Enhance Fracture Healing Research Articles

PGE2 Receptor Subtype 1 (EP1) Regulates Mesenchymal Stromal Cell Osteogenic Differentiation by Modulating Cellular Energy Metabolism.

Mesenchymal stromal cells (MSCs) are multipotent progenitors capable of differentiation into osteoblasts and can potentially serve as a source for cell-based therapies for bone repair. Many factors have been shown to regulate MSC differentiation into the osteogenic lineage such as the Cyclooxygenase-2 (COX2)/Prostaglandin E2 (PGE2) signaling pathway that is critical for bone repair. PGE2 binds four different receptors EP1-4. While most studies focus on the role PGE2 receptors EP2 and EP4 in MSC differentiation, our study focuses on the less studied, receptor subtype 1 (EP1) in MSC function. Recent work from our laboratory showed that EP1-/- mice have enhanced fracture healing, stronger cortical bones, higher trabecular bone volume and increased in vivo bone formation, suggesting that EP1 is a negative regulator of bone formation. In this study, the regulation of MSC osteogenic differentiation by EP1 receptor was investigated using EP1 genetic deletion in EP1-/- mice. The data suggest that EP1 receptor functions to maintain MSCs in an undifferentiated state. Loss of the EP1 receptor changes MSC characteristics and permits stem cells to undergo more rapid osteogenic differentiation. Notably, our studies suggest that EP1 receptor regulates MSC differentiation by modulating MSC bioenergetics, preventing the shift to mitochondrial oxidative phosphorylation by maintaining high Hif1α activity. Loss of EP1 results in inactivation of Hif1α, increased oxygen consumption rate and thus increased osteoblast differentiation. J. Cell. Biochem. 118: 4383-4393, 2017. © 2017 Wiley Periodicals, Inc.

Effect of teriparatide (rh-PTH 1\u201334) versus bisphosphonate on the healing of osteoporotic vertebral compression fracture: A retrospective comparative study

BackgroundTeriparatide (recombinant human parathyroid hormone 1–34) is increasingly used for the treatment of severe osteoporosis because it stimulates bone formation and may potentially enhance fracture healing. The objective of this study was to investigate the effects of teriparatide versus a bisphosphonate on radiographic outcomes in the treatment of osteoporotic vertebral compression fractures (OVCF).MethodsA total of 98 patients undergoing non-operative treatment for recent single-level OVCF were reviewed retrospectively. Thirty-eight patients were treated by a once-daily subcutaneous injection of 20 micrograms of teriparatide (TPD group), whereas 60 patients received 35 mg of alendronate weekly (BP group). Except for these medications, the same treatment protocol was applied to both groups. The radiographic assessments included union status, vertebral kyphosis, and mid-vertebral body height. The rates of fracture site surgical intervention were also compared between the two groups. The mean follow-up period was 27 months (median 22.5, range 2 – 75 months).ResultsCox regression analysis showed that TPD reduced the time-to-union (adjusted relative hazard ratio: 1.86, 95% C.I.: 1.21 – 2.83). The union rate at six months after treatment was 89% in the TPD group and 68% in the BP group; the surgical intervention rate was significantly higher in the TPD group (p = 0.026, adjusted odds ratio: 8.15, 95% C.I.: 2.02 – 43.33). The change in local kyphosis was 4.6° in the TPD group and 3.8° in the BP group (p = 0.495, paired t-test). The change of mid-vertebral body height was 4.4 mm in the TPD group and 3.4 mm in the BP group (p = 0.228, paired t-test). Fracture site surgical interventions were not required in the TPD group; however, two patients in the BP group eventually underwent surgical treatment for symptomatic non-union or vertebral collapse.ConclusionsThis retrospective study suggests that teriparatide may enhance fracture healing and improve the union rate in OVCF.

Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing.

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.

