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As of 2015, the aging population in Japan was the largest in the world. Although the National Database of Health Insurance Claims (NDB) was developed in 2012, long‐term trends regarding hip fracture incidence in Japan remain unclear. In order to clarify the trend in hip fracture incidence from 1992 to 2017, we estimated the number of new hip fractures in 2017, the seventh in a series of nationwide hip fracture surveys performed every 5 years since 1987. We also investigated regional differences in hip fracture incidence. We collected data through a nationwide mail‐in survey of orthopedic institutions in Japan and calculated hip fracture incidence by sex and age, as well as standardized incidence ratio (SIR) across 12 districts. The total number (95% confidence interval) of hip fractures in 2017 was estimated at 193,400 (187,300–199,500), occurring in 44,100 (42,700–45,500) males and 149,300 (144,500–154,100) females. Of all the hip fracture surveys from 1992 to 2017, the 5‐year hip fracture increase rates from 2012 to 2017 was the lowest among female patients. In males, the 5‐year rates from 2012 to 2017 were lower than those from 2007 to 2012. The age‐adjusted incidence rates for patients in both sexes did not show significant change in the 25‐year period. The estimated incidence rates in 2017 for patients aged 70 to 79 years in both sexes were lowest from 1992 to 2017, and declined significantly over the 25‐year period. SIRs differed between northeast and southwest regions. Our findings were similar to those from a previous study in Japan using the NDB from 2012 to 2015. Progress in the development of osteoporosis medication may contribute to the continuous decline in the 70‐year to 79‐year age group. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Backgroud Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. Methods We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. Results The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. Conclusions The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio‐ankle vascular index (CAVI), based on the blood pressure–independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5‐year follow‐up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow‐up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P 2 value increased from 33.8 to 45.2 ( P P =0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01859897.

Objectives This study aimed to identify factors associated with initiation and adherence of osteoporosis medication from a patient perspective. Methods A web-based survey was developed based on health behavior theories. Descriptive analyses were conducted for all survey items. Analyses in a structural equation modeling framework were conducted to identify factors associated with treatment initiation and adherence. Results Five hundred forty-five women completed the questionnaire. A majority were currently receiving medications for osteoporosis (n = 376, 69.0%) and 25.0% of these patients (n = 94) were considered adherent to their treatment. Knowledge was strongly associated with osteoporosis treatment initiation (standard error [SE], 0.58). Greater knowledge of disease was associated with increased likelihood of initiating medication. Medication complexity (SE, 0.49) and perceived susceptibility to fracture and loss of independence (SE, −0.37) were also associated with initiation. Perceived barriers (SE, −0.85) such as inconvenience, lack of efficacy and financial burden were observed to be the greatest obstacle to adherence. The greater the perceived barriers, the less likely patients were to adhere to medication. Patients' perception of self-efficacy (SE, 0.37) also affected adherence. The greater the patient perception of ability to independently manage their medication, the more likely they were to adhere to the medication. Conclusions Different factors were found to be associated with initiation and adherence of osteoporosis medication. Patient knowledge of their disease and the perception of barriers were found to be the most influential. Empowering patients with the knowledge to better understand their disease and decreasing the perception of barriers through education initiatives may be effective in improving patient outcomes.

Objectives This study aimed to assess the effect of 25-hydroxyvitamin D3 (25OHD) which is a hydroxide of vitamin D3 ingestion on upper respiratory tract infection (URTI). Design and Setting A prospective, randomized, double-blind, placebo-controlled study was performed from December 2015 to September 2016 in the Nihonbashi Egawa Clinic, Kei Medical Office TOC Building Medical Clinic, and Medical Corporation Kaiseikai Kita-Shinyokohama Medical Clinic, in Japan. Participants Four hundred twenty eight participants aged 45-74 years were screened by their serum 25-hydoroxyvitamin D concentration. Intervention The participants were randomized to either 25OHD (10 μg/day) or placebo capsule, daily, for 16 consecutive weeks. Measurements The primary outcome measure was the incidence proportion of URTI, and the secondary outcome measures were the physical severity score, the quality-of-life (QOL) score, the duration of URTI, and the incidence proportion of new URTI events every four weeks. Data were collected using cold diary Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) during the intervention. Results Of 428 participants screened, 252 with serum 25-hydroxyvitamn D levels were deficient or insufficient (75 nmol/L or less) were enrolled in this study. Of these, 105 placebo and 110 25OHD group subjects completed the study. For the incidence proportion of URTI, no effect of 25OHD intake was observed. On the other hand, the duration of URTI was shorter in the 25OHD (P = 0.061) compared to placebo. For the incidence proportion of URTI every four weeks, the incidence of new URTI was decreased in both groups over the time of intake. However, when the 25OHD and the placebo were compared, a decrease in the incidence proportion of URTI was seen earlier in the 25OHD. When the total physical severity score and the total QOL score during the study were assessed, they both were significantly improved in the 25OHD compared to placebo. Conclusions The intake of 25OHD may reduce the duration of URTI, the physical severity, and the QOL when suffering from URTI.

We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients’ quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78–1.13, p = .494), 0.86 (95% CI: 0.70–1.05, p = .147), and 1.22 (95% CI: 0.86–1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p

We planned to conduct multi-center, open-labeled, blinded-endpoints, head-to-head randomized trial of minodronate and raloxifene to compare incidences of vertebral and non-vertebral fractures. The study is the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-4). Here, we present the pre-fixed study design. The inclusion criteria are ambulatory older women with osteoporosis, aged > 60 years, and without pre-specified risk factors for secondary osteoporosis and dementia. The subjects who meet selection criteria will be randomly allocated to the raloxifene (60 mg/day) or minodronate (1 mg/day or 50 mg/4 weeks) groups using the central registry. The co-primary endpoints are osteoporotic (vertebral, humeral, femoral, and radial), vertebral, and major osteoporotic (clinical vertebral, humeral, femoral, and radial) fractures. Furthermore, we plan to use the Hochberg procedure to preserve an overall type 1 error rate. In addition, changes in bone mineral density (BMD), hip-structure analysis (HSA) variables, height, bone turnover markers, serum cholesterol and triglyceride concentrations, dental health questionnaire, fall frequency, fall risk index, nursing care level, physical function, quality of life (QOL), and safety profiles were assessed as secondary endpoints. To detect 24% reduction of major osteoporotic fractures with 80% power and a two-sided significance level of 5% with a 2-year observation period, 1734 patients/treatment arm would be required. Subgroup analysis stratified to the following factors age, body mass index, BMD, 25-hydroxyvitamin D concentration, estimated glomerular filtration rate (eGFR), prevalent vertebral fracture number, hypertension status, and diabetes mellitus is pre-specified. The protocol is registered in the trial registry system, and the trial identification number is UMIN000005433.

