Delayed Fracture Healing Research Articles

P021 Quality Improvement Project: Improving Osteoporosis Treatment for Patients with a Neck of Femur Fracture

Abstract Background/Aims The Fracture Liaison Service (FLS) identifies patients >50 who have sustained a fragility fracture (FF). These patients need prompt assessment and decision on appropriate treatment for osteoporosis in order to reduce their risk of sustaining further FFs. Without treatment, 1/5 patients can go on to have a further FFs which carry significant risk to mortality and morbidity. Zoledronate is a bone agent that halves the risk of another FF. Patients with a neck of femur fracture (#NOF) present as one of the most at-risk groups for a further FF. These patients are generally elderly and frail and attendance to outpatient hospital appointments are difficult. Therefore, transforming the FLS from an out-patient-based service, to one that is streamlined to systematically identify and opportunistically treat patients whilst they are still in hospital means delivering timely, effective and efficient patient-centred care. Methods We used various Plan-Do-Study-Act cycles to aim to deliver Zoledronate to ≥ 90% of appropriately assessed in-patients >60 who have had a #NOF within a year of commencing QIP. Results PDSA cycle 1-Involvement of ortho-geriatrician: P-Improve working relationship with ortho-geriatrician with an interest in bone health over a 6-month period; D-Regular meetings with wider MDT; S-Priority of bone health assessments made greater through ward round documentation; A-Expand knowledge throughout the wider ortho-geriatrician team. PDSA cycle 2-Timing of Zoledronate delivery: P-Literature review regarding delivery of Zoledronate timing; D-Discuss as MDT; S-No evidence to suggest delay in fracture healing if given on day 7; A-Adopted process and communicated. PDSA cycle 3-FLS team on the wards as a result of PDSA cycle 2 not improving treatment outcomes: P-FLS nurses to join ortho-geriatrician ward round twice-weekly for 3-month trial period; D-Bank holidays and spike in Covid cases presented a challenge. Solution: Improvement of MDT relationships; S-At the end of the trial period an increase in patients who received treatment was shown and proved our prediction; A-Adaptation to documentation in FLS to streamline and reduce duplication. Conclusion The ability to deliver Zoledronate to ≥ 90% of appropriate patients with a #NOF as an inpatient was reached after 8 months of initiating QIP. Furthermore, maintaining this was consistently achieved throughout the following year and beyond. A few of the main reasons for this included earlier drug delivery, having a dedicated ortho-geriatrician as part of the FLS, and the FLS team attending the wards. A prompt bone health assessment of patients has enabled appropriate treatment to be delivered efficiently. The delivery of Zoledronate as an in-patient has meant that a significantly greater proportion of patients receive treatment, and sooner, in comparison to awaiting an outpatient assessment (that they may not attend). Therefore, this QIP has demonstrated time- and cost-effective management of patients with #NOF requiring Zoledronate. Disclosure G. O'Hara: None. E. Stanley: None. S. Broadhurst: None. M. Hui: None.

Does the use of NSAIDs for analgesia in fracture care contribute to delayed fracture healing?

Does the use of NSAIDs for analgesia in fracture care contribute to delayed fracture healing?

Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model

BackgroundPostmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice).MethodsThe OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine).ResultsBMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization.ConclusionUpregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.

Pulsed electromagnetic fields as a promising therapy for glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is considered the third type of osteoporosis and is accompanied by high morbidity and mortality. Long-term usage of glucocorticoids (GCs) causes worsened bone quality and low bone mass via their effects on bone cells. Currently, there are various clinical pharmacological treatments to regulate bone mass and skeletal health. Pulsed electromagnetic fields (PEMFs) are applied to treat patients suffering from delayed fracture healing and non-unions. PEMFs may be considered a potential and side-effect-free therapy for GIOP. PEMFs inhibit osteoclastogenesis, stimulate osteoblastogenesis, and affect the activity of bone marrow mesenchymal stem cells (BMSCs), osteocytes and blood vessels, ultimately leading to the retention of bone mass and strength. However, the underlying signaling pathways via which PEMFs influence GIOP remain unclear. This review attempts to summarize the underlying cellular mechanisms of GIOP. Furthermore, recent advances showing that PEMFs affect bone cells are discussed. Finally, we discuss the possibility of using PEMFs as therapy for GIOP.

