Biomedical subjects

M Shiraki

Publications and source records attributed to M Shiraki.

At least 37 records · Page 2Linked to original sources

PubMed2000

Possible involvement of the p57(Kip2) gene in bone metabolism.

We previously uncovered that growth stimulation of rat primary osteoblasts by transforming growth factor-beta1 (TGF-beta1) resulted in a dramatic decrease in p57(Kip2), a member of cyclin-dependent kinase (CDK) inhibitors, through the proteasomal degradation pathway (Urano et al., J. Biol. Chem. 274, 12197-12200, 1999). Here we demonstrated that the amount of p57 protein increases markedly, when rat calvarial primary osteoblasts treated with 1,25-dihydroxyvitamin D3 transit from proliferation toward differentiation. Next, we have analyzed the association of four amino acids deletion polymorphism of p57 and bone mineral density (BMD). The p57 genotype was determined in 154 postmenopausal Japanese women. When we separated the subjects into two groups, one having one or two copies of deletion polymorphism and the other without the deletion, the former subjects had higher BMD (Z score of total body, 0.67 +/- 0.93 vs 0. 23 +/- 0.90, mean +/- standard deviation; P = 0.021). Taken together, these findings suggest that the p57 regulated in the osteoblast proliferation and differentiation may play a role in determination of bone mineral density and pathogenesis of osteoporosis.

Aged↗

PubMed2000

Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women.

The pathogenesis of osteoporosis is controlled by genetic and environmental factors. Considering the high prevalence of osteoporosis in homocystinuria, abnormal homocysteine metabolism would contribute to the pathogenesis of osteoporosis. It is known that the polymorphism of methylenetetrahydrofolate reductase (MTHFR), the enzyme catalyzing the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, correlates with hyperhomocysteinemia. In this study, we examined the association of this polymorphism with bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) in 307 postmenopausal women. MTHFR A/V polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We compared BMD, clinical characteristics, and bone metabolic markers among MTHFR groups (AA, AV, VV). The groups did not differ in terms of baseline data. The values of lumbar spine BMD and total body BMD were as follows: lumbar spine: AA, 0.91 +/- 0.18, AV, 0.88 +/- 0.16, VV, 0.84 +/- 0.14 g/cm(2); total body: AA, 0.97 +/- 0.11, AV, 0.96 +/- 0.11, VV, 0.93 +/- 0.09 g/cm(2). In the VV genotype, lumbar spine BMD values were significantly lower than those of the women with the AA genotype (P = 0.016) and total body BMD was significantly lower than those of the women with AA genotype (P = 0.03) and AV genotype (P = 0.04). This is the first report that suggests that the VV genotype of MTHFR is one of the genetic risk factors for low BMD.

Aged↗

PubMed2000

Identification of a novel polymorphism of estrogen receptor-alpha gene that is associated with calcium excretion in urine.

A novel variation of the estrogen receptor-alpha (ERalpha) gene was identified by polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP). It is one base substitution in codon 325 (CCC [allele M] to CCG [allele m]) in exon 4 of the human ERalpha gene. This substitution did not cause an amino acid change. We categorized 306 unrelated Japanese postmenopausal women into three genotypes: MM, Mm, and mm; the frequency of each genotype was 26.5%, 43.1%, and 30.4%, respectively. Then, the association of this polymorphism with bone mineral density (BMD) of lumbar spine and bone-calcium metabolic markers was studied. There was no significant difference in BMD of the lumbar spine or most of the bone metabolic markers. However, the urinary calcium (Ca) excretion ratio (u-Ca/Cre) corrected by creatinine was significantly lower in the genotype mm group compared with the genotype MM group (MM vs mm, 0.247 +/-0.158 vs 0.200 +/- 0.105; P < 0.05). We examined the relationship of restriction fragment length polymorphisms (RFLPs) (PvuII, XbaI) in intron 1 and the polymorphism in exon 4. The frequency of genotype MM was higher in the genotype PPxx, which was reported to be associated with lower BMD in the same population of Japanese postmenopausal women. The ER polymorphism identified in this study might be related to some biological mechanisms that regulate calcium metabolism.