The frequency of hip fractures associated with aging of the population is declining in many countries. Even in Japan, where this frequency has been increasing continually, a shift to decreasing frequency has been noted in recent reports. The objective of this study was to investigate the effects of this decrease and to estimate the number of hip fracture patients and the resulting reduction in national medical care expenditures. The differences in the number of patients were estimated by multiplying the population for each sex and each age group by the fracture rates before the decrease (2007) and after the decrease (2012). Total reduced cost was calculated by multiplying the treatment cost required for hip fracture and the annual medical cost of nursing care. The estimated number of hip fracture patients decreased by approximately 4000 in the elderly female population, and the resulting reduction in medical costs was approximately US$280 million. The number of patients with hip fractures has decreased in elderly Japanese women; as a result, the medical costs for treatment and nursing care might decrease.

Assessment of vertebral fracture is critically important for the diagnosis and treatment of osteoporosis. This study aimed to clarify the effectiveness of the semiquantitative (SQ) method in the assessment of vertebral fractures in Japanese clinical practice. Forty-four physicians (seven experts and 37 nonexperts) assessed the spinal radiographs of 40 patients participating in the Adequate Treatment of Osteoporosis (A-TOP) Japanese Osteoporosis Intervention Trial (JOINT)-02 at the baseline, 12 months, and 24 months using the SQ method. The proportion of diagnosed fracture cases per spine was higher in the nonexpert group than in the expert group at each time point, and was especially high in the upper thoracic spine (T4-T6). The least mean squares spinal fracture index was significantly higher in the nonexpert group than in the expert group for all time points. The kappa statistics were also higher in the expert group than in the nonexpert group for all vertebral levels at all time points. Assessment of vertebral fractures using the SQ method tended to be overestimated by nonexpert physicians compared with the experts, with poor nonexpert interobserver reliability and well-matched expert interobserver reliability. Conscious efforts to avoid overestimation and to obtain higher reliability with the SQ method should be made to achieve more precise diagnoses and treatment of osteoporosis in Japanese clinical practice.

BackgroundDeteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis.ObjectiveOur aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk.MethodsPatients were osteoporotic women aged ≥70 years and with ≥1 risk factor for incident fracture, namely prevalent osteoporotic fracture, bone mineral density (BMD) >–3.0 SD of young adult mean, or high bone turnover marker. Health-related QOL was assessed using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL). When patients were classified into quartiles by total QOL score). Serum 25-hydroxyvitamin D (25[OH]D) level was measured by immunoassay.ResultsA total of 1585 osteoporotic women were included in the study (age range, 70–95 years). Age, body mass index, serum 25(OH)D status (low, normal, or high), bone mineral density, number of prevalent vertebral fractures, presence of hypertension, presence of osteoarthritis, and history of falls were significantly correlated with QOL quartile. Multivariate liner regression analysis indicated that low serum 25(OH)D level (20 ng/mL may be required to maintain patients’ QOL in osteoporosis.

UNLABELLED Dairy foods are postulated to have beneficial effects on blood pressure, body fat, serum lipids, and the incidence of type 2 diabetes. To evaluate the effects of the consumption of milk and dairy products, we performed a randomized dietary intervention trial for 24 wk in Japanese men, aged 20 to 60 y, with 2 or more components of the metabolic syndrome ( CLINICAL TRIAL REGISTRATION UMIN000006353). Subjects were randomized to a control group (n=98) that received dietary intervention focused on weight control supervised by registered dietitians, and a dairy-consumption group (n=102) that received both dietary intervention and regular home dairy delivery of 400 g/d for 24 wk. Co-primary endpoints included waist circumference, blood pressure, fasting blood sugar (FBS), and serum lipids. The dietary intervention decreased energy intake from 2,150 to 1,850 kcal/d in both groups (p

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

The aim of osteoporosis treatment is to prevent future fractures. Although concurrent treatment has been used very frequently for osteoporosis in clinical practice, there are no data on accurate and verified effectiveness of concurrent treatment for fracture prevention in patients with osteoporosis. To clarify the clinical usefulness of concurrent treatment, the Japan Osteoporosis Society has authorized the establishment of the A-TOP (Adequate Treatment of Osteoporosis) research group. The objective of this research is to establish a design for a clinical trial to prove whether concurrent treatment using both alfacalcidol (1-alpha-hydroxycholecalciferol) and alendronate is more effective as compared to treatment using alendronate alone in terms of fracture prevention. The present study was named JOINT (Japanese Osteoporosis Intervention Trial) and is based on a method using national, prospective, randomized, open-labeled, blinded endpoints focusing on postmenopausal osteoporosis with a high risk for fracture. The patients were mainly selected by practitioners and allocated randomly by a central registration system into two groups, of which one received 5 mg/day of alendronate alone, and the other received 1 μg/day of 1-alpha-hydroxycholecalciferol (alfacalcidol) in addition to the alendronate. The endpoints focused primarily on fracture prevention, and the patients' quality of life (QOL) and change in body height, as well as adherence and the adverse events of the treatments were evaluated secondarily. To obtain sufficient statistical power in the events during a 2-year observation period, the patients who are expected to have higher risk were selected to participate in this study, and it was decided that the final plan would involve 890 patients per group (two-sided alpha = 0.05, power = 0.8). Data collection began in November 2003. Correspondence regarding the registration of the investigator and the progress of the study was conducted through a web system from the Public Health Research Foundation to practitioners.

