Stimulation of angiogenesis by cilostazol accelerates fracture healing in mice

Cilostazol, a selective phosphodiesterase‐3 inhibitor, is known to control cyclic adenosine monophosphate (c‐AMP) and to stimulate angiogenesis through upregulation of pro‐angiogenic factors. There is no information, however, whether cilostazol affects fracture healing. We, therefore, studied the effect of cilostazol on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine femur fracture stabilized with an intramedullary screw. Radiological, biomechanical, histomorphometric, histochemical, and protein biochemical analyses were performed at 2 and 5 weeks after fracture. Twenty‐five mice received 30 mg/kg body weight cilostazol p.o. daily. Controls (n = 24) received equivalent amounts of vehicle. In cilostazol‐treated animals radiological analysis at 2 weeks showed an improved healing with an accelerated osseous bridging compared to controls. This was associated with a significantly higher amount of bony tissue and a smaller amount of cartilage tissue within the callus. Western blot analysis showed a higher expression of cysteine‐rich protein 61 (CYR61), bone morphogenetic protein (BMP)‐4, and receptor activator of NF‐kappaB ligand (RANKL). At 5 weeks, improved fracture healing after cilostazol treatment was indicated by biomechanical analyses, demonstrating a significant higher bending stiffness compared to controls. Thus, cilostazol improves fracture healing by accelerating both bone formation and callus remodeling. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1880–1887, 2015.     

Dermal fibroblast‐mediated BMP2 therapy to accelerate bone healing in an equine osteotomy model

This study evaluated healing of equine metacarpal/metatarsal osteotomies in response to percutaneous injection of autologous dermal fibroblasts (DFbs) genetically engineered to secrete bone morphogenetic protein‐2 (BMP2) or demonstrate green fluorescent protein (GFP) gene expression administered 14 days after surgery. Radiographic assessment of bone formation indicated greater and earlier healing of bone defects treated with DFb with BMP2 gene augmentation. Quantitative computed tomography and biomechanical testing revealed greater mineralized callus and torsional strength of DFb‐BMP2‐treated bone defects. On the histologic evaluation, the bone defects with DFb‐BMP2 implantation had greater formation of mature cartilage and bone nodules within the osteotomy gap and greater mineralization activity on osteotomy edges. Autologous DFbs were successfully isolated in high numbers by a skin biopsy, rapidly expanded without fastidious culture techniques, permissive to adenoviral vectors, and efficient at in vitro BMP2 protein production and BMP2‐induced osteogenic differentiation. This study demonstrated an efficacy and feasibility of DFb‐mediated BMP2 therapy to accelerate the healing of osteotomies. Skin cell‐mediated BMP2 therapy may be considered as a potential treatment for various types of fractures and bone defects. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:403–411, 2010     

Shear movement at the fracture site delays healing in a diaphyseal fracture model.

This study tested the hypothesis that interfragmentary axial movement of transverse diaphyseal osteotomies would result in improved fracture healing compared to interfragmentary shear movement. Ten skeletally mature merino sheep underwent a middiaphyseal osteotomy of the right tibia, stabilized by external fixation with an interfragmentary gap of 3 mm. A custom made external fixator allowed either pure axial (n=5) or pure shear movement (n=5) of 1.5 mm amplitude during locomotion by the animals. The movement of the osteotomy gap was monitored weekly in two sheep by an extensometer temporarily attached to the fixator. After 8 weeks the sheep were killed, and healing of the osteotomies was evaluated by radiography, biomechanical testing, and undecalcified histology. Shear movement considerably delayed the healing of diaphyseal osteotomies. Bridging of the osteotomy fragments occurred in all osteotomies in the axial group (100%), while in the shear group only three osteotomies (60%) were partially bridged. Peripheral callus formation in the shear group was reduced by 36% compared to the axial group (p<0.05). In the axial group bone formation was considerably larger at the peripheral callus and in between the osteotomy gaps but not in the intramedullary area. The larger peripheral callus and excess in bone tissue at the level of the gap resulted in a more than three times larger mechanical rigidity for the axial than for the shear group (p<0.05). In summary, fixation that allows excessive shear movement significantly delayed the healing of diaphyseal osteotomies compared to healing under axial movement of the same magnitude.     

