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The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p

This study examined whether the global clinical data for bazedoxifene could be extrapolated to a Japanese population by evaluating the results of a phase 2 study in postmenopausal Japanese women with osteoporosis as compared to those of a pivotal, phase 3 study. The efficacy of bazedoxifene 20 and 40 mg versus placebo on lumbar spine bone mineral density (BMD), bone turnover markers, lipid profile, incidence of fractures, and safety parameters was compared between the Japanese phase 2 study (N = 429) and the global phase 3 study (N = 7,492) during a 2-year period. In the primary population for assessment of bridging, differences in the mean percent change from baseline in lumbar spine BMD at 2 years relative to placebo were greater for women treated with bazedoxifene 20 and 40 mg in the phase 2 study than in the phase 3 study. BMD changes in the bazedoxifene groups were confirmed to be similar between the phase 2 study population and a subset of the phase 3 study population with similar baseline characteristics. The effects of bazedoxifene on incidence of fractures, bone turnover markers, and lipid metabolism were similar between studies. There were no major differences in safety parameters between studies. The greater improvement in lumbar spine BMD and similar results in bone turnover markers, fracture incidence, and safety profile observed with bazedoxifene in the phase 2 study compared with the phase 3 study confirmed the feasibility of extrapolating the global clinical data to a Japanese population.

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.

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.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K

This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (−0.65%, p

The aim of osteoporosis treatment is to prevent future fractures. Although concurrent treatment has been used very frequently for osteoporosis in clinical practice, there are no data on accurate and verified effectiveness of concurrent treatment for fracture prevention in patients with osteoporosis. To clarify the clinical usefulness of concurrent treatment, the Japan Osteoporosis Society has authorized the establishment of the A-TOP (Adequate Treatment of Osteoporosis) research group. The objective of this research is to establish a design for a clinical trial to prove whether concurrent treatment using both alfacalcidol (1-alpha-hydroxycholecalciferol) and alendronate is more effective as compared to treatment using alendronate alone in terms of fracture prevention. The present study was named JOINT (Japanese Osteoporosis Intervention Trial) and is based on a method using national, prospective, randomized, open-labeled, blinded endpoints focusing on postmenopausal osteoporosis with a high risk for fracture. The patients were mainly selected by practitioners and allocated randomly by a central registration system into two groups, of which one received 5 mg/day of alendronate alone, and the other received 1 μg/day of 1-alpha-hydroxycholecalciferol (alfacalcidol) in addition to the alendronate. The endpoints focused primarily on fracture prevention, and the patients' quality of life (QOL) and change in body height, as well as adherence and the adverse events of the treatments were evaluated secondarily. To obtain sufficient statistical power in the events during a 2-year observation period, the patients who are expected to have higher risk were selected to participate in this study, and it was decided that the final plan would involve 890 patients per group (two-sided alpha = 0.05, power = 0.8). Data collection began in November 2003. Correspondence regarding the registration of the investigator and the progress of the study was conducted through a web system from the Public Health Research Foundation to practitioners.

This 2-year study compared 0.5 and 1.0 mg oral estradiol (E(2)), with or without levonorgestrel (LNG), for the treatment of postmenopausal osteoporosis in Japanese women.Japanese women with osteoporosis after natural menopause or bilateral oophorectomy were randomized to receive E(2) 0.5 or 1.0 mg/day with LNG 40 microg as required, or placebo, for 52 weeks. Women treated with E(2) in the first year continued therapy at the same doses in the second year. Efficacy, safety and pharmacokinetics were assessed.There were 73 women randomized to E(2) 0.5 mg, 157 to E(2) 1.0 mg and 79 to placebo. Lumbar bone mineral density at 52 weeks increased significantly more with E(2) 1.0 mg (p0.001) and 0.5 mg (p0.001) than with placebo (no change). After 2 years, a 10% increase in bone mineral density with E(2) 1.0 mg was significantly greater than with E(2) 0.5 mg (8%; p = 0.008). E(2) was associated with an acceptable safety and tolerability profile, with slightly more adverse events with E(2) 1.0 than 0.5 mg. Serum E(2) concentration increased in a dose-dependent manner.This study showed that E(2), at both 1.0 mg and 0.5 mg doses, was effective in increasing bone mineral density with an acceptable safety and tolerability profile in Japanese postmenopausal women with osteoporosis but that the bone mineral density response was higher with the 1.0 mg dose.

Patients who are diagnosed with osteoporosis and beginning treatment often discontinue their osteoporosis medication relatively early after the start of treatment because of their poor recognition of fracture risk and the asymptomatic nature of osteoporosis. In this study we aimed to assess adherence to treatment with 1 microg alfacalcidol (D), 60 mg raloxifene (R) or a combination of both (D + R) for 1 year in postmenopausal Japanese women with osteoporosis or osteopenia. We defined persistence of D and R as continuing to take tablets for more than 7 of any 14 days immediately before the 1-year visit. A total of 137 subjects aged 49-81 years [64.9 +/- 7.0 years, 16.0 +/- 12.7 years since menopause (YSM)] were randomly assigned to each treatment group. The proportions persisting with each treatment group at 1 year were 61.4, 65.3, 55.1% for D, R and D + R groups, respectively whereas the compliance to each therapy as judged by the medical possession ratio (MPR) at 1 year were 77.5, 93.8, 78.4%, respectively. There were no significant differences in persistence, compliance and the number of subjects who discontinued treatment due to adverse events among each group. We found significant inverse correlations in percent changes at 1 year between compliance and serum BAP in R and D + R groups or urinary (u-) CTX in the R group. The changes in the level of serum BAP and u-CTX were significantly higher in high-compliance patients (MPR > 80%) treated with raloxifene alone or concomitantly with alfacalcidol compared to those in low-compliance patients.

