在絕經後婦女，由於雌激素水平的迅速降低，骨質疏鬆、糖尿病、肥胖等代謝性疾病的發病率明顯增加。絕經後骨質疏鬆症的發生，除了因為雌激素對於骨代謝的直接調節以外，可間接作用於骨代謝的糖尿病、肥胖等疾病的影響亦不可忽視。對於絕經後婦女骨質疏鬆症的治療，傳統上採用荷爾蒙替代療法，即給病患提供維持劑量的雌激素。另一方面，三價鉻離子因其具有調節糖代謝、蛋白質代謝和脂質代謝的功效而被廣泛應用於二型糖尿病的治療。然而，目前尚未有研究證實單獨補充三價鉻離子或是將其與荷爾蒙替代療法合併使用是否會對骨密度造成影響。因此，本研究的目的即在於探討單獨使用三價鉻離子及將其與雌二醇併用時對於絕育後雌性大鼠骨代謝的影響。實驗採用了36隻八周齡的雌性SD大鼠，在實施子宮卵巢摘除術後隨機分成六組：對照組（Control），進行子宮卵巢摘除術後以生理鹽水灌胃；鉻離子組（Cr），進行子宮卵巢摘除術後以三價鉻離子溶液灌胃；低劑量雌二醇組（LE2），進行子宮卵巢摘除術後以維持劑量的雌二醇溶液灌胃；低劑量雌二醇加鉻離子組（LE2+Cr），進行子宮卵巢摘除術後以維持劑量的雌二醇與三價鉻離子混合溶液灌胃；高劑量雌二醇組（HE2），進行子宮卵巢摘除術後以二十倍於維持劑量的雌二醇溶液灌胃；高劑量雌二醇加鉻離子組（HE2+Cr），進行子宮卵巢摘除術後以二十倍於維持劑量的雌二醇與三價鉻離子混合溶液灌胃。實驗期間每週稱取大鼠體重並記錄。於實施子宮卵巢摘除術十五周後犧牲大鼠，收集血液樣本測量鈣（Ca）、磷（P）、副甲狀腺素（PTH）及骨鈣蛋白（OC）的濃度以評估骨代謝；取雙側的股骨和脛骨測量松質骨含量（BV/TV）以評估骨密度。結果顯示，在未添加鉻離子的三個實驗組（Control，LE2和HE2組）中，相對體重增長率（VarBW）、骨松質含量（BV/TV）以及PTH含量這三個因素與雌激素劑量具有相關性；其中只有高劑量雌二醇組（HE2）具有明顯的預防骨質疏鬆的作用（以松質骨含量作為評估標準）。在所有的被測項目中，鉻離子組（Cr）與低劑量雌二醇組（LE2）具有相似的結果。但是，當將三價鉻離子與雌二醇併用時，鉻離子會將原本存在於不同劑量雌二醇組間的差異縮小。綜合以上結果，單獨使用三價鉻離子在調節骨代謝方面具有與單獨給予維持劑量的雌二醇類似的功效；將三價鉻離子與維持劑量的雌二醇合並使用亦不會造成明顯差異。但是，若將三價鉻離子與高劑量雌二醇併用，則會削弱高劑量雌二醇的骨保護作用。

In postmenopausal women, the dramatic decrease of estrogen results in a high morbidity of osteoporosis as well as other metabolic disorders like diabetes and obesity. Apart from the direct effect of estrogen on bone metabolism, diabetes and obesity also affect it indirectly. The traditional treatment of women postmenopausal osteoporosis is hormone replacement therapy (HRT), a supplement of maintaining dose estradiol (E2). Trivalent chromium (Cr3+), for its benefit to carbohydrate, protein and lipid metabolism, is widely used in the treatment of type 2 diabetes mellitus. However, whether a supplement of Cr3+ alone or combined with HRT will make some differences on bone mineral density remains uninvestigated. Therefore, the aim of this study is to figure out the effects of Cr3+ alone and combined with E2 on bone metabolism in the model of ovariohysterectomized rats. Thirty-six 8-week-old female Sprague-Dawley rats were randomly divided into 6 groups after ovariohysterectomy: Control (administration of saline), Cr (Cr3+ supplement only), LE2 (a supplement of maintaining-dose E2 only), LE2+Cr (a supplement of maintaining-dose E2 with Cr3+), HE2 (a supplement of 20X maintaining-dose E2 only) and HE2+Cr (a supplement of 20X maintaining-dose E2 with Cr3+). Body weight was measured weekly during 15 weeks’ experiment. Plasma Calcium (Ca), Phosphorus (P), parathyroid hormone (PTH) and osteocalcin (OC) concentrations were measured to evaluate bone metabolism. Bilateral femurs and tibiae were dissected to measure trabecular bone percent (BV/TV%). The results showed an E2-dose-related relationship in variant body weight ratio (VarBW), PTH and BV/TV within None Cr groups (Control, LE2 and HE2 groups) and only high-dose E2 had a significant (P<0.05) effect on preventing osteoporosis according to BV/TV. The Cr group shared similar data (P>0.05) with LE2 group on all the parameters. Moreover, an addition of Cr3+ tended to narrow the E2-dose-related difference between None Cr groups. It is indicated that Cr3+ has an effect on bone metabolism similar to maintaining-dose E2, as well as the combination of Cr3+ and maintaining-dose E2. However, an addition of Cr3+ can weaken the bone protection effect of high-dose E2.

