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Bone & Joint Open
Vol. 5, Issue 6 | Pages 489 - 498
12 Jun 2024
Kriechling P Bowley ALW Ross LA Moran M Scott CEH

Aims

The purpose of this study was to compare reoperation and revision rates of double plating (DP), single plating using a lateral locking plate (SP), or distal femoral arthroplasty (DFA) for the treatment of periprosthetic distal femur fractures (PDFFs).

Methods

All patients with PDFF primarily treated with DP, SP, or DFA between 2008 and 2022 at a university teaching hospital were included in this retrospective cohort study. The primary outcome was revision surgery for failure following DP, SP, or DFA. Secondary outcome measures included any reoperation, length of hospital stay, and mortality. All basic demographic and relevant implant and injury details were collected. Radiological analysis included fracture classification and evaluation of metaphyseal and medial comminution.


The Bone & Joint Journal
Vol. 106-B, Issue 1 | Pages 28 - 37
1 Jan 2024
Gupta S Sadczuk D Riddoch FI Oliver WM Davidson E White TO Keating JF Scott CEH

Aims

This study aims to determine the rate of and risk factors for total knee arthroplasty (TKA) after operative management of tibial plateau fractures (TPFs) in older adults.

Methods

This is a retrospective cohort study of 182 displaced TPFs in 180 patients aged ≥ 60 years, over a 12-year period with a minimum follow-up of one year. The mean age was 70.7 years (SD 7.7; 60 to 89), and 139/180 patients (77.2%) were female. Radiological assessment consisted of fracture classification; pre-existing knee osteoarthritis (OA); reduction quality; loss of reduction; and post-traumatic OA. Fracture depression was measured on CT, and the volume of defect estimated as half an oblate spheroid. Operative management, complications, reoperations, and mortality were recorded.


The Bone & Joint Journal
Vol. 105-B, Issue 6 | Pages 679 - 687
1 Jun 2023
Lou Y Zhao C Cao H Yan B Chen D Jia Q Li L Xiao J

Aims

The aim of this study was to report the long-term prognosis of patients with multiple Langerhans cell histiocytosis (LCH) involving the spine, and to analyze the risk factors for progression-free survival (PFS).

Methods

We included 28 patients with multiple LCH involving the spine treated between January 2009 and August 2021. Kaplan-Meier methods were applied to estimate overall survival (OS) and PFS. Univariate Cox regression analysis was used to identify variables associated with PFS.


Bone & Joint 360
Vol. 12, Issue 2 | Pages 42 - 44
1 Apr 2023

The April 2023 Research Roundup. 360. looks at: Ear protection for orthopaedic surgeons?; Has arthroscopic meniscectomy use changed in response to the evidence?; Time to positivity of cultures obtained for periprosthetic joint infection; Bisphosphonates for post-COVID-19 osteonecrosis of the femoral head; Missing missed fractures: is AI the answer?; Congenital insensitivity to pain and correction of the knee; YouTube and paediatric elbow injuries


Bone & Joint Research
Vol. 11, Issue 11 | Pages 826 - 834
17 Nov 2022
Kawai T Nishitani K Okuzu Y Goto K Kuroda Y Kuriyama S Nakamura S Matsuda S

Aims. The preventive effects of bisphosphonates on articular cartilage in non-arthritic joints are unclear. This study aimed to investigate the effects of oral bisphosphonates on the rate of joint space narrowing in the non-arthritic hip. Methods. We retrospectively reviewed standing whole-leg radiographs from patients who underwent knee arthroplasties from 2012 to 2020 at our institute. Patients with previous hip surgery, Kellgren–Lawrence grade ≥ II hip osteoarthritis, hip dysplasia, or rheumatoid arthritis were excluded. The rate of hip joint space narrowing was measured in 398 patients (796 hips), and the effects of the use of bisphosphonates were examined using the multivariate regression model and the propensity score matching (1:2) model. Results. A total of 45 of 398 (11.3%) eligible patients were taking an oral bisphosphonate at the time of knee surgery, with a mean age of 75.8 years (SD 6.2) in bisphosphonate users and 75.7 years (SD 6.8) in non-users. The mean joint space narrowing rate was 0.04 mm/year (SD 0.11) in bisphosphonate users and 0.12 mm/year (SD 0.25) in non-users (p < 0.001). In the multivariate model, age (standardized coefficient = 0.0867, p = 0.016) and the use of a bisphosphonate (standardized coefficient = −0.182, p < 0.001) were associated with the joint space narrowing rate. After successfully matching 43 bisphosphonate users and 86 non-users, the joint narrowing rate was smaller in bisphosphonate users (p < 0.001). Conclusion. The use of bisphosphonates is associated with decreased joint degeneration in non-arthritic hips after knee arthroplasty. Bisphosphonates slow joint degeneration, thus maintaining the thickness of joint cartilage in the normal joint or during the early phase of osteoarthritis. Cite this article: Bone Joint Res 2022;11(11):826–834


