Bone turnover and microdamage are impacted by skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This study aimed to establish an understanding of microdamage accumulation and load to failure in healthy and osteolytic vertebrae following cancer treatment (stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX)). Forty-two 6-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo) were studied; 22 were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Animals were randomly assigned to four groups: untreated (healthy=5, osteolytic=6), SBRT on day 14 (healthy=6, osteolytic=6), ZA on day 7 (healthy=4, osteolytic=5), and DTX on day 14 (healthy=5, osteolytic=5). Animals were euthanized on day 21. L1-L3 motion segments were compression loaded to failure and force-displacement data recorded. T13 vertebrae were stained with BaSO. 4. and µCT imaged (90kVp, 44uA, 4.9µm) to visualize microdamage location and volume. Damage volume fraction (DV/BV) was calculated as the ratio of BaSO. 4. to bone volume. Differences in mean load-to-failure were compared using three-way ANOVA (disease status, treatment, cells injected). Differences in mean DV/BV between treatment groups were compared using one-way ANOVA. Treatment had a significant effect on load-to-failure (p=0.004) with ZA strengthening the healthy and osteolytic vertebrae. Reduced strength post SBRT seen in the metastatic (but not the healthy) group may be explained by greater tumor involvement secondary to higher cell injection concentrations. Untreated metastatic samples had higher DV/BV (16.25±2.54%) compared to all treatment groups (p<0.05) suggesting a benefit of treatment to bone quality. Focal and systemic cancer treatments were shown to effect load-to-failure and microdamage accumulation in healthy and osteolytic vertebrae. Developing a better understanding of how treatments effect bone quality and mechanical stability is critical for effective management of patients with spinal metastases

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Type-2 Diabetic (T2D) patients experience up to a 3-fold increase in bone fracture risk[1]. Paradoxically, T2D-patients have a normal or increased bone mineral density when compared to non-diabetic patients. This implies that T2D has a deleterious effect on bone quality, whereby the intrinsic material properties of the bone matrix are altered. Creating clinical challenges as current diagnostic techniques are unable to accurately predict the fracture probability in T2D-patients. To date, the relationship between cyclic fatigue loading, mechanical properties and microdamage accumulation of T2D-bone tissue has not yet been examined and thus our objective is to investigate this relationship. Ethically approved femoral heads were obtained from patients, with (n=8) and without (n=8) T2D. To obtain the mechanical properties of the sample, one core underwent a monotonic compression test to 10% strain, the other core underwent a cyclic compression test at a normalized stress ratio between 0.0035mm/mm and 0.016mm/mm to a maximum strain of 3%. Microdamage was evaluated by staining the tissue with barium sulfate precipitate [2] and conducting microcomputed tomography scanning with a voxel size of 10μm. The monotonically tested T2D-group showed no statistical difference in mechanical properties to the non-T2D-group, even when normalised against BV/TV. There was also no difference in BV/TV. For the cyclic test, the T2D-group had a significantly higher initial modulus (p<0.01) and final modulus (p<0.05). There was no difference in microdamage accumulation. Previous population-level studies have found that T2D-patients have been shown to have an increased fracture risk when compared to non-T2D-patients. This research indicates that T2D does not impair the mechanical properties of trabecular bone from the femoral heads of T2D-patients, suggesting that other mechanisms may be responsible for the increased fracture risk seen in T2D-patients

The presence of microdamage in bone and its targeted repair by activating bone remodelling has been controversial partly because it is difficult to locate and difficult to quantify. A number of studies have now validated techniques to locate and quantify microdamage and microdamage repair in human cortical and trabecular bone samples. The purpose of this study is to determine if microcracks accumulate in the cancellous bone of the intertrochanteric region of the proximal femoral shaft and influence the strength of bone. We have used en bloc basic fuchsin staining to identify in vivo microcracks in 70 micron sections. Trabecular bone was sampled in 33 patients undergoing total hip replacement for primary osteoarthritis. The study sample had a median age of 73 years and included 18 women (aged 49 to 84 years) and 15 men (aged 45 to 85 years). Histomorphometry was used to quantify the number of cracks in each case. In a selection of 12 cases the bone sample was also biomechanically tested to determine the cancellous bone strength. We found that microcracks accumulate with age, particularly after the age of about 60 years. This indicates that the bone from the elderly is more susceptible to fatigue damage than bone from the young. In addition, an increased number of microcracks in the cancellous bone significantly reduced the ultimate failure stress of the bone. Bone screws or pins placed in cortical or trabecular bone create microdamage adjacent to an implant, and the area in which this microdamage occurs is the same as that which subsequently remodels. Microdamage may be the result primarily of procedures during prosthetic implantation, but bone screws or pins can create stress concentrations that can be sites for initiation of new cracks. Therefore, if bone remodelling targets bone microdamage for repair then accumulation of microdamage around prosthetic implants may be responsible for the biologic responses which lead to implant loosening. This phenomenon is understudied in orthopaedic research and is an area requiring further investigation

