Masayuki Iki

Bone Mineral Density of the Spine, Hip and Distal Forearm in Representative Samples of the Japanese Female Population: Japanese Population-Based Osteoporosis (JPOS) Study

Abstract: Low bone mineral density (BMD) is one of the most important elements for the diagnosis of osteoporosis and screening people with higher risk of fractures. To establish the criterion value of BMD for the diagnosis of osteoporosis and to estimate the prevalence rate of osteoporosis in Japanese women, we performed a Japanese population-based osteoporosis (JPOS) study. The subjects were 4550 women aged 15 through 79 years randomly selected from seven municipalities throughout Japan. The sample size was determined to ensure that the observed mean BMD would remain within 2.5% from the real value with a probability of 0.95 in each of the 5-year age groups. The study comprised bone mass measurements by dual-energy X-ray absorptiometry at the spine (L2–4), hip and distal forearm, body size measurements and detailed interviews on medical and gynecologic history. After excluding those subjects with apparent or suggested abnormalities affecting bone mass from 3985 women (87.6%) who completed the study, 3465 women remained and served as the subjects. We present 5-year age-specific mean values of BMD and cut-off values for the diagnosis of osteoporosis according to World Health Organization (WHO) and the Japanese Society of Bone and Mineral Research (JSBMR) criteria. The cut-off levels at the spine and the distal radius proposed in this study were similar to those proposed by the JSBMR but the cut-off level at the femoral neck in this study was 4.7% higher than that of the JSBMR. The prevalence rates of osteoporosis according to WHO criteria in the present subjects aged 50 through 79 years were calculated as 38.0% at the spine, 11.6% at the femoral neck and 56.8% at the distal one-third site of the radius, and those in the Japanese female population of the same age were estimated to be 35.1%, 9.4% and 51.2%, respectively. A fivefold difference was observed among the prevalence rates at different skeletal sites, which suggests that the different definitions of osteoporosis should be established for the different skeletal sites. The prevalence rate diagnosed at the femoral neck seemed to be lower in the present study than those reported for Caucasians. This might account for a lower incidence rate of hip fracture in Japanese women.

A Meta‐Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX

Trabecular bone score (TBS) is a gray‐level textural index of bone microarchitecture derived from lumbar spine dual‐energy X‐ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)‐independent predictor of fracture risk. The objective of this meta‐analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual‐level data from 17,809 men and women in 14 prospective population‐based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow‐up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35–1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10‐year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24–1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65–1.87 versus 1.70, 95% CI 1.60–1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.

Trabecular bone score (TBS) predicts vertebral fractures in Japanese women over 10 years independently of bone density and prevalent vertebral deformity: the Japanese Population-Based Osteoporosis (JPOS) cohort study.

Bone strength is predominantly determined by bone density, but bone microarchitecture also plays an important role. We examined whether trabecular bone score (TBS) predicts the risk of vertebral fractures in a Japanese female cohort. Of 1950 randomly selected women aged 15 to 79 years, we analyzed data from 665 women aged 50 years and older, who completed the baseline study and at least one follow‐up survey over 10 years, and who had no conditions affecting bone metabolism. Each survey included spinal imaging by dual‐energy X‐ray absorptiometry (DXA) for vertebral fracture assessment and spine areal bone mineral density (aBMD) measurement. TBS was obtained from spine DXA scans archived in the baseline study. Incident vertebral fracture was determined when vertebral height was reduced by 20% or more and satisfied McCloskey‐Kanis criteria or Genants grade 2 fracture at follow‐up. Among eligible women (mean age 64.1 ± 8.1 years), 92 suffered incident vertebral fractures (16.7/103 person‐years). These women were older with lower aBMD and TBS values relative to those without fractures. The unadjusted odds ratio of vertebral fractures for one standard deviation decrease in TBS was 1.98 (95% confidence interval [CI] 1.56, 2.51) and remained significant (1.64, 95% CI 1.25, 2.15) after adjusting for aBMD. The area under the receiver operating characteristic curve of TBS and aBMD combined was 0.700 for vertebral fracture prediction and was not significantly greater than that of aBMD alone (0.673). However, reclassification improvement measures indicated that TBS and aBMD combined significantly improved risk prediction accuracy compared with aBMD alone. Further inclusion of age and prevalent vertebral deformity in the model improved vertebral fracture prediction, and TBS remained significant in the model. Thus, lower TBS was associated with higher risk of vertebral fracture over 10 years independently of aBMD and clinical risk factors including prevalent vertebral deformity. TBS could effectively improve fracture risk assessment in clinical settings.

Breastfeeding and the prevalence of symptoms of allergic disorders in Japanese adolescents

Background Environmental factors acting early in life are key determinants of the incidence of allergic disease. Whether breastfeeding is protective against allergic disorders remains controversial.

