Effect of bone density on the drill-hole diameter made by a cannulated drill bit in cancellous bone.

BACKGROUND: When a pilot hole is made prior to a screw's insertion into bone, the same drill bit is used irrespective of the bone quality. However, osteoporotic bone is fragile and this may affect the hole diameter, which is of particular concern in cancellous bone. In this study, the relationship between bone density and drill-hole diameter was investigated assuming a pre-drilling process in screw-only osteosynthesis in the metaphysis and epiphysis. METHODS: Two types of drill bit (triple-flute [T] and quadruple-flute [Q]) with different shapes and diameters were prepared: type T bits with 3.5 mm and 4.4 mm diameters, and type Q bits with 3.5 mm and 4.2 mm diameters. Drilling was performed manually in simulated bones with four densities: 5, 10, 15, and 20 pounds per cubic foot. We measured the hole diameters with a coordinate measuring machine and analyzed the relationship between the drill-hole diameters and the densities of the simulated bones. We then compared the screw pull-out strength between the two 3.5-diameter drill bits. RESULTS: In all cases, the diameters of the drill holes were larger than those of the drill bits. The relationship between the drill-hole diameters and the bone densities was a negative linear correlation. Enlarging the hole diameter decreased the screw pull-out strength. CONCLUSIONS: For cannulated drill bits of 3.5, 4.2 and 4.4 mm diameter, the diameter of the drill hole in cancellous bone obtained by the manual drilling technique tends to be larger in low-density (e.g., osteoporotic) compared to high-density (e.g., healthy) bone.

Meniscal Allograft Transplantation Concomitant With Cartilage Repair for Symptomatic Lateral Meniscus-Deficient Knees With Over Two Years of Follow-up.

Background and objective The treatment for symptomatic meniscus-deficient knees with cartilage defects remains challenging on account of insufficient meniscal substitutes. One solution for this might involve combining meniscal allograft transplantation (MAT) and cartilage repair. In this study, we aimed to analyze the effectiveness and safety of MAT concomitant with cartilage repair for symptomatic lateral meniscus-deficient knees in a setting with limited availability of meniscal transplants in Japan. Methods Nine patients who underwent MAT concomitant with osteochondral transplantation (five) and/or autologous chondrocyte implantations (seven) were followed up for at least two years (mean: 51.2 months, range: 24-84 months). Their demographic data and other characteristics were as follows - mean age: 51.7 years, range: 36-67 years; men/women: 4/5; cause: trauma/discoid meniscus: 8/1; cartilage defect size: mean: 6.7 cm2/knee, range: 1.0-11.3. The effectiveness and safety were evaluated clinically by using the Lysholm Knee Scoring Scale (LKSS) and Japanese Orthopaedic Association (JOA) knee score, physical examination, X-rays, and MRI preoperatively and at one, 12, and 24 months after the implantation. Differences between the variables were analyzed using the Friedman test and Scheffe's multiple comparisons. Results The median LKSS and JOA scores significantly improved from 70 points (range: 21-80) and 35 (25-45) preoperatively to 86.5 (65-98) and 87.5 (80-95) at 24 months after surgery, respectively (p<0.001, p=0.0013). The range of motion (ROM), femorotibial angle, and the lateral joint space showed no significant changes. However, lateral meniscal extrusions (LMEs) increased by 3.0 mm (range: 0-6.3 mm) at one month postoperatively and remained unchanged until two years postoperatively. Treatment failure occurred in one case, which was revised by total knee arthroplasty (TKA) at 18 months postoperatively. Additional surgeries were needed in some cases: lateral meniscal tear (three cases), contracture (two cases), and patellar instability (one case). However, neither infection nor allergic reaction was observed in the blood exams. Conclusions Although MAT concomitant with cartilage repair showed good clinical outcomes, half of the cases needed additional surgeries. Based on our findings, this technique should be adopted only in select cases and performed by a handful of highly experienced surgeons.

A Single Case Study Comparing High Tibial Osteotomy With Matrix-Associated Autologous Chondrocyte Implantation With Medial Collateral Ligament Release Treating Bilateral Severe Medial Knee Osteoarthritis.