摘要 i
Abstract ii
Content iii
List of table v
List of figure vi
Chapter 1 Introduction 1
Chapter 2 Literature review 2
2.1. Bone anatomy and metabolism 2
2.1.1. The general anatomy of long bone 2
2.1.2. The constituent of bone 4
2.1.3. Bone remodeling 9
2.1.4. Bone homeostasis 10
2.1.5. Calcium and Phosphorus Metabolism 15
2.2. Chromium 17
2.2.1. Physiology of chromium 17
2.2.2. The effect of Chromium on bone metabolism 18
Chapter 3 Materials and methods 22
3.1. Animals 22
3.2. Experimental design 22
3.3. Variant body weight ratio % (VarBW%) calculation 24
3.4. Histology and histomorphometric evaluations 24
3.5. Plasma measurement 25
3.5.1. Biochemical parameters 25
3.5.2. Hormone parameters 25
3.6. Statistical analysis 26
Chapter 4 Results 28
4.1. The final variant body weight ratio % (VarBW%) 28
4.2. Histology evaluations of trabecular bone structure 28
4.3. Histomorphometric evaluations (BV/TV%) of trabecular bone structure 29
4.3.1. Trabecular bone structure in proximal metaphysis of tibia 29
4.3.2. Trabecular bone structure in distal metaphysis of femur 30
4.3.3. Comparison of BV/TV (%) between tibial proximal metaphysis and femoral distal metaphysis 30
4.3.4. Correlation between BV/TV of tibial proximal metaphysis and femoral distal metaphysis against the final variant body weight ratio (VarBW) 31
4.4 The plasma concentration of bone remodeling markers 31
4.4.1. The plasma concentration of Calcium 31
4.4.2. The plasma concentration of Phosphorus 32
4.4.3. The product of plasma concentration of Calcium and Phosphorus 32
4.4.4. The plasma concentration of parathyroid hormone (PTH) 33
4.4.5. The plasma concentration of osteocalcin (OC) 34
4.4.6. Correlation among BV/TV of tibial proximal metaphysis and femoral distal metaphysis and variant body weight ratio (VarBW) 34
4.4.7. Correlation among BV/TV of tibial proximal metaphysis and femoral distal metaphysis and plasma measurements of bone remodeling 35
4.4.8. Correlation among plasma measurements of bone remodeling 35
Chapter 5 Discussion 55
5.1. The effect of estradiol in different dosages on bone metabolism (comparison among None E2 groups) 55
5.2. The effect of Trivalent Chromium combined with estradiol in different dosages on bone metabolism 57
5.3. Correlation between BV/TV and other parameters 59
5.4. Correlation among plasma measurements of bone remodeling 60
5.5 Conclusion 61
Reference 63

Reference
Aguirre, J. I., Plotkin, L. I. & Stewart, S. A., 2006. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. Journal of Bone and Mineral Research 21(4):605-615.
Akune, T., Ohba, S., Kamekura, S. & Yamaguchi, M., 2004. PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846-855.
Al-Qatati, A., Winter, W. P., Wolf-Ringwall, L. A. & Chatterjeeb, B. P., 2012. Insulin Receptors and Downstream Substrates Associate with Membrane Microdomains after Treatment with Insulin or Chromium(III) Picolinate. Cell Biochemistry and Biophysics:441-450.
Alikhani, M., Alikhani, Z. & Boyd C, C., 2007. Advanced glycation end prod ucts stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40(2):345-353.
Anderson, R. A., 1998. Chromium, glucose intolerance and diabetes. Journal of the Ameracan College of Nutrition 17(6):548-555.
Anderson, R. A., 2000. Chromium in the prevention and control of diabetes. Diabetes Metab 26:22-27.
Arana-Chavez, V. E. & Bradaschia-Correa, V., 2009. Clastic cells: mineralized tissue resorption in health and disease. The International Journal of Biochemistry & Cell Biology 41(3):446-450.
Auwerx, J., Dequeker, J. & Bouillon, R., 1988. Mineral metabolism and bone mass at peripheral and axial skeleton in diabetes mellitus. Diabetes 37:8-12.
Baron, R., Ferrari, S. & Russell, R. G., 2011. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677-692.
Battula, V. L., Chen, Y. & Cabreira MdaG, 2013. Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 122(3):357-366.
Bellido , T., Ali , A. A. & Plotkin, I. L., 2003. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts: a putative explanation for why intermittent administration is needed for bone anabolism.. The Journal of Biological Chemistry 278(50):50259-50272.
Bellido, T., 2014. Osteocyte-driven bone remodeling. Calcified Tissue International 94(1):25-34.
