Milder impact of the COVID-19 pandemic on the practice of orthopaedic surgery in Greece and Cyprus than other European countries.

PURPOSE: The aim of this study was to highlight the impact of the COVID-19 pandemic on the practice of orthopaedics in Greece and Cyprus. METHODS: The survey used the online questionnaire from AGA (Gesellschaft für Arthroskopie und Gelenkchirurgie; Society for Arthroscopy and Joint Surgery) to facilitate the comparison between different European countries. The questionnaire was distributed online to members of the HAOST (Hellenic Association of Orthopaedic Surgery and Trauma), the ΟΤΑΜΑΤ (Orthopaedic and Trauma Association of Macedonia and Thrace) and the CAOST (Cypriot Association of Orthopaedic Surgery and Trauma). The questionnaire consisted of 29 questions, which included demographic data, questions on the impact of the pandemic on the practice of orthopaedic surgery and questions on the impact on the personal and family life of orthopaedic surgeons. RESULTS: The questionnaire was sent to 1350 orthopaedic surgeons in Greece and Cyprus, 303 of whom responded (response rate 22.44%). 11.2% of the participants reported cancellation of overall orthopaedic procedures. According to 35.6-49.8% of the participants, arthroscopic procedures were continued. As regards elective primary arthroplasties, 35.3% of the participants reported that these continued to be performed at their hospitals. Post-operative follow-ups as well as physiotherapy were affected by the pandemic, and changes were also observed in the habits of orthopaedic surgeons in their personal and family lives. CONCLUSION: The orthopaedic service in Greece and Cyprus decreased during the first wave of the COVID-19 pandemic. Arthroscopic procedures and total joint replacements decreased significantly, but not to the same extent as in other countries. Health systems were not fully prepared for the first wave of the pandemic and the various countries took social measures at different times and to different extents. Thus, studying the impact of the pandemic on the practice of orthopaedic surgery in different countries can help health systems to better prepare for future pandemics; public health can then be shielded and hospitals can continue to provide high-quality orthopaedic care. LEVEL OF EVIDENCE: Level V.

Postoperative Administration of Alpha-tocopherol Enhances Osseointegration of Stainless Steel Implants: An In Vivo Rat Model.