CASE: A 62-year-old woman with bilateral severe medial unicompartmental knee osteoarthritis underwent right high tibial osteotomy (HTO) at the age of 49 and left matrix-associated autologous chondrocyte implantation covering with periosteum (pMACI) with medial collateral ligament (MCL) release at age 52 years. At the 13-year follow-up, she could walk and trek with good clinical scores, had high patient satisfaction, and had cartilaginous reparative tissue seen at second-look arthroscopy in her left knee. CONCLUSION: This case suggests that pMACI with MCL release might be a possible alternative to HTO in a varus knee undergoing cartilage replacement surgery when HTO is contraindicated.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Relationship between thread depth and fixation strength in cancellous bone screw.

BACKGROUND: Clarifying the effect of each parameter of screw design on its fixation strength is critical in the development of any type of screw. The purpose of this study was to clarify the relationship between the thread depth and fixation strength of metal screws for cancellous bone. METHODS: Nine types of custom-made screws with the only changed variable being the thread depth were manufactured. Other elements were fixed at a major diameter of 4.5 mm, a thread region length of 15 mm, a pitch of 1.6 mm, and a thread width of 0.20 mm. The pull-out strength and insertion torque of each screw were measured for each of two foam-block densities (10 or 20 pcf). The correlation between the thread depth of the screw and the mechanical findings were investigated with single regression analysis. RESULTS: Regardless of the foam-block density, the pull-out strength significantly increased as the thread depth increased from 0.1 mm to 0.4 mm; after that, the increase was more gradual (p < 0.01, respectively). The relationship between the thread depth and insertion torque was similar. In addition, the insertion torque tended to be more strongly affected by screw depth than the pull-out strength (2.6 times at 20 pcf and 1.4 times at 10 pcf). CONCLUSIONS: The pull-out strength of 4.5-mm-diameter metal screws in a cancellous bone model was found to be biphasic, although linearly correlated with the change in screw depth in both phases. The boundary of the correlation was 0.4 mm regardless of the density of the bone model, with the effect of screw depth on pull-out strength beyond that being small in comparison.

The clinical outcomes of scaphoid nonunion treated with a precisely processed autologous bone screw: a case series.

INTRODUCTION: Metal implants and bioabsorbable implants are frequently used in orthopaedic surgery, but they have some disadvantages. The usefulness of autologous bone has been described, and a method to precisely process autologous bone into implants such as screws and apply the implants clinically has been desired. We created a new system for manufacturing autologous bone screws during surgery and report five cases of scaphoid nonunion treated with precise autologous bone screws made from the tibial cortex using the new system. PATIENTS AND METHODS: From 2012 through 2017, seven patients were diagnosed with scaphoid nonunion at our hospital and based on the inclusion/exclusion criteria, five of them were analyzed herein. The surgery was performed according to Zaidemberg's technique. The bone screw in each case was made from autologous tibial cortex using a numerically controlled lathe (model MTS4, Nano Co., Yokohama, Japan) under sterile conditions. The change in each patient's modified Mayo wrist score between the preoperative examination and at the final survey was determined, as were complications. RESULTS: The median modified Mayo wrist score improved significantly from 65 to 95 points. All patients who were followed for > 2 years fused at a median duration of 3.5 months. Bone regeneration was confirmed at the donor sites in all cases. One fracture at the donor site occurred as a severe complication. CONCLUSIONS: Precisely shaped autologous bone screws manufactured by a computer-assisted machine, together with a vascularized bone graft, may be a useful technique for treating scaphoid nonunions; these screws had good stability and bone replacement. Careful observation of the donor site is required. LEVEL OF EVIDENCE: IV.

Efficacy of duloxetine in patients with knee osteoarthritis or chronic low back pain with early pain reduction: An exploratory post-hoc analysis of Japanese phase 3, 1-year extension studies.

BACKGROUND: Two previous phase 3, double-blind, randomized, placebo-controlled trials showed that duloxetine 60 mg/day for 14 weeks significantly improved pain and quality of life in Japanese patients with knee osteoarthritis or chronic low back pain. In their open-label extension studies, these improvements were maintained for ≥48 weeks. This post-hoc analysis assessed the relationship between initial response to duloxetine and long-term pain reduction and quality of life in patients with knee osteoarthritis or chronic low back pain. METHODS: Patients (knee osteoarthritis: N = 43; chronic low back pain: N = 41) were subdivided based on extent of pain reduction from baseline to Week 4 of duloxetine (≥30%, 10-30%, or <10% reduction in Brief Pain Inventory-Severity average pain score). Outcome measures were changes from baseline for Brief Pain Inventory-Severity and Brief Pain Inventory-Interference at regular intervals up to Week 65. RESULTS: Mean change from baseline in Brief Pain Inventory-Severity was greater in patients with ≥30% early pain reduction than in patients with <10% early pain reduction through Week 27 for both conditions, and also Weeks 47-65 for back pain. Compared with the <10% early pain reduction group, mean change from baseline in the average of seven Brief Pain Inventory-Interference domain scores was greater in the ≥30% or 10-30% early pain reduction groups for knee osteoarthritis (except Weeks 63-65), and in the ≥30% early pain reduction group for chronic low back pain through Week 19. CONCLUSIONS: These results suggest that patients with knee osteoarthritis who respond well to duloxetine in the first month might experience sustained, long-term pain relief with generally greater quality-of-life improvement than patients with poor initial response. Patients with chronic low back pain who had strong initial response may experience a greater long-term pain relief, but not greater quality-of-life improvement, than patients with poor initial response.

