The Morphologic Patella Entry Point Into the Proximal Trochlea Is More Lateral in Recurrent Dislocators Than Controls as Measured by Entry Point-Trochlear Groove Angle.

PURPOSE: To create a metric for evaluating the degree of laterality of the patella's entry into the trochlea, the entry point-trochlear groove (EP-TG) angle, and to evaluate if this laterality is associated with recurrent patella instability. METHODS: The time frame of the study was January 2020 to February 2023. The inclusion criteria were patients treated by the senior author (J.P.F.) (with the exception of 2 patients who were treated by another provider at the institution who was aware of the study) who have been diagnosed with recurrent atraumatic patellar dislocations. Controls without knee pathology were selected from the New Mexico Decedent Imaging Database (NMDID). Simpleware ScanIP was used to create 3-dimensional (3D) models of the distal femurs from computed tomography scans. Anteroposterior images of these 3D models were uploaded to a custom EP-TG angle measuring tool. Three measurers used the tool to measure the EP-TG angle of the distal femurs. RESULTS: Twenty-eight patients were included for the recurrent dislocator group. Twenty-four decedents from the NMDID were selected for the control group, each with a left or right knee chosen randomly for measurement. A 1-sided Mann-Whitney U test, used to evaluate whether the recurrent dislocators had higher EP-TG angle values, yielded a P value <.001, demonstrating a high level of significance. A Bayesian mixed-effect model, used to determine how different the EP-TG angles are between the 2 groups, gave a posterior predictive interval of [11.93°, 19.12°] for the EP-TG angle shift of dislocators. The intraclass correlation coefficient was 0.648. CONCLUSIONS: The morphologic entry point of the patella into the proximal trochlea is more lateral in recurrent patella dislocators than in controls. This increased laterality can be measured by the EP-TG angle, which may be useful information for optimizing treatment of recurrent patella instability. LEVEL OF EVIDENCE: Level III, case control study.

Using preoperative planning software to assess the effect of head length on prosthetic range of motion in a high-risk population: a three-dimensional modeling study.

PURPOSE: Concurrent use of minus heads with tapered stems in total hip arthroplasty (THA) decreases the prosthetic range of motion (pROM). Three-dimensional preoperative templating can simulate the location of the impingement by taking the hip through a virtual pROM. This enables surgeons to simulate how modifying the type of implant, orientation, and position influences impingement. We hypothesized that CT-based modeling would result in a decrease in the pROM, thereby increasing the risk of impingement when minus heads are used. METHODS: Forty-three patients who underwent robotic-assisted primary THAs were included. Prosthetic head diameter (32/36-mm) and head length (minus/zero/plus) were the predictors. Maximum external rotation at full hip extension and internal rotation at 90° and 100° of flexion prior to prosthetic impingement were the outcome variables. A CT-based preoperative planning software was used for pROM estimation and impingement detection. RESULTS: Significant decreases in pROM were found for both head diameters as the head length decreased and was more pronounced in external rotation during full hip extension (changes of 2.8-3.4° for the 32-mm head and 1.6-2.8° for the 36-mm head (p = 0.00011)). The magnitude of loss in pROM when using a minus head was larger than the gain provided by a plus head in tapered stems (p < 0.0001). CONCLUSION: Head length affects the offset and pROM. When the use of minus heads or smaller heads is indicated, 3D preoperative templating for assessing postoperative pROM and impingement provides surgeons with options to consider alternate surgical plans offering additional assurance and protection from dislocation.

Three-Dimensional Printing of Models of Patellofemoral Joint Articular Cartilage in Patients With Patella Instability for Observing Joint Congruity.