A Novel Polymorphism in the Promoter Region for the Human Osteocalcin Gene: The Possibility of a Correlation with Bone Mineral Density in Postmenopausal Japanese Women

We present a polymorphism of the human osteocalcin gene (also known as BGP, for bone Gla protein) due to a 1 base pair (bp) substitution from cytosine to thymine at position 298 nucleotides (nt), which is at position 198 nt upstream from the BGP exon 1. This mutation was detected by single‐strand conformation polymorphism analysis after polymerase chain reaction for the osteocalcin gene fragment (326 bp) and sequencing analysis. The cytosine/thymine polymorphism can be defined by restriction fragment length polymorphism analysis using a modified primer pair and the restriction endonuclease HindIII. The osteocalcin genotype was determined in 160 postmenopausal Japanese women (age 48–80 years). Osteocalcin alleles were designated according to the absence (H) or presence (h) of the HindIII restriction site. There were 12 HH, 49 Hh, and 99 hh individuals, and the allele frequencies were 22.8% for H and 77.2% for h. To determine if genetic variation influences bone mineral density (BMD) and thus can be a determinant of susceptibility to osteoporosis in older women, we examined the association of BMD with the osteocalcin genotypes found in the present study. The subjects with genotype HH had the smallest BMD and those with hh had the greatest BMD among subjects, but these differences did not reach statistical significance. The HindIII genotype showed a significant effect on the prevalence of osteopenia in the subjects, that is, women with genotype HH had a 5.74 times greater risk for osteopenia (p < 0.05) and those with genotype Hh had a 1.59 times greater risk than women with genotype hh. We identified the osteocalcin gene polymorphism, detected with the HindIII genotype, which was suggested to influence bone density and is a possible genetic marker for bone metabolism.

Reference database of biochemical markers of bone turnover for the Japanese female population. Japanese Population-based Osteoporosis (JPOS) Study

The present study was conducted as a part of the Japanese Population-based Osteoporosis (JPOS) Study to establish reference values on the biochemical markers of bone turnover in the general Japanese female population over an applicable age range. The study recruited 3250 women aged 15–79 years, randomly selected from five municipalities throughout Japan, and obtained measurements of serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP); free and total forms of immunoreactive deoxypyridinoline, free pyridinolines and type I collagen cross-linked C-terminal telopeptide (CTx) in urine; serum intact parathyroid hormone (PTH) and 1,25 dihydroxy vitamin D (1,25 (OH)2D); and bone density at the spine, hip and distal forearm. After excluding subjects with apparent or suggested abnormalities affecting bone mass, 2535 (78%) subjects were further analyzed. The authors presented 5-year age-specific mean values of the markers and mean marker levels derived from women aged 30–44 years with normal bone density as a healthy young adult reference. Values of the markers decreased with increasing age before the age of 40, increased steeply among subjects in their 50s, and remained elevated in the elderly. Serum calcium, phosphorus, PTH and 1,25 (OH)2D levels were higher in postmenopausal women than in premenopausal women. However, 1,25 (OH)2D was lower among early postmenopausal subjects. The levels of OC, BAP, CTx, PTH and 1,25(OH)2D were significantly greater for women with osteoporosis than for those without. The diagnostic value of the markers was limited as the sensitivity and specificity ranged from 55% to 60%. These findings will aid health professionals in the correct assessment of bone turnover status in Japanese women over a wide range of age.

Ecological association of water hardness with prevalence of childhood atopic dermatitis in a Japanese urban area.

The prevalence of symptoms of atopic eczema among Japanese children aged 6-7 years is the second highest in 56 countries. Reasons for such a high prevalence are unknown. This ecological study examined whether the positive association of water hardness with atopic dermatitis among British primary-school children also exists in Japan. Study subjects were 458,284 of 489,725 children, aged 6-12 years, in 1,016 public elementary schools in Osaka Prefecture with 44 municipalities. The study used data on water hardness and chlorine content of the water supply; prevalence of atopic dermatitis diagnosed by physicians and episodes of wheezing reported by the parents; and potential confounding factors by socioeconomic and health care status per municipality. The prevalence of atopic eczema was significantly higher in the highest water hardness category than that in the lowest (24.4% [n=2,288/9,362] and 22.9% [n=77,408/33,8267], respectively; adjusted odds ratio 1.12, 95% confidence interval 1.06-1.18; P<0.0001 for trend). A significant and slightly J-shaped relationship between chlorine content of the water supply and prevalence of atopic dermatitis was observed after adjustment for confounding factors. There were no apparent associations of water hardness and chlorine content of the water supply with prevalence of wheeze. Water hardness may increase the risk of atopic dermatitis among elementary-school children in Japan, as well as in the United Kingdom.