日本人成人の牛乳・乳製品摂取状況とメタボリックシンドロームの関係について検討を行うため横断的な調査を行った。対象者は乳業メーカー4企業グループに勤務する従業員とその家族 (20-69歳) とした。自記式のアンケートを郵送し記入を依頼した。解析対象者数は非喫煙男性3,252人, 非喫煙女性3,296人, 喫煙男性2,111名である。メタボリックシンドロームの判定では, 非喫煙男性で積極的支援と判定された者が18%であった。非喫煙女性では腹囲の基準を80 cmとした場合には, 積極的支援と判定された者が10%であった。牛乳・乳製品摂取量により対象者を四分位にわけ, 最も摂取量が少ないグループを基準としたときの, 他のグループのオッズ比をみると, 非喫煙女性では牛乳・乳製品摂取量が増えるにしたがい, 有意に低下していた。非喫煙男性でも同様の傾向がみられた。本研究の結果, 非喫煙者ではメタボリックシンドロームの予防に牛乳・乳製品の摂取が有効である可能性が示された。

PvuII and XbaI restriction fragment length polymorphisms (RFLPs) of the estrogen receptor (ER) gene and its relation to bone mineral density (BMD) were examined in 238 postmenopausal healthy women aged 45-91 years (66.3 +/- 0.6 years, mean +/- standard error of the mean [SEM]) in Japan. The RFLPs were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of and small letters the presence of restriction sites. In the PPxx genotype (n = 18), Z score values of BMD were significantly lower than those for other genotypes (n = 220) (lumbar spine, -0.746 vs. -0.065 [p = 0.022]; total body, -0.482 vs. 0.308 [p = 0.002]). We classified the subjects into three genotypes with allelic haplotype: homozygote of the Px haplotype was expressed as the 11 genotype, heterozygote of the Px haplotype as the 10 genotype, and the one lacking the Px haplotype as the 00 genotype. The PpXx genotype was not included in this analysis because the allelic haplotypes are uncertain. The Px haplotype was associated with a low BMD in postmenopausal women (Z score for the lumbar spine, -0.746 vs. -0.279 vs. 0.083, for the 11, 10, 00 genotypes, respectively [p = 0.029]; Z score for the total body, -0.482 vs. 0.164 vs. 0.427, respectively [p = 0.003]). We suggest that some variation of the ER gene linked to these RFLPs is associated with low BMD and that this at least partly explains the cause of postmenopausal osteoporosis in Japanese women.

Despite lower femoral neck bone mass, Japanese women have a substantially lower incidence of hip fracture than North American whites. Reasons for this discrepancy were sought in a study of 57 Japanese and 119 white American women aged 50-79. All women were in good health. Bone mineral content (BMC) in the femoral neck, femoral neck length (NL), femoral neck angle (theta), cross-sectional moment of inertia (CSMI), safety factor (SF), and fall index (FI) were calculated using dual x-ray absorptiometry. Height and weight were greater in Americans than in Japanese (1.62 versus 1.52 m; p < 0.0001 and 66.0 versus 49.4 kg; p < 0.0001, respectively). Mean BMC in the femoral neck and CSMI were greater in Americans than in Japanese (3.91 versus 3.02 g; p < 0.0001 and 0.99 versus 0.57 cm4; p < 0.0001, respectively). NL was longer in Americans (5.6 versus 4.4 cm; p < 0.0001) and theta was larger in Americans (130 versus 128 degrees; p < 0.01), whereas SF and FI were less in Americans than in Japanese (3.41 versus 5.12; p < 0.0001 and 1.00 versus 1.40; p < 0.0001, respectively). These results indicate that despite lower bone mass, Japanese women have lower risks of structural failure in the femoral neck, attributable primarily to shorter femoral necks and, to a lesser degree, a smaller femoral neck angle. Geometric characteristics of the femoral neck in Japanese women are associated with their lower hip fracture risk, and the measurement of proximal femoral geometry, combined with bone mass, may provide further clinical information about the risk of hip fracture.

SUMMARY: We estimated the number of hip fracture patients in 2007 in Japan and investigated the trends in incidence during a 20-year period from 1987 to 2007. Despite the increasing number of new patients, the incidence of hip fracture in some age groups showed the possibility of decline. PURPOSE: The aims of this study were to estimate the number of hip fracture patients in 2007, to investigate the trends in incidence during a 20-year period from 1987 to 2007, and to show the regional differences in Japan. METHODS: Data were collected through a nationwide survey based on hospitals by the mailing method. Hip fracture incidences by sex and age and standardized incidence ratios by region were calculated. RESULTS: The estimated numbers of new hip fracture patients in 2007 were 148,100 in total (95% CI, 144,000-152,200), 31,300 (30,500-32,100) for men, and 116,800 (113,900-119,700) for women. The incidence rate in men aged 60-69 years and that in women aged 60-79 years were the lowest in the 15-year period from 1992 to 2007. The incidence was higher in western areas of Japan than in eastern areas in both men and women. CONCLUSIONS: Despite the increasing number of new patients, the incidence of hip fracture in some age groups for both men and women showed the possibility of decline. The exact reasons for this are unknown, but drug therapy for osteoporosis and fall prevention programs might have influenced the results. Some nutrient intakes might explain the regional differences not only in Japan but also in some other countries.

Many types of bone densitometry equipment are available in Japan, but the numbers of such machines and the numbers of institutions that offer bone densitometry have not been clarified. We analyzed the data from annual surveys conducted by the Japan Osteoporosis Foundation from 1996 to 2006, and we obtained the following results on the use of densitometry equipment: (1) In 1996 there were 6,687 units of bone densitometry equipment in 6,483 institutions in Japan; in 2006 there were 16,371 units in 15,020 institutions. (2) In 2006, of the types of institutions with bone densitometry equipment, the number of clinics was the highest, followed in order by general hospitals, other types of institutions, screening institutions and university hospitals. Rates of increase in the installation of equipment in clinics and other types of institutions were high during the 11-year period from 1996. (3) From 1996 to 2006 the region of interest most frequently used for bone densitometry was the radius. However, during the 11-year period, the proportion of radial densitometry equipment in all institutions with bone densitometry equipment decreased, whereas the proportion of calcaneal densitometry equipment increased. (4) The number of dual-energy X-ray absorptiometry (DXA) units was the highest from 1996 to 2006. However, the proportion of DXA machines in all institutions with bone densitometry equipment decreased over the 11-year period, whereas the proportion of quantitative ultrasound (QUS) machines increased. (5) In 2006, bone densitometry equipment was available in 118 institutions per million Japanese people. Central DXA (spine/hip) equipment was available in 15 per million, radial DXA equipment in 63 per million, and calcaneal QUS equipment in 44 per million. (6) In 2006, among those places with bone densitometry equipment, 46% of university hospitals, 14% of general hospitals, 12% of screening institutions, 5% of clinics, and 6% of other types of institutions possessed more than one type of densitometry equipment. (7) In 2006, central DXA (spine/hip) was frequently available in university hospitals, radial densitometry equipment in general hospitals and clinics, and calcaneal densitometry equipment in screening institutions and other types of institutions.

