Long waiting time before tooth extraction may increase delayed wound healing in elderly Japanese.

In osteoporosis patients receiving antiresorptive medications, stopping the drug and delaying tooth extraction has been suggested to reduce the risk of osteonecrosis of the jaw (ONJ). However, postponing tooth extraction for ≥ 2 months was associated with an increased risk of delayed wound healing beyond 8 weeks after extraction, a risk factor for developing ONJ. INTRODUCTION: A long waiting time before tooth extraction could result from concern about a potential increased risk of osteonecrosis of the jaw (ONJ) in osteoporosis patients. We clarified whether a long waiting time before tooth extraction during the past year may be associated with an increased risk of delayed wound healing beyond 8 weeks after tooth extraction, which may be a risk factor of ONJ. METHODS: Of 5639 patients aged ≥ 60 years who visited our 20 clinics or hospitals and answered a structured questionnaire, 426 patients (151 men, 275 women) aged 60-96 years comprised the final participants in this study. Self-reported kyphosis was used as a surrogate marker of vertebral fractures. Stepwise logistic regression analysis, adjusted for covariates, was used to calculate the odds ratio (OR) and the 95% confidence interval (CI) for the presence of delayed wound healing longer than 8 weeks after tooth extraction during the past year based on the duration before extraction. RESULTS: Subjects who had waited > 2 months for tooth extraction had a significantly higher risk of delayed wound healing compared with those whose tooth was extracted within 1 month (OR = 7.23; 95% CI = 2.19-23.85, p = 0.001) regardless if antiresorptive medications for osteoporosis were used. The presence of self-reported kyphosis was significantly associated with an increased risk of delayed wound healing (OR = 5.08; 95% CI = 1.11-23.32, p = 0.036). CONCLUSIONS: A long waiting time before tooth extraction may be a risk factor for delayed wound healing beyond 8 weeks after extraction in patients aged ≥ 60 years.

Issues with the surgical treatment of antiresorptive agent-related osteonecrosis of the jaws.

Antiresorptive agent-related osteonecrosis of the jaw is a rare but significant complication in patients using antiresorptive agents such as bisphosphonates and denosumab. Although the disease is well recognized, and many studies have been performed on the management of this condition, the treatment of severe osteonecrosis is still a challenge. Most recent studies have shown an advantage of surgical treatment over conservative treatment for stage 2/3 patients, but there is no consensus on the appropriate surgical procedures for antiresorptive agent-related osteonecrosis of the jaw. Furthermore, patients with severe systemic conditions may not be appropriate for extensive surgical treatment, and the treatment protocol for such patients has not been established. In this review, issues regarding the current surgical treatment for antiresorptive agent-related osteonecrosis of the jaws are discussed, with an emphasis on the clinical aspects.

Significant improvement of bone mineral density and bone turnover markers by denosumab therapy in bisphosphonate-unresponsive patients.

Bone mineral density (BMD) sometimes cannot be improved by long-term bisphosphonate (BP) therapy in osteoporosis (OP). This study showed that lumbar as well as hip BMD significantly increased after denosumab treatment in patients not responsive to BPs. Thus, denosumab may be a strong OP treatment option for BP-unresponsive patients. INTRODUCTION: BMD sometimes cannot be improved by long-term BP therapy. METHODS: We administered denosumab to osteoporotic patients with a poor response to BPs who had been taking them for 2 years or longer. Ninety-eight women with BP-poor responsive OP were enrolled in this study. Mean (standard deviation [SD]) age was 71.2 (6.9) years and mean (SD) duration of BP treatment was 59.9 (34.3) months. We distinguished BP responders from non-responders based on changes in BMD values at denosumab commencement (baseline) from 2 years beforehand. RESULTS: There were no significant differences in age, duration of BP use, bone turnover markers, or BMD at baseline between the groups. Prior to denosumab, BMD had increased significantly in responders and decreased significantly in non-responders. Bone turnover markers had decreased significantly at 4 months of denosumab treatment (P < 0.001) and lumbar and hip BMD were significantly increased at 1 year of therapy in both groups (P < 0.001). Simple correlation coefficients were -0.337 for lumbar and -0.339 for hip BMD changes (both P = 0.001) before and after denosumab treatment. Both at the lumbar spine and hips, decreased BMD before denosumab therapy was significantly associated with an increase in BMD at 1 year of treatment (spine, t value = -3.502, P = 0.001, R = 0.113; hip, t value = -3.526, P = 0.001, R = 0.115). CONCLUSIONS: These results suggest that denosumab may be a strong OP treatment option for BP-unresponsive patients.

Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebo-controlled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study).

In 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. INTRODUCTION: The purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis. METHODS: This 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. RESULTS: The 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. CONCLUSIONS: Once-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.

Comparing immunocompetent and immunodeficient mice as animal models for bone tissue engineering.

OBJECTIVES: To understand the differences and similarities between immunocompetent and immunodeficient mice as ectopic transplantation animal models for bone tissue engineering. MATERIALS AND METHODS: Osteogenic cells from mouse leg bones were cultured, seeded on ß-TCP granules, and transplanted onto the backs of either immunocompetent or immunodeficient nude mice. At 1, 2, 4, and 8 weeks postoperatively, samples were harvested and evaluated by hematoxylin-eosin staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemical staining and quantitative PCR. RESULTS: In immunocompetent mice, inflammatory cell infiltration was evident at 1 week postoperatively and relatively higher expression of TNF-α and IL-4 was observed. In immunodeficient mice, new bone area and the number of TRAP-positive cells were larger at 4 weeks than in immunocompetent mice. The volume of new bone area in immunodeficient mice was reduced by 8 weeks. CONCLUSIONS: Bone regeneration was feasible in immunocompetent mice. However, some differences were observed between immunocompetent and immunodeficient mice in the bone regeneration process possibly due to different cytokine expression, which should be considered when utilizing in vivo animal models.

Panoramic radiography measurements, osteoporosis diagnoses and fractures in Japanese men and women.

OBJECTIVES: The purpose of this study was to investigate the association of the shape of the mandibular cortex on panoramic radiographs with the risk of an osteoporosis diagnosis without prevalent fractures and with the risk of osteoporotic fractures in Japanese men and women. SUBJECTS AND METHODS: One thousand and twenty-one subjects aged 40-89 years, who visited our university hospital and underwent panoramic radiography between 2007 and 2013, participated in this study. Eighty-eight patients received a diagnosis of osteoporosis without prevalent fractures, and 55 were diagnosed with osteoporotic fractures. Blinded to the groupings, we classified the shape of the mandibular cortex on panoramic radiographs as normal, moderately eroded or severely eroded. RESULTS: After adjustment for confounding factors, the odds ratios for an osteoporosis diagnosis associated with moderately eroded and severely eroded mandibular cortices were 1.4 (95% CI, 0.8-2.6) and 2.6 (95% CI, 1.4-5.0), respectively. The odds ratios for an osteoporotic fracture associated with moderately eroded and severely eroded cortices were 0.8 (95% CI, 0.4-1.7) and 1.1 (95% CI, 0.5-2.5), respectively. CONCLUSIONS: Subjects in Japan with eroded mandibular cortices tended to be at increased risk of osteoporosis diagnoses but not of fractures.

Effects of intravenous administration of umbilical cord blood CD34(+) cells in a mouse model of neonatal stroke.

