Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

Effects of Adding Extracorporeal Shockwave Therapy (ESWT) to Platelet-Rich Plasma (PRP) among Patients with Rotator Cuff Partial Tear: A Prospective Randomized Comparative Study.

A rotator cuff tear is a prevalent ailment affecting the shoulder joint. The clinical efficacy of combined therapy remains uncertain for partial rotator cuff tears. In this study, we integrated extracorporeal shockwave therapy (ESWT) with platelet-rich plasma (PRP) injection, juxtaposed with PRP in isolation. Both cohorts exhibited significant improvements in visual analogue scale (VAS), Constant-Murley score (CMS), degrees of forward flexion, abduction, internal rotation, and external rotation, and the sum of range of motion (SROM) over the six-month assessment period. The application of ESWT in conjunction with PRP exhibited notable additional enhancements in both forward flexion (p = 0.033) and abduction (p = 0.015) after one month. Furthermore, a substantial augmentation in the range of shoulder motion (SROM) (p < 0.001) was observed after six months. We employed isobaric tag for relative and absolute quantitation (iTRAQ) to analyze the differential plasma protein expression in serum samples procured from the two groups after one month. The concentrations of S100A8 (p = 0.042) and S100A9 (p = 0.034), known to modulate local inflammation, were both lower in the ESWT + PRP cohort. These findings not only underscore the advantages of combined therapy but also illuminate the associated molecular changes.

The Impact of Chronic Pancreatitis on the Occurrences of Human Cancers: Real-World Data.

Chronic pancreatitis (CP) may induce systemic inflammation, potentially increasing cancer susceptibility. However, the link between CP and extra-pancreatic cancer remains underexplored. Employing Taiwanese National Health Insurance Database data from 2000 to 2017, we compared 5394 CP patients with 21,576 non-CP individuals through propensity score matching. CP patients exhibited a significantly higher cancer risk (adjusted hazard ratio (aHR) of 1.32 for females and 1.68 for males) and cumulative incidence (p < 0.001) compared to non-CP individuals. CP showed notable associations with pancreatic (aHR = 3.51), liver (aHR = 1.62), stomach (aHR = 2.01), and other cancers (aHR = 2.09). In terms of liver cancer, CP was significantly associated with patients without viral hepatitis, regardless of gender (aHR = 2.01 for women; aHR = 1.54 for men). No significant cancer occurrences were observed within the first year following CP diagnosis. Pancreatic or liver cancer developed in approximately half of CP patients within 2-3 years, while gastric cancer in male CP patients predominantly occurred around the fifth year after diagnosis. These findings inform potential cancer-screening plans for CP patients.

Exploring the Relationship between Periodontitis, Anti-Periodontitis Therapy, and Extra-Oral Cancer Risk: Findings from a Nationwide Population-Based Study.

This study aimed to evaluate the systemic impact of periodontitis, previously considered a local disease, on cancer occurrence. We enrolled 683,854 participants, comparing cancer incidence among those with and without periodontitis and assessing the impact of periodontal treatment on cancer risk. Regardless of gender, age, Charlson comorbidity index, or the use of non-steroidal anti-inflammatory drugs, periodontitis patients had a lower overall cancer risk than controls. However, men with periodontitis had a higher risk of prostate cancer (adjusted hazard ratio [aHR] = 1.22; 95% confidence interval [CI] = 1.10-1.35), and both men and women had a higher risk of thyroid cancer (women: aHR = 1.20, 95%CI = 1.04-1.38; men: aHR = 1.51, 95% CI = 1.15-1.99). Patients with periodontitis who received treatment showed a reduced cancer risk (aHR = 0.41; 95% CI = 0.38-0.44) compared to untreated patients. Proper treatment for periodontitis may lower an individual's cancer risk more than if they did not have the disease at all, suggesting that periodontitis is a modifiable risk factor for cancer.

Changes in Serum Bone Metabolism Markers after Living Donor Liver Transplantation (LDLT) and Their Association with Fracture Occurrences.

