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Leslie Tive,1 Alfonso E Bello,2 David Radin,3 Thomas J Schnitzer,4 Ha Nguyen,1 Mark T Brown,5 Christine R West5 1Pfizer Inc, New York, NY, USA; 2Illinois Bone and Joint Institute, Glenview, IL, USA; 3Stamford Therapeutics Consortium, Stamford, CT, USA; 4Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5Pfizer Inc, Groton, CT, USA Purpose: A pooled analysis was conducted to evaluate tanezumab efficacy and safety in patients with osteoarthritis (OA), including subgroup analyses of at-risk patients with diabetes, severe OA symptoms, and those aged ≥65 years.Patients and methods: Data from phase III placebo-controlled clinical trials of patients with moderate-to-severe OA of the knee or hip were pooled to evaluate tanezumab efficacy (four trials) and safety (nine trials). Patients received intravenous tanezumab, tanezumab plus an oral NSAID (naproxen, celecoxib, or diclofenac), active comparator (naproxen, celecoxib, diclofenac, or oxycodone), or placebo. Efficacy assessments included change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores, Patient’s Global Assessment (PGA) of OA, and percentage of patients with ≥30%, ≥50%, ≥70%, and ≥90% improvement in WOMAC pain. Safety assessments included adverse event (AE) documentation and physical and neurologic examinations.Results: Tanezumab significantly improved all efficacy end points in the overall population. Efficacy in at-risk patient subgroups was similar to the overall population. Incidence of AEs was highest in the tanezumab plus NSAID group and lowest in the placebo group. Incidence of AEs in the tanezumab monotherapy and active comparator groups was similar. Overall incidence of AEs was similar across subgroups. AEs of abnormal peripheral sensation were more frequently reported in tanezumab-treated patients compared with placebo or active comparator. Patients receiving active comparator had a slightly higher incidence of AEs suggestive of postganglionic sympathetic dysfunction.Conclusion: Tanezumab consistently provided significant improvement of pain, physical function, and PGA in individuals with OA, including patients with diabetes, severe OA symptoms, or aged ≥65 years. No increased safety risk was observed in at-risk patient subgroups.Trial registration: NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00809354, NCT00864097, NCT00863772, NCT01089725, NCT00985621. Keywords: tanezumab, efficacy, safety, osteoarthritis, nerve growth factor

Tive L, Bello AE, Radin D, et al. J Pain Res. 2019;12:975 —995. The authors have advised there is an error in the middle panels of Figure 6 on page 985. Both panels read “Patients with severe OA” the panel on the right should read “Patients with less severe OA”. The correct Figure 6 is shown below. Read the original article

The mechanism of brain reorganization in pain chronification is unknown. In a longitudinal brain imaging study, subacute back pain (SBP) patients were followed over the course of 1 year. When pain persisted (SBPp, in contrast to recovering SBP and healthy

Objective: Cartilage morphology displays sensitivity to change in osteoarthritis (OA) with quantitative MRI (qMRI). However, (sub)regional cartilage thickness change at 3.0 Tesla (T) has not been directly compared with radiographic progression of joint space narrowing in OA participants and non-arthritic controls.Methods: A total of 145 women were imaged at 7 clinical centres: 86 were non-obese and asymptomatic without radiographic OA and 55 were obese with symptomatic and radiographic OA (27 Kellgren-Lawrence grade (KLG)2 and 28 KLG3). Lyon-Schuss (LS) and fixed flexion (FF) radiographs were obtained at baseline, 12 and 24 months, and coronal spoiled gradient echo MRI sequences at 3.0 T at baseline, 6, 12 and 24 months. (Sub)regional, femorotibial cartilage thickness and minimum joint space width (mJSW) in the medial femorotibial compartment were measured and the standardised response means (SRMs) determined.Results: At 6 months, qMRI demonstrated a -3.7% "annualised" change in cartilage thickness (SRM -0.33) in the central medial femorotibial compartment (cMFTC) of KLG3 subjects, but no change in KLG2 subjects. The SRM for mJSW in 12-month LS/FF radiographs of KLG3 participants was -0.68/-0.13 and at 24 months was -0.62/-0.20. The SRM for cMFTC changes measured with qMRI was -0.32 (12 months; -2.0%) and -0.48 (24 months; -2.2%), respectively.Conclusions: qMRI and LS radiography detected significant change in KLG3 participants at high risk of progression, but not in KLG2 participants, and only small changes in controls. At 12 and 24 months, LS displayed greater, and FF less, sensitivity to change in KLG3 participants than qMRI. [ABSTRACT FROM AUTHOR]