Abstract 69: Stem Cells Harvested from Bone Marrow and Adipose Tissue Demonstrate Equivalent Healing but Through Different Mechanisms in a Murine Model of Irradiated Mandibular Fracture Healing

PURPOSE: The difficulty of harvest and relative scarcity of bone marrow stromal cells (BMSCs) has limited the widespread use and clinical application of this technology, thereby necessitating inquiry into other therapies including adipose-derived stromal cells (ASCs). The goal of this study was to compare the ability of ASCs and BMSCs to heal mandibular defects and understand the mechanism through which this occurs. We hypothesize that ASCs will enhance fracture healing by improving vasculogenesis, while BSMCs will directly affect osteogenesis. METHODS: Male Lewis rats were radiated (35Gy), and subsequently underwent mandibular osteotomy with external fixation with implantation of two million BMSCs (n=12) or ASCs (n=16) marked with Green fluorescent protein (GFP). After 40 days, union rates were evaluated using microCT. Confocal microscopy visualized the contribution of ASCs/BMSCs to the bone regenerate. Quantitative polymerase chain reaction of ASCs/BMSCs compared expression of osteogenic and vasculogenic genes. Coculture of ASCs (n=3) or BMSCs (n=3) with human umbilical vein endothelial cells (HUVECs) was performed in vitro in transwells to measure tubule formation as a marker of vasculogenesis. RESULTS: ASC-implantation resulted in higher union rates than BMSC-implantation (union rate: 94% vs. 66%). These cells contribute indirectly to fracture healing, as GFP was not visualized at the site. BMSCs expressed osteogenic genes including osteopontin to a significantly greater degree than did ASCs, while ASCs expressed greater levels of vascular endothelial growth factor. This translated to greater tubule formation among HUVECs co-cultured with ASCs than with BMSCs (64.3 ± 7.3 vs. 23.3 ± 2.6, p=0.0008), and increased vasculogenesis in vivo in mandibles after ASC implantation. CONCLUSIONS: ASCs heal fracture defects better than BMSCs. This effect is likely mediated by indirect modulation of vasculogenesis, rather than by a direct effect on osteogenesis. Clinicians interested in cell-based therapies for irradiated bone injury should consider ASCs as a promising option, given their abundance, ease of acquisition, and improved fracture healing.

Anterior Tibial Stress Fractures: Intramedullary Nail vs Anterior Tension Band Plating

Lower extremity stress fractures are common overuse injuries in endurance athletes. Most fractures are low risk and respond well to nonsurgical management involving rest, activity modification, and slow resumption of activities after symptom resolution. However, some high-risk fractures or nonunions warrant surgical intervention to prevent fracture completion and continued symptoms. Anterior stress fractures of the tibial shaft are tension-sided high-risk stress fractures with significant risks of delayed union, nonunion, and fracture propagation. The gold standard surgical treatment has traditionally been antegrade tibial intramedullary nailing. However, the risk of anterior knee pain following intramedullary nail placement has prompted clinicians to seek alternative methods of fixation. Anterior tibial plating with biological augmentation is biomechanically sound in that the plate is placed on the tension side, able to resist tensile stress, and biologically sound in that bone graft may be used to enhance fracture healing. The purpose of this article is to describe the presentation, evaluation, and management of patients with anterior tibial shaft stress fracture. The surgical techniques for intramedullary nail and anterior plating are discussed and illustrated in detail.

Local Zinc Chloride Release From a Calcium Sulfate Carrier Enhances Fracture Healing.

