Masatoshi Tomita

Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women.

OBJECTIVE We studied whether vitamin D receptor and estrogen receptor gene polymorphism is associated with the effect of hormone replacement therapy on lumbar-spinal bone mineral density in Japanese women. STUDY DESIGN The subjects were 82 Japanese women aged 40 to 64 years (49.7 +/- 0.6 years, mean +/- SEM) who had taken hormone replacement therapy for >1 year. Genomic deoxyribonucleic acid was extracted from blood and analyzed for restriction fragment length polymorphism with the restriction endonucleases Taq I, Apa I, and Fok I for vitamin D receptor and Pvu II and Xba I for estrogen receptor. RESULTS The subjects with genotype TT had a significantly higher percentage change in bone mineral density per year than those with the Tt genotype (2.8% +/- 0.6% vs -0.8% +/- 1.4%, P =.019). The serum level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen decreased by 13% during 1 year of hormone replacement therapy in subjects with the TT genotype (P =. 001) but did not change in women with the Tt genotype. In multiple regression analysis including age, height (centimeters), weight (kilograms), and polymorphisms of the vitamin D receptor and estrogen receptor genes, only age and Taq I polymorphism of the vitamin D receptor gene were associated independently with change in bone mineral density (P =.001 and.004, respectively). CONCLUSION Taq I polymorphism of the vitamin D receptor gene is associated with the effect of hormone replacement therapy on lumbar-spinal bone mineral density and bone resorption markers in Japanese women. Analysis of the vitamin D receptor alleles may prove useful for selection of the optimum therapy for osteoporosis management.

Effects of uncoupling protein 1 and ß3-adrenergic receptor gene polymorphisms on body size and serum lipid concentrations in Japanese women

OBJECTIVES To investigate whether the -3826 A-G point mutation of the uncoupling protein 1 (UCP1) gene and the Trp64Arg mutation of the beta3-adrenergic receptor (beta3-AR) gene are associated with increased susceptibility to weight gain and hyperlipidemia in postmenopausal women. METHODS We genotyped 312 Japanese women for UCP1 and beta3-AR gene polymorphisms, and investigated their effects on anthropometrical parameters, serum lipid concentrations, and their changes after 4 years. RESULTS Although body mass index (BMI), serum triglyceride, total cholesterol, and low-density lipoprotein levels were significantly higher and high-density lipoprotein levels significantly lower in postmenopausal (n=182) than in premenopausal (n=99) women, there was no significant difference in these parameters between carriers and non-carriers of the G allele in the postmenopausal women. In the premenopausal women, BMI and the 4-year change in body weight (BW) of carriers of the G allele were significantly higher than those of non-carriers of the G allele (P=0.022 and 0.048, respectively). In the postmenopausal women, the 4-year change in the level of serum triglyceride of carriers of the G allele was significantly higher (P=0.049), and the change of high-density lipoprotein was significantly lower (P=0.020) than those of non-carriers of the G allele. The beta3-AR polymorphism showed no apparent affect on these parameters. CONCLUSIONS The -3826 A-G polymorphism of the UCP1 gene is associated with an increase in BW of premenopausal women and with the 4-year changes in serum triglyceride and high-density lipoprotein levels in postmenopausal women.

Lumbar bone mineral density changes during pregnancy and lactation

Objective: To elucidate the change of bone metabolism in the lumbar trabecular and its relationship with serum hormonal changes in pregnancy and lactation. Study design: In a cross‐sectional study, we measured the bone mineral density (BMD) of 2–4 lumbar vertebrae of 571 puerperae at days 3–5 postpartum and 341 healthy, non‐pregnant women (control subjects) of approximately the same age by dual energy X‐ray absorptiometry. In a longitudinal study, we also measured the BMD of 111 puerperae at 3 and 6 months after delivery. Results: The mean BMD at days 3–5 postpartum was significantly lower than that of the control (1.013 ± 0.005 vs. 1.032 ± 0.006 g/cm2, P = 0.019). The lactating group showed BMD decrement to 95.1 ± 0.5% (n = 69) and 94.1 ± 0.7% (n = 61) at 3 and 6 months postpartum, respectively, compared with days 3–5 postpartum, and the amenorrhea group showed the same tendency. The non‐lactating group and resumption of menses group did not show a BMD decrement postpartum. In the lactating group, serum estradiol was significantly lower than in the non‐lactating group at 3 months postpartum, serum prolactin and bone alkaline phosphatase levels were higher than in the non‐lactating group at 3 and 6 months postpartum. Conclusions: Pregnancy may cause a decrease of lumbar BMD, and the lactation and amenorrhea also cause a decrease of BMD. In addition to lactation status, the ovarian dysfunction is one of the factors in bone loss during lactation.

Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with recurrent ovarian cancer.