Objective: To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA).Design: 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified.Results: KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered.Conclusions: The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others. [ABSTRACT FROM AUTHOR]

Purpose: Little is known about the frequency of use of medications to maintain bone health for patients with stroke. This study was undertaken at an urban academic rehabilitation center to determine the prevalence of use of agents that could reduce bone loss in the stroke population. Method: A clinical database was searched for all patients 18 years old and over with stroke. The sample included 1,219 inpatients and 2,776 outpatients. Demographic information (age, gender, and race) and medications were obtained for each patient. Results: Among inpatients with stroke, 7.1% were taking osteoporosis medications (bisphosphonates, calcitonin, parathyroid hormone, or hormone replacement therapy), 11.3% were taking calcium supplements, 5.9% were taking vitamin D supplements, and 45.1% were taking multivitamin supplements. Among outpatients with stroke, 5.7% were taking osteoporosis medication, 5.8% were taking calcium supplements, 2.2% were taking vitamin D supplements, and 16.0% were taking multivitamin supplements. Patients being treated with specific osteoporosis therapies tended to be older and female by calculated odds ratios. The use of multivitamins was not related to age, gender, or race. Conclusion: Overall, relatively few stroke patients were taking osteoporosis medications or supplements. There is a need to increase the recognition, prevention, and treatment of bone loss in this high-risk population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee. [ABSTRACT FROM AUTHOR]

Background: Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce ulcer complications compared with non-selective non-steroidal anti-inflammatory drugs, but evidence is limited, and the possibility that these inhibitors increase cardiovascular events has been raised. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.Methods: 18325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) for 52 weeks, in two substudies of identical design (lumiracoxib vs ibuprofen or naproxen). Randomisation was stratified for low-dose aspirin use and age. The primary endpoint was the difference in time-to-event distribution of upper gastrointestinal ulcer complications (bleeding, perforation, or obstruction); analysis was by modified intention to treat. The principle measure of adverse cardiovascular events was the Antiplatelet Trialists' Collaboration endpoint (myocardial infarction, stroke, or cardiovascular death); this analysis was intention to treat.Findings: 81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1.09% (95% CI 0.82-1.36) with non-steroidal anti-inflammatory drugs (64 events) versus 0.25% (95% CI 0.12-0.39) with lumiracoxib (14 events; hazard ratio 0.21 [95% CI 0.12-0.37], p<0.0001). Reductions in ulcer complications were also significant in the overall population (0.34 [0.22-0.52], p<0.0001) but not in those taking aspirin (0.79 [0.40-1.55], p=0.4876). In the overall population, 0.55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0.65% (59/9117) of those on lumiracoxib reached the cardiovascular endpoint (1.14 [0.78-1.66], p=0.5074).Interpretation: Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with non-steroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study assessed prescribing patterns for rofecoxib and celecoxib in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA), as well as differences in prescribing patterns across physician specialties. METHODS: This was an observational, retrospective, cohort study of a large, US pharmacy claims database. Eligible patients were initiating therapy with rofecoxib or celecoxib and had succeeds, equals 90 days' supply of medication, as well as > or =1 medical claim specific to OA or RA between June 1, 2000, and May 31, 2001. Analyses were stratified according to diagnosis, prescribing physician specialty, and patient demographics. The main outcome measure was mean daily usage (ie, mean daily dose [milligrams]; mean number of pills per day; and mean daily consumption [denoted as DACON], calculated as daily dose divided by most frequently prescribed strength). This was primarily a descriptive study. Tests of statistical significance were not performed because the large sample size would have rendered small differences significant. RESULTS: A total of 58,574 patients with OA (81.8% [n=47,935]) or RA (18.2% [n=10,639]) received 220,627 prescriptions for rofecoxib or celecoxib (47.7% [n=27, 924] and 52.3% [n=30, 650] of patients, respectively) during the study period. Overall, the most frequently prescribed strengths were rofecoxib 25 mg and celecoxib 200 mg. In both OA and RA, the most frequently prescribed mean daily dose of rofecoxib was 25 mg. In OA, the most frequently prescribed mean daily dose of celecoxib was 200 mg; in RA, it was 400 mg. Both pills per day and DACON were higher for celecoxib than rofecoxib. The DACON for rofecoxib was unrelated to physician specialty. Rheumatologists prescribed celecoxib at 20% to 40% higher mean daily doses than did primary care physicians, orthopedic specialists, or other specialists. Regardless of physician specialty, the DACON appeared higher for patients with RA than OA, for men than women, and for younger (aged <65 years) than older patients. CONCLUSIONS: In this analysis, relative to the most frequently prescribed strength, celecoxib-treated patients with OA and RA had higher DACONs than rofecoxib-treated OA and RA patients across all subgroups. These observations may have economic implications in terms of direct effects on cost and the need for formularies to consider overall use patterns in addition to pill costs. However, these conclusions are limited by lack of clinical information (other than an OA or RA diagnosis), inability to ascertain actual use, and potential for selection bias. [ABSTRACT FROM AUTHOR]

