Pre-operative bone quality deficits and risk of complications following spine fusion surgery among postmenopausal women.

Poor bone quality is a risk factor for complications after spinal fusion surgery. This study investigated pre-operative bone quality in postmenopausal women undergoing spine fusion and found that those with small bones, thinner cortices and surgeries involving more vertebral levels were at highest risk for complications. PURPOSE: Spinal fusion is one of the most common surgeries performed worldwide. While skeletal complications are common, underlying skeletal deficits are often missed by pre-operative DXA due to artifact from spinal pathology. This prospective cohort study investigated pre-operative bone quality using high resolution peripheral CT (HRpQCT) and its relation to post-operative outcomes in postmenopausal women, a population that may be at particular risk for skeletal complications. We hypothesized that women with low volumetric BMD (vBMD) and abnormal microarchitecture would have higher rates of post-operative complications. METHODS: Pre-operative imaging included areal BMD (aBMD) by DXA, cortical and trabecular vBMD and microarchitecture of the radius and tibia by high resolution peripheral CT. Intra-operative bone quality was subjectively graded based on resistance to pedicle screw insertion. Post-operative complications were assessed by radiographs and CTs. RESULTS: Among 50 women enrolled (age 65 years), mean spine aBMD was normal and 35% had osteoporosis by DXA at any site. Low aBMD and vBMD were associated with "poor" subjective intra-operative quality. Skeletal complications occurred in 46% over a median follow-up of 15 months. In Cox proportional models, complications were associated with greater number of surgical levels (HR 1.19 95% CI 1.06-1.34), smaller tibia total area (HR 1.67 95% CI1.16-2.44) and lower tibial cortical thickness (HR 1.35 95% CI 1.05-1.75; model p < 0.01). CONCLUSION: Women with smaller bones, thinner cortices and procedures involving a greater number of vertebrae were at highest risk for post-operative complications, providing insights into surgical and skeletal risk factors for complications in this population.

Vitamin D and SARS-CoV-2 Infection: SERVE Study (SARS-CoV-2 Exposure and the Role of Vitamin D among Hospital Employees).

BACKGROUND: Recognition of the role of vitamin D in immune function has led to interest in its relationship with SARS-CoV-2 infection. Although clinical studies to date have had conflicting results, many individuals currently take high doses of vitamin D to prevent infection. OBJECTIVE: The goal of this study was to investigate the relationship between serum 25-hydroxyvitamin D (25OHD) and vitamin D supplement use with incident SARS-CoV-2 infection. METHODS: In this prospective cohort study, 250 health care workers were enrolled at a single institution and observed for 15 mo. Participants completed questionnaires every 3 mo regarding new SARS-CoV-2 infection, vaccination, and supplement use. Serum was drawn at baseline, 6, and 12 mo for 25OHD and SARS-CoV-2 nucleocapsid antibodies. RESULTS: The mean age of the participants was 40 y, BMI 26 kg/m2, 71% were Caucasian, and 78% female. Over 15 mo, 56 participants (22%) developed incident SARS-CoV-2 infections. At baseline, ∼50% reported using vitamin D supplements (mean daily dose 2250 units). Mean serum 25OHD was 38 ng/mL. Baseline 25OHD did not predict incident SARS-CoV-2 infection (OR: 0.98; 95% CI: 0.80, 1.20). Neither the use of vitamin D supplements (OR: 1.18; 95% CI: 0.65, 2.14) or supplement dose was associated with incident infection (OR: 1.01 per 100-units increase; 95% CI: 0.99, 1.02). CONCLUSION: In this prospective study of health care workers, neither serum 25OHD nor the use of vitamin D supplements was associated with the incident SARS-CoV-2 infection. Our findings argue against the common practice of consuming high-dose vitamin D supplements for the presumed prevention of COVID-19.

Association of Biochemically Verified Post-Diagnosis Smoking and Nonmuscle-Invasive Bladder Cancer Recurrence Risk.