Radiographic, Biomechanical and Histological Characterization of Femoral Fracture Healing in Aged CD-1 Mice.

With a gradually increasing elderly population, the treatment of geriatric patients represents a major challenge for trauma and reconstructive surgery. Although, it is well established that aging affects bone metabolism, it is still controversial if aging impairs bone healing. Accordingly, we investigated fracture healing in young adult (3-4 months) and aged (16-18 months) CD-1 mice using a stable closed femoral fracture model. Bone healing was analyzed by radiographic, biomechanical and histological analysis at 1, 2, 3, 4 and 5 weeks after fracture. Our results demonstrated an increased callus diameter to femoral diameter ratio in aged animals at later time points of fracture healing when compared to young adult mice. Moreover, our biomechanical analysis revealed a significantly decreased bending stiffness at 3 and 4 weeks after fracture in aged animals. In contrast, at 5 weeks after fracture, the analysis showed no significant difference in bending stiffness between the two study groups. Additional histological analysis showed a delayed endochondral ossification in aged animals as well as a higher amounts of fibrous tissue at early healing time points. These findings indicate a delayed process of callus remodeling in aged CD-1 mice, resulting in a delayed fracture healing when compared to young adult animals. However, the overall healing capacity of the fractured femora was not affected by aging.

EARLY BISPHOSPHONATE THERAPY POST PROXIMAL FEMORAL FIXATION DOES NOT IMPACT FRACTURE HEALING

There is conjecture on the optimal timing to administer bisphosphonate therapy following operative fixation of low- trauma hip fractures. Factors include recommendations for early opportunistic commencement of osteoporosis treatment, and clinician concern regarding the effect of bisphosphonates on fracture healing. We performed a systematic review and meta-analysis to determine if early administration of bisphosphonate therapy within the first month post-operatively following proximal femur fracture fixation is associated with delay in fracture healing or rates of delayed or non-union.We included randomised controlled trials examining fracture healing and union rates in adults with proximal femoral fractures undergoing osteosynthesis fixation methods and administered bisphosphonates within one month of operation with a control group. Data was pooled in meta-analyses where possible. The Cochrane Risk of Bias Tool and the GRADE approach were used to assess validity.For the outcome of time to fracture union, meta-analysis of three studies (n= 233) found evidence for earlier average time to union for patients receiving early bisphosphonate intervention (MD = −1.06 weeks, 95% CI −2.01 – −0.12, I2= 8%). There was no evidence from two included studies comprising 718 patients of any difference in rates of delayed union (RR 0.61, 95% CI 0.25–1.46). Meta-analyses did not demonstrate a difference in outcomes of mortality, function, or pain.We provide low-level evidence that there is no reduction in time to healing or delay in bony union for patients receiving bisphosphonates within one month of proximal femur fixation.

Fractures and dislocations of the foot and ankle in people with diabetes: a literature review.