Background: Many elderly female residents of long-term care facilities have osteoporosis and could benefit from intervention to increase bone density.Objective: To examine the efficacy and safety of alendronate for treatment of osteoporosis in elderly female residents of long-term care facilities.Design: Multicenter, randomized, double-blind, placebo-controlled 2-year study.Setting: 25 long-term care facilities.Patients: 327 elderly women with osteoporosis.Intervention: Patients were randomly assigned to receive alendronate, 10 mg/d, or placebo. All patients also received vitamin D, 400 IU/d, and some patients received supplemental calcium (total intake, approximately 1500 mg/d).Measurements: Bone mineral density (BMD) of the spine and hip and biochemical markers of bone turnover.Results: Alendronate produced significantly greater increases in BMD than did placebo (24-month differences: spine, 4.4% [95% CI, 3.3% to 5.5%]; femoral neck, 3.4% [CI, 2.3% to 4.4%]). Alendronate produced greater decreases from baseline in biochemical markers of bone turnover than did placebo (P < 0.001).Conclusion: Alendronate increased BMD at both the spine and hip in elderly female residents of long-term care facilities. [ABSTRACT FROM AUTHOR]

Context: Osteoarthritis (OA) is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or specific inhibitors of cyclooxygenase 2 (COX-2).Objective: To assess the relative therapeutic efficacy of rofecoxib, celecoxib, and acetaminophen in adults with OA.Design and Setting: Randomized, parallel-group, double-blind trial, conducted from June 1999 to February 2000, in 29 clinical centers in the United States.Patients: Three hundred eighty-two patients aged at least 40 years who had OA of the knee that was previously treated with NSAIDs or acetaminophen.Interventions: Patients were randomly assigned to receive rofecoxib, 12.5 mg/d (n = 96); rofecoxib, 25 mg/d (n = 95); celecoxib, 200 mg/d (n = 97); or acetaminophen, 4000 mg/d (n = 94) for 6 weeks.Main Outcome Measures: Assessments over days 1 to 6 and over 6 weeks included pain on walking, night pain, pain at rest, and morning stiffness as measured on a Western Ontario McMaster Universities Osteoarthritis Index (100-mm visual analog scale [VAS]) and global response to therapy compared among 4 treatment groups.Results: 79% of patients completed the study. More patients treated with acetaminophen discontinued early due to lack of efficacy than patients treated with COX-2 inhibitors (31% vs 18%-19%). Efficacy assessed in the first 6 days of therapy showed greatest response to rofecoxib, 25 mg/d, followed by rofecoxib, 12.5 mg/d, celecoxib, and acetaminophen, respectively, in terms of relief of pain on walking (-32.2, - 29.0, - 26.4, and -20.6 mm change on the VAS; PConclusion: Rofecoxib, 25 mg/d, provided efficacy advantages over acetaminophen, 4000 mg/d, celecoxib, 200 mg/d, and rofecoxib, 12.5 mg, for symptomatic knee OA. [ABSTRACT FROM AUTHOR]

