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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.

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.

Expression of estrogen receptor (ER) was studied in MC3T3-E1 cells (mouse osteoblastic cell line), HOS TE85 cells (human osteosarcoma cell line), and primary osteoblastic cells derived from mouse calvaria with immunohistochemical techniques. The staining of ER was readily detectable in MC3T3-E1 cells, HOS TE85 cells, and primary osteoblastic cells by using a monoclonal anti-ER antibody that recognizes the DNA binding domain of ER. The immunoreactivity was distributed in the cytoplasm as well as in the nuclei. 17 beta-Estradiol (10(-8) M) did not alter this staining pattern. The expression of ER was confirmed by Northern blot analysis using rat ER cDNA probe, which revealed a 6.5 kb band in MC3T3-E1 cells and a 6.2 kb band in HOS TE85 cells. The mRNA level of ER was not altered by 17 beta-estradiol (10(-8) M). The immunohistochemical studies showed that ER was not detectable in all cells but in a small population of each cell type. This study is the first report to demonstrate the presence of ER immunohistochemically, and our results suggest the heterogeneity of ER expression among osteoblastic cells.

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.

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.

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.

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.

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.

In Japan a number of reported cases of diffuse panbronchiolitis (DPB) have been associated with human T lymphotropic virus type I (HTLV-I) infection. In this study the hypothesis that HTLV-I proviral DNA may be prevalent in DPB was examined using polymerase chain reaction (PCR) for the region of env or the two-step PCR for the pX region of this virus. The presence of HTLV-I proviral DNA was studied in the peripheral blood mononuclear cells (PBMC) obtained from 10 patients with DPB. The presence of proviral DNA in PBMC in 12 patients with chronic obstructive pulmonary disease (COPD), eight patients with idiopathic interstitial pneumonia (IIP), four patients disease were also studied as relevant controls. The lung tissue obtained from 11 patients with DPB, 12 patients with diffuse aspiration bronchiolitis (DAB) at autopsy, and the surgical lung samples obtained from 12 patients with bronchogenic cancer were also studied. Peripheral blood mononuclear cells obtained from one DPB patient and one bronchogenic carcinoma patient were positive for the HTLV-I pX region. The presence of the pX region was also found in the lung tissue of three DPB patients (27.3%) and one DAB patient (8.3%). None of other subjects were positive for HTLV-I proviral DNA, In conclusion, HTLV-I is not the causative virus in the pathogenesis of COPD, IIP, bronchiectasis and bronchogenic carcinoma. There is a likelihood that HTLV-I infection is associated with some cases of DPB; however this association needs further verification.

The aging of society is increasing very rapidly in most of the Asian countries. In Japan, the population of elderly aged 65 years and over is estimated to increase to 17.0% in 2000 – and to 25.0% of the entire population by 2020. The primary aim of geriatric medicine is to promote the health and quality-of-life of the elderly, leading them towards successful and active aging. In this plenary lecture, I would like to cover the following issues. (1) major diseases that cause disability in the elderly; (2) prevention of lifestyle and age-related disease; (3) medical care of the elderly in 21st century; and (4) future perspectives.

[14C]Acetamidino-insulin was synthesized by acetamidination of insulin with methyl [14C]acetimidate hydrochloride. The acetamidino-insulin contains two main components, which can be separated by DEAE-cellulose column chromatography. They correspond to glycineA-1 - PhenylalanineB-1 - Ne - lysineB-29 - [14C]acetamidino-insulin and glycineA-1 - Ne - lysineB-29 - [14C]acetamidino-insulin. These immunological and biological activity was compared with that of native insulin.

Forty female Wistar-Imamichi rats, each weighing 98 gm, were divided into 5 equal groups and the effects of dihydrotachysterol (DHT) on the calcium content and weight of the kidney, heart, aorta and femur were compared in ovariectomized and in intact rats. The effect of DHT was much more pronounced in the ovariectomized than in the intact rats. These findings strongly suggest the protective effect of endogenous estrogens on the DHT-induced progeria-like syndrome in rats.

To evaluate amino acid metabolism in osteoporosis, the effects of oral loading with an amino acid mixture were studied in 11 aged patients with advanced osteoporosis, 5 aged patients with mild osteoporosis, and 7 healthy aged subjects (controls). The osteoporotic patients were free of other major diseases. In all three groups the physical examination, blood chemical determinations, urinalysis and fluoroscopy of the upper gastrointestinal tract gave normal findings; in particular, no liver or kidney disease was indicated by the results of function tests. A diagnosis of vertebral osteoporosis was made when the ratio of vertebral to disc density in the lateral tomogram of the lumbar spine was 1.0 or higher; in the normal subjects, the ratio was always less than 1.0. The presence of compression fracture(s) was considered to indicate severe osteoporosis, whereas the absence of such fractures graded the disease as mild. Gaschromatographic analysis of the serum for certain free amino acids was made on the blood specimens drawn immediately before, and at one, two, three and four hours after oral ingestion of the test amino acid mixture. The serum valine level for the severely osteoporotic group was significantly higher at one hour (215 + 21 μg/ml versus 151 + 9 for the controls) and at four hours (178 + 16 μg/ml versus 139 + 8.7 for the controls) after ingestion of the mixture. The peak height of the serum valine level was also significantly higher in the severely osteoporotic patients (263 + 25 μg/ml) than in the controls (192 + 5.5 μg/ml). In the mildly osteoporotic patients the values were intermediate. For leucine and phenylalanine, the tolerance curves for the osteoporotic patients were similar to those for the controls. The findings are consistent with the hypothesis that possibly there is a deficiency or defect of valine transaminase in osteoporosis.