An internal locking plate to study intramembranous bone healing in a mouse femur fracture model

In most murine fracture models, the femur is stabilized by an intramedullary implant and heals predominantly through endochondral ossification. The aim of the present study was to establish a mouse model in which fractures heal intramembranously. Femur fractures of 16 SKH‐mice were stabilized by an internal locking plate. Femur fractures of another 16 animals were stabilized by an intramedullary screw. Bone repair was analyzed by radiographic, biomechanical, and histological methods. At 2 weeks, histological analysis showed a significantly smaller callus diameter and callus area after locking plate fixation. Cartilage formation within the callus could only be observed after screw fixation, but not after fracture stabilization with the locking plate. Radiological and biomechanical analysis after 2 and 5 weeks showed a significantly improved healing and a higher bending stiffness of fractures stabilized by the locking plate. Fractures stabilized by the locking plate healed exclusively by intramembranous ossification, which is most probably a result of the anatomical reduction and stable fixation. The fractures that healed by intramembranous ossification showed an increased stiffness compared to fractures that healed by endochondral ossification. This model may be used to study molecular mechanisms of intramembranous bone healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:397–402, 2010     

A novel mouse model to study fracture healing of the proximal femur

The majority of fractures, especially in elderly and osteoporotic patients, occurs in metaphyseal bone. However, only a few experimental models exist to study metaphyseal bone healing in mice. Currently used mouse models of metaphyseal fracture healing are either based on drill hole defects, lacking adequate biomechanical stimulation at the site of fracture and therefore endochondral ossification in the fracture callus, or are introduced into the distal part of the mouse femur stabilized by a locking plate, which is challenging due to the small specimen size. Therefore, the aim of the current study was to develop a new mouse model to study metaphyseal fracture healing of the proximal femur. We chose a combination between an open osteotomy and a closed intramedullary stabilization. A 24 G needle was inserted into the femur in a closed manner, then an osteotomy was made with a 0.4-mm Gigli wire saw between the third and the lesser trochanter of the femur using an open approach. Fractured femurs were analyzed using microcomputed tomography and histology at days 14 and 21 after surgery. No animals were lost due to surgery or anesthesia. All animals displayed normal limb loading and a physiological gait pattern within the first three days after fracture. We found robust endochondral ossification during the fracture healing process with high expression of late chondrocyte and early osteogenic markers at day 14 (d14). By day 21 (d21), all fractures had a bony bridging score of 3 or more, indicating successful healing. Callus volume significantly decreased from d14 to d21, whereas high numbers of osteoclasts appeared at the fracture callus until d21, indicating that callus remodeling had already started at d21. In conclusion, we successfully developed a novel mouse model to study endochondral fracture healing of the proximal femur. This model might be useful for future studies using transgenic animals to unravel molecular mechanisms of osteoporotic metaphyseal fracture healing.     

Effect of Stabilization on the Healing Process of Femur Fractures in Aged Mice

Background: The influence of mechanical stability on fracture healing has previously been studied in adult mice, but is poorly understood in aged animals. Therefore, we herein studied the effect of stabilization on the healing process of femur fractures in aged mice. Methods: Twenty-four 18-month-old CD-1 mice were stabilized after midshaft fracture of the femur with an intramedullary screw. In another 24 18-month-old mice, the femur fractures were left unstabilized. Bone healing was studied by radiological, biomechanical, histomorphometric, and protein expression analyses. Results: After 2 and 5 weeks of healing, the callus of nonstabilized fractures compared to stabilized fractures was significantly larger, containing a significantly smaller amount of osseous tissue and a higher amount of cartilaginous tissue. This was associated with a significantly lower biomechanical stiffness during the early phase of healing. However, during the late phase of fracture healing both nonstabilized and stabilized fractures showed a biomechanical stiffness of ～40%. Of interest, Western blot analyses of callus tissue demonstrated that the expression of proteins related to angiogenesis, bone formation and remodeling, i.e. VEGF, CYR61, BMP-2, BMP-4, Col-2, Col-10, RANKL, OPG, did not differ between nonstabilized and stabilized fractures. Conclusion: Nonstabilized fractures in aged mice show delayed healing and remodeling. This is not caused by an altered protein expression in the callus but rather by the excessive interfragmentary movements.     

