability of pharmacologic agents that target β-catenin to improve the quality of fracture repair in old mice. 20 month old mice were treated with Nefopam or the tankyrase inhibitor XAV939 after a tibia fracture. Fractures were examined 21 days later by micro-CT and histology, and 28 days later using mechanical testing. Daily treatment with Nefopam for three or seven days but not ten days improved the amount of bone present at the fracture site, inhibited β-catenin protein level, and increased colony forming units osteoblastic from bone marrow cells. At 28 days, treatment increased the work to fracture of the injured tibia. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site. This data supports the notion that high levels of β-catenin in the early phase of fracture healing in old animals slows osteogenesis, and suggests a pharmacologic approach that targets β-catenin to improve fracture repair in the elderly.

MiRNA-26a-5p Accelerates Healing via Downregulation of PTEN in Fracture Patients with Traumatic Brain Injury

Patients who sustain a traumatic brain injury (TBI) are known to have a significantly quicker fracture healing time than patients with isolated fractures, but the underlying mechanism has yet to be identified. In this study, we found that the upregulation of miRNA-26a-5p induced by TBI correlated with a decrease in phosphatase and tensin homolog (PTEN) in callus formation. In vitro, overexpressing miRNA-26a-5p inhibited PTEN expression and accelerated osteoblast differentiation, whereas silencing of miRNA-26a-5p inhibited osteoblast activity. Reduction of PTEN facilitated osteoblast differentiation via the PI3K/AKT signaling pathway. Through luciferase assays, we found evidence that PTEN is a miRNA-26a-5p target gene that negatively regulates the differentiation of osteoblasts. Moreover, the present study confirmed that preinjection of agomiR-26a-5p leads to increased bone formation. Collectively, these results indicate that miRNA-26a-5p overexpression may be a key factor governing the improved fracture healing observed in TBI patients after the downregulation of PTEN and PI3K/AKT signaling. Upregulation of miRNA-26a-5p may therefore be a promising therapeutic strategy for promoting fracture healing.

Influence of specific osteoporosis drugs on fracture healing

For the treatment of disturbed fracture healing, drugs could be given in addition to surgical procedures. Specific osteoporosis drugs affect the bone metabolism and are used to treat osteoporosis, particularly after afragility fracture has occurred. Therefore, their use would be conceivable to improve adisturbed fracture healing. This article presents the available and upcoming specific osteoporosis drugs and investigates whether these substances affect fracture healing in the context of osteoporosis. Furthermore, it is discussed whether disturbed fracture healing can be improved by the use of these substances. Aliterature search (PubMed) was conducted using key terms. Preclinical studies, clinical studies, reviews and meta-analyses were considered in order to present the current knowledge in aclinically relevant context. Preclinical and clinical studies show that specific osteoporosis drugs have no relevant negative impact on the healing of fragility fractures. Atendency to improve adisturbed fracture healing was attributed to bone anabolic substances; however, studies are inconsistent and there is no approval for this application. Following afragility fracture, osteoporosis should be diagnosed according to the guidelines and, if necessary, treated with specific osteoporosis drugs, since in principle they do not impair fracture healing but significantly reduce the risk of subsequent fractures. Approval to improve fracture healing requires further investigations.

LOC103691336/miR-138-5p/BMPR2 axis modulates Mg-mediated osteogenic differentiation in rat femoral fracture model and rat primary bone marrow stromal cells.

Intramedullary stabilization is frequently used to treat long bone fractures. Since implant removal can become technically very challenging with the potential to cause further tissue damage, biodegradable materials are emerging as alternative options. Magnesium (Mg)-based biodegradable implants have a controllable degradation rate and good tissue compatibility, which makes them attractive for musculoskeletal research. Herein, the degradation of Mg and steel implants, the pathological characteristics and osteoblast differentiation in mice femora were examined. To investigate the molecular mechanism, we analyzed the differentially expressed long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in Mg-implanted or stain-steel-implanted callus tissues. lncRNA LOC103691336 was upregulated in Mg-implanted tissues and most relevant to BMPR2, a kinase receptor of BMPs with an established role in osteogenesis. The knockdown of LOC103691336 attenuated Mg-mediated osteogenic differentiation. Furthermore, miR-138-5p, previously reported to inhibit osteogenic differentiation, could bind to LOC103691336 and BMPR2 in bone marrow stromal cells (BMSCs). LOC103691336 competed with BMPR2 for miR-138-5p binding in BMSCs to attenuate the inhibitory effect of miR-138-5p on BMPR2 expression. Finally, the effect of LOC103691336 knockdown on Mg-mediated osteogenic differentiation could be attenuated by miR-138-5p inhibition. In conclusion, we provided a novel mechanism of Mg implants mediating the osteogenesis differentiation and demonstrated that Mg implants may be promising for improving fracture healing.

