Patients Aged 80 or More With Distal Radius Fractures Have a Lower One-Year Mortality Rate Than Age- and Gender-Matched Controls: A Register-Based Study.

Introduction: With a rapidly ageing population, the number of distal radius fractures (DRFs) in the elderly will increase dramatically. The aim of this retrospective register study was to examine the 1- and 5-year mortality in DRF patients aged 80 years or more and correlate the overall survival to factors not related to the fracture itself. Material and Methods: Patients aged ≥80 diagnosed with DRFs in Lund University Hospital in Sweden in the period 2010-2012 were extracted from the prospective Lund Distal Radius Fracture register. One- and 5-year standardised mortality rates (SMRs) were calculated using the Swedish standard population as a reference. Medical records were searched for non-fracture-related factors including comorbidity, medications, cognitive impairment and type of living. Cox proportional hazard regression models were used to identify prognostic factors for all-cause mortality. Results: The study cohort included 240 patients, with a mean age of 86. The overall 1-year mortality was 5% (n = 11/240) and the 5-year mortality was 44% (n = 105/240). The 1-year SMR was .44 (CI .18-.69, P < .01) when indirectly adjusted for age and gender and compared to the Swedish standard population. The 5-year SMR was .96 (CI .78-1.14). The patients' ability to live independently in their own home had the highest impact on survival. Discussion: The 1-year mortality rate among the super-elderly DRF patients was only 44% of that expected. Possibly, a DRF at this age could be a sign of a healthier and more active patient. Conclusions: The DRF patients aged 80 or more had a substantially lower mortality rate 1 year after fracture compared to the age- and gender-matched standard population. Patients living independently in their own homes had the longest life expectancy. Treatment should not be limited solely because of old age, but individualised according to the patient's ability and activity level.

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.

Co-delivery of rhBMP-2 and zoledronic acid using calcium sulfate/hydroxyapatite carrier as a bioactive bone substitute to enhance and accelerate spinal fusion.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been FDA-approved for lumbar fusion, but supraphysiologic initial burst release due to suboptimal carrier and late excess bone resorption caused by osteoclast activation have limited its clinical usage. One strategy to mitigate the pro-osteoclast side effect of rhBMP-2 is to give systemic bisphosphonates, but it presents challenges with systemic side effects and low local bioavailability. The aim of this in vivo study was to analyze if posterolateral spinal fusion (PLF) could be improved by utilizing a calcium sulfate/hydroxyapatite (CaS/HA) carrier co-delivering rhBMP-2 and zoledronic acid (ZA). Six groups were allocated (CaS/HA, CaS/HA + BMP-2, CaS/HA + systemic ZA, CaS/HA + local ZA, CaS/HA + BMP-2 + systemic ZA, and CaS/HA + BMP-2 + local ZA). 10-week-old male Wistar rats, were randomly assigned to undergo L4-L5 PLF with implantation of group-dependent scaffolds. At 3 and 6 weeks, the animals were euthanized for radiography, µCT, histological staining, or biomechanical testing to evaluate spinal fusion. The results demonstrated that the CaS/HA biomaterial alone or in combination with local or systemic ZA didn't support PLF. However, the delivery of rhBMP-2 significantly promoted PLF. Combining systemic ZA with BMP-2 didn't enhance spinal fusion. Notably, the co-delivery of rhBMP-2 and ZA using the CaS/HA carrier significantly enhanced and accelerated PLF, without inhibiting systemic bone turnover, and potentially reduced the dose of rhBMP-2. Together, the treatment regimen of CaS/HA biomaterial co-delivering rhBMP-2 and ZA could potentially be a safe and cost-effective off-the-shelf bioactive bone substitute to enhance spinal fusion.

Virtual Follow up After Distal Radius Fracture Surgery-Patient Experiences During the COVID-19 Pandemic.