Living donor liver transplantation (LDLT) is lifesaving, but can lead to osteoporosis and fractures. In our 3-year study of 25 LDLT recipients, we observed significant reductions in lumbar spine and femoral neck T scores, along with bone resorption marker reductions and liver regeneration marker increases. Serum calcium levels increased, while osteoprotegerin (OPG) decreased and Dickkopf-related protein 1 (DKK-1) increased. Patients who suffered fractures within 3 years of LDLT had higher serum OPG, lower serum nuclear factor kappa B ligand (RANKL), a higher OPG/RANKL ratio and higher serum DKK-1 levels. OPG, RANKL, OPG/RANKL ratio and DKK-1 levels before LDLT predicted hip or spine fractures within three years after LDLT. Further research is necessary to determine the optimal level of osteoclastic activity for preventing fracture onset.

Cartilage-specific knockout of miRNA-128a expression normalizes the expression of circadian clock genes (CCGs) and mitigates the severity of osteoarthritis.

BACKGROUND: Micro-ribonucleic acids (miRNAs) are involved in osteoarthritis (OA) pathogenesis and clock-controlled genes (CCGs) regulation. However, the interaction between miRNAs and CCGs remains unclear. METHODS: Human OA samples were used to assess CCGs expression. Cartilage-specific miR-128a knockout mouse model was established to investigate miR-128a's role in OA pathogenesis. Destabilization of the medial meniscus (DMM) model was employed to simulate OA. RESULTS: Transcription levels of nuclear receptor subfamily 1 group D member 2 (NR1D2) were lower in both human OA samples and wild-type mice undergoing DMM compared to non-OA counterparts. MiR-128a knockout mice showed reduced disturbances in micro-computed tomographic and kinematic parameters following DMM, as well as less severe histologic cartilage loss. Immunohistochemistry staining revealed a lesser decrease in NR1D2-positive chondrocytes after DMM in miR-128a knockout mice than in wild-type mice. NR1D2 agonist rescued the suppressed expression of cartilage anabolic factors and extracellular matrix deposition caused by miR-128a precursor. CONCLUSIONS: Cartilage-specific miR-128a knockout mice exhibited reduced severity, less disrupted kinematic parameters, and suppressed NR1D2 expression after DMM. NR1D2 enhanced the expression of cartilage anabolic factors and extracellular matrix deposition. These findings highlight the potential of employing miR-128a and CCG-targeted therapy for knee OA.

Micro Ribonucleic Acid-29a (miR-29a) Antagonist Normalizes Bone Metabolism in Osteogenesis Imperfecta (OI) Mice Model.

Osteogenesis imperfecta (OI) is not curative nowadays. This study tried to unriddle the therapeutic potential of micro ribonucleic acid-29a (miR-29a) antagonist in treating OI in a mouse animal model (B6C3Fe a/a-Col1a2oim/J). We showed that the expression levels of miR-29a were higher in bone tissues obtained from the OI mice than from wild-type mice demonstrated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization assay. We established lentivirus-shuttled vector expressing miR-29a antisense oligonucleotide (miR-29a-AS) and miR-29a precursors (pre-miR-29a), showing that the inferior bony architecture in micro-computed tomography and pertinent morphometric parameters could be rescued by miR-29a-AS and deteriorated by pre-miR-29a. The decreased proliferating cell nuclear antigen (PCNA), increased Dickkopf-1 (DKK1), and decreased ß-catenin expression in OI mice could be accentuated by pre-miR-29a and normalized by miR-29a-AS. The decreased osteogenesis and increased osteoclastogenesis in OI mice could also be accentuated by pre-miR-29a and normalized by miR-29a-AS. miR-29a-AS did not seem to possess severe hepatic or renal toxicities.

The Differential Systemic Biological Effects between Computer Navigation and Conventional Total Knee Arthroplasty (TKA) Surgeries: A Prospective Study.