Objectives. The exact aetiology and pathogenesis of microdamage-induced long bone fractures remain unknown. These fractures are likely to be the result of inadequate bone remodelling in response to damage. This study aims to identify an association of osteocyte apoptosis, the presence of osteocytic osteolysis, and any alterations in sclerostin expression with a fracture of the third metacarpal (Mc-III) bone of Thoroughbred racehorses. Methods. A total of 30 Mc-III bones were obtained; ten bones were fractured during racing, ten were from the contralateral limb, and ten were from control horses. Each Mc-III bone was divided into a fracture site, condyle, condylar groove, and sagittal ridge. Microcracks and diffuse microdamage were quantified. Apoptotic osteocytes were measured using TUNEL staining. Cathepsin K, matrix metalloproteinase-13 (MMP-13), HtrA1, and sclerostin expression were analyzed. Results. In the fracture group, microdamage was elevated 38.9% (. sd 2.6. ) compared with controls. There was no difference in the osteocyte number and the percentage of apoptotic cells between contralateral limb and unraced control; however, there were significantly fewer apoptotic cells in fractured samples (p < 0.02). Immunohistochemistry showed that in deep zones of the fractured samples, sclerostin expression was significantly higher (p < 0.03) than the total number of osteocytes. No increase in cathepsin K, MMP-13, or HtrA1 was present. Conclusion. There is increased microdamage in Mc-III bones that have fractured during racing. In this study, this is not associated with osteocyte apoptosis or osteocytic osteolysis. The finding of increased sclerostin in the region of the fracture suggests that this protein may be playing a key role in the regulation of bone microdamage during stress adaptation. Cite this article: N. Hopper, E. Singer, F. Henson. Increased sclerostin associated with stress fracture of the third metacarpal bone in the Thoroughbred racehorse. Bone Joint Res 2018;7:94–102. DOI: 10.1302/2046-3758.71.BJR-2016-0202.R4

Introduction and Objective. Bone remodelling is a continuous process whereby osteocytes regulate the activity of osteoblasts and osteoclasts to repair loading-induced microdamage. While many in vitro studies have established the role of paracrine factors (e.g., RANKL/OPG) and cellular pathways involved in bone homeostasis, these techniques are generally limited to two-dimensional cell culture, which neglects the role of the native extracellular matrix in maintaining the phenotype of osteocyte. Recently, ex vivo models have been used to understand cell physiology and mechanobiology in the presence of the native matrix. Such approaches could be applicable to study the mechanisms of bone repair, whilst also enabling exploration of biomechanical cues. However, to date an ex vivo model of bone remodelling in cortical bone has not been developed. In this study, the objective was to develop an ex vivo model where cortical bone was subjected to cyclic strains to study the remodelling of bone. Materials and Methods. Ex vivo model of bone remodelling induced by cyclic loading: At the day of culling, beam-shape bovine bone samples were cut and preserved in PBS + 5% Pen/Strep + 2 mM L-Glut overnight at 37°C. Cyclic strains were applied with a three-point bend system to induce damage with a regime at 16.66 mm/min for 5,000 cycles in sterile PBS in Evolve® bags (maximum strain 6%). A control group was cultured under static conditions. Metabolic activity: Alamar Blue assays were performed after 1 and 7 days of ex vivo culture for each group (Static, Loaded) and normalized to weight. Bone remodelling: ALP activity was assessed in the media at day 1 and 7. After 24 hours cell culture conditioned media (CM) was collected from each group and stored at −80°C. RAW264.7 cells were cultured with CM for 6 days, after which the samples were stained for TRAP, to determine osteoclastogenesis, and imaged. Histomorphometry: Samples were cultured with calcein for 3 days to label bone formation between day 4 and 7. Fluorescent images were captured at day 7. μCT scanning was performed at 3 μm resolution after labelling samples with BaSO. 4. precipitate to quantify bone damage. Results. Bone was sectioned and cultured to maintain live osteoblasts and osteocytes. CM that was obtained 24 hours after cyclic loading and added to RAW264.7 cells cultures, resulted in significantly increased osteoclastogenic potential compared to that from static samples (4.245±1.65% vs 0.88±0.48%, p<0.001). Calcein and HE staining indicated the presence of structures similar to bone remodelling cones in both groups after 7 days of culture. Also, 7 days post-loading, matrix microdamage in the stimulated area, detected with the BaSO. 4. precipitate, were not significantly increased under the load point in loaded samples (0.11±0.05% of bone volume), while at the support areas it was significantly higher (0.2387±0.06%, p<0.001) compared to the static (0.062±0.02%). Conclusions. This study demonstrates that (1) cyclic strains applied on ex vivo bovine cortical bone successfully induced remodelling as characterized by the formation of bone resorption cones, along with an increase of osteoclast formation, and (2) there was an induction of microdamage post loading as shown by the significant increases in microdamage labelled. This supports previous in vivo studies with an increase in osteoclastogenesis up to 7 days post loading. This is the first evidence of the development of an ex vivo model to study osteon remodelling that could be applied to study bone physiology and repair

