PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.

Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice.

Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180 ppm, 156 mice) from 7 to 22 months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.

Post or perish? Social media strategies for disseminating orthopedic research.

Social media usage, particularly Twitter, among scientists in academia has increased in recent years. However, Twitter's use in scholarly post-publication dissemination of orthopaedic research and musculoskeletal advocacy remains low. To enhance usage of Twitter among musculoskeletal researchers, this article reviews data supporting the professional benefits of using the platform to disseminate scholarly works. Next, we provide a linear workflow for Tweet curation, discuss the importance of data-driven decision making behind tweet curation and posting, and propose new guidelines for professional Twitter usage. Since this workflow may not eliminate all the identified barriers and new institutionalized shifts in policies regarding curation and consumption of social media on Twitter, we also briefly introduce and explore using other social media platforms. We hope this information will be persuasive and compelling to those in the orthopedic research field and be broadly applicable to others in related scientific fields who wish to disseminate findings and engage a public audience on social media. In addition, we encourage the Orthopedic Research Society (ORS) and Journal of Orthopedic Research (JOR) communities to take advantage of the many tools curated by the Wiley editorial office and the ORS social media committee to increase dissemination of their scholarly works online. Twitter and social media can assist in accomplishing our mission of creating a world without musculoskeletal limitations via the timely dissemination of orthopedic information. However, this can only be accomplished if the orthopedic research community has a unified and strong online presence actively engaged in orthopaedic research findings and news.

The Role of Bone Cell Energetics in Altering Bone Quality and Strength in Health and Disease.

PURPOSE OF REVIEW: Bone quality and strength are diminished with age and disease but can be improved by clinical intervention. Energetic pathways are essential for cellular function and drive osteogenic signaling within bone cells. Altered bone quality is associated with changes in the energetic activity of bone cells following diet-based or therapeutic interventions. Energetic pathways may directly or indirectly contribute to changes in bone quality. The goal of this review is to highlight tissue-level and bioenergetic changes in bone health and disease. RECENT FINDINGS: Bone cell energetics are an expanding field of research. Early literature primarily focused on defining energetic activation throughout the lifespan of bone cells. Recent studies have begun to connect bone energetic activity to health and disease. In this review, we highlight bone cell energetic demands, the effect of substrate availability on bone quality, altered bioenergetics associated with disease treatment and development, and additional biological factors influencing bone cell energetics. Bone cells use several energetic pathways during differentiation and maturity. The orchestration of bioenergetic pathways is critical for healthy cell function. Systemic changes in substrate availability alter bone quality, potentially due to the direct effects of altered bone cell bioenergetic activity. Bone cell bioenergetics may also contribute directly to the development and treatment of skeletal diseases. Understanding the role of energetic pathways in the cellular response to disease will improve patient treatment.

Molecular Identification of Spatially Distinct Anabolic Responses to Mechanical Loading in Murine Cortical Bone.

Osteoporosis affects over 200 million women worldwide, one-third of whom are predicted to suffer from an osteoporotic fracture in their lifetime. The most promising anabolic drugs involve administration of expensive antibodies. Because mechanical loading stimulates bone formation, our current data, using a mouse model, replicates the anabolic effects of loading in humans and may identify novel pathways amenable to oral treatment. Murine tibial compression produces axially varying deformations along the cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. To test the hypothesis that load-induced transcriptomic responses at different axial locations of cortical bone would vary as a function of strain magnitude, we loaded the left tibias of 10-week-old female C57Bl/6 mice in vivo in compression, with contralateral limbs as controls. Animals were euthanized at 1, 3, or 24 hours post-loading or loaded for 1 week (n = 4-5/group). Bone marrow and cancellous bone were removed, cortical bone was segmented into the metaphyseal shell, proximal diaphysis, and mid-diaphysis, and load-induced differential gene expression and enriched biological processes were examined for the three segments. At each time point, the mid-diaphysis (highest strain) had the greatest transcriptomic response. Similarly, biological processes regulating bone formation and turnover increased earlier and to the greatest extent at the mid-diaphysis. Higher strain induced greater levels of osteoblast and osteocyte genes, whereas expression was lower in osteoclasts. Among the top differentially expressed genes at 24-hours post-loading, 17 had known functions in bone biology, of which 12 were present only in osteoblasts, 3 exclusively in osteoclasts, and 2 were present in both cell types. Based on these results, we conclude that murine tibial loading induces spatially unique transcriptomic responses correlating with strain magnitude in cortical bone. © 2022 American Society for Bone and Mineral Research (ASBMR).