Bone Density↗

PubMed2000

Effects of phosphorus-containing calcium preparation (bone meal powder) and calcium carbonate on serum calcium and phosphorus in young and old healthy volunteers: a double-blinded crossover study.

To evaluate the effects of bone meal powder (BEC) on calcium and phosphorus metabolism, a calcium absorption test was conducted using a preparation of calcium carbonate (CAC) as the control drug. A total of 12 healthy volunteers, consisting of 6 younger (aged 20-29 years, 3 men and 3 women) and 6 older (aged 60-69 years, 3 men and 3 women) persons, were subjected to a double-blinded crossover study. Serum calcium (s-Ca) level significantly increased to 105.3% +/- 1.9% (P < 0.01 vs the basal value; mean +/- SD) from the basal value in the BEC group and to 104.4% +/- 2.7% (P < 0.01) in the CAC group at 3h post load. Urinary excretions of calcium (u-Ca/glomerular filtration rate, u-Ca/GF) after BEC and CAC load rose to 226.6% +/- 154.5% (P < 0.05) and 211.1% +/- 148.0% (P < 0.05), respectively. Serum phosphorus (s-P) levels after BEC load increased to 110.0% +/- 15.1% (P < 0.05), whereas that after CAC load showed no significant change (99.3% +/- 7.9%). On the other hand, urinary excretion of phosphorus (u-P/GF) after CAC load decreased to 60.0% +/- 32.4% (P < 0.01) and that in the BEC group showed no significant change (92.5% +/- 49.5%). The increase in s-Ca led to decrease in serum intact parathyroid hormone (i-PTH) level [77.3% +/- 33.4% (P < 0.05) for BEC and 69.5% +/- 20.3% (P < 0.01) for CAC] although s-P was increased by the BEC load. The responses to BEC and CAC administration were compared in the younger and the older groups. The responses in the younger and the older group showed fundamentally the same trends and to the same extent. However, the changes in serum ionized calcium (i-Ca) and i-PTH levels at 1.5 h post load were significantly smaller in the older group than in the younger group (P < 0.01; P < 0.05). The increment in s-P level after BEC load in the older group was larger than that in the younger group. In conclusion, BEC can modulate not only calcium but also phosphorus metabolism in both younger and older subjects. Further investigations are required to evaluate the effects of BEC on bone density and safety for renal function in long-term observations.

Adult↗

PubMed2000

Association of estrogen receptor beta (ESR2) gene polymorphism with blood pressure.

We investigated the association between a dinucleotide (cytosine-adenine; CA) repeat polymorphism located in the flanking region of the human estrogen receptor beta (ESR2) gene and systemic blood pressure in 187 healthy postmenopausal Japanese women. The genotype was classified as "A" through "O" according to the number of these repeats from 18 to 32. When we separated the subjects into two groups-- bearing at least one "I" allele (26 CA repeats) and those who did not--we found that the former subjects had significantly higher systolic blood pressure than the latter (mean +/- SD, 146.0 +/- 25.0 vs 136.6 +/- 23.4; P = 0.032). These data suggest that genetic variation at the ESR2 locus may be associated with some determinants of blood pressure, and that there is a possible involvement of this polymorphism in causing hypertension in Japanese women.

Aged↗

PubMed2000

Association of bone mineral density with a dinucleotide repeat polymorphism at the calcitonin (CT) locus.