PIT23 THE COST BURDEN OF NONUNION FOLLOWING LONG BONE FRACTURE IN A COMMERCIALLY INSURED POPULATION IN THE UNITED STATES

There are currently no studies evaluating resource utilisation and costs for fracture non-union compared with routine healing for a wide variety of fracture types. The purpose of this study is to present an analysis on the burden of ten different types of fracture non-union vs routine healing. In a large US claims database, all adult patients diagnosed with a long-bone fracture in 2012 were stratified into two cohorts: with and without subsequent claims of a non-union diagnosis based on ICD-9-CM diagnosis codes. Healthcare resource use and medical costs of fracture were compared in patients with and without non-union. Out of 4,963 patients with long bone fractures, 3% (n=163) had a subsequent diagnosis of fracture non-union within 2 years of their fracture. The overall non-union rate varied significantly by fracture type. The highest non-union rates were for the humeral shaft (18%), followed by the tibial shaft (10%) and femoral shaft (9%). The lowest nonunion rates were for the lower end radius/ulna (2%) and elbow (2%). Overall, medical costs of non-union fracture patients were higher than that of the routine healing cohort. This was true for all types of fracture. The mean total care cost for non-union patients was more than double that of patients without a non-union ($35,317 vs $102,989, P = 0.0006). Patients whose fractures fail to heal routinely often have significantly greater healthcare resource use and, in turn, incur higher medical costs. Future research should be focused on strategies to improve fracture healing rates with the goal to reduce costs for patients, third party payers, employers, and governments by decreasing usage of healthcare services.

Erythropoietin does not improve fracture healing in aged mice.

Fracture healing in the elderly is associated with a declined healing potential caused by multiple factors including a delay of vascularization. Erythropoietin (EPO) has been demonstrated to improve vascularization and fracture healing in adult mice. We, therefore, hypothesized that EPO in aged mice also improves fracture healing. For this purpose, EPO was given daily in a femoral fracture model in aged mice and compared to vehicle-treated controls using radiological, biomechanical, histomorphometric and Western blot techniques. Blood analyses revealed significantly higher concentrations of hemoglobin and a higher hematocrit in EPO-treated animals at 14 and 35 days after fracture. Micro-computed tomography (μCT) indicated that the fraction of bone volume/tissue volume within the callus did not differ between the two groups. However, μCT showed a 3-fold increased tissue mineral density (TMD) in the callus of EPO-treated animals compared to controls. The callus TMD of the EPO-treated animals was also 2-fold higher when compared to the TMD of the unfractured contralateral femur. Interestingly, biomechanical analyses revealed a reduced bending stiffness in femurs of EPO-treated animals at day 35. The histomorphometrically analyzed callus size and callus composition did not show significant differences between the study groups. However, Western blot analyses exhibited an increased expression of osteoprotegerin (OPG), but in particular of receptor activator of NF-κB ligand (RANKL) in the callus of the EPO-treated animals. Further histological analyses of the callus tissue showed that this was associated with an increased number of newly formed blood vessels and a higher number of tartrate-resistant acid phosphatase (TRAP)+ cells. Conclusion: In fracture healing of aged mice EPO treatment increases callus TMD as well as OPG and RANKL expression, indicating an accelerated bone turnover when compared to controls. However, EPO does not improve fracture healing in aged mice. The process of fracture healing may be altered by EPO due to a deterioration of the microcirculation caused by the worsened rheological properties of the blood and due to an increased bone fragility caused by the accelerated bone turnover. Thus, EPO may not be used to improve fracture healing in the elderly.

Successful treatment of pathologic femoral shaft fracture associated with large arteriovenous malformations using a 3-dimensional external fixator and teriparatide: a case report

BackgroundArteriovenous malformations (AVMs) are rare congenital vascular lesions associated with early quiescence, late expansion, and, ultimately, infiltration and destruction of local soft tissue and bone. The extremities are a common location. Incidence of bony involvement by AVM has been reported as high as 31%. However, there are few reports on management of pathologic fracture associated with AVM. Teriparatide is a recombinant parathyroid hormone (PTH) analogue consisting of the 1–34 fragment of PTH. Recently, some reports have shown the ability of teriparatide to improve fracture healing. Here, we present a case of pathologic femoral shaft fracture associated with large AVMs that was treated successfully by external fixation and teriparatide.Case presentationA 68-year-old Japanese woman, previously diagnosed as having large AVMs, sustained a right femoral shaft fracture due to a fall. At the time of admission, she presented with massive swelling and venous varicosities of the right thigh. Plain radiography of the right thigh revealed femoral shaft fracture with bony erosion and calcification of soft tissue. We planned closed reduction and intramedullary nailing with a unilateral external fixator following embolization of the feeding artery. However, closed reduction using the fracture table was difficult. When we attempted open reduction, massive bleeding (1000 mL) after incision of subcutaneous tissue occurred. Finally, we carefully applied a Taylor Spatial Frame. Fracture displacement was corrected successfully and bony union was obtained with administration of teriparatide 15 months after the initial surgery. The patient is able to walk using 1 cane.ConclusionWe present the first report of pathologic fracture associated with large AVMs that achieved bony union using a 3-dimensional external fixator and teriparatide.