PURPOSE: Our goal was to determine the association between biochemically verified post-diagnosis smoking exposure and nonmuscle-invasive bladder cancer (NMIBC) recurrence risk. MATERIALS AND METHODS: We conducted a prospective study of 354 NMIBC patients with a smoking history undergoing care between 2015 and 2018. Patients contributed at least 2 biospecimens during followup which were tested for cotinine to determine biochemically verified post-diagnosis smoking exposure (yes/no). Our primary endpoint was time to first recurrence after study start date. We examined whether post-diagnosis smoking exposure was associated with recurrence risk in multivariable Cox proportional hazards models that accounted for demographics, clinicopathological variables, time since diagnosis and pack-years. RESULTS: Patients were predominantly White, male and had a median age of 68 years. Most patients had Ta disease (62%) and tumors of high grade (68%). Intravesical bacillus Calmette-Guérin was given to 63% of the cohort. Patients were followed for a median of 3.6 years since study start. Post-diagnosis smoking exposure was detected in 22% of patients, and 38.7% (137) of patients experienced a recurrence during followup. In multivariable models, only bacillus Calmette-Guérin treatment and prior recurrence rate were significantly associated with recurrence. There was no association between post-diagnosis smoking exposure and recurrence risk (HR: 0.73, 95% CI: 0.45-1.20). CONCLUSIONS: In a cohort of patients with predominantly high risk NMIBC, post-diagnosis smoking exposure was not associated with NMIBC recurrence. However, smoking cessation support remains a critical component of cancer care given that the benefits of quitting extend far beyond NMIBC recurrence.

Clinical Characteristics and Fracture Patterns Among Postmenopausal Women with Isolated Osteoporosis at the Forearm.

Patients found to have isolated osteoporosis at the 1/3 radius (1/3RO) represent a therapeutic dilemma. It is unknown whether 1/3RO is associated with an increased risk of fragility fractures, and is therefore unclear whether these patients should be treated similarly to those with osteoporosis at central sites. This retrospective study investigated the clinical significance of 1/3RO by comparing medical history, fracture prevalence, areal BMD, and Trabecular Bone Score in postmenopausal women with 1/3RO (n = 107) to age-matched women with osteoporosis at the hip and/or spine (PMO, n = 214), and to controls without osteoporosis at any site (n = 214). We then compared the clinical and densitometric characteristics among women with 1/3RO according to fracture history. The mean age of the 535 women included in the study was 71 ± 8 yr. Women with 1/3RO had BMD in the osteopenic range at all other sites (mean spine T-score = -1.0, total hip = -1.4, femoral neck = -1.7). Women with 1/3RO reported similar calcium and vitamin D intake, prevalence of primary hyperparathyroidism, chronic kidney disease, and other comorbidities compared to the other groups. The prevalence of an osteoporotic fracture of the spine, hip, wrist, or humerus tended to be higher among women with PMO compared to 1/3RO or controls (PMO: 31%, 1/3RO: 21%, Controls: 23%, p = 0.07). Among women with 1/3RO, fracture prevalence was related to older age. No other clinical characteristic distinguished women with and without fracture. Neither BMD at other sites nor TBS differed according to fracture history. Among postmenopausal women with 1/3RO, those who are older are at an increased risk of fracture, even when T-scores at other sites are well above the osteoporosis threshold. Additional research is needed to confirm our results, and to assess whether treatment should be considered to reduce fracture risk in older women with 1/3RO.

The Skeletal Consequences of Bariatric Surgery.

PURPOSE OF REVIEW: This review outlines the recent findings regarding the impact of bariatric surgery on bone. It explores potential mechanisms for skeletal changes following bariatric surgery and strategies for management. RECENT FINDINGS: Bone loss following bariatric surgery is multifactorial. Probable mechanisms include skeletal unloading, abnormalities in calciotropic hormones, and changes in gut hormones. Skeletal changes that occur after bariatric surgery are specific to procedure type and persist for several years post-operatively. Studies suggest that while bone loss begins early, fracture risk may be increased later in the post-operative course, particularly after Roux-en-Y gastric bypass (RYGB). Further research is needed to assess the extent to which skeletal changes following bariatric surgery result in fragility. Current management should be geared toward prevention of bone loss, correction of nutritional deficiencies, and incorporation of weight bearing exercise. Pharmacologic treatment should be considered for high-risk patients.