Calcitonin (CT), a calcium-regulating hormone, lowers the calcium level in serum by inhibiting bone resorption. Because CT may play a role in the pathogenesis of osteoporosis, genetic variations in or adjacent to the CT gene may be associated with variations in bone mineral density (BMD). The present study examined the correlation between a dinucleotide (cytosine-adenine; CA) repeat polymorphism at the CT locus and BMD in 311 Japanese postmenopausal women (mean age, 64.1 years). Seven alleles were present in this population; each allele contained 10, 11, 16, 17, 18, 19, or 20 CA repeats. Thus, we designated the respective genotypes A10, A11, A16, A17, A18, A19, and A20. The A10 and A17 alleles were the predominant alleles in the population studied. Z scores (a parameter representing deviation from the age-specific weight-adjusted average BMD) were compared between individuals that possessed one or two alleles of each genotype and those that did not possess the allele. Subjects who possessed one or two A10 alleles had lower BMD Z scores than those who did not (lumbar 2-4 BMD Z score; -0.148 +/- 1.23 vs 0.182 +/- 1.54; P = 0.04). No significant relationships were observed between allelic status and background data or biochemical parameters. The significant association observed between BMD and genetic variations at the CT locus implies that polymorphism at this locus may be a useful marker for the genetic study of osteoporosis.

Aged↗

PubMed2000

Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis.

Aims: patients with liver cirrhosis exhibit abnormal fuel metabolism, including increased fat and decreased glucose oxidation. Such altered energy metabolism is similar to that observed after starvation and could lead to malnutrition. We therefore studied whether nocturnal energy supplementation might improve the fuel metabolism in cirrhotic patients. Methods: 12 cirrhotic patients and 14 healthy controls participated in this study. Subjects in the two groups ate isonitrogenous (1.2 g/kg/day) and isocaloric (35 kcal/day) diets for 1 week before and during the study. On day 1 of the study, indirect calorimetry was carried out in the morning after an overnight fast. The next morning, the same measurement was performed after the patients took a liquid nutrient (Ensure Liquid(R), 250 kcal) at 23:00 on day 1. Respiratory quotient (RQ), resting energy expenditure (REE), and substrate oxidation rates of glucose (% CHO), fat (% FAT) and protein were estimated from measured VO(2), VCO(2) and urinary nitrogen. Results: Significant decreases in RQ, and % CHO and a significant increase in % FAT were observed at baseline in cirrhotic patients as compared with controls. After the nocturnal energy supplementation, RQ, % CHO and % FAT in cirrhotic patients were significantly recovered, ending at levels close to normal. Conclusions: These results suggest that nocturnal energy supplementation could be useful to correct abnormal fuel metabolism and to prevent malnutrition in cirrhosis.

Journal Article↗

PubMed2000

Association of transforming growth factor beta1 genotype with therapeutic response to active vitamin D for postmenopausal osteoporosis.

Transforming growth factor beta (TGF-beta) is an important regulator of bone metabolism, its effects being intertwined with those of estrogen and vitamin D. A T-->C polymorphism in exon 1 of the TGF-beta1 gene, which results in the substitution of proline for leucine, is associated with bone mineral density (BMD). However, it is not known whether this polymorphism affects the response to treatment with active vitamin D or to hormone replacement therapy (HRT) in individuals with osteoporosis. Changes in BMD at the lumbar spine (L2-L4 BMD) were compared among TGF-beta1 genotypes in 363 postmenopausal Japanese women who were divided into three groups: an untreated, control group (n = 130), an active vitamin D treatment group (n = 117), and an HRT group (n = 116). TGF-beta1 genotype was determined with an allele-specific polymerase chain reaction assay. In the control group, the rate of bone loss decreased according to the rank order of genotypes TT (homozygous for the T allele) > TC (heterozygous) > CC (homozygous for the C allele), with a significant difference detected between the CC and TT genotypes. The positive response of L2-L4 BMD to HRT increased according to the rank order of genotypes TT < TC < CC, although the differences among genotypes were not statistically significant. Individuals with the CC genotype responded to active vitamin D treatment with an annual increase in L2-L4 BMD of 1.6%, whereas those with the TT or TC genotypes similarly treated lost bone to a similar extent as did untreated subjects of the corresponding genotype. These results suggest that TGF-beta1 genotype is associated with both the rate of bone loss and the response to active vitamin D treatment.