Total knee arthroplasty combined with medial patellofemoral ligament augmentation using a Leeds-Keio ligament for 'Windswept deformity' with ipsilateral valgus deformity and permanent patellar dislocation: A case report and a literature review.

We present a 'Windswept deformity' in patient who had osteoarthritis with a mild varus and very severe valgus with ipsilateral permanent patellar dislocation. An 83-year-old woman could not walk for the past a few years due to bilateral knee pain. The femorotibial angle was 196° in the right knee pre-operatively and 134° in the left knee with permanent patellar dislocation. She underwent a staged total knee arthroplasty (TKA) for the right knee, and a semi-constrained TKA for the left knee with medial patellofemoral ligament (MPFL) augmentation using a Leeds-Keio (LK) ligament. At the final follow-up three years after surgery, bilateral knee pain and the extension lag had disappeared and range of motion (ROM) was 0° in extension and 130° in flexion for both knees without patellar re-dislocation. This clinical case indicates that the unconstrained and semi-constrained type of TKA combined with the MPFL augmentation using an LK ligament is effective to treat a 'Windswept deformity'.

Efficacy of duloxetine for multisite pain in patients with knee pain due to osteoarthritis: An exploratory post hoc analysis of a Japanese phase 3 randomized study.

BACKGROUND: Central sensitization, including dysfunction of descending inhibitory pain pathways, may contribute to multisite pain in patients with chronic musculoskeletal conditions. Duloxetine is a centrally acting analgesic that effectively reduces pain in patients with knee osteoarthritis. Here we assessed the efficacy of duloxetine (60 mg/day) in Japanese patients (N = 353) with pain due to knee osteoarthritis based on the number of painful body sites, determined using the Michigan Body Map. METHODS: Post hoc analysis of a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT02248480). RESULTS: At Week 14, the change from baseline in Brief Pain Inventory-Severity average pain score ("pain reduction") was significantly greater with duloxetine compared with placebo in patients with 3, 4, or ≥5 painful sites, but not in patients with 1 or 2 painful sites. In patients with ≥3 painful sites (57% of patients), pain reduction was significantly greater with duloxetine (n = 100) compared with placebo (n = 101) throughout the study (least squares mean change from baseline to Week 14: -2.68 vs -1.68). Greater pain reduction with duloxetine (n = 77) than placebo (n = 75) also occurred in patients with ≤2 painful sites, although the between-group difference was significant only at Week 4. CONCLUSIONS: These results are consistent with duloxetine enhancing the activity of descending inhibitory pain pathways that are dysfunctional in patients with central sensitization and multisite pain. In addition, these results suggest that duloxetine may be an effective choice of analgesic for patients with knee osteoarthritis and multisite pain.

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis.

Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.

Epstein-Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity.

Epstein-Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt's lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium is hampered, because of the lack of good in vitro model to pursue oncogenic process. Our primary nasopharyngeal epithelial cell cultures developed pseudostratified epithelium at the air-liquid interface, which was susceptible to EBV infection. Using the highly sensitive RNA in situ hybridization technique, we detected viral infection in diverse cell types, including ciliated cells, goblet cells, and basal cells. EBV-encoded small RNA-positive cells were more frequently detected in the suprabasal layer than in the basal layer. We established the most physiologically relevant EBV infection model of nasopharyngeal epithelial cells. This model will advance our understanding of EBV pathogenesis in the development of NPC.

Reference values for the locomotive syndrome risk test quantifying mobility of 8681 adults aged 20-89 years: A cross-sectional nationwide study in Japan.