The Effect of TNF Inhibition on Bone Density and Fracture Risk and of IL17 Inhibition on Radiographic Progression and Bone Density in Patients with Axial Spondyloarthritis: a Systematic Literature Review.

PURPOSE OF REVIEW: Osteoporosis in axial spondyloarthritis may be modified by therapy. The purpose of this systematic review is to describe (i) the effect of TNFi on BMD, (ii) the effect of secukinumab on BMD, and (iii) the effect of secukinumab on radiographic disease progression in axSpA. RECENT FINDINGS: We searched PubMed, Embase, and Cochrane using the following retrieval languages: spondyloarthritis, ankylosing spondylitis, TNF, IL-17, x-rays, and osteoporosis. Twenty-nine studies were included; 27 re: TNFi and BMD, and 2 re: IL-17 blockers and x-ray progression. TNFi over 2-4 years increased BMD of the lumbar spine (3.2-14.9%) and hip (2.26-4.7%) without reducing vertebral fractures. Secukinumab reduced radiographic progression; none (73%) and minimal (79%) at 4 years. No data on IL-17 blockade and bone were found. TNFi therapy improves bone density but not vertebral fracture rates. Secukinumab improves symptoms and may slow radiographic progression. Data is lacking regarding the effects of secukinumab on BMD and fractures. These are important questions which may impact the choice of therapy.

The Skeletal Effects of Inhaled Glucocorticoids.

The skeletal effects of inhaled glucocorticoids are poorly understood. Children with asthma treated with inhaled glucocorticoids have lower growth velocity, bone density, and adult height. Studies of adults with asthma have reported variable effects on BMD, although prospective studies have demonstrated bone loss after initiation of inhaled glucocorticoids in premenopausal women. There is a dose-response relationship between inhaled glucocorticoids and fracture risk in asthmatics; the risk of vertebral and non-vertebral fractures is greater in subjects treated with the highest doses in the majority of studies. Patients with COPD have lower BMD and higher fracture rates compared to controls, however, the majority of studies have not found an additional detrimental effect of inhaled glucocorticoids on bone. While the evidence is not conclusive, it supports using the lowest possible dose of inhaled glucocorticoids to treat patients with asthma and COPD and highlights the need for further research on this topic.

POTASSIUM CITRATE DECREASES BONE RESORPTION IN POSTMENOPAUSAL WOMEN WITH OSTEOPENIA: A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL.

OBJECTIVE: Diets rich in animal protein, such as the typical American diet, are thought to create a high acid load. An association between acid load and bone loss has led to the idea that providing positive alkaline salt therapy could have beneficial effects on bone metabolism. The objective of this study was to investigate the effects of potassium citrate (K-citrate), 40 mEq daily, over 1 year on bone resorption and formation. METHODS: A randomized, double-blind, placebo-controlled trial of 83 women with postmenopausal osteopenia. Levels of bone turnover markers, specifically urinary N-telopeptide of collagen type 1 (u-NTX), amino-terminal propeptide of type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) were compared. Changes in bone mineral density (BMD) were also examined. RESULTS: K-citrate decreased both u-NTX (P = .005) and serum P1NP (P<.001) starting at month 1 and continuing through month 12. No significant change was seen in BSAP or OC. No significant change was seen in lumbar or hip BMD between the 2 groups. CONCLUSION: In women with postmenopausal osteopenia, treatment with K-citrate for 1 year resulted in a significant decrease in markers of turnover. The effect on markers of bone formation was not consistent. K-citrate may serve as a potential treatment for bone loss that is well tolerated and without any significant known long-term consequences.

Identifying functional anti-Staphylococcus aureus antibodies by sequencing antibody repertoires of patient plasmablasts.

