Association between P1NP value and increases in bone mineral density in patients with postmenopausal osteoporosis treated with romosozumab.

OBJECTIVES: The present study aimed to investigate the effectiveness of treatment with romosozumab for one year and association between bone turnover markers and changes in bone mineral density (BMD) in patients with postmenopausal osteoporosis (PMO). METHODS: Participants were 53 treatment-naïve PMO patients. Correlations of percent changes (Δ) in lumbar (L) and total hip (TH) BMD 12 months after initiating romosozumab with baseline demographic factors and parameters of N-terminal propeptide of type 1 collagen (P1NP) and tartrate-resistant acid phosphatase (TRACP)-5b at baseline and months 1, 3 and 6 were assessed. Multiple regression analysis was performed on factors significantly correlated with ΔL-BMD and ΔTH-BMD at month 12. RESULTS: ΔL-BMD and ΔTH-BMD at month 12 were 17.5% and 8.1%, respectively. Multiple regression analysis revealed that a high P1NP value at month 3 predicted large increases in L-BMD and TH-BMD at month 12. High total amount of P1NP values from baseline to month 6 was associated with large increases in L-BMD and TH-BMD at month 12, and was most strongly correlated with the P1NP value at month 3. CONCLUSIONS: A high P1NP value at month 3 predicted large increases in both L-BMD and TH-BMD at month 12 in PMO patients treated with romosozumab.

Choice of and response to treatment in patients with early-diagnosed rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

OBJECTIVE: Various guidelines recommend that patients with early rheumatoid arthritis (RA) try to achieve clinical remission within 6 months, and early therapeutic intervention is important to this end. This study aimed to investigate short-term treatment outcomes of patients with early-diagnosed RA in clinical practice and to examine predictive factors for achieving remission. METHODS: Of the 210 patients enrolled in the multicenter RA inception cohort, 172 patients who were followed up to 6 months after treatment initiation (baseline) were included. Logistic regression analysis was used to examine the impact of baseline characteristics on achievement of Boolean remission at 6 months. RESULTS: Participants (mean age, 62 years) initiated treatment after a mean of 19 days from RA diagnosis. At baseline and 3 and 6 months after treatment initiation, proportions of patients using methotrexate (MTX) were 87.8%, 89.0%, and 88.3%, respectively, and rates of Boolean remission were 1.8%, 27.8%, and 34.5%, respectively. Multivariate analysis revealed that physician global assessment (PhGA) (Odds ratio (OR): 0.84, 95% confidence interval (CI): 0.71-0.99) and glucocorticoid use (OR: 0.26, 95% CI: 0.10-0.65) at baseline were independent factors that predicted Boolean remission at 6 months. CONCLUSION: After a diagnosis of RA, satisfactory therapeutic effects were achieved at 6 months after the initiation of treatment centered on MTX according to the treat to target strategy. PhGA and glucocorticoid use at treatment initiation are useful for predicting the achievement of treatment goals.

Predictive factors for achievement of treatment goals in patients with postmenopausal osteoporosis treated with denosumab.

OBJECTIVES: To investigate efficacy of long-term treatment with denosumab and predictive factors for achievement of treatment goals in patients with postmenopausal osteoporosis (PMO). METHODS: We enrolled 111 PMO patients who had T-scores ≤-2.5 either at the lumbar spine (L-) or femoral neck (FN-), who had never been treated for osteoporosis, and who could be followed for at least 3 years. We first evaluated changes in bone mineral density (BMD) for up to 7 years. We next defined the treatment goal as the achievement of a T-score >-2.5 at month 36 and performed multivariate analysis to identify predictive factors for achievement of the goal. RESULTS: Lumbar spine- and femoral neck bone-mineral density increased yearly for 7 years. Among 87 patients with baseline L-T-scores ≤-2.5, better baseline L-T-scores predicted achievement of L-T-scores >-2.5 at month 36. The cut-off value for baseline L-T-score was -3.4. Among 76 patients with baseline FN-T-scores ≤-2.5, better baseline FN-T-scores predicted achievement of FN-T-scores >-2.5 at month 36. The cut-off value for baseline FN-T-scores was -2.8. CONCLUSIONS: Long-term treatment with denosumab was effective in PMO patients. As better baseline T-score predicted achievement of T-scores >-2.5, early initiation of treatment will contribute to better outcome.

