Effect of Diabetic Medications on Bone Metabolism
Condition: Osteoporosis; Type 2 Diabetes Mellitus
MeSH terms: Osteoporosis; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      Subjects with diabetes and pre-diabetes are said to have increased bone loss when compared to
      the general population. Pioglitazone a thiazolidinedione, is a Food and Drug Administration
      (FDA) approved oral anti-diabetic agent for the treatment of type 2 diabetes. Though there
      are many benefits for using thiazolidinediones in the treatment of type 2 diabetes, there is
      data that indicates that rosiglitazone therapy results in a significant decrease in total
      body bone mineral density in mice. Whether it is true in humans is not clear. If the animal
      data can be extrapolated to humans, thiazolidinediones may pose a significant risk of adverse
      effects on bone. This study hypothesizes that treatment with the thiazolidinedione
      pioglitazone may result in significant reduction in bone mineral density. The aims of this
      are: 1. to evaluate the effect of pioglitazone on skeletal health; 2. to measure the bone
      mineral density (BMD) of the spine and hip, as well as bone turnover markers, at different
      times of persons taking thiazolidinediones and others not taking them; 3. to determine the
      change in BMD and bone turnover markers within different groups at different times; and 4. to
      compare these changes.
    

Detailed description: 
      The prevalence rate of diabetes among veterans is 16% in general and 27% at out medical
      center compared to 6.3% among United States population. Subjects with diabetes and
      prediabetes said to have increased bone loss compared to the general population.
      Pioglitazone, a thiazolidinedione, is a Food and Drug Administration (FDA) approved oral
      anti-diabetic agent for the treatment of type 2 diabetes. Most of the pleiotropic effects of
      teh thiazolidinediones are beneficial in atherosclerosis and cancer, in addition to improving
      insulin resistance. Data from studies in mice show that rosiglitazone and pioglitazone
      therapy results in a significant decrease in total body bone mineral density was observed.
      Whether it is true in humans is not clear. There are no prospective studies to date. Subjects
      with diabetes are already at an increased risk for femoral fractures. If the animal data can
      be can be extrapolated to humans, thiazolidinedione pioglitazone may result in significant
      risk of adverse skeletal effects. This study hypothesizes that treatment with the
      thiazolidinedione pioglitazone may result in a significant reduction in bone mineral density.
      The aims of the study include: 1. To prospectively evaluate the effect of pioglitazone on
      skeletal health, we will study 140 subjects with diabetes receiving pioglitazone as part of
      their diabetes management and compare them with 140 diabetic controls (matched for age, sex,
      body mass index (BMI), smoking and alcohol history), not treated with pioglitazone. 2. To
      measure the bone mineral density by DXA at AP spine and hip, as well as bone turnover
      markers-procollagen type 1C-terminal propeptide (P1CP), and procollagen type 1N-terminal
      propeptide (P1NP), bone specific alkaline phosphatase, osteocalcin, plasma C-telopeptide
      (CTx) and N-telopeptide (NTx) at baseline, six and 12 months of follow-up. 3. To determine
      the change in BMD and bone turnover markers within each group from baseline to follow-up at
      six and 12 months. 4. To compare the changes in the BMD and bone turnover markers between
      groups at baseline and follow-up at six and 12 months.

      Subjects: Prospectively study 140 subjects with type 2 diabetes and on pioglitazone, age, and
      sex matched controls.

      Sample Size: The sample size is based on the primary objective of comparing the levels bone
      turnover markers and bone mineral density changes in diabetes with or without avandia.

      Number of visits: 140 subjects with diabetes and on pioglitazone and 140 subjects with
      diabetes not on pioglitazone

        1. Subjects will be studies at three visits.

        2. The procedures to be done include assessment of bone mineral density measurement by dual
           X-ray absorptiometry (DXA), measurement of bone turnover markers like serum osteocalcin
           and urinary N-telopeptide after the informed consent. About 15ml (one tablespoonful) of
           blood will be drawn at each visit for the study.

        3. All the baseline measurements will be repeated at 6 months and at one year.

        4. Statistical analysis of the data will be done to compare the changes in bone turnover
           markers and bone mineral density between the two groups.

      Site of the study: Overton Brooks VAMC Diabetics clinic and Primary care clinics.

      If our hypothesis is proven correct, subjects with diabetes requiring thiazolidinediones
      should have bone turnover markers and BMD measurement at baseline and have serial follow up.
      Identification of subjects at high risk will allow health care providers to initiate
      necessary protective measures to protect the bone to decrease the fracture risk.

      Potential Impact on Veterans Health Care: Identification of subjects at high risk will allow
      health care providers to initiate necessary preventive measures to protect the bone and
      decrease the risk of fractures, or avoid the use of TZDs altogether in select patients. Since
      the prevalence of diabetes is very high among veterans, evaluation of a possible risk of
      skeletal health with the use of pioglitazone is highly relevant to VA health care.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        subjects with type 2 diabetes and less than 55 years with or without pioglitazone as part
        of their therapy for diabetes
      
Biospecimen description: 
      Urine and serum samples collected for the study will be spin and stored at -70 degree C and
      assays run intermittently
    
Keywords: Bone Density; C-telopeptide; Dual-Energy X-Ray Absorptiometry; N-telopeptide; Osteocalcin; Osteoporosis; Thiazolidinediones; Type 2 Diabetes Mellitus