Aged↗

PubMed2000

Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis.

We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline (DPD) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group (chi2 = 10.935; p = 0.0273). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were -1.8 +/- 0.6%, -2.4 +/- 0.7%, and -3.3 +/- 0.8% for the control group, and 1.4 +/- 0.7%, -0.1 +/- 0.6%, and -0.5 +/- 1.0% for the vitamin K2-treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group (p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 +/- 0.3 ng/ml and 1.6 +/- 0.1 ng/ml, respectively (p < 0.0001), while the serum level of OC measured by the conventional radioimmunoassay (RIA) showed a significant rise (42.4 +/-6.9% from the basal value) in the treated group at 24 months (18.2 +/- 6.1% for the controls;p = 0.0081). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule.

Absorptiometry, Photon↗

PubMed1999

Ectopic expression of human p53 inhibits entry into S phase and induces apoptosis in the Drosophila eye imaginal disc.

Transgenic flies in which ectopic expression of human p53 was targeted to the Drosophila eye imaginal disc were established. On sectioning of adult fly eyes which displayed a severe rough eye phenotype, most ommatidia were found to be fused and irregular shapes of rabdomeres were observed. In addition, many pigment cells were lost. In the developing eye imaginal disc, photoreceptor cell differentiation was initiated normally despite the ectopic expression of p53. However, expression of p53 inhibited cell cycle progression in eye imaginal disc cells and the S phase zone (the second mitotic wave) behind the morphogenetic furrow was almost completely abolished. Furthermore, expression of p53 induced extensive apoptosis of eye imaginal disc cells, and co-expression of baculovirus P35 in the eye imaginal disc suppressed the p53-induced rough eye phenotype. These results are consistent with the known functions of human p53 and indicate the existence of signaling systems with elements corresponding to human p53 in Drosophila eye imaginal disc cells. Genetic crosses of transgenic flies expressing p53 to a collection of Drosophila deficiency stocks allowed us to identify several genomic regions, deletions of which caused enhancement or suppression of the p53-induced rough eye phenotype. The transgenic flies established in this study should be useful to identify novel targets of p53 and its positive or negative regulators in Drosophila.

Animals↗

PubMed1999

Association of bone mineral density with a polymorphism of the peroxisome proliferator-activated receptor gamma gene: PPARgamma expression in osteoblasts.

The peroxisome proliferator-activated receptor gamma (PPARgamma) protein as well as its transcript was detected in primary osteoblasts derived from rat calvariae. To analyze the possible involvement of PPARgamma in the human bone metabolism, association between bone mineral density (BMD) and a polymorphism of PPARgamma gene was investigated in Japanese postmenopausal women. We examined a polymorphism corresponding to a silent C --> T transition located in exon 6 of the PPARgamma gene, that was previously reported to be associated with plasma leptin levels in the obese. The frequencies of the C and T alleles in the population studied here were 0.851 and 0.149, respectively. When we separated the subjects into two groups, one bearing at least one T allele (CT + TT) and the other which did not (CC), the former subjects had lower BMD (Z score of total body; 0.056 +/- 1.00. L2-4; -0.25 +/- 1.26, mean +/- standard deviation). These data suggest that there is an association between the restriction fragment length polymorphism (RFLP) of PPARgamma gene and BMD and the possible involvement of this single nucleotide polymorphism (SNP) in the cause of postmenopausal osteoporosis in Japanese women.

Aged↗

PubMed1999

A double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. The Alendronate Phase III Osteoporosis Treatment Research Group.