A case of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with isolated lesions of the thoracic spine.

We report a case of isolated lesions of the thoracic spine attributed to synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. A 55-year-old woman who suffered from 6 months of back pain had vertebral osteomyelitis on magnetic resonance imaging (MRI). There were no laboratory findings suggestive of infection, malignancy, or autoimmune disease. Radiography, computed tomography (CT), and MRI of the thoracic spine showed mixed lesions of sclerosis and erosion, whereas bone scintigraphy did not show accumulation at any site except the thoracic spine. No lesions in the anterior chest wall or sacroiliac joints were apparent from CT and MRI. No lesions other than at the thoracic spine were observed. As the isolated lesions of the thoracic spine were considered not to have resulted from infection, malignancy, or autoimmune disease, the patient was referred to our department for differential diagnosis. Given that isolated sterile hyperostosis/osteitis among adults is included in the modified diagnostic criteria for SAPHO syndrome, we suspected that the mixed lesions of sclerosis and erosion of the thoracic spine in this case may reflect SAPHO syndrome with chronic non-bacterial osteitis (CNO) of the thoracic spine. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) was initiated and led to alleviation of her back pain, although the thoracic spine lesions remained on the 6-month MRI. Based on the CNO of the thoracic spine and the rapid response to NSAIDs, the final diagnosis was SAPHO syndrome with isolated lesions of the thoracic spine.

Factors associated with frailty in rheumatoid arthritis patients with decreased renal function.

OBJECTIVES: To investigate factors associated with frailty in rheumatoid arthritis (RA) patients with decreased renal function. METHODS: RA patients who visited outpatient clinics from June to August 2021 were included (N = 625). Patients with estimated glomerular filtration rate <60 ml/min/1.73 m2 were defined as having decreased renal function (N = 221) and divided into the non-frailty (N = 153) and frailty (N = 58) groups. Patient characteristics were compared between the two groups by univariate analysis. Significant factors in univariate analysis were assessed by logistic regression analysis to determine their association with frailty in patients with decreased renal function. RESULTS: Patients in the frailty group were older (74.0 vs.79.0 years) and had a longer duration of disease (11.1 vs. 17.8 years), higher Disease Activity Score erythrocyte sedimentation rate (DAS28-ESR; 2.99 vs. 3.80), higher Health Assessment Questionnaire Disability Index (0.42 vs. 1.43), and a lower rate of methotrexate (MTX) use (46.4% vs. 25.9) compared to those in the non-frailty group. Factors associated with frailty in patients with decreased renal function were age (odds ratio: 1.07), duration of disease (1.06), DAS28-ESR (1.85), and MTX use (0.42). CONCLUSIONS: Among factors associated with frailty in RA patients with decreased renal function, improving DAS28-ESR is likely to be the most feasible approach to promote recovery from frailty (200/200 words).

Risk factors for denosumab discontinuation in patients with postmenopausal osteoporosis.

OBJECTIVES: Persistence with treatment is key to achieving successful treatment outcomes in patients with osteoporosis. We investigated risk factors for denosumab discontinuation in patients with postmenopausal osteoporosis (PMO). METHODS: A total of 333 patients with PMO who had never received osteoporosis treatment were included in this study. Baseline demographics and retention rate of denosumab were evaluated in all patients. Univariate analysis was performed in patients divided into two groups according to whether they had continued or discontinued denosumab. A Cox proportional hazards model was used to determine risk factors for denosumab discontinuation. RESULTS: The mean age was 80.7 years, the body mass index (BMI) was 21.5 kg/m2, and T-scores for the lumbar spine and femoral neck were -2.7 and -2.8, respectively. The retention rate of denosumab at 36 months was 50.3%. Patients who continued denosumab were younger and had higher BMI, serum albumin (Alb) levels, lumbar spine bone mineral density, and fewer vertebral fractures (VFs), compared with those who discontinued denosumab. The Cox proportional hazards model revealed that a low BMI, low serum Alb levels, and a high number of VFs are independent risk factors for denosumab discontinuation. CONCLUSIONS: A low BMI, low serum Alb levels, and a high number of VFs were associated with denosumab discontinuation in patients with PMO.