This is the first report that the combination of paclitaxel and cisplatin is feasible in a patient with recurrent ovarian cancer undergoing hemodialysis. Paclitaxel at a dose of 150 mg/m2 was administered as a 3-h continuous i.v. infusion. Thirty minutes after paclitaxel administration, cisplatin was administered at a dose of 30 mg/m2 for 30 min. Hemodialysis was started 30 min after completion of the cisplatin infusion and performed for 5 h. The maximum plasma concentrations of paclitaxel, total platinum and free platinum were 3.26, 2.44 and 1.84 μg/ml, respectively. The AUC of paclitaxel and free platinum were 15.3 and 1.76 μg·h/ml, respectively. The pelvic tumor size was reduced by 42% on MRI after the second course of this therapy. Grade IV neutropenia and grade III thrombopenia were observed. We conclude that paclitaxel and cisplatin combination chemotherapy is efficacious and feasible for an ovarian cancer patient under hemodialysis.

Effect of vitamin D receptor and estrogen receptor gene polymorphism on the relationship between dietary calcium and bone mineral density in Japanese women.

In a longitudinal analysis of the results of bone mineral density (BMD) screenings conducted in local communities, we examined the effect of lifestyle improvements on BMD and investigated the influence of allelic variations of the vitamin D receptor (VDR) and estrogen receptor (ER) genes. The subjects were 484 women (age, 24–80 years) who underwent BMD screenings at least twice between 1994 and 2002. We conducted BMD measurements of the lumbar spine by dual-energy X-ray absorptiometry and performed a simple questionnaire survey of lifestyle factors. Women receiving pharmacotherapy, or those with bone fractures, were excluded, leaving 338 women eligible for the study. They were retrospectively divided into three groups: (i) premenopause, women who were at least 5 years preceding menopause; (ii) perimenopause, women who were within 5 years before or after menopause; and (iii) postmenopause, women who were at least 5 years past menopause. There was no correlation at all between improvements of lifestyle factors (i.e., calcium intake from dairy products and time spent walking) and fluctuations in lumbar-spine BMD after 1, 3, or 5 years in the pre-, peri-, and postmenopausal groups. For women in the postmenopausal group, the PP genotype for the ER gene correlated with a significantly higher initial BMD than those with the Pp and pp genotypes (P = 0.04). After 3 years, presence of the TT genotype of Taq I of VDR gene polymorphism exhibited positive correlations (r = 0.29, P = 0.03) with the improvements in calcium intake and in lumbar spine BMD for the perimenopausal group, whereas the Tt genotype showed negative correlations (r = −0.48, P = 0.04). After 1, 3, and 5 years, presence of the Tt genotype showed a tendency toward a negative correlation with the increases in calcium intake and in lumbar spine BMD for the pre- and perimenopausal groups, although almost of these were not significantly different. In this study, we could not prove a positive correlation between the improvement of lifestyle and the fluctuation of BMD within a 5-year timeframe, although the polymorphisms within the VDR gene may have some influence.

Association of vitamin D and estrogen receptor gene polymorphism with the effects of longterm hormone replacement therapy on bone mineral density

We longitudinally studied whether vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphisms in Japanese women influenced the effect of longterm hormone replacement therapy (HRT) on bone mineral density (BMD) in the lumbar spine. The 81 subjects were aged 40 to 64 years (mean ± SEM, 49.5 ± 0.6 years), and had received sequential or continuous HRT regimens, including 0.625 mg of conjugated equine estrogen and 2.5 to 5 mg of medroxy-progesterone acetate, for at least 3 years. Genomic DNA was extracted from blood cells, and analyzed for restriction fragment length polymorphism, using the restriction endonucleases Taq I, Apa I, and Fok I for VDR, and Pvu II and Xba I for ER. At 1 year, subjects with a Taq I genotype of TT (i.e., site absent) showed a significantly greater increase in BMD with treatment (ΔBMD) than subjects with the Tt genotype (2.6 ± 0.5% vs −0.8 ± 1.4%; P = 0.016). A small difference between genotypes remained at 2 years (3.8 ± 0.6% vs 0.8 ± 1.6%; P = 0.069), but no significant difference between genotypes was seen at 3 years. In multiple regression analyses, ΔBMD at 1 year was significantly affected by VDR-Taq I, Apa I, and ER-Pvu II genotypes and by age at treatment initiation, although at 3 years or more, ΔBMD was significantly affected only by age. These results indicate that Taq I VDR gene polymorphism predicted the effect on lumbar BMD for the first year of HRT in Japanese women, and that the differences in BMD versus the polymorphism disappeared if the treatment was continued for over 2 years.

Effect of Haemodialysis on the Pharmacokinetics of Antineoplastic Drugs

Since renal failure itself creates an immunocompromised situation, malignant tumours in haemodialysis patients are increasing due to the prolonged lifespan of these patients. In treating these patients with anticancer agents, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs with extensive renal excretion. On the other hand, if an anticancer drug is removed significantly by haemodialysis, dosage increase would be required to ensure adequate therapeutic efficacy. We address in this review the clinical pharmacokinetic aspects of antineoplastic therapy, and the application of pharmacokinetic principles to the adjustment of dosage of anticancer agents in haemodialysis patients.