Long-term -- often lifelong -- care of patients with chronic disease is always a challenge. Measure what you do against our experts' clinical protocols for six common conditions. [ABSTRACT FROM AUTHOR]

The American College of Rheumatology (ACR) recently provided an update to the guidelines published in 1995 on the management of osteoarthritis (OA) of the knee and hip. Members of the Ad Hoc Committee on OA Guidelines followed an evidence-based medicine approach to revise the guidelines by reviewing an extensive literature search of the Cochrane and Medline databases and published abstracts, and discussing evidence with expert rheumatologists. The goal of the guidelines is to provide recommendations to control patients' OA pain, improve function and health-related quality of life, and avoid therapeutic toxicity. As in the original guidelines, nonpharmacologic interventions involving patient education and physical measures are recommended following initial diagnosis of OA. The pharmacologic algorithm was updated to include currently available therapeutic agents. Acetaminophen remains first-line therapy because of its cost, efficacy, and safety profiles. Cyclooxygenase-2-selective inhibitors (coxibs) have been included as an alternative to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk for upper gastrointestinal adverse events. Tramadol is an available alternative for patients who have a contraindication to coxibs or nonselective NSAIDs or for those who have not responded to previous oral therapy. Intra-articular injections or topical therapy may be used as monotherapy, or as an adjunct to oral analgesia. Surgical treatment of OA remains a last resort for patients who have failed to respond to nonpharmacologic and pharmacologic treatment approaches, and have progressive limitation in their activities of daily living. Several therapies for the prevention or treatment of OA are currently under investigation, including nutritional supplements, such as glucosamine and chondroitin, disease-modifying OA drugs, and devices, such as acupuncture and electromagnetic therapy. It is anticipated that the guidelines for the management of OA will continue to evolve as new therapies become available. © 2002 by the United States Cancer Pain Relief Committee. [ABSTRACT FROM AUTHOR]

Background: The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.Methods: 18325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat.Findings: 81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0.75 [0.20-2.79], p=0.6669), overall (0.66 [0.21-2.09], p=0.4833), and in patients taking aspirin (0.47 [0.04-5.14], p=0.5328).Interpretation: The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin. [ABSTRACT FROM AUTHOR]

Background: Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis.Methods: We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers).Results: Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups.Conclusions: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fifty-two (54.2%) studies included a global assessment measure. The PGIC was most common (n = 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n = 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n = 9; 17.3%), satisfaction (n = 8; 15.4%), or overall health status/recovery (n = 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n = 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n = 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development., (Copyright © 2024 International Association for the Study of Pain.)