The Bone & Joint Journal
Vol. 103-B, Issue 11 | Pages 1648 - 1655
1 Nov 2021
Jeong S Hwang K Oh C Kim J Sohn OJ Kim JW Cho Y Park KC

Aims. The incidence of atypical femoral fractures (AFFs) continues to increase. However, there are currently few long-term studies on the complications of AFFs and factors affecting them. Therefore, we attempted to investigate the outcomes, complications, and risk factors for complication through mid-term follow-up of more than three years. Methods. From January 2003 to January 2016, 305 patients who underwent surgery for AFFs at six hospitals were enrolled. After exclusion, a total of 147 patients were included with a mean age of 71.6 years (48 to 89) and 146 of whom were female. We retrospectively evaluated medical records, and reviewed radiographs to investigate the fracture site, femur bowing angle, presence of delayed union or nonunion, contralateral AFFs, and peri-implant fracture. A statistical analysis was performed to identify the significance of associated factors. Results. The mean follow-up period was 70.2 months (36 to 191). There were 146 AFFs (99.3%) in female patients and the mean age was 71.6 years (48 to 89). The AFFs were located in the subtrochanter and shaft in 52 cases (35.4%) and 95 (64.6%), respectively. The preoperative mean anterior/lateral femoral bowing angles were 10.5° (SD 5.7°)/6.1° (SD 6.2°). The postoperative mean anterior/lateral bowing values were changed by 8.7° (SD 5.4°)/4.6° (SD 5.9°). Bisphosphonates had been used contemporarily in 115 AFFs (78.2%) for a mean of 52.4 months (1 to 204; SD 45.5) preoperatively. Nailing was performed in 133 AFFs (90.5%), and union was obtained at a mean of 23.6 weeks (7 to 85). Delayed union occurred in 41 (27.9%), and nonunion occurred in 13 (8.8%). Contralateral AFF occurred in 79 patients (53.7%), and the use of a bisphosphonate significantly influenced the occurrence of contralateral AFFs (p = 0.019). Peri-implant fractures occurred in a total of 13 patients (8.8%), and a significant increase was observed in cases with plating (p = 0.021) and high grade of postoperative anterolateral bowing (p = 0.044). Conclusion. The use of a bisphosphonate was found to be a risk factor for contralateral AFF, and high-grade postoperative anterolateral bowing and plate fixation significantly increased the occurrence of peri-implant fractures. Long-term follow-up studies on the bilaterality of AFFs and peri-implant fractures are warranted. Cite this article: Bone Joint J 2021;103-B(11):1648–1655


The Bone & Joint Journal
Vol. 103-B, Issue 9 | Pages 1497 - 1504
1 Sep 2021
Rotman D Ariel G Rojas Lievano J Schermann H Trabelsi N Salai M Yosibash Z Sternheim A

Aims

Type 2 diabetes mellitus (T2DM) impairs bone strength and is a significant risk factor for hip fracture, yet currently there is no reliable tool to assess this risk. Most risk stratification methods rely on bone mineral density, which is not impaired by diabetes, rendering current tests ineffective. CT-based finite element analysis (CTFEA) calculates the mechanical response of bone to load and uses the yield strain, which is reduced in T2DM patients, to measure bone strength. The purpose of this feasibility study was to examine whether CTFEA could be used to assess the hip fracture risk for T2DM patients.

