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Fracture healing is a process in which many factors interact. In addition to many treatments, physical and biological therapy methods that affect different steps of this process, there are many biological and chemical agents that cause fracture union delay. Although the number of studies on fracture healing is increasing day by day, the mechanism of fracture healing, which is not fully understood, still attracts the attention of all researchers. In this study, we aimed to investigate the effects of favipiravir and hydroxychloroquine used in the treatment of COVID-19. In this study, 48 male Wistar rats weighing 300 ± 50 g were used. Each group was divided into eight subgroups of six rats each to be sacrificed at the 2nd and 4th weeks and evaluated radiologically and histologically. Favipiravir (group 1), hydroxychloroquine (group 2), favipiravir + hydroxychloroquine (group 3), and random control (group 4) were used. A statistically significant difference was observed between the 15th day histological scoring averages of the groups (p < 0.05). Although there was no statistically significant difference between the 15th day radiological score distributions of the groups (p > 0.05), we obtained different results in terms of complete bone union distributions and radiological images of the fracture line. Although favipiravir has a negative effect on fracture union in the early period, favipiravir may have a positive effect on fracture union in the late period. We did not find any effect of hydroxychloroquine on fracture union., (© 2024. The Author(s).)

Teriparatide is an anabolic drug sometimes administered to patients who have atypical femoral fracture (AFF). However, whether teriparatide has beneficial effects on bone healing remains uncertain. The present study aimed to analyze the association between teriparatide and bone healing in complete AFF. A total of 59 consecutive cases (58 patients) who underwent intramedullary nailing for complete AFF were categorized based on postoperative use of teriparatide into the non-teriparatide (non-TPTD, n = 34) and teriparatide groups (TPTD, n = 25). Time-to-bone union was evaluated and compared between the two groups. Additionally, multiple regression analysis was performed to evaluate factors affecting time-to-bone union. All participants were women, with a mean age of 77.6 years (range: 62-92). No significant difference in time-to-bone union was found between the non-TPTD and TPTD groups (5.5 months vs. 5.8 months, p = 0.359). Two patients in the non-TPTD group underwent reoperation (p = 0.503) due to failure caused by inadequate fixation, and both achieved bone healing after additional fixation with blocking screws. Multiple regression analysis revealed that the anterior gap of the fracture site postoperatively was a factor affecting time-to-bone union (p = 0.014). The beneficial effect of teriparatide on bone healing in complete AFF could not be confirmed. Additional randomized controlled trials are required. Nonetheless, appropriate techniques, including efforts to reduce the gap on the tensile side during the surgery, are important for reliable bone healing., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Bisphosphonates (BPs) are one of the most often used drugs to lower fracture risk in osteoporosis patients; nonetheless, BPs have been linked to atypical femoral fracture (AFF). Teriparatide (TPTD) is a parathyroid hormone analogue and anabolic drug that may accelerate fracture repair. TPTD has been considered as a possible treatment for AFF, particularly those caused by BP use. We evaluate the effect of TPTD on AFF in this systematic review and meta-analysis., Materials and Methods: A thorough search of: Web of Science, Scopus, PubMed, and Cochrane was conducted on August 2, 2023. Trials evaluating the effect of TPTD on the incidence of: complete bone healing, non-union, early and delayed bone union, progression of incomplete AFF to complete AFF, and time to bone union were included. Using Review Manager (RevMan) version 5.4, the risk ratio (RR) and mean difference (MD) with the corresponding 95% confidence interval (CI) were estimated for dichotomous and continuous outcomes, respectively. The Newcastle-Ottawa Scale was used to assess the quality of studies., Results: Eight studies met the eligibility criteria and were included in our analysis. TPTD significantly increased the incidence of early bone union (RR = 1.45, 95% CI [1.13, 1.87], P = 0.004) and time to bone union (MD = -1.56, 95% CI [-2.86, -0.26], P = 0.02) compared to the control group. No significant differences were observed in terms of complete bone healing (RR = 1.09, 95% CI [0.99, 1.13], P = 0.12), non-union (RR = 0.48, 95% CI [0.22, 1.04], P = 0.06), and progression of incomplete AFF to complete AFF (RR = 0.27, 95% CI [0.04, 1.97], P = 0.19)., Conclusions: TPTD is an effective therapy for enhancing and hastening healing following AFF, particularly in postoperative settings. Future large randomized clinical trials are needed to confirm or dispute the results., (© 2023. The Author(s).)

Introduction: The primary aim of this study was to determine the effectiveness and safety of an intraarticular triamcinolone injection for the treatment of stiffness after the operative treatment of proximal humerus fractures., Materials and Methods: 88 patients who underwent plate fixation for proximal humerus fractures were enrolled. The patients were randomly divided into two groups, with Group I receiving a glenohumeral injection of triamcinolone 8 weeks postoperatively and Group II receiving no injection postoperatively. Outcomes were measured and compared based on the range of motion (ROM) and functional scores. Follow-up outcomes were assessed at initial, 3, 6 and 12 months postoperatively and at the last follow-up. Shoulder trauma series were taken at every visit to evaluate the fracture healing. The mean follow-up period was 25.37 (± 3.85) months Group I and 24.24 (± 6.23) months for group II., Results: In both groups, the final outcome of the ROM and functional outcome was significantly better at last F/U than at postoperative 8 weeks. Group I had significantly better results than Group II at postoperative 3 and 6 month in terms of forward flexion, external rotation, and VAS for pain. Also, Group I showed better performance in terms of ASES and Constant score at postoperative 3 months. The fracture union rate did not differ between Groups I and II., Conclusions: Postoperative glenohumeral injection of triamcinolone is a safe and effective treatment modality for shoulder stiffness after internal fixation of proximal humerus fractures during the early period of rehabilitation.

Non-steroidal selective androgen receptor modulators, including ostarine, have been developed as an alternative to steroidal hormones. Ostarine has shown a beneficial effect on bone in experimental studies, but no data regarding the effect of ostarine on bone healing have yet been reported. We investigated effects of ostarine on bone healing in ovariectomized rats. Sprague-Dawley rats (3 months old) were ovariectomized (Ovx, n = 46) or left intact (Non-Ovx, n = 10). After 8 weeks, an osteotomy of the tibia metaphysis was created in all rats, and the Ovx rats were divided into four groups: untreated Ovx (n = 10) and three Ovx groups (each of 12 rats) treated with ostarine at doses of 0.04, 0.4, or 4 mg/kg BW (OS-0.04, OS-0.4, and OS-4 groups). Five weeks later, bone healing was analyzed. The OS-4 dose enhanced callus formation, increased callus density, accelerated bridging time of the osteotomy, and elevated alkaline phosphatase gene expression in callus and its protein expression in serum. In the Ovx group, most of the callus parameters were diminished. All OS treatments increased the weight of the gastrocnemius muscle, but only partly enhanced uterus weight in OS-0.4 and OS-4. Serum cholesterol level was reduced, and serum phosphorus was elevated in OS-0.04 and OS-4. Ostarine appeared to have a positive effect on early bone healing in ovariectomized rats. Considering its favorable effect on non-osteotomized bone and muscle, this treatment could be further explored as a therapy for osteoporosis. However, possible metabolic side effects should first be evaluated.