Three-dimensional (3D) modeling and printing are increasingly used in the field of orthopaedic surgery for both research and patient care. One area where they are particularly helpful is in improving our understanding of the patellofemoral (PF) joint. Heretofore, morphological studies that use 3D models of the PF joint have primarily been based on computed tomography imaging data and thus do not incorporate articular cartilage. Here, we describe a method for creating 3D models of the articular surfaces of the PF joint based on magnetic resonance imaging. Models created using this technique can be used to improve our understanding of the morphology of the articular surfaces of the PF joint and its relationship to joint pathologies. Of particular interest is our finding of articular congruity in printed articular cartilage surfaces of dysplastic PF joints of recurrent patella dislocators.

Single-Cell Transcriptomics of Bone Marrow Stromal Cells in Diversity Outbred Mice: A Model for Population-Level scRNA-Seq Studies.

Genome-wide association studies (GWASs) have advanced our understanding of the genetics of osteoporosis; however, the challenge has been converting associations to causal genes. Studies have utilized transcriptomics data to link disease-associated variants to genes, but few population transcriptomics data sets have been generated on bone at the single-cell level. To address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions from five diversity outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model to generate cell type-specific transcriptomic profiles of mesenchymal lineage cells from large populations of mice to inform genetic studies. By enriching for mesenchymal lineage cells in vitro, coupled with pooling of multiple samples and downstream genotype deconvolution, we demonstrate the scalability of this model for population-level studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were similar from a transcriptomic perspective to cells isolated in vivo. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell types. SCENIC was used to reconstruct gene regulatory networks (GRNs), and we observed that cell types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of bone mineral density (BMD) heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically informative model to generate cell type-specific transcriptomic profiles of mesenchymal lineage cells in large populations. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia.

Iron deficiency is a potent stimulator of fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism, that is classically thought to be produced by bone-embedded osteocytes. Here, we show that iron-deficient transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibit elevated circulating FGF23 and Fgf23 messenger RNA (mRNA) upregulation in the bone marrow (BM) but not the cortical bone. To clarify sites of Fgf23 promoter activity in Tmprss6-/- mice, we introduced a heterozygous enhanced green fluorescent protein (eGFP) reporter allele at the endogenous Fgf23 locus. Heterozygous Fgf23 disruption did not alter the severity of systemic iron deficiency or anemia in the Tmprss6-/- mice. Tmprss6-/-Fgf23+/eGFP mice showed green fluorescence in the vascular regions of BM sections and showed a subset of BM endothelial cells that were GFPbright by flow cytometry. Mining of transcriptomic data sets from mice with normal iron balance revealed higher Fgf23 mRNA in BM sinusoidal endothelial cells (BM-SECs) than that in other BM endothelial cell populations. Anti-GFP immunohistochemistry of fixed BM sections from Tmprss6-/-Fgf23+/eGFP mice revealed GFP expression in BM-SECs, which was more intense than in nonanemic controls. In addition, in mice with intact Tmprss6 alleles, Fgf23-eGFP reporter expression increased in BM-SECs following large-volume phlebotomy and also following erythropoietin treatment both ex vivo and in vivo. Collectively, our results identified BM-SECs as a novel site for Fgf23 upregulation in both acute and chronic anemia. Given the elevated serum erythropoietin in both anemic models, our findings raise the possibility that erythropoietin may act directly on BM-SECs to promote FGF23 production during anemia.

Three-Dimensional Printing of the Patellofemoral Joints of Patellar Instability Patients.

Three-dimensional (3D) modeling and printing comprise an important tool for orthopaedic surgeons. One area in which 3D modeling has the potential to dramatically improve our understanding of biomechanical kinematics is pathologies of the patellofemoral joint, in particular trochlear dysplasia. We describe a method for creating 3D printed models of the patellofemoral joint, including computed tomography image acquisition, image segmentation, model creation, and 3D printing. The models created can help surgeons understand and plan surgery for recurrent patellar dislocations.

Hip Abduction Can Be Considered the Sole Posterior Precaution Strategy to Lower the Rate of Impingement After Posterior Approach Total Hip Arthroplasty With Large Femoral Head: A Computer Simulation Study.

