Itsuo Gorai

Diagnostic criteria for primary osteoporosis: year 2012 revision

In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.

Diagnostic criteria of primary osteoporosis

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.

The Predictive Value of Biochemical Markers of Bone Turnover for Bone Mineral Density in Postmenopausal Japanese Women

To examine the predictive value of biochemical markers of bone turnover for bone loss pre‐ and postmenopausally, we measured two markers of bone formation, bone‐specific alkaline phosphatase (BALP) and intact osteocalcin (OC); four markers of bone resorption, urinary cross‐linked N‐telopeptides of type I collagen (NTx), type I collagen C‐telopeptide breakdown products (CTx), hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP); serum OC N‐terminal (OC‐N); and two serum cytokines, soluble interleukin‐6 receptor (sIL‐6R) and IL‐1r antagonist at baseline and 1 year, as well as lumbar spine bone mineral density (BMD) at baseline and 1, 2, 3, 4, and 5 years after trial in 82 premenopausal (44.8 ± 5.4 years old) and 325 postmenopausal (60.2 ± 6.1 years old) healthy Japanese women. In premenopausal women, stratification of the baseline value of each biochemical marker into quartiles did not cause any significant difference in the change in BMD. Stratification of the NTx baseline value in postmenopausal women showed significant differences in rate of bone loss to the first year among those subjects with each quartile (Q1 [0.28 ± 0.28%], Q2 [−0.32 ± 0.34%], Q3 [−1.50 ± 0.31%], and Q4 [−2.43 ± 0.35%]) except for the difference between Q1 and Q2. The predictive value of NTx for BMD was greater in early postmenopausal women within 5 years after menopause than in late postmenopausal women with more than 5 years since menopause (YSM). Quartile analysis of the other biochemical markers and serum cytokines did not show any significant capacity for differentiating between bone loss rates. Moreover, when the changes in the lumbar spine BMD to the second and third years were stratified into quartiles by the baseline NTx, the ratios of bone loss to the second and the third years were significantly higher in those women with higher NTx (Q4; −3.15 ± 0.56% and −4.06 ± 0.57%, respectively) than in those with lower NTx (Q1; −0.74 ± 0.44% and −1.03 ± 0.51%, respectively). In conclusion, baseline urinary NTx was the most sensitive predictor of bone loss in the lumbar spine after 1, 2, and 3 years. Markers of bone resorption can be used clinically to predict future BMD in postmenopausal women.

Uterine carcinosarcoma is derived from a single stem cell: An in vitro study

Expression of intermediate filaments (IFs) has been suggested to be a reliable marker for differentiating epithelial and non‐epithelial tumors. Moreover, the c‐erbB‐2 and p53 genes are considered to be involved relatively early in the process of human carcinogenesis. In order to elucidate the origin of uterine carcinosarcomas, we analyzed IF, c‐erbB‐2 and p53 expression in and the ultrastructural characteristics of clones derived from a human uterine‐carcinosarcoma cell line, EMTOKA. The expression of IFs and other proteins in the EMTOKA clones was identical to that in the EMTOKA cell line. It and its 7 clones all expressed cytokeratins 8, 17, 18 and 19, vimentin, epithelial membrane antigen, S‐100, myoglobin, type‐II collagen, α‐smooth‐muscle actin, placental alkaline phosphatase and epidermal‐growth‐factor receptor. The c‐erbB‐2 and p53 expression levels of all the cell types of the EMTOKA cell line and its clones were the same. Interestingly, an ultrastructural study showed that the EMTOKA cell line and its clones at early and late passages possessed the characteristics of epithelial cell types without either transitional forms between the epithelial and stromal components or differentiation into sarcomatous components. The results of this study lend particular support to the combination tumor hypothesis that a precursor (stem) cell gives rise both to epithelial and to mesenchymal components during the histogenesis of uterine carcinosarcoma, the epithelial component of which appears to be dominant, suggesting that the established cell lines derived from a common stem cell. Int. J. Cancer 72:821–827, 1997.

Differential Gene Expression of TGF-β Isoforms and TGF-β Receptors During the First Trimester of Pregnancy at the Human Maternal-Fetal Interface

PROBLEM: The transforming growth factor (TGF)‐βs are multifunctional cytokines, and they play a role in the controlled growth of trophoblasts. Moreover they are thought to be important in maternal‐fetal interaction during early gestation.