Summary The present study estimated the 10-year probability using the Japanese version of WHO fracture risk assessment tool (FRAX™) in order to determine fracture probabilities that correspond to intervention thresholds currently used in Japan and to resolve some issues for its use in Japan. Introduction The objective of the present study was to evaluate a Japanese version of the WHO fracture risk assessment (FRAX™) tool to compute 10-year probabilities of osteoporotic fracture in Japanese men and women. Since lumbar spine bone mineral density (BMD) is used preferentially as a site for assessment, and densitometers use Japanese reference data, a second aim was to investigate the suitability and impact of this practice in Japan. Methods Fracture probabilities were computed from published data on the fracture and death hazards in Japan. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck BMD. Fracture probabilities were determined that were equivalent to intervention thresholds currently used in Japan. The difference between T-scores derived from international reference data and that using Japanese-specific normal ranges was estimated from published sources. The gradient of risk of BMD for fracture in Japan was compared to that for BMD at the lumbar spine in the Hiroshima cohort. Results The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current intervention thresholds ranged from approximately 5% at the age of 50 years to more than 20% at the age of 80 years. The use of femoral neck BMD predicts fracture as well as or better than BMD tests at the lumbar spine. There were small differences in T-scores between those used for the model and those derived from a Japanese reference population. Conclusions The FRAX™ tool has been used to determine possible thresholds for therapeutic intervention, based on equivalence of risk with current guidelines. The approach will need to be supported by appropriate health economic analyses. Femoral neck BMD is suitable for the prediction of fracture risk among Japanese. However, when applying the FRAX™ model to Japan, T-scores and Z-scores should be converted to those derived from the international reference.

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 GA; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

1) 高齢者の定義の見直しについて東京都老人医療センター及び老人総合研究所において長年蓄積されてきた医学的, 社会学的データを解析した結果, 65歳以上を高齢者とする現行の定義を変え, 75歳以上を高齢者と定義することを提案する。2) 高齢者医療の理念と戦略3) 統合医療の概念4) 高齢者医療の質を高めるためには, 医療従事者が統合医療の概念についての理解を深めて, 漢方医学が西洋医療の主要なパートナーであるとの認識の下に, 患者さんのための統合医療を行なう体制を確立することが必須である。

Dentists request a discontinuation of antiresorptive agents, such as bisphosphonate, before and after tooth extractions to prevent osteonecrosis of the jaw (ONJ). However, little is known about how this affects ONJ and osteoporosis treatment and how medical professionals and dentists cooperate to treat ONJ in patients with osteoporosis. This study aimed to clarify the impact of ONJ on osteoporosis treatment in Japan. A structured questionnaire including 14 key clinical queries was sent to 488 medical professionals as part of the Japanese Osteoporosis Intervention Trial (JOINT)-04, and 206 responses were received. A total of 173 respondents had received discontinuation requests from dentists. Of these, 28 respondents experienced 30 adverse events including ten fractures and one incidence of ONJ. The respondents who refused discontinuation requests observed no cases of ONJ. Approximately 16 % of respondents had patients who discontinued osteoporosis treatment, following a requested drug discontinuation, after tooth extraction. Dentists requested discontinuations for many medications that were not associated with the incidence of ONJ. Approximately 76 % of respondents had never requested oral health care from dentists before osteoporosis treatment and 72 % reported no cooperation between dentists and medical professionals in their region. Our results suggest that drug discontinuation may increase adverse events and disturb osteoporosis treatment without completely preventing ONJ. Currently, both medical professionals and dentists in Japan still continue to recommend their own treatment position. A forum to share information about ONJ among medical professionals, dentists, and patients is required.

Conventionally, “elderly” has been defined as a chronological age of 65 years old or older, while those from 65 through 74 years old are referred to as “early elderly” and those over 75 years old as “late elderly.” However, the evidence on which this definition is based is unknown. We have attempted to review the definition of elderly by analyzing data from long-term longitudinal epidemiological studies, and clinical and pathological studies that have been accumulated at the Tokyo Metropolitan Geriatric Hospital and the Tokyo Metropolitan Institute of Gerontology. Our recommendation might be a starting point in developing a strategy for a successful society by reviewing the definition of elderly based on comprehensive evidence in all aspects of social, cultural and medical sciences.

In drug developments for osteoporosis, large-scale and longterm fracture prevention studies have been required. We investigated whether or not it was possible to reduce the sample size and observation period under new selection criteria for an osteoporotic fracture-prevention study. A Poisson regression model was used to identify independent risks for incident vertebral fracture in 515 postmenopausal women who had had no intervention for osteoporosis; this group was a subset of Nagano Cohort participants. The total observation period for this group was 2,577 person-years, and a total of 146 new vertebral fractures were observed. Risk assessment for incident vertebral fracture among numerical covariates revealed that the following items showed significant independent risks for incident fractures; namely, baseline age (hazard ratio [HR]; 1.84; 95% confidence interval (CI), 1.44-2.35; P < 0.001), number of preexisting vertebral fractures (HR, 1.28; 95% CI, 1.17-1.40; P < 0.001), baseline lumbar bone mineral density (LBMD) (HR, 0.79; 95% CI, 0.71-0.88; P < 0.001), and urinary excretion of deoxypyridinoline (DPD) (HR, 1.18; 95% CI, 1.03-1.35; P = 0.016). Because the initial urinary excretion of DPD was found to be a risk for incident vertebral fracture, in addition to the conventional risks, we assessed whether or not the sample size or observation period could be reduced by the incorporation of the urinary excretion of DPD into the selection criteria of a fracture-prevention study. The assessment of sample size was calculated, using the log rank test, at a two-tailed significance level of 5% and with a power of 80%. When osteoporotic patients with preexisting fracture were selected (conventional criteria), the 3-year probability of vertebral fracture was estimated as 14.3% in the present population. On the other hand, the new vertebral fracture rate during 3 years in the osteoporotic patients with preexisting fracture plus high urinary DPD (HR, above 1.0); (new selection criteria) was estimated as 23.2%. When the HR between test drug and placebo was changed from 0.4 to 0.8, the required sample size for any level of HR showed a 40% reduction for the new selection criteria compared to the conventional criteria. Therefore, the addition of urinary DPD level to the selection criteria is useful to reduce sample size in an osteoporosis fracture-prevention study.