BACKGROUND: Studies suggest that posterior hip precautions are unnecessary after total hip arthroplasty; however, many surgeons and patients choose to follow these precautions to some extent. In this study, we hypothesized that 20° of hip abduction would be sufficient to prevent impingement and dislocation in motions requiring hip flexion when using larger prosthetic heads (≥36 mm) when the acetabular implant is placed within a reasonable orientation (anteversion:15-25° and inclination: 40-60°). METHODS: Using a robotic hip platform, we investigated the effect of hip abduction on prosthetic and bony impingement in 43 patients. For the flexed seated position, anterior pelvic tilt angles of 10 and 20° were chosen, while anterior pelvic tilt angles of 70 and 90° were chosen for the bending forward position. An additional 10° of hip external rotation and 10 or 20° of hip internal rotation were also added to the simulation. One hip received a 32-mm head; otherwise, 36-, 40-mm, or dual-mobility heads were used. The study power was 0.99, and the effect size was 0.644. RESULTS: In 65% of the cases, bone-bone impingement between the calcar and anterior-inferior iliac spine was the main type of impingement. The absolute risk of impingement decreased between 0 and 16.3% in both tested positions with the addition of 20° hip abduction. CONCLUSION: With modern primary total hip arthroplasty stems (low neck diameter) and an overall acceptable cup anteversion angle, small degrees of hip abduction may be the only posterior hip precaution strategy required to lower the risk of dislocation among patients. Future studies can potentially investigate the concept of personalized hip precautions based on preoperative computer simulations, utilized implants, hip-spine relations, and final implant orientation.

How metal augments, polyethylene thickness and stem length affect tibial baseplate load transfer in revision total knee arthroplasty.

BACKGROUND: It is unclear howmetal augments,polyethylene (PE) liner thickness, and length of cemented stemcontribute to load transferwhen reconstructing uncontained tibial metaphyseal bone loss of Anderson Orthopedic Research Institute (AORI) Type II defects during revision total knee arthroplasty (rTKA).The aimof this study is to understand the impact of these three variableson load transfer through the tibial baseplate. For a fixed defect depth, we hypothesized that there is a particular combination of liner and augment thickness and stem length that minimizes bone stress, reducing the risk of aseptic loosening. METHODS: We conducted a finite element analysis (FEA) to model stresses at the bone-cement interface with different iterations of metal augments, PE liner thicknesses andfully-cemented stems lengths. RESULTS: For a 20 mm tibial defect, constructs with thicker metal augments and thinner polyethylene liners were superior. Constructswith a fully cemented stem further reduced bone stress on the tibial plateau. Bone stress was lowest when a 100 mm fully-cemented stem was used, while stems between 30 mm - 80 mm produced similar results. CONCLUSIONS: When addressing a tibial bone defect of AORI Type II in rTKA, our FEA model demonstrates that surgeons should opt to use the thickest metal augments in combination with afully-cemented stem with an added length of at least 30 mm, which allows for surgical flexibility together with the most stable construct.Our study is notably limited by lack of modeling of knee joint moments, which are important when considering micromotion, bone-implant interface and stem effectiveness.

Simulating Prophylactic Fixation Methods for Osteoporotic Femoral Neck Fracture Prevention.