Background: Pain associated with osteoarthritis (OA) is frequently disabling; treatments are often ineffective or intolerable. Fasinumab selectively inhibits nerve-growth factor and has shown efficacy for the management of OA pain., Methods: In this randomized, double-blind, phase III safety study, patients with moderate-to-severe OA pain and history of inadequate pain relief received placebo or fasinumab (at 1, 3, 6, and 9 ​mg every 4 weeks [Q4W] and 1 and 6 ​mg every 8 weeks [Q8W] for 52 weeks). Primary safety endpoints included adverse events, adjudicated arthropathies (AAs), and joint replacements (JRs). Co-primary endpoints of an efficacy sub-study were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores. During the study, higher fasinumab doses were discontinued for safety; 1 ​mg doses continued., Results: Of 13,945 patients screened, 5331 were randomized; 1074 were included in the efficacy sub-study. AAs and JRs occurred in all groups. Increased severity of disease at baseline was associated with higher rates of AAs and JRs. A dose-dependent risk of AA or JR was observed for fasinumab; in the 1 ​mg groups, only a small percentage of patients with JR had prior AA. Fasinumab significantly improved WOMAC pain and physical function scores compared with placebo; least squares mean differences versus placebo were -1.22 and ​-1.20 for 1 ​mg Q4W and -0.73 and ​-0.74 for 1 ​mg Q8W, respectively ( P< 0.001)., Conclusion: AAs and JRs showed a dose relationship to fasinumab and were associated with baseline OA status. Fasinumab achieved statistically significant improvements in WOMAC pain and physical function scores compared with placebo., Competing Interests: JM, SE, CW, TH, KCT, HEH, YP, NT, AM, GM, and NB are all employees of and shareholders in Regeneron Pharmaceuticals, Inc. SJD, HG, GPG, and PD are all employees of and shareholders in Regeneron Pharmaceuticals, Inc., who report having three patents pending with Regeneron Pharmaceuticals, Inc. TJS reports grants/contracts paid to his institution by 10.13039/100009857Regeneron Pharmaceuticals, Inc., 10.13039/100004319Pfizer Inc., 10.13039/100004312Eli Lilly and Company, 10.13039/100002429Amgen Inc., Grünenthal, 10.13039/100019832Galapagos NV, 10.13039/100004336Novartis AG, Techfields Inc., Paradigm Pharmaceuticals Inc., Kolon TissueGene, Inc., 10.13039/100014927Anika Therapeutics, and Taiwan Liposome Company, Ltd.; consulting fees paid to him by 10.13039/100004319Pfizer Inc., 10.13039/100004312Eli Lilly and Company, IBSA Pharma Inc., 10.13039/100004330GlaxoSmithKline Pharmaceuticals, Biosplice Therapeutics, Collegium Pharmaceutical, Xalud Therapeutics, Grünenthal, Techfields Inc., 10.13039/100019832Galapagos NV, Unity Biotechnology, Paradigm Pharmaceuticals Inc., 10.13039/100004325AstraZeneca, 10.13039/100004330GlaxoSmithKline Pharmaceuticals, Genascense, Tremeau Pharmaceuticals, Inc., Moebius Medical; and participating in and receiving payment for a data safety monitoring board or advisory board by IQVIA, 10.13039/100004325AstraZeneca, Alira Health, and Horizon Therapeutics. JDD is an employee of and shareholder in Regeneron Pharmaceuticals, Inc., who reports having two patents pending with Regeneron Pharmaceuticals, Inc. MF is an employee of and shareholder in Teva Pharmaceutical Industries Ltd. and reports having received payment from Teva Pharmaceutical Industries Ltd. for travel and attendance at investigator meetings., (© 2024 The Authors.)

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., Competing Interests: L.E.C. and N.S. have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

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., (© 2024. The Author(s) and Pfizer.)

Objective: To determine whether sex influences the analgesic efficacy of systemic pharmacological treatment in patients with knee osteoarthritis., Design: A systematic review, guided by Cochrane methods, sourced studies from Medline, Cochrane Library, Embase, and CINAHL Plus with Full Text as of October 10, 2022. Eligible studies were double-blind RCTs evaluating systemic pharmacological treatments for knee osteoarthritis in adults, with minimum 30-day treatment duration, reporting sex-specific results or mentioning sex subgroup analysis for analgesic efficacy. The risk of bias was assessed using the Cochrane Risk of Bias tool version 2 (RoB 2)., Results: 9 studies (5201 participants) met inclusion criteria, analyzing drugs including duloxetine, etoricoxib, tapentadol, naproxcinod, lutikizumab, and rofecoxib. Only one study reported sex-specific results. Review findings suggested no significant sex-based differences in treatment efficacy, however, data were limited due to a lack of sex-specific reporting or inclusion of sex in subgroup analyses., Conclusions: Current evidence does not support the existence of sex differences in the analgesic efficacy of systemic knee osteoarthritis treatments. However, this conclusion is substantially limited by the paucity of sex-specific reporting of results or subgroup analyses in most primary studies, emphasizing the need for future research to report on sex-stratified data to allow for comprehensive, personalized treatment strategies., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s).)

Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits' dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.