Background: Osteoporosis is believed to result from the interaction among multiple environmental and genetic determinants that regulate bone-mineral density (BMD). Methods: To investigate a potentially predisposing genetic factor in the onset of osteoporosis, we looked for a possible association between BMD in adult Japanese women and known polymorphisms in the leukemia inhibitory factor receptor gene (LIFR). Results: An association analysis of chromosomes from 384 volunteer subjects revealed significant correlation between the −603T > C variant of LIFR and radial BMD (r = 0.11, P = 0.032) in this test population. Comparisons of mean values of adjusted radial BMD among separate genotypic groups implied an allelic dosage effect, because homozygous carriers of T alleles of that SNP had the highest adjusted BMDs (0.403 ± 0.054 g/cm2); women homozygous for the C-allele had the lowest (0.373 ± 0.042 g/cm2), and heterozygous individuals had intermediate scores (0.394 ± 0.056 g/cm2). Conclusion: This polymorphism in LIFR may be an important determinant of predisposition to postmenopausal osteoporosis.

The risk-reducing effect of alendronate on vertebral fractures has been consistently reported. In a 2-year, randomized, double-blind, active drug-controlled (1 microg alfacalcidol) double-dummy study, we also reported that alendronate (5.0 mg) had a fracture-reducing effect in Japanese patients with preexisting vertebral fractures. The present report describes the risk-reducing effect of alendronate (5.0 mg) for 3 years in postmenopausal osteoporotic patients. The 3-year treatment period consisted of the original 2-year double-blind study followed by a 1-year extension. A total of 170 postmenopausal female patients were involved in the third year; 90 received alendronate and 80 received alfacalcidol. Both efficacy and safety were analyzed in these 170 patients. Vertebral fracture was determined by quantitative morphometry, and vertebral bone mineral density (BMD) was measured by the DXA method (dual-energy X-ray absorptiometry). The primary efficacy endpoint was the incidence of vertebral fracture, excluding fracture cases that occurred in the first 6 months after treatment initiation. The cumulative incidence of vertebral fracture at 3 years was 7.8% (7/90) in the alendronate group and 18.8% (15/80) in the alfacalcidol group, indicating a significantly reduced risk of fractures in the alendronate group (relative risk = 0.41, 95% CI = 0.18-0.97). Lumbar spine BMD increased by 9.2% in the alendronate group (n = 26) and by 1.4% in the alfacalcidol group (n = 22) at 3 years. The safety profile of alendronate during 3 years of treatment was similar to that of alfacalcidol. The present study thus demonstrated that treatment with alendronate 5.0 mg for 3 years increased vertebral BMD and reduced the risk of vertebral fractures in Japanese, postmenopausal women with osteoporosis.

Background: Wnt-β-catenin signaling pathway is involved in the regulation of bone mineral density (BMD). Secreted frizzled-related protein (sFRP) 4 that antagonize Wnt signals may modulate Wnt-β-catenin signaling pathway in the bone. Therefore, we analyzed expression of sFRP4 mRNA in primary osteoblasts and the association of a single nucleotide polymorphism (SNP) in the sFRP4 gene with BMD. Methods: Expression levels of sFRP4 mRNA were analyzed during the culture course of rat primary osteoblasts. Association of a SNP in the sFRP4 gene at Arg262 (CGC to CGT) with BMD was examined in 372 healthy post-menopausal Japanese women. Results: sFRP4 mRNA was detected and increased during the differentiation of rat primary osteoblasts. As an association study of the SNP in the sFRP4 gene, the subjects without the T allele (CC; n = 129) had significantly higher lumbar BMD than the subjects bearing at least one T allele (TT + CT; n = 243) (Z score; 0.054 versus−0.324; P = 0.0188). Conclusion: sFRP4 mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the sFRP4 gene locus is associated with BMD, suggesting an involvement of sFRP4 gene in the bone metabolism.

The tolerability and pharmacokinetics of risedronate after a single oral administration and during multiple oral administrations were examined in healthy adult male volunteers. In the single dose study, the dose was increased gradually from 1 mg to 2.5, 5, 10, or 20 mg. Subsequently, risedronate was given by multiple administration, 5 mg per dosing, once daily, for 7 days. The observed adverse events, whose causality was possibly related or unknown, included headache, diarrhea, increased body temperature, increased CK-BB, and increased urinary Beta(2)-microglobulin excretion rate. However, none of these adverse events was clinically significant. The results thus showed that risedronate was well tolerated when delivered as a single administration of up to 20 mg or as a multiple administration of up to 5 mg/day. In the multiple dose study, changes in urinary deoxypyridinoline suggested the bone antiresorptive activity of risedronate. In the single dose study, AUC and C(max), after the administration of risedronate at 1, 2.5, 5, 10, and 20 mg, increased dose dependently, and the T(max), t(1/2), and urinary excretion rates were nearly constant. Therefore, the pharmacokinetic profile of risedronate was considered to show linearity in a dosage range of up to 20 mg. Furthermore, the results obtained in the multiple administration study indicated that the plasma concentrations of risedronate reached a steady state on day 4 of administration. The plasma concentrations of risedronate after the administration of 2.5 mg risedronate to the Japanese population were nearly comparable to the serum concentrations after the administration of 5 mg risedronate to the United Kingdom study population.