Post-traumatic osteoarthritis (PTOA) is a subset of osteoarthritis, which occurs secondary to traumatic joint injury which is known to cause pathological changes to the osteochondral unit. Articular cartilage degradation is a primary hallmark of OA, and is normally associated with end-stage disease. However, subchondral bone marrow lesions are associated with joint injury, and may represent localized bone microdamage. Changes in the osteochondral unit have been traditionally studied using explant models, of which the femoral-head model is the most common. However, the bone damage caused during harvest can confound studies of microdamage. Thus, we used a novel patellar explant model to study osteochondral tissue dynamics and mechanistic changes in bone-cartilage crosstalk. Firstly, we characterized explants by comparing patella with femoral head models. Then, the patellar explants (n=269) were subjected to either mechanical or inflammatory stimulus. For mechanical stimulus 10% strain was applied at 0.5 and 1 Hz for 10 cycles. We also studied the responses of osteochondral tissues to 10ng/ml of TNF-α or IL-1β for 24hrs. In general the findings showed that patellar explant viability compared extremely well to the femoral head explant. Following IL-1β or TNF-α treatment, MMP13, significantly increased three days post exposure, furthermore we observed a decrease in sulfate glycoaminoglycan (sGAG) content. Bone morphometric analysis showed no significant changes. Contrastingly, mechanical stimulation resulted in a significant decrease sGAG particularly at 0.5Hz, where an increase in MMP13 release 24hrs post stimulation and an upregulation of bone and cartilage matrix degradation markers was observed. Furthermore, mechanical stimulus caused increases in TNF-α, MMP-8, VEGF expression. In summary, this study demonstrates that our novel patella explant model is an excellent system for studying bone-cartilage crosstalk, which responds well to both mechanical and inflammatory stimulus and is thus of great utility in the study of PTOA

Joint registries report that 25–40% of UKR revisions are performed for pain. Proximal tibial strain and microdamage are possible causes of this “unexplained” pain. The aim of this study was to examine the effect of UKR implant design and material on proximal tibial cortical strain and cancellous microdamage. Composite Sawbone tibias were implanted with cemented UKR components: 5 fixed bearing all-polyethylene (FB-AP), 5 fixed bearing metal backed (FB-MB), and 5 mobile bearing metal backed implants (MB-MB). Five intact tibias were used as controls. Tibias were loaded in 500N increments to 2500N. Cortical surface strain was measured using digital image correlation (DIC). Cancellous microdamage was measured using acoustic emission (AE), a technique which detects elastic waves produced by the rapid release of energy during microdamage events. DIC showed significant differences in anteromedial cortical strain between implants at 1500N and 2500N in the proximal 10mm only (p<0.001) with strain shielding in metal backed implants. AE showed significant differences in cancellous microdamage (AE hits), between implants at all loads (p=0.001). FB-AP implants displayed significantly more hits at all loads than both controls and metal backed implants (p<0.001). FB-AP implants also differed significantly by displaying AE hits on unloading (p=0.01), reflecting a lack of implant stiffness. Compared to controls, the FB-AP implant displayed 15x the total AE hits, the FB-MB 6x and the MB-MB 2.7x. All-polyethylene medial UKR implants are associated with greater cancellous bone microdamage than metal backed implants even at low loads