Neonatal stroke occurs in approximately 1/4000 live births and results in life-long neurological impairments: e.g., cerebral palsy. Currently, there is no evidence-based specific treatment for neonates with stroke. Several studies have reported the benefits of umbilical cord blood (UCB) cell treatment in rodent models of neonatal brain injury. However, all of the studies examined the effects of administering either the UCB mononuclear cell fraction or UCB-derived mesenchymal stem cells in neonatal rat models. The objective of this study was to examine the effects of human UCB CD34(+) cells (hematopoietic stem cell/endothelial progenitor cells) in a mouse model of neonatal stroke, which we recently developed. On postnatal day 12, immunocompromized (SCID) mice underwent permanent occlusion of the left middle cerebral artery (MCAO). Forty-eight hours after MCAO, human UCB CD34(+) cells (1×10(5)cells) were injected intravenously into the mice. The area in which cerebral blood flow (CBF) was maintained was temporarily larger in the cell-treated group than in the phosphate-buffered saline (PBS)-treated group at 24h after treatment. With cell treatment, the percent loss of ipsilateral hemispheric volume was significantly ameliorated (21.5±1.9%) compared with the PBS group (25.6±5.1%) when assessed at 7weeks after MCAO. The cell-treated group did not exhibit significant differences from the PBS group in either rotarod (238±46s in the sham-surgery group, 175±49s in the PBS group, 203±54s in the cell-treated group) or open-field tests. The intravenous administration of human UCB CD34(+) cells modestly reduced histological ischemic brain damage after neonatal stroke in mice, with a transient augmentation of CBF in the peri-infarct area.

Integration of proteomics into systems biology of cancer.

Deciphering the complexity and heterogeneity of cancer, benefits from integration of proteomic level data into systems biology efforts. The opportunities available as a result of advances in proteomic technologies, the successes to date, and the challenges involved in integrating diverse datasets are addressed in this review.

Characteristics of family caregivers with sleep dissatisfaction in Japan: identification using CHAID dendrograms.

The rapid increase in the population of the elderly has raised several social issues. The current study focused on sleep dissatisfaction in family caregivers to identify family caregivers with a heavy care burden. This study aimed to detect the characteristics of caregivers who are most likely to have sleep dissatisfaction. A chi-squared automatic interaction detection technique was used to analyze data collected from 92 research care managers who collected demographic and sleep dissatisfaction information from 280 caregivers and their care recipients. Caregivers whose care recipients were unstable and bedridden were most likely to have sleep dissatisfaction. When care recipients were not stable or non-bedridden, had severe dementia symptoms, and were physically independent, their caregivers were the second most likely to have sleep dissatisfaction. When care recipients were not stable or non-bedridden, had moderate dementia symptoms, and did not need help in transferring, their caregivers had the lowest risk of sleep dissatisfaction. Although many recent studies have found a high prevalence of insomnia among the elderly, describing the characteristics of caregivers who are most likely to have sleep dissatisfaction is a significant challenge. When care recipients are physically independent, the severity of the recipient's dementia symptoms relates to the caregiver's dissatisfaction with his/her sleep. In physically dependent care recipients, the severity of the recipient's dementia did not contribute to the caregiver's dissatisfaction with his/her sleep.

Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.

Increasing evidences show that immune response affects the reparative mechanisms in injured brain. Recently, we have demonstrated that CD4(+)T cells serve as negative modulators in neurogenesis after stroke, but the mechanistic detail remains unclear. Glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), a multifaceted regulator of immunity belonging to the TNF receptor superfamily, is expressed on activated CD4(+)T cells. Herein, we show, by using a murine model of cortical infarction, that GITR triggering on CD4(+)T cells increases poststroke inflammation and decreases the number of neural stem/progenitor cells induced by ischemia (iNSPCs). CD4(+)GITR(+)T cells were preferentially accumulated at the postischemic cortex, and mice treated with GITR-stimulating antibody augmented poststroke inflammatory responses with enhanced apoptosis of iNSPCs. In contrast, blocking the GITR-GITR ligand (GITRL) interaction by GITR-Fc fusion protein abrogated inflammation and suppressed apoptosis of iNSPCs. Moreover, GITR-stimulated T cells caused apoptosis of the iNSPCs, and administration of GITR-stimulated T cells to poststroke severe combined immunodeficient mice significantly reduced iNSPC number compared with that of non-stimulated T cells. These observations indicate that among the CD4(+)T cells, GITR(+)CD4(+)T cells are major deteriorating modulators of poststroke neurogenesis. This suggests that blockade of the GITR-GITRL interaction may be a novel immune-based therapy in stroke.