Background: It is known that the process of arteriosclerosis is affected by sex and estrogen. The present study was thus undertaken to examine the effects of these factors on arterial calcification, a form of arteriosclerosis, using a rat model of vitamin D toxicity. Methods and results: Vehicle or 5 µg/kg per day 1α(OH)D3 was given to male and female 30-week-old Fisher rats for 2 weeks. Arterial calcification, evaluated by calcium content in the aorta, was 70% more marked in male rats compared to that in female rats, whereas calcium content in the aorta was similar in vehicle-treated male and female rats. Next, the effects of ovariectomy and estrogen replacement (estradiol dipropionate 20 µg/kg per week) were examined in female rats given 5 µg/kg per day 1α(OH)D3 for 2 weeks. Calcium content in the aorta was significantly higher in ovariectomized rats than in sham-operated rats and in ovariectomized and estrogen-replaced rats. No difference between the groups was seen when vehicle was given to the animals. Conclusions: These results suggest that sex and estrogen can modify the process of arterial calcification. The mechanisms remain to be determined, although the effects were independent of serum calcium level.

Background: Estrogen deficiency in postmenopausal women causes an increased production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α. These cytokines are associated with an increase of bone turnover and an acceleration of bone loss. Tumor necrosis factor-α is known to promote osteoclastogenesis via TNFR1, one of the tumor necrosis factor receptors (TNFR). Therefore, the purpose of the present report was to investigate the association of TNFR1 gene polymorphism with bone mineral density (BMD) in postmenopausal Japanese women. Methods: The question of whether a polymorphism of the TNFR1 gene would correlate with osteoporosis in 320 unrelated healthy postmenopausal women in Japan, was investigated. A single nucleotide polymorphism (SNP) located at Pro12 (CCA to CCG) in exon 1 of TNFR1 was utilized. Results: The subjects were categorized into three genotypes: AA, AG, and GG. The frequency of each genotype was 72.2%, 23.8%, and 4.0%, respectively. The association of this polymorphism with BMD of the lumbar spine and total body, and several bone metabolic markers was then examined. Concerning the TNFR1 gene, the AA group had significantly low total body BMD, compared with the AG + GG group (Z score; 0.285 vs 0.568; P = 0.03), although BMD of the lumbar spine was not statistically different. Conclusion: These results suggest an association between this SNP of the TNFR1 gene and BMD, and an involvement of TNFR1 in postmenopausal osteoporosis among Japanese.

Background: The purpose of the present paper was to investigate a possible contribution of plasma homocysteine to cognitive impairment. To this end the relationship between plasma homocysteine levels and cognitive performance test results were investigated in elderly patients with diabetes. Methods: A total of 144 elderly patients (39 men and 105 women) with diabetes mellitus, who were free of clinical stroke, were studied. Plasma levels of homocysteine, folate, vitamin B12, vitamin B6, and the C677T polymorphism of methylene tetrahydrofolate reductase were determined. Cognitive function was assessed with the Wechsler Adult Intelligence Scale, Revised (digit symbol substitution, backward digit span, similarities, picture arrangement), Stroop test, Benton Visual Retention Test, and Mini-Mental State Examination (MMSE). Results: In elderly women with diabetes, elevated homocysteine levels in the plasma were significantly associated with impairment of cognitive performance assessed with the MMSE, digit symbol substitution test, similarities, Stroop test, and Benton visual retention test, but not the backward digit span test. Multiple logistic regression analyses revealed that the associations between the log-transformed plasma homocysteine level and low scores of the MMSE and digit symbol substitution test remained significant after adjustment for age, education, hemoglobin (Hb)A1c, systolic blood pressures, insulin treatment, serum levels of folate, vitamin B12, and vitamin B6, and the presence of asymptomatic cerebral infarction on brain magnetic resonance images. Conclusions: Elevated plasma homocysteine level was independently associated with cognitive impairment in elderly diabetic women. Because the cause of the association between homocysteine and cognitive impairment remains unclear, future intervention studies are necessary to examine whether reducing plasma homocysteine levels prevents cognitive decline in elderly patients with diabetes mellitus.

Background: The purpose of the present study was to investigate the possible contribution of plasma homocysteine to asymptomatic cerebral infarction (CI) or leukoaraiosis. Methods: The relationship between plasma homocysteine concentrations and cerebral lesions was investigated in 233 elderly diabetic patients (mean age: 74 years) who were divided into three groups based on the neurological and brain MR findings: asymptomatic cerebral infarction (CI), symptomatic CI, and a control group with no evidence of cerebrovascular disease. Plasma total homocysteine concentrations were measured by high-performance liquid chromatography. The C677T polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene was assessed by PCR-RFLP. The total score of T2 high-intensity lesions on the brain MR images was summed from the focal T2 high-intensity scores in 24 areas of the brain. Results: Diabetic patients with asymptomatic or symptomatic CI had significantly higher homocysteine concentrations in plasma than the control group. The plasma homocysteine concentration was more strongly associated with the presence and number of small infarctions or infarction of the putamen, which may explain the association between increased plasma homocysteine concentrations and asymptomatic CI in elderly diabetic patients. In the diabetic patients, high plasma homocysteine concentrations were also significantly associated with high scores of total T2 high-intensity lesions or focal T2 high-intensity scores in some periventricular regions. Although there was no significant relationship between the MTHFR TT genotype and CI, a significant association was found between the MTHFR TT genotype and total T2 high-intensity scores. Conclusion: An elevated plasma homocysteine concentration is independently associated with asymptomatic CI and T2 high-intensity lesions on brain MR images in elderly patients with diabetes mellitus. The association between the MTHFR TT genotype and periventricular T2 high-intensity lesions, but not with CI, suggests an important effect of C677T MTHFR gene mutation on leukoaraiosis, independent of hyperhomocysteinemia in elderly diabetic patients.

The effects of bezafibrate and pravastatin on remnant-like lipoprotein particles (RLPs) and lipoprotein subclasses were compared in type 2 diabetes. Bezafibrate (400 mg/day) and pravastatin (10 mg/day) were given to 27 Japanese diabetics in a randomized crossover design. RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) were measured by an immunoseparation technique. LDL and HDL were separated each into three subclasses (large, medium, small) and their cholesterol (C) contents were measured by an HPLC method. RLP-C was reduced more effectively by pravastatin (bezafibrate -16.0% vs. pravastatin -40.6%, P0.05), whereas RLP-TG was reduced more effectively by bezafibrate (-55.2% vs. -35.0%, P0.05). Further, pravastatin decreased large and small LDL-C levels equally (large; -23.6%; medium; -17.2%, small; -21.0%), while bezafibrate produced a relatively larger reduction in small LDL-C (-12.1; -16.9; -21.5%). Whereas bezafibrate significantly decreased large HDL-C and increased medium and small HDL-C (-49.6; 34.1; 35.8%), pravastatin significantly increased only medium HDL-C (5.2; 9.4; 5.9%). Bezafibrate reduced RLP-C and RLP-TG more effectively in patients with high TG levels, whereas pravastatin's effect was not markedly influenced by the initial TG level. Thus measurements of RLP-C, RLP-TG, and HPLC subclasses revealed that bezafibrate and pravastatin differently influence the lipoprotein status in type 2 diabetes.

