臺灣博碩士論文加值系統

糖尿病是一種全球普遍卻又對人體健康有著重大影響的疾病，與骨質疏鬆也有著密切的關係。但是其中機轉目前仍未完全清楚。Thiazolidinedione(TZD)據國外研究顯示可能會造成老年女性骨鬆與骨折機率增加；但對青壯年或男性的影響目前仍無結論。而我國針對thiazolidinedione影響骨代謝的相關研究更是缺乏。高尿鈣被認為是一種骨質疏鬆的危險因子。有一項研究顯示使用愛妥糖(一種在臨床上廣為使用的TZD)可能會直接抑制副甲狀腺素分泌而導致尿鈣增加，繼而造成骨質流失。而近年來處方率越來越高的Dipeptidyl peptidase-4 (DPP4)抑制劑則被認為不會影響骨質與鈣質平衡。本研究將探討愛妥糖相較糖漸平(一種DPP4抑制劑)是否會影響腎臟對於鈣質的排出，期能藉此研究進一步了解TZD對於骨骼系統所造成之影響及可能的病生理機轉。
本計劃為多中心前瞻性研究（台大總院、雲林分院），並將以隨機分配對照實驗的方式來進行。研究對象為年滿40歲以上男性或停經後女性目前使用口服降血糖藥(不包括TZD或DPP4i) 控制已超過3個月，且最近三個月糖化血色素為7.0~8.5%未達標之第二型糖尿病病人。並排除黃斑部水腫、中重度視網膜病變、心衰竭（NYHA class III~IV）、慢性腎病變(stage4~5)病人、活動性肝病者（AST 或ALT大於正常上限之2.5倍）、其他內分泌腺功能異常、血中維生素D低下、骨質疏鬆併骨折病史或目前骨折正接受治療或癌症患者。
符合條件之志願者隨機分為A、B組。二組分別加上愛妥糖或糖漸平治療連續48週。期間每12週檢測一次血糖及肝、腎功能。且試驗前以及第48週檢測血中鈣、鎂、磷離子、肌酸酐、副甲狀腺素、維生素D及尿液鈣、肌酸酐濃。尿鈣排出多寡以Spot urine calcium creatinine ratio(SUCCR)、Fractional excretion of calcium (FECa)、estimated daily calcium(mg/day)估算。並比較組內前後以及組間差異。
本研究共收案18人(pioglitazone 9人、linagliptin 9人)，結果發現各組在使用藥物前後或是兩組相比較的SUCCR(p=1.00)、FECa(p=0.78)、estimated daily calcium amount (p=0.94)，皆無統計學上差異。
總結，使用愛妥糖相較於糖漸平對於第二型糖尿病患者尿鈣的排出並無差異。

Context: Diabetes mellitus is a common disease with much impact on human’s health and is related to osteoporosis. But the mechanism remains unclear. The foreign researches revealed thiazolidinedione (TZD) would increase the risk of osteoporosis and bone fracture, especially elderly women. However, it is still controversial in terms of the youth and men. Hypercalciuria has been reported to be a risk of osteoporosis, and one study also found pioglitazone might suppress parathyroid hormone secretion and cause increased calciuria. In Taiwan, the prescription of dipeptidyl peptidase 4(DPP4) inhibitors is increasing in the past few years. DPP4-inhibitors have been found to have neutral effect on bone and calcium homeostasis. However, there is few related study to analyze the relationship between TZD, DPP4 inhibitor, especially the effect on urine calcium excretion. Therefore, we designed a randomized controlled trial to evaluate the effect of pioglitazone versus linagliptin on urine calcium excretion.
Design: This is a 48-week multicenter (National Taiwan university hospital and National Taiwan university hospital, Yun-Lin branch) randomized controlled study. We examined the effects of pioglitazone (30mg/day) or linagliptin (5mg/day) on bone metabolism, aiming at urine calcium excretion. This study recruited adult (age more than 40 years) type 2 diabetes patients who were on oral antidiabetic drugs (excluding TZD and DPP4 inhibitor) prior to this study with a recent HbA1c between 7.0~8.5%.
Eligible volunteers were randomized (1:1) into group A and B. During the following 48 weeks, group A and B received OAD(s)+ pioglitazone and OAD(s)+ linagliptin respectively. Serum calcium, phosphorus, magnesium, creatinine, intact parathyroid hormone, 25(OH)D, urine calcium, creatinine level were checked prior and after 48 weeks’ treatment. The primary objective is to assess the effect of pioglitazone versus linagliptin on kidney by measurement of fractional excretion of calcium (FECa), Spot Urine Calcium Creatinine ratio (SUCCR), and estimated daily calcium amount over the 48 weeks treatment period. The within-group and between-group differences were examined.