Stiffness Matters: Part I-The Effects of Plate Stiffness on the Biomechanics of ACDF In Vitro.

STUDY DESIGN: In vitro biomechanical testing of human cadaveric cervical and goat cervical motion segments. OBJECTIVE: The aim of this study was to measure the effects of plate stiffness on load-sharing, instantaneous axis of rotation (IAR), and posterior element loading after anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is intended to create an environment, which facilitates sufficient stability and biomechanical conditions to promote bone formation. The relationship between cervical plate stiffness, load-sharing, and the IAR is complex. The ideal cervical plate is sufficiently stiff to limit interbody motion but is compliant enough to facilitate load-sharing rather than stress-shielding. METHODS: Anterior cervical plates of distinct bending stiffnesses were applied to human and goat cervical motion segments following ACDF. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads, posterior element strain, and the IAR were measured during flexion/extension for each plate. RESULTS: Load-sharing in the interbody space, posterior element strain, and the location of the IAR were all significantly affected by plate stiffness. More compliant plates resulted in more load sharing, less posterior element strain, and a more dorsally located IAR relative to stiffer plates. CONCLUSION: A more compliant plate fosters more consistent load-sharing through the entire range of flexion/extension, which may promote faster bone formation and better fusion. A more compliant plate causes less posterior element strain, which may reduce facet joint loads and in turn reduce facet joint arthrosis. An ideal plate may be one that is stiff enough to minimize interbody motion and yet compliant enough to allow consistent load-sharing and minimal increase in posterior element strain. LEVEL OF EVIDENCE: N/A.

Stiffness Matters: Part II-The Effects of Plate Stiffness on Load-Sharing and the Progression of Fusion Following Anterior Cervical Discectomy and Fusion In Vivo.

STUDY DESIGN: Real time in vivo measurement of forces in the cervical spine of goats following anterior cervical discectomy and fusion (ACDF). OBJECTIVE: To measure interbody forces in the cervical spine during the time course of fusion following ACDF with plates of different stiffnesses. SUMMARY OF BACKGROUND DATA: Following ACDF, the biomechanics of the arthrodesis is largely dictated by the plate. The properties of the plate prescribe the extent of load-sharing through the disc space versus the extent of stress-shielding. Load-sharing promotes interbody bone formation and stress-shielding can inhibit maturation of bone. However, these principles have never been validated in vivo. Measuring in vivo biomechanics of the cervical spine is critical to understanding the complex relationships between implant design, interbody loading, load-sharing, and the progression of fusion. METHODS: Anterior cervical plates of distinct bending stiffnesses were placed surgically following ACDF in goats. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads were measured in vivo in real time during the course of fusion for each plate. RESULTS: Interbody forces during flexion/extension were highly dynamic. In animals that received high stiffness plates, maximum forces were in extension whereas in animals that received lower stiffness plates, maximum forces were in flexion. As fusion progressed, interbody load magnitude decreased. CONCLUSION: The magnitude of interbody forces in the cervical spine is dynamic and correlates to activity and posture of the head and neck. The magnitude and consistency of forces in the interbody space correlates to plate stiffness with more compliant plates resulting in more consistent load-sharing. The magnitude of interbody forces decreases as fusion matures suggesting that smart interbody implants may be used as a diagnostic tool to indicate the progression of interbody fusion. LEVEL OF EVIDENCE: N/A.