Infection by Staphylococcus aureus is on the rise, and there is a need for a better understanding of host immune responses that combat S. aureus. Here we use DNA barcoding to enable deep sequencing of the paired heavy- and light-chain immunoglobulin genes expressed by individual plasmablasts derived from S. aureus-infected humans. Bioinformatic analysis of the antibody repertoires revealed clonal families of heavy-chain sequences and enabled rational selection of antibodies for recombinant expression. Of the ten recombinant antibodies produced, seven bound to S. aureus, of which four promoted opsonophagocytosis of S. aureus. Five of the antibodies bound to known S. aureus cell-surface antigens, including fibronectin-binding protein A. Fibronectin-binding protein A-specific antibodies were isolated from two independent S. aureus-infected patients and mediated neutrophil killing of S. aureus in in vitro assays. Thus, our DNA barcoding approach enabled efficient identification of antibodies involved in protective host antibody responses against S. aureus.

Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. In this study, we show that erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), reduces the severity of established collagen-induced arthritis, a mouse model of RA, and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with collagen-induced arthritis and patients with RA. Taken together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefits in the treatment of RA.

Epidural Steroid Injections and Fracture Incidence Among Older Individuals with Radiculopathy.

Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.

Epidural steroid injections (ESIs) are a common and often effective treatment for many types of back pain. Steroids given orally or intravenously are known to be harmful to bone and increase the risk of broken bones or fractures. However, whether steroids given as epidural injections increase the risk of fractures is less clear. This study used Medicare data to investigate whether older individuals who had received ESI for back pain had a higher likelihood of fractures than similar individuals who did not. Approximately 250 000 individuals were included in our analyses. Rates of any fracture were 39% higher among individuals who received ESI. Rates of spine fractures, an area particularly vulnerable to the effects of steroids, were 54% higher. Our results demonstrate that ESI treatment in older individuals is associated with an increased risk of any fracture, and specifically of spine fracture. These findings suggest that there may be lasting harmful skeletal effects of ESI in older patients. Further research into strategies to minimize bone loss and reduce fracture risk in this population is needed.

Synthesis, characterization and comparative biological activity of a novel set of Cu(II) complexes containing azole-based ligand frames.

The synthesis and spectroscopic characterization of three complexes containing a substituted 2-(2-pyridyl)benzothiazole (PyBTh) group in the ligand frame are reported along with the comparative biological activity. The ligands have been substituted at the 6-position with either a methoxy (Py(OMe)BTh) or a methyl group (Py(Me)BTh). Reaction of Py(OMe)BTh with either CuCl2 or Cu(NO3)2·2.5 H2O yielded the monomeric [Cu(Py(OMe)BTh))2(NO3)]NO3·1.5 MeOH, (1·1.5 MeOH) complex or the dimeric [Cu(Py(OMe)BTh)Cl2]2 (2), respectively, with the nuclearity of the complex dependent on the starting Cu(II) salt. Reaction between the methyl substituted ligand and Cu(NO3)2·2.5 H2O resulted in the isolation of Cu(Py(Me)BTh)(NO3)2·0.5 THF (3·0.5 THF). Complexes 1-3 were fully characterized. Cyclic voltammetry measurements were performed on all three complexes as well as on [Cu(PyBTh)2(H2O)](BF4)2 (4), a compound previously reported by us which contains the unsubstituted 2-(2-pyridyl)benzothiazole ligand. The biological activity was studied and included concentration dependent DNA binding and cleavage, antibacterial activity, and cancer cell toxicity. All complexes exhibited DNA cleavage activity, however 2 and 4 were found to be the most potent. Mechanistic studies revealed that the nuclease activity is dependent on an oxidative mechanism reliant principally on O2-. Antibacterial studies revealed complex 4 was more potent compared to 1-3. Cancer cell toxicity studies were carried out on HeLa, PC-3, and MCF7 cells with 1-4, Cu(QBTh)(NO3)2(H2O) and Cu(PyBIm)3(BF4)2. The differences in the observed toxicities suggests the importance of the ligand and its substituents in modulating cell death.

Additively manufactured micro-lattice dielectrics for multiaxial capacitive sensors.