This study examined the efficacy of calcium sulfate (CaSO4) as a carrier for intramedullary delivery of zinc chloride (ZnCl2) to treat fracture healing in a BB Wistar rat model. A non-carrier-mediated injection of 3.0 mg/kg of ZnCl2 has previously been shown to enhance fracture healing. A heterogeneous mixture of ZnCl2 and CaSO4 was administered into the intramedullary femoral canal and a mid-diaphyseal femur fracture was created unilaterally. Early and late parameters of fracture healing were assessed using biomechanical testing, radiographic scoring, quantitative histomorphometry (for percentage of new cartilage and bone within the fracture callus), and long-term histologic evaluation. Fractures treated with 1.0 mg/kg of ZnCl2/CaSO4 demonstrated a significantly higher maximum torque to failure compared with both CaSO4 (P = 0.048) and saline (P = 0.005) controls at 4 weeks postfracture (396.4 versus 251.3 versus 178.7 N mm, respectively). Statistically significant increases in torsional rigidity, effective shear modulus, and effective shear stress were also found, as well as a 3.5 times increase in radiographic score (based on bone union). Histologic examination of the fracture callus indicated enhanced chondrogenesis at day 14 postfracture, with increased percent cartilage for the ZnCl2/CaSO4 group compared with saline (P = 0.0004) and CaSO4 (P = 0.0453) controls. Long-term radiographic and histologic evaluation revealed no abnormal bone formation or infection up to 12 weeks postoperatively. The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site.

Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase

ObjectivesWe investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days.Materials and MethodsUnilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry.ResultsWhen compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42.ConclusionThis study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression.Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:–97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2.

A Concert between Biology and Biomechanics: The Influence of the Mechanical Environment on Bone Healing.

In order to achieve consistent and predictable fracture healing, a broad spectrum of growth factors are required to interact with one another in a highly organized response. Critically important, the mechanical environment around the fracture site will significantly influence the way bone heals, or if it heals at all. The role of the various biological factors, the timing, and spatial relationship of their introduction, and how the mechanical environment orchestrates this activity, are all crucial aspects to consider. This review will synthesize decades of work and the acquired knowledge that has been used to develop new treatments and technologies for the regeneration and healing of bone. Moreover, it will discuss the current state of the art in experimental and clinical studies concerning the application of these mechano-biological principles to enhance bone healing, by controlling the mechanical environment under which bone regeneration takes place. This includes everything from the basic principles of fracture healing, to the influence of mechanical forces on bone regeneration, and how this knowledge has influenced current clinical practice. Finally, it will examine the efforts now being made for the integration of this research together with the findings of complementary studies in biology, tissue engineering, and regenerative medicine. By bringing together these diverse disciplines in a cohesive manner, the potential exists to enhance fracture healing and ultimately improve clinical outcomes.

Effect of Cold Hip Bath on Autonomic Variables in Healthy Individuals - A Randomized Control Trial

Objectives: Laksha Guggulu, an Ayurvedic formulation advocated to enhance the fracture healing in ancient Indian texts, was selected to validate its effect on fracture healing on certain scientific parameters like Radiological, Serological and Histopathological studies in an experimental rat model. Methods: Eighteen Wistar rats (Rattus norvegicus) were taken to create identical fractures by a transverse osteotomy of Radial bone of their left fore limb under Ketamine and Xylazine anesthesia (intraperitoneally). Intact ulna acted as an internal splint hence, no other external or internal support to the fractures was given. Post operatively injectable antibiotic (Gentamicin) was given. These osteotomised rats were divided into three groups of six each. Group I rats were given 13.5mg/100gm body weight of the trial drug (Laksha Guggulu) twice daily through oral route. Group II rats were given half of the Group I dose of the trial drug whereas in Group III, no drug was given (Control group). The drug was given oraly with Cow’s milk. Total duration of trial was of four weeks. Healing was assessed Radiologically, Biochemically and Histopathologically. Results: Assessment of results was done according to pre-designed protocol and data analysis done statistically. Histopathological and Serological studies revealed significant results in Group I animals as compared to Group II and Group III. Radiologically the difference between the groups was not detectable. Conclusion: Laksha Guggulu has got a definite role in the enhancement of fracture healing by forming early and improved quality of the callus. However, further studies on large sample size, with more advanced investigations like Histomorphometery, Bone turnover markers and Micro CT scanning are required

Sialoglycoprotein isolated from the eggs of Gadus morhua enhances fracture healing in osteoporotic mice.