Bieńko, M., Radzki , P. R. & Wolski, D., 2017. The peripheral quantitative computed tomographic and densitometric analysis of skeletal tissue in male Wistar rats after chromium sulfate treatment.. Annals of Agricultural and Environmental Medicine 24(3):446-452.
Boivin, G., Bala, Y. & Doublier, A., 2008. The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients. Bone 43(3):532-538.
Boivin, G. & Meunier, P. J., 2002. The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography. Calcified Tissue International 70(6):503-511.
Bonewald, L. F., 2007. Osteocytes as dynamic multifunctional cells. Annals of the New York Academy of Sciences 1116:281-290.
Bonewald, L. F., 2011. The amazing osteocyte. Journal of Bone and Mineral Research 26(2):229-238.
Boyce, B. F., Hughes, D. E., Wright, K. R. & Xing, L., 1999. Recent advances in bone biology provide insight into the pathogenesis of bone diseases. Laboratory Investigation 79(2):83-94.
Boyce, B. F. & Xing, L., 2008. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of Biochemistry and Biophysics 473(2):139-146.
Boyle, W. J., Simonet, W. S. & Lacey, D. L., 2003. Osteoclast differentiation and activation. Nature 423:337-342.
Brody, S., Carlstrom, K. & Lagrelius, A., 1987. Adrenal steroids in post-menopausal women: relation to obesity and to bone mineral content. Maturitas 9:25-32.
Brown, R. O., Forloines, L. S., Cross, R. E. & Heizer, W. D., 1986. Chromium deficiency after long-term total parenteral nutrition. Dig Dis Sci 32:661-664.
Burger, E. H. & Klein-Nulend, J., 1999. Mechanotransduction in bone—role of the lacuno-canalicular network. The FASEB Journal 13(8):101-112.
Buysschaert, M., Cauwe, F. & Jamart, J., 1992. Proximal femur density in type 1 and 2 diabetic patients. Diabete Metab 18:32-37.
Calvi, L. M., Sims, N. A. & Hunzelman, J. L., 2001. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. The Journal of Clinical Investigation 107(3):277-286.
Canalis, E. M., Dietrich, J. W., Maina, D. M. & Raisz, L. G., 1977. Hormonal control of bone collagen synthesis in vitro: effects of insulin and glucagon. Endocrinology 100:668-674.
Capulli, M., Paone, R. & Rucci, N., 2014. Osteoblast and osteocyte: games without frontiers. Archives of Biochemistry and Biophysics 561:3-12.
Cenci, S., Weitzmann, M. N. & Roggia, C., 2000. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α. The Journal of Clinical Investigation 106(10):1229-1237.
Civitelli, R., Lecanda, F., Jørgensen, N. R. & Steinberg, T. H., 2002. Intercellular junctions and cell-cell communication in bone. In: Principles of Bone Biology. San Diego(Calif): Academic Press:287-302.
Clodfelder, B. J. & Vincent, J. B., 2005. The time-dependent transport of chromium in adult rats from thr bloodstream to the urine. J Biol Inorg Chem 10:383-393.
Cohick, W. S. & Clemmons, D. R., 1993. The insulin-like growth factors. Annu Rev Physiol 55:131-153.
College, O., n.d. OpenStax College, Anatomy and Physiology. [Online]
Available at: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22@8.108.
Compston, J., Flahive, J., Hosmer, D. & Watts, N., 2014. Relationship of weight, height, and body mass index with fracture risk at different sites in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW). J Bone Miner Res 29:487-493.
Conover , C. A., 2008. Insulin-like growth factor-binding proteins and bone metabolism.. Am J Physiol Endocrinol Metab 294:10-14.
Crockett, J. C., Mellis, D. J., Scott, D. I. & Helfrich, M. H., 2011. New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis. Osteoporosis International 22(1):1-20.
Cruzoe-Souza, M., Sasso-Cerri, E. & Cerri, P. S., 2009. Immunohis- ´tochemical detection of estrogen receptor beta in alveolar bone cells of estradiol-treated female rats: possible direct action of estrogen on osteoclast life span. Journal of Anatomy 215(6):673-681.
Cummings, S. R., Kelsey, J. L., Nevitt, M. C. & O''Dowd, K. J., 1985. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178-208.
Dallas, S. L., Prideaux, M. & Bonewald, L. F., 2013. The Osteocyte: An Endocrine Cell … and More. Endocr Rev 34(5):658-690.
Damoulis, P. D. & Hauschka, P. V., 1997. Nitric oxide acts in conjunction with proinflammatory cytokines to promote cell death in osteoblasts. Journal of Bone and Mineral Research 12(3):412-422.
Daynes, R. A., Araneo, B. A. & Ershler, W. B., 1993. Altered regulation of IL-6 production with normal aging. J Immunol 150:5219-5230.
De Leeuw, I. & Abs, R., 1977. Bone mass and bone density in maturity type diabetics measured by the 125I photon-absorption technique. Diabetes 26:1130-1135.
Dempster, D. W., Cosman , F. & Parisien, M., 1993. Anabolic actions of parathyroid hormone on bone. Endocr Rev 14:690-709.