To evaluate the efficacy and safety of alendronate, a double-masked, active (alfacalcidol) controlled comparative study for 48 weeks was carried out in a total of 210 Japanese patients with osteoporosis. The doses of alendronate and alfacalcidol were 5 mg/day and 1 microgram/day, respectively. The lumbar bone mineral density (LBMD) values observed at 12, 24, 36 and 48 weeks after the initiation of alendronate treatment were 3.53 +/- 0.53%, 5.37 +/- 0.62%, 5.87 +/- 0.74% and 6.21 +/- 0.59% (mean +/- SE), respectively, higher than the baseline value. Corresponding values in the alfacalcidol group were 1.50 +/- 0.43%, 0.69 +/- 0.63%, 1.12 +/- 0.60% and 1.36 +/- 0. 63%, respectively. There was a significant difference between the two groups at each time point (p<0.05 or p<0.001). The bone turnover markers were depressed during treatment in the alendronate group: -32.2% for alkaline phosphatase, -53.7% for N-terminal osteocalcin and -45.0% for urinary deoxypyridinoline compared with the corresponding baseline values. On the contrary, no notable changes in these parameters were observed in the alfacalcidol group. Treatment with alendronate caused a transient decrease in serum calcium concentrations associated with an increase in the serum level of intact parathyroid hormone. In contrast, treatment with alfacalcidol resulted in a tendency of these parameters to change in the opposite direction. No difference in fracture incidence between the two groups was observed. The overall safety of alendronate was comparable to that of alfacalcidol. In conclusion, although it was a relatively short-term study of 48 weeks, the results of the present study indicate that alendronate at the daily dose of 5 mg was effective in increasing LBMD and that no serious drug-related adverse events were observed in the alendronate-treated patients. Alendronate is more efficacious than alfacalcidol in increasing bone mineral density, although the mechanisms of the actions of the two drugs are apparently different.

Aged↗

PubMed1999

Association study of parathyroid hormone gene polymorphism and bone mineral density in Japanese postmenopausal women.

Association of BST B1 restriction fragment length polymorphism (RFLP) of the parathyroid hormone (PTH) gene with bone mineral density (BMD) was examined in 383 healthy postmenopausal women in Japan who were unrelated. The RFLP was represented as B or b, the capital letter signifying the presence of and the small letter the absence of restriction site for BST B1. The frequency of each genotype-BB, Bb, and bb-was 82.5%, 16.7%, and 0.8%, respectively. When we statistically compared age, years after menopause, body height, and body weight between the BB genotype and the Bb genotype groups, there was no significant difference between the groups. However, the lumbar BMD and the score of BMD adjusted for age and body weight (Z score) were significantly lower in the group of genotype Bb than in the BB: 0.859 +/- 0.019 g/cm2 versus 0.925 +/- 0. 011 (mean +/- SE, P = 0.01) and -0.412 +/- 0.138 versus 0.067 +/- 0. 082 (mean +/- SE, P = 0.01). In addition, the Z score of total body BMD in the Bb genotype group was lower than that in the BB group. Comparison of serum and urinary biochemical bone metabolic markers suggested that the subjects with Bb genotype might be in a relatively higher state of bone turnover than those with BB genotype. These results suggest that the polymorphism in the PTH gene would be a useful genetic marker for lower BMD and the susceptibility for osteoporosis.

Absorptiometry, Photon↗

PubMed1999

Treatment effects of bisphosphonates on ovariectomy-induced osteopenia in rats: comparison between clodronate and etidronate.