Osteoporosis is a common disease in the elderly, which is related to fracture healing delay. In this study, the effects of treatment with sialoglycoprotein isolated from the eggs of Gadus morhua (Gm-SGP) on tibial fracture healing in ovariectomized (OVX) osteoporotic female C57BL/6J mice for 56 days post-fracture were investigated. The result showed that Gm-SGP treatment significantly increased serum angiogenic factors and bone formation markers on day 5 and 11 post-fracture when compared with the OVX group. In addition, histological results in the Gm-SGP group showed a stronger endochondral ossification, a stronger bony consolidation and a stronger bony callus remodeling capability on day 11, 24 and 35 post-fracture, respectively, in comparison with the OVX group. Meanwhile, micro-computerized tomography revealed that the Gm-SGP group had stronger bony callus remodeling capability as evidenced by higher BV/TV and Tb.N but lower Tb.Sp and shorter lengths of callus maximum cross section than the OVX group on day 24 post-fracture. Besides, the tibial callus bending stiffness was significantly enhanced in the Gm-SGP group as compared with the OVX group on day 56 post-fracture. Moreover, gene expression suggested that Gm-SGP promoted vascular invasion and endochondral ossification on day 11 post-fracture as well as bone formation on day 11 and 24 post-fracture via up-regulating the expression of angiogenesis factors (including VEGF, PDGF and Ang1), entochondrostosis factors (including Col2a1, Aggrecan, Col10a1 and MMP-13) and osteogenesis markers (including Col1a1, BMP-2 and OCN). This research suggests that Gm-SGP significantly improve fracture healing which is delayed by OVX-induced osteoporosis. The present study may contribute to providing important implications for the utilization of Gm-SGP from fish eggs as a functional food to enhance fracture healing.

Osthole Promotes Bone Fracture Healing through Activation of BMP Signaling in Chondrocytes.

Osthole is a bioactive coumarin derivative and has been reported to be able to enhance bone formation and improve fracture healing. However, the molecular mechanism of Osthole in bone fracture healing has not been fully defined. In this study we determined if Osthole enhances bone fracture healing through activation of BMP2 signaling in mice. We performed unilateral open transverse tibial fracture procedure in 10-week-old C57BL/6 mice which were treated with or without Osthole. Our previous studies demonstrated that chondrocyte BMP signaling is required for bone fracture healing, in this study we also performed tibial fracture procedure in Cre-negative and Col2-Cre;Bmp2flox/flox conditional knockout (KO) mice (Bmp2Col2Cre) to determine if Osthole enhances fracture healing in a BMP2-dependent manner. Fracture callus tissues were collected and analyzed by X-ray, micro-CT (μCT), histology, histomorphometry, immunohistochemistry (IHC), biomechanical testing and quantitative gene expression analysis. In addition, mouse chondrogenic ATDC5 cells were cultured with or without Osthole and the expression levels of chondrogenic marker genes were examined. The results demonstrated that Osthole promotes bone fracture healing in wild-type (WT) or Cre- control mice. In contrast, Osthole failed to promote bone fracture healing in Bmp2Col2Creconditional KO mice. In the mice receiving Osthole treatment, expression of cartilage marker genes was significantly increased. We conclude that Osthole could promote bone strength and enhance fracture healing by activation of BMP2 signaling. Osthole may be used as an alternative approach in the orthopaedic clinic for the treatment of fracture healing.

Effectiveness of Teriparatide on Fracture Healing: A Systematic Review and Meta-Analysis.

PurposeNowadays, the efficacy of teriparatide in treating osteoporosis was widely accepted, but the discussion about using teriparatide to enhance fracture healing hasn’t come to an agreement. This meta-analysis was conducted to evaluate the effectiveness of teriparatide for fracture healing.MethodsWe searched PubMed, the Cochrane Library, and Embase in August 2016 for randomized controlled trials (RCTs) which concerned the treatment of teriparatide for fracture healing.ResultsFinally, a total of 380 patients were randomly assigned in the 5 trials included in this meta-analysis. There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain.ConclusionsThis analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing. Moreover, teriparatide administration had no apparent adverse effects. These results should be interpreted with caution because of some clear limitations. If we want to confirm whether teriparatide improves fracture healing, more high-quality randomized controlled trials are needed.