The Effect of Multiple Pregnancies on Lumbar Bone Mineral Density in Japanese Women

OBJECTIVE To elucidate the effect of multiple pregnancies on lumbar spine bone mineral density (BMD). METHODS The BMD of the lumbar spines (L2-L4) of 1,113 healthy women was measured within 7 days of childbirth. In addition 113 women had spine BMD measurements after their next delivery. RESULTS In the cross-sectional study, there was no apparent effect of parity on lumbar BMD. In the longitudinal study, the mean BMD after the next delivery was significantly higher than that after the initial delivery (1.019 +/- 0.115 g/cm(2) vs. 1.006 +/- 0.117 g/cm(2), P = 0.001, paired t test) with a percent change (DeltaBMD%) of 1.4 +/- 4.2%. Multiple regression analysis to identify independent predictors of DeltaBMD% showed a negative correlation with maternal age at the subsequent delivery (P = 0.033) but no correlation of DeltaBMD% with the length of lactation between the scans. CONCLUSION Multiple pregnancies may not reduce maternal lumbar BMD, although the percentage decrease in BMD was greater in older women at the subsequent delivery. The length of lactation between the scans had no effect on these results.

Effects of a beta 3 adrenergic receptor agonist on bone and bone marrow adipocytes in the tibia and lumbar spine of the ovariectomized rat.

The object of this study was to investigate the effects of a b3 adrenergic receptor agonist (ARa) and estrogen on bone remodeling and bone marrow adipocyte differentiation. Ten-week-old female Sprague-Dawley rats underwent sham operation (Sham) or were ovariectomized (OVX) and were divided into four groups: Sham, Sham+ARa, OVX, and OVX+ARa groups. They were given orally the b3-ARa, BRL 35135, or vehicle daily for 4 weeks and their tibial and lumbar spinal bone and fat histomorphometric parameters were measured. In tibial proximal metaphysis, the adipocyte number per bone marrow unit volume (N.A/MV), and the percent adipocyte volume (AV/MV) values of the OVX and OVX+ARa groups were significantly higher than the Sham and Sham+ARa groups (P = 0.004, P = 0.008 in OVX, respectively), but ARa administration had no effect on bone remodeling or adipocyte differentiation. N.A/MV and AV/MV correlated negatively with the bone volume (BV/TV, r = -0.67, P = 0.001; r = -0.62, P = 0.004, respectively), and they correlated with the bone resorption parameters, i.e., the eroded surface (ES/BS), osteoclast surface (Oc.S/BS), and osteoclast number (N.Oc/BS) in tibial proximal metaphysis. In tibial distal metaphysis, the adipocyte volume per cell (AV/N.A) values of the OVX and OVX+ARa groups were significantly higher than those of the Sham and Sham+ ARa group (P = 0.003 in OVX). In the lumbar spine, the AV/N.A values of the Sham+ARa and OVX+ARa groups were significantly lower than the Sham and OVX groups values (P < 0.0001 in ARa administration), but OVX did not affect adipocyte differentiation. Beta3-ARa administration affects the bone marrow adipocyte differentiation, which is site-specific difference, although mainly negative in the context of bone.

Effects of Pregnancy and Lactation on Trabecular Bone and Marrow Adipocytes in Rats

Abstract. Changes in the structure and metabolism of trabecular bone and marrow adipocytes in rats during pregnancy and the early stage of postpartum were evaluated by investigating bone mineral density (BMD) and bone and fat histomorphometry. Forty-nine female virgin Sprague-Dawley rats aged 200 days were mated and divided into seven groups: (1) beginning controls; (2) antepartum-on-day-7; (3) antepartum-on-day-21; (4) nonlactating on the fourth postpartum day; (5) nonlactating on the sixth postpartum day; (6) nonlactating on the eighth postpartum day; (7) lactating on the eight postpartum day. The significant decreases occurred in the trabecular bone at the end of pregnancy and lactation, and the bone formation increases and the bone structure is almost recovered in nonlactating rats within 6 days of postpartum. The percent adipocyte volume, adipocyte number, and unit adipocyte volume significantly decreased during postpartum whether lactating or nonlactating, and they significantly showed negative correlation with the osteoid volume values. The serum triglyceride value and body weight of the seven groups correlated significantly with the unit adipocyte volume value (r = 0.49, P= 0.004; r = 0.58, P= 0.0005, respectively). We concluded that bone resorption and formation are regulated separately during late pregnancy and lactation and that the recovery of BMD from lactation appears to rely on an acceleration of bone formation. Furthermore, the metabolism of the marrow adipocyte may be correlated with bone formation rates, serum triglyceride value, and body weight during pregnancy and early stage of puerperium.