Methods

A retrospective cohort study was undertaken using autonomous CTFEA performed on existing abdominal or pelvic CT data comparing two groups of T2DM patients: a study group of 27 patients who had sustained a hip fracture within the year following the CT scan and a control group of 24 patients who did not have a hip fracture within one year. The main outcome of the CTFEA is a novel measure of hip bone strength termed the Hip Strength Score (HSS).


Bone & Joint Research
Vol. 10, Issue 8 | Pages 488 - 497
10 Aug 2021
Cleemann R Sorensen M West A Soballe K Bechtold JE Baas J

Aims

We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants.

Methods

An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia.


The Bone & Joint Journal
Vol. 103-B, Issue 4 | Pages 635 - 643
1 Apr 2021
Ross LA Keenan OJF Magill M Brennan CM Clement ND Moran M Patton JT Scott CEH

Aims

Debate continues regarding the optimum management of periprosthetic distal femoral fractures (PDFFs). This study aims to determine which operative treatment is associated with the lowest perioperative morbidity and mortality when treating low (Su type II and III) PDFFs comparing lateral locking plate fixation (LLP-ORIF) or distal femoral arthroplasty (DFA).

Methods

This was a retrospective cohort study of 60 consecutive unilateral (PDFFs) of Su types II (40/60) and III (20/60) in patients aged ≥ 60 years: 33 underwent LLP-ORIF (mean age 81.3 years (SD 10.5), BMI 26.7 (SD 5.5); 29/33 female); and 27 underwent DFA (mean age 78.8 years (SD 8.3); BMI 26.7 (SD 6.6); 19/27 female). The primary outcome measure was reoperation. Secondary outcomes included perioperative complications, calculated blood loss, transfusion requirements, functional mobility status, length of acute hospital stay, discharge destination and mortality. Kaplan-Meier survival analysis was performed. Cox multivariate regression analysis was performed to identify risk factors for reoperation after LLP-ORIF.


Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_4 | Pages 39 - 39
1 Mar 2021
Pavan M Barbera C Galesso D Beninatto R Pluda S
Full Access

Osteoarthritis (OA) is a joint degenerative disease leading to chronic pain and disability, thus resulting in a major socioeconomic health burden. OA, which has long been believed to be a cartilage disease, is now considered a whole-joint disorder affecting various anatomical structures, including subchondral bone. Hyaluronic Acid (HA) is commonly used as intra-articular viscosupplementation therapy for its mechanical features and biological effects. Bisphosphonates (BPs) are antiresorptive agents inhibiting recruitment and maturation of osteoclast precursors and activity of mature osteoclasts in the bone. Pre-clinical evidences in the literature, show that intra-articular BPs could impact on OA progression, slowing down or reversing it. The combination of HA biological and mechanical role and Alendronate (ALD) antiresorptive effect could be an interesting strategy for OA treatment. This study describes the synthesis and characterization of FID-134, a new chemical derivative of HA conjugated with ALD by means of a covalent bond, cleavable in physiological condition. FID-134 was synthesized starting from 500 kDa HA: chemical structure and functionalization degree with ALD were investigated by NMR and ICP-OES. Kinetics of ALD release from FID-134 was determined in TRIS buffer at 37°C and compared to a simple mixture of HA+ALD. 20mg/mL formulations of FID-134 and HA+ALD were investigated for viscoelastic properties, in absence and presence of Ca. 2+. ions. The cytotoxicity of FID-134 and free ALD were tested on Saos-2 osteoblasts (ATCC HTB-85) and on primary bovine chondrocytes (PBC) at day 1, 3 and 7. The efficacy of FID-134 was assessed in an inflammatory arthritis in vitro model, where bovine cartilage biopsies were exposed to IL-1β/OSM (10ng/mL) for 3 weeks; at the same time, cartilage explants were treated with FID-134. Collagen release in the surnatants was quantified and compared to controls. FID-134 structure was confirmed by NMR and the 20% mol/mol functionalization degree was determined by ICP-OES. Only about 50% of total bound ALD was released from FID-134 within 7 days, resulting slower compared to HA+ALD mixture. In presence of Ca. 2+. ions, viscoelastic properties of FID-134 dramatically improved, while HA+ALD formulation remained unaffected. The cytotoxicity of ALD was evident at 100 μM on Saos-2 and PBC after 3 days, while no cytotoxicity was observed at 7 days with FID-134. In the cartilage explant model, a strong collagen release was detected in inflammatory conditions after 3 weeks; this tendency was reversed, and collagen release halved when FID-134 was added to the biopsies. The synthesized HA-ALD adduct, FID-134, opens the door for a new approach for OA treatment. The results suggest that FID-134 could be beneficial in cartilage degradation and in restoration of subchondral bone function. Finally, local administration and controlled BP release would likely overcome the drawbacks of ALD oral administration, such as unspecific features and long-term toxic side effects


Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_3 | Pages 68 - 68
1 Mar 2021
AlFayyadh F Farii HA Farahdel L Turcotte R Frazer A
Full Access

The aim was to analyze the efficacy of zoledronic acid (ZA) versus denosumab in the prevention of pathological fractures in patients with bone metastases from advanced cancers by evaluating all available randomized controlled trials (RCTs) on this subject.

A systematic search of electronic databases (PubMed and MEDLINE) was performed to identify all published RCTs comparing zoledronic acid with denosumab in prevention of pathological fractures in bone metastases. Risk of bias of the studies was assessed. The primary outcomes evaluated were pathological fractures.

Four RCTs (7320 patients) were included. Denosumab was superior to ZA in reducing the likelihood of pathological fractures, when all tumour types were combined (OR 0.86, 95% CI [0.74, 0.99], p = 0.04). Denosumab was not significantly favoured over ZA in endodermal origin (breast and prostate) (OR 0.85, 95% CI [0.68, 1.05], p = 0.13) and mesodermal origin tumours (solid tumours and MM) (OR 0.87, 95% CI [0.71, 1.06], p = 0.16).

Denosumab significantly reduces the likelihood of pathological fractures in comparison to ZA in patients with bone metastases. When pathological fractures were grouped by tumour origin (endodermal or mesodermal), there was no significant difference between denosumab and ZA. Further long-term studies are needed to confirm the effectiveness of these treatment regimens.


The Bone & Joint Journal
Vol. 103-B, Issue 2 | Pages 309 - 320
1 Feb 2021
Powell-Bowns MFR Oag E Ng N Pandit H Moran M Patton JT Clement ND Scott CEH

Aims

The aim of this study was to determine whether fixation, as opposed to revision arthroplasty, can be safely used to treat reducible Vancouver B type fractures in association with a cemented collarless polished tapered femoral stem (the Exeter).

Methods

This retrospective cohort study assessed 152 operatively managed consecutive unilateral Vancouver B fractures involving Exeter stems; 130 were managed with open reduction and internal fixation (ORIF) and 22 with revision arthroplasty. Mean follow-up was 6.5 years (SD 2.6; 3.2 to 12.1). The primary outcome measure was revision of at least one component. Kaplan–Meier survival analysis was performed. Regression analysis was used to identify risk factors for revision following ORIF. Secondary outcomes included any reoperation, complications, blood transfusion, length of hospital stay, and mortality.


Orthopaedic Proceedings
Vol. 102-B, Issue SUPP_11 | Pages 123 - 123
1 Dec 2020
Fong ELS Prabha EL Carney TJ
Full Access