Femoral non-union with malalignment: reconstruction and biological stimulation with the chipping technique

IntroductionThe purpose of this study was to investigate the effectiveness of the chipping technique for the treatment of femoral non-unions associated with malalignment. Patients and methodsA total of 21 femoral non-unions were managed with the chipping procedure and re-fixation. 15 of them had malalignment (angular or rotational deformity or limb length discrepancy). The deformities were simultaneously corrected by a combination of chipping and temporal external fixator. The median age of patients were 41 years (range, 19–73 years). The median time from injury or the final surgery to the initial chipping procedure was 24 months (range: 9–240 months). Femoral non-unions were classified as hypertrophic in 9, oligotrophic in 5 and atrophic in 7. Clinical and radiological assessment was performed. ResultsAll femoral non-unions radiographically healed with one (19 cases) or two (2 cases) chipping procedures without bone grafting. Pre-existing angular deformity was corrected from 14° to 2°, external rotation 27° to 0°, and limb length discrepancy 16–7 mm. There were no major complications, although swelling of thigh and anemia was common after surgery. ConclusionChipping the non-union site was associated with a favorable outcome. It biologically enhances fracture healing and should be considered as a treatment option for femoral non-unions with malalignment.

Clinical analysis of Cervus and Cucumis Polypeptide injection based on real world hospital information system

To analyze the clinical application of Cervus and Cucumis Polypeptide injection in the real world, in order to define the characteristics of clinical drug use and correlation, and provide reference for risk management and further study for Cervus and Cucumis Polypeptide injection. Descriptive analysis and association rules analysis were performed on 37 721 cases using Cervus and Cucumis Polypeptide injection in 26 hospitals nationwide. Cervus and Cucumis Polypeptide injection were mostly adopted by patients aged between 45 and 64(39.84%); mainly used to treat fracture patients in clinic(17 362 cases, 33.97%); 12 mL(41.81%) was the commonest dosage. And the course of treatment mainly lasted for 1-3 days(28 467 cases, 76.26%), which was basically consistent with the description of package insert. In clinic, traditional Chinese medicines, such as blood activating and stasis removing agents and Bushen Zhuanggu agents, were frequently combined with it(rule support degree of 19.38%). Such western medicine as antibiotics and nutritional drugs were frequently combined with it(rule support 39.9%). The main single combined medicine were vitamin C(13 202 cases, 35%), and Jintiange capsule(7 285 cases, 19.31%). The commonly used combined drug pairs were Hulisan capsule and Jintiange capsule (rule support 4.458%), phenobarbital and ceftazidime azole oxazoline(rule support degree of 10.62%). Cervus and Cucumis Polypeptide injection is mainly adopted by elderly patients in clinic, used to treat fracture patients, and often combined with blood activating and stasis removing agents, Bushen Zhuanggu agents, antibiotics, and nutritional medicine to enhance fracture healing. In clinical application, attention shall be paid to drug safety of elderly patients and types of combined medicines and their interaction, so as to prevent adverse reactions.

Potential Role of Local Estrogen in Enhancement of Fracture Healing: Preclinical Study in Rabbits.

Effects of estrogen on bone metabolism and its protective role on prevention of osteoporosis are well documented. However, the efficacy of estrogen treatment on bone healing is not well investigated. The drug can be delivered both systemically or locally to the bone with differences in concentrations and side effects. The aim of this study was to investigate the effect of local and systemic administration of estrogen on the fracture healing process. Standardized tibial fractures with 4 millimeter gaps were created in twenty four adult male Dutch rabbits. Fractures were fixed using intramedullary wires and long leg casts. Rabbits were randomly divided into three groups. Group A was treated with twice a week administration of long acting systemic estrogen; group B was treated with a similar regimen given locally at the fracture gap; and group C received sham normal saline injections (control). Fracture healing was assessed at six weeks post fracture by gross examination, radiographic and histomorphometric analysis. Group B had significantly higher gross stability, radiographic union and gap reduction than the two other groups. Histomorphometric analysis showed higher cartilaginous proportion of periosteal callus area in the control group. Our results showed that estrogen may enhance fracture healing of long bone in rabbits. Furthermore, local estrogen treatment might have better effect than systemic treatment.