Devogelaer , J. P., Crabb6, J. & Nagant de Deuxchalsnes, C., 1987. Bone mineral density in Addison''s disease: evidence for an effect of adrenal androgens on bone mass. BMJ 294:798-800.
Dowling, H. J., Offenbacher, E. G. & Pi-Sunyer, F. X., 1989. Absorption of inorganic trivalent chromium from the vascular perfused rat small intestine. J Nutr. 119:1138-1145.
Ducros, V., 1992. Chromium metabolism, a literature review. Biol Trace Elem Res. 32:65-77.
Ducy, P., Zhang, R., Geoffroy, V. & Ridall, A. L., 1997. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89(5):747-754.
Eghbali-Fatourechi, G., Khosla, S., Sanyal, A. & Boyle, W. J., 2003. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. The Journal of Clinical Investigation 111(8):1221-1230.
Emerton, K. B., Hu, B. & Woo, A. A., 2010. Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 46(3):577-583.
Evans, G. W. & Pouchnik, D. J., 1993. Composition and biological activity of chromium-pyridine carboxylate complexes. J Inorgan Chem 49:177-187.
Evans, G. W., Swenson, G. & Waiters, K., 1995. Evans G W, Swenson G, Waiters K. Chromium picolinate decreases calcium excretion and increases dehydroepiandrosterone (DHEA) in postmenopausal women (abstract). FASEB J.
Faloni, A. P., Sasso-Cerri, E., Katchburian, E. & Cerri, P. S., 2007. Decrease in the number and apoptosis of alveolar bone osteoclasts in estrogen-treated rats. Journal of Periodontal Research 42(3):193-201.
Felson, D. T., Zhang, Y., Hannan, M. T. & Anderson, J. J., 1993. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res 8(5):567-573.
Fernandez-Perez, L. & Flores-Morales, A., 2012. Estrogens in the control of growth hormone actions in liver. Intech Open Access Publisher.
Franz-Odendaal, T. A., Hall, B. K. & Witten, P. E., 2006. Buried alive: how osteoblasts become osteocytes. Developmental Dynamics 235(1):176-190.
Gambacciani, M. & Levancini, M., 2014. Hormone replacement therapy and the prevention of postmenopausal osteoporosis. Prz Menopauzalny 13(4):213-220.
Gentry, R. & Wade, G., 1976. Sex differences in sensitivity of food intake, body weight, and running-wheel activity to ovarian steroids in rats. J Comp Physiol Psychol 90:747-754.
Gimble, J., Robinson, C., Wu, X. & Kelly, K., 1996. Peroxisome proliferator activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol 50:1087-1094.
Glass, D. A., Bialek, P. & Ahn, J. D., 2005. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Developmental Cell 8(5):751-764.
Glimcher, M. J., 1998. The nature of the mineral phase in bone. Metabolic Bone Disease:23-50.
Graves, A. R., Curran, P. K., Smith, C. L. & Mindell, J. A., 2008. The Cl−/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453(7196):788-792.
Greco, E., Fornari, R., Rossi, F. & Santiemma, V., 2010. Is obesity protective for osteoporosis? Evaluation of bone mineral density in individuals with high body mass index. Int J Clin Pract 64:817-820.
Greco, E., Francomano, D., Fornari, R. & Marocco, C., 2013. Negative association between trunk fat, insulin resistance and skeleton in obese women. World J Diabetes 4:31-39.
Gregorio, F., Cristallini, S., Santeusanio, F. & Filipponi, P., 1994. Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes?. Diabetes Res Clin Pract 23(1):43-54.
Gu, G., Mulari, M., Peng, Z. & Hentunen, T. A., 2005. Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption. Biochemical and Biophysical Research Communications 335(4):1095-1101.
Hill, P. A., Reynolds, J. J. & Meikle, M. C., 1995. Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function. Endocrinology 136:124-131.
Hofbauer, L. C. & Heufelder, A. E., 2001. Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology. Journal of Molecular Medicine 79(5-6):243-253.
Hughes, D. E., Dai, A., Tiffee, J. C. & Li, H. H., 1996. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-β. Nature Medicine 2(10):1132-1136.
Hu, H., Hilton, M. J., Tu, X. & Yu, K., 2005. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132(1):49-60.
Hui, S. L., Epstein, S. & Johnston, C. C., 1985. A prospective study of bone mass in patients with type I diabetes. J Clin Endocrinol Metab 60:74-80.
Iida-Klein, A. & Hahn, T. J., 1991. Insulin acutely suppresses parathyroid hormone second messenger generation in UMR-106-01 osteoblast-like cells: differential effects on phospholipase C and adenylate cyclase activation. Endocrinology 129:1016-1024.
Iida-Klein, A., Ituarte, H. G. & Hahn, T. J., 1987. Insulin modulates the effects of parathyroid hormone on mitogenesis and cAMP generation in osteoblast-like cells. Clin. Res 35: 623A.