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.

Background: 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 a fragility fracture has occurred. Therefore, their use would be conceivable to improve a disturbed fracture healing., Objective: 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., Material and Methods: A literature 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 a clinically relevant context., Results: Preclinical and clinical studies show that specific osteoporosis drugs have no relevant negative impact on the healing of fragility fractures. A tendency to improve a disturbed fracture healing was attributed to bone anabolic substances; however, studies are inconsistent and there is no approval for this application., Conclusion: Following a fragility 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.

Bone fractures represent a significant medical morbidity among aged population with osteoporosis. Bone morphogenetic proteins (BMPs) are suggested to have therapeutic potential to enhance fracture healing in such patients. Though BMP-mediated fracture healing has been well-documented in preclinical models, there has been no clinical study that demonstrated unequivocally that indeed a BMP when presented with an appropriate scaffold could provide basis for robust outcome for delayed or non-union diaphyseal bone fractures. This review presents a comprehensive insight towards the existing knowledge on the role of BMP signaling in bone formation and maintenance. Also therapeutic options based on BMP biology are discussed.A novel osteoinductive autologous bone graft substitute (ABGS) aimed to accelerate bone regeneration was developed and is currently being tested in the clinical setting. It comprises of a biologically compatible autologous carrier made from the patient's peripheral blood (autologous blood coagulum, ABC) and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices and renders the carrier flexible, malleable, and injectable ensuring the ease of use. The ongoing clinical trials result will provide more detailed insights into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and potentially provide novel and safe therapeutic options for bone repair.

Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma-induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its soluble form (sIL-6R). Herein, we investigated whether IL-6 classic and trans-signaling play different roles in bone regeneration after severe injury. Twelve-week-old C57BL/6J mice underwent combined femur osteotomy and thoracic trauma. To study the function of IL-6, either an anti-IL-6 antibody, which inhibits both IL-6 classic and trans-signaling, or a soluble glycoprotein 130 fusion protein (sgp130Fc), which selectively blocks trans-signaling, were injected 30 min and 48 h after surgery. Bone healing was assessed using cytokine analyses, flow cytometry, histology, micro-computed tomography, and biomechanical testing. Selective inhibition of IL-6 trans-signaling significantly improved the fracture healing outcome after combined injury, as confirmed by accelerated cartilage-to-bone transformation, enhanced bony bridging of the fracture gap and improved mechanical callus properties. In contrast, global IL-6 inhibition did not affect compromised fracture healing. These data suggest that classic signaling may mediate beneficial effects on bone repair after severe injury. Selective inhibition of IL-6 trans-signaling might have therapeutic potential to treat fracture healing complications in patients with concomitant injuries.

Purpose: Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs)., Methods: Male Fischer 344 rats were used for cell isolation and in vivo experiments. Bone marrow-derived E-EPCs and L-EPCs were kept in culture for seven to ten days and four weeks, respectively. For each treatment group, we seeded one million cells on a gelatin scaffold before implantation in a segmental defect created in a rat femur; control animals received a cell-free scaffold. Bone healing was monitored via radiographs for up to ten weeks after surgery. In vitro, secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 was quantified by ELISA for both cell populations. Tube formation assays were also performed., Results: Final radiographs showed complete (four out of five rats) or partial (one out of five rats) union with E-EPC treatment. In contrast, complete healing was achieved in only one of five animals after L-EPC implantation, while control treatment resulted in nonunion in all animals. In vitro, E-EPCs released more VEGF, but less BMP-2 than L-EPCs. In addition, L-EPCs formed longer and more mature tubules on basement membrane matrix than E-EPCs. However, co-culture with primary osteoblasts stimulated tubulogenesis of E-EPCs while inhibiting that of L-EPCs., Conclusions: We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing.

Purpose: Fracture healing encompasses a succession of dynamic multifactorial metabolic events, which ultimately re-establishes the integrity of the biomechanical properties of the bone. Up to 10% of the fractures occurring annually will need additional surgical procedures because of impaired healing. The aim of this article is to review the current literature regarding the use of bone marrow aspirate concentrate (BMAC) and its effectiveness in the management of bone defects., Methods: We have included all published clinical literature investigating the development, techniques and applications of BMAC. Language, design and risk of bias did not deter the initial inclusion of any study. Our search was exclusively limited to studies involving human subjects. A PRISMA compliant search was carried out as published in 2009. This included the online databases: PubMed, EMBASE, clinical trial.gov and the Cochrane library from 1960 to the end of May 2015. MeSH terms used included: "Bone" AND "Marrow" AND "Aspirate" AND "Concentrate" AND "Bone Defects" AND "NONUNION". Eligible studies were independently appraised by two authors using the Critical Appraisal Skills Program checklist. For the purpose of narrative review, relevant studies were included irrespective of methodology or level of evidence., Results: Thirty-four of the 103 (48 PubMed and 55 EMBASE) results yielded by the preliminary search were included. Exclusions included three duplicate records, six letters, 17 non-orthopaedics related studies and four records irrelevant to our search topic. The CASP appraisal confirmed a satisfactory standard of 31 studies. They all had clearly defined objectives, were well designed and conducted appropriately to meet them. The published studies reported the use of BMAC in non-union and fracture healing (15 studies), bone defects (nine studies), spine fusion (two studies), distraction osteogensis (two studies) and complications related to the use of BMAC (seven studies)., Conclusions: Stem cells found in BMAC have the potential to self-renew, undertake clonal expansion and differentiate into different musculoskeletal tissues. The commercial processing of BMAC needs to be optimized in order to achieve a consistent end product, which will provide predicable and translatable results. The future potential of cell characterization in order to determine the optimum cell for repair/regeneration of bone also needs to be explored., Level of Evidence: Systematic Review of minimum level IV studies.

