A One-year Randomized Controlled Trial Evaluating the Impact of Pioglitazone Versus Linagliptin on Bone Turnover Markers
A One-year Randomized Controlled Trial Evaluating the Impact of Pioglitazone Versus Linagliptin on Bone Turnover Markers
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, specially
 elderly women. However, it is still controversial in terms of the youth and men. In
 Taiwan,there is few related study to analyze the relationship between TZD and steoporosis.

 This is a multicenter randomized controlled study.
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. In Taiwan,
 there is few related study to analyze the relationship between TZD and osteoporosis.

 This is a multicenter randomized controlled study.This study will recruit adult (age ³40
 years) type 2 diabetes patients who is on metformin (³1500mg/day) currently with recent HbA1c
 between 7.0~8.5%.Patient who has history of macular edema, congestive heart failure (NYHA Fc
 III, IV), chronic renal failure (stage IV, V), AST or ALT above 2.5 times upper limit,
 Medical history of endocrinopathies, osteoporosis with bone fracture, cancer will be
 excluded. Current bone fracture undergoing treatment, pregnancy, breast feeder will also be
 excluded.

 This is a 3-year project and will enroll 160 eligible volunteers who are to randomized into
 group A and B (80 in each). During the next 48 weeks group A and B will receive
 metformin+pioglitazone and metformin+linagliptin respectively. Blood sugar, renal, and liver
 functions will be examined every 12 weeks. Calcium, phosphorus, vitamin D level, and bone
 turnover markers (N-terminal propeptide of type 1 procollagen, bone-specific alkaline
 phosphatase, osteocalcin, serum C- telopeptide, type 5 tartrate resistant acid phosphatase
 (TRAP), pyridinoline and deoxypyridinoline crosslinks) will be checked each 6 months.

 All the blood samples will be sent to one core laboratory center. The within-group
 differences will be examined by repeated-measure ANOVA. The between-group differences will be
 examined by Student's t test.
Inclusion Criteria:

 -  1. Males or females ≥ 40 years of age at Visit 1and females in postmenopause for one
 year

 -  Documentation of type 2 diabetes mellitus as evidenced by one or more of the following
 criteria:

 1. With typical symptoms and random blood sugar ≥ 200 mg/dl

 2. 8-hour fasting blood sugar ≥ 126 mg/dl

 3. Oral glucose tolerance test ≥ 200 mg/dl

 4. HbA1c≥ 6.5%

 -  Only receiving oral anti-diabetic drugs (excluding TZDs or DPP-4 inhibitors) till
 visit 1 at least 3 months, and the HbA1c is between 7.0~8.5 % in recent 3 months.

 -  Written informed consent (and assent when applicable) obtained from subject or
 subject's legal representative and ability for subject to comply with the requirements
 of the study.

 Exclusion Criteria:

 -  DM on oral anti-diabetic drugs less than 3 months.

 -  Receiving treatment of TZDs or DPP-4 inhibitors prior to this study.

 -  Presence of a condition or abnormality that in the opinion of the Investigator would
 compromise the safety of the patient or the quality of the data.

 -  AST, ALT over 2.5 times of the upper limit.

 -  Chronic kidney disease, stage 4 and 5.

 -  Congestive heart failure, NYHA class III, IV

 -  History of osteoporosis.

 -  History of diseases known to affect bone metabolism:

 Abnormal thyroid function or history of hyperthyroidism, Cushing's syndrome, hypogonadism,
 acromegaly, history of hypopituitarism or status post pituitary surgery and/or
 radiotherapy, hematopoietic disorders.

 -  History of moderate to severe Diabetic macular edema (DME)

 -  History of moderate to severe diabetic retinopathy.

 -  History of fracture over lumbar spine or hip joint or femoral head or forearm or any
 site of bone fracture undergoes treatment currently.

 -  Who had taken any of the following medications prior to screening:

 Corticosteroid, heparin, anticonvulsants, aluminum-containing antacid, proton pump
 inhibitor, immunosuppressant user within 3 months. Bisphosphonate, systemic fluoride
 treatment, PHT analogue, calcitonin, Denosumab, Strontium ranelate, hormone replacement
 therapy (androgen/estrogen/progesterone, thyroxine, growth hormone), selective estrogen
 receptor modulator /SERM (Tamoxifene, Raloxifene), selective tissue estrogenic activity
 regulator /STEAR (Tibolone), aromatase inhibitors within 1 year.

 -  History of cancer.

 -  Bed-ridden patients.