Changes in Bone Turnover With Increased Incretin Hormone Exposure

Patients with Type 2 Diabetes Mellitus (T2DM) are at an increased risk of fracture, despite
having bone mineral density (BMD) similar to age and sex matched cohorts. Recent studies
have indicated that changes in incretin (INtestinal seCRETion of INsulin) hormones in the
setting of T2DM may play a role in bone metabolism. Two of these incretin hormones, gastric
inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to be
involved in bone turnover regulation, in addition to their effect in increasing insulin
secretion and decreasing glucagon secretion in a glucose-dependent manner. In addition, the
rise in glucagon-like peptide-2 (GLP-2) in the postprandial state has been found to have a
direct effect on reduced bone resorption in a non-fasting state and treatment with GLP-2
improved BMD in postmenopausal women. Due to their glucose lowering effects, incretins have
been a therapeutic target for the treatment of T2DM through GLP-1 receptor analogs or
inhibition of incretin metabolism via dipeptidyl peptidase 4 (DPP-4) inhibitors (i.e.
sitagliptin). Inhibition of DPP-4 leads to an approximate doubling of GLP-1 and GIP levels
but also leads to reduced breakdown of GLP-2.

Less is known about the effect of incretin-directed therapies, specifically sitagliptin, and
bone metabolism. To our knowledge, two studies have looked at the direct effects of
currently available incretin-directed therapies on bone metabolism. Exenatide (a GLP-1
analog) treatment of insulin resistant and type 2 diabetic rats resulted in osteogenic
effects with increased osteocalcin levels following treatment. In a study of female
non-diabetic Sprague-Dawley rats treated with pioglitazone, rosiglitazone, sitagliptin, vs.
placebo, no significant change in bone mineral density was seen in the sitagliptin or
placebo treated rats (compared to significant loss of bone mineral density in the TZD
groups). Even fewer published studies are available evaluating changes in bone metabolism
with the use of incretin hormones in humans. The majority of the human studies have been
completed with GLP-2. These studies show a dose-dependent effect of GLP-2 on bone resorption
and, preliminarily, show improved bone mineral density in postmenopausal women treated with
GLP-2. However, the changes in incretin activity vary in persons with glucose intolerance
and T2DM. Therefore, it is important to understand the potential effects of these
medications on bone metabolism in persons prescribed these medications for treatment of
their T2DM.

Inclusion Criteria:

- Postmenopausal women (as defined by age >55 years old or amenorrhea for >1years)

- Type 2 DM currently not on diabetes-specific medication(s) or treated with
monotherapy of metformin or a sulfonylurea. Patients treated with insulin monotherapy
will also be eligible if the total daily dose of insulin is <10units.

- Hemoglobin A1c (HbA1c) of 6.5-9.0%

Exclusion Criteria:

- Use of an incretin mimetic (i.e. exenatide), a DPP-4 inhibitor (i.e. sitagliptin,
saxagliptin), a thiazolidinedione, or oral glucocorticoids in the 6 months prior to
the study will not be eligible

- Known osteoporosis or patients treated with an osteoporosis-specific medication
(bisphosphonate, teriparatide) or estrogen (including Selective Estrogen Receptor
Modulators (SERMs)) or those who anticipate imminent treatment with one of these
medications will be excluded from the study

- Chronic kidney disease (calculated GFR <30 ml/min) or a disease known to affect bone
turnover (i.e. Paget Disease, Osteogenesis Imperfecta, HIV) will be excluded from the
study.

- History of pancreatitis