Diabetes (DM) increases fracture risk, and bone quality depends on type diabetes type, duration, and other comorbidities. Diabetes is associated with a 32% increased relative risk (RR) of total fractures and 24% increased RR of ankle fractures compared with patients without DM. Type 2 DM is associated with a 37% increased RR of foot fractures compared with patients without DM. The incidence of ankle fractures in the general population is 169/100,000 per year, while foot fractures occur less frequently, with an incidence of 142/100,000 per year. Biomechanical properties of bone are negatively impacted by stiff collagen, contributing to the increased risk of fragility fractures in patients with DM. Systemic elevation of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), interleukin-1β (IL-1β), and interleukin 6 (IL-6), impact bone healing in patients with DM. Fractures in patients with DM, can be associated with poorly regulated levels of RANKL (receptor activator of nuclear transcription factor kappa-b ligand) leading to prolonged osteoclastogenesis, and net bone resorption. One of the most salient factors in treating fractures and dislocations of the foot and ankle is to recognize the difference between patients with uncomplicated and complicated DM. Complicated diabetes is defined as 'end organ damage', and for the purposes of this review, includes patients with neuropathy, peripheral artery disease (PAD) and/or chronic renal disease. Uncomplicated diabetes is not associated with 'end organ damage'. Foot and ankle fractures in patients with complicated DM pose challenges, and surgery is associated with increased risks of impaired wound healing, delayed fracture healing, malunion, infection, surgical site infection, and revision surgery. While patients with uncomplicated DM can be treated like patients without DM, patients with complicated DM require close follow-up and robust fixation methods should be considered to withstand the anticipated prolonged healing period. The aims of this review are as follows: (1) to review pertinent aspects of DM bone physiology and fracture healing, (2) to review the recent literature on treatment of foot and ankle fractures in patients with complicated DM, and (3) to provide treatment protocols based on the recent published evidence.

MLK3 silence suppressed osteogenic differentiation and delayed bone formation via influencing the bone metabolism and disturbing MAPK signaling.

Mixed lineage kinase 3 (MLK3) is a member of a serine/threonine MAP3K family, and it has been demonstrated to play critical roles in various biological activities and disease progression. Previous studies showed that impaired skeletal mineralization and spontaneous tooth fracture in the MLK3-deficient mice, suggesting MLK3 actively participated in the bone formation. However, the detailed function and underlying mechanisms remain obscure. The MLK3 knockout (KO) mouse was applied in the present study, and multi-omics were performed to compare the metabolites and gene expression between wild type (WT) and KO mice. The bone fracture model was successfully established, and the healing process was evaluated by X-ray, micro-CT examination, histomorphometry and immunohistochemistry (IHC) staining. On the other hand, the effects of MLK3 on osteogenic differentiation were assessed by alkaline phosphatase (ALP) activity, Alizarin red S (ARS) staining and qRT-PCR examination. Finally, the downstream signaling pathways were screened out by RNA-sequencing (RNA-seq) and then validated by Western blotting. In the present study, imbalanced bone metabolism was observed in these MLK3 KO mice, suggesting MLK3 may participate in bone development. Moreover, MLK3 -/- mice displayed abnormal bone tissues, impaired bone quality, and delayed fracture healing. Further investigation showed that the inhibition of MLK3 attenuated osteoblast differentiation in vitro. According to the RNA-seq data, MAPK signaling was screened out to be a downstream pathway, and its subfamily members extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal protein kinase (JNK) were subjected to Western blotting examination. The results revealed that although no differences in their expression were observed between MSCs derived from WT and KO mice, their phosphorylated protein levels were all suppressed in MLK3 -/- MSCs. In conclusion, our results demonstrated that loss of MLK3 suppressed osteoblast differentiation and delayed bone formation via influencing metabolism and disturbing MAPK signaling. The findings based on the current study demonstrated that MLK3 promoted osteogenesis, stimulated new bone formation and facilitated fracture healing, suggesting that MLK3 may serve as a potential therapeutic target for bone regeneration. MLK3 activator therefore may be developed as a therapeutic strategy for bone fracture.

The History of Shock Wave Medicine Development in China

The History of Shock Wave Medicine Development in China

Fracture healing in a polytrauma rat model is influenced by mtDNA:cGAS complex mediated pro-inflammation