The majority of patients with a distal radius fracture (DRF) are elderly, a group known to experience difficulties with new technology, partly due to a low level of digital literacy. At the beginning of the coronavirus disease 2019 pandemic, during the spring 2020, patients that underwent DRF surgery had regular follow-ups replaced by video calls from their surgeon and physiotherapist. Afterward, patients answered questionnaires regarding health and digital literacy and took part in semistructured interviews regarding the experience of the virtual follow-up. By systemic text condensation, 2 major categories were identified: (1) The video call-new, but surprisingly simple: All but 1 found it easier than expected, and (2) Video calls-the patient's choice: All but 1 patient preferred video calls to physical visits for follow-up. This is the first mixed methods study to assess patients' experiences of digital follow-up after DRF surgery. This study indicates that digital follow-up was highly appreciated, even among patients with low levels of digital literacy. Digital technologies must be made suitable even for patients with inadequate levels of digital literacy.

Association Between Radiographic and Clinical Outcomes Following Distal Radial Fractures: A Prospective Cohort Study with 1-Year Follow-up in 366 Patients.

BACKGROUND: Several studies of distal radial fractures have investigated final displacement and its association with clinical outcomes. There is still no consensus on the importance of radiographic outcomes, and published studies have not used the same criteria for acceptable alignment. Previous reports have involved the use of linear or dichotomized analyses. METHODS: The present study included 438 patients who were managed with either reduction and cast immobilization or surgery for the treatment of distal radial fractures. Radiographic outcomes were determined on the basis of radiographs that were made 3 months after the injury. Clinical outcome was determined on the basis of the QuickDASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire) score, range of motion, and grip strength at 1 year after the injury. Nonlinear relations were analyzed with cubic splines. RESULTS: Three hundred and sixty-six patients (84%) had both radiographic and clinical follow-up. Seventy patients were lost to follow-up. The mean age was 57 years (range, 18 to 75 years), and 79% of the patients were female. Dorsal tilt was the radiographic parameter that was most strongly associated with the QuickDASH score, grip strength, and range of motion. We found nonlinear relations. Clinical outcomes were found to worsen with increasing dorsal tilt, with the cutoff value being approximately 5°. CONCLUSIONS: We found that clinical outcomes following distal radial fractures have a nonlinear relationship with dorsal tilt, with worse outcomes being associated with increasing dorsal tilt. The decline in clinical outcome starts at 5°, but there is unlikely to be a noticeable difference in capability as measured with the QuickDASH until 20° of dorsal tilt (based on the minimum clinically important difference) in a population up to 75 years old. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Systemic rifampicin shows accretion to locally implanted hydroxyapatite particles in a rat abdominal muscle pouch model.

Introduction: biomaterials combined with antibiotics are routinely used for the management of bone infections. After eluting high concentrations of antibiotics during the first week, sub-inhibitory concentrations of antibiotics may lead to late repopulation of recalcitrant bacteria. Recent studies have shown that systemically given antibiotics like tetracycline and rifampicin (RIF) could seek and bind to locally implanted hydroxyapatite (HA). The aim of this in vivo study was to test if systemically administered rifampicin could replenish HA-based biomaterials with or without prior antibiotic loading to protect the material from late bacterial repopulation. Methods: in vivo accretion of systemically administered RIF to three different types of HA-based materials was tested. In group 1, nano (n)- and micro (m)-sized HA particles were used, while group 2 consisted of a calcium sulfate / hydroxyapatite (CaS / HA) biomaterial without preloaded antibiotics gentamycin (GEN) or vancomycin (VAN), and in group 3, the CaS / HA material contained GEN (CaS / HA + GEN) or VAN (CaS / HA + VAN). The above materials were implanted in an abdominal muscle pouch model in rats, and at 7 d post-surgery, the animals were assigned to a control group (i.e., no systemic antibiotic) and a test group (i.e., animals receiving one single intraperitoneal injection of RIF each day (4 mg per rat) for 3 consecutive days). Twenty-four hours after the third injection, the animals were sacrificed and the implanted pellets were retrieved and tested against Staphylococcus aureus ATCC 25923 in an agar diffusion assay. After overnight incubation, the zone of inhibition (ZOI) around the pellets were measured. Results: in the control group, 2 / 6 CaS / HA + GEN pellets had a ZOI, while all other harvested pellets had no ZOI. No pellets from animals in test group 1 had a ZOI. In test group 2, 10 / 10 CaS / HA pellets showed a ZOI. In test group 3, 5 / 6 CaS / HA + GEN and 4 / 6 CaS / HA + VAN pellets showed a ZOI. Conclusions: in this proof-of-concept study, we have shown that a locally implanted biphasic CaS / HA carrier after 1 week can be loaded by systemic RIF administration and exert an antibacterial effect. Further in vivo infection models are necessary to validate our findings.

