Systemically administered zoledronic acid activates locally implanted synthetic hydroxyapatite particles enhancing peri-implant bone formation: A regenerative medicine approach to improve fracture fixation.

Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri­implant bone formation compared to the unaugmented implants at 6-weeks. We then evaluated the optimal timing (day 1, 3, 7 and 14) of ZA administration to achieve a robust effect on peri­implant bone formation. Using fluorescent ZA, we demonstrated that the uptake of ZA in the CaS/HA material was the highest at 3- and 7-days post-implantation and the uptake kinetics had a profound effect on the eventual peri­implant bone formation. We furthered our concept in a feasibility study on trochanteric fracture patients randomized to either CaS/HA augmentation or no augmentation followed by systemic ZA treatment. Radiographically, the CaS/HA group showed signs of increased peri­implant bone formation compared with the controls. Finally, apart from HA, we demonstrated that the concept of biologically activating a ceramic material by ZA could also be applied to ß-tricalcium phosphate. This novel approach for fracture treatment that enhances immediate and long-term fracture fixation in osteoporotic bone could potentially reduce reoperations, morbidity and mortality. STATEMENT OF SIGNIFICANCE: • Fracture fixation in an ageing population is challenging. Biomaterial-based augmentation of fracture fixation devices has been attempted but lack of satisfactory biological response limits their widespread use. • We report the biological activation of locally implanted microparticulate hydroxyapatite (HA) particles placed around an implant by systemic administration of the bisphosphonate zoledronic acid (ZA). The biological activation of HA by ZA enhances peri­implant bone formation. •Timing of ZA administration after HA implantation is critical for optimal ZA uptake and consequently determines the extent of peri­implant bone formation. • We translate the developed concept from small animal models of implant integration to a proof-of-concept clinical study on osteoporotic trochanteric fracture patients. • ZA based biological activation can also be applied to other calcium phosphate biomaterials.

A New Augmentation Method for Improved Screw Fixation in Fragile Bone.

Pertrochanteric fractures (TF) due to osteoporosis constitute nearly half of all proximal femur fractures. TFs are treated with a surgical approach and fracture fixation is achieved using metallic fixation devices. Poor quality cancellous bone in osteoporotic patients makes anchorage of a fixation device challenging, which can lead to failure of the fracture fixation. Methods to reinforce the bone-implant interface using bone cement (PMMA) and other calcium phosphate cements in TFs have been described earlier but a clear evidence on the advantage of using such biomaterials for augmentation is weak. Furthermore, there is no standardized technique for delivering these biomaterials at the bone-implant interface. In this study, we firstly describe a method to deliver a calcium sulphate/hydroxyapatite (CaS/HA) based biomaterial for the augmentation of a lag-screw commonly used for TF fixation. We then used an osteoporotic Sawbones model to study the consequence of CaS/HA augmentation on the immediate mechanical anchorage of the lag-screw to osteoporotic bone. Finally, as a proof-of-concept, the method of delivering the CaS/HA biomaterial at the bone-implant interface as well as spreading of the CaS/HA material at this interface was tested in patients undergoing treatment for TF as well as in donated femoral heads. The mechanical testing results indicated that the CaS/HA based biomaterial increased the peak extraction force of the lag-screw by 4 times compared with un-augmented lag-screws and the results were at par with PMMA. The X-ray images from the patient series showed that it was possible to inject the CaS/HA material at the bone-implant interface without applying additional pressure and the CaS/HA material spreading was observed at the interface of the lag-screw threads and the bone. Finally, the spreading of the CaS/HA material was also verified on donated femoral heads and micro-CT imaging indicated that the entire length of the lag-screw threads was covered with the CaS/HA biomaterial. In conclusion, we present a novel method for augmenting a lag-screw in TFs, which could potentially reduce the risk of fracture fixation failure and reoperation in fragile osteoporotic patients.

Ollier Disease: A Case Series and Literature Review.