Comparison of healing process in open osteotomy model and closed fracture model

OBJECTIVE: Comparison of the healing process in open osteotomy and closed fracture models that were used to study fracture healing. DESIGN: Randomized, prospective study in experimental animals, with a recovery duration of two and four weeks. SETTING: Unrestricted cage activity with weight bearing as tolerated. ANIMALS: Thirty-four skeletally mature, female New Zealand White rabbits. INTERVENTIONS: Closed fractures and open osteotomies of the tibial diaphysis were reduced and immobilized with four-pin, double-bar external fixators. MAIN OUTCOME MEASUREMENTS: Callus circumference was measured with a tape measure, bridging callus was assessed on biplane radiographs and evaluated histologically, and torsional stiffness and maximum torque were measured. RESULTS: Periosteum damage was more severe and hematoma formation was smaller in the osteotomy model, resulting in a delay in biological healing and restoration of the biomechanical properties. CONCLUSIONS: Investigators should consider the difference between the closed fracture and open osteotomy models when selecting an animal model to investigate fracture healing.     

Effect of repeated irrigation and debridement on fracture healing in an animal model.

The initial management of open fractures often requires repeated irrigation and debridement of the open wound and stabilization of the fracture. However, washing out the fracture hematoma could delay the early healing process of stable fractures. Because delayed union and non-union are serious complications, the effect of repeated irrigation and debridement on the fracture healing process was investigated. Twenty-four rabbits received unilateral, transverse. mid-tibial open osteotomies with a 3 mm gap. The osteotomy site was thoroughly irrigated and stabilized with double-bar external fixators. The osteotomy sites in the study groups underwent repeat irrigation and debridement on either the third day (Group II), the fourth day (Group III), or consecutively on the first and second days (Group IV) after the index procedure. The bone healing was assessed with weekly radiographs and peripheral quantitative computerized tomographs. In Group I (control), all osteotomies healed radiographically before the tenth week. In Group II, five out of six osteotomies healed radiographically before the tenth week. In Group III, only two of five osteotomies healed before the tenth week. In Group IV, none of the osteotomies had healed by week fifteen. All of the non-healed osteotomies exhibited atrophic non-unions at fifteen weeks. Compared to the control group at the tenth week, the average bone mineral content at the osteotomy site and the area of high mineral density callus (> or = 890 mg/cm3) were significantly lower in Groups III (63%, p = 0.002 and 95%, p = 0.05, respectively) and IV (99%, p < 0.001 and 100%, p = 0.05, respectively). The results of this study suggest that repeated irrigation and debridement, associated with persistent rigid immobilization, may contribute to the development of delayed unions or atrophic non-unions.     

Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate.

This study evaluated factors influencing fracture (n = 197) and osteotomy (n = 200) healing in children with moderate to severe OI. Pamidronate treatment was associated with delayed healing after osteotomy, but not after fracture. The data suggest that both pamidronate and mechanical factors influence bone healing in this cohort. INTRODUCTION: Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). However, the effect of this treatment on bone healing is not well characterized. We therefore retrospectively analyzed the healing of lower limb fractures and osteotomies in children with moderate to severe OI, both before and after the start of pamidronate treatment. MATERIALS AND METHODS: Bone healing was evaluated on standard radiographs after 197 lower limb fractures (132 femur and 65 tibia) in 82 patients (age at fracture, 0.0-19.9 years) and 200 intramedullary rodding procedures in 79 patients (age at surgery, 1.2-19.8 years). Delayed healing was diagnosed when a fracture or osteotomy line was at least partially visible 12 months after the event. RESULTS: Delayed fracture healing was observed more frequently during than before pamidronate treatment. However, the effect of pamidronate was no longer significant when age differences were taken into account (odds ratio [OR], 1.76; 95% CI, 0.61-5.10). Better mobility status was a strong independent predictor of delayed healing after fractures that occurred during pamidronate treatment. After osteotomies, delayed healing was more frequent when pamidronate had been started before surgery (OR, 7.29; 95% CI, 2.62-20.3), and this effect persisted after adjustment for multiple confounders. During pamidronate treatment, older age (OR per year of age, 1.25; 95% CI, 1.06-1.47) and osteotomy of the tibia (OR, 3.51; 95% CI, 1.57-7.82) were independent predictors of delayed healing. CONCLUSIONS: This study suggests that pamidronate therapy is associated with delayed healing of osteotomy sites after intramedullary rodding procedures. Better mobility status, but not pamidronate treatment, seems to be predictive of delayed healing after fractures.     