Age and symptoms at onset of ankylosing spondylitis in Japanese patients.

OBJECTIVES: To examine the age at onset and initial symptoms as clinical features of ankylosing spondylitis in Japanese patients. METHODS: This retrospective study included 60 Japanese patients diagnosed with ankylosing spondylitis at our institute between January 2004 and June 2021. Initial symptoms were considered pain in axial joints and/or extra-axial joints. If a patient had initial symptoms at multiple sites, each site was counted. We assessed trends for the number of patients and sites of initial symptoms according to age at onset. RESULTS: Mean age (± standard deviation) at onset was 28.9 (± 14.3) years. Approximately one-third of patients experienced onset before age 20. The back was the most common site of initial symptoms (36.7%), followed by the hip (26.7%), knee (15%), buttocks (15%), neck (10%), finger (6.7%), shoulder (3.3%), and others (including overlapping sites). Thirty-two (53.3%) and 25 (41.7%) patients had initial symptoms only in axial joints and only in extra-axial joints, respectively. The proportion of patients with initial symptoms only in extra-axial joints significantly decreased with increasing age (p = .024). CONCLUSIONS: Sites of initial symptoms were frequently the back, hip, knee, and buttocks, and 41.7% had initial symptoms only in extra-axial joints. Younger onset patients frequently had extra-axial involvement.

Disease activity at baseline is an independent predictor of frailty at one year in pre-frail patients with rheumatoid arthritis; a multicenter retrospective observational study.

OBJECTIVES: To investigate factors predicting frailty for one year in pre-frail patients with rheumatoid arthritis (RA). METHOD: A total of 298 RA patients who were pre-frail in 2020 were evaluated in this structured, retrospective observational study. Of the 298 patients, 42 who were frail and 256 who were not in 2021 were assigned to the frailty and non-frailty groups, respectively. After comparing characteristics of both groups using univariate analysis, predictive factors of frailty were assessed by logistic regression analysis. The proportion of frail patients in 2021 by DAS28-ESR level in 2020 was examined by the Cochran-Armitage trend test and chi-squared test. After dividing pre-frail patients into those with DAS28-ESR ≥3.2 and DAS28-ESR <3.2 in 2020, one-year change in DAS28-ESR in the frailty and non-frailty groups for both subgroups were compared by the paired t-test. RESULTS: The frailty group was older (mean: 71.0 vs. 65.4 years) and had a higher DAS28-ESR (mean: 3.22 vs. 2.70) than the non-frailty group. DAS28-ESR was identified as a predictive factor for frailty (OR: 1.49). Among patients with DAS28-ESR ≥3.2 in 2020, DAS28-ESR improved in the non-frailty group in 2021 (mean: 3.97 in 2020 vs. 3.13 in 2021) but did not in the frailty group (3.97 in 2020 vs. 3.81 in 2021). Among those with DAS28-ESR <3.2 in 2020, DAS28-ESR was unchanged in the non-frailty group in 2021 (2.15 in 2020 vs. 2.23 in 2021) but increased in the frailty group (2.53 in 2020 vs. 3.23 in 2021). CONCLUSIONS: Disease activity at baseline is an independent predictor of frailty one year later in pre-frail patients with RA.

Locomotive syndrome in rheumatoid arthritis patients during the COVID-19 pandemic.

