Search

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.

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.

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.

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.

Twin and family studies had shown that genetic factors are important determinants of bone mass. Multiple genes might be involved. One candidate gene, the reversion-induced LIM gene ( RIL), is a PDZ and LIM-domain-containing protein and has been localized within the cytokine cluster of chromosome 5 (5q31.1). In a genetic study of 370 adult Japanese women, we investigated the correlation between radial bone mineral density (BMD) and a genetic variation (-3333T--C) of the 5'-flanking region of RIL gene. A significant association was identified between the RIL variation -3333T--C and radial BMD ( r=0.15, P=0.003). The variation of the RIL locus may be an important determinant of osteoporosis.

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.

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.

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.

A novel variation of the estrogen receptor-alpha (ERalpha) gene was identified by polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP). It is one base substitution in codon 325 (CCC [allele M] to CCG [allele m]) in exon 4 of the human ERalpha gene. This substitution did not cause an amino acid change. We categorized 306 unrelated Japanese postmenopausal women into three genotypes: MM, Mm, and mm; the frequency of each genotype was 26.5%, 43.1%, and 30.4%, respectively. Then, the association of this polymorphism with bone mineral density (BMD) of lumbar spine and bone-calcium metabolic markers was studied. There was no significant difference in BMD of the lumbar spine or most of the bone metabolic markers. However, the urinary calcium (Ca) excretion ratio (u-Ca/Cre) corrected by creatinine was significantly lower in the genotype mm group compared with the genotype MM group (MM vs mm, 0.247 +/-0.158 vs 0.200 +/- 0.105; P0.05). We examined the relationship of restriction fragment length polymorphisms (RFLPs) (PvuII, XbaI) in intron 1 and the polymorphism in exon 4. The frequency of genotype MM was higher in the genotype PPxx, which was reported to be associated with lower BMD in the same population of Japanese postmenopausal women. The ER polymorphism identified in this study might be related to some biological mechanisms that regulate calcium metabolism.

Osteoporosis as well as osteopenia are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlation between measures of bone mass and a number of genetic factors. Certain genes (e.g., cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor-alpha) are capable of regulating metabolism, formation, and resorption of bone; all processes that determine bone mass. We tested 192 sib-pairs of adult Japanese women from 136 families for genetic linkage between osteoporosis and osteopenia phenotypes and allelic variants at the tumor necrosis factor-alpha (TNFA) locus, using a dinucleotide-repeat polymorphism located near the gene. The TNFA locus showed evidence for linkage to osteoporosis, with mean allele sharing of 0.478 (P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant affected pairs. Linkage with osteopenia was also significant in concordant affected pairs (P = 0.017). Analyses limited to the post-menopausal women in our cohort showed similar or even stronger linkage for both phenotypes. The results provide evidence that genetic variations within the TNFA locus or adjacent genes affect regulation of mineral metabolism in bone and some of them confer risk for osteoporosis in adult women.

Osteopenia and osteoporosis are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlations between levels of bone mass and a number of genetic factors. The genes involved could regulate metabolism, formation and resorption of bone, all processes that determine bone mass. We tested 192 sibling pairs of adult Japanese women from 136 families for genetic linkage between osteopenia and allelic variants of four candidate genes (interleukin-6, interleukin-6 receptor, calcium-sensing receptor, and matrix gla protein) using qualitative and quantitative methods, and using as genetic markers dinucleotide-repeat polymorphisms present in or near each of those loci. The interleukin-6 locus showed evidence of linkage to osteopenia analyzed as a qualitative trait, with mean allele sharing of 0.40 (P=0.0001) in discordant pairs and 0.55 (P=0.04) in concordant affected pairs. Variation at this locus was also linked to decreased bone mineral density measured as a quantitative trait (P=0.02). Analyses limited only to the post-menopausal women showed similar or even stronger results. No other locus among those tested showed any evidence of linkage by either method. The results provided strong evidence that genetic variation at the interleukin-6 locus affects regulation of bone mineral metabolism and confers risk for osteopenia and osteoporosis in adult women.