Soft sensors that can perceive multiaxial forces, such as normal and shear, are of interest for dexterous robotic manipulation and monitoring of human performance. Typical planar fabrication techniques have substantial design constraints that often prohibit the creation of functionally compelling and complex architectures. Moreover, they often require multiple-step operations for production. Here, we use an additive manufacturing process based on continuous liquid interface production to create high-resolution (30-micrometer) three-dimensional elastomeric polyurethane lattices for use as dielectric layers in capacitive sensors. We show that the capacitive responses and sensitivities are highly tunable through designs of lattice type, thickness, and material-void volume percentage. Microcomputed tomography and finite element simulation are used to elucidate the influence of lattice design on the deformation mechanism and concomitant sensing behavior. The advantage of three-dimensional printing is exhibited with examples of fully printed representative athletic equipment with integrated sensors.

The performance of artificial intelligence chatbot large language models to address skeletal biology and bone health queries.

Artificial intelligence (AI) chatbots utilizing large language models (LLMs) have recently garnered significant interest due to their ability to generate humanlike responses to user inquiries in an interactive dialog format. While these models are being increasingly utilized to obtain medical information by patients, scientific and medical providers, and trainees to address biomedical questions, their performance may vary from field to field. The opportunities and risks these chatbots pose to the widespread understanding of skeletal health and science are unknown. Here we assess the performance of 3 high-profile LLM chatbots, Chat Generative Pre-Trained Transformer (ChatGPT) 4.0, BingAI, and Bard, to address 30 questions in 3 categories: basic and translational skeletal biology, clinical practitioner management of skeletal disorders, and patient queries to assess the accuracy and quality of the responses. Thirty questions in each of these categories were posed, and responses were independently graded for their degree of accuracy by four reviewers. While each of the chatbots was often able to provide relevant information about skeletal disorders, the quality and relevance of these responses varied widely, and ChatGPT 4.0 had the highest overall median score in each of the categories. Each of these chatbots displayed distinct limitations that included inconsistent, incomplete, or irrelevant responses, inappropriate utilization of lay sources in a professional context, a failure to take patient demographics or clinical context into account when providing recommendations, and an inability to consistently identify areas of uncertainty in the relevant literature. Careful consideration of both the opportunities and risks of current AI chatbots is needed to formulate guidelines for best practices for their use as source of information about skeletal health and biology.

Artificial intelligence chatbots are increasingly used as a source of information in health care and research settings due to their accessibility and ability to summarize complex topics using conversational language. However, it is still unclear whether they can provide accurate information for questions related to the medicine and biology of the skeleton. Here, we tested the performance of three prominent chatbots­ChatGPT, Bard, and BingAI­by tasking them with a series of prompts based on well-established skeletal biology concepts, realistic physician­patient scenarios, and potential patient questions. Despite their similarities in function, differences in the accuracy of responses were observed across the three different chatbot services. While in some contexts, chatbots performed well, and in other cases, strong limitations were observed, including inconsistent consideration of clinical context and patient demographics, occasionally providing incorrect or out-of-date information, and citation of inappropriate sources. With careful consideration of their current weaknesses, artificial intelligence chatbots offer the potential to transform education on skeletal health and science.

Psoas muscle cross sectional area relates to bone density and microarchitecture in candidates for spine fusion surgery.

Prior studies demonstrate that muscle and bone health are integrally related, and both independently impact orthopedic surgery outcomes. However, relationships between bone density, in vivo microarchitecture, and muscle area have not been previously investigated in orthopedic surgery patients. This study assessed associations between psoas cross sectional area (CSA), bone mineral density (BMD), and microstructure in a cohort undergoing spine fusion. Pre-operatively, bilateral psoas CSA was measured on axial lumbar spine CT in the L3-L4 disc space. To adjust for body size, Psoas Muscle Index (PMI) was calculated (CSA divided by the square of patient height). High resolution peripheral quantitative CT (HR-pQCT, XtremeCT2) assessed volumetric BMD (vBMD), cortical (Ct) and trabecular (Tb) microarchitecture at the distal radius and tibia. Areal BMD (aBMD) was measured by DXA at the lumbar spine (LS), total hip (TH), femoral neck (FN), and the 1/3 radius (1/3R). Pearson correlations related psoas CSA and bone imaging parameters before and after correcting for height and weight. Among 88 patients included, mean age was 63 ± 12 years, BMI was 28 ± 7 kg/m2, 47 (53 %) were female. Larger psoas CSA was associated with higher vBMD, greater Ct thickness and better Tb microarchitecture (higher Tb number and lower Tb separation) at the tibia and radius. Larger psoas CSA was also associated with greater aBMD at TH and FN bilaterally and 1/3R (r 0.33 to 0.61; p < 0.002 for all comparisons). Psoas CSA was not associated with aBMD at the LS. Similar results were observed when relating PMI, and adjusting for age, height and weight to HR-pQCT and DXA measurements. Investigation of subgroups by sex demonstrated that relationships were similar magnitude among women but not the men. Patients who underwent primary compared to revision spine surgery had similar associations. Our results demonstrate a link between psoas muscle size and peripheral bone microarchitecture among patients undergoing posterior lumbar spinal fusion. Given the importance of both muscle and skeletal integrity to the success of spine surgery, further study regarding the associations between measurements of psoas muscle, bone microarchitecture, and surgical outcomes is warranted.