This study aimed to longitudinally evaluate the development of locomotive syndrome (LS) in rheumatoid arthritis (RA) patients during the COVID-19 pandemic using the 25-question Geriatric Locomotive Function Scale (GLFS-25). Subjects were 286 RA patients (female, 70.6%; mean age, 64.2 years) who had GLFS-25 and Clinical Disease Activity Index (CDAI) data available for a 1-year period during the COVID-19 pandemic and who did not have LS at baseline. Associations between subject characteristics and development of LS were determined using logistic regression analysis. Among the 286 patients, 38 (13.3%, LS group) developed LS at 1 year after baseline. In the LS group, scores of the GLFS-25 categories "GLFS-5" and "Social activities" were significantly increased at 1 year relative to baseline. GLFS-5 is a quick 5-item version of the GLFS-25, including questions regarding the difficulty of going up and down stairs, walking briskly, distance able to walk without rest, difficulty carrying objects weighing 2 kg, and ability to carry out load-bearing tasks and housework. A significant correlation was also observed between changes in "Social activities" and that of "GLFS-5." Multivariable logistic regression analysis revealed that the development of LS was significantly associated with BMI (OR: 1.11 [95% confidence interval (CI): 1.00-1.22]) and CDAI (OR: 1.08 [95%CI: 1.00-1.16]) at baseline. Adequate exercise and tight control of RA disease activity are important for preventing the development of LS in view of restrictions on going out imposed during the COVID-19 pandemic. GLFS-5 is useful for evaluating the physical function of RA patients.

Relationship between the number of lymph nodes dissected and prognosis in muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy.

OBJECTIVES: Many studies have shown a good prognostic association with a large number of lymph node dissections. However, most of these studies did not include patients who have received neoadjuvant chemotherapy. The purpose of this study was to verify the relationship between survival outcomes and the number of lymph nodes removed during radical cystectomy in patients with muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy. METHODS: This retrospective study considered patients who were diagnosed with clinical ≥T2N0M0 muscle-invasive bladder cancer and treated with radical cystectomy at the Nagoya University Hospital and affiliated hospitals from January 2004 to December 2019. We excluded patients who had a history of upper tract urothelial cancer or non-urothelial carcinoma. The association between prognosis and the number of lymph nodes removed was investigated. RESULTS: We retrospectively enrolled a total of 477 patients. The mean number of lymph nodes dissected was 14. Two hundred and twenty-six patients (47.4%) received neoadjuvant chemotherapy. More extensive lymphadenectomy (≥15 lymph nodes) correlated with better 5-year overall survival across all patients (68% vs. 57%, p = 0.01). In patients who received neoadjuvant chemotherapy, there was no difference in overall survival according to the number of dissected lymph nodes (66% vs. 71%, p = 0.433). In patients who did not receive neoadjuvant chemotherapy, ≥15 lymph nodes dissected was associated with significantly better overall survival (70.3% vs. 46.9%, p < 0.01). CONCLUSIONS: No association between more aggressive lymph node dissection and prognosis was found in patients who underwent neoadjuvant chemotherapy. Conversely, extended lymph node dissection is desirable for patients who have not received neoadjuvant chemotherapy.

Influence of frailty on patient global assessment in rheumatoid arthritis.

AIM: Patient Global Assessment (PtGA; range 0-10 cm) is an important indicator of clinical outcomes, including physical function, in self-assessment of patients with rheumatoid arthritis (RA). Frailty is a concept that encompasses not only physical, but also mental, psychological and social vulnerability. This study aimed to investigate the influence of frailty on PtGA in patients with RA. METHODS: Among 581 patients with RA who completed a questionnaire survey on frailty between June and August 2020, 559 who completed the Kihon Checklist (KCL; a 25-item questionnaire with seven domains) were included. The proportion of patients with PtGA ≤1 was compared between the frailty (KCL score ≥8), pre-frailty (KCL score 4-7) and robust (KCL score 0-3) groups. Factors associated with PtGA ≤1 were examined using multivariate logistic regression models. RESULTS: Of the 559 patients, 221 (39.5%) had frailty. The proportion of patients with PtGA ≤1 was significantly lower in the frailty group (33.9%) than in the robust (65.4%, P < 0.001) and pre-frailty (55.7%, P < 0.001) groups. Multivariate analysis revealed that frailty (vs robust, OR 0.37, 95% CI 0.22-0.69), as well as disease duration and tender joint count, were factors independently associated with PtGA ≤1. When each domain of the KCL was examined, activities of daily living, physical strength, isolation and depressive mood were factors associated with PtGA ≤1. CONCLUSION: Frailty affects PtGA in patients with RA. As frailty impacts the physical, mental and social vulnerability aspects of PtGA, a multifaceted approach, including inflammation suppression, is required to improve PtGA in patients with RA. Geriatr Gerontol Int 2022; 22: 399-404.