BACKGROUND: The locomotive syndrome risk test was developed to quantify the decrease in mobility among adults, which could eventually lead to disability. The purpose of this study was to establish reference values for the locomotive syndrome risk test for adults and investigate the influence of age and sex. METHODS: We analyzed 8681 independent community dwellers (3607 men, 5074 women). Data pertaining to locomotive syndrome risk test (the two-step test, the stand-up test, and the 25-question geriatric locomotive function scale [GLFS-25]) scores were collected from seven administrative areas of Japan. RESULTS: The reference values of the three test scores were generated and all three test scores gradually decreased among young-to-middle-aged individuals and rapidly decreased in individuals aged over 60 years. The stand-up test score began decreasing significantly from the age of 30 years. The trajectories of decrease in the two-step test score with age was slightly different between men and women especially among the middle-aged individuals. The two physical test scores were more sensitive to aging than the self-reported test score. CONCLUSION: The reference values generated in this study could be employed to determine whether an individual has mobility comparable to independent community dwellers of the same age and sex.

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of anterior cruciate ligament injury - Secondary publication.

BACKGROUND: This clinical guideline presents recommendations for the management of patients with anterior cruciate ligament (ACL) injury, endorsed by the Japanese Orthopaedic Association (JOA) and Japanese Orthopaedic Society of Knee, Arthroscopy and Sports Medicine (JOSKAS). METHODS: The JOA ACL guideline committee revised the previous guideline based on "Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014", which proposed a desirable method for preparing clinical guidelines in Japan. Furthermore, the importance of "the balance of benefit and harm" was also emphasized. This guideline consists of 21 clinical questions (CQ) and 23 background questions (BQ). For each CQ, outcomes from the literature were collected and evaluated systematically according to the adopted study design. RESULTS: We evaluated the objectives and results of each study in order to make a decision on the level of evidence so as to integrate the results with our recommendations for each CQ. For BQ, the guideline committee proposed recommendations based on the literature. CONCLUSIONS: This guideline is intended to be used by physicians, orthopedic surgeons, physical therapists, and athletic trainers managing ACL injuries. We hope that this guideline is useful for appropriate decision-making and improved management of ACL injuries.

Effect of the positional relationship between the interference screw and the tendon graft in the bone tunnel in ligament reconstruction.

PURPOSE: To reveal the effects of the positional and length relationships between the interference screws (ISs) and the tendon graft in the bone tunnel on the fixation strength in ligament reconstruction. METHODS: We compared three IS positions on the anterior (the Anterior group) or posterior (the Posterior group) or side (the Side group) of the tendon graft in relation to the pullout direction. The tendon graft was pulled at 0°, 30°, 60°, and 90° to the bone tunnel, and the maximum pullout load at each angle was compared among the groups. We also investigated the relationship between the length of the tendon graft and the length of the IS in the bone tunnel. The direction of the pullout force was the same as that of the Anterior group, and the maximum load was compared between groups in which the tendon graft was longer or shorter than the IS. RESULTS: The maximum loads of the Anterior group were significantly greater than those of the Posterior and Side groups at the traction angles of 30° and 60°, respectively. An IS shorter than the tendon graft was found to provide significantly superior fixation strength compared to an IS longer than the tendon graft. CONCLUSIONS: Better fixation strength was achieved when the IS was placed on the side of the anchorage tunnel on which the tendon graft was loaded and the IS was shorter than the tendon graft.

Response to duloxetine in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese Phase III randomized study.

PURPOSE: To assess whether patients with knee osteoarthritis pain who have early pain reduction or treatment-related adverse events of special interest (TR-AESIs; constipation, decreased appetite, malaise, nausea, somnolence, thirst) with duloxetine treatment are more likely to have later improvements in pain and quality of life (QOL) relative to placebo than patients without these early indicators. PATIENTS AND METHODS: This was a post hoc analysis of 14-week randomized trial of Japanese patients with knee osteoarthritis pain (Brief Pain Inventory [BPI]-Severity average pain score ≥4) receiving duloxetine 60 mg/day (n=177 analyzed) or placebo (n=176). Primary trial outcome was change from baseline in BPI-Severity average pain at Week 14. Subgroups included early pain reduction (≥30%, 10%-30%, or <10% decrease in BPI-Severity average pain at Week 4) and early TR-AESIs (with/without TR-AESIs by Week 2). Measures included changes from baseline in BPI-Severity average pain, QOL (BPI-Interference, Western Ontario and McMaster Universities Osteoarthritis Index), Patient Global Impression of Improvement (PGI-I), and response rate (proportion achieving ≥30% or ≥50% pain reduction at Week 14). RESULTS: The ≥30% early pain reduction subgroup (n=93) had significantly greater improvements in pain, QOL, and PGI-I and higher ≥30% and ≥50% response rates than placebo; the 10%-30% (n=45) and the <10% (n=33) pain reduction subgroups did not show the same (except 10%-30% group: PGI-I at Week 10 and some QOL at Weeks 10 and/or 14). Both TR-AESI subgroups (with, n=52; without, n=125) had significantly greater improvements in pain, PGI-I, and most QOL measures and higher response rates than placebo. CONCLUSION: Early efficacy responses to duloxetine treatment, but not early TR-AESIs, may predict later pain reduction and QOL improvements in Japanese patients with knee osteoarthritis pain. CLINICALTRIALSGOV: NCT02248480.