Objectives. Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs. Methods. We present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use. Results. Six broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed. Conclusions. This article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes. Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144–153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1

Osteoarthritis (OA) is the most common musculoskeletal disease in the EU and is characterized by cartilage degeneration, pain and restricted movement. Post-Traumatic OA (PTOA) is a specific disease subset that occurs subsequent to traumatic injury, such as ACL rupture and makes up 12% of the overall disease burden. Our current understanding PTOA is that initial injury affects multiple tissues, and many/all contribute to overall ‘joint failure.’ MRI scans show that subchondral bone marrow lesions (BMLs) are present in 80% of ACL rupture cases in the immediate aftermath of joint injury. Their presence indicates an acute consequence in subchondral bone. It has also been suggested that BMLs overlap with, or directly represent, bone microdamage. Microdamage is known to induce osteoclast-mediated remodelling in bone. Therefore, the inhibition of subchondral bone remodelling, particularly in the early phase post-injury, may be a candidate therapeutic approach for preventing PTOA. Finally, the contiguous link between subchondral bone and articular cartilage, can allow transport of small molecules across this boundary, this suggests that bone/cartilage crosstalk is likely to be a key factor in PTOA development after injury. This presentation will summarize recent advances in our understanding these phenomena in both animal and human studies

Objectives. Up to 40% of unicompartmental knee arthroplasty (UKA) revisions are performed for unexplained pain which may be caused by elevated proximal tibial bone strain. This study investigates the effect of tibial component metal backing and polyethylene thickness on bone strain in a cemented fixed-bearing medial UKA using a finite element model (FEM) validated experimentally by digital image correlation (DIC) and acoustic emission (AE). Materials and Methods. A total of ten composite tibias implanted with all-polyethylene (AP) and metal-backed (MB) tibial components were loaded to 2500 N. Cortical strain was measured using DIC and cancellous microdamage using AE. FEMs were created and validated and polyethylene thickness varied from 6 mm to 10 mm. The volume of cancellous bone exposed to < -3000 µε (pathological loading) and < -7000 µε (yield point) minimum principal (compressive) microstrain and > 3000 µε and > 7000 µε maximum principal (tensile) microstrain was computed. Results. Experimental AE data and the FEM volume of cancellous bone with compressive strain < -3000 µε correlated strongly: R = 0.947, R. 2. = 0.847, percentage error 12.5% (p < 0.001). DIC and FEM data correlated: R = 0.838, R. 2. = 0.702, percentage error 4.5% (p < 0.001). FEM strain patterns included MB lateral edge concentrations; AP concentrations at keel, peg and at the region of load application. Cancellous strains were higher in AP implants at all loads: 2.2- (10 mm) to 3.2-times (6 mm) the volume of cancellous bone compressively strained < -7000 µε. Conclusion. AP tibial components display greater volumes of pathologically overstrained cancellous bone than MB implants of the same geometry. Increasing AP thickness does not overcome these pathological forces and comes at the cost of greater bone resection. Cite this article: C. E. H. Scott, M. J. Eaton, R. W. Nutton, F. A. Wade, S. L. Evans, P. Pankaj. Metal-backed versus all-polyethylene unicompartmental knee arthroplasty: Proximal tibial strain in an experimentally validated finite element model. Bone Joint Res 2017;6:22–30. DOI:10.1302/2046-3758.61.BJR-2016-0142.R1