Activation of transient receptor potential vanilloid 4 protects articular cartilage against inflammatory responses via CaMKK/AMPK/NF-κB signaling pathway.

Transient receptor potential vanilloid 4 (TRPV4) plays an important role in chondrocytes via Ca2+ signaling. However, its role in the progression of osteoarthritis is unclear. This study aimed to evaluate the effects of TRPV4 activation on articular cartilage and chondrocytes stimulated with interleukin (IL)-1ß. Bovine and human articular chondrocytes were stimulated with various agents, including IL-1ß, GSK1016790A (GSK101; a TRPV4 agonist), Compound C (an AMP-activated protein kinase (AMPK) inhibitor), and STO-609 (a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor), and were processed for Western blot analysis and real-time PCR. The dimethylmethylene blue (DMMB) assay and Safranin O staining were also performed. GSK101 reversed the IL-1ß-induced increase in expression of matrix metalloproteinase (MMP)-13 and decrease in expression of aggrecan. GSK101 also decreased proteoglycan release in the DMMB assay and retained Safranin O staining of articular cartilage tissue. Furthermore, GSK101 increased AMPK phosphorylation and decreased IL-1ß-induced nuclear factor kappa B (NF-κB) phosphorylation. Compound C and STO-609 reversed the suppressive effects of GSK101 on NF-κB activation and MMP-13 expression. In conclusion, TRPV4 activation had chondroprotective effects on articular cartilage stimulated with IL-1ß by activating CaMKK/AMPK and suppressing the NF-κB pathway. TRPV4 activators may offer a promising therapeutic option for preventing the progression of osteoarthritis.

Metabolic changes in synovial cells in early inflammation: Involvement of CREB phosphorylation in the anti-inflammatory effect of 2-deoxyglucose.

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. But, changes in the metabolism of normal synovial membranes or synovial cells during the early stages of inflammation remains unknown. Moreover, there are still many aspects of inflammatory signaling pathways altered by glycolysis inhibitors, that remain unclear. In this study we found that, in normal, non-pathological bovine synovial cells, most of ATP synthesis was generated by mitochondrial respiration. However, during the early of stages inflammation, initiated by lipopolysaccharide (LPS) exposure, synovial cells shifted to glycolysis for ATP production. The glycolysis inhibitor 2-deoxyglucose (2DG) reversed LPS induced increases in glycolysis for ATP production and suppressed the expression of inflammatory cytokines and proteolytic enzymes. 2DG suppressed the phosphorylation of the transcription factor cAMP response element binding protein (CREB) enhanced by LPS. Treatment with a CREB inhibitor reversed the expression of LPS-stimulated inflammatory cytokines and proteolytic enzymes. This study showed that changes in metabolism occur during the early stages of inflammation of synovial cells and can be reversed by 2DG and signaling pathways associated with CREB phosphorylation.

Efficacy of add-on iguratimod in patients with rheumatoid arthritis who inadequately respond to either tocilizumab or tumor necrosis factor alpha inhibitors.

OBJECTIVES: This study aimed to evaluate the efficacy of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA patients) who inadequately respond to either tocilizumab (TCZ) or tumor necrosis factor alpha inhibitors (TNFi). METHODS: Twenty-three RA patients treated with TCZ (the TCZ group) and 23 RA patients treated with TNFi (the TNFi group) were enrolled in this 24-week retrospective study from our multicenter registry. All inadequate responders to either TCZ or TNFi received add-on IGU. Baseline demographics and disease activity at 24 weeks after initiating add-on IGU were compared between the two groups. RESULTS: Baseline clinical disease activity index (CDAI) values in the TCZ group and TNFi group were 14.1 and 11.8 (p = .24 between the two groups). At 24 weeks, CDAI values in the TCZ group and TNFi group were 5.1 and 7.5 (p = .002 and .002 compared to baseline, respectively) and ΔCDAI values were -9.0 and -4.3 (p = .007 between the two groups). Multiple linear regression analysis revealed that add-on IGU in the TCZ group was associated with greater improvement in CDAI relative to the TNFi group. CONCLUSION: Add-on IGU was more effective in inadequate responders to TCZ than in inadequate responders to TNFi.