Objective: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings., Method: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored., Results: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106)., Conclusion: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188., Competing Interests: Declaration of Competing Interest John A. Carrino has received consulting fees from Covera Health, Globus, and Pfizer, and is on the medical advisory board of Image Analysis Group, Image Biopsy Lab and Carestream. Timothy E McAlindon has served on an advisory board for Pfizer, Samumed, Seikagaku, Flexion Therapeutics, Sanofi, Roche, Astellas, and Regeneron. Tom J. Schnitzer has received grants from Kolon TissueGene, Pfizer, Regeneron, Galapagos, Eli Lilly & Company, Paradigm, TLC, Ltd, Anika, Novartis; personal fees and non-financial support from Pfizer, Eli Lilly & Company, Regeneron, Aptinyx, Calibr, GSK, Astra-Zeneca, Genascence, Biosplice, Xalud, IBSA, IQVIA and Vertex. Ali Guermazi has received consulting fees from AstraZeneca, Merck Serono, Pfizer, Organogenesis, Novartis and TissueGene, and is a shareholder of Boston Imaging Core Lab LLC. Marc C Hochberg has received consulting fees from Bone Therapeutics, Bristol Myers Squibb, Eli Lilly, EMD Serono, Novartis Pharma AG, Pfizer, Regenosine, Samumed LLC, Theralogix LLC, TissueGene Inc., TLC Biopharmaceuticals, Inc., and Zynerba; is a member of the Data Safety Monitoring Committee for clinical trials conducted by Covance, Galapagos, ICON plc, IQVIA, and SunPharma; received royalties from Elsevier (Editor, Rheumatology 7e and Editor-in-Chief, Seminars in Arthritis and Rheumatism) and UpToDate™; and has stock ownership in BriOri Biotech and Theralogix LLC. Philip Conaghan has received consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, Genascence, GlaxoSmithKline, Janssen, Levicept, Novartis, Pfizer, Stryker and UCB. Mark T Brown, Aimee Burr, Robert J. Fountaine, Glenn C Pixton, Christine West and Kenneth M Verburg are employees of Pfizer and have stock/stock options. Lars Viktrup is an employee and stockholder of Eli Lilly and Company., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: The neural mechanisms for the persistence of pain after a technically successful arthroplasty in osteoarthritis (OA) remain minimally studied, and direct evidence of the brain as a predisposing factor for pain chronicity in this setting has not been investigated. We undertook this study as a first effort to identify presurgical brain and clinical markers of postarthroplasty pain in knee OA. Patients with knee OA (n = 81) awaiting total arthroplasty underwent clinical and psychological assessment and brain magnetic resonance imagining. Postoperative pain scores were measured at 6 months after surgery. Brain subcortical anatomic properties (volume and shape) and clinical indices were studied as determinants of postoperative pain. We show that presurgical subcortical volumes (bilateral amygdala, thalamus, and left hippocampus), together with shape deformations of the right anterior hippocampus and right amygdala, associate with pain persistence 6 months after surgery in OA. Longer pain duration, higher levels of presurgical anxiety, and the neuropathic character of pain were also prognostic of postsurgical pain outcome. Brain and clinical indices accounted for unique influences on postoperative pain. Our study demonstrates the presence of presurgical subcortical brain factors that relate to postsurgical persistence of OA pain. These preliminary results challenge the current dominant view that mechanisms of OA pain predominantly underlie local joint mechanisms, implying novel clinical management and treatment strategies., (Copyright © 2023 International Association for the Study of Pain.)

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI., Introduction: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes., Methods: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment., Results: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength., Conclusion: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Purpose: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI., Methods: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI., Results: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences., Conclusions: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men., Competing Interests: Declaration of Competing Interest Courtney M. Mazur, W. Brent Edwards, Ifaz T. Haider, Ying Fang, Leslie R. Morse, Thomas J. Schnitzer, Narina Simonian, and Karen L. Troy each declare that they have no conflict of interest., (Copyright © 2023 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Patients often take opioids to relieve osteoarthritis (OA) pain despite limited benefits and potential harms. This study aimed to compare cross-sectional perspectives of patients that were taking prescription opioid (N = 471) or nonopioid medications (N = 185) for OA in terms of satisfaction, expectations of effectiveness, and concerns. Patients prescribed opioids (>7 days) reported more prior treatments (2.47 vs. 1.74), greater mean pain intensity (5.47 vs. 4.11), and worse quality of life (EQ-5D-5L index value mean 0.45 vs. 0.71) than patients prescribed nonopioid medications (all p < 0.0001). Based on linear regression models adjusting for demographics and pain intensity, patients prescribed opioids were less satisfied with overall regimen (3.40 vs. 3.67, p = 0.0322), had less belief that medications were meeting effectiveness expectations (2.72 vs. 3.13, p < 0.0001), and had more concerns about treatments being "not very good" (3.66 vs. 3.22, p = 0.0026) and addiction (3.30 vs. 2.65, p < 0.0001) than patients prescribed nonopioid regimens. When the models were replicated for subgroups with ≥30 days' medication regimen duration, the findings were consistent with the main analyses. Patients have concerns about the risk of opioid addiction, but those with greater disease burden and more prior treatments continue taking opioid regimens.