Ultrasound for bone tissue engineering and regenerative medicine

We will review the role of ultrasound in bone tissue engineering and regenerative medicine, for enhancement of fracture healing and reactivation of a failed healing process. These approaches rely typically either on the direct stimulation of the healing process or in the delivery at the injury site of scaffold-embedded biologics such as cells, signaling molecules, and genetic material. Different options are available for ultrasound enhancement of fracture healing such as low intensity pulsed ultrasound (LIPUS) and shock waves, for the delivery of regenerative factors and encoding genes, and for the assembly and patterning of scaffolds. A main emphasis will be put on LIPUS-related bioeffects, the most widespread and studied technique. Pronounced bioeffects on tissue regeneration have been reported employing intensities within a diagnostic range. We will describe the current knowledge of the biological response to LIPUS, involving numerous cell types and molecular pathways, hypothesis about LIPUS biophysics, and our recent findings on mechanosensitive transcriptional response of cells after LIPUS. We will also present the use of focused ultrasound to spatiotemporally control the delivery of growth factors, either by induction of transgene expression controlled by a heat-activated and ligand-dependent gene-switch, or by triggered release using acoustic droplets vaporization within biopolymer scaffolds.

The administration of intermittent parathyroid hormone affects functional recovery from trochanteric fractured neck of femur: a randomised prospective mixed method pilot study.

AimsWe wished to assess the feasibility of a future randomised controlled trial of parathyroid hormone (PTH) supplements to aid healing of trochanteric fractures of the hip, by an open label prospective feasibility and pilot study with a nested qualitative sub study. This aimed to inform the design of a future powered study comparing the functional recovery after trochanteric hip fracture in patients undergoing standard care, versus those who undergo administration of subcutaneous injection of PTH for six weeks.Patients and MethodsWe undertook a pilot study comparing the functional recovery after trochanteric hip fracture in patients 60 years or older, admitted with a trochanteric hip fracture, and potentially eligible to be randomised to either standard care or the administration of subcutaneous PTH for six weeks. Our desired outcomes were functional testing and measures to assess the feasibility and acceptability of the study.ResultsA total of 724 patients were screened, of whom 143 (20%) were eligible for recruitment. Of these, 123 were approached and 29 (4%) elected to take part. However, seven patients did not complete the study. Compliance with the injections was 11 out of 15 (73%) showing the intervention to be acceptable and feasible in this patient population.Take home message: Only 4% of patients who met the inclusion criteria were both eligible and willing to consent to a study involving injections of PTH, so delivering this study on a large scale would carry challenges in recruitment and retention. Methodological and sample size planning would have to take this into account. PTH administration to patients to enhance fracture healing should still be considered experimental.Cite this article: Bone Joint J 2016;98-B:840–5.

Antagonizing midkine accelerates fracture healing in mice by enhanced bone formation in the fracture callus.

Background and PurposePrevious findings suggest that the growth and differentiation factor midkine (Mdk) is a negative regulator of osteoblast activity and bone formation, thereby raising the possibility that a specific Mdk antagonist might improve bone formation during fracture healing.Experimental ApproachIn the present study, we investigated the effects of a monoclonal anti‐Mdk antibody (Mdk‐Ab) on bone healing using a standardized femur osteotomy model in mice. Additional in vitro experiments using chondroprogenitor and preosteoblastic cells were conducted to analyse the effects of recombinant Mdk and Mdk‐Ab on differentiation markers and potential binding partners in these cells.Key ResultsWe demonstrated that treatment with Mdk‐Ab accelerated bone healing in mice based on increased bone formation in the fracture callus. In vitro experiments using preosteoblastic cells showed that Mdk‐Ab treatment abolished the Mdk‐induced negative effects on the expression of osteogenic markers and Wnt/β‐catenin target proteins, whereas the differentiation of chondroprogenitor cells was unaffected. Phosphorylation analyses revealed an important role for the low‐density lipoproteinLDL receptor‐related protein 6 in Mdk signalling in osteoblasts.Conclusions and ImplicationsWe conclude that Mdk‐Ab treatment may be a potential novel therapeutic strategy to enhance fracture healing in patients with orthopaedic complications such as delayed healing or non‐union formation.

Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway.

Low-magnitude high-frequency vibration (LMHFV) has been proven to promote osteoporotic fracture healing. Mechanical stimulation was reported to enhance SDF-1/CXCR4 signalling in mesenchymal stem cells (MSCs). We hypothesised that LMHFV promoted osteoporotic fracture healing by enhancing MSC migration through the SDF-1/CXCR4 pathway. 152 ovariectomised SD-rats received closed femoral fracture in groups of vibration+MSC (VMG) (20min/d, 5d/week), vibration+MSC+AMD3100 (VMAG; AMD, a CXCR4 inhibitor) (1mg/kg/d, intraperitoneal), MSC (MG) (1×106 MSC, intracardiac) or control (CG) for a treatment duration of 2, 4 or 8 weeks. MSC migration was evaluated by ex-vivo green fluorescent protein signal in the callus; and fracture healing was examined by weekly radiographs, endpoint computed-tomography and mechanical test. At week-2 and week-4, ex-vivo callus GFP intensity of VMG was significantly higher than other groups (p<0.05). From week-2 to week-3, both callus width and callus area in VMG were significantly larger; and from week-7 to week-8, smaller than other groups (p<0.05). At week-8, high-density bone volume fraction, bone volume fraction, bone mineral density and stiffness in VMG were significantly higher than other 3 groups (p<0.05). This study demonstrated that LMHFV promoted MSC migration and fracture healing in osteoporotic rats. This effect was attenuated by CXCR4 inhibitor, providing strong evidence that SDF-1-mediated MSC migration was one of the important mechanisms through which LMHFV enhanced fracture healing.

Use of teriparatide in osteoporotic fracture patients

Teriparatide [PTH (1–34)] is a genetically engineered analog of human parathyroid hormone that acts as an anabolic drug by increasing activity in both osteoblasts and osteoclasts. Intermittent (once-daily) doses of teriparatide seem to stimulate osteoblast activity and therefore result in a net increase of bone formation. It is recommended for use in post-menopausal women (PMW), men with hypogonadal osteoporosis, as well as men and women with glucocorticoid-induced osteoporosis. In vivo studies have generated important findings regarding teriparatide's role in the enhancement of fracture healing. The intention of this article is to review the clinical findings of teriparatide to stimulate fracture healing. The drug was shown in a prospective randomized, double blind study to achieve earlier radiographic cortical bridging of three of four cortices (7.4 weeks) compared to patients who were assigned to the placebo group (9.1 weeks). Another study compared mean time for healing and functional outcome in two groups of elderly women who had suffered osteoporotic pelvic fractures: one group received daily 100 μg parathyroid hormone (1–84) injections, while the other group received no treatment. Patients who received the PTH (1–84) injections accelerated radiographic and clinical fracture healing (7.8 weeks) when compared to patients who received no treatment (12.6 weeks, p<0.001). Numerous case series state the safety and potential benefits of teriparatide use in patients recovering from fractures. In the following scenarios, teriparatide might be considered in patients with osteoporosis and a fracture: (1) patients with severe osteoporosis with use of bisphosphonates for a number of years with a fracture not expected to predictably unite, e.g. atypical femur fracture or open tibia fracture, (2) in cases where an osteoporotic patient has failed fracture healing and is considering surgical treatment e.g. non-union surgery. It seems prudent to reevaluate these patients frequently and reconsider which drug class of osteoporotic drug is best for the patient. Finally, it must be stressed that we do not recommend teriparatide in osteoporotic patients that may be well treated with bisphosphonates and a fracture is expected to heal uneventfully, nor when patients with metabolically normal bone have a fracture.