Introduction: Geriatric patients who suffer femoral neck fractures have high morbidity and mortality. Prophylactic fixation of the femoral neck is a potential avenue to reduce the incidence of femoral neck fractures. We studied 3 different implants traditionally used to stabilize the femoral neck: 6.5 mm cannulated screws (CANN), the femoral neck system (FNS) (Depuy Synthes), and the dynamic hip screw (DHS) (Depuy Synthes). Materials and Methods: Five osteoporotic Sawbone femurs were used for each model and a control group. Two scenarios were investigated: single leg stance to measure construct stiffness and lateral impact to measure construct stiffness, energy to fracture, and qualitative examination of fracture patterns. Stiffness for each femur and energy to fracture for the lateral impact scenario were calculated and compared between groups using one-way ANOVA. Results: DHS showed significantly higher stiffness than the other 2 implants and the control in single leg stance. In the lateral impact scenario, the DHS and CANN were significantly stiffer FNS and the control. Femurs implanted with CANN tended to fracture at the greater trochanter while FNS fractured in a transverse subtrochanteric pattern, and DHS fractured obliquely in the subtrochanteric region. Discussion: FNS and DHS experienced fracture patterns less amenable to surgical correction. CANN and DHS proved better able to resist external forces in the lateral fall scenario. CANN also proved better able to resist external forces in the single leg stance scenario and experienced a more amenable fracture pattern in the lateral fall scenario. Conclusions: FNS was less able to resist external forces compared with the other implants. This work informs the potential implications between the choice of implants that, although historically have not been used prophylactically, may be considered in the future for prophylactic stabilization of the femoral neck. Cadaveric study and clinical trials are recommended for further study.

Finite Element Evaluation of the Femoral Neck System as Prophylactic Fixation to Prevent Contralateral Hip Fractures.

Introduction: Hip fractures cause significant morbidity and mortality for geriatric patients, and incidence is increasing as the population ages. Following a primary hip fracture, up to 20% may suffer a contralateral hip fracture within 5 years despite fracture risk reduction measures, including fall prevention and osteoporosis pharmacologic treatment. The aim of this study is to assess whether insertion of the Femoral Neck System (Depuy Synthes, West Chester, PA) into the contralateral proximal femur may strengthen the bone and decrease the incidence of contralateral hip fractures. Materials and Methods: ScanIP, an image processing software was used to produce 3-dimensional models of a cadaver femur with the implanted device. Models were meshed and exported to Abaqus for finite element analysis to evaluate the device's ability to reduce stress in the proximal femur. Results were analyzed for element-wise volume and von-Mises stresses. Results: The implant reduced peak stress and bone failure at all levels of bone quality. Specifically in osteoporotic bone, the implant decreased peak stress by 27%, proximal femur trabecular bone failure by 5% and cortical bone failure by 100% in the femoral neck. Conclusions: Our results from computer generated finite element analyses indicate that the Femoral Neck System may strengthen an osteoporotic proximal femur in the event of a lateral fall. Further investigation with expanded finite element analysis and cadaveric biomechanical studies are needed to validate these results.

Evaluating surface coatings to reduce bone cement adhesion to point of care 3D printed molds in the intraoperative setting.

BACKGROUND: Polymethyl methacrylate, or "bone cement," can be used intraoperatively to replace damaged or diseased bone and to deliver local antibiotics. 3D printed molds allow surgeons to form personalized and custom shapes with bone cement. One factor hindering the clinical utility of anatomically accurate 3D printed molds is that cured bone cement can be difficult to remove due to the strong adhesion between the mold and the bone cement. One way to reduce the adhesion between the 3D printed mold and the cured bone cement is with the use of a surface coating, such as a lubricant. This study sought to determine the optimal surface coating to prevent bone cement adhesion to 3D printed molds that could be utilized within a sterile operating room environment. METHODS: Hemispheric molds were 3D printed using a stereolithography printer. The molds were coated with four sterile surface coatings available in most operating theatres (light mineral oil, bacitracin ointment, lubricating jelly, and ultrasound transmission gel). Polymethyl methacrylate with tobramycin antibiotic was mixed and poured into the molds. The amount of force needed to "push out" the cured bone cement from the molds was measured to determine the efficacy of each surface coating. Tukey's multiple comparison test was performed to compare the results of the pushout test. RESULTS: The average pushout force for the surface coatings, in increasing order, were as follows (mean ± standard deviation) --- bacitracin ointment: 9.10 ± 6.68 N, mineral oil: 104.93 ± 69.92 N, lubricating jelly: 147.76 ± 63.77 N, control group: 339.31 ± 305.20 N, ultrasound transmission gel 474.11 ± 94.77 N. Only the bacitracin ointment required significantly less pushout force than the control (p = 0.0123). CONCLUSIONS: The bacitracin ointment was the most effective surface coating, allowing the bone cement to be pushed out of the mold using the least amount of force. In addition, the low standard deviation speaks to the reliability of the bacitracin ointment to reduce mold adhesion compared to the other surface coatings. Given its efficacy as well as its ubiquitous presence in the hospital operating room setting, bacitracin ointment is an excellent choice to prevent adhesion between bone cement and 3D printed molds intraoperatively.

