There is conjecture on the optimal timing to administer bisphosphonate therapy following operative fixation of low- trauma hip fractures. Factors include recommendations for early opportunistic commencement of osteoporosis treatment, and clinician concern regarding the effect of bisphosphonates on fracture healing. We performed a systematic review and meta-analysis to determine if early administration of bisphosphonate therapy within the first month post-operatively following proximal femur fracture fixation is associated with delay in fracture healing or rates of delayed or non-union.

We included randomised controlled trials examining fracture healing and union rates in adults with proximal femoral fractures undergoing osteosynthesis fixation methods and administered bisphosphonates within one month of operation with a control group. Data was pooled in meta-analyses where possible. The Cochrane Risk of Bias Tool and the GRADE approach were used to assess validity.

For the outcome of time to fracture union, meta-analysis of three studies (n= 233) found evidence for earlier average time to union for patients receiving early bisphosphonate intervention (MD = −1.06 weeks, 95% CI −2.01 – −0.12, I²= 8%). There was no evidence from two included studies comprising 718 patients of any difference in rates of delayed union (RR 0.61, 95% CI 0.25–1.46). Meta-analyses did not demonstrate a difference in outcomes of mortality, function, or pain.

We provide low-level evidence that there is no reduction in time to healing or delay in bony union for patients receiving bisphosphonates within one month of proximal femur fixation.

Bone is capable of regeneration, and defects often heal spontaneously. However, cartilage, tendon, and ligament injuries usually result in replacement if the site by organized scar tissue, which is inferior to the native tissue. The osteogenic potential of mesenchymal stem cells (MSCs) has already been verified. MSCs hold great potential for the development of new treatment strategies for a host of orthopedic conditions. The multi-lineage potential and plasticity of MSCs allow them to be building blocks for a host of nonhematopoietic tissues, including bone. More recently, several groups have reported on the successful clinical application of tissue engineering strategies in the repair of bony defects in patients secondary to trauma and tumor resection. Advances in fabrication of biodegradable scaffolds that serve as beds for MSC implantation will hopefully lead to better biocompatibility and host tissue integration. Current strategies for bone tissue engineering include the use of osteoconductive matrix devices that promote bony ingrowth, and the delivery of osteoinductive growth factors, including bone morphogenetic protein (BMP) family, BMP-2 and BMP-7, to bony defect sites. Minimal toxicity has been observed in animal models involving genetically-manipulated stem cells transduced with retroviral and adenoviral vectors. Gene therapy using stem cells as delivery vehicles is a powerful weapon that can be used in a plethora of clinical situations that would benefit from the osteoinductive, proliferative, and angiogenic effects of growth factors. With better understanding of the biology of stem cells in the future and with enhancement of technologies that are capable to influence, modify, and culture these cells, a new field of regenerative skeletal medicine may emerge.

Patellar fractures account for approximately 1% of all fractures. Open reduction and internal fixation is recommended to restore extensor continuity and articular congruity. However, complications such as nonunion and symptomatic hardware, still exist. Furthermore, there is a risk of re-fracturing of the healed bone during the removal of the implants. Magnesium (Mg), a biodegradable metal, has elastic moduli and compressive yield strength that are comparable to those of natural bone. Our previous study showed that released Mg ions enhanced fracture healing. However, Mg-based implants degrade rapidly after implantation and lead to insufficient mechanical strength to support the fracture. Microarc oxidation (MAO) is a metal surface coating that reduces corrosion. We hypothesized that Mg pins, with or without MAO, would enhance fracture healing radiologically, mechanically, and histologically, while MAO would decrease degradation of Mg pins.

Patellar fracture was performed on forty-eight 18-week-old female New Zealand White rabbits according to established protocol. Briefly, the patella is osteotomized transversely and a tunnel (1.1mm) was drilled longitudinally through the two bone fragments. A pin (1 mm, stainless steel, Mg, or MAO-Mg) was inserted into the tunnel. The reduced construct was stabilized with a figure-of-eight band wire (⊘ 0.6 mm stainless steel wire). Cast immobilization was applied for 6 weeks. The rabbits were euthanized at week 8 and 12 post-operation. Microarchitecture and mechanical properties of the repaired patella were analyzed with microCT and tensile testing respectively. Histological sections of the repaired patella were stained. To evaluate the effect of the MAO treatment on degradation rate of Mg pin, the volume of the Mg pins in the patella was measured with microCT.