Distal femur reaming-free total knee arthroplasty (TKA) was reported to possess lower risk of acute myocardial infarction (AMI) or venous thromboembolism (VTE) than conventional TKA in a retrospective population-based study. We tried to offer prospective biological evidence by comparing the levels of AMI and VTE serum surrogate markers among the patients undertaking navigation and conventional TKAs to support these observations. Thirty-four participants undertaking navigation TKA and 34 patients receiving conventional TKA were recruited between February 2013 and December 2015. Blood samples were drawn from all participants before TKA, and 24 and 72 h after TKA, to assess the concentration of soluble P-selectin, matrix metalloproteinase-9 (MMP-9), C-reactive protein (CRP), and interleukin-8 (IL-8) between the participants undergoing navigation and conventional TKAs. We showed that significantly lower serum levels of soluble P-selectin 24 h after, as well as CRP 24 and 72 h after TKA could be observed in the navigation cohort. The more prominent surge of serum soluble P-selectin and CRP were perceived 24 and 72 h after TKA among the participants undergoing conventional TKA. Based upon our prospective biological evidence, the merits of navigation TKA are strengthened by lower levels of AMI and VTE serum surrogate markers.

The Antagonism of Neuropeptide Y Type I Receptor (Y1R) Reserves the Viability of Bone Marrow Stromal Cells in the Milieu of Osteonecrosis of Femoral Head (ONFH).

Neuropeptide Y (NPY)-Y1 receptor (Y1R) signaling is known to negatively affect bone anabolism. Our study aimed at investigating the impact of NPY-Y1R signaling in the pathogenesis of glucocorticoid-related osteonecrosis of the femoral head (ONFH). Femoral heads were retrieved from 20 patients with and without ONFH, respectively. The bone marrow stromal cells (BMSCs) from ONFH femoral heads were treated with Y1R agonists and antagonists for subsequent analysis. We showed that the local NPY expression level was lower in ONFH heads. The Y1R agonists and antagonists disturb and facilitate the survival of BMSCs. The transcription of stromal derived factor-1 (SDF-1) was enhanced by Y1R antagonists. Our study showed that the local NPY expression level was lower in ONFH heads. Y1R antagonists facilitate the survival of BMSCs and stimulate the transcription of SDF-1 by BMSCs. These findings shed light on the role of NPY-Y1R signaling in the pathogenesis of ONFH.

Decreased Expression of Leptin among Patients with Shoulder Stiffness.

Shoulder stiffness (SS) is a disease that is fibroblastic and inflammatory in nature. Leptin is an adipokine-mediating the fibroblastic and inflammatory processes of various diseases. Our study tried to investigate the role of leptin in SS pathogenesis. Subacromial bursa from stiff and non-stiff shoulders were obtained for reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunoblotting. Subacromial fluid was obtained for enzyme-linked immunosorbent assay. We showed that the expression level of leptin was lower in the subacromial bursae from the stiff shoulders in RT-PCR analysis (p < 0.001) and immunoblotting (p < 0.001). The concentration of leptin was also lower in the subacromial fluid derived from stiff shoulders. The leptin level in the subacromial fluid was positively associated with the constant score, total range of motion, flexion, abduction, and external rotation. The synovial fibroblasts derived from stiff shoulder-retrieved subacromial bursa were treated by 0, 1, and 3 µM leptin. Under RT-qPCR analysis, leptin was shown to dose-dependently decrease the transcription of IL-6, IL-10, and IL-13, but without impact on IL-1ß and IL-4 (p < 0.001, p = 0.001, p = 0.001, p = 0.137, and p = 0.883 by ANOVA test, respectively). These results shed light on the role of leptin in orchestrating the disease processes of SS.

Protective Effects of Higher Exposure to Aspirin and/or Clopidogrel on the Occurrence of Hip Fracture among Diabetic Patients: A Retrospective Cohort Study.