Catalysis-Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass.

Biallelic ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency induces vascular/soft tissue calcifications in generalized arterial calcification of infancy (GACI), and low bone mass with phosphate-wasting rickets in GACI survivors (autosomal hypophosphatemic rickets type-2). ENPP1 haploinsufficiency induces early-onset osteoporosis and mild phosphate wasting in adults. Both conditions demonstrate the unusual combination of reduced accrual of skeletal mineral, yet excess and progressive heterotopic mineralization. ENPP1 is the only enzyme that generates extracellular pyrophosphate (PPi), a potent inhibitor of both bone and heterotopic mineralization. Life-threatening vascular calcification in ENPP1 deficiency is due to decreased plasma PPi; however, the mechanism by which osteopenia results is not apparent from an understanding of the enzyme's catalytic activity. To probe for catalysis-independent ENPP1 pathways regulating bone, we developed a murine model uncoupling ENPP1 protein signaling from ENPP1 catalysis, Enpp1T238A mice. In contrast to Enpp1asj mice, which lack ENPP1, Enpp1T238A mice have normal trabecular bone microarchitecture and favorable biomechanical properties. However, both models demonstrate low plasma Pi and PPi, increased fibroblast growth factor 23 (FGF23), and by 23 weeks, osteomalacia demonstrating equivalent phosphate wasting in both models. Reflecting findings in whole bone, calvarial cell cultures from Enpp1asj mice demonstrated markedly decreased calcification, elevated transcription of Sfrp1, and decreased nuclear ß-catenin signaling compared to wild-type (WT) and Enpp1T238A cultures. Finally, the decreased calcification and nuclear ß-catenin signaling observed in Enpp1asj cultures was restored to WT levels by knockout of Sfrp1. Collectively, our findings demonstrate that catalysis-independent ENPP1 signaling pathways regulate bone mass via the expression of soluble Wnt inhibitors such as secreted frizzled-related protein 1 (SFRP1), whereas catalysis dependent pathways regulate phosphate homeostasis through the regulation of plasma FGF23. © 2022 American Society for Bone and Mineral Research (ASBMR).

The Enthesopathy of XLH Is a Mechanical Adaptation to Osteomalacia: Biomechanical Evidence from Hyp Mice.

A major comorbidity of X-linked hypophosphatemia (XLH) is fibrocartilaginous tendinous insertion site mineralization resulting in painful enthesophytes that contribute to the adult clinical picture and significantly impact physical function. Enthesophytes in Hyp mice, a murine model of XLH are the result of a hyperplastic expansion of resident alkaline phosphatase, Sox9-positive mineralizing fibrochondrocytes. Here, we hypothesized hyperplasia as a compensatory physical adaptation to aberrant mechanical stresses at the level of the entheses interface inserting into pathologically soft bone. To test this hypothesis, we examined the Achilles insertion of the triceps surae developed under normal and impaired loading conditions in Hyp and WT mice. Tensile stiffness, ultimate strength, and maximum strain were measured and compared. Biomechanical testing revealed that under normal loading conditions, despite inserting into a soft bone matrix, both the enthesophyte development (9 weeks) and progression (6-8 months) of Hyp mice were equivalent to the mechanical properties of WT mice. Unloading the insertion during development significantly reduced alkaline phosphatase, Sox9-positive fibrochondrocytes. In WT mice, this correlated with a decrease in stiffness and ultimate strength relative to the control limb, confirming the critical role of mechanical loading in the development of the enthesis. Most significantly, in response to unloading, maximum strain was increased in tensile tests only in the setting of subchondral osteomalacia of Hyp mice. These data suggest that mineralizing fibrochondrocyte expansion in XLH occurs as a compensatory adaptation to the soft bone matrix.