At week 8, both Mg and Mg-MAO showed higher ratio of bone volume to tissue volume (BV/TV) than the control while there was no significant different between Mg and Mg-MAO. At week 12, Control, Mg, and Mg-MAO groups showed enlarged patella when compared to the normal patella. Tissue volume (TV) and bone volume (BV) of the patella in Mg and Mg-MAO were larger than those in the Control group. However, the Control had higher ratio of bone volume to tissue volume (BV/TV), TV density, and BV density than Mg and Mg-MAO. Tensile testing showed that the mechanical properties of the repaired patella (failure load, stiffness, ultimate strength, and energy-to-failure) of Mg and Mg-MAO were higher than that of the control at both week 8 and week 12. Histological analysis showed that there was significant new bone formation in the Mg and Mg-MAO group compared with the Control group at week 8 and 12. The degradation rate of the MAO-coated Mg pins was significantly slower than those without MAO at week 8 but no significant difference was detected at week 12.

Mechanical, microarchitectural, and histological assessments showed that Mg pins, with or without MAO, enhanced fracture healing of the repaired patella compared to the Control. MAO treatment enhanced the corrosion resistance of the Mg pins at the early time point.

Predictable fracture healing fails to occur in 5–10% of cases. This is particularly concerning among individuals with osteoporosis. With an increasing aging population, one in three women and one in five men above the age of 50 experience fragility fractures. As such, there is a critical need for an effective treatment option that could enhance fracture healing in osteoporotic bone. Lithium, the standard treatment for bipolar disorder, has been previously shown to improve fracture healing through modulation of the Wnt/beta-catenin pathway. We optimised the precise oral lithium administration parameters to improve mechanical strength and enhance healing of femoral fractures in healthy rats. A low dose of Lithium (20 mg/kg) administered seven days post fracture for a two week duration improved torsional strength by 46% at four weeks post fracture compared to non-treated animals. Application of lithium to enhance fracture healing in osteoporotic bone would have a significant healthcare impact and requires further study. Aim: To evaluate the efficacy of optimal lithium administration post fracture on quality of fracture healing in a rat osteoporotic model. Hypothesis: Lithium treatment in osteoporotic rats will improve the structural and mechanical properties of the healing bone despite the impaired nature of bone tissue.

Sprague Dawley female rats (∼350 g, age ∼3 months) were bilaterally ovariectomised and maintained for 3 months to establish the osteoporotic phenotype. A unilateral, closed mid-shaft femoral fracture was created using a weight-drop apparatus. At seven days post fracture, the treatment group received 20 mg/kg-wt lithium chloride via oral gavage daily for 14 days. The control group received an equivalent dose of saline. All animals were sacrificed at day 28 and the femurs harvested bilaterally. Treatment efficacy was evaluated based on torsional loading and stereologic analysis.

Lithium treatment positively impacted the healing femurs, with an average yield torque ∼1.25-fold higher than in the saline group (200±36 vs. 163±31 N-mm, p=0.15). Radiographically, the lithium-treated rats had a high level of restored periosteal continuity, larger bridging and intercortical callus at the fracture site. These hallmarks of healing were generally absent in the saline group. The Lithium group had significantly higher total volume (624±32 vs. 568±95 mm3), lower bone volume fraction (41±4 vs. 50±5%) and higher theoretical torsional rigidity (477±50 vs. 357±93 kN-mm2) compared to the saline group. Torsional strength and stereology values were similar for the contralateral femurs of the two groups.

Lithium was found to enhance fracture healing in osteoporotic bone under the dosing regimen optimised in healthy femora. This is promising data as treatment represents an easily translatable pharmacological intervention for fracture healing that may ultimately reduce the healthcare burden of osteoporotic fractures.

Little literature exists about how trauma-induced anemia affects bone healing. Moreover, the definition of anemia has now changed. Until recently, anemia was defined as peripheral Hemoglobin (Hgb) of less than 10 grams/deciliter (gm/dL). Contemporary literature defines anemia as Hgb < 8gm/dL.

This re-definition prompted three questions: (1) Does the presence of hemorrhagic anemia (Hgb< 10gm/dL) alter bone healing rates?; (2) If not, does the newer definition (Hgb< 8gm/dL) influence bone healing?; (3) If so, does the newer definition result in more profound changes in bone healing than those previously seen?