Purpose: The incidence of low energy pelvic fractures (FPFs) in the elderly is increasing. Comorbidities, decreased bone-quality, problematic fracture fixation and poor compliance represent some of their specific difficulties. In the absence of uniform management, a standard operating procedure (SOP) was introduced to our unit, aiming to improve the quality of services provided to these patients., Methods: A cohort study was contacted to test the impact of (1) using a specific clinical algorithm and (2) using different antiosteoporotic drugs. Multivariate regression analysis was used to determine prognostic factors. Study endpoints were the time-to-healing, length-of-stay, return to pre-injury mobility, union status, mortality and complications., Results: A total of 132 elderly patients (≥65 years) admitted during the period 2012-2014 with FPFs were enrolled. High-energy fractures, acetabular fractures, associated trauma affecting mobility, pathological pelvic lesions and operated FPFs were used as exclusion criteria. The majority of included patients were females (108/132; 81.8%), and the mean age was 85.8 years (range 67-108). Use of antiosteoporotics was associated with a shorter time of healing (p = 0.036). Patients treated according to the algorithm showed a significant protection against malunion (p < 0.001). Also, adherence to the algorithm allowed more patients to return to their pre-injury mobility status (p = 0.039)., Conclusions: The use of antiosteoporotic medication in elderly patients with fragility pelvic fractures was associated with faster healing, whilst the adherence to a structured clinical pathway led to less malunions and non-unions and return to pre-injury mobility state.

Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.

Osthole has been found to restore bone mass in preclinical osteoporotic models. In the present study, we investigated the effects of osthole on bone fracture repair in mice. Adult C57BL/6 mice were subjected to transverse femoral fractures and administrated orally with 20 mg/kg osthole and vehicle solvent daily from week 1 post-operation. Fracture callus were analyzed by plain radiography, micro-computed tomography, histology, molecular imaging and immunohistochemistry and tartrate-resistant acid phosphatase staining. Results demonstrated that osthole treatment enhanced removal of cartilage and bony union during reparative stage without significant interfering on remodeling process. In vivo molecular imaging showed bone formation rate of the treatment group was almost twofold of control group at week 2 post-operation. Osthole augmented the expression of alkaline phosphatase and collagen type X in hypertrophic chondrocytes as well as expression of bone morphogenetic protein-2, osteocalcin and alkaline phosphatase in osteoblastic cells, indicating it promoted mineralization of hypertrophic cartilage and woven bone growth simultaneously during endochondral healing. In summary, osthole promotes endochondral ossification via upregulation of maturation osteogenic marker genes in chondrocytes and subsequently accelerates fracture repair and bony fusion., Competing Interests: Zhongrong Zhang, Wing Nang Leung, Gang Li, Yau Ming Lai and Chun Wai Chan declare that they have no conflict of interest. Ethical Approval All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Animal Experimentation Ethics Committee of the Chinese University of Hong Kong (Ref. No. 13/012/GRF).

The aim of the present study was to study the effect of combined therapy of teriparatide (PTH) or strontium ranelate (SR) with whole-body vibration (WBV) on bone healing and muscle properties in an osteopenic rat model. Seventy-two rats (3 months old) were bilaterally ovariectomized (Ovx), and 12 rats were left intact (Non-Ovx). After 8 weeks, bilateral transverse osteotomy was performed at the tibia metaphysis in all rats. Thereafter, Ovx rats were divided into six groups (n = 12): (1) Ovx-no treatment, (2) Ovx + vibration (Vib), (3) SR, (4) SR + Vib, (5) PTH, and (6) PTH + Vib. PTH (40 μg/kg BW sc. 5×/week) and SR (613 mg/kg BW in food daily) were applied on the day of ovariectomy, vibration treatments 5 days later (vertical, 70 Hz, 0.5 mm, 2×/day for 15 min) for up to 6 weeks. In the WBV + SR group, the callus density, trabecular number, and Alp and Oc gene expression were decreased compared to SR alone. In the WBV + PTH group, the cortical and callus widths, biomechanical properties, Opg gene expression, and Opg/Rankl ratio were increased; the cortical and callus densities were decreased compared to PTH alone. A case of non-bridging was found in both vibrated groups. Vibration alone did not change the bone parameters; PTH possessed a stronger effect than SR therapy. In muscles, combined therapies improved the fiber size of Ovx rats. WBV could be applied alone or in combination with anti-osteoporosis drug therapy to improve muscle tissue. However, in patients with fractures, anti-osteoporosis treatments and the application of vibration could have an adverse effect on bone healing.

Bimagrumab (BYM338) is a novel fully human monoclonal antibody that exerts strong promyogenic effects on skeletal muscle by blocking activin type II receptors (ActRII). We investigated whether such blockade of ActRII by bimagrumab manifests any detrimental effect on outcomes of bone healing in a rat fibula osteotomy model. Animals (n = 150) were divided into 11 groups and received weekly treatment with either bimagrumab (10 or 100 mg/kg) or vehicle. Progression and outcomes of bone healing were assessed by lateral radiographs in vivo as well as by peripheral quantitative computed tomography (pQCT), 4-point bending test, and microscopic examination of the excised fibula at Day 29 or later. The radiographic progression of bone healing showed no significant differences between treatment groups in any comparative setting. In 3-month-old animals, pQCT revealed slightly reduced immature callus size and bone mineral content in bimagrumab-treated animals compared with vehicle-treated animals at Day 29 (p < 0.05). There were, however, no differences in mature callus size, bone mineral density, or biomechanical competency. The aforementioned effects on immature callus size were not present when the treatment was initiated 4 weeks post osteotomy or when treating 6-month-old animals. In summary, these findings suggest that there is no major impact of ActRII blockade on overall fracture healing, and delayed treatment initiation can bypass the small and transient effect of the therapy on immature callus formation observed in younger animals. Verification of these findings in humans is the subject of an ongoing clinical trial on elderly hip fracture patients.

Purpose: The aim of this study is evaluation of the efficacy of the use of platelet rich plasma (PRP) in management of femoral neck fractures., Materials and Methods: This is a prospective study that was conducted between February 2010 and March 2013. A total of 60 patients were included in this study, categorized randomly into two groups. Group A included fracture neck femur treated by closed reduction and internal fixation with three cannulated screws and group B by addition of PRP to internal fixation. We planned to compare time of healing, need for revision and incidence of complications between the two groups., Results: Union occurred in 53 patients (88.33 %) in both groups, 25 cases (83.3 %) in group A and 28 cases (93.3 %) in group B, including three cases (5 %) with avascular necrosis (AVN): two in group A (6.7 %) and one case in group B (3.3 %).Revision surgery was done for six cases (20 %) in group A and for two cases (6.7 %) in group B. In both groups, all united cases had good to excellent clinical outcome as regards Harris hip score (HHS) at the end of the follow up., Conclusion: Despite advances in surgical techniques and medical care, the risk of nonunion and avascular necrosis (AVN) after treatment of femoral neck fractures have not been changed appreciably in the last 50 years. Results of this study generally showed that both the median clinical and radiographic healing time were lower in group B compared to group A.