Osteoporosis is a mineral bone disease arising from the predominance of osteoclastic bone resorption. Bisphosphonates which inhibit osteoclasts are commonly used in osteoporosis treatment, but are not without severe adverse effects like osteonecrosis of the jaw. The mechanisms behind the development of such phenomena is not well understood. Bone homeostasis is achieved through an intimate cross-talk between osteoclasts and osteoblasts. Thus, it is important to visualise activities of these cells simultaneously in situ. Currently, there are means to visualise osteoclast shape and numbers with tartrate-resistant alkaline phosphatase (TRAP) staining but no practical and accurate methods to quantify osteoclast activity in situ. This investigation aims to establish the use of ELF97, a substrate of TRAP, to visualise and quantify osteoclast activity. This provides vital clues to mechanisms of various bone disorders. TRAP dephosphorylation of ELF97 results in a detectable fluorescent product at areas of osteoclast activity. Osteoclastic activity was initiated in zebrafish by inducing crush injuries in tail fin rays. Colocalisation of ELF97 fluorescence with osteoclast-specific DsRed in transgenic zebrafish, visualised under confocal microscopy, is used to further establish the specificity of ELF97 to sites of osteoclastic activity. Quantification is established by comparing fluorescence between wild type, osteoclast-deficient mutants and bisphosphonate-treated zebrafish. The utility of ELF97 will also be investigated in terms of the stability of the florescent product. The investigation revealed that ELF97 and DsRed fluorescence were found commonly at crush sites with osteoclastic activity. Wild type zebrafish had greater fluorescence compared to osteoclast-deficient (p<0.0001) and bisphosphonate-treated zebrafish (p<0.0001) after 7 and 14 days post-crush, revealing that fluorescence from ELF97 corresponds to expected osteoclastic activity. Fluorescence of tail fins treated with ELF97 did not diminish over a period of 21 days of storage, demonstrating its stability. ELF97 is thus a useful means to visualise osteoclast activity, potentially crucial in more advanced investigations to understand bone disorders. It could be used in combination with other cellular markers in whole biological samples to study and experimentally manipulate bone remodelling


Bone & Joint Research
Vol. 9, Issue 10 | Pages 709 - 718
1 Oct 2020
Raina DB Liu Y Jacobson OLP Tanner KE Tägil M Lidgren L

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health.

Cite this article: Bone Joint Res 2020;9(10):709–718.


Bone & Joint Open
Vol. 1, Issue 9 | Pages 512 - 519
1 Sep 2020
Monzem S Ballester RY Javaheri B Poulet B Sônego DA Pitsillides AA Souza RL

Aims

The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones.

Methods

Three groups (seven per group) of 12-week-old mice were: 1) ovariectomized and 20 weeks thereafter treated weekly for 24 weeks with 100 μm/kg subcutaneous ibandronate (OVX+IBN); 2) ovariectomized (OVX); or 3) sham-operated (SHAM). Quantitative fracture analysis generated biomechanical properties for the femoral neck. Tibiae were microCT scanned and trabecular (proximal metaphysis) and cortical parameters along almost its whole length measured.


Bone & Joint Research
Vol. 9, Issue 1 | Pages 29 - 35
1 Jan 2020
Choi J Lee YS Shim DM Seo SW

Aims

Receptor activator of nuclear factor-κB ligand (RANKL) is a key molecule that is expressed in bone stromal cells and is associated with metastasis and poor prognosis in many cancers. However, cancer cells that directly express RANKL have yet to be unveiled. The current study sought to evaluate how a single subunit of G protein, guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), transforms cancer cells into RANKL-expressing cancer cells.

Methods

We investigated the specific role of GNAQ using GNAQ wild-type cell lines (non-small-cell lung cancer cell lines; A549 cell lines), GNAQ knockdown cell lines, and patient-derived cancer cells. We evaluated GNAQ, RANKL, macrophage colony-stimulating factor (M-CSF), nuclear transcription factor-κB (NF-κB), inhibitor of NF-κB (IκB), and protein kinase B (Akt) signalling in the GNAQ wild-type and the GNAQ-knockdown cells. Osteoclastogenesis was also evaluated in both cell lines.


The Bone & Joint Journal
Vol. 101-B, Issue 10 | Pages 1285 - 1291
1 Oct 2019
MacKenzie SA Ng RT Snowden G Powell-Bowns MFR Duckworth AD Scott CEH

Aims

Currently, periprosthetic fractures are excluded from the American Society for Bone and Mineral Research (ASBMR) definition of atypical femoral fracture (AFFs). This study aims to report on a series of periprosthetic femoral fractures (PFFs) that otherwise meet the criteria for AFFs. Secondary aims were to identify predictors of periprosthetic atypical femoral fractures (PAFFs) and quantify the complications of treatment.