Iida-Klein, A., Varlotta, V. & Hahn, T. J., 1989. Protein kinase C activity in UMR-106-01 cells: effects of parathyroid hormone and insulin. J Bone Min Res 4:767-774.
Jilka, L. R., Weinstein, S. R., Bellido, T. & Roberson, P., 1999. Increased bone formation byprevention of osteoblast apoptosis with parathyroid hormone.. The Journal of Clinical Investigation. 104(4):439-446.
Jilka, R. L., Hangoc, G. & Girasole, G., 1992. Increased osteoclast development after estrogen loss: mediation by interleukin-6.. Science 257:88-91.
Kaji, H., Sugimoto, T., Kanatani, M. & Nasu, M., 1996. Estrogen blocks parathyroid hormone (PTH)-stimulated osteoclast-like cell formation by selectively affecting PTH-responsive cyclic adenosine monophosphate pathway. Endocrinology 6:2217-2224.
Kanis, A. J., McCloskey, V. E. & Johansson, H., 2013. European guidance for the diagnosis and management of osteoporosis in postmenopausal women.. Osteoporosis International 24(1):23-57.
Kawamoto, S., Ejiri, S., Nagaoka, E. & Ozawa, H., 2002. Effects of oestrogen deficiency on osteoclastogenesis in the rat periodontium. Archives of Oral Biology 47(1):67-73.
Kearns, A. E. & Kallmes, D. F., 2008. Osteoporosis primer for the vertebroplasty practitioner: expanding the focus beyond needles and cement. AJNR Am. J. Neuroradiol 29:1816-1822.
Khosla, S., Oursler, M. J. & Monroe, D. G., 2012. Estrogen and the skeleton. Trends in Endocrinology and Metabolism 23(11):576-581.
Kim, D. S., Kim, T. W. & Kang, J. S., 2004. Chromium picolinate supplementation improves insulin sensitiviy in Goto-Kakizaki diabetic rats. Journal of Trace Elements in Medicine and Biology 17:243-247.
Kim, K., Lee, S. H., Kim, J. H. & Choi, Y., 2006. NFATc1 induces osteoclast fusion via up-regulation of osteoclast fusion and increased bone formation. Nature Medicine 12(12):1403-1409.
Kim, K., Shin, D., Lee, S. & Im, J., 2010. Relation between obesity and bone mineral density and vertebral fractures in korean postmenopausal women. Yonsei Med J 51:857-863.
Kini, U. & Nandeesh, B. N., 2012. Physiology of Bone Formation, Remodeling, and Metabolism . In: Radionuclide and Hybrid Bone Imaging. Berlin: Springer-Verlag .
Kornak, U., Kasper, D. & Bosl, M. R., 2001. Loss of the CIC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104(2):205-215.
Kousteni, S., Chen, J. R. & Bellido, T., 2002. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298(5594):843-846.
Kream, B. E., Smith, M. D., Canalis, E. & Raisz, L. G., 1985. Characterization of the effect of insulin on collagen synthesis in fetal rat bone. Endocrinology 116:296-302.
Kuryl, T. & Debski, B., 2008. The effect of microelements supplementation on beta-oxidation activity in healthy and type 1 diabetic rats. Cent Eur J Public Health 16:205-208.
Lacey, D. L., Timms, E., Tan, H. L. & Kelley, M. J., 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165-176.
Lefavi, R., Dennis, W. G., Keith, R. & Anderson, R., 1993. Lipid-lowering effect of a dietary chromium (Ⅲ) — Nicotinic acid complex in male athletes. Nutrition Research 13:239-249.
Levin, M., Boisseau, V. C. & Avioli, L. V., 1976. Levin M, Boisseau V C, Avioli L V. Effects of diabetes mellitus on bone mass in juvenile and adult onset diabetes. N Engl J Med 294:241-245.
Ljusberg, J., Wang, Y. & Lang, P., 2005. Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. The Journal of Biological Chemistry 280(31):28370-28381.
Longhini, R., Oliveira, P. A., Sasso-Cerri, E. & Cerri, P. S., 2014. Cimetidine reduces alveolar bone loss in induced periodontitis in rat molars. Journal of Periodontology 85(8):1115-1125.
Luxenburg, C., Geblinger, D. & Klein, E., 2007. The architecture of the adhesive apparatus of cultured osteoclasts: from podosome formation to sealing zone assembly. PLoS ONE 2(1).
MacNair, P., Madsbod, S. & Christiansen, C., 1978. Osteopenia in insulin-treated diabetes mellitus. Diabetologia 15:87-90.
Magni, P., Dozio, E., Galliera, E. & Ruscica, M., 2010. Molecular aspects of adipokine–bone interactions. Curr Mol Med 10:522-532.
Manolagas, S. C., 2000. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews 21(2):115-137.
Martin-Millan, M., Almeida, M. & Ambrogini, E., 2010. The estrogen receptor in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Molecular Endocrinology 24(2):323-334.
Martin, R. & Zissimos, S., 1991. Relationships between marrow fat and bone turnover in ovariectomized and intact rats. Bone 12:123-131.