Diabetic osteoporosis continues to surge worldwide, increasing the risk of fracture. We have previously demonstrated that haploinsufficiency of endogenous parathyroid hormone-related peptide (PTHrP) impairs fracture healing. However, whether an exogenous supply of PTHrP can repair bone damage and accelerate fracture healing remains unclear. This study aimed to assess the efficacy and safety of PTHrP in healing fractures. Standardized mid-diaphyseal femur fractures were generated in 12-week-old wild-type and leptin receptor null Lepr(-/-) mice. After administration of PTHrP for 2 weeks, callus tissue properties were analyzed by radiography, micro-computed tomography, histology, histochemistry, immunohistochemistry, and molecular biology techniques. At 2 weeks post-fracture, cartilaginous callus areas were reduced, while total callus and bony callus areas were increased in PTHrP-treated Lepr(-/-) animals and control wild-type mice, compared with vehicle-treated Lepr(-/-) mice. The following parameters were enhanced both in Lepr(-/-) mice after treatment with PTHrP and vehicle-treated wild-type animals, compared with vehicle-treated Lepr(-/-) mice: osteoblast numbers; tissue alkaline phosphatase (ALP) and Type I collagen immunopositive areas; mRNA levels of ALP, Type I collagen, osteoprotegerin, and receptor activator for nuclear factor-κ B ligand; protein levels of Runt-related transcription factor 2 and insulin-like growth factor-1; and the number and surface of osteoclasts. In conclusion, exogenous PTHrP by subcutaneous injection promotes fracture repair in Lepr(-/-) mice by increasing callus formation and accelerating cell transformation: upregulated osteoblastic gene and protein expression, increased endochondral bone formation, osteoblastic bone formation, and osteoclastic bone resorption. However, complete repair was not obtained in PTHrP-treated Lepr(-/-) mice as in control wild-type animals.

The following questions were addressed: whether therapy with strontium ranelate (SR) should be continued or interrupted if the fractures occur during SR treatment and whether SR could be applied directly after fracture to improve bone healing. Sprague-Dawley rats (3 month old) were ovariectomized (Ovx, n = 48) or left intact (n = 12). After 8 weeks, a bilateral transverse osteotomy of the tibia metaphysis was created in all rats. Ovx rats were divided into four groups: Ovx; SR applied directly after Ovx until osteotomy (prophylaxis, SR pr, 8 weeks); SR applied after osteotomy (therapy, SR th, 5 weeks); SR applied during the whole experiment (pr + th, 13 weeks). SR dosage was 625 mg/kg body weight/day, administered in the feed. Five weeks later, tibiae were analyzed by biomechanical, histological, micro-CT, and gene expression analyses. The SR pr + th treatment increased total bone mineral density (BMD), bone volume fraction, cortical BMD and volume, callus area and density, serum alkaline phosphatase, tartrate-resistant acid phosphatase mRNA, accelerated osteotomy bridging, and callus formation at weeks 2 and 3 of healing and decreased the osteoprotegerin/receptor activator of nuclear factor kB ligand mRNA ratio. SR th enlarged callus area and improved callus formation during the 5th week of healing. SR pr improved cortical BMD preserving bone after SR discontinuation (5-week rest); the bone healing was not affected. SR content in the tibia metaphysis was the highest in SR pr + th group and was not different between SR pr and SR th. SR has a positive effect on osteoporotic bone healing in rat and SR treatment can be continued after the fracture occurs or applied directly after the fracture.

We present the case of a 33-year-old male patient with multiple fractures and typical radiographical and clinical characteristics of osteogenesis imperfecta (OI) type III. Furthermore, the patient has suffered from hypogonadotropic hypogonadism since childhood. On the basis of antiresorptive therapy, no further fractures occurred within several years. Recently, recurrent nontraumatic fractures without bone healing were observed. Decreased bone mineral density was assessed by dual X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) showed impaired trabecular bone structure. Due to recurrent fragility fractures and severe deterioration of bone structure, an osteoanabolic treatment with teriparatide was initiated to potentially stimulate fracture healing and to increase bone formation.

About 5-10% of all bone fractures suffer from delayed healing, which may lead to non-union. Bone morphogenetic proteins (BMPs) can be used to induce differentiation of osteoblasts and enhance the formation of the bony callus, and bisphosphonates help to retain the newly formed callus. The aim of this study was to investigate if scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) can identify differences in the mineral composition of the newly formed bone compared to cortical bone from a non-fractured control. Moreover, we investigate whether the use of BMPs and bisphosphonates-alone or combined-may have an effect on bone mineralization and composition. Twelve male Sprague-Dawley rats at 9 weeks of age were randomly divided into four groups and treated with (A) saline, (B) BMP-7, (C) bisphosphonates (Zoledronate), and (D) BMP-7 + Zoledronate. The rats were sacrificed after 6 weeks. All samples were imaged using SEM and chemically analyzed with EDS to quantify the amount of C, N, Ca, P, O, Na, and Mg. The Ca/P ratio was the primary outcome. In the fractured samples, two areas of interest were chosen for chemical analysis with EDS: the callus and the cortical bone. In the non-fractured samples, only the cortex was analyzed. Our results showed that the element composition varied to a small extent between the callus and the cortical bone in the fractured bones. However, the Ca/P ratio did not differ significantly, suggesting that the mineralization at all sites is similar 6 weeks post-fracture in this rat model.

This study investigated the fracture-healing effects of α-lipoic acid (α-LA), which was applied orally once daily in preventive treatment mode during 1 month after fracture induction. Rats were randomly divided into sham-operated group (group 1), femoral fracture control (group 2), femoral fracture + 25 mg/kg α-LA (group 3), and femoral fracture + 50 mg/kg α-LA (group 4). Rats in the experimental groups were orally administered 25 or 50 mg/kg α-LA once daily for 30 days starting from postoperative day 1. Thirty days postoperatively, the rats underwent X-ray imaging and were then euthanized for blood and tissue collection. Histopathological, biochemical, molecular, computed tomography (CT), and mechanical strength tests were performed on samples. The serum levels of osteocalcin (OC), osteopontin (OP), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) did not differ significantly between groups 2 and 3. Serum OC, OP, TNF-α, and IL-6 levels in group 4 were significantly lower than those in group 3. From X-ray images, staging for fracture healing was scored as <2 in group 2, >2 in group 3, and >3 in group 4. In group 2, the average score of less than 2 suggests insufficient fracture healing; those of both the α-LA groups were >2, indicating progression of healing. Transforming growth factor beta (TGF-β) messenger RNA (mRNA) levels were significantly higher in the sham group than in the femoral fracture control. Both doses of α-LA increased TGF-β mRNA expression compared to the fracture group. CT results and biomechanical testing at 4 week after fracture demonstrated that α-LA has fastened bone healing, which was confirmed by stereological analyses in which 50 mg/kg α-LA increased the number of osteoclasts. Our findings indicate that α-LA supplementation promotes healing of femoral fractures in rats.