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 Mullerian ducts are strongly influenced by natural estrogen, estradiol (E2) and diethylstilbestrol (DES) in their development. We screened E2 and DES responsive genes using a microarray analysis in human primitive Mullerian duct cell line, EMTOKA cells expressed estrogen receptor (ER) beta. c-myc oncogene and other target genes expression was detected in cells treated by high-dose DES, but ER antagonist ICI 182,780 could not prevent c-myc induction above. Results of our present study suggested the presence of ER independent pathway in oncogenes induction process by high-dose DES treatment in a human primitive Mullerian duct cell line.

The target to treat osteoporosis is prevention for future fractures. After the evaluation of cathepsin K inhibitors (CKIs) which was developed as antresorptive agents, there is evidence that these agents also possess anabolic activity, suggesting that CKIs differ from so called antiresorptive agents such as bisphosphonates and denosumab. The classification of agents for treatment of osteoporosis has been changed. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) and Atypical femoral fractures (AFFs) have been the problems when the therapy continues relatively for a long period. However, there is no clear guidance on when fracture risk has been reduced to an acceptably low level. As a consequence, some patients at low risk for fracture may be treated for longer than necessary, whereas others at high risk for fracture may have treatment stopped when they might benefit from continuation of the same treatment or a change to a more potent therapeutic agent. Therefore, a "treat-to-target" strategy for the management of patients with osteoporosis has been developed to describe the potential clinical utility of evaluating changes bone density and bone turnover markers, and events of fractures.

A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile.

In spite of the benefits of bone mass measurement by dual-energy X-ray absorptiometry (DXA), the use of DXA has limitations. It is unable to assess a true bone density, and cannot discriminate between the trabecular and cortical bone compartments. Ultradistal radius bone density was measured using peripheral quantitative computed tomography (pQCT) to determine reference values for total bone density (BD), trabecular bone density (TBD), polar strength strain index (pSSI), total bone mineral content (BC), trabecular bone mineral content (TBC), cortical bone density (CBD), cortical bone mineral content (CBC) and polar cross-sectional moment of inertia (pCSMI) in the Japanese female population, and to ascertain the cut-off values of the measured indicators that could most efficiently discriminate osteoporotic subjects with vertebral fractures. A total of 5266 healthy Japanese women aged 20-89 years were included in this study to determine Japanese reference values. Additionally, 621 who had undergone radiographic examination of the thoracic and lumbar spine at the time of pQCT measurement were selected to determine the cut-off values of BD, TBD, pSSI and other indicators for vertebral fractures. All the healthy subjects were divided into 5 year age groups. The BD showed nonsignificant changes from the 20-24 year age group to the 45-49 year age group, and fell significantly thereafter. The TBD maintained a plateau until the 40-44 year group, which corresponds to the young adult mean (YAM) values of the lumbar spine, femoral neck and radius BMDs measured using DXA. The TBD decreased significantly thereafter. The pSSI did not change significantly from the 20-24 year age group to the 45-49 year age group, and decreased slightly in the 50-54 year age group and markedly after 55-59 years. The cut-off values for the discrimination of vertebral fractures were obtained by the calculation of sensitivities, specificities and the area under the curves obtained using age-adjusted receiver operating characteristics (ROC) analysis. Odds ratios and 95% confidence limits (CL) were calculated using age-adjusted logistic analysis. The cut-off values for vertebral fractures, the area under the ROC curves (AUC) and odds ratios were 270.1 mg/cm3 (-2.2 SD, 66.6% of YAM), 0.689+/-0.025, 2.10 (1.63, 2.70) for BD, 104.8 mg/cm3 (-2.2 SD, 53.5% of YAM), 0.699+/-0.023, 2.17 (1.69, 2.77) for TBD and 192.8 mm3 (-1.9 SD, 59.8% of YAM), 0.631+/-0.028, 1.72 (1.34, 2.21) for pSSI, respectively. These findings suggest that ultradistal radius BMD measured using pQCT can be used to discriminate women with vertebral fractures.