Result: Total 18 (pioglitazone 9, linagliptin 9) subjects were randomized into 2 group evenly and completed 48-week study. Linaglitin has neutral effect on urine calcium excretion and PTH level as expected. Compared with linagliptin, pioglitazone also demonstrated neutral effect on SUCCR (p=1.00), FECa (p=0.78), and estimated daily calcium amount (p=0.94).
Conclusion: Urine calcium excretion fraction, daily urine calcium amount and serum iPTH level remained unchanged after a 48-week treatment in both groups, which suggests that pioglitazone has similar neutral effect as linagliptin on urine calcium excretion.

Outline
I. Introduction and literature review---------6
1. Background --------------------------------6
2. Study rationale and literature review------6
II. Study design and method--------------------9
1. Study design-------------------------------9
2. Study objects-----------------------------10
3. Rationale of enrollment-------------------11
4. Criteria for evaluation-------------------11
5. Subject selection-------------------------11
6. Concurrent medication---------------------14
7. Study treatments--------------------------15
8. Study procedure and guidelines------------15
III. Results-----------------------------------17
IV. Discussion--------------------------------18
V. Anticipation and clinical application-----20
VI. Summary ----------------------------------21
VII. Reference---------------------------------23
VIII. Table and figure--------------------------28

Ali A, W. R., Stewart S, et al. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005; 146: 1226–35.
Berberoglu Z1, G. A., Bayraktar N, Yazici AC, Bascil Tutuncu N, Guvener Demirag N. Rosiglitazone decreases serum bone-specific alkaline phosphataseactivity in postmenopausal diabetic women. Journal of Clinical Endocrinologyand Metabolism. 2007; 92(9): 3523–30.
Bone HG, L. R., McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013; 98(12): 4691-701.
Combs TP, W. J., Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O''Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller DE. Induction of adipocyte complement- related protein of 30 kDa by PPAR gamma agonists: a potential mechanism of insulin sensitization. . Endocrinology. 2002; 143: 998–1007.
Cooper C, A. E., Jacobsen SJ, O''Fallon WM, Melton LJ 3rd. Population-based study of survival after osteoporotic fractures. . Am J Epidemiol. 1993; 137: 1001-05.
Council for Economic Planning and Development, T., Rep. of China. Year-End Population by Three-Stage Age Group, Dependency Ratio and Index of Ageing for Taiwan Area: 2008. Population projections for Taiwan areas. 2007: 2008-56.
de Liefde II, v. d. K. M., de Laet CE, van Daele PL, Hofman A, Pols HA. Bonemineral density and fracture risk in type-2 diabetes mellitus: the RotterdamStudy. . Osteoporosis International. 2005 Dec; 16(12): 1713-20.
Dormandy JA1, C. B., Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005 Oct 8; 366(9493): 1279-89.
Giustina A, M. G., Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. . Endocr Rev. 2008 Aug; 29(5): 535-59.
Grey A1, B. M., Gamble G, Wattie D, Horne A, Davidson J, Reid IR. The peroxisome proliferator-activatedreceptor- agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. Journal of Clinical Endocrinology & Metabolism. 2007 Apr; 92(4): 1305–10.
Grey A, B. M., Fenwick S, Horne A, Gamble G, Drury PL, Reid IR. The skeletal effects of pioglitazone in type 2 diabetes or impaired glucose tolerance: a randomized controlled trial. Eur J Endocrinol. 2013 Dec 21; 170(2): 257-64.
Jones AN, B. R., Lindstrom MJ, Penniston KL, Hansen KE. Adjustment for body mass index and calcitrophic hormone levels improves the diagnostic accuracy of the spot urine calcium-to-creatinine ratio. Osteoporos Int. 2010; 21(8): 1417-25.
Kahn SE, H. S., Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O''Neill MC, Zinman B, Viberti G; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355(23): 2427–43.
Kahn SE, Z. B., Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G; Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008; 31(5): 845-51.
Laxmayya Sava, S. P., Umesh More, and Alka Sontakke. Serum calcium measurement: Total versus free (ionized) calcium. Indian J Clin Biochem. 2005; 20(2): 158-61.