Aspirin and clopidogrel are commonly prescribed alone or together among the type 2 diabetes mellitus (T2DM) patients, and both agents could affect bone metabolism. This study aimed at demonstrating the effects of the dosage and the duration of aspirin and/or clopidogrel alone or together on the occurrence of hip fracture among T2DM patients. We chose the patients newly diagnosed with T2DM and divided them into four subgroups which are under aspirin monotherapy (78,522 patients), clopidogrel monotherapy (12,752 patients), dual therapy (7209 patients), and patients not taking antiplatelet drugs (401,686 patients). We found that only higher dosage (>360 cumulative daily defined dose (cDDD)) and longer duration (≥3 years) of antiplatelet agents could be associated with lower fracture risk. Compared with the subjects taking <1-year dual agents, the risk of hip fracture was 0.38-fold for the patients taking ≥3-year dual agents. Lower dosage (28−179 cDDD) and shorter duration (1~2 years) could even be associated with higher fracture risk. Overall, the best regimen to fend off the hip fracture was the use of aspirin and clopidogrel for ≥3 years.

Incidence of Hip Fractures among Patients with Chronic Otitis Media: The Real-World Data.

Chronic otitis media (COM) has been considered as a localized disease, and its systemic impact is poorly understood. Whether COM-induced inflammation could be associated with systemic bone loss and hip fracture is unknown at present. Our study tried to determine the risk of hip fracture among COM patients. We selected the comparison individuals without the COM coding and paired the controls with COM patients by gender, age, and comorbidities (including osteoporosis) by about a one-to-two ratio. Our study showed that the incidence of hip fracture was 4.48 and 3.92 per 1000 person-years for comparison and COM cohorts respectively. The cumulative incidence of hip fracture is higher in the COM cohort (p < 0.001). After adjustment for gender, age, and comorbidities, the COM patients had a 1.11-fold (aHR = 1.11; 95% CI = 1.05−1.17) risk of hip fracture than the control subjects. Among COM patients, a history of hearing loss is associated with higher (aHR = 1.21; 95% CI = 1.20−1.42) fracture risk. Our study showed that COM patients, especially those with hearing loss, are susceptible to a higher risk for hip fracture.

The Association between Iron-Deficiency Anemia (IDA) and Septic Arthritis (SA): The Real-World Data.

Background and Objectives: Iron-deficiency anemia (IDA) could predispose the afflicted individuals to various infections and musculoskeletal disorders. This study attempted to investigate the association between IDA and septic arthritis (SA), a musculoskeletal disease. Materials and Methods: We investigated all the eligible subjects in the Taiwanese longitudinal health insurance database (LHID) between 2000 and 2012. Subjects with the diagnosis of IDA (International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM): 280) were allocated to the IDA cohort. The control subjects were randomly matched to every subject with IDA coding by age and sex at the 1:4 ratio. All of the recruited subjects were followed since the index date to the onset of SA (ICD-9-CM: 711.0), withdrawal from the insurance (including death), or 31 December 2013. Results: The cumulative incidence of SA was assessed. We showed that the cumulative incidence of SA was higher in the IDA cohort than in the control cohort (p-value < 0.0001). After adjustment of the comorbidities, the IDA patients had a 2.53-fold risk of SA compared to control subjects (aHR = 2.53, 95% CI = 1.89−3.38). Conclusions: IDA was associated with an increased risk of SA.

Avoidance of intramedullary violation in computer-assisted total knee arthroplasty lowers the incidence of periprosthetic joint infection compared with conventional total knee arthroplasty: A propensity score matching analysis of 5342 cases.