Chemosensitivity to the drugs plays a crucial role in the treatment of ovarian cancer. In this study, we evaluate the cytotoxicity of chemotherapeutic agents in six ovarian cancer cell lines; four clear cell adenocarcinoma and two serous papillary adenocarcinoma, using seven single drugs and seven sets of drug combinations with tetrazolium-based semiautomated colorimetric (MTT) assay. The drug concentration which produced 50% growth inhibition (IC50) of cisplatin was within clinically achievable range in five cell lines. The area under the curve (AUC) at IC50 of cyclophosphamide was below the clinically achievable AUC in two serous papillary cell lines. Paclitaxel was more effective in clear cells than serous papillary cells. The intensification of cytotoxicity was observed in the combinations of paclitaxel and cisplatin, and cyclophosphamide and cisplatin or 5-fluorouracil irrespective of histopathological characteristics of the original tumor. Our results indicate that ovarian cancer cell lines respond to chemotherapeutic agents heterogeneously depending upon histopathological features, indicating individualized regimens may improve survival in ovarian cancer patients.

A 37-year-old postpartum woman was presented with abdominal pain supposed to be caused by uterine involution or puerperal endometritis after vaginal delivery. During the pregnancy, she was suspected to have a subserosal myoma by ultrasound examination. The pain was finally revealed to be originated from the chemical peritonitis caused by the rupture of the mature cystic teratoma of the ovary by Kristeller's maneuver performed during vaginal delivery. When a pregnant or puerperal woman complains about abdominal pain, we need to consider the possibility of chemical peritonitis resulting from the rupture of mature cystic teratoma of the ovary.

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 objective of this study was to examine the value of NTx, a urinary cross-linked N-telopeptides of type I collagen, as a marker of bone resorption. We assessed changes in pre- and postmenopausal bone resorption by evaluating the correlation of NTx with L2-4 bone mineral density (BMD) in a total of 1100 Japanese women, aged 19-80 years [272 premenopausal (45.2 +/- 6.2 years) and 828 postmenopausal (59.5 +/- 6.2 years)]. Postmenopausal women were divided into three groups based on the range of BMD (normal, osteopenic, and osteoporotic). Within each group, subjects were further segregated according to years since menopause (YSM). NTx values were then evaluated for each group. Our results showed that BMD was significantly decreased (P < 0.05) and NTx was significantly increased (P < 0.01) after menopause in age-matched analysis. Consistent with a previous report, NTx was inversely correlated with BMD for the entire cohort of study subjects (r = -0.299), although NTx correlated better with premenopausal than postmenopausal BMD (r = -0.240 versus r = -0.086). This may have been due to the fact that elevated values of NTx were exhibited over the entire range of BMD present in the postmenopausal women, suggesting that NTx might respond faster to the estrogen withdrawal than BMD. In all postmenopausal women, regardless of the range of BMD, the increase in NTx reached a peak within 5 YSM. After 11 YSM, however, NTx remained elevated in the osteoporotic group but it decreased in the osteopenic group, and showed no significant change in the group of postmenopausal women with normal BMD. These findings suggest that bone resorption is dramatically increased within 5 years after menopause but remains increased only in osteoporotic women.

We examined sequential changes of bone-resorbing cytokines and bone metabolic markers and the effect of ovarian hormones on bone metabolism during the menstrual cycle in 10 healthy Japanese women, aged 22-43 yr, with normal ovarian function. Serum soluble interleukin-6 receptor (sIL-6R) showed a significant variation; a rise during the early and late follicular periods followed by a fall during the early luteal period (P = 0.0423, P = 0.0334) and an increase during the mid and late luteal periods. There were significant changes in the levels of markers of bone formation: a rise in serum bone-specific alkaline phosphatase (ALP) during the mid and late follicular (P = 0.0265) periods and a fall in serum carboxyl-terminal propeptide of type I procollagen (PICP) during the midluteal period (P = 0.0161). As for the levels of bone resorption markers, urinary type I collagen C-telopeptide breakdown products (CTx) and free deoxypyridinoline (D-Pyr) decreased significantly during the early and midfollicular periods, urinary free D-Pyr and serum pyridinoline cross-linked carboxyl-terminal telopeptide of type I collagen (ICTP) (P = 0.0440) increased significantly during the early luteal period, and urinary CTx, free D-Pyr, and serum ICTP decreased significantly during the late luteal period (P = 0.0170-0.0008). The serum PTH level was significantly higher during the follicular than the luteal period (P = 0.0132). Serum sIL-6R significantly correlated with urinary CTx (r = 0.190, P < 0.05) and serum ALP (r = 0.209, P < 0.05) and serum estradiol with intact osteocalcin (r = 0.309, P < 0.0005) and serum ALP (r = 0.181, P < 0.05). These observations strongly suggest that cyclic variations in the levels of bone formation and resorption markers and of a bone-resorbing cytokine may be modulated by cyclic changes in serum steroid hormones during the menstrual period. In addition, the specific days of biochemical events in the menstrual cycle are crucial for evaluating osteoclastic and osteoblastic activities in pre- and perimenopausal women or in women starting GnRH agonist therapy.