Opioids are often prescribed for osteoarthritis (OA) pain, despite recommendations to limit use due to minimal benefits and associated harms. This study aimed to assess physicians' practice patterns and perceptions regarding opioids by specialty one year following the Centers for Disease Control and Prevention (CDC) published guidance on opioid prescribing. The 139/153 (90.8%) physicians who reported prescribing opioids in the previous year reported decreased prescribing for mild OA (51.3%, 26.5% and 33.3% of primary care physicians, rheumatologists, and orthopaedic surgeons, respectively), moderate OA (50.0%, 47.1% and 48.1%) and severe OA (43.6%, 41.2% and 44.4%). Prescribing changes were attributed to the CDC guidelines for 58.9% of primary care physicians, 59.1% of rheumatologists, and 73.3% of orthopaedic surgeons. Strong opioids were mostly reserved as third-line treatment. Although treatment effectiveness post-CDC guidelines was not assessed, perceptions of efficacy and quality of life with opioids significantly differed across specialties, whereas perceptions of safety, convenience/acceptability and costs did not. Physicians generally agreed on the barriers to opioid prescribing, with fear of addiction and drug abuse being the most important. Across specialties, physicians reported decreased opioid prescribing for OA, irrespective of OA severity, and in most cases attributed changes in prescribing to the CDC guideline.

Introduction: We sought to predict analgesic response to daily oral nonsteroidal anti-inflammatory drugs (NSAIDs) or subcutaneous tanezumab 2.5 mg (every 8 weeks) at week 16 in patients with moderate-to-severe osteoarthritis, based on initial treatment response over 8 weeks., Methods: Data were derived from three randomized controlled trials of osteoarthritis. A two-step, trajectory-focused, analytics approach was used to predict patients as responders or non-responders at week 16. Step 1 identified patients using a data-element combination method (based on pain score at baseline, pain score at week 8, pain score monotonicity at week 8, pain score path length at week 8, and body site [knee or hip]). Patients who could not be identified in step 1 were predicted in step 2 using a k-nearest neighbor method based on pain score and pain response level at week 8., Results: Our approach predicted response with high accuracy in NSAID-treated (83.2-90.2%, n = 931) and tanezumab-treated (84.6-91.0%, n = 1430) patients regardless of the efficacy measure used to assess pain, or the threshold used to define response (20%, 30%, or 50% improvement from baseline). Accuracy remained high using 50% or 20% response thresholds, with 50% and 20% yielding generally slightly better negative and positive predictive value, respectively, relative to 30%. Accuracy was slightly better in patients aged ≥ 65 years relative to younger patients across most efficacy measure/response threshold combinations., Conclusions: Analyzing initial 8-week analgesic responses using a two-step, trajectory-based approach can predict future response in patients with moderate-to-severe osteoarthritis treated with NSAIDs or 2.5 mg tanezumab. These findings demonstrate that prediction of treatment response based on a single dose of a novel therapeutic is possible and that predicting future outcomes based on initial response offers a way to potentially advance the approach to clinical management of patients with osteoarthritis., Gov Identifiers: NCT02528188, NCT02709486, NCT02697773., (© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Introduction: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment., Methods: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56., Results: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints., Conclusions: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo., Clinicaltrials: gov: NCT02528253., (© 2022. The Author(s).)

Introduction: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo., Methods: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression., Results: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments., Conclusions: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188)., (© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)