Abundance of calpain and aggrecan-cleavage products of calpain in degenerated human intervertebral discs.

OBJECTIVE: To assess the expression of calpains and calpain-induced aggrecan fragmentation in early and advanced stages of degeneration of human intervertebral discs (IVDs). DESIGN: Disc tissue samples of 55 patients (mean age, 51.2 ± 22.3 years) who underwent intervertebral fusion were divided into groups with early and advanced degeneration based on the Thompson magnetic resonance imaging (MRI) scale. In advanced degeneration group, five patients (mean age, 35.5 ± 11.4 years) of lumbar disc herniation (LDH) were included. Protein levels of m- and µ-calpains and their inhibitor calpastatin were assayed, and immunohistochemical techniques were used to localize and quantify the production of the enzymes. To investigate calpain activity, we assayed purified aggrecan fragmentation in disc tissue by Western blotting and immunohistochemistry with VPGVA antibody, which recognizes the m-calpain generated neo-epitope GVA. RESULTS: Discs at early stages of degeneration expressed low levels of m- and µ-calpains and calpastatin, and few cells expressed degenerative enzymes. At more advanced stages of degeneration, the expression and number of cells immunopositive for m-calpain, µ-calpain and calpastatin were significantly higher. Further finding showed that anti-GVA-reactive aggrecan fragments were significantly higher in discs at advanced compared with early stages of degeneration. Herniated disc samples showed stronger expression and more cells immunopositive for calpains, calpastatin and GVA in the nucleus pulposus than in the annulus fibrous. CONCLUSIONS: The expression of calpains, together with m-calpain-induced degradation products of extracellular matrix, was correlated with the degree of disc degeneration in human IVD tissue. These findings suggest that calpains may be involved in IVD degeneration via proteoglycan (PG) cleavage.

Detecting young Japanese adults with undetected low skeletal bone density using panoramic radiographs.

OBJECTIVE: The cortical width below the mental foramen of the mandible determined from panoramic radiographs is a useful screening tool for identifying elderly individuals with a low skeletal bone mineral density (BMD). However, whether the mandible cortical width (MCW) is useful for identifying a low skeletal BMD in men and women of 40 years or younger is not known. METHODS: The BMD of the calcaneus was measured by ultrasonography bone densitometry in 158 men and 76 women aged 18-36 years. A logistic regression analysis adjusted for age was used to calculate the odds ratios and 95% confidence interval (CI) of having a low calcaneal BMD, according to the quartiles of the MCW. The areas under the receiver operator characteristic curve (AUC) for identifying participants with a low calcaneal BMD using the MCW were assessed to evaluate the diagnostic efficacy of the MCW. RESULTS: In men, the adjusted odds ratios of a low calcaneal BMD associated with the second, third and lowest quartiles of MCW were 5.66 (95% CI, 0.61-52.23), 5.43 (95% CI, 0.59-50.18) and 33.22 (95% CI, 3.97-276.94), respectively, compared with the highest quartile, while no significant trend in the adjusted odds ratios was observed in women. The AUC for identifying participants with a low calcaneal BMD based on the MCW was 0.796 (95% CI, 0.702-0.890) in men and 0.593 (95% CI, 0.398-0.788) in women. CONCLUSION: MCW determined from panoramic radiographs can be used to identify undetected low calcaneus BMD in young adult men, but not in young adult women.

Radiographic findings and prognosis of simple bone cysts of the jaws.