Objective: Low back pain is one of the most common subjective symptoms presenting in Japan, but has no established curative therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for low back pain, and are generally effective in alleviating pain; however, such drugs are frequently associated with adverse effects such as gastrointestinal symptoms. The present study thus investigated the effectiveness of a compound supplement containing piperines, theanine, creatine, α -lipoic acid, and proteoglycan for managing the subjective symptoms of low back pain. Methods: We conducted a double-blind, placebo-controlled, parallel-comparison study in 79 adult men and women with chronic low back pain. Subjects took either placebo or the investigational compound supplement containing long pepper extract powder at a dose of 150 mg (45 μ g as piperines), theanine at 50 mg, creatine at 250 mg, α -lipoic acid at 3 mg, and salmon nasal cartilage extract powder at 50 mg (10 mg as proteoglycan) or placebo for 8 weeks. Subjective symptoms were assessed immediately before starting to take the supplement or placebo (baseline), 4 weeks after the start (Week 4), and 8 weeks after the start (Week 8). Results: Japan Low Back Pain Evaluation Questionnaire (JLEQ) scores were significantly lowered at Week 4 and Week 8 in the supplement group compared to those measured at baseline, and they were significantly lower at Week 8 compared to those of the placebo group (P=0.022). Approximately 30% of the JLEQ score of low back pain in the supplement group showed significantly improved compared to the placebo group. No clinically significant adverse events were reported during the study period. Conclusions: The compound supplement tested herein, provided some relief for subjects with low back pain, and therefore could be useful in managing low back pain, and safe alternative or complement to NSAID therapy.

Because mice deficient in klotho gene expression exhibit multiple aging phenotypes including osteopenia, we explored the possibility that the klotho gene may contribute to age-related bone loss in humans by examining the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the white and the Japanese. Screening of single-nucleotide polymorphisms (SNPs) in the human klotho gene identified 11 polymorphisms, and three of them were common in both populations. Associations of the common SNPs with bone density were investigated in populations of 1187 white women and of 215 Japanese postmenopausal women. In the white population, one in the promoter region (G-395A, p = 0.001) and one in exon 4 (C1818T, p = 0.010) and their haplotypes (p0.0001) were significantly associated with bone density in aged postmenopausal women (or = 65 years), but not in premenopausal or younger postmenopausal women. These associations were also seen in Japanese postmenopausal women. An electrophoretic mobility shift analysis revealed that the G-A substitution in the promoter region affected DNA-protein interaction in cultured human kidney 293 cells. These results indicate that the klotho gene may be involved in the pathophysiology of bone loss with aging in humans.

Background: The interleukin-1 receptor antagonist (IL-1RA) plays an important role in bone metabolism, and molecular defects are implicated in the pathogenesis of osteoporosis. Studies performed in Caucasian populations have demonstrated an association between allelic variants of the IL-1RA gene and bone mineral density (BMD). Methods: In the study reported here, we examined whether variation of the IL-1RA gene would correlate with osteoporosis among 287 Japanese postmenopausal women. Results: The allele frequencies and distribution in this ethnic group were remarkably different from those reported for Caucasians and phenotypes such as Z scores of lumbar spine (L2–4) and total body BMD, as well as various biochemical markers related to bone metabolism, were not significantly different among groups of IL-1RA genotypes in the present study. Conclusion: Our results emphasize the importance of considering ethnic background in assessing the etiological significance of candidate genes in osteoporosis.

Background: Exposure to pesticide is associated with an elevated risk of Parkinson’s disease (PD). Oxidative stress is also implicated in the etiology of PD. Paraoxonase (PON1) detoxifies organophosphates and exhibits antioxidant properties. It was postulated that polymorphisms of the PON1 gene lead to increased risk of PD. Methods: The seven polymorphisms of the PON1 gene were typed and neuropathologic examination performed in 360 Japanese people (191 men and 169 women) consecutively autopsied at a general hospital. Results: Thirty-three patients (18 men and 15 women) were diagnosed with pathologically verified idiopathic PD (pviPD). The proportion of male patients with pviPD was highest in the AA genotype (29.4%) of the G(−824)A polymorphism, followed by the GA genotype (9.3%), and least in the GG genotype (6.0%). These genotypic distributions and allele frequency were significantly different between male patients with and without pviPD (P = 0.021 and P = 0.012, respectively). The odds ratio for the −824 A allele versus the −824G allele was 2.47 (95% CI 1.23–4.96). No association between pviPD and the PON1 polymorphisms was found in the female patients. Conclusion: Possession of the −824A allele may increase the risk of PD in Japanese men.

Using cross-sectional and prospective analyses, the risk factors for macroangiopathy (MA) in nonobese Type 2 diabetic patients were evaluated. In the cross-sectional study, we determined a cutoff point for each variable at which changes in the prevalence of total MA reached statistically significant levels. In the prospective study, those who met more than four out of seven control criteria as set forth in the Multiclinical Study for Diabetic Macroangiopathy (MSDM) had less risk of MA in Type 2 diabetes initially diagnosed without MA compared with those who fulfilled less than three factors. These results suggest that multiple risk factor control is the most effective and reasonable way to lower the incidence of MA in Type 2 diabetes.