Skeletal muscle and visceral adipose radiodensities are pre-surgical, non-invasive markers of aggressive kidney cancer.

INTRODUCTION: Most studies on body composition in kidney cancer have been conducted among patients with metastatic disease. Given that aggressive tumours can adversely impact body composition and even non-metastatic tumours can be aggressive, we evaluated associations between pre-surgical body composition features and tumour pathological features in patients with non-metastatic clear cell renal cell cancer (ccRCC). METHODS: The Resolve Cohort consists of 1239 patients with non-metastatic ccRCC who underwent nephrectomy at Memorial Sloan Kettering Cancer Center between 2000 and 2020. The cross-sectional areas and radiodensities of skeletal muscle, visceral adipose, and subcutaneous adipose tissues were determined from pre-surgical computed tomography (CT) scans at the third lumbar vertebrae using Automatica software. Pearson's correlation coefficients describe inter-relationships among BMI and body composition variables, while odds ratios (OR) and 95% confidence intervals (CI) estimate associations between continuous body composition features (per 1-standard deviation) and advanced stage (Stage III vs. Stages I-II) and high Fuhrman grade (Grades 3-4 vs. 1-2) from multivariable logistic regression models that considered the potential impact of biological sex, contrast enhanced CTs, and early age at onset of ccRCC. RESULTS: The cohort was predominantly male (69%), white (89%), and had a median age of 58. The proportion of patients presenting with advanced stage and high-grade disease were 31% and 51%, respectively. In models that adjusted for demographics and all body composition variables simultaneously, decreasing skeletal muscle radiodensity (i.e., more fat infiltration) but increasing visceral adipose tissue radiodensity (i.e., more lipid depletion) were associated with advanced tumour features. Per 8.4 HU decrease in skeletal muscle radiodensity, the odds of presenting with advanced stage was 1.61 (95% CI: 1.34-1.93). Per 7.22 HU increase in visceral adipose tissue radiodensity, the odds of presenting with advanced stage was 1.45 (95% CI: 1.22-1.74). Skeletal muscle index (i.e., sarcopenia) was not associated with either tumour feature. Similar associations were observed for Fuhrman grade, a more direct marker of tumour aggressiveness. Associations did not differ by sex, contrast use, or age at onset of ccRCC. CONCLUSIONS: Lipid infiltrated skeletal muscle, but lipid depleted visceral adipose tissue were independently associated with advanced tumour features in non-metastatic ccRCC. Findings highlight the importance of evaluating the full range of body composition features simultaneously in multivariable models. Interpreting pre-surgical CTs for body composition for patients may be a novel and non-invasive way to identify patients with aggressive renal tumours, which is clinically relevant as renal biopsies are not routinely performed.

Long-term Pegvisomant Therapy of Acromegaly: Effects on Bone Density, Turnover and Microstructure Using HRpQCT.

Context: Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. Methods: We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. Results: In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. Conclusion: In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis.