Osteogenic gene regulation and relative acceleration of healing by adenoviral‐mediated transfer of human BMP‐2 or ‐6 in equine osteotomy and ostectomy models

This study evaluated healing of equine metatarsal osteotomies and ostectomies in response to percutaneous injection of adenoviral (Ad) bone morphogenetic protein (BMP)‐2, Ad‐BMP‐6, or beta‐galactosidase protein vector control (Ad‐LacZ) administered 14 days after surgery. Radiographic and quantitative computed tomographic assessment of bone formation indicated greater and earlier mineralized callus in both the osteotomies and ostectomies of the metatarsi injected with Ad‐BMP‐2 or Ad‐BMP‐6. Peak torque to failure and torsional stiffness were greater in osteotomies treated with Ad‐BMP‐2 than Ad‐BMP‐6, and both Ad‐BMP‐2‐ and Ad‐BMP‐6‐treated osteotomies were greater than Ad‐LacZ or untreated osteotomies. Gene expression of ostectomy mineralized callus 8 weeks after surgery indicated upregulation of genes related to osteogenesis compared to intact metatarsal bone. Expression of transforming growth factor beta‐1, cathepsin H, and gelsolin‐like capping protein were greater in Ad‐BMP‐2‐ and Ad‐BMP‐6‐treated callus compared to Ad‐LacZ‐treated or untreated callus. Evidence of tissue biodistribution of adenovirus in distant organs was not identified by quantitative PCR, despite increased serum antiadenoviral vector antibody. This study demonstrated a greater relative potency of Ad‐BMP‐2 over Ad‐BMP‐6 in accelerating osteotomy healing when administered in this regimen, although both genes were effective at increasing bone at both osteotomy and ostectomy sites. © 2008 Orthopaedic Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:764–771, 2008     

大鼠股骨干开放骨折愈合模型的建立及生物力学性能评价

目的: 比较闭合骨折髓内钉固定和开放骨折钢板固定大鼠股骨干骨折愈合模型的建立及生物力学性能。方法: 将40只8周龄SD雄性大鼠通过随机数字表法分为两组,分别建立左侧股骨干闭合骨折髓内钉内固定模型和开放骨折钢板内固定模型,每组20只。建立骨折模型后,分别于术后4、6、8、12周4个时间点对两组大鼠进行分批次处死后取材,测量骨折处骨痂的最大横截面积、体积,计算骨痂的最大载荷、最大载荷恢复率。比较两种不同骨折愈合模型的力学性能。结果: 两种骨折模型的平均手术时间比较,差异有统计学意义(P<0.001).两种骨折模型组术后各时间点的平均骨痂最大横截面积和平均骨痂体积差异具有统计学意义(P<0.05).两种骨折固定模型组术后各时间点的平均最大载荷以及平均最大载荷恢复率,差异均具有统计学意义(P<0.05).结论: 骨折愈合过程中,闭合骨折髓内钉固定模型的力学性能优于开放骨折钢板内固定模型,提示轴向的力学刺激在骨折愈合过程中起重要作用。     

Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model

BACKGROUND: Approximately 5% to 20% of fractures have delayed or impaired healing. Therefore, it is desirable to develop new therapies to enhance fracture-healing that can be used in conjunction with traditional treatment methods. The purpose of this study was to evaluate the ability of a single application of recombinant human bone morphogenetic protein-2 to accelerate fracture-healing in a rabbit ulnar osteotomy that heals spontaneously. METHODS: Bilateral mid-ulnar osteotomies (approximately 0.5 to 1.0 mm wide) were created in seventy-two skeletally mature male rabbits. The limbs were assigned to one of three groups: those treated with an absorbable collagen sponge containing recombinant human bone morphogenetic protein-2, those treated with an absorbable collagen sponge containing buffer, and those left untreated. In the first two groups, an 8 20-mm strip of absorbable collagen sponge containing either 40 g of recombinant human bone morphogenetic protein-2 or buffer only was wrapped around the osteotomy site. The rabbits were killed at two, three, four, or six weeks after surgery. In addition, twenty-four age-matched rabbits were used to provide data on the properties of intact limbs. The retention of recombinant human bone morphogenetic protein-2 at the osteotomy site was determined with scintigraphic imaging of (125)I-labeled recombinant human bone morphogenetic protein-2. After the rabbits were killed, the limbs were scanned with peripheral quantitative computed tomography to assess the area and mineral content of the mineralized callus. The limbs were then tested to failure in torsion, and undecalcified specimens were evaluated histologically. RESULTS: Gamma scintigraphy of (125)I-recombinant human bone morphogenetic protein-2 showed that 73% +/- 6% (mean and standard deviation) of the administered dose was initially retained at the fracture site. Approximately 37% +/- 10% of the initial dose remained at the site one week after surgery, and 8% +/- 7% remained after two weeks. The mineralized callus area was similar in all groups at two weeks, but it was 20% to 60% greater in the ulnae treated with recombinant human bone morphogenetic protein-2 than in either the ulnae treated with buffer or the untreated ulnae at three, four, and six weeks (p < 0.05). Biomechanical properties were similar in all groups at two weeks, but they were at least 80% greater in the ulnae treated with recombinant human bone morphogenetic protein-2 at three and four weeks than in either the ulnae treated with buffer (p < 0.005) or the untreated ulnae (p < 0.01). By four weeks, the biomechanical properties of the ulnae treated with recombinant human bone morphogenetic protein-2 were equivalent to those of the intact ulnae, whereas the biomechanical properties of both the ulnae treated with buffer and the untreated ulnae had reached only approximately 45% of those of the intact ulnae. At six weeks, the biomechanical properties were similar in all groups and were equivalent to those of the intact ulnae. The callus geometry and biomechanical properties of the ulnae treated with buffer were equivalent to those of the untreated ulnae at all time-points. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that treatment with an absorbable collagen sponge containing recombinant human bone morphogenetic protein-2 enhances healing of a long-bone osteotomy that heals spontaneously. Specifically, osteotomies treated with recombinant human bone morphogenetic protein-2 healed 33% faster than osteotomies left untreated. The results of this study provide a rationale for testing the ability of recombinant human bone morphogenetic protein-2 to accelerate healing in patients with fractures requiring open surgical management.     

Local delivery of growth factors from coated titanium plates increases osteotomy healing in rats

Different methods for the stabilization of long bone fractures are used in clinic. Besides the development of further stabilization devices, the use of new materials, the modification of the surfaces, and the local application of stimulating factors for enhancement of healing are from great interest. Previous studies successfully used a biodegradable poly(d,l-lactide) coating as a local drug delivery system of growth factors from intramedullary (IM) implants to enhance fracture healing. In this study, we developed a new rat model (n = 60) for plate osteosynthesis and used a plate for stabilization and as a local drug delivery system for the growth factors IGF-I and TGF-beta1. A four-hole titanium plate was used for stabilization of a 0.6-mm osteotomy gap of the femur. The space between the inner holes was coated with 50 microg IGF-I and 10 microg TGF-beta1 incorporated in the poly(d,l-lactide) coating or with the coating alone. After 42 days, biomechanical tests and histomorphological analyses were performed to investigate osteotomy healing. Radiologically small differences were detectable between the groups. The biomechanical torsional testing revealed a significantly higher maximum load of the osteotomized femura after treatment with growth factors compared to the uncoated group. In the histomorphometric analyses measuring the callus composition, a significantly higher percentage of mineralized tissue in the osteotomy callus was assessed in the growth factor treated group compared to the uncoated. In conclusion, the local application of IGF-I and TGF-beta1 from a biodegradable coating enhances the osteotomy healing as shown in the biomechanical testing and the histomorphometry. Bioactive plates could be used in clinic for fracture stabilization and for local and controlled application of growth factors to stimulate bone healing.     