PurposeThe mitochondrial DNA (mtDNA) activated cyclic guanosine monophosphate–adenosine monophosphate synthase—stimulator of interferon genes (cGAS-STING) signaling pathway is a key player in mediating immune responses in autoimmune disorders and cancer. However, its role in severe trauma associated fracture healing is unknown. This study investigated if the cGAS-STING signaling pathway contributes to delayed bone healing in polytrauma (PT) fractures.MethodsFor preliminary analyses, therapeutic dosage of RU.521 (cGAS inhibitor) (n = 2) was determined in C57BL/6 J mice by mass spectrometry, and IFNβ expression levels in serum and bronchioalveolar fluid (BALF) at 6 and 24 h (h) in RU.521/vehicle + mtDNA injected mice (n = 3/treatment and time point) was measured by ELISA. In the main study, plasma mtDNA was quantified by qPCR in a clinically relevant delayed fracture healing PT rat model with burn injury, blunt trauma, and a femoral fracture at 3 h post-trauma (hpt). Next, PT rats received either RU.521 (12 mg/kg in povidone; n = 8) or vehicle (povidone only; n = 5) immediately after injury and were followed up for 5 weeks post-trauma to assess bone regeneration by radiography and histology.ResultsIFNβ levels were significantly decreased only at 24 h in BALF of RU.521 treated mice. At 3hpt mtDNA was significantly elevated in PT rats compared to rats without injury. When treated with RU.521, PT rats showed improvement in bone healing compared to vehicle control PT rats.ConclusionsThese data reveal that the cGAS-STING signaling pathway influences trauma-induced delayed bone healing. However, further evaluation of this pathway at the cellular and molecular levels to augment PT associated detrimental effects is needed.

Modified internal fixator combined with sacroiliac screws in treatment of Tile C1.3 pelvic fracture

To investigate the effectiveness of modified internal fixator (INFIX) to fix the anterior pelvic ring for Tile C1.3 pelvic fracture by comparing with the traditional INFIX. The patients with Tile C1.3 pelvic fractures admitted between April 2018 and June 2021 were taken as the study objects. Of them, 55 cases were included in the study according to the selection criteria. During operation, the anterior pelvic ring was fixed with the modified INFIX in 30 cases (modified group) and with the traditional INFIX in 25 cases (control group). The posterior pelvic ring in 55 cases was fixed with sacroiliac screws. There was no significant difference between the two groups in gender, age, cause of injury, time from injury to operation, and combined injury ( P>0.05). The operation time, intraoperative blood loss, and complications were recorded and compared between the two groups. The X-ray film was taken to evaluate the reduction of the anterior pelvic ring after operation, grade the reduction according to the Matta scoring standards, and observe the fracture healing and healing time. The function was evaluated according to Majeed scoring standards during follow-up. The operation time of the modified group was significantly longer than that of the control group ( Z=-3.837, P<0.001), but there was no significant difference in the intraoperative blood loss between the two groups ( t=-1.831, P=0.076). All patients were followed up 12-18 months (mean, 14 months). X-ray film reexamination showed that the excellent and good rate of Matta scoring for anterior pelvic ring reduction in the modified group was 88.00%, which was significantly better than that in the control group (63.33%) ( χ 2=4.373, P=0.037). All fractures healed, and the fracture healing time of the modified group and the control group was (12.04±3.59) and (14.83±4.83) weeks respectively, with a significant difference ( t=2.401, P=0.020). At last follow-up, the excellent and good rates of Majeed scoring were 80.00% in the modified group and 76.67% in the control group, with no significant difference ( χ 2=0.089, P=0.766). In the modified group, 2 cases (8%) had complications, all of which were incision infection above pubic symphysis. In the control group, 9 cases (30%) had complications, including 5 cases of lateral femoral cutaneous nerve injury, 2 cases of femoral nerve paralysis, and 2 cases of delayed fracture healing. The incidence of complications was significantly lower in the modified group than in the control group ( χ 2=4.125, P=0.042). Compared with the traditional INFIX, the modified INFIX to fix the anterior pelvic ring for Tile C1.3 pelvic fracture has fewer complications, better stability, shorter fracture healing time, and lower risk of nerve injury.

Management of Osteoporosis Medication after Osteoporotic Fracture.