BACKGROUND: Conventional total knee arthroplasty (CONV-TKA) inevitably perturbs femoral medullary canal, disturbs medullary micro-architecture and increases blood loss and inflammatory responses. We hypothesized that avoidance of intramedullary violation may lower the incidence of periprosthetic joint infection (PJI). The aim of this study was to verify whether computer-assisted total knee arthroplasty (CAS-TKA) lowers the incidence of PJI as compared with CONV-TKA. METHODS: A propensity score matching study of 5342 patients who underwent CAS-TKA (n = 1085) or CONV-TKA (n = 4257) for primary osteoarthritis of the knee from 2007 to 2015 in our institute was performed. Patients who underwent CAS-TKA were matched to those who received CONV-TKA at a 1:2 ratio according to demographics and comorbidities. PJI was defined according to the Musculoskeletal Infection Society diagnostic criteria from the 2013 International Consensus Meeting. RESULTS: After controlling potential risk factors, the use of CAS-TKA resulted in a lower incidence of PJI as compared with CONV-TKA [adjusted hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.18-0.99]. The same trend in PJI reduction was observed with the usage of CAS-TKA under sensitivity testing [HR, 0.33; 95% CI, 0.12-0.95]. The cumulative incidence of PJI was lower in the CAS-TKA group than the CONV-TKA group (log-rank test, p = 0.013). CONCLUSION: Avoidance of intramedullary violation during TKA may play a pivotal role in lowering the incidence of PJI. The use of CAS-TKA can reduce the incidence of PJI, with a better survival rate in terms of being free of PJI, as compared with CONV-TKA.

Cre/LoxP Genetic Recombination Sustains Cartilage Anabolic Factor Expression in Hyaluronan Encapsulated MSCs Alleviates Intervertebral Disc Degeneration.

(1) Background: Inexplicable low back and neck pain frequently results from spinal disc degeneration with an imbalanced intervertebral disc (IVD) cell homeostasis. We hypothesize that introducing MSC expressing a sustained cartilage-anabolic factor in the IVD may stimulate the mucoid materials secreted from the IVD cells, promote the MSC's chondrogenesis and maintain the hydration content providing mechanical strength to decelerate the disc degeneration progression; (2) Methods: This study expressed a cartilage-anabolic factor runx1 by a baculoviral vector (BV) transduced MSCs through a Cre/LoxP gene editing and recombination system for sustained recombinant runx1 transcription factor production. The Cre/LoxP BV modified MSCs were encapsulated by hyaluronan hydrogel, due to its' vital composition in ECM of a healthy disc and transplanted to a punctured coccygeal disc in rats through micro-injection, followed by X-ray radiography and histological analysis at the 4- and 12-weeks post-transplantation; (3) Results: Data reveals the Cre/LoxP BV system-mediated long-termed runx1 gene expression, possessing good biosafety characteristics in the in vitro cell transduction and in vivo MSCs transplantation, and maintained superior hydration content in the disc than that of mock transduced MSCs; (4) Conclusions: This proof-of-concept study fulfills the need of implanting therapeutic cells accompanied with microinjection in the disc, such as a discography and paves a road to manufacture composite hyaluronan, such as peptide modified hyaluronan as an MSC carrier for IVD regeneration in the future study.

The association between gallstone disease (GSD) and hip fracture: a nationwide population-based study.

Objectives: Despite the high prevalence of gallstone disease (GSD), the shared risk factors of GSD and osteoporosis, and the known association between hip fracture and hepatobiliary diseases, the association between hip fracture and GSD is not currently clear. Therefore, we performed a nationwide population-based study to investigate the association between GSD and hip fracture to determine the impact of cholecystectomy on the risk of fracture.Methods: In this study, we assessed all subjects in the longitudinal health insurance database (LHID) between 2000 and 2011, excluding those subjects aged >20 years old and those with a previous history of hip fracture (ICD-9-CM 820). Among those that were included, subjects with at least two or more outpatient visits or with one record of hospitalization under the coding of GSD (ICD-9-CM code: 574) were allocated to the GSD cohort. The remaining subjects were designated to the control cohort. All participants were followed till the onset of hip fracture, withdrawal from the NHI, or the end of 2013.Results: We found that the cumulative incidence of hip fracture was higher in the GSD cohort than in the control cohort (log-rank test: p-value < 0.01). After adjustment, the GSD patients had a 1.21-fold risk of hip fracture compared to control subjects (aHR = 1.21, 95% CI = 1.21-1.30). Comparison between those subjects without GSD and those without cholecystectomy revealed that the risk of hip fracture was higher among GSD patients that had not undergone cholecystectomy (aHR = 1.17, 95% CI = 1.06-1.29) or those that had undergone cholecystectomy (aHR = 1.22, 95% CI = 1.06-1.41).Conclusion: Based upon these results, we concluded that GSD was associated with an increased risk of hip fracture regardless of whether the patient had undergone cholecystectomy.