Biomechanical restoration of metastatic cancer-induced peri-acetabular bone defects by ablation-osteoplasty-reinforcement-internal fixation technique (AORIF): To screw or not to screw?

BACKGROUND: Minimally invasive percutaneous polymethyl methacrylate cement augmentation procedures offer numerous clinical advantages for patients with periacetabular osteolytic metastatic bone defects in contrast to open reconstructive procedures that are associated with many complications. Several techniques, such as Ablation-Osteoplasty-Reinforcement-Internal Fixation (AORIF), cementoplasty alone, and screw fixation alone are currently used. There is no consensus on optimal skeletal reinforcement of diseased bones. The purpose of this study was to determine the most effective technique of percutaneous acetabular augmentation for joint preservation, with respect to resilience on cyclic loading and fracture pattern at maximal load to failure. METHODS: Five cohorts of hemipelvis composite bones with uniform periacetabular defects and various types of reinforcement techniques were utilized to simulate osteolytic metastasis in the weight bearing dome of the acetabulum. Five groups of hemipelves underwent finite element analysis and biomechanical testing for load to failure, energy absorption to failure, stress relaxation on cyclic loading, and fracture locations. RESULTS: The combination of screws and bone cement augmentation demonstrated significant higher energy absorption than the cement or screw only groups (p < 0.05), and better protection of acetabulum from displaced intraarticular fractures than the screws alone oror cement only groups (p < 0.05). Resilience to cyclic loading was higheest in the screw with cement fixation group than the screw only repair (p < 0.01), though not the cement fixation only group. INTERPRETATION: These data support the hypothesis that cementoplasty combined with screw augmentation such as the AORIF technique provides the best protection of acetabulum from massive metastatic cancer-induced acetabular fractures compared to augmentation with screws or cement alone.

Lag Screw Trajectory in Supination-External Rotation Fractures: Does the Direction of the Fibula Lag Screw Have an Effect?

BACKGROUND: The fracture obliquity of supination-external rotation injury of the fibula is often amenable to lag screw insertion. The purpose of the study was to determine whether biomechanical differences exist between lag screws inserted from an anterior to posterior direction and from a posterior to anterior direction and the thickness of the anterior and posterior fibular cortices were correlated with biomechanical testing. METHODS: Ten cadaver fibulae were harvested and submitted to material testing following 3.5-mm cortical screw insertion from either an anterior to posterior direction or a posterior to anterior direction. Screw torsional insertion strength and axial pullout strength were measured. Computed tomography images of 40 consecutive patients undergoing preoperative planning for fractures excluding the fibula were examined to define fibular cortical thickness and correlate anatomic findings with the biomechanical testing. RESULTS: The axial pullout strength of lag screws inserted from posterior to anterior was significantly greater than that of lag screws inserted from anterior to posterior (p < 0.05). Screw insertion torque measurements demonstrated a similar trend although the data did not reach statistical significance (p = 0.056). The anterior cortex of the distal fibula exhibited a radiographically greater thickness than that of the posterior cortex at the same level (p < 0.001). CONCLUSIONS: For oblique fractures of the distal fibula, posterior to anterior lag screw insertion exhibited improved biomechanical properties when compared with a similar screw inserted from anterior to posterior. These results correlated with the thicker cortical bone present along the anterior fibula.

Finite Element Analysis of Cannulated Screws as Prophylactic Intervention of Hip Fractures.