Patients and Methods

This was a retrospective case control study of consecutive patients with periprosthetic femoral fractures between 2007 and 2017. Two observers identified 16 PAFF cases (mean age 73.9 years (44 to 88), 14 female patients) and 17 typical periprosthetic fractures in patients on bisphosphonate therapy as controls (mean age 80.7 years (60 to 86, 13 female patients). Univariate and multivariate analysis was performed to identify predictors of PAFF. Management and complications were recorded.


Bone & Joint Research
Vol. 8, Issue 7 | Pages 349 - 356
1 Jul 2019
Starlinger J Kaiser G Thomas A Sarahrudi K

Objectives

The osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) balance is of the utmost importance in fracture healing. The aim of this study was therefore to investigate the impact of nonosteogenic factors on OPG and RANKL levels.

Methods

Serum obtained from 51 patients with long bone fractures was collected over 48 weeks. The OPG and serum sRANKL (soluble RANKL) concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Smoking habit, diabetes, and alcohol consumption were recorded.


The Bone & Joint Journal
Vol. 101-B, Issue 2 | Pages 147 - 153
1 Feb 2019
Mai DH Oh C Doany ME Rokito AS Kwon YW Zuckerman JD Virk MS

Aims

The aim of this study was to investigate the effects of preoperative bisphosphonate treatment on the intra- and postoperative outcomes of arthroplasty of the shoulder. The hypothesis was that previous bisphosphonate treatment would adversely affect both intra- and postoperative outcomes.

Patients and Methods

A retrospective cohort study was conducted involving patients undergoing arthroplasty of the shoulder, at a single institution. Two patients with no previous bisphosphonate treatment were matched to each patient who had received this treatment preoperatively by gender, age, race, ethnicity, body mass index (BMI), and type of arthroplasty. Previous bisphosphonate treatment was defined as treatment occurring during the three-year period before the arthroplasty. The primary outcome measure was the incidence of intraoperative complications and those occurring at one and two years postoperatively. A total of 87 patients were included: 29 in the bisphosphonates-exposed (BP+) group and 58 in the non-exposed (BP-) group. In the BP+ group, there were 26 female and three male patients, with a mean age of 71.4 years (51 to 87). In the BP- group, there were 52 female and six male patients, with a mean age of 72.1 years (53 to 88).


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_16 | Pages 96 - 96
1 Nov 2018
Perdikouri C Lidén E Diefenbeck M
Full Access

Nitrogen-containing bisphosphonates such as Zoledronic Acid (ZA) are used clinically for the treatment of skeletal diseases related with increased bone resorption. The gold standard is to administrate the drug through a systemic pathway, however this is often associated with high dosages, risk of side-effects, reduced site-specific drug delivery and hence, limited drug-effectiveness. A controlled local drug delivery, via a biomimetic bone graft, could be beneficial by direct and time-regulated application of significantly lower drug dosage at the site of interest. Thus, higher efficacy and reduced side-effects could be expected. In this experimental in vivo study, we examined the effect of ZA when used together with a Calcium Sulphate/Hydroxyapatite biomaterial in a femoral condyle bone defect in rats and compared local to systemic administration. The following groups were used: group1: empty defect (no biomaterial & no treatment), group2: biomaterial alone, group3: biomaterial + systemic ZA (0.1mg ZA/kg – single subcutaneous injection), group4–6: biomaterial conjugated with ZA at different concentrations, (0.07 to 0.70 mg ZA/mL of paste, corresponding to 0.0024 to 0.024 mg ZA/kg). The animals were sacrificed at 6 weeks and toxicological examination was performed. Bone regeneration was evaluated using qualitative and quantitative micro-CT analysis and Histomorphometry. The results showed a significant difference between the groups, suggesting that ZA has an overall effect on bone healing. The most pronounced effect was seen with the local application of approximately 10 times less ZA-dosage when compared to systemic use (p<0.001). This study demonstrates the importance of local ZA administration in bone regeneration.