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SummaryTooth extraction in patients receiving bisphosphonates is thought to be a risk factor for osteonecrosis of the jaw (ONJ); however, ONJ did not develop, even when tooth extraction was performed with continued oral bisphosphonate therapy. A drug holiday from bisphosphonates before tooth extraction may not be necessary.IntroductionIt is controversial whether bisphosphonate withdrawal is necessary prior to invasive procedures such as tooth extraction in order to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to evaluate the clinical safety of continuing oral bisphosphonate therapy in patients undergoing tooth extraction.MethodsWe prospectively enrolled 132 patients (20 men, 112 women) who were receiving oral bisphosphonates for the prevention or treatment of osteoporosis and required tooth extraction. All patients were managed using an identical protocol, which included preoperative antibiotic prophylaxis and did not necessarily require complete wound closure. The patients were classified into groups according to the duration of bisphosphonate administration: < 2 years (n = 51), 2–5 years (n = 41), 5–10 years (n = 28), and > 10 years (n = 12). The groups were compared regarding the time taken for the extraction socket to heal, and the occurrence of BRONJ. Follow-up duration was at least 3 months.ResultsA total of 274 teeth were removed. Long-term oral bisphosphonate therapy for > 5 years significantly delayed the healing of the extraction socket in comparison with administration for < 5 years; however, BRONJ did not develop in any group. There was no prolongation of wound healing due to systemic risk factors such as glucocorticoid administration and diabetes mellitus. There were no adverse skeletal events such as bone fracture.ConclusionsPatients who underwent tooth extraction with continued oral bisphosphonate therapy showed delayed healing of the extraction socket as the cumulative administration period prolonged, but BRONJ did not develop.

SummaryA 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial (the TWICE study) conducted in Japanese primary osteoporosis patients with a high risk of fractures demonstrated that a 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen of teriparatide, while also improving safety.IntroductionWhile a 56.5-μg once-weekly regimen of teriparatide has high efficacy for osteoporosis, treatment continuation rates are low, with one of the major causes being adverse drug reactions such as nausea or vomiting. The TWICE study was therefore conducted to investigate whether a twice-weekly regimen with 28.2-μg teriparatide can provide comparable efficacy to the 56.5-μg once-weekly regimen while improving safety.MethodsA 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial was conducted in Japan. Patients with primary osteoporosis aged ≥ 65 years at high risk of fractures (n = 553) were randomly allocated to the 28.2-μg twice-weekly group (n = 277) or the 56.5-μg once-weekly group (n = 276). The primary endpoint was the percentage change in lumbar spine (L2–L4) bone mineral density (BMD) at final follow-up.ResultsThe percentage changes in lumbar spine (L2–L4) BMD at final follow-up in the 28.2-μg twice-weekly and 56.5-μg once-weekly groups were 7.3% and 5.9%, respectively; the difference (95% confidence interval [CI]) in percentage change was 1.3% (0.400–2.283%). Since the lower limit of the 95% CI was above the pre-specified non-inferiority margin (− 1.6%), non-inferiority of the 28.2-μg twice-weekly group was demonstrated. Adverse drug reactions were significantly less frequent in the 28.2-μg twice-weekly group (39.7% vs 56.2%; p < 0.01); the incidence of major adverse drug reactions was lower, and the number of subjects who discontinued due to adverse drug reactions was less in the 28.2-μg twice-weekly group.ConclusionsA 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen while improving safety.Clinical trial registrationJapicCTI-163477.

SummaryIn a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures.IntroductionThe purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis.MethodsThis was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months.ResultsThe 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17–0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p < 0.0001). No new adverse events or osteonecrosis of the jaw were observed in this study.ConclusionsOnce-yearly administration of ZOL 5 mg to Japanese patients with primary osteoporosis reduced the risk of new morphometric vertebral fractures and was found to be safe.