The energy-storing human Achilles tendon and equine superficial digital flexor tendon (SDFT) show no adaptation to exercise unlike muscle and bone, and are prone to injury. Injury involves microdamage accumulation until there is sufficient weakening for rupture to occur during normal athletic activity. Anatomically opposing positional tendons, such as the common digital extensor tendon (CDET) in the horse rarely suffer exercise–induced injury. Tenocytes maintain the extra-cellular matrix, but in energy-storing tendons they appear unable to adequately repair microdamage as it occurs. Tenocytes have been classified subjectively into 3 subtypes on the basis of histological nuclear morphology. Long, thin type 1 cells are thought to be less synthetically active than cigar-shaped type 2 cells, but their exact morphology and relative proportions in different tendon sites and ages has not been clearly defined. We hypothesised that tenocytes are separable into morphologically distinct subtypes, reflecting differences in age and functional requirements within and between specific tendons. Samples were taken from tensional and compressed regions of the SDFT and CDET of 5 neonates, 5 foals (1–6 m), 5 young adults (2–6 y) and 5 old horses (18–33 y) Cell nuclei were counted and measured in digital images from histological sections by computerised image analysis. Total tenocyte densities and proportions of the 3 subtypes were calculated for each age group, as were nuclear length:width ratios. Length:width ratio distributions for all horses were evaluated using a normality test followed by a paired t-test. There was a significantly higher total cellularity in the SDFT than the CDET, with a higher proportion of type 1 tenocytes in the CDET. With age, total cellularity decreased in all tendon sites and an increase in the proportion of type 1 tenocytes was observed in tensional regions. Foal and neonatal tendons contained significantly higher proportions of type 2 tenocytes than older tendons. The morphology of the two main subtypes in all age groups was significantly different; type 1 tenocytes had a higher nuclear length:width ratio (mean ± SD = 9.6 ± 2.5) than type 2 (mean ± SD =4.7 ±1.1) (p< 0.001). We were able to objectively separate tenocytes into 3 distinct subtypes based on nuclear length:width ratio measurements. There were significant differences in proportions of subtypes with tendon site and age. The positional tendon had significantly lower cellularity and a higher proportion of type 1 tenocytes; these cells may be less functionally active but sufficient to maintain the matrix in a tendon which is not subjected to high levels of strain. The SDFT continues to grow up to 2 years of age and is subjected to high strains, explaining the need for relatively higher proportions of type 2 cells. There is however an age-related increase in type 1 cells in both tendons which may explain an inability of the adult energy-storing tendon to adapt to exercise and to repair microdamage. Understanding the stimulus for age-related changes in tenocyte subtype proportions in tendons with different functions may help us understand the pathogenesis of exercise-induced tendon injury and to develop more appropriate training regimens

Aims. Surgeons and most engineers believe that bone compaction improves implant primary stability without causing undue damage to the bone itself. In this study, we developed a murine distal femoral implant model and tested this dogma. Methods. Each mouse received two femoral implants, one placed into a site prepared by drilling and the other into the contralateral site prepared by drilling followed by stepwise condensation. Results. Condensation significantly increased peri-implant bone density but it also produced higher strains at the interface between the bone and implant, which led to significantly more bone microdamage. Despite increased peri-implant bone density, condensation did not improve implant primary stability as measured by an in vivo lateral stability test. Ultimately, the condensed bone underwent resorption, which delayed the onset of new bone formation around the implant. Conclusion. Collectively, these multiscale analyses demonstrate that condensation does not positively contribute to implant stability or to new peri-implant bone formation. Cite this article:Bone Joint Res. 2020;9(2):60–70

Advances in the performance and longevity of total joint arthroplasty (TJA) have been enabled by related progress in implant materials, device designs, and surgical techniques. Successful TJA also depends upon adequate bone quality to provide an enduring mechanical foundation. Bone quality can be defined as the ability to repetitively withstand physiologically-relevant loads without excess deformation or fracture. It is now recognized that bone quality encompasses more than just material quantity, i.e. densitometrically-measured bone mass. Bone quality is also determined by: material composition and arrangement, cortical and cancellous structure, and extent of microdamage. These properties, together with the appropriate mass, confer bone with the biomechanical competence needed to meet the repetitive load-bearing demands imposed by total joint implants. The need for TJA continues to increase in the aging global baby-boomer population. Unfortunately, this group is also experiencing increases in related comorbidities including: osteoporosis, kidney dysfunction, and diabetes, among others. Collectively these three comorbidities afflict more than 74 million Americans, and each is increasing at 2–8% annually. More importantly, each of these comorbidities negatively affects bone quality through alterations in bone turnover independent of bone mass changes commonly associated with these diseases. Specifically, alterations in bone turnover result in abnormal mineral-to-matrix ratios as measured by Fourier transform infra-red (FTIR) spectroscopy (Fig. 1) and altered Young's moduli (shape-independent resistance to deformation) as measured by nanoindentation (Fig. 2). These parameters are related to bones' fracture toughness and load-bearing capabilities, respectively. Also, low bone turnover is associated with mechanically important structural changes, i.e., decreased trabecular thickness (Fig. 3), cortical thickness and cancellous volume. Furthermore, low bone turnover may result in reducing the repair rate of physiologically – induced bone microdamage. This may lead to increases in the number or length of bone cracks, crack coalescence, and ultimately reduced energy needed for fracture. Therefore, patients needing TJA who also have comorbidities associated with abnormal bone quality are at risk for inferior arthroplasty results. Recognition and treatment of the TJA-relevant biomechanical implications of these comorbidities may help improve outcomes