OBJECTIVE: The aim was to evaluate the possibility of radiographic prediction of the prognosis of simple bone cysts (SBCs) of the jaws. METHODS: The relationship between the radiographic findings and treatment outcome (healing or recurrence) was investigated in 31 cases treated in the authors' hospital and 108 published cases. RESULTS: In 17 of our 31 cases, the lesions had radiographic findings of a preserved lamina dura adjacent to the lesion, with a smooth margin, and no or smooth bone expansion, and all of them healed after surgery. In the other 14 cases, there was resorption of the lamina dura, a scalloped margin, nodular bone expansion, root resorption, a sclerotic mass or multiple cavities, and nine cases of recurrence. Although there was incomplete information in the published case studies, similar results were noted. CONCLUSIONS: It was concluded that there was a relationship between the radiographic features of the lesions and prognosis. Radiographic examination should be used not only for discovering and diagnosing the lesions, but also for predicting possible prognosis.

Triage screening for osteoporosis in dental clinics using panoramic radiographs.

Many patients with osteoporosis go undiagnosed because typically no symptoms are present before a fracture. Triage screening to refer patients to appropriate medical professionals for further investigation would be useful to address the increase in the incidence of osteoporotic fractures. Dental clinics may offer a new triage screening pathway because dentists frequently take radiographs of bones in the course of dental treatment. A major premise for such triage screening in dental clinics is that dentists can readily use a screening tool in their dental practice. For example, cortical width and shape of the mandible detected on panoramic radiographs may be appropriate indices for triaging individuals with osteoporosis. To date, several investigators have demonstrated significant associations between cortical indices on panoramic radiographs and bone mineral density of the skeleton generally, such as the spine and femur, biochemical markers of bone turnover and risk of osteoporotic fractures. Further, in two recent Japanese clinical trials, approximately 95% of women who were identified by trained dentists in their clinics using cortical shape findings did have osteopenia or osteoporosis. These findings support the possibility that dental clinics may offer a new triage platform to identify individuals with otherwise undetected osteoporosis.

Decreased circulating CD34+ cells are associated with progression of diabetic nephropathy.

AIMS: Circulating progenitor cells such as CD34+ cells play a key role in maintenance of vascular endothelial function and neovascularization, and a decrease in the number of CD34+ cells is associated with cardiovascular disease. However, the contribution of circulating progenitor cells to microvascular disease, such as diabetic nephropathy, is unclear. This study was therefore designed to clarify the association between diabetic nephropathy and circulating CD34+ cells. METHODS: We measured circulating CD34+ cell numbers in 85 Type 2 diabetic patients aged 40-70 years with normo- and microalbuminuria and determined the association with urinary albumin excretion rate (UAER). RESULTS: The number of circulating CD34+ cells significantly correlated with log UAER (r = -0.289, P = 0.008). Furthermore, in patients with low numbers of CD34+ cells (0.68 > cells/microl, lowest quartile of CD34+ cell number) UAER increased significantly after 12 months compared with baseline [from 34.3 +/- 7.0 to 53.6 +/- 10.8 mg/g creatinine (gCr), P < 0.05], whereas in patients with a high number of CD34+ cells (1.0 < cells/microl, highest quartile of CD34+ cell number) UAER did not change (from 16.7 +/- 4.8 to 20.1 +/- 3.0 mg/gCr). CONCLUSIONS: These results suggest that a decreased number of circulating CD34+ cells is involved in the progression of diabetic nephropathy and may be a predictor of the disease.

Detection of post-menopausal women with low bone mineral density and elevated biochemical markers of bone turnover by panoramic radiographs.