Outcomes of surgical treatment for osteochondritis dissecans of the elbow: evaluation by lesion location.

BACKGROUND: For treatment of advanced elbow osteochondritis dissecans (OCD), we have used surgical treatment. Although favorable treatment outcomes have been reported for centrally located OCD, treatment outcomes are generally questionable and the choice of surgical method is controversial for laterally located OCD. Our purpose was to evaluate the treatment outcomes based on lesion location. METHODS: The patients were 30 young (mean age, 14 years) male athletes who underwent surgical treatment of elbow OCD and were monitored for more than 1 year. Osteochondral autografts harvested from the knee were transplanted to centralized (13 patients) or lateral localized (9 patients) OCD lesions. For lateral widespread (8 patients) OCD lesions, a detached osteochondral fragment was fixed using small osteochondral plugs. When the remaining cartilage defect was large after fragment fixation, a large-sized osteochondral plug was transplanted to the defect. Treatment outcomes were evaluated by the Japanese Orthopaedic Association score, elbow range of motion (ROM), and radiographic findings. RESULTS: The Japanese Orthopaedic Association score significantly improved in patients with centralized, lateral localized, and lateral widespread types of OCD. ROM significantly improved in patients with centralized and lateral localized, and they returned to playing sports within 6 months. However, patients with lateral widespread OCD exhibited no significant ROM improvement, and returning to sports was difficult for 3 patients because of poor osseous integration of the fixed osteochondral fragment. CONCLUSIONS: Osteochondral autograft transplantation provided favorable outcomes for centralized and lateral localized elbow OCD lesions. However, for lateral widespread OCD lesions, reconstruction of the entire capitellar lesion area may be necessary.

Safety and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis: an open-label, long-term, Phase III extension study.

PURPOSE: To assess long-term safety, tolerability, and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis. METHODS: In this open-label extension study (NCT02335346), Japanese patients with knee osteoarthritis and pain (Brief Pain Inventory [BPI] - Severity average pain score ≥4 at start of randomized trial) who had previously received duloxetine 60 mg/day or placebo for 14 weeks in a double-blind randomized trial entered the extension and received duloxetine 60 mg/day for 48 weeks. The primary outcome was safety/tolerability, secondary outcomes were change in BPI-Severity (BPI-S) average pain, BPI-Interference (BPI-I), Patient Global Impression-Improvement (PGI-I), Clinical Global Impression-Improvement (CGI-I), 36-item Short-Form Health Survey (SF36), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and exploratory outcomes were knee range of motion (efficacy outcome) and Kellgren-Lawrence grade (safety outcome). RESULTS: Of 323 patients who completed the randomized trial, 93 (50 placebo, 43 duloxetine) entered the extension. Most patients (85, 91.4%) experienced an adverse event, most commonly constipation, nasopharyngitis, somnolence, and dry mouth (≥10% of patients). There were eight serious adverse events in seven patients and no deaths. No obvious duloxetine-related changes were observed in laboratory tests, vital signs, or electrocardiograms. The change from baseline in BPI-S average pain score was significant throughout the extension. Significant reductions in BPI-I, PGI-I, CGI-I, WOMAC, and SF36 scores were also maintained through 52 weeks. There were no substantial changes in range of motion or Kellgren-Lawrence grade. CONCLUSION: In Japanese patients with chronic knee pain due to osteoarthritis, long-term treatment with duloxetine was well tolerated and associated with sustained improvements in pain and health-related quality of life without radiographic deterioration.