Recombinant human bone morphogenetic protein 2 enhances bone healing in an experimental model of fractures at risk of non-union

INTRODUCTION: Identification of patients at risk of developing non-union and institution of procedures preventing non-union could be attractive in routine fracture management. We investigated whether recombinant human bone morphogenetic protein (rhBMP-2) delivered in a hyaluronic acid carrier could prevent non-union development in an experimental non-union model, which simulates the clinical situation of open mid-tibial fractures. METHODS: Sixteen rabbits underwent a standard non-union operation comprising mid-tibial osteotomy, excision of periosteum and endosteum, and plate fixation. Before closure of the wound eight rabbits received interfragmentary deposition of 200 microg rhBMP-2 delivered in a hyaluronan gel carrier, and eight rabbits received gel carrier alone. RESULTS: After 7 weeks, torsional failure moment of the osteotomy and energy absorbed at failure, macroscopic and radiographic appearance, callus area, and interfragmentary bone volume fraction confirmed that rhBMP-2 delivery significantly improved bone healing. Blood flow at the osteotomy site, measured using radiolabelled microspheres, was not higher in the united osteotomies than in non-united osteotomies. DISCUSSION: rhBMP-2 delivered in a hyaluronic acid carrier-induced formation of competent bone in an experimental model of compromised healing. We, therefore, propose interfragmentary deposition of rhBMP-2 delivered in a hyaluronic acid carrier to patients encountering fractures at risk of non-union or delayed union.     

Mechanical effects of intramedullary reaming on osteotomy healing in rats

The effect of intramedullary reaming on the healing of stable femoral osteotomies was studied. In one group of rats reaming of the medullary cavity was performed, and a partial, transverse osteotomy was made at the mid-shaft. In the control group only the osteotomy was made. At 0, 15, 30, 60, and 90 days following operation the bending moment and the bending rigidity of the osteotomies were evaluated. There were no significant differences in these biomechanical parameters between the two groups during the experimental period. The results indicate that reaming of the medullary cavity of diaphyseal bone does not significantly impair the healing of fractures that are rigidly fixated.     

Osteotomy Healing in Children With Osteogenesis Imperfecta Receiving Bisphosphonate Treatment

A decade ago our group had reported that osteotomy healing was commonly delayed in children with moderate to severe osteogenesis imperfecta (OI) who were treated with intravenous pamidronate infusions. We subsequently maintained a bisphosphonate infusion–free interval of 4 months after osteotomy and changed the surgical approach (use of an osteotome instead of a power saw). In addition, zoledronic acid has become the standard intravenous bisphosphonate for treatment of OI at our institution. In the present study, we compared osteotomy healing before and after these changes were instituted. We evaluated bone healing post‐osteotomy on standard radiographs after 261 intramedullary rodding procedures involving osteotomies (139 femur, 112 tibia) in 110 patients (age at surgery 1.2 to 20.4 years). Delayed healing was diagnosed when the osteotomy line was visible 12 months after the event. We observed delayed bone healing after 48 of the 114 osteotomies (42%) performed with the new approach, and in 106 of the 147 osteotomies (72%) using the previous approach (p = 0.001). The odds for delayed osteotomy healing were significantly lower with the new approach even after adjustment for age, sex, height Z‐score, weight Z‐score, OI type, and bone involved (odds ratio = 0.17; 95% confidence interval 0.16–0.47). Thus, delayed osteotomy healing occurred less frequently in the past 10 years than in the decade before that. It is likely that this improved result is attributable to the implemented changes in both medical and surgical management. © 2015 American Society for Bone and Mineral Research.     