Bone-specific alkaline phosphatase (bone ALP) levels are considered to reflect osteoblastic activity and can therefore be used as a marker of bone formation. However, bone ALP is difficult to distinguish from other ALP isoforms since the kidney, liver, and bone isoenzymes are encoded by the same gene and only differ because of post-translational modification of their carbohydrate side chains. The aim of this study was to purify and separate bone ALP which could be used to raise specific antisera against human bone ALP, from Saos-2, a human osteogenic sarcoma cell line. The procedure involved two steps. The first step, cultivation of 10(5) Saos-2 cells, yielded approximately 1 U ALP. Subsequent butanol extraction achieved 1.82-fold purification. For the second step, separating bone ALP, we used serial lectin affinity chromatography to distinguish between the carbohydrate side chains of the various ALP isoforms. A sample of the butanol extract was fractionated into three peaks (I, II, and III) by concanavalin A. Peaks II and III were subsequently identified as types IIa and IIIb bone ALP using pea lectin and wheat germ agglutinin columns, respectively. The specific activity of bone ALP was measured using commercial kits. Since bone ALP accounted for at least 84% of the total ALP activity after the final separation, this method appears more convenient and reproducible than others using bone or Pagetic sera. The bone ALP purified in this study could be used to raise monoclonal antibodies against bone-specific ALP.

The adjuvant effect of mannan-coated liposomes on human immunodeficiency virus type-1 (HIV-1) DNA vaccine and the mechanism of this enhancement were studied. Coating of cationic liposomes with mannan significantly enhanced the ability of this vaccine to induce an HIV-specific delayed-type hypersensitivity (DTH) response. HIV-specific cytotoxic T-cell (CTL) activity elicited by DNA vaccination was also significantly enhanced with the mannan-liposome cocktail. This mannan-liposome-mediated activity was greatly inhibited by in vivo injection of anti-interferon (IFN)-gamma antibody, which suggests that IFN-gamma plays an important role in this HIV-specific immune response. The results of both isotype-specific antibody and cytokine analysis revealed that mannan-liposome-mediated DNA vaccination enhances Th1-mediated immunity.

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 (P0.01), or late follicular period (P0.05), and between early luteal period and late luteal period (P0.05). The levels of HP and LP showed a rise during the early an 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.

Extramammary Paget's disease of the vulva (EMPDV) is a rare gynecologic malignancy. We examined two cases of EMPDV in which cytologic study led to early detection of disease recurrence.In case 1, a 71-year-old woman, recurrence was detected with malignant cells from the vaginal Papanicolaou smear a few months after radical surgery for endometrial cancer. An asymptomatic perineal erythematous lesion was identified and diagnosed as EMPDV by biopsy specimen. She underwent curative surgery, but during the follow-up period, malignant cells appeared again in her vaginal Papanicolaou smear, which led to early detection of the recurrent disease that was macroscopically invisible. In case 2, an 80-year-old woman presented with the complaint of perineal pruritus and was diagnosed with EMPDV. Twenty-two months after the curative primary surgery, bilateral groin lymphadenopathies appeared, and the cytologic specimen by fine needle aspiration biopsy from the lymph nodes led to early detection of the recurrence without her experiencing negative side effects such as severe pain.Cytologic examination is a simple but efficient diagnostic measure without major negative side effects, provided the procedures are applied adequately and performed correctly.

Vitamin D insufficiency is prevalent in osteopenic and osteoporotic postmenopausal women. The persistent increase in circulating parathyroid hormone (PTH) caused by vitamin D insufficiency reduces bone density response to antiresorptive agents in these postmenopausal women. It is not well known whether administration of raloxifene might increase serum PTH secondary to the suppression of serum calcium in postmenopausal women with osteopenia or osteoporosis. We tried to assess whether raloxifene might affect serum PTH and whether the addition of alfacalcidol to raloxifene therapy could have favorable effects on bone mineral density (BMD) and bone turnover as compared to raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia (≤2.0 SD based on young Japanese women). A total of 169 subjects were randomly assigned to groups receiving 60 mg raloxifene (R), or 1 μg alfacalcidol (D), or a combination of both (R + D) for 2 years. Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured at randomization. The modified ‘intention to treat’ method was used. We compared the groups using a Tukey–Kramer test for changes in L- and TH-BMD and calcium metabolism when significant differences were found using one-way ANOVA. The parameters in each group during the experimental period were analyzed by means of paired t tests. Baseline 25(OH)D and i-PTH were 23.7 ng/ml and 38.4 pg/ml, respectively. At 6 months, i-PTH demonstrated a significant increase (+21.0%) in the R-group whereas significant decreases in i-PTH were observed in the D-group and combination-group (−15.9 and −8.9%, respectively). There were significant increases in L-BMD in the R + D-group (+4.1% at 1 year and +4.7% at 2 years, P < 0.0001) and in the R-group (+2.9% at 1 year and +2.8% at 2 years, P < 0.001), but the difference between the groups did not reach a significant level. Vitamin D status at randomization did not affect the subsequent BMD response in coadministration of alfacalcidol with raloxifene. Supplementation with alfacalcidol to raloxifene therapy demonstrates a greater bone-sparing effect by suppressing the secondary increment of serum PTH than when raloxifene is used alone.

It is generally considered that drugs with different pharmacological actions are prescribed when combination therapy is undertaken. Vitamin D insufficiency or deficiency is prevalent in osteopenic and osteoporotic postmenopausal women. Combination therapy of raloxifene with other agents including vitamin D has been reported and its effect on fracture prevention remains to be elucidated.