Matsuo, K. & Irie, N., 2008. Osteoclast-osteoblast communication. Archives of Biochemistry and Biophysics 473(2):201-209.
Mattheeuws, D., Rottiers, R. & Kaneko, J., 1984. Diabetes mellitus in dogs: relationship of obesity to glucose tolerance and insulin response. Am J Vet Res 45:98-103.
McCarty, M. F., 1995. Anabolic Effects of Insulin on Bone Suggest a Role for Chromium Picolinate in Preservation of Bone Density. Medical Hypotheses 45:241-246.
Meema, E. & Meema, S., 1967. The relationship of diabetes mellitus and body weight to osteoporosis in elderly females. Can Med Assoc J 96:132-139.
Miao, D. & Scutt, A., 2002. Recruitment, augmentation and apoptosis of rat osteoclasts in 1,25-(OH)2D3 response to short term treatment with 1,25-dihydroxyvitamin D3 in vivo. BMC Musculoskeletal Disorders 7:3-16.
Morales, A. J., Nolan , J. J., Nelson, J. C. & Yen, C. S., 1994. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 78:1360-1367.
Mulari, M., Vaaraniemi, J. & Vaananen, H. K., 2003. Intracellular membrane trafficking in bone resorbing osteoclasts. Microscopy Research and Technique 61(6):496-503.
Mullender, M. G., Van Der Meer, D. D., Huiskes, R. & Lips, P., 1996. Osteocyte density changes in aging and osteoporosis. Bone 18(2):109-113.
Nakashima, K., Zhou, X. & Kunkel, G., 2002. The novel zinc finger-containing transcription factor Osterix is required for osteoblast differentiation and bone formation. Cell 108(1):17-29.
Nakashima, T., Hayashi, M. & Fukunaga, T., 2011. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature Medicine 17(10):1231-1234.
Negishi-Koga, T. & Takayanagi, H., 2012. Bone cell communication factors and Semaphorins. BoneKEy Reports 1.
Nelson, R. W., Himsel, C. A., Feldman, E. C. & Bottoms, G. D., 1990. Glucose tolerance and insulin response in normal-weight and obese cats. Am J Vet Res 51:1357-1362.
Nestler, J. E., McClanahan, M. A., Clore , J. N. & Blackard, W. G., 1992. Insulin inhibits adrenal 17,20-1yase activity in man. J Clin Endocrinol Metab 74:362-367.
Newton, D. C. & Nunamaker, M. D., 1985. Textbook of Small Animal Orthopaedics. s.l.:J.B. Lippincott Company.
Noble, B. S., Stevens, H., Loveridge, N. & Reeve, J., 1997. Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20(3):273-282.
Nordin, B. E., Robertson, A. & Seamark, R. F., 1985. The relation between calcium absorption, serum dehydroepiandrosterone, and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metah 60:651-657.
Oktar, F. N., Agathopoulos, S., Ozyegin, L. S. & Gunduz, O., 2007. Mechanical properties of bovine hydroxyapatite (BHA) composites doped with SiO2, MgO, Al2O3, and ZrO2. J. Mater. Sci. Mate. Med. 18:2137-2143.
Orentreich, N., Brink, J. L., Rizer , F. L. & Vogelman, J. H., 1984. Age changes and sex differences in serum dehydrnepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59:551-555.
Ott, E. A. & Kivipelto, J., 1999. Influence of chromium tripicolinate on growth and glucose metabolism in yerlinghorses. Journal of Animal Science 77:3022-3030.
Oursler, M. J., Osdoby, P., Pyfferoen, J. & Riggs, B. L., 1991. vian osteoclasts as estrogen target cells. Proceedings of the National Academy of Sciences of the United States of America 88(15):6613-6617.
Pacifici, R., 1996. Journal of Bone and Mineral Research 11(8):1043-1051.
Pagan, J. D., Jackson, S. G. & Duren, S. E., 1995. The effect of chromium supplementation on metabolic response to exercise in thoroughbred horses. In: P. Lyons & K. A. Jacques, eds. Biotechnology in the Feed Industry. UK: Nottingham University Press:249-256.
Parker, L. N., 1989. Adrenal Androgens in Clinical Medicine. San Diego, CA: Academic Press.
Paul, R. & Bailey, A., 1996. Glycation of collagen: the basis of its central role in the late complications of ageing and diabetes. Int J Biochem Cell Biol 28(12):1297-1310.
Phan, T. C., Xu, J. & Zheng, M. H., 2004. Interaction between osteoblast and osteoclast: impact in bone disease. Histology and Histopathology 19(4):1325-1344.
Plotkin, L. I., 2014. Apoptotic osteocytes and the control of targeted bone resorption. Current Osteoporosis Reports 12(1):121-126.
Poole, K. E., Bezooijen, R. L. & Loveridge, N., 2005. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. The FASEB Journal 19(13):1842-1844.
Rabinowitz, M. B., Gonick, H. C., Levin, S. R. & Davidson, M. B., 1983. Clinical trial of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men. Biol Trace Elem Res. 5:449-466.