Evaluation of an Injectable Biphasic Calcium Sulfate/Hydroxyapatite Cement for the Augmentation of Fenestrated Pedicle Screws in Osteoporotic Vertebrae: A Biomechanical Cadaver Study.

Cement augmentation of pedicle screws is one of the most promising approaches to enhance the anchoring of screws in the osteoporotic spine. To date, there is no ideal cement for pedicle screw augmentation. The purpose of this study was to investigate whether an injectable, bioactive, and degradable calcium sulfate/hydroxyapatite (CaS/HA) cement could increase the maximum pull-out force of pedicle screws in osteoporotic vertebrae. Herein, 17 osteoporotic thoracic and lumbar vertebrae were obtained from a single fresh-frozen human cadaver and instrumented with fenestrated pedicle screws. The right screw in each vertebra was augmented with CaS/HA cement and the un-augmented left side served as a paired control. The cement distribution, interdigitation ability, and cement leakage were evaluated using radiographs. Furthermore, pull-out testing was used to evaluate the immediate mechanical effect of CaS/HA augmentation on the pedicle screws. The CaS/HA cement presented good distribution and interdigitation ability without leakage into the spinal canal. Augmentation significantly enhanced the maximum pull-out force of the pedicle screw in which the augmented side was 39.0% higher than the pedicle-screw-alone side. Therefore, the novel biodegradable biphasic CaS/HA cement could be a promising material for pedicle screw augmentation in the osteoporotic spine.

Bone Remodeling after Ulna Head Replacement in Distal Radioulnar Joint Arthroplasty: A Radiographic Comparison between a Partial and a Total Ulna Head Concept.

Background Ulna head arthroplasty has become an eligible solution for injury or disease in the distal radioulnar joint. Bone resorption beneath the prosthetic head is often reported, but mechanism poorly understood. Purpose The aims were to evaluate bone remodeling and radiological instability in two conceptually different distal radioulnar joint arthroplasties: the total and the partial ulna head replacement. Patients and Methods We conducted a retrospective radiographic assessment of 51 ulna head arthroplasties; 26 Herbert ulna (total ulna head replacement) and 25 First Choice (partial ulna head replacement), to analyze periprosthetic bone resorption and radiologic instability. Intraoperative/immediate postoperative and 1-year radiographs were reviewed by two independent assessors. The radiographic follow-up averaged 13 (10-17) months. The size of the stem in relation to the diameter of the ulna (filling ratio) was measured on the intraoperative/immediate postoperative radiographs. Bone resorption beneath the collar of the prothesis was measured on the 1-year radiographs and expressed as a bone resorption index (BRI) between the length of the resorption and the length of the implant stem. Radiological stability was measured on both the preoperative and the 1-year lateral radiographs. Results The total ulna head prothesis presented with more extensive bone resorption beneath the prosthetic head than the partial ulna head prothesis at 1-year post surgery ( p <0.001). The filling ratio did not influence the 1-year bone resorption and there was no difference regarding radiological instability between the two prosthetic designs. Conclusion The pattern of bone adaptions after an ulna head prothesis may differ due to design and concept of the prosthesis.

Extended local release and improved bacterial eradication by adding rifampicin to a biphasic ceramic carrier containing gentamicin or vancomycin.