婦人科細胞診標本中に性器外悪性腫瘍由来の細胞が出現する頻度はきわめて低いとされている. これらの症例の原発臓器として, 欧米では乳癌の頻度が高いのに対して, 本邦では胃癌の報告が圧倒的に多い. また, 転移性子宮癌は不正性器出血などの症状を伴い広汎な全身転移の一部として発見されることが多く, 予後不良であるとされている.今回われわれは, 乳癌根治術2年後に子宮内膜吸引細胞診標本中に, 乳癌由来の腫瘍細胞が出現した転移性子宮癌の1例を経験した. 摘出子宮における転移巣は比較的小さいものであったが, 子宮内膜間質から筋層へかけて発育していた. また, 術前検査で肝左葉への転移も発見されたため, 術中肝動注用カテーテルを設置し, 術後肝動注化学療法を施行したところ奏功し, CT上肝転移巣はほぼ消失した. 術後1年以上を経たが患者は全身状態良好で再燃徴候はなく, 外来にて経過観察中である.

The Japanese Society for Bone and Mineral Research developed the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL) to evaluate the disease-specific Health-Related QOL, which is specific for osteoporosis of Japanese patients. JOQOL was revised in 2000; it consisted of 38 items with the scale graded from 0 to 4 and a total full score of 152. To elucidate the reliability and validity of the revised JOQOL, we enrolled 193 postmenopausal women as subjects and diagnosed them as having osteoporosis or osteopenia. The mean age of the subjects was 68.2 +/- 8 years; 58 subjects (30.1%) had at least one vertebral fracture. Among them, 83 patients were retested for reliability. The mean lapse from the time of test to that of retest was 23.7(+/- 9.5) days. The subjects were questioned using the JOQOL, Medical Outcomes Study Short Form 36 (SF-36), along with questions on subjects' characteristics and their ADL. The JOQOL scores at the test and the retest were significantly correlated (r = 0.973) without significant difference between their mean scores. All the JOQOL items showed significant correlations at the test and the retest (Kendall's tau = 0.599-0.947). Cronbach's alpha coefficient of JOQOL was 0.918. These results proved the high reliability of JOQOL. The JOQOL score showed negative correlation with age (r = -0.183). The subjects with vertebral fractures had significantly lower JOQOL scores than the subjects without fractures. The JOQOL showed a significant correlation with all the scores in each domain of eight of SF-36 (r = 0.350-0.839). These results were consistent with that of the preceding study. It is concluded that the reliability and the validity of JOQOL were demonstrated in this study.

A number of clinical risk factors that provide information on fracture risk over and above that given by BMD have been defined. WHO proposed FRAX (fracture risk assessment tool) in which the fracture probability could be calculated by the use of risk factors with or without BMD. The proposed independent risk factors are age, a prior fragility fracture, a parental history of hip fracture, smoking, use of systemic corticosteroids, excess alcohol intake, secondary osteoporosis, and rheumatoid arthritis. Management algorithms in postmenopausal women based on an health analysis have been proposed in several countries including UK, Sweden, Germany, USA and Canada.

It is crucial to select drugs for the prevention of fracture in postmenopausal osteoporosis. In early postmenopausal women with climacteric symptoms hormone replacement therapy (HRT) would be a first choice. Selective estrogen receptor modulator (SERM) could be prescribed in postmenopausal women who had been treated with HRT. Osteoporotic women with high risk of future fractures would be administered bisphosphonates. It is highly recommended that the doctor's decision on the drug (s) for each patient with osteoporosis could be made after obtaining the informed consent.

A case of ovarian endometrioid adenofibroma of borderline malignancy with an increased serum estradiol level, which rapidly disappeared after removal of the tumor, is reported. Vaginal cytologic analysis showed estrogenic effects, and endometrial cystic glandular hyperplasia was thought to be the reason for genital bleeding. To determine the origin of estradiol production in the tumor, stromal cells were enzymatically isolated from the tumor and cultured in vitro. Estradiol levels in the cultured media increased in parallel with cell growth. This is the first report showing estrogen secretion from stromal cells in an ovarian endometrioid adenofibroma.

The determination of C-terminal telopeptide of type I collagen degradation products (CTX) was made by using the monoclonal antibody recognizing the eight amino acids that are specific for alpha1 chain of type I collagen. CTX values show a diurnal variation, with a nadir from 1 to 11 o'clock in the afternoon, increase at midnight with peaks from 2 to 8 o'clock in the morning. The levels of CTX at peaks are approximately twice those at a nadir, which implies the sampling of serum and urine should be made at an identical time at each patient. There were significant correlations in patients on hormone replacement therapy (HRT) between lumbar spine bone density at 2-yr and percent changes of serum, or urinary CTX at 3-month and the percent change of CTX at 3-month alone could predict the percent change of lumbar spine bone density at 2-yr.