INTRODUCTION. The increasing incidence of periprosthetic femoral fractures (PFF) after total hip arthroplasty presents growing concerns due to challenges in treatment and increased mortality. PFF are often observed when the prosthesis is implanted in varus, especially with blade-type stems. To help elucidate its impact on the PFF risk, the specific research question is: What is the effect of misalignment of a blade-type stem (resulting in down-sized prosthesis) on 1)the distribution and magnitude of cortical stresses and 2)implant-bone micromotion. METHOD. We developed two finite element models consisting of an average female femur implanted within a generic blade-type stem prosthesis, (i)in neutral alignment, and (ii)oriented in 5° of varus, coupled with corresponding down-sizing of the prosthesis. Each model consisted of 1.1million elements, while the average mesh length at the implant-bone interface was 0.4mm. Elastic moduli of 15GPa(cortex), 150MPa(trabecular bone), and 121GPa(implant), and Poisson's ratio of 0.3 were assumed. The distal end was fixed and the interface was defined as a surface-to-surface contact with friction coefficients (dynamic 0.3; static 0.4). Walking and stair-climbing were simulated by loading the joint contact and muscle forces after scaling to the subjects’ body weight. The peak von Mises stress and the average stress within the surface having 1cm diameter and the center at where the peak stress occurred at each contacting area, the interfacial micromotion along medial, lateral side were analyzed. For statistical analysis, two-tailed t-test was performed between the neutral and varus cases over four loading cycles with significance level of p<0.05. RESULTS. Neutral alignment led to three areas of cortical/implant contact with focal load transfer via those areas, whereas varus placement limited to two areas (Figure 1). In both simulations, the greatest stress was observed at the proximal medial contact. With varus, average and peak stresses increased by 39% and 65% during walking and 28% and 35% during stair-climbing, respectively (Table 1). Micromotion was greatest over the proximal third of the interface, especially along lateral side (Figure 2). The 90. th. percentile values with the varus exceeded the neutral by 35% with walking and 28% with stair-climbing over the lateral interface. DISCUSSION. The proximal medial location of the greatest stress correlates well with clinical observations in PFF involving a posteromedial calcar fragment. Based on current lesser stress than the reported yield stress, loading during daily living activities may result in microdamage rather than an immediate PFF. However, impact loading such as hammering for stem insertion may introduce PFF at the location, especially with in varus. The increase in interfacial micromotion is expected to lead to increase in the risk for implant loosening, also leading to PFF. Further study is needed to confirm the validity and generalizability of these findings. SIGNIFICANCE/CLINICAL RELEVANCE. This study demonstrates the importance of proper alignment of femoral stems of a blade-type design. The misalignment (resulting in down-sizing) increased stress up to 65% and micromotion up to 35% around prosthesis, even during daily activities, thus increased attention to proper implant alignment and sizing is suggested when using components of this design. For any figures or tables, please contact the authors directly

Introduction: When subjected to strain or strain rates are higher than usual, the bone remodels to repair microdamage and to strengthen itself. During the initial resorption phase of remodeling, the bone is transitorily weakened and microdamage can accumulate leading to stress fracture. Methods: To determine whether short –term suppression of bone turnover using bisphosphonates can prevent the initial loss of bone during the remodeling response to high bone strain and strain rates and potentially prevent stress fractures, we conducted a randomized, double blind, placebo-controlled trial of 324 new infantry recruits known to be at high risk for stress fracture. Recruits were given a loading dose of 30 mg of residronate or placebo daily for 10 doses during the first two weeks of basic training and then a once a week maintenance dose for following 12 weeks. Recruits were monitored by biweekly orthopedic examinations during 15 weeks of basic training for stress fractures. Bone scans for suspected tibial and femoral stress fractures and radiographs for suspected metatarsal stress fractures were used to verify stress fracture occurrence. Results: By the intension to treat analysis and per protocol analysis, there was no statistically significant difference in the tibial, femoral, metatarsal, or total stress fracture incidence between the treatment group and the placebo. Discussion: We conclude that prophylactic treatment with residronate in a training population at high risk for stress fracture using a maintenance dosage for the treatment of osteoporosis does not lower stress fracture risk

Aims

The aim of this study was to produce clinical consensus recommendations about the non-surgical treatment of children with Perthes’ disease. The recommendations are intended to support clinical practice in a condition for which there is no robust evidence to guide optimal care.