INTRODUCTION: The frequency of hip fractures, a major cause of morbidity and mortality for geriatric patients, is expected to increase exponentially in the next few decades. The aim of this study is to assess the ability of stainless-steel cannulated screws to reduce the risk of a femoral neck fracture, if placed prophylactically prior to a fall. MATERIALS AND METHODS: We created finite element models from computed tomography (CT) scan-based 3D models of a geriatric patient through 3D-image processing and model generation software. We used linear finite element simulations to analyze the effect of cannulated screws in the proximal femur in single-leg stance and lateral fall, which were processed for peak von Mises stresses and element failure. FINDINGS: Prophylactically placed cannulated screws significantly reduced failure in an osteoporotic proximal femur undergoing lateral fall. Three implanted screws in an inverted triangle formation decreased proximal femoral trabecular failure by 21% and cortical failure by 5%. This reduction in failure was achieved with a 55% decrease in femoral neck failure and 14% in lateral cortex failure. CONCLUSION: Our results indicate that cannulated hip screws in an inverted triangle formation may strengthen an osteoporotic proximal femur in the event of a lateral fall. Mechanical testing on cadaveric or composite models is required to validate these results.

Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength.

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency.

Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z-score < -2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next-generation sequencing revealed heterozygous loss-of-function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild-type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten-week-old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro-CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

High dose vitamin D supplementation does not rescue bone loss following Roux-en-Y gastric bypass in female rats.

Postoperative bone loss and increased fracture risk associated with Roux-en-Y gastric bypass (RYGB) have been attributed to vitamin D/calcium malabsorption and resultant secondary hyperparathyroidism (HPT). Adequate vitamin D supplementation (VDS), particularly in an older female population, reduces incidence of secondary HPT but the effect on bone loss and fracture risk remains unclear. To investigate whether VDS corrects the RYGB bone phenotype, 41 obese adult female rats were randomized to RYGB with 1000 IU (R1000) or 5000 IU (R5000) vitamin D/kg food or a sham surgical procedure with either paired (PF) or ad libitum (AL) feeding. Bone turnover markers, urinary calcium/creatinine ratio (CCR), and serum calciotropic and gut hormones were assessed throughout a 14-week postoperative period. Femurs were analyzed by micro-computed tomography (µCT), three-point bending test, and histomorphometry. 1000 IU animals had low 25­hydroxyvitamin D (25(OH)D), high serum parathyroid hormone (PTH), and very low urine CCR levels. 5000 IU corrected the 25(OH)D and secondary HPT but did not increase urine CCR or serum levels of 1,25­dihydroxyvitamin D (1,25(OH)D) significantly between RYGB groups. Compared to sham animals at 14 weeks, RYGB animals had significantly higher serum osteocalcin (OCN) and C-terminal telopeptide (CTX) levels. The gut hormone peptide tyrosine tyrosine hormone (PYY) was higher in the RYGB groups, and leptin was lower. µCT and biomechanical testing revealed RYGB females had decreased cortical and trabecular bone volume and weaker, stiffer bone than controls. Histomorphometry showed decreased bone volume and increased osteoid volume with increased mineral apposition rate in RYGB compared to controls. No differences in bone phenotype were identified between 1000 IU and 5000 IU groups, and osteoclast numbers were comparable across all four groups. Thus, in our model, 5000 IU VDS corrected vitamin D deficiency and secondary HPT but did not rescue RYGB mineralization rate nor the osteomalacia phenotype. Longer studies in this model are required to evaluate durability of these detrimental effects. Our findings not only underscore the importance of lifelong repletion of both calcium and vitamin D but also suggest that additional factors affect skeletal health in this population.

Fat and Bone: PGC-1α Regulates Mesenchymal Cell Fate during Aging and Osteoporosis.

PGC-1α is a transcriptional co-activator associated with PPARγ that regulates thermogenic gene expression in brown fat. In this issue, Yu et al. (2018) show that PGC-1α regulates marrow mesenchymal stromal cell lineage allocation in vivo, inhibiting marrow adipogenesis and associated bone loss in the aging skeleton and following ovariectomy-induced osteoporosis.