AIMS: There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). METHODS: The CaS/HA composites containing RIF/GEN/VAN, either alone or in combination, were first prepared and their injectability, setting time, and antibiotic elution profiles were assessed. Using a continuous disk diffusion assay, the antibacterial behaviour of the material was tested on both planktonic and biofilm-embedded forms of standard and clinical strains of Staphylococcus aureus for 28 days. Development of bacterial resistance to RIF was determined by exposing the biofilm-embedded bacteria continuously to released fractions of antibiotics from CaS/HA-antibiotic composites. RESULTS: Following the addition of RIF to CaS/HA-VAN/GEN, adequate injectability and setting of the CaS/HA composites were noted. Sustained release of RIF above the minimum inhibitory concentrations of S. aureus was observed until study endpoint (day 35). Only combinations of CaS/HA-VAN/GEN + RIF exhibited antibacterial and antibiofilm effects yielding no viable bacteria at study endpoint. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with CaS/HA-VAN/GEN + RIF. CONCLUSION: Our in vitro results indicate that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for local delivery in clinically demanding bone infections.Cite this article: Bone Joint Res 2022;11(11):787-802.

Comparative effectiveness research on proximal femoral nail versus dynamic hip screw in patients with trochanteric fractures: a systematic review and meta-analysis of randomized trials.

BACKGROUND: The treatments for trochanteric fractures try to regain early mobility and limit morbidity and risk of reoperations. The most currently used dynamic hip screw (DHS) and the proximal femoral nail (PFN) are both with pros and cons. We aimed to assess the comparative effectiveness of these interventions for trochanteric fractures by evaluating the surgical performance and postoperative outcomes. METHODS: PubMed, Web of Science and Cochrane Central Register were searched for RCTs comparing DHS and PFN for trochanteric fractures. All selected studies and the risk of bias were assessed. Clinical data including operative time, intraoperative blood loss, intraoperative fluoroscopy time, successful closed reduction and complications like nonunion, implant failure and reoperation were recorded. Random-effects models were used in Review Manager software, and GRADE was applied for the interpretation of the evidence. RESULTS: From 286 identified trials, twelve RCTs including 1889 patients were eligible for inclusion; six RCTs directly comparing DHS with PFN, while other six compared DHS with proximal femoral nail antirotation (PFNA). Compared to DHS, PFN had shorter operative time and led to less intraoperative blood loss. However, DHS need less intraoperative fluoroscopy time than PFN. No difference was seen for the achievement of closed reduction. For risk of postoperative complications, no difference was seen between PFN and DHS for non-union, risk of implant failure and revision surgery. CONCLUSIONS: PFN(A) resulted in a shorter operative time and less intraoperative blood loss compared to DHS. However, no difference was seen for postoperative complications. Trial registration PROSPERO: CRD42021239974.

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.

Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin.

Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

Forecasting effects of "fast-tracks" for surgery in the Swedish national guidelines for distal radius fractures.

BACKGROUND AND PURPOSE: National guidelines for treatment of distal radius fractures (DRFs) were presented in Sweden in 2021. In the guidelines, a fast-track is recommended for 4 subgroups of highly unstable DRFs. Regardless of the results of the closed reduction these are recommended for surgery within 1 week of injury. This study aims to evaluate the potential consequences of the newly presented national guidelines on incidence of surgical interventions. PATIENTS AND METHODS: In all, 1,609 patients (1,635 DRFs) with primary radiographs after a DRF between 2014 and 2017 at two Swedish hospitals were included in a retrospective cohort study. An estimation was made of the percentage of patients in the historical pre-guidelines cohort, that would have been recommended early primary surgery according to the new national guidelines compared to treatment implemented without the support of these guidelines. RESULTS: On a strict radiological basis, 32% (516 out of 1635) of DRFs were classified into one of the 4 defined subgroups. At 9-13 days follow-up, cast treatment was converted into delayed primary surgery in 201 cases. Out of these, 56% (112 out of 201) fulfilled the fast-track criteria and would with the new guidelines have been subject to early primary surgery. INTERPRETATION: The fast-track regimen in the new guidelines, has a high likelihood of identifying the unstable fractures benefitting from early primary surgery. If the proposed Swedish national guidelines for DRF treatment are implemented, a greater proportion of fractures would be treated with early primary surgery, and a delayed surgery avoided in the majority of cases. The potential benefits in relation to possible costs when using the fast-track criteria in every day practice are still unknown.