A systematic review and a meta-analysis of data of literature were performed to evaluate the efficacy of clodronate in the reduction of risk of fractures in patients with osteoporosis or tumour diseases. A systematic review was conducted to identify original articles, reviews, and any other literature report suitable for the purposes of the meta-analysis, limited to prospective randomized trials that included a placebo or an untreated control arm. The search has identified 18 trials, 13 of which in patients with cancer diseases (breast cancer and multiple myeloma were prevalent), 4 in patients with osteoporosis/low BMD, and 1 in elderly women living in community. A placebo control arm was used in 13 trials. Treatment and follow-up duration ranged from 3 months to 5 years. The meta-analysis showed that treatment with clodronate was associated with a reduction of the probability of new fractures compared with controls (OR = 0.572, 95% CI 0.465-0.704 for new vertebral fractures; OR = 0.668, 95% CI 0.494-0.905 for new non-vertebral fractures; and OR = 0.744, 95% CI 0.635-0.873 for new overall fractures in those articles where vertebral and non-vertebral new fractures were not considered separately). Similar findings were observed in the separate analysis in patients with cancer forms or osteoporosis. The results of the meta-analysis have demonstrated that clodronate is effective in reducing the risk of vertebral, non-vertebral, and overall fractures in patients with skeletal fragility.

Purpose: Minimally invasive techniques that introduce cement and bone substitutes inside the fractured vertebral body are a new treatment line with clinically proven efficacy. However, mechanical behaviours between different fillers throughout fracture evolution is yet to be clarified, as many substances are available for introduction into the vertebral body fracture., Methods: We comparatively studied biomechanical properties of tricalcium phosphate, tricalcium phosphate with bone morphogenetic protein (rhBMP-7) and autologous bone marrow aspirate with rhBMP-7 in vivo to determine what substance is optimal for repairing vertebral lesions in a porcine model. This biomechanical study was carried out with an Instron-type testing machine. Data registered were necessary strength to reach vertebral fracture [Newtons (N)], shortening (millimeters) of the vertebra, energy absorption until vertebral fracture (Joules) and vertebral unit stiffness., Results: For statistical study, we used the SPSS 16 package at a significance level of α = 0.05. In the presentation of the results, mean, standard deviation of mean, median and interquartile range (IQR) were analysed. Mean and standard deviation (SD) of strength in newtons (N) for the vertebral fracture are 756 N (SD = 253) in group 1, 1,500 N (SD = 1598) in group 2 and 1,230 N (SD = 1,598) in group 3. Stiffness after fracture was 229 N (SD = 123) in group 1, 277 N (SD = 135) in group 2 and 404 N (SD = 325) in group 3., Conclusions: The association of tricalcium phosphate and BMP-7 generates major vertebral resistance to external energy, the cause of such fractures. In such fractures, minor shortening occurs as soon as the vertebral body is fractured. Autologous bone marrow and BMP-7 provides increased biomechanical behavior, and the vertebral body is thus significantly strengthened.

Purpose: Despite the popularity and an increased use of bone morphogenetic protein to improve bone healing in patients with congenital pseudoarthrosis of the tibia (CPT), no previous study has compared its efficacy against any other procedure., Methods: We randomised 20 consecutive patients (mean age 4.1 years) with CPT (Crawford type IV) associated with neurofibromatosis type 1(NF1) and no previous history of surgery into two groups. Group 1 received recombinant human bone morphogenetic protein-7 (rhBMP-7) along with intramedullary Kirschner (K)-wire fixation and autologous bone grafting; group 2 received only K wire and grafting. Outcome measures were time to achieve union, Johnston grade, tibial length and the American Orthopaedic Foot and Ankle Society (AOFAS) score, which were evaluated preoperatively and at five year follow-up., Results: Study results showed that patients in group 1 achieved primary bone union at a mean of 14.5 months [standard error (SE) 5.2], whereas group 2 took a mean of 17.11 months (SE 5.0). However, the log-rank test showed no difference in healing times between groups at all time points (P = 0.636). There was a statistically significant pre- to post operative improvement (P < 0.05) within groups for the other outcome measures., Conclusion: In a five year follow-up, these results suggest that rh-BMP-7 and autologous bone grafting is no better than autologous grafting alone.

Purpose: Increasing numbers of atypical femoral fractures have been reported among long-term bisphosphonate users. We evaluated clinical characteristics of atypical femoral fractures throughout Korean multicenter studies., Methods: We retrospectively analysed the bone mineral density, prodromal symptoms before femoral fracture, and medication history of osteoporosis in 76 cases of atypical femoral fracture., Results: The mean age of cases was 71.4 ± 8.8 (range, 43-89) years old. The mean follow-up period after the fracture operation was 24.5 ± 12.9 (range, 12-79) months. BMI was 23.2 ± 3.0 on average. The mean BMD of femur was -1.9 ± 1.4 (range, -4.8 to 1.3). Prodromal symptoms including thigh pain before femoral fracture appeared in 22 (28.9 %) of 76 patients. All patients included in the study used bisphosphonate. The duration of taking bisphosphonate before fracture was 36.8 ± 50.8 (one-204 months) months. Fifty-seven (75 %) of 76 patients were taking the medication for more than three years. Delayed union occurred in 43 (56.5 %) of 76 patients. Delayed union was defined as a fractured bone that did not completely heal within six months of injury. The group of having taken anti-osteoporotic medication for more than three years showed relatively longer union period compared to that for a shorter period medication group (4.8 ± 2.5 months vs 9.3 ± 3.7 months, p = 0.017). The delayed union developed in 43 (56.5 %) of 76 patients and showed a significantly higher incidence in the group with long-term therapy (five/43 vs 38/43, p = 0.021). The bilateral femoral fractures developed in 23 (30.2 %) of 76 patients and showed a high incidence in the group medicated more than three years (two/23 vs 21/23, p = 0.039)., Conclusions: The longer bisphosphonates are used, the more the cases of delayed union and the more frequent the development of bilateral fractures following unilateral fractures. With regard to the delayed union, the methods of the acceleration of fracture healing may be beneficial in atypical femoral fracture patients who had been receiving long-term bisphosphonates therapy. Careful observation is required for contra-lateral femurs due to a high incidence of bilateral atypical femoral fractures.

