Thomas J. Schnitzer

To evaluate synovial fluid biomarkers of cartilage degradation, inflammation, and pain in participants with knee osteoarthritis pain treated with subcutane

Objective: Chronic low back pain (cLBP) is a leading cause of global disability, with current treatments offering limited and inconsistent relief. D-cycloserine (DCS), a partial NMDA receptor agonist and FDA-approved antimicrobial, has shown promise in preclinical models for reducing neuropathic pain and its negative emotional impact. Building on these findings and a positive pilot study, we conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of DCS in adults with cLBP. Methods: Participants with cLBP (n=203) were randomized to receive 200 mg DCS or placebo twice daily for 12 weeks, followed by a 12-week placebo phase. The primary outcome was pain intensity (numeric rating scale, NRS) at 12 weeks; secondary outcomes included pain intensity at 24 weeks, safety, and patient-reported psychological measures. Results: DCS had negligible effects on pain compared to placebo at both 12 weeks (adjusted effect: −0.07/10 NRS units, 95% CI: (−0.67, 0.53), p = 0.78) and at 24 weeks (adjusted effect: −0.22/10 NRS units, 95% CI: (−0.84, 0.40), p = 0.39). Adverse events were similar between groups. Exploratory outcomes also showed no significant effects. Conclusion: Our results indicate that 12 weeks of DCS 400 mg/day does not provide clinically meaningful analgesia in cLBP, though it is well tolerated. These findings highlight the challenges of translating preclinical neuropathic pain results to heterogeneous clinical pain populations.

Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI). To date, most research has focused on pharmaceutical intervention using antiresorptives to prevent bone loss during the acute phase of SCI; however, limited research has investigated treatments for established osteoporosis during chronic SCI. Romosozumab, a monoclonal antibody with both antiresorptive and anabolic effects, has demonstrated significant increases in BMD for women with established PMO. Therefore, the purpose of this study was to examine the efficacy of monthly treatment with romosozumab to improve DXA-derived areal BMD at the hip, and CT-derived BMC and strength at the hip and knee in women with chronic SCI and an inability to ambulate. Twelve female participants with chronic SCI were recruited to receive 1 yr of monthly subcutaneous injections of romosozumab (210 mg). DXA and CT scans were taken at baseline, and months 3, 6, and 12 to quantify bone mineral, and finite element (FE) analysis was used to predict bone strength. Longitudinal mixed effects models were employed to determine the impact of treatment on bone properties. After 12 mo of treatment, areal BMD at the lumbar spine and total hip were significantly increased with median changes of 10.2% (IQR: 8.3–15.2%, p<.001) and 4.2% (IQR: 3.4–7.7%, p = .009), respectively. Improvements at the hip were primarily due to increases in trabecular, not cortical, bone and effects were sufficient to significantly increase FE-predicted strength by 20.3% (IQR: 9.5–37.0%, p = .004). Treatment with romosozumab did not lead to any significant improvement in bone mineral at the distal femur or proximal tibia. These findings provide promising results for romosozumab treatment to improve bone mineral and reduce fracture risk at the hip, but not the knee, in women with chronic SCI. Spinal cord injury (SCI) is associated with profound bone loss and an increased risk of fracture, particularly at the knee. Previous treatment options to increase BMD in individuals with SCI and osteoporosis have been ineffective. Romosozumab is a novel pharmaceutical treatment for PMO. The purpose of this research was to investigate the effects of monthly treatment with romosozumab on BMD and strength in 12 women with chronic SCI. After 1 yr of treatment, BMD and strength showed marked improvement at the hip, but not the knee, which is the primary anatomical location of interest. Therefore, while romosozumab treatment in chronic SCI shows promise for reducing fracture risk at the hip, fracture risk at the knee is unlikely to be affected.

Background: To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. Methods: Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). Results: ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were − 0.416 (− 0.796, − 0.060), − 0.195 (− 0.371, − 0.028), and − 0.196 (− 0.373, − 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. Conclusion: Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. Trial Registration: Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

Joint acoustic emissions (JAEs) have been used as a noninvasive sensing modality of joint health for different conditions such as acute injuries, osteoarthritis (OA), and rheumatoid arthritis (RA). Recent hardware improvements for sensing JAEs have made at-home sensing to supplement clinical visits a possibility. To complement these advances, models must be improved for JAEs to function as generalizable predictors of joint health. Addressing this need, this work investigates the effects of recording setup, location-specific factors, and participant population on previously validated JAE models. The effect of recording setup is first investigated by testing a model developed previously for a wearable brace to predict erythrocyte sedimentation rate (ESR) in participants with RA on benchtop data, resulting in an area under the receiver-operating characteristic curve (AUC), sensitivity, and specificity of 0.79, 0.73, and 0.81, respectively. Investigating the effects of participant population type and location-specific factors, a feature-based model and a convolutional neural network (CNN) were both trained with healthy and RA data to predict ESR level, and then tested on a new dataset containing healthy, preradiographic OA (Pre-OA), and OA data. The feature-based model had an AUC of 0.69 and 0.94, a sensitivity of 0.38 and 0.80, and a sensitivity of 1, while the CNN had an AUC of 0.85 and 0.99, a sensitivity of 0.50 and 1, and a specificity of 0.90 for detecting Pre-OA and OA, respectively. The ability to generalize models across setup, location, and participant population provides a foundation for using JAEs as a measure of joint health.