Longitudinal in vivo biodistribution of nano and micro sized hydroxyapatite particles implanted in a bone defect.

Hydroxyapatite (HA) has been widely used as a bone substitute and more recently as a carrier for local delivery of bone targeted drugs. Majority of the approved HA based biomaterials and drug carriers comprise of micrometer sized particulate HA (mHA) or granules and can therefore only be used for extracellular drug release. This shortcoming could be overcome with the use of cell penetrating HA nanoparticles (nHA) but a major concern with the clinical use of nHA is the lack of data on its in vivo biodistribution after implantation. In this study, we aimed to study the in vivo biodistribution of locally implanted nHA in a clinically relevant tibial void in rats and compare it with mHA or a combination of mHA and nHA. To enable in vivo tracking, HA particles were first labelled with 14C-zoledronic acid (14C-ZA), known to have a high binding affinity to HA. The labelled particles were then implanted in the animals and the radioactivity in the proximal tibia and vital organs was detected at various time points (Day 1, 7 and 28) post-implantation using scintillation counting. The local distribution of the particles in the bone was studied with micro-CT. We found that majority (>99.9%) of the implanted HA particles, irrespective of the size, stayed locally at the implantation site even after 28 days and the findings were confirmed using micro-CT. Less than 0.1% radioactivity was observed in the kidney and the spleen at later time points of day 7 and 28. No pathological changes in any of the vital organs could be observed histologically. This is the first longitudinal in vivo HA biodistribution study showing that the local implantation of nHA particles in bone is safe and that nHA could potentially be used for localized drug delivery.

A combined fracture and mortality risk index useful for treatment stratification in hip fragility fractures.

OBJECTIVES: In this study, we aimed to assess the stratification ability of the Fracture and Mortality Risk Evaluation (FAME) index for reoperation, new fragility fracture, and mortality during one-year follow-up. PATIENTS AND METHODS: Between November 2018 and July 2019, a total of 94 consecutive hip fragility fracture patients from two centers (20 males, 74 females; mean age: 79.3±8.9 years; range, 57 to 100 years) were retrospectively analyzed. The patients were classified into high, intermediate, and low fracture and mortality risk groups according to the Fracture Risk Assessment Tool (FRAX) score and Sernbo score, respectively, as well as nine combined categories according to the FAME index. Hospital records were reviewed to identify re-fractures (reoperations, implant failure, new fragility fractures on any site) and mortality at one year following the FAME index classification. RESULTS: Overall re-fracture and mortality rates were 20.2% and 33%, respectively. High fracture risk category (FRAX-H) was significantly associated with higher re-fracture (odds ratio [OR]: 2.9, 95% confidence interval [CI]: 1-8.2, p=0.037) and mortality rates compared to others (OR: 3.7, 95% CI: 1.5-9.3, p=0.003). The patients classified within the FRAX-H category (n=35) had different mortality rates according to their Sernbo classification; i.e., patients classified as low mortality risk (Sernbo-L) (n=17) had lower mortality rates compared to others in this group (n=18) (35.3% and 66.7%, respectively), indicating a low statistical significance (OR: 0.3, 95% CI: 0.1-1.1, p=0.063). Similarly, within patients classified in Sernbo-L category (n=64), those classified as high fracture risk (FRAX-H) (n=17) had significantly higher re-fracture rates compared to others in this group (n=47) (35.3% and 8.5%, respectively), (OR: 5.9; 95% CI: 1.4-24.5), (p=0.017). Multivariate logistic regression analyses adjusting for covariates (age, sex, length of hospital stay and BMI) yielded similar results. CONCLUSION: The FAME index appears to be a useful stratification tool for allocating patients in a randomized-controlled trial for augmentation of hip fragility fractures.

Different microbial and resistance patterns in primary total knee arthroplasty infections - a report on 283 patients from Lithuania and Sweden.