Twin studies have shown strong correlations between bone mass and genetic factors. Some of the genes involved could regulate bone metabolism and bone formation and resorption, all processes that determine bone mass. One candidate gene, interleukin 6 (IL-6), has been implicated in the pathogenesis of bone loss because it stimulates osteoclasts. We investigated a possible association between the CA repeat polymorphism at the IL-6 gene locus and the bone mineral density (BMD) of radial bone in 472 postmenopausal Japanese women. Genotypes were classified into six groups according to the number of CA repeats present, from 13 to 18. BMD was expressed as adjusted BMD, which was the body mass index (BMI)- and age-adjusted average BMD. The 73 women who possessed an A1 allele (134 bp, containing 18 repeats of CA) had significantly lower adjusted BMD than those participants (n = 399) who did not carry an allele of that size (mean +/- SD values, 0.294 +/- 0.064 vs 0.312 +/- 0.061 g/cm2; P = 0.0221). This result suggests that genetic variation at the IL-6 gene locus is associated with some determinants of BMD in postmenopausal women.

New diagnostic criteria of primary osteoporosis (2000 version) was presented. The basic concepts are as follows. Firstly, estimation of low bone mass should be made by lumbar BMD by DXA. However, when measurement of lumbar BMD is not appropriate due to fracture or deformities of the spine, hip, radial, calcaneal, or metacarpal BMD should be used. X ray picture of the spine should be used when DXA is not available. Secondary, in cases with fragility fractures, or in cases with BMD below 70% of young adult mean, differential diagnosis should be made in order to rule out other diseases with low BMD than primary osteoporosis.

Menatetrenone (2-methyl 1,3-tetraprenyl-1,4-naphtoquinone; vitamin K2) is a vitamin K homolog. To evaluate its efficacy on cortical bone mineral density and its safety, a 24-week double-blind placebo-controlled study was conducted by enrolling 80 osteoporotic patients. Patients were given either 90 mg/day of vitamin K2 (n = 39) or a placebo (n = 41). Bone density was assessed on the X-ray film of the right second metacarpal bone using the microdensitometric method. In the vitamin K2 group, bone density increased by 2.20% ± 2.48% from the baseline; in the placebo group, it decreased by −7.31% ± 3.65% (P = .037, K2 vs placebo). Urinary excretion of γ-carboxyglutamic acid (Gla) significantly increased from 72.61 ± 4.08 nmole/mg creatinine before treatment to 88.36 ± 5.35 in the 24th week after completion of the vitamin K2 treatment (P = .008). In the placebo group, there were no significant changes in urinary Gla excretion. In the 24th week of the treatment, the urinary calcium/creatinine ratio in the vitamin K2 group decreased from 0.137 ± 0.018 to 0.118 ± 0.016; in the placebo group, it increased from 0.153 ± 0.018 to 0.189 ± 0.029. As a result, the 24-week levels in the vitamin K2 and placebo groups became significantly different (P = .028). There were a few adverse effects attributable to vitamin K2. Our findings suggest that vitamin K2 at a dosage of 90 mg/day is effective in maintaining peripheral cortical bone density and is safe in treatment for osteoporosis.

To investigate the role of hyperinsulinemia/msulin resistance in vasomotor tone regulation, we studied the effects of vasoactive substances on tension and intracellular free calcium concentration ([Ca2+]i) of aortic smooth muscle derived from rats that were made hyperinsulinemic by insulin infusion and from Zucker obese rats with insulin resistance. The tension and [Ca2+]i of fura 2-loaded aortic strip preparations without endothelium were simultaneously measured by using a fluorimeter. Ten male Wistar rats received a continuous subcutaneous infusion of insulin (18 nmol · kg−1 · day−1) for 2 weeks with osmotic minipumps (INS group). A control group of 10 rats received vehicle. The plasma imnranoreactive insulin concentration in the INS group increased to 930 ± 54 Pmol/1. The increase in [Ca2+]i and tension by KCI and phenylephrine (PE) were lower in the INS group without alteration of the [Ca2+]itension relationship. The responses to serotonin (5-HT) in the INS group were similar to those in the control group. In contrast, responses to KCI, PE, and 5-HT were markedly enhanced in Zucker obese rats compared with those in Zucker lean rats. The pretreatment of aortic preparations from lean rats with Bay K 8644 significantly enhanced the responses to KCI to the level observed in the preparations from obese rats; however, Bay K 8644 failed to affect the responses to KCI in obese rats. These results suggest that enhanced vascular contractile responses to vasoactive substances, possibly due to altered function of the voltage-dependent Ca2+ channel in vascular smooth muscle, may play an important role in the pathogenesis of hypertension in the insulin resistance syndrome.