We studied the effects of clodronate and etidronate on bone loss induced by ovariectomy (OVX) in rats. Drug administration was initiated 8 weeks after the surgery and continued for 12 weeks (twice per week, s.c.). Lumbar (L4-L5) bone mineral density (BMD) and femoral BMD in the sham-operated group were increased to 113% and 114%, respectively, whereas those in OVX group were suppressed to 98.8% and 105%. Clodronate significantly restored the suppressed BMD over the entire dose range used (4-25 mg/kg). Etidronate restored BMD only at 4 mg/kg. In a histomorphometric analysis of lumbar vertebrae, both bisphosphonates depressed the amount of labeled surface, which was increased by OVX, to 11.9%-20.1% of the OVX group value for clodronate and to 0.23%-9.7% of the OVX group value for etidronate. The osteoid area was significantly increased by etidronate treatment over the entire dose range (OS/BS, 175%-295%). On the other hand, the osteoid area in the clodronate group did not increase at any dose tested (OS/BS, 38.1%-49.9%). Urinary excretion of deoxypyridinoline and plasma level of osteocalcin were elevated in the OVX group (162%-182% and 123%, respectively), suggesting that OVX enhanced bone turnover. Both bisphosphonates suppressed the bone turnover accelerated by OVX, and the data indicated that both bisphosphonates recovered BMD by means of inhibition of bone resorption. These data suggested that clodronate and etidronate reversed osteopenia induced by ovariectomy in rats. As judged from the dose response of BMD and histomorphometric findings, clodronate showed a wider safety margin than etidronate.

Amino Acids↗

PubMed1998

Rates of change in spinal bone density among Japanese women.

To determine the rates of change in bone mineral density (BMD) at the spine in healthy Japanese women, longitudinal measurements of spinal BMD using dual X-ray absorptiometry were collected from 984 women over 17 years of age (mean age 51.6) at eight medical research centers. They were followed up for 20.9 months on average without any treatment influencing bone and calcium metabolism. Measurements of BMD obtained by two different scanners were converted into standardized BMD (sBMD) values. The multiple linear regression model predicts that spinal sBMD increases up to about 23 years of age: the estimated average rates of increases were 0.13%/year for women aged 20 years. After the age of 23, the sBMD began decreasing: the rates of loss increased by 0.045%/year for each year increase in age among premenopausal women. In perimenopausal women, the rate of loss was 2. 1%/year. In postnatural menopausal women, the rates of loss decreased exponentially with increasing years since menopause. The rates of loss increased by 0.04%/year for 1 kg decrease in body weight or by 0.1%/year for 1 kg/m2 decrease in body mass index. No significant differences in changes in sBMD were found between scanners and between centers after multiple adjustment. We conclude that the rates of change in spinal sBMD are associated with age in premenopausal women, and with years since menopause and weight or BMI in postmenopausal women. Caution is needed, however, when using data from different densitometers to evaluate rates in bone loss in multicenter trials.

Adolescent↗

PubMed1998

Polymorphism of insulin-like growth factor I gene and bone mineral density.

The polymorphism of insulin-like growth factor-I (IGF-I) gene was examined in Japanese postmenopausal women to analyze the genetic background for osteoporosis. In this study, the dinucleotide (cytosine-adenine; CA) repeat sequence lying upstream of the transcription initiation site of this gene was examined. We named the most frequent allele including (CA) 19 as J allele. There were 6 alleles (J-4 containing 17 CA repeats: (CA)17, [J-2 (CA)18, J (CA)19, J + 2 (CA)20, J + 4 (CA)21, J + 6 (CA)22]) in the Japanese population. The genotype distribution was different from that of Caucasians. There was no different in bone mineral density (BMD) between the group with one or two alleles of each genotype and that without that genotype. When we separate the subjects into three groups having two alleles, one allele, and no alleles, the three subjects who possess the allele 'J-2' in both strands had low BMD (Z score of L2-4; -1.24 +/- 0.56, total body; -0.943 +/- 0.59, mean +/- SE). On the other hand, sequence of IGF-I gene in this study was different from reported sequence of IGF-I gene; that was 2 base pair (bp) deletion following 3'end of CArepeat (-645adenine/-646guanine). The present study showed that there was no association between the microsatellite polymorphism of IGF-I gene and BMD in Japanese postmenopausal women, but some possibility remains that the microsatellite polymorphism of IGF-I gene is useful to detect a kind of particular osteoporosis.