BACKGROUND: The microbiology and the susceptibility patterns of infected total knee arthroplasties (TKAs) vary depending on demographic, local antimicrobial stewardship, and surgical factors. We wanted to compare the recent microbial profile and antimicrobial resistance pattern in revisions due to infections after primary TKAs in Sweden and Lithuania. Our hypothesis was that there is a difference in bacteriology and resistance pattern based on patient related, societal and local hospital factors as almost similar praxis have been applied for TKA surgery, short term systemic prophylaxis and routine use of local gentamicin containing bone cement. METHODS: Primary TKAs revised for the first time due to verified or suspected infection were collected nationwide in Sweden during 2018, and in Lithuania between 2011 and 2020 from a single major TKA revision centre in Kaunas. We identified 202 TKAs in Sweden from the Swedish Knee Arthroplasty Register and 84 from Kaunas revised due to infection. We collected available culture reports and evaluated the type of microorganisms with antimicrobial resistance pattern at revision. RESULTS: The majority of the infected cases in Sweden were early-type prosthetic joint infection (PJI) (44%), whereas late-type PJI (52%) were more common in the Kaunas cases. Gram-positive bacteria prevailed in both Sweden (55%) and Lithuania (80%). Staphylococcus aureus was the most frequent organism identified in both countries (33% in Sweden and 34% in Lithuania). More polymicrobial infections were observed in Sweden than in Lithuania (16 and 6% respectively). Methicillin resistance in Staphylococcus aureus and coagulase-negative staphylococci were higher in Lithuania (4/28 and 19/29) than in Sweden (1/42 and 9/41). CONCLUSIONS: The type of infections, microbial profile, and drug resistance pattern differed between Sweden and Lithuania. Societal and local hospitals factors with emerging resistance in Lithuania are the most plausible explanation for the difference. Lack of complete data on a national level in Lithuania underlines the importance of adding microbiology of PJIs in implant registers for national aggregation and allow cross country comparisons.

Manufacturing of Human Tissues as off-the-Shelf Grafts Programmed to Induce Regeneration.

Design criteria for tissue-engineered materials in regenerative medicine include robust biological effectiveness, off-the-shelf availability, and scalable manufacturing under standardized conditions. For bone repair, existing strategies rely on primary autologous cells, associated with unpredictable performance, limited availability and complex logistic. Here, a conceptual shift based on the manufacturing of devitalized human hypertrophic cartilage (HyC), as cell-free material inducing bone formation by recapitulating the developmental process of endochondral ossification, is reported. The strategy relies on a customized human mesenchymal line expressing bone morphogenetic protein-2 (BMP-2), critically required for robust chondrogenesis and concomitant extracellular matrix (ECM) enrichment. Following apoptosis-driven devitalization, lyophilization, and storage, the resulting off-the-shelf cartilage tissue exhibits unprecedented osteoinductive properties, unmatched by synthetic delivery of BMP-2 or by living engineered grafts. Scalability and pre-clinical efficacy are demonstrated by bioreactor-based production and subsequent orthotopic assessment. The findings exemplify the broader paradigm of programming human cell lines as biological factory units to engineer customized ECMs, designed to activate specific regenerative processes.

Sustained and controlled delivery of doxorubicin from an in-situ setting biphasic hydroxyapatite carrier for local treatment of a highly proliferative human osteosarcoma.