Age, menopause, bone turnover markers and lumbar bone loss in healthy Japanese women

The change in lumbar vertebral bone mineral density (BMD) during a 2-year study period was examined in 167 healthy middle-aged and elderly Japanese women with reference to age, menopausal status and bone turnover markers at baseline. The perimenopausal and postmenopausal groups of the subjects showed a significant loss of BMD during the study period but the premenopausal women did not. The annual percent decrease of BMD (delta BMD) in the perimenopausal women (-2.40% in average) was significantly greater than that in either of the premenopausal (-0.01%) or over-all postmenopausal women (-0.85%). The subjects who had been postmenopausal for less than 10 years showed a significant bone loss. delta BMD in the postmenopausal women became less marked as the postmenopausal duration increased. The bone loss was accelerated for about 10 years after menopause. The pattern and magnitude of bone loss of Japanese women seemed to be similar to those of Caucasian women. The regression equation for delta BMD based on the bone turnover markers at baseline was shown to be significant in the postmenopausal women and the serum level of bone-specific alkaline phosphatase isoenzyme had a significant relation to delta BMD. However, this equation accounted for only 17.3% of the total variance of delta BMD and, hence, its validity was not sufficiently high for the prediction of bone loss in clinical settings.

Biochemical markers of bone turnover predict bone loss in perimenopausal women but not in postmenopausal women-the Japanese Population-based Osteoporosis (JPOS) Cohort Study

IntroductionThe predictive value of biochemical markers of bone turnover for subsequent change in bone density in a population sample of healthy women with a wide range of ages has not been fully established.MethodsWe followed 1,283 women aged 15–79 years at baseline selected randomly from the inhabitants of three areas in Japan for 6 years, and examined 1,130 subjects with no disease or administration of drugs affecting bone metabolism. The annual change in bone density at the spine, total hip, and distal one third of the radius was determined during the follow-up period by dual x-ray absorptiometry and was compared among the groups using different levels of biochemical markers at baseline, including serum osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP), free and total (tDPD) forms of immunoreactive deoxypyridinoline, and type I collagen crosslinked C-terminal telopeptide (CTX) in urine.ResultsPremenopausal women aged 45 years or older with elevated levels of OC, bone ALP, CTX, or tDPD showed significantly greater bone loss at most skeletal sites during the follow-up period than those with lower levels, after adjustment for the effects of age, height, weight, dietary calcium intake, regular exercise, and current smoking. The greatest coefficient of determination of the model was observed in the association between CTX and bone loss at the hip during the first 3 years of follow-up (42.8%). These subjects were pooled with perimenopausal women at baseline, and those who still menstruated at follow-up in this pooled group showed significant but more modest associations, whereas those who entered menopause during the follow-up period showed clear associations. However, early postmenopausal women with less than 5 or 10 years since menopause showed an association that was limited mostly to the distal radius, and other postmenopausal groups had virtually no association.ConclusionBiochemical markers of bone turnover may predict bone loss in women undergoing menopausal transition but may not predict bone loss in postmenopausal women.

Cut-off Values of Body Mass Index, Waist Circumference, and Waist-to-Height Ratio to Identify Excess Abdominal Fat: Population-Based Screening of Japanese Schoolchildren

Background School-based screening and prevention programs for adiposity generally target school children in grades 4 and 6 (age 9–11 years). The aims of this study were to evaluate the validity of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) in identifying abdominal adiposity in fifth-grade Japanese school children and to determine optimal cut-off values for anthropometric measures. Methods The target population was fifth-grade school children enrolled in 2 schools in Shizuoka, Japan between 2008 and 2010; 422 of the 466 children participated in the present study. Abdominal adiposity was defined as percent trunk fat in the 95th percentile or higher, as determined by dual-energy x-ray absorptiometry (DXA). We analyzed the validity of BMI, WC, and WHtR using receiver operating characteristic (ROC) curve analysis. The Youden index was used to determine cut-off values of BMI, WC, and WHtR that identify excess abdominal fat. Results Optimal cut-off values to identify abdominal adiposity were 20.8 kg/m2 (BMI), 76.5 cm (WC), and 0.519 (WHtR) for boys, and 19.6 kg/m2 (BMI), 73.0 cm (WC), and 0.499 (WHtR) for girls. Areas under the ROC curve were 0.983 (BMI), 0.987 (WC), and 0.981 (WHtR) for boys, and 0.981 (BMI), 0986 (WC), and 0.992 (WHtR) for girls. Conclusions BMI, WC, and WHtR successfully identified a high proportion of children with excess abdominal fat as measured by DXA, demonstrating that these measures are useful indices for school screening.