To examine the characteristic features of risk factors for macroangiopathy (MA) in nonobese Japanese NIDDM patients, 899 NIDDM patients with and without MA were registered from 40 facilities. Of these, 386 subjects were identified as having any form of MA (total MA); these included 211 with ischemie heart disease (IHD), 163 with cerebrovascular disease (CVD), and 77 with peripheral vascular disease (PVD). Univariate analyses revealed the following common risk factors for total MA, IHD, CVD, and PVD: age, hypertension, systolic blood pressure (sBP) or diastolic blood pressure (dBP), duration of diabetes, diabetic microangiopathy (retinopathy, nephropathy, and neuropathy), low HDL cholesterol level, and higher LDL cholesterol/HDL cholesterol ratio. Additional significant risk factors for specific conditions were also identified, respectively, as male sex for total MA, IHD, and PVD, smoking for IHD and PVD, and high fasting plasma glucose level for total MA and CVD. With stepwise multivariate logistic regression analysis, older age, duration of diabetes, smoking, and low LDL cholesterol/HDL cholesterol ratio were identified as significant and independent risk factors for total MA, IHD, CVD, and PVD. Other risk factors identified were high dBP for IHD, CVD, and PVD, high sBP for total MA, and low BMI for PVD. These results clearly demonstrated that duration of diabetes, smoking, hypertension, and dyslipidemia are major risk factors for MA in NIDDM patients. Since the mean BMI was similar for both groups (∼23 kg/m2) and there were no significant differences in immunoreactive insulin levels before and after 75-g oral glucose challenge testing, obesity and hyperinsulinism at the time of the analyses were not considered to play an important role for the pathogenesis of MA in Japanese NIDDM patients. By using the χ2 test, cutoff points were determined for six of the most commonly measured risk factors. The cutoff point was the level beyond which a significantly higher prevalence of MA occurred. The cutoff points (rounded slightly upward in some cases) for fasting plasma glucose, sBP, dBP, serum total cholesterol level, serum triglyceride level, and BMI were 140 mg/dl, 140 mmHg, 80 mmHg, 180 mg/dl, 120 mg/dl, and 23 kg/m2, respectively. When these cutoff points were used as control criteria, the prevalence of MA was significantly lower in subjects whose risk factor measurements remained under the proposed control criteria for four or more of the six variables. In conclusion, in nonobese NIDDM patients, age, hypertension, and dyslipidemia were found to be risk factors for MA. Duration of diabetes was also demonstrated as an independent risk factor, indicating the close association of deranged glucose metabolism with the pathogenesis of MA in NIDDM patients. It seems to be crucial to control these risk factors for the prevention of MA in NIDDM patients.

A total of 127 patients with involutional osteoporosis were randomly divided into two groups. The elcatonin group consisted of 67 patients who received 20 units of elcatonin per week administered intramuscularly, together with 0.6g calcium lactate (100mg as calcium) given orally three times daily for 24 weeks. The other 60 patients were assigned to a control group receiving 0.6g calcium lactate orally three times daily. Forty patients were withdrawn from the study treatment or dropped out during the study. The other 87 patients (consisting of 45 in the elcatonin group, and 42 in the control group) were measured for lumbar vertebral bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA). The BMD was increased significantly (P < 0.05) by 1.87 ± 0.79% (mean ± standard error) in the elcatonin group and decreased by 0.61 ± 0.93% in the control group at the end of the study. The difference between the two groups was statistically significant (P < 0.05). The results of the present study demonstrated that elcatonin increases the BMD in patients with involutional osteoporosis.

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.

Tobacco smoke is associated with pulmonary emphysema via elastase-antielastase and oxidant-antioxidant imbalance. This study addressed the tobacco smoke-induced changes in the lungs of weanling rats with vitamin E depletion. Three-week-old Wistar rats fed on vitamin E-depleted or normal diet were intermittently exposed to tobacco smoke by Hamburg II machines for 4 weeks. Tobacco smoke significantly suppressed body weight increases, particularly in the vitamin E-depleted group. In the normal diet group, tobacco smoke induced emphysematous changes with significant increases in the mean linear intercept (Lm) and the destructive index (DI), which was supported by an increase in elastase-like activity and a decrease in elastase inhibitory capacity (EIC) in bronchoalveolar lavage (BAL) fluid. Vitamin E depletion alone altered neither Lm nor DI. In tobacco-exposed animals in addition to vitamin E depletion, elastase-like activity, EIC in BAL fluid and DI were comparable to that in tobacco-exposed animals on a normal diet. However, Lm was markedly decreased with thickened epithelium and shrunk alveolar space. These results suggest that vitamin E depletion, when linked to tobacco exposure, might induce impaired lung development in the weanling rats, which is different from the emphysematous changes.