We reviewed the charts of patients treated for long bone, diaphyseal fractures over a ten-year period at a Level 1 Trauma Centre to determine rates of fracture healing when anemia by either definition was present. Patients who were skeletally immature, died during hospitalisation, or had incomplete medical records were excluded. All charts were reviewed for: development of anemia, need for blood transfusion, quantity of blood administered and subsequent association with bone healing. Inclusion criteria were met by 627 patients (700 individual fractures).

When anemia was defined as Hgb< 10gm/dL, there was an 81.5% healing rate among anemic patients vs 88.8% in non-anemic patients (p=0.013); with a definition of Hgb< 8gm/dL, healing rates were 81.3% and 86.2%, respectively (p=0.041). Tibial healing was especially noted to be influenced (p = 0.002 and 0.0001, respectively). Femoral healing was likewise, but less dramatically, affected (p = 0.0082 and 0.0843). ANOVA showed no significance for open vs closed status, or NSAID use.

Our study found a statistically significant difference in long bone healing between patients who developed anemia and those who did not. This is the first evidence based clinical review demonstrating that hemorrhagic anemia has a significant impact on the healing rates of long bone fractures, especially those of the tibia.

Introduction

HIV is known to affect many of the processes involved in fracture healing. Recent work has suggested that CD4 cells may act as suppressor in the regulation of fracture healing. There are no clinical studies looking at fracture healing in patients with open fractures in these patients.

Aim

Silver is known for its excellent antimicrobial activity, including activity against multiresistant strains. The aim of the current study was to analyze the biocompatibility and potential influence on the fracture healing process a silver-coating technology for locking plates compared to silver-free locking plates in a rabbit model.

Introduction

The optimal treatment of high-energy tibia fractures remains controversial. The role of external fixators has been shown to be crucial. This study aimed to compare the effectiveness of using either Taylor Spatial Frame (TSF) or Ilizarov frames in treatment of high-energy tibia fractures in a tertiary trauma referral centre.

Background

Identification of novel therapeutics to accelerate acute fracture healing remains critical. A prostaglandin EP-2 receptor agonist (CP-533,536) has demonstrated acceleration of fracture healing in preclinical models. The objective of this study is to assess the efficacy of a single dose of CP-533,536 in subjects with a closed fracture of the tibial shaft using radiographic measurements compared to placebo treatment.

Introduction

Bisphosphonates are among the most commonly prescribed drugs in Osteoporotic Patients. Their mode of action is anti-resorptive. Since remodeling is a key step in fracture healing, there has been concern regarding the effect of bisphosphonates on fracture healing.

Patients with spinal cord injuries have been seen to have increased healing of attendant fractures. This for the main has been a clinical observation with laboratory work confined to rats. While the benefits in relation to quicker fracture healing are obvious, this excessive bone growth (heterotopic ossification) also causes unwanted side effects, such as decreased movement around joints, joint fusion and renal tract calculi. However, the cause for this phenomenon remains unclear.

This paper evaluates two groups with spinal column fractures – those with neurological compromise (n=10) and those without (n=15), and compares them with a control group with isolated long bone fractures (n=12). Serum was taken from these patients at five specific time intervals post injury (1 day, 5 days, 10 days, 42 days (6 weeks) and 84 days (12 weeks)). These samples were then analysed for levels of Transforming Growth Factor-Beta (TGF-β using the ELISA technique. This cytokine has been shown to stimulate bone formation after both topical and systemic administration.

Results show TGF-β levels of 142.79+/-29.51 ng/ml in the neurology group at 84 days post injury. This is higher than any of the other time points within this group (p=0.009 vs. all other time points, ANOVA). Furthermore, this level is also higher than the levels recorded in the no neurology (103.51+/-36.81 ng/ml) and long bone (102.28=/-47.58 ng/ml) groups at 84 days post-injury (p=0.009 and p=0.04 respectively, ANOVA).

In conclusion, the results of this work, carried out for the first time in humans, offers strong evidence of the causative role of TGF-β in the increased bone turnover and attendant complications seen in patients with acute spinal cord injuries.