The aim of this study was to provide helpful information for use in selection of an appropriate medication after osteoporotic fractures through conduct of a literature review. In addition, a review of the recommendations of several societies for prevention of subsequent fractures was performed and the appropriate choice of medication for treatment of atypical femur fractures was examined. Clinical perspective was obtained and an updated search of literature was conducted across PubMed and MEDLINE and relevant articles were selected. The articles were selected manually according to relevance, and the references for identified articles and reviews were also evaluated for relevance. The following areas are reviewed: Commonly prescribed osteoporosis medications: BPs (bisphosphonates), denosumab, and SERMs (selective estrogen receptor modulators) in antiresorptive medications and recombinant human parathyroid hormone teriparatide, recently approved Romosuzumab in anabolic agents, clinical practice guidelines for the management of osteoporosis, osteoporotic fracture, and atypical femur fracture. Most medications for treatment of osteoporosis do not delay fracture healing and the positive effect of teriparatide on fracture healing has been confirmed. In cases where an osteoporotic fracture is diagnosed, risk assessment should be performed for selection of very high-risk patients in order to prevent subsequent fractures, and administration of anabolic agents is recommended.

Correlation analysis of serum CTRP3 and PGC-1α expression with traumatic fracture healing

To investigate the relationship between serum C1q/tumor necrosis factor-related protein-3(CTRP3) and peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α) on predictive value of expression level on fracture healing. From January 2019 to January 2020, 80 patients with traumatic tibial plateau fractures were treated by internal fixation with support plates through the posterior approach of the knee joint. The patients were followed up for 12 months. According to the criteria for delayed fracture healing, the patients were divided into two groups:54 patients in fracture healing group included 24 males and 30 females, aged 29 to 75 years old with an average of (52.36±13.17) years;In the delayed healing group, there were 26 cases, 13 males and 13 females, aged from 29 to 75 with an average od (53.82±13.52) years. The serum levels of CTRP3, PGC-1αand 25 hydroxyvitamin D3[25(OH)D3] in patients with traumatic fracture were detected by enzyme-linked immunosorbent assay(ELISA);Blood phosphorus and calcium levels were measured by automatic biochemical analyzer, and the product of calcium and phosphorus was calculated;Pearson's method was used to analyze the correlation between serum CTRP3, PGC-1αand bone biochemical indexes in patients with delayed union one week after operation;The predictive value of serum levels of CTRP3 and PGC-1αon traumatic fracture healing was analyzed by receiver operating characteristic curve(ROC curve). PGC-1α, calcium phosphorus product and 25(OH)D3 in the fracture healing group were higher than those in the delayed healing group at 1 and 4 weeks after operation(P<0.05). Serum CTRP3 was positively correlated with PGC-1α(r=0.637, P<0.05) and positively correlated with calcium phosphorus product and 25(OH)D3(P<0.05). The areas under the curve(AUC) of serum ctrp3 and PGC-1α levels in predicting traumatic fracture healing were 0.845 and 0.855, respectively. The cutoff values were 188.678 pg/ml and 2.697 ng/ml, respectively. The specificity was 96.2% and 80.8%, and the sensitivity was 53.7% and 77.8%;The predicted AUC was 0.904, the specificity was 88.5%, and the sensitivity was 81.5%. The serum levels of CTRP3 and PGC-1 in patients with delayed union of traumatic fracture at 1 and 4 weeks after operation α The expression level is of certain reference value to predict the fracture healing status of patients.

Biophysical Stimulation in Delayed Fracture Healing of Hand Phalanx: A Radiographic Evaluation.

Phalangeal fractures are common events among the upper limbs accounting for 10% of all human body fractures. Fracture complete healing process may persevere several months or years. Most phalangeal fractures present favorable union within 3 to 6 weeks. In the literature, biophysical stimulation has yielded favorable outcomes in the treatment of hand fractures. A survey involving hospitals in the US reported the use of biophysical stimulation (72%) in relation to nonhealing fractures at three months after trauma. A noninvasive procedure such as biophysical stimulation may be preferential prior to consideration of invasive procedures. In this retrospective study, we analyzed 80 phalangeal fractures, 43 of which did not show any radiographic sign of healing 30 days after surgery; on radiograms, we calculated radiographic data and the total active motion (TAM) for clinical comparison. All radiographic images were evaluated using Adobe Photoshop CS3 (version 10.0, Adobe Systems Inc., San Jose, CA, USA). We calculated the index of relative bone healing each month after surgery starting from 30 days, which was considered as T1, and followed up for a total of 6 months after stimulation (T6) with better results in stimulated groups. We concluded that prompt administration of biophysical stimulation supports fracture healing and yields an important improvement in the union rate compared with nontreatment. Above all, our patients experienced less injury-related distress between the fracture and repair period, which consequently reduced immobilization time, envisaging an early rehabilitation interval, with a better patient hand outcome.