We aimed to assess whether circulating sex steroids would influence bone density and bone loss, whether part of this influence could be explained by genetic variation measured as polymorphisms in candidate genes affecting circulating hormone levels, or whether gene polymorphisms would have direct effects on bone in 229 postmenopausal Japanese women aged 46 years and over who had been followed for eight years (Yokohama Cohort). Bone mineral density (BMD) in the lumbar spine (L), femoral neck (FN), total hip (T) and distal radius (R) was measured every year, and endogenous sex steroid levels were determined at the start of the study. We investigated the polymorphisms of estrogen-metabolizing enzyme gene, CYP17; estrogen biosynthesis (high activity, A2/A2), CYP1A1; hydroxylation (high inducibility, vt/vt) and COMT; inactivation (low activity, L/L) with PCR-based restriction fragment length polymorphism assays. Dehydroepiandrosterone (DHEA) and androstenedione (AND) levels significantly correlated with bone density in both the axial (L) and the appendicular skeleton (FN, T and R) (r=0.194-0.229; P0.05) whereas estradiol (E2) and AND showed significant correlations with bone change only at the axial skeleton (r=0.205 and r=-0.139, respectively; P0.05) on the total cohort. These correlations remained significant in thin/normal-weight women [body mass index (BMI)25 kg/m2)] even after adjustment for years since menopause (YSM) and BMI or age and BMI, suggesting an interaction of BMI and sex steroid/BMD association. On the total cohort, a difference in endogenous DHEA levels between CYP17 homozygote A2 and non-homozygote A2; an increasing trend in AND levels from COMT L/L, L/H, to H/H; and a difference in TS level between COMT homozygote L and non-homozygote L were separately observed. All observations were significant for unadjusted and adjusted analysis, except for COMT and TS. In thin/normal-weight women (BMI25 kg/m2), the same effects of CYP17 genotypes on DHEA were observed as on the total cohort. CYP17 and COMT genes showed some direct influence on bone density. Mean percent change in T-BMD was negative for CYP17 non-homozygote A2 in contrast to a positive value for homozygote A2. Mean percent change in R-BMD showed the difference between COMT homozygote L and non-homozygote L with a larger decrease for the homozygote L. Together, CYP17 and COMT genotypes might have some effect on bone both directly and indirectly through their effects on endogenous sex steroids in postmenopausal Japanese women.

We conducted a prospective, randomized, multicenter, open-label 2-year trial with 76 postmenopausal women agedor =60 years with low (T-score less than -1) lumbar bone mineral density (BMD). The hormone replacement therapy (HRT) group received a low dose of conjugated estrogen (CEE) at a dose of 0.31 mg/day +/- medroxyprogesterone acetate (MPA) 2.5 mg/day. Group HRT/D received the same dose of HRT together with alfacalcidol in a daily dose of 1.0 microg/day. Changes in lumbar BMD measured by dual energy X-ray absorptiometry (DXA) were followed every 6 months for 2 years. The lumbar BMD of group HRT increased 3.37% [95% confidence interval (CI) 1.6%-5.2%], 4.00% (95%CI 1.6%-6.4%), and 2.32% (95%CI -0.7% to 5.3%) at 12, 18, and 24 months, respectively, when the baseline value was taken as 0%. Lumbar BMD of group HRT/D showed a significant increase beyond 6 months. The percent increases for this group at 6, 12, 18, and 24 months were 6.18 (95%CI 1.3%-6.6%), 6.18% (95%CI 3.9%-8.5%), 7.17% (95%CI 4.3%-10.0%), and 8.75% (95%CI 6.0%-11.5%), respectively. In addition, there was a significant difference in the changes of the lumbar BMD between the two groups at 24 months, suggesting that the combination of HRT and alfacalcidol is more effective than HRT alone in terms of the BMD effect. This study is the first prospective trial demonstrating an additive effect of alfacalcidol on lumbar BMD in postmenopausal women receiving low-dose HRT. It suggests that the combination therapy can be considered to be a promising mode of treatment for bone loss after menopause.

Tibolone is so called tissue specific compound, which works as estrogen in bone and inhibits postmenopousal bone loss and does not stimulate mammary tissue. Tibolone has been used as medication for postmenopausal vasomotor symptoms.

Both onset and cessation of menstruation have strong genetic inclination. We aimed to identify genetic factors influencing the onset of menarche and natural menopause in a Japanese population by investigating the polymorphisms of estrogen receptor-alpha and estrogen-metabolizing enzyme genes. Three hundred seventeen postmenopausal Japanese women, aged 46 yr and over, were enrolled in this study under informed consent. Genomic DNA was extracted from peripheral leukocytes, and PCR-based restriction fragment length polymorphism assays were used to determine estrogen receptor-alpha: PvuII, XbaI, and estrogen-metabolizing enzymes; CYP17, estrogen biosynthesis (high activity, A2/A2, CYP1A1), hydroxylation (high inducibility, vt/vt, and COMT), inactivation (low activity, L/L) genotypes. There were no significant differences in ages at menarche and natural menopause or years of menstruation among each PvuII or XbaI genotype and seven combinations of PvuII and XbaI genotypes. We found that ages at menarche in women with A1/A2 (higher activity of CYP17; 13.6 +/- 1.2 yr) were significantly earlier than in those with A1/A1 (lower activity of CYP17; 14.1 +/- 1.3 yr). There were no significant differences in age at natural menopause and years of menstruation among each CYP17, CYP1A1, or COMT genotype. The small sample size of each combination of estrogen-metabolizing genotypes made it impractical to evaluate the effects of the interdependency of each genotype, including extreme genotype categories such as A2/A2L/Lvt/vt vs. A1/A1H/Hwt/wt genotypes, on ages at menarche and/or natural menopause. The results suggest that the estrogen-metabolizing CYP17 genotype influences age at menarche in healthy postmenopausal Japanese women.