Early and Late Postmenopausal Bone Loss is Associated with BsmI Vitamin D Receptor Gene Polymorphism in Japanese Women

Abstract. To determine whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) and bone loss in the Japanese population, VDR BsmI RFLPs were analyzed in 191 postmenopausal Japanese women by comparing B allele and b allele DNA sequences, and a point mutation was confirmed. We examined VDR BsmI restriction fragment length polymorphism (RFLP) with an amplification refractory mutation system (ARMS) using this point of mutation. The frequency of VDR BsmI alleles in the Japanese population was significantly different from that in whites. The bb genotype was identified in 79.6%, of the subjects, the Bb genotype in 19.3%, and the BB genotype was in only 1.1%. We find no significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods, serial measurements of vertebral BMD revealed that subjects with the Bb genotype lost BMD faster than those with the bb genotype (P= 0.001). We conclude that there is a significant relationship between RFLPs of BsmI VDR and the annual rates of bone loss during early and late postmenopausal periods in the Japanese population.

Specific Changes of Urinary Excretion of Cross-Linked N-Telopeptides of Type I Collagen in Pre- and Postmenopausal Women: Correlation with Other Markers of Bone Turnover

Abstract. Urinary excretion of cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a specific marker of bone resorption [18]. We assessed a new immunoassay for NTx as an indicator of changes in bone resorption caused by spontaneous menopause and compared cross-sectionally the levels of urinary NTx, hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), hydroxyproline (OH-Pr), other serum biochemical indices, and lumbar spine and proximal femur bone mineral density (BMD). Eighty-one Japanese women aged 22–77 participated in this study; 36 were premenopausal and 45 were postmenopausal. Urinary HP, LP, and NTx stayed at low levels in the premenopausal period and rose 21%, 30%, and 67% in the postmenopausal period, respectively. The rise in LP and NTx was statistically significant (P < 0.01), suggesting that NTx is mostly released from bone matrix when bone resorption is accelerated. When premenopausal women were divided into two age groups and postmenopausal women were divided into two groups according to years since menopause (YSM) there were significant differences in LP and NTx between women <4 YSM and women aged <40 and those women aged 41+ (P < 0.01 and P < 0.05, respectively). A significant 110% increase in urinary NTx and a 48% increase in urinary LP were observed in postmenopausal women compared with age-matched premenopausal women aged 45–55. All biochemical markers other than serum PTH correlated significantly with each other (r = 0.243–0.858, P < 0.05–0.0001). Urinary NTx inversely correlated with lumbar spine BMD. When postmenopausal women were divided into three groups, the correlation between bone resorption and formation markers in women 0-1 YSM was greater than in women 2–10 YSM and in women 11 + YSM, indicating that resorption and formation are coupled at the early postmenopausal period. We conclude that urinary NTx is responsive to changes in bone metabolism caused by estrogen deficiency and may be a more sensitive and specific marker than HP, LP, or OH-Pr in the early postmenopausal years.

Urinary biochemical markers for bone resorption during the menstrual cycle

In order to analyze the effects of serum ovarian steroid hormones on bone metabolism during the menstrual cycle, we have measured urinary levels of type I collagen cross-linked N-telopeptide (NTx), hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), and hydroxyproline (OH-Pr) in nine healthy Japanese women, aged 22–43 years, with normal ovarian function. The cycles were synchronized by serum LH peaks, and follicular and luteal periods were normalized by lengths. Serum gonadotropins and ovarian sex steroids showed significantly different cyclic variations during the menstrual periods. Urinary NTx remained unchanged during the early follicular period, showed a rise during the mid- and late follicular period, and a fall during the mid- and late luteal periods. There were significant differences in NTx levels between early follicular period and midfollicular period (P<0.01), or late follicular period (P<0.05), and between early luteal period and late luteal period (P<0.05). The levels of HP and LP showed a rise during the early and midfollicular periods and a fall during the midluteal period. The correlation of NTx with urinary OH-Pr was better than with urinary HP or LP (r=0.731 versus r=0.449 or r=0.634). This variation suggests that cyclic changes in serum ovarian sex steroids might modulate bone resorption markers during the menstrual cycle.

Clinical Trials Express: Fracture Risk Reduction With Denosumab in Japanese Postmenopausal Women and Men With Osteoporosis: Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT)

Context: Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis. Objective: The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo. Design and Setting: A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted. Patients: Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures. Intervention: Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D. Main Outcome Measure: The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo. Results: Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194–0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study. Conclusion: These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis.

Guidelines on the use of biochemical markers of bone turnover in osteoporosis (2001)

1 Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan 2 Department of Orthopedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan 3 Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, Japan 4 Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan 5 Department of Obstetrics and Gynecology, Yokohama City University Medical School, Yokohama, Japan 6Research Institute and Practice for Involutional Diseases, Nagano, Japan 7 Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Japan 8 Endocrinology Section, Tokyo Metropolitan Geriatric Hospital, Tokyo Japan 9 Department of Geriatric Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan 10 R & D Department, Mitsubishi Kagaku BCL, Tokyo, Japan