Myeloid cell-derived catecholamines influence bone turnover and regeneration in mice.

Catecholamine signaling is known to influence bone tissue as reuptake of norepinephrine released from sympathetic nerves into bone cells declines with age leading to osteoporosis. Further, β-adrenoceptor-blockers like propranolol provoke osteoprotective effects in osteoporotic patients. However, besides systemic adrenal and sympathetic catecholamine production, it is also known that myeloid cells can synthesize catecholamines, especially under inflammatory conditions. To investigate the effects of catecholamines produced by CD11b+ myeloid cells on bone turnover and regeneration, a mouse line with specific knockout of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in CD11b+ myeloid cells (THflox/flox/CD11b-Cre+, referred to as THCD11b-Cre) was generated. For bone phenotyping, male mice were sacrificed at eight and twelve weeks of age and harvested bones were subjected to bone length measurement, micro-computed tomography, fluorescence-activated cell sorting of the bone marrow, gene expression analysis, histology and immunohistochemistry. Support for an age-dependent influence of myeloid cell-derived catecholamines on bone homeostasis is provided by the fact that twelve-week-old, but not eight-week-old THCD11b-Cre mice, developed an osteopenic phenotype and showed increased numbers of neutrophils and T lymphocytes in the bone marrow, while CCL2, IL-6, IL-4 and IL-10 mRNA expression was reduced in sorted myeloid bone marrow cells. To investigate the influence of myeloid cell-derived catecholamines on fracture healing, mice received a diaphyseal femur osteotomy. Three days post-fracture, immunohistochemistry revealed an increased number of macrophages, neutrophils and cytotoxic T lymphocytes in the fracture hematoma of THCD11b-Cre mice. Micro-computed tomography on day 21 showed a decreased tissue mineral density, a reduced bone volume and less trabeculae in the fracture callus indicating delayed fracture healing, probably due to the increased presence of inflammatory cells in THCD11b-Cre mice. This indicates a crucial role of myeloid cell-derived catecholamines in immune cell-bone cell crosstalk and during fracture healing.

Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs.

Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

The effect of anti-retroviral therapy on fracture healing : an in vivo animal model.

AimsA number of anti-retroviral therapies (ART) have been implicated in potentially contributing to HIV-associated bone disease. The aim of this study was to evaluate the effect of combination ART on the fracture healing process.MethodsA total of 16 adult male Wistar rats were randomly divided into two groups (n = eight each): Group 1 was given a combination of Tenfovir 30 mg, Lamivudine 30 mg, and Efavirenz 60 mg per day orally, whereas Group 2 was used as a control. After one week of medication preload, all rats underwent a standardized surgical procedure of mid-shaft tibial osteotomy fixed by intramedullary nail with no gap at the fracture site. Progress in fracture healing was monitored regularly for eight weeks. Further evaluations were carried out after euthanasia by micro-CT, mechanically and histologically. Two blinded orthopaedic surgeons used the Radiological Union Scoring system for the Tibia (RUST) to determine fracture healing.ResultsThe fracture healing process was different between the two groups at week 4 after surgery; only two out of eight rats showed full healing in Group 1 (ART-treated), while seven out of eight rats had bone union in Group 2 (control) (p = 0.040). However, at week eight postoperatively, there was no statistical difference in bone healing; seven out of eight progressed to full union in both groups.ConclusionThis study demonstrated that combination ART resulted in delayed fracture healing at week 4 after surgery in rats, but did not result in the development of nonunion.Cite this article: Bone Joint Res 2022;11(8):585–593.