Dear Editor, Raloxifene, one of selective estrogen receptor modulators, has been widely prescribed to relatively early postmenopausal women with osteoporosis and osteopenia since postmenopausal women on hormone therapy (HT) stopped the medication, and the number of postmenopausal women starting HT decreased, mainly because of the increased risks of breast cancer and cardiovascular diseases after the Women’s Health Initiative (WHI) report (1). Saito et al. showed that reduction in BMD in postmenopausal dialysis women both with and without type 2 diabetes was suppressed by raloxifene therapy, indicating raloxifene treatment is useful and could be a possibility for women with type 2 diabetes (2). Before we reach the conclusion, I am afraid that there might be some problems that have to be made clear although the trial was well organized. First, the number of subjects is very small (100 or fewer). Second, the subjects are rather early postmenopausal women (range: 50-87 years). The criteria of postmenopausal status were not defined. Third, do 19 diabetic subjects on diet therapy alone really need hemodialysis? Fourth, the values of HbA1c are not shown in non-diabetic group. Fifth, the speed of sound (SOS) does not measure BMD although the SOS has been shown to be significantly correlated with lumbar BMD. Finally, the changes in serum Ca, P, intact PTH (i-PTH) and BAP have not been evaluated in the text. We have recently shown that raloxifene alone could induce a significant increase in circulating i-PTH, which might diminish the beneficial effect of raloxifene on BMD, and that the addition of alfacalcidol to raloxifene demonstrated a greater bone sparing effect by normalizing serum i-PTH level than raloxifene alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia (3). In our study i-PTH significantly increased and corrected serum calcium significantly decreased at 6 month and thereafter in subjects on raloxifene alone therapy, which might be caused by inhibition of bone resorption. Our result is not in agreement with the reports that raloxifene lowered serum PTH in postmenopausal women with osteoporosis (4) and that raloxifene did not affect PTH levels in those with primary hyperparathyroidism (5) although serum calcium decreased in both studies. However the authors did not mention whether raloxifene has any effects on i-PTH secretion and serum Ca, i-PTH in diabetic patients was lower than in non-diabetic patients after one year. As shown in tables 1 and 2 (2), i-PTH levels decreased one year after raloxifene therapy (54.7 ng/L) in diabetic subjects compared to control (71.9 ng/L) or baseline (78.2 ng/L), suggesting that raloxifene might have some influences on i-PTH secretion, possibly suppressing i-PTH secretion where hemodialysis patients have secondary hyperparathyroidism. In contrast, corrected serum Ca levels did not change remarkably after raloxifene therapy (2.27 mmol/L) vs. control (2.13 mmol/L) or baseline (2.22 mmol/L). The discrepancy between this study and our study could be explained by the difference in vitamin D status of the subjects; in this study vitamin D is co-administered (vitamin D replete) whereas in our study it is not (vitamin D insufficiency or deficiency), suggesting that raloxifene might exert its inhibitory effect on PTH secretion only when vitamin D status is replete or sufficient. In any way this study shows that raloxifene therapy could be useful in postmenopausal dialysis patients both with and without type 2 diabetes.

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

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.

A total of 79 Japanese women who were within 5 years of menopause were randomly assigned 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] 1.0 microg/day, conjugated estrogens 0.625 mg/day, a combination of both, or control (no treatment). Lumbar spine and proximal femur bone mineral density (BMD) and biochemical indices were monitored over 2 years. In the 1alpha(OH)D3-treated group, there was a nonsignificant decrease in lumbar spine BMD compared with controls, and no significant loss in the femoral neck compared with controls. In the estrogen-treated group, there was a nonsignificant increase in spine BMD (+2.17% in the first year and +1.71% in the second year), and no loss in femoral neck BMD. The combination of conjugated estrogens +1alpha(OH)D3 was more effective in increasing BMD in the spine (+3. 68% in the first year and +3.63% in the second year) and femur (+2. 56% in the first year and +4.44% in the second year) BMD. There was a significant difference in lumbar spine BMD in both the first and second years between the combination-treated group and the 1alpha(OH)D3-treated and control groups (P0.01). Serum osteocalcin (OC) significantly decreased in the combination-treated group (-23.8% in the first year) and the estrogen-treated group (-37. 6% and -41.2% at 6 and 18 months, respectively), and serum alkaline phosphatase (Alp) decreased significantly in the first year in the combination-treated (-31.5%), estrogen-treated (-27.3%), and 1alpha(OH)D3-treated (-7.9%) groups, whereas serum OC increased (+45. 4% in the first year) in women without treatment. The results of this study indicate that early postmenopausal bone loss in the femoral neck is prevented by conjugated estrogens, 1alpha(OH)D3, or both, whereas bone loss in the spine is not prevented by 1alpha(OH)D3. Estrogen proves effective in preventing early postmenopausal bone loss by markedly inhibiting bone turnover. Moreover, a synergistic bone-sparing effect can be expected when estrogen is administered concomitantly with 1alpha(OH)D3 rather than when used alone.

