Hideo Yoneshima

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.

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.

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.

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.

Age-Specific Values and Cutoff Levels for the Diagnosis of Osteoporosis in Quantitative Ultrasound Measurements at the Calcaneus with SAHARA in Healthy Japanese Women: Japanese Population-Based Osteoporosis (JPOS) Study

To establish the reference values of the quantitative ultrasound (QUS) indices in healthy Japanese women and to propose a diagnostic criterion for osteoporosis by means of the QUS indices, 659 healthy women aged 20-79 years recruited from a larger cohort study (JPOS study), were examined for bone mass measurements by QUS at the calcaneus (SAHARA, Hologic Inc., USA) and by dual-energy X-ray absorptiometry at the spine, hip, and distal forearm. We presented 10-year age-specific mean values and T-scores of the QUS indices. The pattern of decrease in the T-score appeared to be linear in the QUS indices and total hip BMD but not in BMD at the spine. The T-score of the QUS of indices of the subjects in their 70s were significantly higher than that of BMD at the spine. The prevalence rates of osteoporosis in the subjects aged 50 and older diagnosed by QUS (8.7% for SOS, 10.7% for BUA) were similar to that diagnosed by total hip BMD (11.5%) and significantly lower than that by the spine BMD (36.1%) when the WHO criteria were applied. We performed receiver-operating characteristic analysis to set a cutoff level of the QUS indices for the diagnosis of osteoporosis to accurately identify the subjects diagnosed by either the spine or total hip BMD. The highest likelihood ratios for SOS and BUA were obtained at the cutoff levels of 1,517.7 m/sec (T-score: -1.58) with the sensitivity of 0.65 and the specificity of 0.65 and 59.5 dB/MHz (T-score: -1.52) with 0.66 and 0.69, respectively. The diagnostic accuracy of QUS indices for osteoporosis was not superior to that of age. However, the QUS indices showed a significant contribution to forming the diagnosis of osteoporosis independently of age and body size in multivariate diagnostic models developed by the logistic regression analysis. Therefore, the cutoff values presented in this study may be used as a tentative criterion until the cutoff levels for the QUS indices are set according to the fracture risk.

Biochemical markers of bone turnover may predict progression to osteoporosis in osteopenic women: the JPOS Cohort Study

We evaluated the value of bone turnover markers, including osteocalcin (OC) and bone-specific alkaline phosphatase in the serum, and type I collagen C-terminal telopeptide and free and total deoxypyridinoline (tDPD) in the urine of fasting patients, in an attempt to predict which osteopenic women [i.e., those with ≥70% and <80% of the young adult mean (YAM) bone mineral density (BMD)] would progress to the osteoporosis level of BMD (<70% of YAM). Of the 1153 women without defects in bone metabolism who completed the 3-year follow-up, 147, 161, and 144 women were judged by dual X-ray absorptiometry to be osteopenic from baseline measurements of BMD in the spine (LS), hip (TH), and distal radius (DR), respectively. Progression to the osteoporotic level of BMD was noted for 23.8%, 16.1%, and 12.5% of the subjects with osteopenia of the LS, TH, and DR, respectively, while most of them were in the lower half of the osteopenic level of BMD at baseline. Among the subjects in this lower-level osteopenia category, a significantly higher OC level was observed for the subjects with osteoporosis progression at the LS than those without. The subjects with progression at DR showed a significantly higher tDPD level. The association between OC level and disease progression remained unchanged after adjustments for age, body size, and BMD at baseline. The subjects in the upper one-third category of OC levels showed a 6.4 fold greater risk of progression at LS (95% confidence interval, 1.8–23.1) compared with those in the lower one-third category after the adjustments for age, body size, and BMD at baseline. Receiver operating characteristics analysis showed that the area under the curve was 0.716 for the OC level in the prediction of osteoporosis progression at LS. The levels of OC and tDPD may be useful in predicting which osteopenic women will progress to osteoporosis.

Effects of the Cdx-2 Polymorphism of the Vitamin D Receptor Gene and Lifestyle Factors on Bone Mineral Density in a Representative Sample of Japanese Women: The Japanese Population-based Osteoporosis (JPOS) Study

Using a large-scale representative sample of the Japanese female population, we examined the effects of a single nucleotide polymorphism within a binding site of Cdx-2 in the promoter region of the vitamin D receptor gene on bone mineral density (BMD), and the interactions between this polymorphism and lifestyle factors on BMD. Fifty women were randomly selected from each of the 5-year age-stratified populations (15–79 years) in each of three chosen municipalities as a part of the Japanese Population-based Osteoporosis Study. BMD at the lumbar spine, hip, and distal forearm was measured using dual-energy X-ray absorptiometry at baseline and again in a follow-up study conducted 3 years later. Information on lifestyle factors was collected in a questionnaire and followed up in interviews. The G-to-A polymorphism within the Cdx-2 binding site was determined by a TaqMan allelic discrimination assay. At baseline, 1,340 women were analyzed. The baseline BMD in the ultradistal forearm in premenopausal women with the GG genotype was significantly lower than in those with other genotypes. There was no association between the Cdx-2 genotype and the change in BMD at any of the skeletal sites. We found significant associations between daily milk consumption and baseline BMD at some skeletal sites but only in subjects with the GG genotype. In conclusion, the Cdx-2 polymorphism alone did not have a substantial effect on BMD in Japanese women. However, this polymorphism might have some effect in women with low calcium intake.