Doxorubicin (DOX) is a cornerstone drug in the treatment of osteosarcoma. However, achieving sufficient concentration in the tumor tissue after systemic administration with few side effects has been a challenge. Even with the most advanced nanotechnology approaches, less than 5% of the total administered drug gets delivered to the target site. Alternatives to increase the local concentration of DOX within the tumor using improved drug delivery methods are needed. In this study, we evaluate a clinically approved calcium sulfate/hydroxyapatite (CaS/HA) carrier, both in-vitro and in-vivo, for local, sustained and controlled delivery of DOX to improve osteosarcoma treatment. In-vitro drug release studies indicated that nearly 28% and 36% of the loaded drug was released over a period of 4-weeks at physiological pH (7.4) and acidic pH (5), respectively. About 63% of the drug had been released after 4-weeks in-vivo. The efficacy of the released drug from the CaS/HA material was verified on two human osteosarcoma cell lines MG-63 and 143B. It was demonstrated that the released drug fractions functioned the same way as the free drug without impacting its efficacy. Finally, the carrier system with DOX was assessed using two clinically relevant human osteosarcoma xenograft models. Compared to no treatment or the clinical standard of care with systemic DOX administration, the delivery of DOX using a CaS/HA biomaterial could significantly hinder tumor progression by inhibiting angiogenesis and cell proliferation. Our results indicate that a clinically approved CaS/HA biomaterial containing cytostatics could potentially be used for the local treatment of osteosarcoma. STATEMENT OF SIGNIFICANCE: The triad of doxorubicin (DOX), methotrexate and cisplatin has routinely been used for the treatment of osteosarcoma. These drugs dramatically improved the prognosis, but 45-55% of the patients respond poorly to the treatment with low 5-year survival. In the present study, we repurpose the cornerstone drug DOX by embedding it in a calcium sulfate/hydroxyapatite (CaS/HA) biomaterial, ensuring a spatio-temporal drug release and a hypothetically higher and longer lasting intra-tumoral concentration of DOX. This delivery system could dramatically hinder the progression of a highly aggressive osteosarcoma compared to systemic administration, by inhibiting angiogenesis and cell proliferation. Our data show an efficient method for supplementary osteosarcoma treatment with possible rapid translational potential due to clinically approved constituents.

Augmenting a dynamic hip screw with a calcium sulfate/hydroxyapatite biomaterial.

Internal fixation failure in hip fractures can lead to reoperation. Calcium sulfate/hydroxyapatite (CaS/HA) is a biomaterial that can be used for augmenting fracture fixation. We aimed to determine whether an injection of 2 ml CaS/HA increases the fixation of a dynamic hip screw inserted in synthetic and human trabecular bone. The study consists of two parts: 1) synthetic bone blocks (n = 74), with three subgroups: empty (cannulated screw, no injection), cannulated, and fenestrated; and 2) osteoporotic human femoral heads (n = 29), with the same subgroups. The heads were imaged using µCT. Bone volume fraction, insertion angle, and head diameter were measured. Pullout tests were performed and peak force, stiffness, and work were measured. The fenestrated group showed increases in pullout strength compared to no injection in the synthetic blocks. The cannulated group showed a higher pullout strength in low-density blocks. In the femoral heads, the variation was larger and there were no significant differences between groups. The bone volume fraction correlated with the peak force and work, and the insertion angle correlated with the stiffness. CaS/HA can improve the fixation of a dynamic hip screw. For clinical use, spreading of the material around the threads of the screw must be ensured.

Dual modality neutron and x-ray tomography for enhanced image analysis of the bone-metal interface.

The bone tissue formed at the contact interface with metallic implants, particularly its 3D microstructure, plays a pivotal role for the structural integrity of implant fixation. X-ray tomography is the classical imaging technique used for accessing microstructural information from bone tissue. However, neutron tomography has shown promise for visualising the immediate bone-metal implant interface, something which is highly challenging with x-rays due to large differences in attenuation between metal and biological tissue causing image artefacts. To highlight and explore the complementary nature of neutron and x-ray tomography, proximal rat tibiae with titanium-based implants were imaged with both modalities. The two techniques were compared in terms of visualisation of different material phases and by comparing the properties of the individual images, such as the contrast-to-noise ratio. After superimposing the images using a dedicated image registration algorithm, the complementarity was further investigated via analysis of the dual modality histogram, joining the neutron and x-ray data. From these joint histograms, peaks with well-defined grey value intervals corresponding to the different material phases observed in the specimens were identified and compared. The results highlight differences in how neutrons and x-rays interact with biological tissues and metallic implants, as well as the benefits of combining both modalities. Future refinement of the joint histogram analysis could improve the segmentation of structures and tissues, and yield novel information about specimen-specific properties such as moisture content.