To examine the association between physical frailty and risk of needing long-term care, and compare the predictive value and clinical usefulness of a simple frailty scale (FRAIL) with that of the original Cardiovascular Health Study (CHS) criteria. A 6-year prospective cohort study of community-dwelling older adults in a west Japanese suburban town. 1,554 older adults aged 65 years and over who were initially free of long-term care needs at baseline. Physical frailty was defined by the CHS criteria and the FRAIL scale. The onset of needing long-term care was ascertained using national records of certification of long-term care needs. Cox proportional hazard models were used to estimate the association between physical frailty and risk of needing long-term care. Decision curve analysis was performed to compare the clinical usefulness of the two physical frailty criteria. During a median follow-up of 5.8 years, 244 were ascertained as needing long-term care. Baseline physical frailty was significantly associated with elevated risk of needing long-term care, with a multivariable-adjusted hazard ratio (HR) of 2.00 (95% confidence interval [CI], 1.32–3.02) for being frail and 1.50 (95% CI, 1.10–2.03) for being pre-frail as defined by the CHS criteria, compared with being robust (p for trend = 0.001). Similar results were found for physical frailty defined by the FRAIL scale, with a multivariable-adjusted HR (95% CIs) of 2.11 (1.25–3.56) for being frail and 1.73 (1.28–2.35) for being pre-frail vs. being robust (p for trend < 0.001). The two physical frailty criteria had similar net benefits in identifying individuals at high risk for needing long-term care. Physical frailty is significantly associated with an increased risk of needing long-term care in community-dwelling older adults in Japan. Compared with the original CHS criteria, the simple FRAIL scale has comparable predictive value and clinical usefulness for identifying individuals at risk for needing long-term care.

AbstractBackgroundOlder adults' mental health and physical frailty have been a frequent research focus, but few studies have investigated the relationship between them. ObjectivesTo investigate the association between mental health and physical frailty in community-dwelling older Japanese people. DesignCross-sectional study from the Itoshima Frail Study. SettingItoshima City, Fukuoka, Japan. ParticipantsA total of 919 community-dwelling older individuals aged 65–75 years. MeasurementsPhysical frailty was measured based on five criteria proposed by the Fried scale, and the subjects were classified into three groups: robust, pre-frailty, and frailty. Psychological distress was used to assess the subjects' mental health, with the Kessler 6-Item Psychological Distress Scale (K6) score; the subjects were divided into three groups based on their K6 score: 0–1, 2–4, and ≥5. Psychological distress was defined by K6 score ≥5. Ordinal logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) between the psychological distress and physical frailty status. ResultsPsychological distress was identified in 190 subjects (20.7%). Forty-six subjects (5.0%) presented with physical frailty, and 24 subjects (2.6%) had both psychological distress and physical frailty. With the increase in the K6 score, more subjects had pre-frailty and physical frailty (p<0.001). Significant positive associations were observed between psychological distress and the risks of pre-frailty (OR 2.94, 95%CI: 1.95–4.43) and frailty (OR 10.71, 95%CI: 4.68–24.51), even in a multivariable-adjusted analysis. In a subgroup analysis of components of frailty, one-point increment in K6 score was associated with higher odds of shrinking and fatigue. ConclusionA severe psychological distress was associated with increased risks of physical frailty and the frailty sub-items of shrinking and fatigue in community-dwelling older Japanese adults.

This study aimed to propose appropriate management for odontogenic chronic rhinosinusitis. Thirty-one adult patients with odontogenic chronic rhinosinusitis undergoing maxillary extraction were retrospectively analysed. Patients with (n = 21) and without (n = 10) oroantral fistula on computed tomography were classified. Functional endoscopic sinus surgery was performed when sinusitis did not improve after extraction. The critical indicators for surgical requirement in the management of odontogenic chronic rhinosinusitis were analysed. Sinusitis significantly improved after extraction in both groups. Patients without oroantral fistula had significantly more severe remnant sinusitis than those with oroantral fistula after extraction on computed tomography (p = 0.0037). The requirement for functional endoscopic sinus surgery was statistically significant for patients without orofacial fistula over those with orofacial fistula (p < 0.0001). The surgical improvement ratio was 93 per cent. The absence of oroantral fistula and severe sinusitis can be critical indicators for the requirement of functional endoscopic sinus surgery after extraction in the management of odontogenic chronic rhinosinusitis.