Systemic effects of platelet-rich plasma local injection on serum and urinary anabolic metabolites: A prospective randomized study.

Platelet-rich plasma (PRP) is widely utilized in the treatment of sports injuries. However, potential systemic effects after localized PRP injection are unclear at present. In this prospective randomized study, 24 Taiwanese male athletes with tendinopathy were randomized into a PRP group (n = 13) or a saline group (n = 11). The concentrations of serum and urine biomarkers were quantified by enzyme-linked immunosorbent assay assessment as well as gas chromatographic and mass spectrometric analysis, respectively. The results showed no significant differences in serum levels of growth hormone, insulin-like growth factor-1, insulin-like growth factor-binding protein 3, vascular endothelial growth factor, platelet-derived growth factor-BB, or serum substance P(SP) between the two groups before intervention, nor at 1, 2, or 7 days after intervention. However, a significant decrease in the serum SP level 1 and 7 days after PRP injection was observed. Regarding urinary concentrations of metabolites of anabolic androgenic steroids (AAS), no between-group differences before intervention, nor at 1, 2, or 7 days after intervention, were observed. Our study failed to observe significant surge of serum anabolic molecules and urinary excretion of anabolic AAS metabolites after PRP injection.

Resistin enhances IL-1ß and TNF-α expression in human osteoarthritis synovial fibroblasts by inhibiting miR-149 expression via the MEK and ERK pathways.

Resistin is a cysteine-rich adipokine that promotes the release of inflammatory cytokines, particularly interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), which are critical pro-inflammatory mediators in osteoarthritis (OA) pathogenesis. We describe evidence of significantly higher levels of resistin, IL-1ß, and TNF-α expression in OA knee synovial tissue compared with that from non-OA knees. Resistin-induced enhancement of IL-1ß and TNF-α expression in human OA synovial fibroblasts (OASFs) were attenuated by MEK and ERK inhibitors, as well as their respective siRNAs. Our data reveal that resistin enhances the expression of TNF-α and IL-1ß in OASFs by inhibiting miR-149 expression via MEK and ERK signaling. Our findings elucidate the inter-relationships between resistin and pro-inflammatory mediators during OA pathogenesis and could help to facilitate the development of synovium-targeted therapy in OA.

Corrigendum to "The Epidemiology of Hip Fracture among Subjects with Pyogenic Liver Abscess (PLA): A Nationwide Population-Based Study".

[This corrects the article DOI: 10.1155/2020/5901962.].

Epidemiology of fatal/non-fatal suicide among patients with chronic osteomyelitis (COM): a nationwide population-based study.

OBJECTIVE: Chronic osteomyelitis (COM) can induce systemic inflammation, and systemic inflammation may be associated with suicide tendency. However, no studies have investigated the correlation between COM and suicide tendency. METHODS: The aim of this population-based study was to determine the epidemiology of fatal/non-fatal suicide among COM patients. Subjects with at least two outpatient visits or one course of inpatient care diagnosed with COM were recruited into a COM cohort. The control/COM subject ratio was approximately 4:1 matched by age, sex, major depression coding and index year (COM patients). Subjects with suicide attempts before COM diagnosis and subjects aged <20 years were excluded. RESULTS: COM patients had 1.93 (95% confidence interval [CI]: 1.11-3.36) times the risk of fatal/non-fatal suicide as control subjects. Considering death as the competing event of fatal/non-fatal suicide, COM patients had 1.76 (95% CI: 1.03-3.01) times the risk of fatal/non-fatal suicide (competing risk regression model). The effect of COM on fatal/non-fatal suicide was more prominent among diabetic patients. COM severity also correlated with the risk of fatal/non-fatal suicide. CONCLUSIONS: More attention must be paid to suicide tendency among COM patients.