Absorptiometry, Photon↗

PubMed1998

The long-term effect of menopause on postmenopausal bone loss in Japanese women: results from a prospective study.

The aim of this study was to elucidate perimenopausal bone loss in relation to menstrual conditions and to investigate the long-term effect of menopause on bone loss in aged women. The rate of change in bone mineral density (BMD) was measured twice at an exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) at the lumbar spine in 176 pre- and postmenopausal healthy women 41-65 years of age. Serum follicle-stimulating hormone, intact and N-fragment osteocalcin (OC), three types of vitamin D3, parathyroid hormone (PTH), and calcitonin were also determined. Women who exercised regularly or had anatomical changes at the lumbar spine were excluded from this study. The subjects were divided into eight groups based on their menstrual status and years since menopause. Annual bone loss at the lumbar spine of premenopausal women with regular menstruation was -0.2+/-1.9% (95% confidence interval, -0.9 approximately -0.4%) and was not statistically different from zero, while that of women with irregular menstruation or at menopausal transition was -2.1+/-3.4% (-3.4 approximately -0.8%), and -3.3+/-2.3% (-5.2 approximately -0.3%), respectively, and was significantly different from zero. Serum OC levels of women at menopausal transition were significantly higher than those of women with regular menstruation, suggesting that bone loss had commenced in these women. The rate of annual change in BMD of women who were menopausal for 1-3, 4-6, 10-12, and more than 13 years was -3.1+/-4.0% (-4.7 approximately -1.5%), -1.2+/-2.6% (-2.2 approximately -0.2%), -1.0+/-3.0% (-2.3 approximately -0.3%), and -2.3+/-2.1% (-3.7 approximately -1.0%), respectively, and was significantly less than zero. But the annual bone loss of women who were menopausal for 7-9 years was -1.5+/-2.6% (-3.0 approximately -0.1%) and was not statistically significant from zero. These results indicate that postmenopausal women lose BMD in two phases. The early bone loss is rapid and commences during irregular menstruation, then is attenuated within 6 years after the onset of menopause. The second bone loss commences after the attenuation of the first bone loss. Among bone metabolic hormones, intact PTH alone showed an age-related increase and was suggested as being a causal factor of bone loss in women who were menopausal for 13 years or more.

Absorptiometry, Photon↗

PubMed1998

A placebo-controlled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. The Alendronate Research Group.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent inhibitor of bone resorption. The efficacy and safety of 36 weeks of treatment with alendronate were evaluated in Japanese women with osteoporosis, osteoporotic osteopenia or artificial menopause. The bone mineral density (BMD) of the lumbar vertebrae, markers of bone and calcium metabolism and clinical symptoms were monitored. A total of 113 randomly selected patients with osteoporosis or osteopenia were enrolled in the study, of whom 12 were excluded from the analyses because of lack of data. As a result, 101 patients were evaluated for the safety of the drug. Since eight patients were excluded from the efficacy analysis, 93 were evaluated. The incidence of adverse effects in the placebo (P), alendronate 2.5 mg/day (L) and alendronate 10 mg/day (H) groups increased with increasing dose of alendronate, being 6.1, 14.3 and 18.2%, respectively. The most common adverse effects were gastrointestinal symptoms, none of which was serious. Lumbar BMD increased after 36 weeks of drug administration to 5.21%, 5.64% and -0.90% in the L, H and P groups, respectively (P < 0.001, L vs. P and H vs. P). Serum alkaline phosphatase activity, serum osteocalcin and urinary deoxypyridinoline excretion were significantly decreased in a dose-related manner. Serum calcium and phosphorus were also significantly decreased after alendronate administration. Serum intact PTH was transiently increased. The present results indicate that alendronate effectively decreases bone turnover in a dose-related manner and increases lumbar BMD at a dosage of 2.5 mg/day, the lowest dose used in this study, in Japanese patients with osteoporosis.

Adult↗