BACKGROUND: Alpha-tocopherol, a well-known antioxidative agent, may have a positive effect on bone formation during the remodeling phase of secondary fracture healing. Fracture healing and osseointegration of implants share common biological pathways; hence, alpha-tocopherol may enhance implant osseointegration. QUESTIONS/PURPOSES: This experimental study in rats assessed the ability of alpha-tocopherol to enhance osseointegration of orthopaedic implants as determined by (1) pull-out strength and removal torque and (2) a histomorphological assessment of bone formation. In addition, we asked, (3) is there a correlation between the administration of alpha-tocopherol and a reduction in postoperative oxidative stress (as determined by malondialdehyde, protein carbonyls, reduced and oxidized glutathione and their ratio, catalase activity and total antioxidant capacity) that develops after implantation of an orthopaedic implant? METHODS: This blinded study was performed in study and control groups, each consisting of 15 young adult male Wistar rats. On Day 0, a custom-designed stainless-steel screw was implanted in the proximal metaphysis of both tibias of all rats. On Day 1, animals were randomized to receive either alpha-tocopherol (40 mg/kg once per day intraperitoneally) or saline (controls). Animals were treated according to identical perioperative and postoperative protocols and were euthanized on Day 29. All animals completed the study and all tibias were suitable for evaluation. Implant pullout strength was assessed in the right tibias, and removal torque and histomorphometric evaluations (that is, volume of newly formed bone surrounding the implant in mm, percentage of newly formed bone, percentage of bone marrow surrounding the implant per optical field, thickness of newly formed bone in µm, percentage of mineralized bone in newly formed bone, volume of mature newly formed bone surrounding the implant in mm and percentage of mineralized newly formed bone per tissue area) were performed in the left tibias. The plasma levels of alpha-tocopherol, malondialdehyde, protein carbonyls, glutathione, glutathione disulfide, catalase, and the total antioxidant capacity were evaluated, and the ratio of glutathione to oxidized glutathione was calculated. RESULTS: All parameters were different between the alpha-tocopherol-treated and control rats, favoring those in the alpha-tocopherol group. The pullout strength for the alpha-tocopherol group (mean ± SD) was 124.9 ± 20.7 newtons (N) versus 88.1 ± 12.7 N in the control group (mean difference -36.7 [95% CI -49.6 to -23.9]; p < 0.001). The torque median value was 7 (range 5.4 to 8.3) versus 5.2 (range 3.6 to 6 ) N/cm (p < 0.001). The newly formed bone volume was 29.8 ± 5.7 X 10 versus 25.2 ± 7.8 X 10 mm (mean difference -4.6 [95% CI -8.3 to -0.8]; p = 0.018), the percentage of mineralized bone in newly formed bone was 74.6% ± 8.7% versus 62.1% ± 9.8% (mean difference -12.5 [95% CI -20.2 to -4.8]; p = 0.003), the percentage of mineralized newly formed bone per tissue area was 40.3 ± 8.6% versus 34.8 ± 9% (mean difference -5.5 [95% CI -10.4 to -0.6]; p = 0.028), the glutathione level was 2 ± 0.4 versus 1.3 ± 0.3 µmol/g of hemoglobin (mean difference -0.6 [95% CI -0.9 to -0.4]; p < 0.001), the median glutathione/oxidized glutathione ratio was 438.8 (range 298 to 553) versus 340.1 (range 212 to 454; p = 0.002), the catalase activity was 155.6 ± 44.6 versus 87.3 ± 25.2 U/mg Hb (mean difference -68.3 [95% CI -95.4 to -41.2]; p < 0.001), the malondialdehyde level was 0.07 ± 0.02 versus 0.14 ± 0.03 µmol/g protein (mean difference 0.07 [95% CI 0.05 to 0.09]; p < 0.001), the protein carbonyl level was 0.16 ± 0.04 versus 0.27 ± 0.08 nmol/mg of protein (mean difference -0.1 [95% CI 0.05 to 0.15]; p = 0.002), the alpha-tocopherol level was 3.9 ± 4.1 versus 0.9 ± 0.2 mg/dL (mean difference -3 [95% CI -5.2 to -0.7]; p = 0.011), and the total antioxidant capacity was 15.9 ± 3.2 versus 13.7 ± 1.7 nmol 2,2-diphenyl-1-picrylhydrazyl radical/g of protein (mean difference -2.1 [95% CI -4.1 to -0.18]; p = 0.008). CONCLUSIONS: These results using an in vivo rat model support that postoperatively administered alpha-tocopherol can enhance the osseointegration of an orthopaedic implant, although a cause and effect relationship between the administration of alpha-tocopherol and a reduction in postoperative stress cannot be securely established. CLINICAL RELEVANCE: These findings suggest that postoperative administration of alpha-tocopherol is a promising approach to enhance osseointegration of orthopaedic implants in patients. Further studies with different animal models and/or different implants and those evaluating the alpha-tocopherol dose response are needed before performing clinical trials that will examine whether these promising, preliminary results can be extrapolated to the clinical setting as well.

The effect of smoking on clinical and radiographic variables, and acute phase reactants in patients with ankylosing spondylitis.