SUMMARY BACKGROUND: Ollier disease is the most common nonhereditary type of enchondromatosis. Enchondromas are common, usually benign intraosseous cartilaginous tumors that form near the growth plate cartilage predominantly unilaterally in the metaphyses and diaphyses of tubular bones. They usually affect the long bones of the hand, the humerus, and the tibia, followed by flat bones, such as the pelvis. The estimated prevalence of Ollier disease is 1 in 100,000 and while it is linked with somatic heterozygous mutations in IDH1 or IDH2 genes, exact etiology is unknown. The risk of malignant transformation towards chondrosarcoma is up to 30-35% and it is clinically suspected when pain and a rapid increase in the size of the lesions is seen. CASE PRESENTATIONS: We report two clinical cases of patients diagnosed with Ollier disease. In both cases transformation to chondrosarcoma was observed. CONCLUSIONS: Ollier disease is a rare disorder, defined by the presence of multiple enchondromas and an asymmetric distribution of the cartilage lesions that can be extremely variable in terms of size, location, age, gender. Constant monitoring of patients is important due to the high risk of malignancy. Because the disease is very rare and the manifestations vary widely, each patient's case must be evaluated, and the treatment strategy adopted individually.

A ceramic bone substitute containing gentamicin gives good outcome in trochanteric hip fractures treated with dynamic hip screw and in revision of total hip arthroplasty: a case series.

BACKGROUND: The primary objective was to investigate the clinical and radiological outcome in patients undergoing major hip surgery using a novel antibiotic containing bone substitute for local augmentation in trochanteric fracture fixation or revision of total hip arthroplasty (THA). METHODS: We implanted a novel biphasic bone substitute CERAMENT™|G consisting of hydroxyapatite, calcium sulphate and gentamicin for bone regeneration and local antibiotic delivery in 20 patients treated surgically for trochanteric femoral fracture or uncemented hip revision. Preoperative, postoperative, 3 months and 1 year clinical and radiological assessment were performed including registration of any complications. In one trochanteric fracture patient, histological analyses were performed of bone biopsies taken at removal of hardware. RESULTS: None of the trochanteric fractures or revision of THA showed any large migration. No local wound disturbances were seen and no infection was observed at one year follow-up. All trochanteric fractures healed at 3 months with a minimal sliding screw displacement on average 3 mm. Radiological analysis showed signs of bone remodeling and new bone formation in the substitute, illustrated also by histology in the biopsies taken from one trochanteric fracture at one year post-op. CONCLUSIONS: Local CERAMENT™|G was shown to be safe in a limited prospective major hip surgery study. Remodeling of the bone graft substitute was observed in all patients. TRIAL REGISTRATION: EU-CTR2018-004414-18 Retrospectively registered on November 20, 2018.

Antibiotic Containing Bone Substitute in Major Hip Surgery: A Long Term Gentamicin Elution Study.

Objectives: The objective is to present the antibiotic elution from a locally implanted gentamicin containing hydroxyapatite and calcium sulphate bone substitute with an extended follow up of 30 days. We also compare the pharmacokinetics of the ceramic bone substitute with a published study on gentamicin containing poly (methyl methacrylate) (PMMA) bone cement used in primary total hip arthroplasty. Methods: Gentamicin release was measured in the urine for a month and the serum for 4 days in 10 patients operated for trochanteric hip fractures and 10 patients in uncemented hip revisions. 17 patients were followed up at one year and 3 patients at 6 months. Results and Discussion: The gentamicin concentrations measured in serum were low and approximately 100 times less than in urine during the first days, indicating high local concentrations at the implant site. The elution from the biphasic bone substitute showed a stronger burst and higher gentamicin concentrations for the first week compared to that reported for PMMA used in hip arthroplasty. Also, for the bone substitute a complete gentamicin elution was obtained after 30 days, while for the PMMA cement sub-inhibitory MIC levels of gentamicin were still present in urine 60 days past surgery. No infections were detected. Conclusions: A new biphasic bone substitute containing antibiotics could potentially be used to prevent infection in patients treated for trochanteric hip fractures or uncemented hip revisions. The gentamicin elution from the bone substitute is efficient with high initial local gentamicin concentrations and complete release at 30 days.