OBJECTIVES: The detection of an eroded mandibular cortex on panoramic radiographs and questionnaire-based screening tools show similar diagnostic efficacies for identifying osteoporosis in post-menopausal women. We evaluated whether both tools also have similar diagnostic performances in identifying women with osteoporosis and elevated biochemical markers of bone turnover who have a high risk of fracture. METHODS: Urinary N-telopeptide cross-links of type I collagen (NTx) (corrected for creatinine) and serum levels of total non-bone-specific alkaline phosphatase (ALP) were measured in 99 post-menopausal women aged 44-70 years (mean +/- standard deviation (SD), 54.6 +/- 5.2 years) who underwent bone mineral density (BMD) assessment and panoramic radiography. BMD was measured at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. The Female Osteoporosis Self-assessment Tool for Asia (FOSTA), which is based on age and weight, was used as the questionnaire-based screening tool. Osteoporosis was defined as a BMD T-score of -2.5 or less at either the lumbar spine or the femoral neck. RESULTS: Urinary NTx and serum ALP were significantly associated with cortical erosion, but not with the FOSTA. The areas under the receiver operating characteristics (ROC) curve for identifying participants with osteoporosis were 0.784 for FOSTA and 0.827 for the detection of cortical erosion, and for identifying participants with osteoporosis and elevated urinary NTx they were 0.700 for FOSTA and 0.807 for the detection of cortical erosion. CONCLUSIONS: Our results suggest that panoramic radiography is superior to questionnaire-based screening for identifying women who are at high risk of fracture.

A computer-aided diagnosis system to screen for osteoporosis using dental panoramic radiographs.

OBJECTIVES: An eroded inferior cortex of the mandible detected on dental panoramic radiographs is useful for identifying post-menopausal women with low skeletal bone mineral density (BMD) or osteoporosis. The purposes of this study were to develop a computer-aided diagnosis (CAD) system that automatically determines cortical erosion of the mandible on dental panoramic radiographs and to assess the validation of this CAD system. METHODS: A CAD system was developed based on mathematical morphology for identifying post-menopausal women with low skeletal BMD or osteoporosis, based on World Health Organization criteria, by identifying whether the endosteal margin of mandibular cortical bone was eroded. The sensitivity, specificity, predictive value, accuracy and likelihood for a positive risk result were calculated using dichotomous 2 x 2 tables using 100 panoramic radiographs. RESULTS: For identifying women with low skeletal BMD, the sensitivity and specificity were 76.8% and 61.1%, respectively, the positive and negative predictive values were 90.0% and 36.7%, accuracy was 74.0% and the likelihood for positive risk was 1.96. The respective values for identifying women with osteoporosis were 94.4% and 43.8%, the positive and negative predictive values were 48.6% and 93.3%, respectively, the accuracy was 62.0% and the likelihood for positive risk was 1.68. CONCLUSION: Our results suggest that a CAD system applied to dental panoramic radiographs may be useful for identifying post-menopausal women with low skeletal BMD or osteoporosis.

Bone marrow stromal cell therapy improves femoral bone mineral density and mechanical strength in ovariectomized rats.

BACKGROUND: This study aimed to determine the influence of bone marrow stromal cells (BMSC) on the degree and sustainability of ovariectomy-induced bone loss. METHODS: Allogenic BMSC were injected into either the left or right femur of 15 ovariectomized rats (OVX). Saline was injected into the contralateral femur as a vehicle control. Five rats were killed at 8 weeks and 5 rats at 24 weeks. The other five OVX rats received serial injections 4 weeks after the first injection and were killed 24 weeks after the first injection. To confirm osteoporotic model, five rats received sham operation. Bone mineral density (BMD) was measured using dual-energy X-ray absorptometry. Mechanical properties were evaluated by three-point bending. RESULTS: The OVX rats showed significantly lower BMD compared with that of the sham operated rats. BMD at the femoral mid-shaft was significantly greater in the BMSC-injected bones compared with the control bones. At week 8, ultimate load and stiffness were also improved in the BMSC-injected bones compared with controls. At 24 weeks, the stiffness of control and BMSC-injected bones was statistically indistinguishable. The additional injection aided preservation of both BMD and mechanical properties. DISCUSSION: The present study suggests that bone strength may be improved by direct BMSC injection.