Background: A number of medications are approved for treatment of osteoporosis. As mode of action usually is anti-catabolic/anti-resorptive or anabolic, it is of interest to know whether these drugs affect not only normal bone remodeling, but also fracture healing., Objective: The purpose of this paper is to give a short overview of the potential effect of various anti-osteoporotic medication on fracture healing., Methods: A narrative literature review was performed to describe the current knowledge., Results: Anti-catabolic/anti-resorptive drugs: for bisphosphonates, the most common class of drugs in this group, experimental studies have shown a larger and stronger callus and delayed remodeling but no evidence of delayed healing. A human monoclonal antibody to RANKL is another anti-catabolic drug, with the only report to date showing enhanced healing in an animal model. Strontium ranelate is a drug where both anti-catabolic and a weak anabolic effect have been proposed, with experimental data ranging from no effect to significant increase in both callus volume and strength. Anabolic drugs: PTH has demonstrated accelerated healing of various experimental fractures and of distal radius and pelvic fractures in humans. While the exact mechanism is not fully understood, PTH results in increased recruitment and differentiation of chondrocytes and enhancement of endochondral ossification. A monoclonal antibody to block sclerostin is another potential anabolic pathway, where animal data have shown increase in bone mass and strength. The potential effect on fracture healing is yet to be studied., Conclusion: There are still large gaps in the understanding of the potential effect of anti-osteoporotic drugs on fracture healing, although based on present knowledge a recent or present fracture should not be considered as a contraindication to such treatment.

Introduction: Osteoporosis-related hip fractures are associated with high mortality and costs. The optimum type of treatment for such fractures is controversial. To shed some light on this issue, the surgical treatment and management of osteoporotic hip fractures were discussed during a hip fracture surgical working group at the 2009 International Society For Fracture Repair Annual Meeting comprising leading experts in the field., Materials and Methods: The working group consisted of eight orthopaedic surgeons, six industry representatives and one research scientist. Eleven participants were from Europe and four were from the USA and Canada. Two chairmen posed 12 questions relating to the surgical treatment and management of osteoporotic hip fractures. Each question was discussed and key points were noted., Results: Surgery should commence within 24-48 h but the patient should be optimized if presenting with ≥3 comorbidities. Specialized centres integrating orthopaedics, geriatricians and rheumatologists could be a solution for the lack of specialist care post-surgery. Surgical technique is important in fracture fixation, as is the implant, but there has been no improvement in implant design in the past 50 years. As a consequence, malunion has become unjustifiably accepted. Fracture healing can be accelerated using pharmaceuticals which are also important in secondary prophylaxis. All displaced femoral neck fractures in geriatric patients should be treated with hip replacement, the choice between using cemented or uncemented fixation being at the surgeon's discretion., Discussion and Conclusion: This working group discussion highlighted several important issues which could be of interest to the orthopaedic community.

Purpose: The purpose of this study was to evaluate the impact of tobacco abuse in the consolidation of fractures., Methods: We retrospectively identified all patients with a diaphyseal fracture (femur, tibia, or humerus), between January 1999 and December 2010, in our orthopaedic trauma registry (Erasme hospital, Brussels, Belgium). Thirty-eight diaphyseal nonunions (ten femurs, 16 tibias and 12 humerus) were identified. Each nonunion was paired (on age, sex and location) with two control-healed fractures (76 control patients). The chi-squared test and a binary logistic regression were used for statistical analysis., Results: In multivariate analysis, smoking (tobacco use) was significantly associated with nonunion, whether the fracture was open or closed (p < 0.01). In univariate analysis, open fracture was associated with a higher risk of nonunion (p < 0.05), while external fixation was associated with better bone healing (p < 0.05)., Conclusion: Tobacco is confirmed as a deleterious factor for diaphyseal bone healing.

Objectives: Both inflammation and angiogenesis are crucial for normal fracture healing. The goal of this work was to determine how anti-inflammatory treatment affects angiogenesis during early stages of fracture repair., Methods: Tibia fractures were created in adult mice and animals were treated with indomethacin (2 mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6 days after fracture. Animals were killed at 7, 14, and 28 days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7 days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7 days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization., Results: Indomethacin significantly decreased bone and cartilage formation at 7 days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3 days after fracture but did not affect the recruitment of macrophages or neutrophils to injured limbs. Indomethacin-treated fractures had similar length density and surface density of vasculature as the controls at 3 days after injury. At 7 days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28 days after injury, indomethacin-treated fractures still exhibited defects in fracture repair., Conclusions: Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.

Proton pump inhibitors (PPIs), which are widely used in the treatment of dyspeptic problems, have been shown to reduce osteoclast activity. There is no information, however, on whether PPIs affect fracture healing. We therefore studied the effect of the PPI pantoprazole on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analyses at 2 and 5 weeks after fracture. Twenty-one mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls (n = 21) received equivalent amounts of vehicle. In pantoprazole-treated animals biomechanical analysis revealed a significantly reduced bending stiffness at 5 weeks after fracture compared to controls. This was associated with a significantly lower amount of bony tissue within the callus and higher amounts of cartilaginous and fibrous tissue. Western blot analysis showed reduced expression of the bone formation markers bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich protein (CYR61). In addition, significantly lower expression of proliferating cell nuclear antigen indicated reduced cell proliferation after pantoprazole treatment. Of interest, the reduced expression of bone formation markers was associated with a significantly diminished expression of RANKL, indicating osteoclast inhibition. Pantoprazole delays fracture healing by affecting both bone formation and bone remodeling.

Background: Complex patterns of impaired bone healing can result in a severe economic and social burden for the patient. Herein we describe the local application of recombinant human bone morphogenetic protein 7 (BMP-7). The goal of this prospective study is to review the indications, application and validation of this therapy., Material and Method: From June 2002 to June 2008, we applied 101 BMP-7 treatments in 101 nonunions of 98 patients. The average age of the patients was 50 years (18-88 years). The gender composition was 29 women (30%) and 69 men (70%). Before BMP-7 application, patients had already underwent surgical treatement an average of 3.3 times (median 3, 1- to 13-times). We used BMP-7 "off-label" in all long bones., Results: In 93 cases (92%), we observed proper bone healing. The average healing time was 4.8 months (range 1.5-11 months). The average time from injury to BMP-7 application was 18.4 months (3-84 months). In 65 cases, BMP-7 application was combined with re-osteosynthesis and autologous bone grafting. Serious side effects were not observed., Conclusions: BMP-7 should not be used as general treatment of nonunion in all patients, but appears to be effective for the treatment of complex cases. In clinical practice, the decision to proceed with off-label use of BMP-7 should be made on a case-by-case basis.

Purpose: Anticoagulant therapy with low molecular weight heparins (LMWH) and mechanical compression is considered the gold standard for the prevention of thrombosis. However, evidence exists that LMWHs impair bone metabolism. The aim of this study was therefore to analyse alterations in the expression of M-CSF, VEGF and TGF-ß1 after treatment with enoxaparin in patients with long bone fracture to investigate the effect of LMWH on human fracture healing., Methods: A total of 81 patients with long bone fractures were included in the study and divided into two groups. One group comprised patients who received enoxaparin and the other group, patients who did not receive enoxaparin postoperatively. Growth factor levels were analysed in patients' serum and different groups were retrospectively compared., Results: M-CSF serum concentrations were found to be significantly higher only at 48 weeks after surgery in enoxaparin. Mean overall VEGF serum concentration was higher in patients with enoxaparin. TGF-β1 serum concentrations were higher at 48 weeks after surgery in patients with enoxaparin., Conclusion: This is the first comparative systemic measurement of M-CSF, VEGF and TGF-ß1 serum levels in patients with and without enoxaparin after long bone fracture. Significant differences of the expression of the growth factors after enoxaparin therapy were only observed at week 48 after surgery for M-CSF and TGF-ß1.