Age-related fragility fractures are highly correlated with the loss of bone integrity and deteriorated morphology of the osteocytes. Previous studies have reported low-magnitude high-frequency vibration(LMHFV) promotes osteoporotic diaphyseal fracture healing to a greater extent than in age-matched normal fracture healing, yet how osteoporotic fractured bone responds to the mechanical signal has not been explored. As osteocytes are prominent for mechanosensing and initiating bone repair, we hypothesized that LMHFV could enhance fracture healing in ovariectomized metaphyseal fracture through morphological changes and mineralisation in the osteocyte Lacuno-canalicular Network(LCN). As most osteoporotic fractures occur primarily at the metaphysis, an osteoporotic metaphyseal fracture model was established.

A total of 72 six-month old female Sprague-Dawley rats (n=72) were obtained(animal ethical approval ref: 16–037-MIS). Half of the rats underwent bilateral ovariectomy(OVX) and kept for 3 months for osteoporosis induction. Metaphyseal fracture on left distal femur was created by osteotomy and fixed by a plate. Rats were then randomized to (1) OVX+LMHFV(20 mins/day and 5 days/week, 35Hz, 0.3g), (2) OVX control, (3) SHAM+LMHFV, (4) SHAM control. Assessments of morphological structural changes, functional markers of the LCN(Scanning Electron Microscopy, FITC-Imaris, immunohistochemistry), mineralization status(EDX, dynamic histomorphometry) and healing outcomes(X-ray, microCT, mechanical testing) were performed at week 1, 2 and 6 post-fracture. One‐way ANOVA with post-hoc test was performed. Statistical significance was set at p < 0.05.

Our results showed LMHFV could significantly enhance the morphology of the LCN. There was a 65.3% increase in dendritic branch points(p=0.03) and 93% increase in canalicular length(p=0.019) in the OVX-LMHFV group at week 2 post-fracture. Besides, a similar trend was also observed in the SHAM+LMHFV group, with a 43.4% increase in branch points and 53% increase in canaliculi length at week 2. A significant increase of E11 and DMP1 was observed in the LMHFV groups, indicating the reconstruction of the LCN. The decreasing sclerostin and increasing FGF23 at week 1 represented the active bone formation phase while the gradual increase at week 6 signified the remodelling phase. Furthermore, Ca/P ratio, mineral apposition rate and bone formation rate were all significantly enhanced in the OVX+LMHFV group. The overall bone mineral density in BV was significantly raised in the OVX+LMHFV group at week 2(p=0.043) and SHAM+LMHFV at week 6(p=0.04). Quantitative analysis of microCT showed BV/TV was significantly increased at week 2 in OVX+LMHFV group(p=0.008) and week 6(p=0.001) in both vibration groups. In addition, biomechanical testing revealed that the OVX+LMHFV group had a significantly higher ultimate load(p=0.03) and stiffness(p=0.02) at week 2.

To our best knowledge, this is the first report to illustrate LMHFV could enhance osteocytes' morphology, mineralisation status and healing outcome in a new osteoporotic metaphyseal fracture animal model. Our cumulative data supports that the mechanosensitivity of bone would not impair due to osteoporosis. The revitalized osteocyte LCN and upregulated osteocytic protein markers implied a better connectivity and transduction of signals between osteocytes, which may foster the osteoporotic fracture healing process through an enhanced mineralisation process. This could stimulate further mechanistic investigations with potential translation of LMHFV to our fragility fracture patients.

1133 patients with an intracapsular fracture of femoral neck treated by internal fixation were prospectively studied. All surviving patients were followed up for a minimum of one year from injury. The overall incidence of non-union was 229 (20.2%) and the incidence of avascular necrosis was 61 (5.4%). Fracture non-union was less common for undisplaced fracture in comparison to displaced fractures (48 out of 565 (8.5%) versus 181 out of 568 (31.9%)) and in males than females (45 out of 271 (16.6%) versus 184 out of 862 (21.3%)). The incidence of non-union progressively increased with age from one out of 17 (5.9%) in those aged below 40 years to 84 out of 337 (24.9%) in those in their seventies. For those in their eighties the incidence of non-union began to fall, but if those patients who died within one year from injury were excluded, then the incidence was found to continue to increase. For avascular necrosis there was a falling incidence with age from 9 out of 68 (13.2%) in those aged less than 50 years to 10 out of 388 (2.6%) in those aged over 80 years.

The information from this large series of patients treated by contemporary methods enables the surgeon to use the three factors of age, sex and presence of fracture displacement to predict the risk of non-union or avascular necrosis occurring.