To investigate the association between smoking and clinical, inflammatory and radiographic parameters in patients with ankylosing spondylitis (AS). One hundred and six tumour necrosis factor inhibitor naïve patients with AS were included in the study. The erythrocyte sedimentation rate, C-reactive protein, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI) and modified Stroke AS Spine Score (mSASSS) were assessed cross-sectionally for each patient. Smoking history was obtained, and smoking pack years were calculated. Current smokers had significantly higher BASDAI (p < 0.001) and a trend for higher BASFI (p = 0.059). Ever smokers had significantly higher BASFI (p = 0.035) and a trend for higher mSASSS (p = 0.063) compared to never smokers. Pack years (smoking intensity) were positively correlated with duration of inflammatory back pain (r = 0.628, p < 0.001), BASFI (r = 0.443, p < 0.001) and mSASSS (r = 0.683, p < 0.001). Multivariate regression analyses showed that current smoking was independently associated with a higher BASDAI score [regression coefficient (B) = 14.75, p < 0.001] and increasing pack years were independently associated with higher mSASSS (B = 0.26, p = 0.005). In patients with AS, current smoking was strongly and independently associated with higher disease activity, and cumulative smoking exposure with more radiographic spinal damage. In AS smokers, smoking cessation should be strongly recommended.

The comparative effect of teriparatide and denosumab on activins, follistatins, and inhibins in women with postmenopausal osteoporosis.

The activins-follistatins-inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 mo with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (P=.01) and activin AB (P=.004) and the ratios activin A/follistatin (P=.006), activin B/follistatin (P=.007), activin AB/follistatin (P<.001), and activin AB/ follistatin-like 3 (FSTL3) (P=.034). The significant P for trend in group × time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for BMI and LS BMD but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-mo changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD. Clinical Trials identifier: NCT04206618. ClinicalTrials.gov  https://clinicaltrials.gov/search?term=NCT04206618.

Bone and the muscle comprise 2 tissues that are considered to interact with each other, not only through mechanical but also through endocrine signals. Several components of the activins­follistatins­inhibins (AFI) hormonal system have been shown to be secreted by the muscle and affect the bone possibly contributing to this interplay. We have previously investigated the levels of the AFI molecules in case­control studies and reported differences between osteoporotic vs osteopenic vs postmenopausal and premenopausal women with normal BMD. In this 12-mo, non-randomized, open-labeled, head-to-head comparative study, we prospectively compared the effect of antiosteoporotic agents with opposite effect on bone metabolism, that is, teriparatide vs denosumab, on the circulating concentrations of all known molecules of the AFI system in postmenopausal women with osteoporosis. We observed increases of activins after teriparatide treatment, but no effect after denosumab treatment on any of the AFI molecules studied. Since activins are mainly acting in an autocrine way and since activin B and AB have not been extensively studied, further studies in the basic research, preclinical, and clinical research fields are required to expand these observations and fully elucidate physiology and any therapeutic potential.

Current Progress and Future Perspectives in Contact and Releasing-Type Antimicrobial Coatings of Orthopaedic Implants: A Systematic Review Analysis Emanated from In Vitro and In Vivo Models.

Background: Despite the expanding use of orthopedic devices and the application of strict pre- and postoperative protocols, the elimination of postoperative implant-related infections remains a challenge. Objectives: To identify and assess the in vitro and in vivo properties of antimicrobial-, silver- and iodine-based implants, as well as to present novel approaches to surface modifications of orthopedic implants. Methods: A systematic computer-based review on the development of these implants, on PubMed and Web of Science databases, was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Overall, 31 in vitro and 40 in vivo entries were evaluated. Regarding the in vitro studies, antimicrobial-based coatings were assessed in 12 entries, silver-based coatings in 10, iodine-based in 1, and novel-applied coating technologies in 8 entries. Regarding the in vivo studies, antimicrobial coatings were evaluated in 23 entries, silver-coated implants in 12, and iodine-coated in 1 entry, respectively. The application of novel coatings was studied in the rest of the cases (4). Antimicrobial efficacy was examined using different bacterial strains, and osseointegration ability and biocompatibility were examined in eukaryotic cells and different animal models, including rats, rabbits, and sheep. Conclusions: Assessment of both in vivo and in vitro studies revealed a wide antimicrobial spectrum of the coated implants, related to reduced bacterial growth, inhibition of biofilm formation, and unaffected or enhanced osseointegration, emphasizing the importance of the application of surface modification techniques as an alternative for the treatment of orthopedic implant infections in the clinical settings.