Osteoporotic fracture healing is critical to clinical outcome in terms of functional recovery, morbidity, and quality of life. Osteoporosis treatments may affect bone repair, so insights into their impact on fracture healing are important. We reviewed the current evidence for an impact of osteoporosis treatments on bone repair. Treatment with bisphosphonate in experimental models is associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. Experimental data for denosumab and raloxifene suggest no negative implications for bone repair. The extensive experimental results for teriparatide indicate increased callus formation, improved biomechanical strength, and greater external callus volume and total bone mineral content and density. Case reports and a randomized trial have produced mixed results but are consistent with a positive impact of teriparatide on clinical fracture healing. Studies with strontium ranelate in models of fracture healing indicate that it is associated with improved bone microstructure, callus volume, and biomechanical properties. Finally, there is experimental evidence for a beneficial effect of some of the agents currently being developed for osteoporosis, notably sclerostin antibody and DKK1 antibody. There is currently no evidence that osteoporosis treatments are detrimental for bone repair and some promising experimental evidence for positive effects on healing, notably for agents with a bone-forming mode of action, which may translate into therapeutic applications.

The effects of bisphosphonate treatment schedule on fracture healing have not previously been tested. We evaluated the effect of ibandronate dosing interval duration on healing following surgical "fracture" (osteotomy) using a rat femoral fracture model. Six-week-old rats (n = 160) underwent osteotomy and were then allocated into vehicle control (CNT) or an ibandronate treatment group: 5 μg/kg daily (DAY, 5 days/week), 75 μg/kg once every 3 weeks (I-3), 150 μg/kg once every 6 weeks (I-6), resulting in the same total ibandronate dose over the study. Rats were killed after 6 or 18 weeks. At 18 weeks, all fracture lines had disappeared in the CNT and I-6 groups; approximately 10% of fracture lines remained in the DAY and I-3 groups. Ibandronate-treated groups showed large callus areas around the fractures, which shrank between 6 and 18 weeks after surgery; the extent of shrinkage decreased with shorter dosing interval. In histomorphometry, callus remodeling was suppressed by ibandronate; this became more apparent at shorter dose intervals. The structural properties of osteotomized femora were increased in the DAY group compared with CNT, but intrinsic material properties reduced inversely and became closer to those of CNT in response to increased dosing interval. Ibandronate induced formation of large calluses around osteotomies but delayed woven bone remodeling into lamellar bone and reduced intrinsic material properties in a rat fracture model. Extending the dosing interval of intermittent ibandronate treatment appeared to reduce the suppression of callus remodeling caused by ibandronate, which would have delayed healing after osteotomy.

Purpose: This review evaluates the application of bone morphogenetic proteins (BMPs) in delayed bone repair, aiming at a broad audience from clinicians to scientists. Next to an overview of the role of the different BMPs, their antagonists and their current applications, special attention is focused on new scientific developments improving the effects of BMP-based therapy for bone repair., Methods: Publication searches in PubMed and Embase revealed 850 relevant articles on the criteria 'BMP' AND 'bone repair' (as of May 2011). The abstracts were carefully reviewed and papers were selected according to the content., Results: The resulting publications showed that BMP-2 and BMP-7 are clearly the most extensively evaluated BMPs, in general with positive results on bone healing, comparable to the use of unspecific preparations such as autologous bone grafts or platelet-rich plasma., Conclusions: Although the efficacy of BMPs as stimulators of bone repair has been demonstrated in model systems and clinical studies, the use of BMPs to enhance fracture healing in the clinical setting is still controversial. Issues such as when, where and how much of which BMP is the most effective and profitable to use still have to be elucidated. But optimisation of the BMP products used in combination with cheaper production methods will inevitably stimulate the clinical use of BMPs for bone fracture healing in the near future.

Purpose: This review was written to analyse the potential role of the cholinergic anti-inflammatory pathway in smoking-induced impairment of the bone healing process., Methods: Literature in PubMed was reviewed by entering the following keywords "smoking AND bone healing", "cholinergic anti-inflammatory pathway AND tumour necrosis factor", "tumour necrosis factor AND bone healing". All the related papers were recruited and carefully selected according to the content of this paper., Results: Literature review indicated that tumour necrosis factor alpha (TNF-α) plays a pivotal role in the fracture healing process. In brief, TNF-α may accelerate the endochondral ossification process by increasing matrix metalloproteinases (MMPs) level, chondrocyte apoptosis, as well as osteoclast formation, therefore reducing the cartilaginous stage leading to the acceleration of fracture healing. Nicotine is the main effective ingredient of tobacco, which has been found to inhibit the secretion of TNF-α through activation of the cholinergic anti-inflammatory pathway., Conclusions: It is reasonable to believe that the nicotine in tobacco at least partly contributes to the delayed fracture healing by inhibiting TNF-α secretion through the activation of the cholinergic anti-inflammatory pathway. An in-depth study of this issue will contribute to the clinical treatment of nonunion, as well as the development of new therapies to accelerate bone healing.

Fracture consolidation is a crucial goal to achieve as early as possible, but pharmacological stimulation has been neglected so far. Teriparatide has been considered for this purpose for its anabolic properties. We set up a murine model of closed tibial fracture on which different doses of teriparatide were tested. Closed fracture treatment avoids any bias introduced by surgical manipulations. Teriparatide's effect on callus formation was monitored during the first 4 weeks from fracture. Callus evolution was determined by histomorphometric and microhardness assessment. Daily administration of 40 μg/kg of teriparatide accelerated callus mineralization from day 9 onward without significant increase of sizes, and at day 15 the microhardness properties of treated callus were similar to those of bone tissue. Teriparatide considerably improved callus consolidation in the very early phases of bone healing.

Clinical management of delayed healing or nonunion of long bone fractures and segmental bone defects poses a substantial orthopaedic challenge. Surgical advances and bone tissue engineering are providing new avenues to stimulate bone growth in cases of bone loss and nonunion. The reamer-irrigator-aspirator (RIA) device allows surgeons to aspirate the medullary contents of long bones and use the progenitor-rich "flow-through" fraction in autologous bone grafting. Dexamethasone (DEX) is a synthetic steroid that has been shown to induce osteoblastic differentiation. A series of 13 patients treated with RIA bone grafting enhanced with DEX for nonunion or segmental defect was examined retrospectively to assess the quality of bony union and clinical outcomes. Despite the initial poor prognoses, promising results were achieved using this technique; and given the complexity of these cases the observed success is of great value and warrants controlled study into both standardisation of the procedure and concentration of the grafting material.