Caseinphosphopeptide in a dose of 87.5 mg was administered to 35 normal post-menopausal women as a part of a standard test meal containing a calcium load of 250 mg. Absorption of calcium was tested both with and without caseinphosphopeptide, using an intrinsic45Ca label in the calcium source. The mean quotient of absorption with/without caseinphosphopeptide was greater than 1.0, but nonsignificantly so. However, when analysis was confined to women with low absorption values, caseinphosphopeptide administration was associated with significantly better absorption of co-ingested calcium. Those findings suggest that caseinphosphopeptide supplementation is particularly useful, for persons with low basal absorptive performance.

The present study was performed to evaluate the role of central vasopressin in cardiovascular regulation. First, a novel vasopressin V1 antagonist (OPC21268) was injected intracerebroventricularly in conscious rats. In water-deprived animals, the mean arterial blood pressure (MABP) and heart rate were significantly decreased compared with euhydrated control rats. There was, however, no significant difference in the concentration of vasopressin in the perfusate of cerebrospinal fluid between groups. Second, vasopressin was intracerebroventricularly injected in male and female homozygous Brattleboro rats. The increase in MABP was greater in males than in females. These results suggest that central vasopressin is involved in blood pressure regulation in pathophysiological states.

The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting.Eligible patients were postmenopausal women with severe osteoporosis who were aged 70 years or older and had several risk factors for incident fractures. The primary endpoint was prevention of incident fractures, and the anti-fracture efficacy was evaluated in relation to the baseline serum 25(OH)D level.A total of 2164 patients were randomized to alendronate plus alfacalcidol (combination therapy) or alendronate alone (monotherapy). Although the overall difference in the incidence of vertebral fracture between the two groups was not significant, the combination therapy group had a significantly reduced risk of vertebral fractures after the first 6 months (HR, 0.53). In subgroup analyses, the combination therapy group was superior in the strata of number of prevalent vertebral fractures of ≥2 (HR, 0.51) and grade 3 of prevalent vertebral fractures (HR, 0.55). The rate of non-vertebral weight-bearing bone fractures was significantly lower in the combination therapy group than in the monotherapy group during the follow-up period (HR, 0.31). A lower baseline 25(OH)D level was associated with a higher incidence of non-vertebral weight-bearing bone fractures (HR, 3.42) despite alendronate use. Although one patient given the combination therapy had mild hypercalcemia, serious hypercalcemia and unknown adverse events were not encountered. Because of the limitations presented in this study, these results may not apply to female patients with longer than 2 years of treatments, and to male osteoporosis patients.The combination therapy was no more effective for overall vertebral fracture prevention. However, subgroup analysis has shown that it was more effective for fracture prevention in patients with severe vertebral deformity, multiple prevalent vertebral fractures, and for non-vertebral weight-bearing bone fracture prevention.

The ultimate aim of prevention and treatment of osteoporosis is the prevention of bone fractures. Since 80% of fractures can be explained by reductions in bone mass, not only is inhibition of reduction in bone mass extremely important but it is also useful as an index for the evaluation of preventive therapeutic effects. Bone mass is reduced with aging, but the degree of reduction varies. Bone mass generally reaches its peak level in the 30s and 40s and decreases thereafter. There is a group, the fast loser group, in which loss of bone mass is rapid after menopause with a correspondingly increased risk for developing osteoporosis. There is also a group in which the maximum bone mass shows low peak levels and this group can be considered to be at increased risk for osteoporosis. Since there are fast losers and normal losers, it is very important that fast losers be identified at an early stage so that preventative measures can be taken, since treatment is difficult once bone mass has gone below the fracture threshold level. Once fast losers have been identified, the next step is determining the best method of treatment. It is well known that osteoporosis is caused by an imbalance in bone metabolism, i.e., an uncoupling of bone resorption and formation. From the standpoint of bone metabolism, the disease can be divided into two types: the high turnover type and the low turnover type. In the high turnover type, the rates of both bone resorption and formation are accelerated. However, since bone resorption exceeds bone formation, this leads to a reduction in bone mass. In the other group, even though the rates of bone resorption and formation are low, the rate of bone resorption exceeds formation so the bone mass is reduced. Most cases of postmenopausal osteoporosis are of the high turnover type. Many cases of senile osteoporosis are of the low turnover type, and this is considered to be caused by the decreased activity of osteoblasts associated with aging. It is not clear whether or not the high or low turnover types represent different forms of the disease with different etiologies or simply represent different stages of the same disease, as classification of the disease into these two types from the standpoint of bone turnover is very important when determining the appropriate method of treatment. In conclusion, in the high turnover type, the most effective means of treatment is to suppress bone resorption by giving antiresorbers. However, in the low metabolic turnover type, drugs that increase the rate of bone formation are recommended.