Racek, J., Trefil, L., Rajdl, D. & Mudrova, V., 2006. Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus. Biol Trace Elem Res 109:215-230.
Rahnama M, J.-J. I. J. R. e. a., 2015. Analysis of the Influence of Hormone Replacement Therapy on Osteocalcin Gene Expression in Postmenopausal Women.. BioMed Research International 2015(3), p. 416929.
Raisz, L. C., Canalis, E. M. & Dietrich, J., 1978. Hormonal regulation of bone formation. Recent Prog Horm Res 34:335-356.
Raisz, L. G. & Rodan, G. A., 1998. Embryology and cellular biology of bone. In: Metabolic Bone Disease and Clinically Related Disorders. New York(NY): Academic Press:1-22.
Raskin, P., Stevenson, M., Barilla, D. E. & Pak, C., 1978. The hypercalciuria of diabetes mellitus: its amelioration with insulin. Clin Endocrinol (Oxf) 9(4):329-335.
Reid, I., 2012. Relationships among body mass, its components, and bone. Bone 31:547-555.
Reid, I., Evans, M., Cooper, G. & Ames, R. W., 1993. Reid I, Evans M, Cooper G, Ames RW, Stapleton J. Circulating insulin levels are related to bone density in normal postmenopausal women.. Am J Physiol Endocrinol Metab 265(4):655-659.
Riales, R. & Albrink, M. J., 1981. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am J Clin Nutr 34:2670-2678.
Rinaldo, F. S., Gisela, R. S. S., Estela, S. C. & Manuel, J. S., 2015. Biology of bone tissue: structure, function, and factors that influence bone cells. BioMed Research International.
Ringe, J. D., Kuhlencordt, F. & Kruse, H. P., 1976. Bone mineral determinations on long-term diabetics. Am J Roentgenol:1300-1301.
Robinson, L. J., Yaroslavskiy, B. B. & Griswold, R. D., 2009. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-α with BCAR1 and Traf6. Experimental Cell Research 315(7):1287-1301.
Robling, A. G., Castillo, A. B. & Turner, C. H., 2006. Biomechanical and molecular regulation of bone remodeling. Annual Review of Biomedical Engineering 8:455-498.
Rochefort, G. Y., Pallu, S. & Benhamou, C. L., 2010. Osteocyte: the unrecognized side of bone tissue. Osteoporosis International 21(9):1457-1469.
Rodriguez, J., Montecinos, L., Rios, S. & Reyes, P., 2000. Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J Cell Biochem 79:557-565.
Roodman, G. D., 1999. Cell biology of the osteoclast.. Exp Hematol 27:1229-1241.
Sahin, K., Tuzcu, M., Orhan, C. & Agca, C. A., 2011. The Effects of Chromium Complex and Level on Glucose Metabolism and Memory Acquisition in Rats Fed High-Fat Diet. BIological Trace Element Research, 143(2):1018-1030.
Schnoke, M., Midura, B. S. & Midura, J. R., 2009. Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair.. Bone 45(3):590-603.
Sekiya, I., Larson, B., Vuoristo, J. & Cui, J., 2004. Adipogenic differentiation of human adult stem cells from bone marrow stroma (MSCs). J Bone Miner Res 19:256-264.
Shaw, M. A., Whitaker, E. M., Hervey, E. & Hervey, G. R., 1983. The effects of ovarian hormones on regulation of energy blance in Zucker rats. J Endocrinol 98:165-171.
Sims, N. A. & Gooi, J. H., 2008. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Seminars in Cell and Developmental Biology 19(5):444-451.
Sodek, J. & McKee, M. D., 2000. Molecular and cellular biology of alveolar bone. Periodontology 2000 24(1):99-126.
Souza Faloni, A. P., Sasso-Cerri, E., Rocha, F. R. & Katchburian, E., 2012. Structural and functional changes in the alveolar bone osteoclasts of estrogen-treated rats. Journal of Anatomy 220(1):77-85.
Subiyatno, A., Mowat, D. N. & Yang, W. Z., 1996. Metabolite and hormonal responses to glucose or propionate infusions in periparturient diary cows supplemented with chromium. Journal of Diary Science 79:1436-1445.
Sundararaman, P. G., Sridhar, G. R., Sujatha, V. & Anita, V., 2012. Serum chromium levels in gestational diabetes mellitus. Indian J Endocrinol Metab 1:70-73.
Taelman, P., Kaufman, J. M., Janssens, X. & Vermeulen, A., 1989. Persistence of increased bone resorption and possible role of dehydroepiandrosterone as a bone metabolism determinant in osteoporotic women in late postmenopause. Maturitas 11:65-73.
Takagaki, M., Kakai, Y. & Satoyoshi, M., 1995. Matrix mineralization and the differentiation of osteocyte-like cells in culture. Journal of Bone and Mineral Research 10(2):231-242.
Takayanagi, H., 2007. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature Reviews Immunology 7(4):292-304.
Tate, M. L., 2003. Whither flows the fluid in bone?’ An osteocyte’s perspective. Journal of Biomechanics 36(10):1409-1424.