Bone extract from reindeer induces new ectopic bone formation (BF) in muscle pouches, but its feasibility in experimental bone lesions has not been evaluated. We investigated the effects of implants, containing 2, 5, 15, 20 or 50 mg of reindeer bone extract in a collagen carrier, on the healing of 8-mm femur defects in 78 rats. We used 30 µg of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a collagen carrier, collagen and untreated defects as controls. Bone healing was evaluated with radiographs, peripheral quantitative computed tomography (pQCT), biomechanics and histology. In comparison with empty defects, the groups receiving bone extracts showed more BF at three weeks and had better bone union (BU), larger mean cross-sectional bone area at the defect site in groups receiving higher doses of extract, showed greater torsional stiffness of the bones and higher maximum breaking load of bones at six weeks. In comparison to all other groups, in the rhBMP-2 group, BF and BU were best at the three- and six-week follow-up, bone area was largest and mechanical test results were best. Although rhBMP-2 is superior for new bone regeneration, native reindeer bone extract is also effective in the six-week follow-up period.

Strontium ranelate (SrR) is a new agent used in the treatment of osteoporosis and is suggested to reduce bone resorption and increase bone formation. We investigated whether SrR influences the macro- and nanomechnical properties of healing fractures in rats. A closed tibia fracture model was used to study fracture healing in rats after 3 and 8 weeks of healing. Two groups of rats were treated with SrR (900 mg/kg/day) mixed into the food, while two groups served as control animals. The healing fractures were investigated by three-point bending, dual energy X-ray absorptiometry, energy-dispersive X-ray spectroscopy (EDX), and nanoindentation. There was a 100-fold increase (P < 0.001) in serum Sr after 3 and 8 weeks of SrR treatment. The callus volume was significantly higher in the SrR-treated group than in control animals (P < 0.01) after 3 weeks of healing. This was accompanied by a significant increase in callus bone mineral content (P < 0.05). However, after 8 weeks of healing, no difference was found in either callus volume or bone mineral content. SrR did not influence maximum load or stiffness of the fractures after either 3 or 8 weeks of healing. EDX showed that Sr was incorporated into the callus; however, this did not influence the nanomechanical properties. In conclusion, SrR stimulates callus formation but has no effect on callus remodeling. Sr is incorporated into the newly formed callus tissue, but this has no deteriorating effect on the mechanical properties of rat tibial fractures at either the macroscopic or nanoscopic level after 3 or 8 weeks of healing.

Two cases of increased bone density after callus distraction are described following percutaneous administration of 3.5 mg recombinant bone morphogenetic protein-7 (rhBMP-7). Both patients underwent segmental resection and segmental transport for osteomyelitis of the long bones (femur and tibia) but no callus maturation occurred. After percutaneous administration of rhBMP-7 the callus density increased in both cases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for postoperative pain control. However, concerns regarding the potential deleterious effects of NSAIDs on bone healing have compelled many physicians to avoid NSAIDs in patients with healing fractures, osteotomies, and fusions. We systematically reviewed and analyzed the best clinical evidence regarding the effects of NSAID exposure on bone healing. Medline, Embase, and Cochrane electronic databases were searched for prospective and retrospective clinical studies of fracture, osteotomy, and fusion studies of patients with NSAID exposure and nonunion as an outcome. Study quality was assessed using the Newcastle-Ottawa Scale. Data on study design, patient characteristics, and risk estimates were extracted. Pooled effect estimates were calculated. Subanalyses were performed by bone type and by NSAID dose, duration, and route of administration. In the initial analysis of 11 cohort and case-control studies, the pooled odds ratio for nonunion with NSAID exposure was 3.0 (95% confidence interval 1.6-5.6). A significant association between lower-quality studies and higher reported odds ratios for nonunion was observed. When only higher-quality studies were considered, seven spine fusion studies were analyzed, and no statistically significant association between NSAID exposure and nonunion was identified (odds ratio = 2.2, 95% confidence interval 0.8-6.3). There was no increased risk of nonunion with NSAID exposure when only the highest-quality studies were assessed. Randomized controlled trials assessing NSAID exposure in fracture, fusion, and osteotomy populations are warranted to confirm or refute the findings of this meta-analysis of observational studies.

Long-term use of glucocorticoid (GC) not only reduces bone mass and strength, which leads to a greater risk of fracture, but also hinders fracture repair. In this study, we produced open fractures in GC-treated mice and investigated the effects of human parathyroid hormone 1-34 (hPTH) on fracture repair. Swiss-Webster mice were randomly divided into five groups. Three groups of GC-treated mice were given prednisolone, which was slowly released from subcutaneously implanted pellets at the rate of 1.4 mg/kg/day. Placebo pellets were implanted into the animals in two placebo groups. Three weeks later, osteotomies at the midshaft femora were performed and intramedullary pins were inserted to stabilize the fracture site under general anesthesia. Following fracture surgery, three GC groups were treated subcutaneously with vehicle, PTH at a low dose (40 ug/kg/day), and PTH at a high dose (80 ug/kg/day), respectively. Two placebo groups were given vehicle and PTH at a dose of 40 ug/kg/day, respectively. Radiographs, dual-energy X-ray absorptiometry, and mechanical testing (four-point bending) were used to evaluate fracture repair at 4 weeks after fracture surgery. Callus development, endochondral ossification, and recovery of mechanical strength at the fracture sites in GC animals treated with vehicle were significantly suppressed compared to placebo animals. Normally, PTH accelerates fracture repair. In GC-treated mice, PTH fails to improve endochondral ossification and mechanical properties compared to vehicle treatment, suggesting that the anabolic effect of PTH on fracture healing can be attenuated by GC administration in mice.

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.

Platelet-rich plasma (PRP), a platelet concentrate made of autogenous blood, has been used to improve bone and soft tissue defect healing in recent years. The aim of this study was to assess the effect of PRP on articular cartilage defects in a rabbit model. Forty-eight osteochondral defects created in the femoropatellar groove were (a) left untreated, (b) treated with autogenous PRP in a poly-lactic-glycolic acid (PLGA), or (c) with PLGA alone. Platelets were enriched 5.12-fold compared to normal blood in the PRP. After four and 12 weeks, the explanted tissue specimens were assessed by macroscopic examination, micro-computed tomography, and histological evaluation. Macroscopic examination, micro-computed tomography and histology of the newly formed cartilage and bone in the defect differ significantly between the PRP-treated and the untreated groups, and stimulatory effect of PRP on osteochondral formation was observed. In conclusion, PRP in PLGA improves osteochondral healing in a rabbit model.