To assess the relationship between physical frailty and subsequent decline in global cognitive function in the non-demented elderly. A prospective population-based study in a west Japanese suburban town, with two-year follow-up. Community-dwellers aged 65 and older without placement in long-term care, and not having a history of dementia, Parkinson’s disease and depression at baseline, who participated in the cohort of the Sasaguri Genkimon Study and underwent follow-up assessments two years later (N = 1,045). Global cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Physical frailty was identified according to the following five components: weight loss, low grip strength, exhaustion, slow gait speed and low physical activities. Linear regression models were used to examine associations between baseline frailty status and the MoCA scores at follow-up. Logistic regression models were used to estimate the risk of cognitive decline (defined as at least two points decrease of MoCA score) according to baseline frailty status. Seven hundred and eight non-demented older adults were included in the final analyses (mean age: 72.6 ± 5.5 years, male 40.3%); 5.8% were frail, and 40.8% were prefrail at baseline. One hundred and fifty nine (22.5%) participants experienced cognitive decline over two years. After adjustment for baseline MoCA scores and all confounders, being frail at baseline was significantly associated with a decline of 1.48 points (95% confidence interval [CI], -2.37 to -0.59) in MoCA scores, as compared with non-frailty. Frail persons were over two times more likely to experience cognitive decline (adjusted odds ratio 2.28; 95% CI, 1.02 to 5.08), compared to non-frail persons. Physical frailty is associated with longitudinal decline in global cognitive function in the non-demented older adults over a period of two years. Physically frail older community-dwellers should be closely monitored for cognitive decline that can be sensitively captured by using the MoCA.

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro , was independent of IAβ g7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor–mediated up-regulation of caspase 8–homologous FLICE (Fas-associated death-domain-like interleukin 1β–converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.

Many types of cancer display heterogeneity in various features, including gene expression and malignant potential. This heterogeneity is associated with drug resistance and cancer progression. Recent studies have shown that the expression of a major protein quality control ubiquitin ligase, carboxyl terminus of Hsc70-interacting protein (CHIP), is negatively correlated with breast cancer clinicopathological stages and poor overall survival. Here we show that CHIP acts as a capacitor of heterogeneous Bcl-2 expression levels and prevents an increase in the anticancer drug-resistant population in breast cancer cells. CHIP knockdown in breast cancer cells increased variation in Bcl-2 expression levels, an antiapoptotic protein, among the cells. Our results also showed that CHIP knockdown increased the proportion of anticancer drug-resistant cells. These findings suggest that CHIP buffers variation in gene expression levels, affecting resistance to anticancer drugs. In single-cell clones derived from breast cancer cell lines, CHIP knockdown did not alter the variation in Bcl-2 expression levels and the proportion of anticancer drug-resistant cells. In contrast, when clonal cells were treated with a mutagen, the variation in Bcl-2 expression levels and proportion of anticancer drug-resistant cells were altered by CHIP knockdown. These results suggest that CHIP masks genetic variations to suppress heterogeneous Bcl-2 expression levels and prevents augmentation of the anticancer drug-resistant population of breast cancer cells. Because genetic variation is a major driver of heterogeneity, our results suggest that the degree of heterogeneity in expression levels is decided by a balance between genetic variation and the buffering capacity of CHIP.

Precise fluorescence-guided surgery (FGS) for pancreatic cancer has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX model enabled FGS to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence, which bright-light surgery or single-color FGS could not. FGS, with color-coded cancer and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.