Osteocytes (OCY) are the end stage differentiation cells of the osteoblast lineage, and are incorporated in the bone matrix during bone formation. In doing so, OCY control the mineralisation of osteoid. OCY form a dense inter-connected network of cell bodies and cell processes throughout the mineralised matrix of bone. OCY viability depends on interstitial fluid flow along the OCY canaliculi, driven by pulsatile blood flow and loading of the skeleton. Maintenance of the density and viability of OCY are essential for bone health because OCY perform many important functions in bone. Firstly, OCY appear to initiate bone repair of bone microdamage. Secondly, OCY are almost certainly the cells, which initiate new bone formation in response to increased loading of bone. Thirdly, OCY are able to regulate the amount of new bone formation in bone remodelling cycles, at least in part by the production of a molecule called sclerostin (SCL). Mutations in the SCL gene, or deletion of the SCL gene in transgenic mice, are associated with particularly dense, fracture resistant bones. This information has led to development of anti-SCL antibodies as a potential anabolic therapy for bones. Bone loss in ovariectomised aged rats was shown recently to be reversed by treatment with neutralising SCL antibodies. There is also some data to suggest that these antibodies may promote fracture healing. Reduced OCY viability and/or density have been reported in association with osteoporotic fracture. OCY viability seems to be dependent on skeletal loading, adequate skeletal blood flow and estrogen in females. OCY viability is adversely affected by hypoxia, unloading of the skeleton and pharmacobiology, such as chronic exposure to glucocorticoids. Both micro and macro-fractures result in disruption of the OCY network, as do procedures such as drilling and cutting of bone. Because of the important roles of OCY in bone, new approaches to bone health may require the identification of agents to protect these cells from harmful influences in disease and ageing

Introduction: Tendon injury is an important cause of injury in racehorses, with flexor tendon and suspensory ligament injuries accounting for 46% of all musculoskeletal injuries at British racecourses (. 1. ). In the galloping horse the superficial digital flexor tendon (SDFT) undergoes strains that are close to the functional limit of the tendon (. 2. ) and it is hypothesised that exercise induces cumulative microdamage in the SDFT of skeletally mature horses which may predispose to clinical disease. We hypothesised that matrix metalloproteinases (MMPs) play a role in the process of tendon degeneration induced by cyclical loading and investigated this using an in vitro model. Methods: Mid-metacarpal SDFTs were harvested from Thoroughbred horses that were euthanased for non-orthopaedic reasons. Tendon explants (2mm x 2mm x 60mm) were maintained in DMEM and placed in custom designed loading cassettes which were cyclically loaded in an incubator using a Dartec materials testing device for 24 hours with 5% strain and at a frequency of 1Hz. Control explants were placed in similar cassettes but were not loaded. The ultimate tensile strength (UTS) of the tendon was assessed using a destructive test at the end of the 24 hour loading period. The experiments were repeated using non-viable tendon explants, or in the presence of a pan-MMP specific inhibitor (Illomastat, 25 μM). Results: Cyclical loading induced a 30% decrease in the UTS of tendons of immature and young mature (< 10 years of age) horses but this increased to a 50% reduction in older (10–30 years of age) horses compared to controls. This loss of UTS was prevented in tendon explants with non-viable cells or with a pan-MMP inhibitor applied to the live explants prior to cyclical loading. Conclusions: The results suggest that an MMP mediated mechanism plays a pivotal role in tendon degeneration following cyclical loading in vitro. Current work including analysis of gene expression and quantification of MMPs within the tendon tissue aims to identify the key MMPs responsible for the loss of tendon UTS following cyclical loading. This will hopefully enable therapeutic strategies to be developed to slow or stop the age-associated tendon degeneration that predisposes to overstrain injury, and thereby help prevent this common orthopaedic disease in horses