Monocyte Chemotactic Proteins Mediate the Effects of Hyperglycemia in Chondrocytes: In Vitro Studies.

Chemokines are secreted by a large variety of cells. They are involved in controlling cell trafficking, maturation, and differentiation. However, the specific responses and effects of chemokines on specific skeletal cell types under high glucose conditions have not been investigated. Chondrocytes play an important role in osteoarthritis and fracture healing. Delayed fracture healing is one of the major health complications caused by diabetes, so the goal of this study was to evaluate the response of several chemokines to high glucose conditions in chondrocyte cells and analyze their role in the catabolic effect of hyperglycemia. ATDC5 chondrocytes were cultured in normal and high glucose media, and mRNA expression levels of several chemokines and chondrocyte differentiation markers were quantified. Bindarit, a specific inhibitor of monocyte chemotactic proteins (MCPs), was used to determine the role of MCPs in mediating the effects of high glucose conditions in chondrocyte cells. High glucose treatment upregulated the expression of three Mcps, as well as the expression of matrix metalloproteinase 13 (Mmp13) and Osteocalcin (Oc). Furthermore, bindarit treatment downregulated Mmp13 and Oc but upregulated Collagen 2 (Col2) mRNA levels in chondrocytes treated with high glucose. Moreover, treatment of chondrocytes with ascorbic acid reduced the effect of high glucose conditions on the expression of chemokines and Mmps. These data together suggest that MCPs mediate the catabolic effect of high glucose in chondrocytes.

Early bisphosphonate therapy post proximal femoral fracture fixation does not impact fracture healing: a systematic review and meta-analysis.

There is conjecture on the optimal timing to administer bisphosphonate therapy following operative fixation of low-trauma hip fractures. Factors include recommendations for early opportunistic commencement of osteoporosis treatment, and clinician concern regarding the effect of bisphosphonates on fracture healing. We performed a systematic review and meta-analysis to determine if early administration of bisphosphonate therapy within the first month post-operatively following proximal femur fracture fixation is associated with delay in fracture healing or rates of delayed or non-union. We included randomized controlled trials examining fracture healing and union rates in adults with proximal femoral fractures undergoing osteosynthesis fixation methods and administered bisphosphonates within 1 month of operation with a control group. Data were pooled in meta-analyses where possible. The Cochrane Risk of Bias Tool and the GRADE approach were used to assess validity. For the outcome of time to fracture union, meta-analysis of three studies (n=233) found evidence for earlier average time to union for patients receiving early bisphosphonate intervention (MD=-1.06 weeks, 95% CI -2.01--0.12, I2 = 8%). There was no evidence from two included studies comprising 718 patients of any difference in rates of delayed union (RR 0.61, 95% CI 0.25-1.46). Meta-analyses did not demonstrate a difference in outcomes of mortality, function or pain. We provide low-level evidence that there is no reduction in time to healing or delay in bony union for patients receiving bisphosphonates within 1 month of proximal femur fixation.

Delayed Fracture Healing.

Physiologic bone healing involves numerous parameters, such as microstability, fracture morphology, or tissue perfusion, to name just a few. Slight imbalances or a severe impairment of even one of these factors may, as the figurative weakest link in the chain, crucially or completely inhibit the regenerative potential of a fractured bone. This review revisits the physiology and pathophysiology of fracture healing and provides an insight into predispositions, subtypes, diagnostic tools, and therapeutic principles involved with delayed fracture healing and nonunions. Depending on the patients individual risk factors, nonunions may develop in a variety of subtypes, each of which may require a slightly or fundamentally different therapeutical approach. After a detailed analysis of these individual factors, additional diagnostic tools, such as magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI, sonography, or contrast-enhanced ultrasonography, may be indicated to narrow down the most likely cause for the development of the nonunion and therefore help find and optimize the ideal treatment strategy.