Ultrasound bone densitometry of the calcaneus, determined with Sahara, in healthy Japanese adolescents: Japanese Population-based Osteoporosis (JPOS) Study

To establish the reference values for quantitative ultrasound (QUS) indices (speed of sound [SOS]), and broadband ultrasonic attenuation [BUA]) in healthy Japanese adolescents, and to evaluate the effects of age and body size on QUS in comparison with their effects on bone mineral density (BMD), 632 healthy adolescents aged 12 through 17 years recruited from a larger cohort study (Japanese Population-based Osteoporosis [JPOS] Study), were examined in terms of bone mass measurements by QUS at the calcaneus (Sahara; Hologic) and by dual-energy X-ray absorptiometry at the distal one-third radius and ultradistal forearm. We present sex- and age-specific mean values of the QUS and BMD indices. BMD increased significantly up to 17 years of age in males and up to 16 years in females. However, the age-related change in the QUS indices in males was not as clear as that seen for BMD and no age-related change in the QUS indices was observed in females. Significant positive correlation coefficients between BMD and body size were observed in both sexes even after adjusting for the effect of age. SOS showed no correlation with body size and BUA showed a positive but weak correlation with body size in both sexes. Thus, the relationships of age and body size to BMD and QUS were different from each other, even though the QUS indices had significant positive correlations with BMD, allowing for the effect of age.

Reference Data of Forearm Bone Mineral Density in Healthy Japanese Male and Female Subjects in the Second Decade Based on Calendar Age and Puberty Onset: Japanese Population based Osteoporosis (JPOS) Study

Abstract: Osteoporosis is a major public health problem in Japan. The second decade is an important period in which to attain a high peak bone mass. However, normal values of forearm bone mineral density (BMD) are not well known in children and adolescents. BMD at one-third of forearm length proximal to the ulnar end plate (BMD1/3) and the ultradistal forearm (BMDud) was measured using dual-energy X-ray absorptiometry (DXA) in 1207 (631 males, 576 females) Japanese subjects aged 9–18 years. Puberty onset was assessed by questionnaire, by obtaining the time that pubic hair appeared in males and the time that menstruation started in females. BMD1/3 and BMDud increased steadily with age in males. In relation to puberty development, these parameters also increased after puberty onset although the increase in BMD1/3 was not statistically significant after the fifth year from puberty onset and that of BMDud was not significant after the sixth year from puberty onset. BMD1/3 and BMDud increased with age and then plateaued in females. The increase in BMD1/3 was not statistically significant after 15–16 years of age and that of BMDud was not significant after 13–14 years of age. In relation to puberty development, the increase in BMD1/3 leveled out after the fourth year from puberty onset and that of BMDud also plateaued after the third year from puberty onset. We provide reference values of forearm BMD in Japanese children and adolescents by DXA according to calendar age and puberty development. Peak bone mass of the forearm may be in the late second decade in Japanese females.

Peroxisome proliferator-activated receptor gamma polymorphism is related to peak bone mass: the JPOS study

SummaryWe analyzed 1,217 women to examine the effect of peroxisome proliferator-activated receptors gamma (PPARγ) C161 → T on bone status. Among 664 premenopausal women, the C161 → T is associated with low bone mineral density (BMD) at the total hip and femoral neck. Moreover, the odds ratio for osteopenia or osteoporosis at the femoral neck was 1.98 for premenopausal CT/TT genotypes.IntroductionThe impact of PPARγ on BMD has not been conclusively established. We examined if PPARγ C161T polymorphism is associated with BMD and its change.MethodsWe conducted a baseline survey in 1996 and a 10-year follow-up survey, Japanese Population-based Osteoporosis Study, with a sample population representative of Japanese women. Of these, 1,217 participants in the 1996 survey were analyzed cross-sectionally, while longitudinal analysis was performed on 563 women. A P value  < 0.0042 (=0.05/12 for three menstrual statuses and four skeletal sites) was considered statistically significant after Bonferroni correction in multiple testing for cross-sectional analysis.ResultsThe total hip and femoral neck BMDs were significantly higher for CC genotype than for CT/TT genotypes among 664 premenopausal women (P = 0.0020, P = 0.0022, respectively). Compared to the CC genotype, the odds ratio for osteopenia or osteoporosis (T-scores below −1) at the femoral neck was 1.98 for premenopausal CT/TT genotypes with statistical significance (P = 0.0041). Change of BMD at either skeletal site during the follow-up period was not significantly different for either menstrual status.ConclusionsWe conclude that the PPARγ C161T is associated with low peak bone mass.