Lazarenko OP, R. S., Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. . Endocrinology. 2007; 148(6): 2669–80.
Lecka-Czernik B, M. E., Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma ligands on adipocyte versus osteoblast differentiation. Endocrinology. 2002; 143(6): 2376–84.
Lin YC, P. W. Bone mineral density in adults in Taiwan: results of the Nutrition and Health Survey in Taiwan 2005-2008. Asia Pac J Clin Nutr. 2011; 20(2): 283-91.
Loke YK, S. S., Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009; 180(1): 32-9.
Maeda N, T. M., Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001; 50(9): 2094-99.
Mancini T, M. G., Doga M, Carpinteri R, Simetovic N, Vescovi PP, Giustina A. Vertebral fractures in males with type 2 diabetes treated with rosiglitazone. . Bone. 2009; 45(4): 784-88.
Meier C, K. M., Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008; 168(8): 820–25
Monami M, D. I., Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care. 2011; 34(11): 2474-6.
Okazaki R, M. M., Toriumi M, Taguchi M, Hirota Y, Fukumoto S, Fujita T, Tanaka K, Takeuchi A. Short-term treatment with troglitazone decreases bone turnover in patients with type 2 diabetes mellitus. Endocrine Journal. 1999; 46(6): 795–801.
Okazaki R, T. M., Fukumoto S, Miyamoto M, Fujita T, Tanaka K, Takeuchi Y. Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro. . Endocrinology. 1999; 140(11): 5060-65.
Oshima K, N. A., Matsuda M, Iwaki M, Fukuhara A, Hashimoto J, Yoshikawa H, Shimomura I. Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. . Biochem Biophys Res Commun. 2005; 331(2): 520-26.
Park S, P. M. Pathophysiology and management of calcium stones. Urol Clin North Am. 2007; 34(3): 323-34.
Schwartz AV, S. D., Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR; Study of Osteoporotic Features Research Group. Older women with diabetes have an increased risk of fracture: a Prospective Study. Journal of Clinical Endocrinologyand Metabolism. 2001; 86(1): 32-38.
Schwartz AV, S. D., Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91(9): 3349–54.
Sorocéanu MA, M. D., Bai XY, Su H, Goltzman D, Karaplis AC. Rosiglitazoneimpacts negatively on bone by promoting osteoblast/osteocyte apoptosis. Jour-nal of Endocrinology. 2004; 183(1): 203–16.
Strotmeyer ES, C. J., Schwartz AV, Nevitt MC, Resnick HE, Bauer DC, Tylavsky FA, de Rekeneire N, Harris TB, Newman AB. Nontraumatic fracture risk withdiabetes mellitus and impaired fasting glucose in older white and black adults:the health, aging, and body composition study. . Archives of Internal Medicine. 2005; 165(14): 1612-17
Tee MC, H. D., Wiseman SM. Ionized vs serum calcium in the diagnosis and management of primary hyperparathyroidism: which is superior? Am J Surg. 2013; 205(5): 591-6.
Tornvig L, M. L., Justesen J, Falk E, Kassem M. Troglitazone treatment increases bone marrow adipose tissue volume but does not affect trabecular bone volume in mice. . Calcif Tissue Int. 2001; 69(1): 46-50.
Vianna AGD, d. L. C., Pechmann LM, Polesel MG, Marino EC, Borba VZC, Barreto FC. Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial. Diabetol Metab Syndr. 2017; 15(9): 35.
Wan Y, C. L., Evans RM. . PPAR-gamma regulates osteoclastogenesis in mice. . Nat Med. 2007; 13(12): 1496-503.
Watanabe S, T. Y., Fukumoto S, Fujita H, Nakano T, Fujita T. Decrease inserum leptin by troglitazone is associated with preventing bone loss in type 2diabetic patients. Journal of Bone and Mineral Metabolism. 2003; 21(3): 166–71.
Wong, K. a. W., ZQ. Prevalence of type 2 diabetes mellitus of Chinese populations in Mainland China, Hong Kong, and Taiwan. Diabetes Research And Clinical Practice. 2006; 73(2): 126-34.
Yaturu S, B. B., Jain SK. Thiazolidinedione treatment decreases bone mineraldensity in type 2 diabetic men. . Diabetes Care. 2007; 30(6): 1574–6.
Zanchi A, P.-B. A., Burnier M, Bonny O. Effects of pioglitazone on renal calcium excretion. J Clin Endocrinol Metab. 2011; 96(9): E1482-5.