Shozo Yano

Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women

OBJECTIVE Although total fat body mass (FM) is considered to be one of the major determinants of bone mass, the mechanism by which FM and bone mass are positively correlated remains unclear. Leptin, the product of the obese (ob) gene, is secreted from adipocytes and its plasma levels are known to be positively correlated with %fat (FM divided by total body weight). There is recent evidence suggesting that leptin directly stimulates osteoblastic differentiation. Thus it is possible that the anabolic action of this hormone on bone may participate in the positive correlation between FM and bone mass. In this study, we analysed the relationships between either plasma leptin levels or %fat vs. bone mineral density (BMD) values as well as the presence of vertebral compression fractures, and evaluated whether or not plasma leptin levels were associated with BMD or bone fragility in a manner independent of FM.

Determinants of bone mineral density and spinal fracture risk in postmenopausal Japanese women

Abstract: The present study analyzed the factors that determine bone mineral density (BMD) and predict spinal fracture risk in postmenopausal Japanese women. Two hundred and five postmenopausal Japanese women aged 48–84 years (mean age 64 years) were enrolled in the cross-sectional study. BMD of the lumbar spine, femoral neck and total body as well as body composition were measured by dual-energy X-ray absorptiometry (DXA). Mid-radial BMD was measured by single-photon absorptiometry. We also determined serum levels of insulin-like growth factor (IGF)-I, IGF binding protein-2, -3 and osteocalcin as well as urinary levels of pyridinoline (Pyr), deoxy-Pyr (D-Pyr) and growth hormone. Multiple regression analysis revealed that lean body mass (LBM) was positively correlated with BMD at all sites. In contrast, femoral neck BMD was highly related to fat mass as well as LBM, although fat mass was not an independent correlate of total body and mid-radial BMD. LBM and urinary D-Pyr were crucial determinants at all sites except the mid-radius in stepwise regression analysis. Fat mass and serum IGF-I were determinants of femoral neck and mid-radial BMD, respectively. In terms of reproductive history, parity affected lumbar BMD. Factors affecting BMD differed according to the site. On the other hand, lumbar BMD as well as serum levels of IGF-I and albumin were selected as predictors of spinal fracture risk in multiple logistic regression analysis. Lumbar BMD, serum IGF-I and LBM were selected in women with lumbar BMD above 0.727 g/cm2. In conclusion, the present study indicates that LBM is a more important determinant of BMD than fat mass at any site except the femoral neck. Age, serum IGF-I and urinary D-Pyr were also determinants of BMD, dependent on the regions measured. Lumbar BMD and LBM as well as serum levels of IGF-I and albumin were useful markers which predicted the risk of osteoporotic spinal fractures in postmenopausal Japanese women.

The Presence and Severity of Vertebral Fractures is Associated with the Presence of Esophageal Hiatal Hernia in Postmenopausal Women

Abstract: We examined the relationship between the presence of esophageal hiatal hernia (HH) assessed by endoscopy and the presence of vertebral fractures (VFs) in 87 Japanese postmenopausal women (age range 52–87 years). We found that 29 (63%) of 46 patients with HH (71.2 ± 6.1 years, mean ± SD) had one or more VFs, compared with 14 (34%) of 41 patients without HH (70.8 ± 6.8 years), which was a significant difference in the frequency of VFs (c2= 7.242; p= 0.0071). The average number of VFs per patient was significantly higher for the patients with HH than for those without HH (1.67 ± 1.75 vs 0.68 ± 1.21, p= 0.0032). There were no significant differences in absolute or age-matched bone mineral density (BMD) values at the lumbar spine (0.656 ± 0.131 vs 0.662 ± 0.148 g/cm2; Z-score, –0.35 ± 1.17 vs –0.26 ± 1.00) and there were no significant differences in biochemical parameters, age, years since menopause or body mass index (BMI) between the two groups. When patients were divided into those with reflux esophagitis (RE) (n= 30, 70.2 ± 7.3 years) and those without RE (n= 57, 71.4 ± 5.9 years), no significant differences were detected in any of the above parameters including the presence or number of VFs. The patients were further subdivided into four groups: those with ‘HH only’ (n= 23, 72.3 ± 4.6 years), with ‘RE only’ (n= 7, 70.9 ± 7.7 years), with ‘both’ (n= 23, 70.0 ± 7.3 years) and with ‘neither’ (n= 34, 70.8 ± 6.7 years). One or more VFs were found in 12 (52%), 1 (14%), 17 (74%), and 13 (38%) patients in each group, respectively, and the difference in frequency was significant (c2= 10.748; p= 0.0132). The average number of VFs per patient in each group was 1.57 ± 2.06, 0.14 ± 0.38, 1.78 ± 1.41 and 0.79 ± 1.30, respectively, and there were significant differences between the ‘both’ and ‘neither’ groups, and between the ‘both’ and ‘RE only’ groups (p<0.05). When univariate logistic regression analysis was performed with the presence of HH as a dependent variable and each of the presence of VFs, the number of VFs per patient, absolute or age-matched BMD values at the lumbar spine, BMI and plasma albumin as independent variables, the presence of VFs and the number of VFs per patient were selected as indices affecting the presence of HH (odds ratio: 3.29 and 1.59, 95% confidence interval: 1.36–7.94 and 1.14–2.23; pu2009=u20090.0080 and 0.0064, respectively). These results show that the presence and severity of VFs are associated with the presence of HH but not of RE in Japanese postmenopausal women, and suggest that kyphosis induced by multiple VFs might predispose elderly women to a complication with HH.

Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients

The present study was performed to investigate the association of calcium-sensing receptor (CaSR) genotypes with parathyroid hormone (PTH) secretion in hemodialysis patients. Subjects were 122 Japanese hemodialysis patients, including 39 patients with diabetes mellitus (DM). The CaSR polymorphisms tested were codon 990 in intracellular domain (A/A, A/G, and G/G groups) as well as T to C base change of intron 4 (T/T, T/C, and C/C groups). Statistical analysis of these polymorphisms revealed that the serum PTH level was significantly higher in the A/A group than in the G/G group in the former. In addition, the serum PTH level was also significantly higher in patients displaying C allele, as compared with the T/T group in the latter. This association of two polymorphisms with the serum PTH level was observed only in non-DM patients. Although two polymorphisms affected the PTH level independently, patients who possessed both genotypes (AAC+) had a markedly high level of PTH not only in the non-DM group but also in the DM group. The present findings indicate the possibility of the prediction for the extensive progression of secondary hyperparathyroidism through analyzing the CaSR polymorphisms in chronic hemodialysis patients.

Association of polymorphic alleles of the calcium‐sensing receptor gene with the clinical severity of primary hyperparathyroidism

OBJECTIVE Primary hyperparathyroidism (pHPT) is a heterogeneous disease in its clinical course and severity. Previous studies have suggested an association between the clinical severity of pHPT and the genotypes of vitamin D receptor, oestrogen receptors and PTH molecules. The Ca‐sensing receptor (CaR) is activated by an extracellular calcium ion and controls PTH secretion, and thus polymorphisms of CaR might be associated with the magnitude of PTH secretion and the clinical severity of pHPT. In this study, we examined the relationship between CaR polymorphisms and biochemical markers in pHPT patients.

Familial Hypocalciuric Hypercalcemia Caused by an R648stop Mutation in the Calcium-Sensing Receptor Gene †

In this study, we report an 84‐year‐old female proband in a Japanese family with familial hypocalciuric hypercalcemia (FHH) caused by an R648stop mutation in the extracellular calcium‐sensing receptor (CaR) gene. At the age of 71 years, she presented with hypercalcemia (11.4 mg/dl), hypocalciuria (Cca/Ccr = 0.003), hypermagnesemia (2.9 mg/dl), and a high‐serum parathyroid hormone (PTH) level (midregion PTH, 3225 [160–520] pg/ml). At the age of 74 years, a family screening was carried out and revealed a total of 9 hypercalcemic individuals (all intact PTH values <62 pg/dl) among 17 family members tested, thus, being diagnosed as FHH. Two and one‐half of three clearly enlarged parathyroid glands were resected, because persistently high PTH levels (intact PTH, 292 pg/ml; midregion PTH, 5225 pg/ml) and the presence of a markedly enlarged parathyroid gland by several imaging modalities (ultrasonography, computed tomography [CT], magnetic resonance imaging [MRI], and subtraction scintigraphy) suggested coexistent primary hyperparathyroidism (pHPT); however, hypercalcemia persisted postoperatively. Histological and immunohistochemical examination revealed that the resected parathyroid glands showed lipohyperplasia as well as normally expressed Ki67, vitamin D receptor (VDR), and the CaR. Sequence analysis disclosed that the proband and all affected family members had a heterozygous nonsense (R648stop) mutation in the CaR gene. This mutation is located in the first intracellular loop; thus, it would be predicted to produce a truncated CaR having only one transmembrane domain (TMD) and lacking its remaining TMDs, intracellular loops, and C‐terminal tail. Western analysis of biotinylated HEK293 cells transiently transfected with this mutant receptor showed cell surface expression of the truncated protein at a level comparable with that of the wild‐type CaR. The mutant receptor, however, exhibited no increase in intracellular free calcium concentration (Ca2+i) when exposed to high extracellular calcium concentrations (Ca2+o). The probands clinical course was complicated because of associated renal tubular acidosis (RTA) and nephrotic syndrome. However, it was unclear whether their association affected the development of elevated serum PTH and parathyroid gland enlargement. This report is the first to show that an R648stop CaR mutation yields a truncated receptor that is expressed on the cell surface but is devoid of biological activity, resulting in FHH.