Thomas, T., Burguera, B. & Melton, L. J., 2001. Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women. Bone 29(2):114-120.
Tiano, J. P., Tate, C. R., Yang, B. S. & Marchi, R. D., 2015. Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis. Scientific Reports.
Tilg, H. & Moschen, A., 2008. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14:222-231.
Tomkinson, A., Reeve, J., Shaw, R. W. & Noble, B. S., 1997. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. Endocrine Society Journals and Publications 82:3128-3135.
Tryfonidou, M. A., Hazewinkel, H. A. & Kooistra, H. S., 2010. Calciotropic Hormones. In: Clinical Endocrinology of Dogs and Cats. s.l.:Die Deutsche Nationalbibliothek:253-264.
Turner, R. T., Lifrank, E. T. & Beckner, M., 1990. Dehydroepiandrosterone reduces cancellous bone osteopenia in ovariectomized rats. Am J Physiol 258:673-677.
Tuzcu, A., Bahceci, M., Dursun, M. & Parmaksiz, Y., 2004. Can long-term exposure to chromium improve insulin sensitivity in chromium mine workers?. Journal of Trace Elements in Experimental Medicine 17:55-63.
Ubaidus, S., Li, M. & Sultana, S., 2009. FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling. Journal of Electron Microscopy 58(6):381-392.
Vaananen, K., 2005. Mechanism of osteoclast mediated bone resorption—rationale for the design of new therapeutics. Advanced Drug Delivery Reviews 57(7):959-971.
Vanderschueren, D., Vandenput, L., Boonen, S. & Lindberg, M. K., 2004. Androgens and bone. Endocrine Reviews 25(3):389-425.
Vogt, M. T., Cauley, J. A., Kuller LH, L. H. & Nevitt, M. C., 1997. Bone mineral density and blood flow to the lower extremities: the study of osteoporotic fractures.. J Bone Miner Res 12(2):283-289.
Wakasugi, M., Wakao, R., Tawata, M. & Gan, N., 1993. Bone mineral density measured by dual energy X–ray absorptiometry in patients with non-insulin-dependent diabetes mellitus. Bone 14(1):29-33.
Wei, J., Xu, H., Davies, J. L. & Hemmings, G. P., 1992. Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci 51:1953-1956.
Weitzmann, M. N. & Pacifici, R., 2006. Estrogen deficiency and bone loss: an inflammatory tale. The Journal of Clinical Investigation 116(5):1186-1194.
Wenk, C., Gebert, S. & Pfirter, H., 1995. Chromium supplements in the feed for growing pigs: influence on growth and meat quality. Archives of Animal Nutrition 48:71-81.
Wettenhall, R. H., Schwartz, P. L. & Bornstein, J., 1969. Actions of insulin and growth hormone on collagen and chondroitin sulfate synthesis in bone organ cultures. Diabetes 18:280-284.
Wientroub, S., Eisenberg, D., Tardiman, R. & Weissman, S., 1980. Is diabetic osteoporosis due to microangiopathy?. Lancet 2(8201), p. 983.
Wild, R. A., Buchanan, J. R., Myers, C. & Demers, L. M., 1987. Declining adrenal androgens: an association with bone loss in aging women. Proc Soc Exp Biol Med 186:355-360.
Wong, P. W., Tiano, P. J., Liu, S. & Hewitt, C. S., 2010. Extranuclear estrogen receptoralpha stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis.. Proc Natl Acad Sci USA 107:13057-13062.
Wysocka, E., Cymerys, M., Mielcarz, G. & Bryl, W., 2011. The way of serum chromium utilization may contribute to cardiovascular risk factors in centrally obese persons. Arch Med Sci. 7:257-263.
Xiong, J., Onal, M., Jilka, R. L. & Weinstein, R. S., 2011. Matrix-embedded cells control osteoclast formation. Nature Medicine 17(10):1235-1241.
Yamaza, T., Goto, T., Kamiya, T. & Kobayashi, Y., 1998. Study of immunoelectron microscopic localization of cathepsin K in osteoclasts and other bone cells in the mouse femur. Bone 23(6):499-509.
Yavropoulou, M. P. & Yovos, J. G., 2008. Osteoclastogenesis— current knowledge and future perspectives. Journal of Musculoskeletal Neuronal Interactions 8(3):204-216.
Yoshida, H., Hayashi, S. I. & Kunisada, T., 1990. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442-444.
Zaidi, M., Inzerillo, A. M., Moonga, B. S. & Bevis, P. J., 2002. Forty years of calcitonin—where are we now? A tribute to the work of Iain Macintyre, FRS. Bone 30(5):655-663.
Zhao, X., Wu, Z.-X., Zhang, Y. & Yan, Y.-B., 2011. Anti-osteoporosis activity of Cibotium barometz extract on ovariectomy-induced bone loss in rats. Journal of Ethnopharmacology, 137(3):1083-1088.
楊, 榮., 1997. 骨質疏鬆症-病因、診斷、治療. 台北市: 合計圖書出版社.