The purpose of this study was to determine incidence and regional distribution of hip fracture throughout Japan. The incidence rate of hip fracture in Japan was estimated by a nationwide survey for departments of orthopedics of all hospitals with 200 beds or more and supplementary survey for all medical institutions in three prefectures.

The reference value of L2-4 bone mineral density (BMD) was calculated in Japanese population by using cross-calibration formulae among the different types of dual energy X-ray absorptiometry (DEXA) and dual photon absorptiometry (DPA). The scan data of lumbar spine were collected from 16 institutes equipped 3 types of DEXA and 3 types of DPA. After subtraction of inadequate scan data, a total of 1038 cases (376 males and 662 females) were accepted to be a representative “normal” population of Japanese. The L2-4 BMD values were adjusted to one equipment by using cross-calibration equations. There were significant decrease in L2-4 BMD in both sexes at age of seventies or more (9.5% decrease in males and 27.5% in females from the peak bone density). When the cut-off value of L2-4 BMD set to 0.8 g/cm2 (QDR), 0.88 (DPX) and 0.77 (XR), 80% of correct discrimination between “normal” and osteoporotics was achieved in the forties and the fifties. Therefore, these values can utilize to diagnose early bone loss. There was significant correlation between L2-4 BMD value and the total score of criteria for involutional osteoporosis. In summary, the BMD values obtained by cross-calibration in the different equipments might be acceptable for the reference value of Japanese population as well as for the detection of early bone loss, tentatively. Further investigations are currently undergoing.

Using a dual photon absorptiometer Dualomex HC-1 based on the scinticamera system utilizing153Gd, bone density of the lumbar vertebrae was measured to set up normative values for each group in both sexes along with fracture threshold.

Hyperhomocysteinemia is an independent risk factor for atherosclerotic disease. Because serum markers of inflammation and the metabolic syndrome are also associated with atherosclerotic disease and insulin resistance, we investigated whether plasma homocysteine (Hcy) levels were associated with serum markers of inflammation and factors of metabolic syndrome in 223 elderly patients with type 2 diabetes mellitus. The levels of plasma Hcy and serum interleukin-6 (IL-6), high-sensitivity C-reactive protein, and C-peptide were measured. The C677T mutation of methylenetetrahydrofolate reductase (MTHFR) gene was detected using the polymerase chain reaction-restriction fragment length polymorphism method. The number of abnormal metabolic factors (presence of diabetes, blood pressureor =130/85 mm Hg, triglyceridesor =150 mg/dL, high-density lipoprotein cholesterol35 mg/dL (men) or39 mg/dL (women), or body mass index25 kg/m 2 ) was assessed. Elevated plasma Hcy levels correlated significantly with serum IL-6 ( r = 0.25, P.001), C-peptide ( r = 0.22, P.01), and the number of abnormal metabolic factors ( r = 0.20, P.01), but not with C-reactive protein. Multiple linear regression analysis revealed that log-transformed IL-6, serum C-peptide, vitamin B12 , and creatinine were significant determinants of plasma Hcy levels. The correlation between Hcy and IL-6 levels was strongest in those with TT genotype of C677T MTHFR among 3 genotypes. The association between plasma Hcy and serum IL-6 levels supports the hypothesis that the activation of innate immunity is involved in the pathogenesis of arteriosclerosis in patients with diabetes mellitus who are homozygous for the TT genotype of C677T MTHFR.

To facilitate geriatric research on the roles of genetic polymorphisms of candidate genes, two databases were developed based on data obtained from autopsy examinations of elderly subjects: the geriatric autopsy database (GEAD) and the Japanese single nucleotide polymorphisms (SNP) database for geriatric research (JG-SNP) which is accessible on the Internet (http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html). The data for the GEAD were derived from 1074 consecutive autopsy cases (565 male and 509 female cases) with an average age of 80 years. The GEAD was installed on a stand-alone Windows 2000 server using Oracle 8i as the database application. The GEAD contains clinical diagnoses of 26 geriatric diseases, histories of smoking and alcohol consumption, pathological findings (720 items), severity of atherosclerosis, genetic polymorphism data, etc. On the JG-SNP website, case distribution corresponding to a specified SNP or disease can be searched or downloaded. Although there are several Internet-based SNP databases such as dbSNP, no databases are available at present on the web that contain both SNP data and phenotypic data. As autopsy studies can provide large amounts of accurate medical information, including the presence of undiagnosed diseases such as latent cancers, the GEAD is a unique and excellent database for research on genetic polymorphisms.