Functioning ovarian carcinoid tumors are well known to cause carcinoid syndrome. Recently, strumal and trabecular ovarian carcinoid tumors are reported to cause severe constipation possibly because of tumor-producing peptide YY (PYY). We studied a case of primary ovarian strumal carcinoid who had had severe constipation until the tumor was removed by surgical operation. Immunohistochemically, many tumor cells were strongly positive for PYY. By Northern blot and reverse transcription polymerase chain reaction analyses, PYY mRNA was expressed in a complete form as detected in normal human colon mucosa. From these findings, an ovarian strumal carcinoid is strongly suggested to express complete PYY mRNA and therefore complete PYY protein that results in severe constipation.

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.

An osteocalcin (OC) nitrogen (N)-terminal sandwich enzyme immunoassay that employs anit-N-20 (amino acids 1-20) polyclonal and monoclonal antibodies has been developed. This assay has demonstrated the existence of a heterogeneity in the OC N-terminal fragments observed in the serum of a patient with Paget's disease and a normal child. The elevation of the serum OC N-terminal value that occurs in Paget's disease was considered to be comparable to the serum alkaline phosphatase (ALP) elevations that also occur. The size of the peaks corresponding to N-terminal OC fragments in Paget's serum decreased 3 months after bisphosphonate treatment. Serum levels of OC N-terminals, and other biochemical indices, were determined for 67 premenopausal and 181 postmenopausal Japanese women. Serum OC N-terminal levels increased significantly (41.2%) in postmenopausal women compared with age-matched premenopausal women. These results strongly suggest that serum OC N-terminal levels reflect bone turnover rates when bone resorption is dominant.

© Munksgaard, Copenhagen PROBLEM: The transforming growth factor (TGF)-sss 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. METHOD OF STUDY: Human decidual and villous tissues in the first trimester were Northern blotted and amplified by reverse transcription-polymerase chain reaction to measure the expression of TGF-β1, -β2, and -β3 and their receptors, types I and II, at the first trimester of pregnancy. In addition, their cell-specific expression at the maternal-fetal interface was determined by in situ hybridization. RESULTS: Each isoform of TGF-β was expressed in both decidual and villous tissues. Because most TGF-β1 gene expression was found in villous tissues, TGF-β2 mRNA was expressed preferentially in the decidual tissues. TGF-β3 transcripts were expressed in the nonpregnant endometrium. CONCLUSIONS: The results suggest that each isoform of TGF-β plays some specific role in decidualization and placentation. Furthermore, it is predicted that they regulate the maternal-fetal interaction at early gestation.

We compared immune responses to intranasal and intramuscular DNA vaccinations against human immunodeficiency virus type 1 with monophosphoryl lipid A (MPL) used as an adjuvant. Both routes of vaccination resulted in similar levels of cell-mediated immunity, but the intestinal secretory immunoglobulin A response was higher following intranasal immunization than after intramuscular immunization. MPL demonstrated its adjuvanticity in vaccination by both routes.

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

Two permanent human ovarian clear cell adenocarcinoma lines (OVISE and OVTOKO) were established from metastatic tumors of two patients who were treated with five to six courses of CAP chemotherapy. The two cell lines grow on monolayers and showed a variety in both size and shape: small or moderately sized cuboidal cells, columnar cells, spindle-shaped cells, and malignant tumor giant cells. The cell lines have been in culture for 4 to 6 years, the passage number varying from 160 to 220. The mean population-doubling time of the two cells was 60 to 70 hr. The OVISE cells shed tumor-associated antigens CA19-9, CA125, and TPA in the culture medium, whereas the OVTOKO cells did not secrete them at detectable levels. Immunohistochemical analysis showed that coexpression of cytokeratins and vimentin was preserved in the two cell lines, which is a feature of cultured epithelial origin. Cytokeratin polypeptides 7, 8, 18, and 19 were expressed in both cell lines. The EGF receptor was more intensely expressed in the OVTOKO cells than in the OVISE cells. The estrogen and progesterone receptors were negative in both cell lines. The two cell lines showed no chemosensitivity to anticancer drugs including cisplatin, doxorubicin, cyclophosphamide, and etoposide. Heterotransplantation of the two cell lines reflected the origin of cells. Intraperitoneal transplantation of the OVTOKO cells yielded peritoneal implantation and distant metastasis, whereas that of the OVISE cells showed no dissemination and metastasis. These new ovarian clear cell adenocarcinoma lines will provide a relevant experimental system for further investigations into the intrinsic alterations responsible for malignant progression and chemoresistance.