加齢による骨代謝の変化とエストロゲンの生理学的意義に関する研究 (<シンポジウム>2. 中高年女性の加齢による変化)

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The diminution of bone mineral density (BMD) in women is initiated at the onset of menopause and estrogen withdrawal causes rapid bone loss in early postmenopausal years, leading to an increase in a risk of osteoporotic fracture. Several cytokines are considered to be involved in the decrease of BMD due to estrogen deficiency. Recently, it has been reported that estrogen is important for bone maturation and mineralization in men as well as in women. In this study, we investigated the involvement of estrogen deficiency in bone metabolism of postmenopausal women as compared with premenopausal women and assessed the factors relating to postmenopausal bone loss. In experimental study, at 4 weeks after ovariectolly (OVX), in OVX mice, femoral BMD decreased whereas the number of bone marrow cells was greatly increased. Two explore the endogenous bone-resorbing factors involved in estrogen deficiency, we examined the bone-resorbing activity in the supernatant fraction of mouse bone marrow collected from ovariectomized mice. Only anti-interleukin (IL)-1a antibody completely neutralized the bone-resorbing activity in bone marrow supernatants from OVX mice. The concurrent addition of IL-1, IL-6, sIL-6 receptor (R) and prostaglandin (PG)E_2 co-operatively induced bone resorption. The effect of L-1a on collagenase and gelatinase activities and matrix metalloproteinase (MMP)-2 and MMP-13 mRNA expression was analyzed using IL-1a supplemented medium of organ culture of newborn mouse calvaria and osteoblasts from newborn mouse calvaria, respectively. IL-1a increased collagenase and gelatinase activities as compared with those of control medium and stimulated MMP-2 and MMP-13 mRNA expression. Human osteoblast-like cells, HOS TE 85 cells, showed aromatase activity, which was determined using ^3H-androstenedione as a substrate and addition of retinoic acid, TPA, bone morphogenic protein (BMP)-2 and dexamethasone increased their aromatase activity. As determined by RT-PCR method, retinoic acid and TPA increased aromatase mRNA expression of HOS TE 85 cells. At 3 weeks after orchidectomy (ORX,), in ORX mice, the weight of seminal vesicles and femoral BMD decreased whereas the number of bone marrow cells was greatly increased. The change of hemopoiesis and bone metabolism induced by ORX were completely restored by the treatment with 1 μg of E_2 but not with 10 μg of DHT. In clinical study, several risk factors relating to low bone mass were assessed. Lumbar spine BMD significantly correlated with years since menopause (YSM) (r=-0.366), body weight (r=0.350), age (r=-0.340), body mass index (BMI) (r=0.242), and height (r=0.212) in the postmenopausal women. In order to investigate an association between vitamin D receptor (VDR) gene polymorphism and BMD or bone loss, we examined VDR BsmI RFLP with amplification refractory mutation system (ARMS) and could not find any significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods vertebral BMD with the Bb genotype decreased faster than that with the bb genotype (p=0.001). When we divided the subjects whose ages were from 45 to 55 years into two subgroups (pre- and postmenopausal) to assess the effects of menopause on biochemical markers of bone resorption, we found a significant 110% increase in cross-linked N-telopeptides of type I collagen (NTx) and a 48% increase in lysylpyridinoline (LP) in postmenopausal women compared with age-matched premenopausal women. The ROC analysis showed that the cutoff BMD values for discrimination of women with vertebral fracture varied according to the sites and methods of measurement ranging 59.0% of young adult mean value (YAM) of radial trabecular BMD by pQCT to 83.8% of young adult mean value (YAM) of femoral neck BMD by DXA.
社団法人日本産科婦人科学会の論文
1997-08-01

加齢による骨代謝の変化とエストロゲンの生理学的意義に関する研究 (<シンポジウム>2. 中高年女性の加齢による変化)

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