Predictors of glucocorticoid-free remission in patients with polymyalgia rheumatica treated with prednisolone.

AIM: This study aimed to identify predictive factors of glucocorticoid (GC)-free remission in patients with polymyalgia rheumatica (PMR) treated with prednisolone (PSL). METHOD: Among 75 PMR patients in our single-center registry, this retrospective study targeted 20 patients who achieved GC-free remission (Remission group) and 30 patients who continued treatment with PSL (PSL group) at 30 months from the initiation of PSL treatment (baseline). RESULTS: There was no significant difference between Remission and PSL groups in baseline demographics. C-reactive protein (CRP) decreased more rapidly at 1 and 3 months from baseline in the Remission group than in the PSL group (P = .013 and .046, respectively). Multivariate logistic regression analysis revealed that the normalization of CRP at 1 month was associated with the achievement of GC-free remission (odds ratio = 5.83, 95% CI = 1.28-26.51, P = .023). In addition, when CRP at 1 month was ≤ 0.17 mg/dL, as determined by receiver operating characteristic curve analysis, both the daily PSL dose and cumulative PSL dose were lower, and the rate of GC-free remission higher, at 30 months compared to when CRP at 1 month was > 0.17 mg/dL (P = .010, .049 and .004, respectively). CONCLUSION: The normalization of CRP within 1 month from baseline predicted GC-free remission in PMR patients treated with PSL, and resulted in a lower cumulative PSL dose.

The clinical benefit of sequential therapy with androgen receptor axis-targeted agents alone in patients with castration-resistant prostate cancer: A propensity score-matched comparison study.

BACKGROUND: The optimal sequential therapy for castration-resistant prostate cancer (CRPC) remains unknown. In recent years, some doubts have emerged regarding the clinical benefit of sequential therapy with androgen receptor axis-targeted agents (ART) such as abiraterone (ABI) or enzalutamide (ENZ) for patients with CRPC. We compared the effect of ART-to-ART (AA) sequential therapy after castration resistance with that of docetaxel (DTX)-combined sequential therapy (ART to DTX or DTX to ART) in patients with CRPC. METHODS: We retrospectively identified and analyzed the data of 315 patients with CRPC treated in our seven affiliated institutions between 2009 and 2019. All patients received either DTX or ART (ABI or ENZ) as the first- or second-line therapy after castration resistance. We compared the overall survival (OS) and the second progression-free survival (PFS2), calculated from the initiation of first-line therapy after castration resistance, between the AA sequence group and the DTX-combined sequence group. PFS2 was defined as the period from the start of first-line treatment after castration resistance to progression on second-line treatment. To minimize selection bias from possible confounders, we performed propensity score matching using one-to-one nearest neighbor matching without replacement. RESULTS: Overall, 106 and 209 patients were administered the AA sequential therapy and DTX-combined sequential therapy, respectively. The clinicopathological variables of patients were well balanced after propensity score matching, and there were no significant differences between the two groups. In the propensity score-matched cohort, OS was not significantly different between the two groups (median, 37.9 vs. 45.4 months; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.68-1.79; p = .701), while PFS2 was significantly shorter in the AA group than in the DTX-combined group (median, 12.9 vs. 21.6 months; HR, 1.70; 95% CI, 1.16-2.48; p = .007). CONCLUSIONS: Certain patients with CRPC can benefit from ART-to-ART sequential therapy in a daily clinical setting.

Hyaluronan suppresses enhanced cathepsin K expression via activation of NF-κB with mechanical stress loading in a human chondrocytic HCS-2/8 cells.