Association of activins, follistatins and inhibins with incident hip fracture in women with postmenopausal osteoporosis: a proof of concept, case-control study.

PURPOSE: The activins-follistatins-inhibins (AFI) hormonal system is considered to regulate muscle and bone mass. We aimed to evaluate AFI in postmenopausal women with an incident hip fracture. METHODS: In this post-hoc analysis of a hospital based case-control study, we evaluated circulating levels of the AFI system in postmenopausal women with a low-energy hip fracture admitted for fixation compared with postmenopausal women with osteoarthritis scheduled for arthroplasty. RESULTS: Circulating levels of follistatin (p = 0.008), FSTL3 (p = 0.013), activin B and AB (both p < 0.001), as well as activin AB/follistatin and activin AB/FSTL3 ratios (p = 0.008 and p = 0.029, respectively) were higher in patients than controls in unadjusted models. Differences for activins B and AB remained after adjustment for age and BMI (p = 0.006 and p = 0.009, respectively) and for FRAX-based risk for hip fracture (p = 0.008 and p = 0.012, respectively) but were lost when 25OHD was added to the regression models. CONCLUSIONS: Our data indicate no major changes in the AFI system in postmenopausal women at the time of hip fracture compared to postmenopausal women with osteoarthritis except for higher activin B and AB levels, whose significance, however, was lost when 25OHD was added to the adjustment models. CLINICAL TRIALS: Clinical Trials identifier: NCT04206618.

The effect of a new oral anticoagulant (Rivaroxaban) on implants pull-out strength. An experimental study in rats.

OBJECTIVES: Thromboprophylaxis reduces the risk of surgery related deep venous thrombosis and pulmonary embolism. The classical anticoagulants (heparin and LWMH) were associated with systemic osteoporosis, poor bone healing and materials' osseointegration. There is a lack of data concerning the effect of the new orally administered anticoagulants on osseointegration. The aim of this study is to investigate the possible effect of rivaroxaban, a direct anti-Xa factor, on osseointegration. METHODS: Twenty eight white, male, Wistar rats were divided into two groups: Group A, study group (n=14) and group B, control group (n=14). In all animals under general anesthesia one screw was inserted on the right tibia. For twenty eight days the animals of group A received intraperitoneal rivaroxaban injections 5mgr/kgr every day. The animals of group B received intraperitoneal equal amount of normal saline injections. At the end of the four weeks all animals were sacrificed and their right tibias were excised and underwent the pull-out test. RESULTS: The mean values of pull-out test were 92,10±19,12N for the control group and 95,46±21,02N for the study group. The statistical analysis using t-test showed no significant difference (p=0,665) for the pull-out test. CONCLUSIONS: These results indicate that Rivaroxaban hasn't got any deleterious effect on the osseointegration of implants on rats.

Correlation between semitendinosus and gracilis tendon cross-sectional area determined using ultrasound, magnetic resonance imaging and intraoperative tendon measurements.

The purpose of this study was to examine the correlation in semitendinosus (ST) and gracilis (GT) tendon cross-sectional area (CSA) evaluated directly during anterior cruciate ligament (ACL) surgery and pre-operatively using ultrasound (US) and magnetic resonance imaging (MRI). A total of 14 patients undergoing ACL reconstruction with a quadruple ST-GT graft by the same orthopaedic surgeon participated in this study. Pre-operative evaluation included determination of ST and GT CSA area using US and MRI. Intraoperative measurement of the diameters of the ST, GT and the final ACL graft using a closed-hole sizing block with 0.5-mm increments was made and this diameter was used to estimate tendon CSA. The correlation between graft diameter and CSA were 0.563 (GT) and 0.807 (ST) for MRI and 0.498 (GT) and 0.612 (ST) for US. The final ACL graft diameter displayed a correlation coefficient of 0.813 with MRI CSA and 0.518 with US CSA. No differences in CSA were observed between intraoperative, MRI and US methods (p>0.05). The intraclass correlation coefficients between the US, MRI and intraoperative graft methods for the ST and GT data ranged from 0.502 to 0.903 with an estimation error ranging from 1.41% to 2.26%. These results indicate that in clinical situations where MRI is contra-indicated or not accessible, US can provide measurable values which could predict sufficient diameter of the ACL graft. In addition, determination of tendon CSA using US displays errors less than 2% which is similar to that observed using MRI. This suggests that the application of US can be applied to in vivo examination of the ST and GT CSA.