Osteoclasts are bone-eroding cells that develop from monocytic precursor cells in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclasts are essential for physiological bone remodeling, but localized excessive osteoclast activity is responsible for the periarticular bone destruction that characteristically occurs in patients with rheumatoid arthritis (RA). The origin of osteoclasts at sites of bone erosion in RA is unknown. Natural killer (NK) cells, as well as monocytes, are abundant in the inflamed joints of patients with RA. We show here that such NK cells express both RANKL and M-CSF and are frequently associated with CD14(+) monocytes in the RA synovium. Moreover, when synovial NK cells are cocultured with monocytes in vitro, they trigger their differentiation into osteoclasts, a process dependent on RANKL and M-CSF. As in RA, NK cells in the joints of mice with collagen-induced arthritis (CIA) express RANKL. Depletion of NK cells from mice before the induction of CIA reduces the severity of subsequent arthritis and almost completely prevents bone erosion. These results suggest that NK cells may play an important role in the destruction of bone associated with inflammatory arthritis.

Persistent Deficits in Bone Quality in Treated Acromegaly: Evidence From Assessments of Microstructure.

Purpose: Fractures are increased in patients with acromegaly, both before and after successful acromegaly treatment. Abnormalities of bone microstructure, which may underlie this fragility, are present in active acromegaly but to what extent these improve with acromegaly treatment or persist despite biochemical remission remains unclear. To examine these questions, we studied the effects of acromegaly treatment and remission on bone quality. Methods: Sixty-five women and men with acromegaly were studied. Subgroups underwent assessments of areal bone mineral density by dual x-ray absorptiometry, trabecular bone score (TBS), and volumetric bone mineral density, microarchitecture, stiffness and failure load of the distal radius and tibia by high-resolution peripheral quantitative tomography in a longitudinal study before and after acromegaly treatment and in a cross-sectional study in which patients were compared to sex-, age-, and body mass index-matched healthy controls. Results: In the longitudinal study, significant increases in total, cortical, and trabecular densities at the radius and tibia and increased stiffness and failure load of the tibia occurred with acromegaly treatment. In the cross-sectional study, patients in biochemical remission after surgery had larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to controls. TBS did not change with acromegaly treatment but correlated with some microstructural parameters. Conclusion: We show, for the first time, that volumetric bone mineral density and microarchitecture of the peripheral skeleton improve with acromegaly treatment but remain abnormal in patients in remission after surgery compared to controls. These abnormalities, known to be associated with fractures in other populations, may play a role in the pathogenesis of persistent fragility in treated acromegaly.

Peripheral cortical bone density predicts vertebral bone mineral properties in spine fusion surgery patients.

Spine fusion surgery is one of the most common orthopedic procedures, with over 400,000 performed annually to correct deformities and pain. However, complications occur in approximately one third of cases. While many of these complications may be related to poor bone quality, it is difficult to detect bone abnormalities prior to surgery. Areal BMD (aBMD) assessed by DXA may be artifactually high in patients with spine pathology, leading to missed diagnosis of deficits. In this study, we related preoperative imaging characteristics of both central and peripheral sites to direct measurements of bone quality in vertebral biopsies. We hypothesized that pre-operative imaging outcomes would relate to vertebral bone mineralization and collagen properties. Pre-operative assessments included DXA measurements of aBMD of the spine, hip, and forearm, central quantitative computed tomography (QCT) of volumetric BMD (vBMD) at the lumbar spine, and high resolution peripheral quantitative computed tomography (HRpQCT; Xtreme CT2) measurements of vBMD and microarchitecture at the distal radius and tibia. Bone samples were collected intraoperatively from the lumbar vertebrae and analyzed using Fourier-transform Infrared (FTIR) spectroscopy. Bone samples were obtained from 23 postmenopausal women (mean age 67 ± 7 years, BMI 28 ± 8 kg/m2). We found that patients with more mature bone by FTIR, measured as lower acid phosphate content and carbonate to phosphate ratio, and greater collagen maturity and mineral maturity/crystallinity (MMC), had greater cortical vBMD at the tibia and greater aBMD at the lumbar spine and one-third radius. Our data suggests that bone quality at peripheral sites may predict bone quality at the spine. As bone quality at the spine is challenging to assess prior to surgery, there is a great need for additional screening tools. Pre-operative peripheral bone imaging may provide important insight into vertebral bone quality and may foster identification of patients with bone quality deficits.