Tumour necrosis factor alpha (TNFalpha) has come to be regarded as a potential osteoporotic factor, because it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with oestrogen deficiency. We recently described genetic linkage between the TNFalpha locus and human osteoporosis by sib-pair analysis. However, the molecular mechanism by which this locus regulates bone mineral density (BMD) remains unknown.We investigated whether the observed linkage reflects a sequence variation which might affect expression of the TNFalpha gene or alter the function of TNFalpha protein.We examined three single-nucleotide polymorphisms (SNPs) of the TNFalpha gene in a group of 390 postmenopausal Japanese women living in northern Japan. Minor-allele frequencies for the three SNPs (-1031C, -863A and -857T) in this population were 0.16, 0.13 and 0.20, respectively.Among the three SNPs examined, we observed a significant correlation only between the presence of a T allele at nt -1031 and decreased BMD, by analysis of variance. Among the three genotypic groups at nt -1031, mean BMD values were significantly higher in the T-negative genotype (C/C homozygotes; mean SD = 0.342 +/- 0.052 g cm(-2)), compared with T-positive genotypes (T/T homozygotes, 0.309 +/- 0.062 g cm(-2); p = 0.0253 and T/C heterozygotes, 0.305 +/- 0.062 g cm(-2); p = 0.0164).Given the lines of evidence from different genetic studies, we suggest that TNFalpha may play a role in pathogenesis of osteoporosis.

Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 +/- 6.13 ng/mL (mean +/- SD) in Japanese women in Tokyo, 1.22 +/- 1.85 in Japanese women in Hiroshima, and 0.37 +/- 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.

The purpose of this study was to assess the relationship between experiences of falls or fear of falling and functional fitness in the elderly. A total of 41 women, aged 66-88, who visited Fall Prevention Clinic in Tokyo Metropolitan Geriatric Hospital, underwent an interview and functional assessment. We used a questionnaire about falls, fear of falling, activity restriction, and twelve variables were used to assess functional fitness. Data were collected from June 2000 to November 2001. The subjects were classified into four subgroups: the faller group (n = 29) were subjects who had at least one or more experiences of falling accidents in the past one year; the non-faller group (n = 12) were subjects who did not have any falling accidents in the past one year; the activity restricted group (n = 12) were subjects who were restricted from going out because of fear of falling; the activity non-restricted group (n = 23) consisted of subjects who did not have any restriction concerning going out because of fear of falling. The results were: 1) Among all subjects, 85.4% had fear of falling. Among the subjects who had fear of falling. 34.3% had restricted outdoor activities due to the fear of falling. 2) Where 86.2% of the faller group responded that they had fear of falling. 83.3% of the non-faller group also responded as having fear of falling. Of the faller group, 44.0% had some restriction concerning going out because of fear of falling. In the non-faller group, 10.0% of them showed some restriction concerning going out because of fear of falling. The rate of activity restriction in the faller group was significantly higher (p < 0.05) than in the non-faller group. 3) The faller group had significantly reduced LNG with eyes open and closed, one-leg balance with eyes open, tandem walking, grip strength, and leg extension than the non-faller group. 4) The activity-restricted group exhibited significantly reduced one-leg balance with eyes open, Up & Go test, grip strength, and leg extension than the activity non-restricted group. In conclusion, lower leg strength and walking ability as well as history of falls are significant predictors of activity restriction in elderly women related to fear of falling.

Hip fracture greatly impairs quality of life in patients with osteoporosis. Measurement of bone mineral density (BMD) in the hip, which is closely related to fracture risk, is therefore diagnostically important. Furthermore, since in some elderly individuals lumbar BMD may be overestimated because of vertebral fracture or spondylosis deformans, measurement of hip BMD is also important. However, hip BMD is unlikely to be measured as often as lumbar BMD in Japan. A questionnaire survey was conducted to determine how many institutions measure hip BMD. A total of 861 institutions responded to the survey, 596 (69%) of which performed hip bone densitometry. The number of such institutions per million population was calculated to be 4.7. Measurement of hip BMD was more frequent in university hospitals than in general hospitals, clinics, and non-medical institutions. Furthermore, 298 (51%) of 590 institutions measured hip BMD in more than 75% of all bone densitometry examinees. This is the first report on the current status of utilization of hip bone densitometry in Japan.

Calcitonin (CT), a calcium-regulating hormone, lowers the calcium level in serum by inhibiting bone resorption. Because CT may play a role in the pathogenesis of osteoporosis, genetic variations in or adjacent to the CT gene may be associated with variations in bone mineral density (BMD). The present study examined the correlation between a dinucleotide (cytosine-adenine; CA) repeat polymorphism at the CT locus and BMD in 311 Japanese postmenopausal women (mean age, 64.1 years). Seven alleles were present in this population; each allele contained 10, 11, 16, 17, 18, 19, or 20 CA repeats. Thus, we designated the respective genotypes A10, A11, A16, A17, A18, A19, and A20. The A10 and A17 alleles were the predominant alleles in the population studied. Z scores (a parameter representing deviation from the age-specific weight-adjusted average BMD) were compared between individuals that possessed one or two alleles of each genotype and those that did not possess the allele. Subjects who possessed one or two A10 alleles had lower BMD Z scores than those who did not (lumbar 2-4 BMD Z score; -0.148 +/- 1.23 vs 0.182 +/- 1.54; P = 0.04). No significant relationships were observed between allelic status and background data or biochemical parameters. The significant association observed between BMD and genetic variations at the CT locus implies that polymorphism at this locus may be a useful marker for the genetic study of osteoporosis.

We investigated the expression of parathyroid hormone-related protein (PTHrP) in atherosclerotic lesions and the role of PTHrP in the development of arterial neointima formation. Immunohistochemical staining of PTHrP in the neointima of rat aorta produced by balloon injury and of rat femoral artery produced by non-obstructive polyethylene cuff placement, and in the atherosclerotic lesion of human coronary artery was performed using anti-human PTHrP-(1-34) antibody. Anti-muscle actin antibody, HHF-35, and anti-macrophage antibody, HAM-56, were used to identify smooth muscle cells and macrophages, respectively. Immunoreactivity of PTHrP was detected in the thickened intima of rat and human lesions where the predominant cell types were smooth muscle cells or macrophages dependently on the lesion type. In the next series of experiments, we examined the effect of PTHrP on the development of cuff-induced intimal thickening of rat femoral artery. Either PTHrP-(1-34) or PTHrP-(7-34), a PTH/PTHrP receptor antagonist, suspended in pluronic F-127 gel was locally applied around the rat femoral artery. Intimal thickening induced by cuff placement was evaluated 2 weeks later. PTHrP-(1-34) dose-dependently inhibited intimal thickening determined as intima/media ratio and % stenosis whereas PTHrP-(7-34) dose-dependently enhanced that. These results suggest that PTHrP, which is expressed in atherosclerotic lesions, inhibits the development of neointimal formation.