Circulating semaphorin-4D and plexin-B1 levels in postmenopausal women with low bone mass: the 3-month effect of zoledronic acid, denosumab or teriparatide treatment.

OBJECTIVE: The evaluation of circulating semaphorin-4D (sema4D) and plexin-B1 in postmenopausal women with low bone mass and the effect of antiresorptive or osteoanabolic treatment. METHODS: Serum samples were obtained from postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion (n = 30), denosumab injection (n = 30) or teriparatide initiation (n = 28) and from controls matched for age, age at menopause and body mass index (n = 30) at the same time points. MAIN OUTCOME MEASURES: Circulating sema4D and plexin-B1. RESULTS: Circulating sema4D increased following denosumab (p = 0.026), whereas decreased following teriparatide (p = 0.013). Sema4D/plexin-B1 ratio increased following denosumab (p = 0.004). At baseline, sema4D and plexin-B1 levels were higher in patients pre-treated with bisphosphonates compared to naïve ones (p < 0.001 and p = 0.001, respectively). In bivariate correlations sema4D was inversely correlated with serum carboxyterminal telopeptide of type 1 collagen (rs -0.282, p = 0.002), intact parathyroid hormone (rs -0.388, p < 0.001) and 25(OH)D (rs -0.316, p < 0.001), whereas there was a trend towards correlation with lumbar spine bone mineral density (rs -0.191, p = 0.053). CONCLUSIONS: Sema4D levels are independently associated with previous bisphosphonate treatment, intact parathyroid hormone and 25(OH)D levels. Denosumab and teriparatide seem to exert an opposite effect on circulating sema4D levels. Further studies are needed to evaluate whether sema4D mediates the coupling effect that occurs following both antiresorptive and osteoanabolic treatment.

Denosumab in treatment-naïve and pre-treated with zoledronic acid postmenopausal women with low bone mass: Effect on bone mineral density and bone turnover markers.

PURPOSE: To compare denosumab-induced changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone markers and free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) between treatment naïve postmenopausal women with low bone mass (naïve group) and those who were previously treated with a single zoledronic acid infusion (post-Zol group). PROCEDURES: Procollagen type 1N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx) and sRANKL levels were measured in serum samples obtained at baseline and 3, 6 and 12months after denosumab initiation. LS and FN BMD were measured at baseline and 12months. RESULTS: LS and FN BMD increased significantly in both naïve and post-Zol group (p<0.001 and p=0.025 vs. p<0.001 and p=0.017, respectively). Despite the higher P1NP and CTx levels in naïve patients at baseline (both p<0.001), denosumab caused comparable decreases in both groups at month 3, which returned to post-Zol group baseline levels at month 6 and 12 in all patients. Similarly, sRANKL levels decreased significantly at month 3 in both groups and returned to baseline levels at months 6 and 12. CONCLUSIONS: In patients previously treated with zoledronic acid, sequential denosumab treatment is effective in terms of BMD increases and bone turnover suppression. Despite the lower baseline levels in patients pre-treated with zoledronic acid, bone markers are similarly decreased in both groups following denosumab administration and maintain their reversibility. Denosumab reversibly suppresses endogenous free sRANKL levels in both naïve and zoledronic acid pre-treated patients.