Cathepsin K is a protease known to be involved in not only bone remodeling and resorption, but also articular cartilage degradation that leads to osteoarthritis (OA). Hyaluronan (HA) plays a pivotal role in maintaining homeostasis within articular chondrocytes. Intra-articular supplementation of high molecular weight hyaluronan (HMW-HA) has been widely used in OA treatment. However, its prospective mechanism of action is still unclear. In this study, we examined the suppressive effect of HA on enhanced cathepsin K expression induced by mechanical stress loading. A human chondrocytic HCS-2/8 cells were cultured in silicon chambers and subjected to cyclic tensile stress (CTS) loading. CTS loading significantly increased messenger ribonucleic acid and protein expression of cathepsin K, which appeared to be suppressed by pre-treatment with HMW-HA. Activation of nuclear factor-kappa B (NF-κB) was induced by CTS loading, and suppressed by pre-treatment with HMW-HA. Helenalin, a chemical inhibitor of NF-κB, clearly suppressed the enhanced expression of cathepsin K, as well as NF-κB activation induced by CTS loading. The suppressive effect of HMW-HA on enhanced cathepsin K expression via NF-κB inhibition impacts the effectiveness of HMW-HA in OA treatment. Our findings provide new evidence supporting the biological effectiveness of intra-articular HMW-HA injections for treatment of OA.

Propensity score-matched comparison of docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant intraductal carcinoma of the prostate.

OBJECTIVE: To evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castration-resistant prostate cancer (CRPC) with intraductal carcinoma of the prostate (IDC-P) using a propensity score-matched analysis. PATIENTS AND METHODS: We retrospectively identified 309 patients with CRPC from February 2007 to February 2016 at Nagoya University and its affiliated hospitals. All patients received initial androgen-deprivation therapy (ADT). After progression to CRPC, they received docetaxel or ARAT (abiraterone or enzalutamide) as first-line life-prolonging therapy. Docetaxel (70-75 mg/m2 ) every 3 weeks vs enzalutamide (160 mg) once daily orally or abiraterone (1 g) once daily plus prednisone (5 mg) twice daily orally was administered. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis. A propensity score analysis with a 1:1 ratio using an optimal matching algorithm was used to adjust for confounding factors. RESULTS: Overall, 234 patients were analysed. Propensity score-matching identified 85 patients in each group. There were no significant differences in patient characteristics between the groups. The median OS in the docetaxel group was 38.2 vs 58.3 months in the ARAT group (P = 0.03). For patients with IDC-P, OS was significantly longer in the ARAT group than the docetaxel group (P = 0.01), and there was no significant difference in each group, as in patients without IDC-P (P = 0.67). A multivariate analysis showed that the presence of IDC-P, duration of primary ADT, visceral metastasis, and administration of ARAT as the first-line treatment for CRPC were independent prognostic factors for OS. CONCLUSION: Administration of ARAT as the first-line treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.

Predictors of denosumab efficacy in treating osteoporosis in patients with rheumatoid arthritis: a Japanese multicenter study.

We investigated 2-year outcomes of denosumab treatment for osteoporosis in patients with rheumatoid arthritis (RA) and predictors of good outcomes. Study participants were 74 females treated with denosumab for 24 months. After investigating baseline demographics and overall time course for each patient, we divided all cases into two groups according to percent change (%) in bone mineral density (BMD) of lumbar spine (LS-) and total hip (TH-) at 24 months (-24m); two thirds of the patients were allocated to the good outcome group (LS-GO and TH-GO), and the other third to the non-good outcome group (LS-NG and TH-NG). We performed multivariate analysis to confirm predictors of greater increases in LS- and TH-BMD. LS-BMD-24m and TH-BMD-24m increased significantly from baseline. We observed greater %LS-BMD-24m in LS-GO group than in LS-NG group, while %TH-BMD-24m showed no significant group-dependent difference. N-terminal propeptide of type 1 collagen (P1NP) and tartrate-resistant acid phosphatase (TRACP)-5b decreased more in LS-GO group than in LS-NG group at each time point. We observed greater %TH-BMD-24m in TH-GO group than in TH-NG group, while %LS-BMD-24m showed no significant group-dependent difference. Only P1NP-6m showed a larger decrease in TH-GO group relative to TH-NG group. Multivariate analysis confirmed that the larger decrease in P1NP-6m was associated with the greater increase in LS-BMD-24m, while the combined use of biologics was associated with the greater increase in TH-BMD-24m. In conclusions, denosumab increased BMD in RA patients with osteoporosis. The combined use of biologics and denosumab may provide useful treatment options.