Derotation of post-traumatic femoral deformities by closed intramedullary sawing

Different techniques and devices have been used for correction osteotomies of bones in patients with malalignments. The most frequently used technique for rotational deformities of the femur and tibia is open osteotomy with an oscillating saw and pre-drilled holes with all well-known drawbacks of open surgery. An intramedullary device with an adapted minimal-invasive surgical technique allows intramedullary osteotomy of the bone preserving the surrounding soft tissue. We performed femoral osteotomies with an intramedullary saw followed by static interlocking nailing in 14 patients with post-traumatic rotational deformity in the femur. Twelve patients had an external rotational deformity of the femur ranging between 26 and 63 degrees , one had an additional leg-shortening of about 4 cm. Two patients had internal rotational deformities. In two patients with delayed fracture healing union was achieved within one year without secondary surgery. Post-operative clinical assessment and CT-scans revealed good derotation results with deformities of less than 4 degrees in all cases. No device-related complications were observed. Therefore, we conclude that "closed" osteotomy with an intramedullary saw is a minimal-invasive, safe and reliable option for derotation procedures in the femur.     

Mechanical effects of intramedullary reaming in pinned osteotomies in rats

The biomechanical effects of intramedullary reaming on the healing of femoral osteotomies were studied. In rats, transverse osteotomies at the midshaft of both femurs were made. On the left side only, reaming of the medullary cavity was performed, and the osteotomies were then stabilized by intramedullary pinning. At 15, 30, 60, and 90 days after osteotomy, the production of callus, the bending moment, and the bending rigidity were evaluated. There were no significant differences in these biomechanical parameters between the right unreamed and the left reamed femurs during the experimental period. The results indicate that reaming of the medullary cavity of diaphyseal bone does not significantly impair or improve the healing of pinned osteotomies in rats.     

Sclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats

Sclerostin is a negative regulator of bone formation. Sclerostin monoclonal antibody (Scl‐Ab) treatment promoted bone healing in various animal models. To further evaluate the healing efficiency of Scl‐Ab in osteotomy healing, we investigated the time course effects of systemic administration of Scl‐Ab on fracture repair in rat femoral osteotomy model. A total of 120 six‐month‐old male SD rats were subjected to transverse osteotomy at the right femur mid‐shaft. Rats were treated with vehicle or Scl‐Ab treatment for 3, 6, or 9 weeks. Fracture healing was evaluated by radiography, micro‐CT, micro‐CT based angiography, 4‐point bending mechanical test and histological assessment. Scl‐Ab treatment resulted in significantly higher total mineralized callus volume fraction, BMD and enhanced neovascularization. Histologically, Scl‐Ab treatment resulted in a significant reduction in fracture callus cartilage at week 6 and increase in bone volume at week 9, associated with a greater proportion of newly formed bone area at week 6 and 9 by fluorescence microscopy. Mechanical testing showed significantly higher ultimate load in Scl‐Ab treatment group at week 6 and 9. This study has demonstrated that Scl‐Ab treatment enhanced bone healing in a rat femoral osteotomy model, as reflected in increased bone formation, bone mass and bone strength. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:997–1005, 2014.     

Metaphyseal fracture healing follows similar biomechanical rules as diaphyseal healing

It is generally supposed that the pattern of fracture healing in trabecular metaphyseal bone differs from that of diaphyseal fractures. However, few experimental studies to date have been performed, even though clinically many fractures occur in metaphyseal bone. Particularly, the influence of biomechanical factors has not yet been investigated under standardized conditions. Our aim was to correlate the interfragmentary strain (IFS) with the bone‐healing outcome in a controlled metaphyseal fracture model in sheep. Twelve sheep received a partial osteotomy in the distal femoral condyle close to the trochlea. The determination of the IFS by in vivo X‐ray analyses and a finite element model revealed that the deflection of the osteotomy gap by the patello‐femoral force during walking provoked increasing strains of up to 40%. Bone healing was evaluated after 8 weeks by the assessment of the bone mineral density and by histomorphometry in regions of interest that displayed differing magnitudes of IFS. In areas with strains below 5% significantly less bone formation occurred compared to areas with higher strains (6–20%). For strains larger than 20% fibrocartilage layers were observed. Low IFS (<5%) led to intramembranous bone formation, whereas higher strains additionally provoked endochondral ossification or fibrocartilage formation. It is therefore proposed that metaphyseal bone healing follows similar biomechanical principles as diaphyseal healing. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:425–432, 2011