glucagon-like-peptide-2 and Osteoporosis--Postmenopausal

We have previously shown that a single subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women results in a dose-dependent decrease in the nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX and u-CTX) and u-DPD, markers of bone resorption. In contrast, bone formation, as assessed by serum osteocalcin and procollagen type I N-terminal propeptide (PINP), appeared to be unaffected by treatment with exogenous GLP-2. These effects were further investigated in a 14-day study. The aim was to demonstrate that a parenteral formulation of GLP-2 is safe and well tolerated after repeated dosing in healthy postmenopausal women for 14 days. It was further investigated whether the effects on bone turnover markers were sustained throughout the study period. The study was a double-blind placebo-controlled trial with 60 postmenopausal women and 2 different doses of GLP-2 (1.6 mg and 3.2 mg GLP-2) against a saline control. The data for bone resorption revealed a similar reduction on Day 1 and Day 14, both based on time course and AUC. There were no signs of tachyphylaxis and no serious adverse reaction. Both GLP-2 doses resulted in similar and significant (p<0.001) reduction in bone resorption indicating that the maximum efficacious dose has been approached. Osteocalcin and PINP levels were unaffected at Day 1 and Day 14, suggesting a disassociation between bone resorption and bone formation during GLP-2 treatment.

Topics: Aged; Area Under Curve; Bone Resorption; Calcium; Collagen Type I; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucagon-Like Peptide 2; Humans; Injections, Subcutaneous; Osteocalcin; Osteogenesis; Osteoporosis, Postmenopausal; Peptide Fragments; Peptides; Phosphates; Premenopause; Procollagen

Osteoporosis results from an imbalance in bone remodeling, which is known to follow a circadian rhythm determined by a functional relationship between intestine and bone tissue. Specific intestinal peptides have been identified as mediators. Glucagon-like peptide 1 and glucagon-like peptide 2, have been associated with bone health. Our main objective was to determine whether postprandial plasma levels of glucagon-like peptide 1, glucagon-like peptide 2 and dipeptidyl-peptidase 4 activity, are associated with osteoporosis in non-diabetic postmenopausal women. We studied non-diabetic postmenopausal women with osteoporosis diagnosed by dual-energy X-ray absorptiometry (cases, n = 43) and age-matched (±1 yr) controls without osteoporosis or a history of osteoporotic fracture (n = 43). We measured postprandial plasma levels of glucagon-like peptide 1, glucagon-like peptide 2, and dipeptidyl-peptidase 4 activity, bone mineral density, and baseline levels of bone remodeling markers and analyzed the food intake using a food-frequency questionnaire. Postprandial glucagon-like peptide 1 values were lower (p < 0.001) in cases, μ (SEM) = 116.25 (2.68), than in controls, μ (SEM) = 126.79 (2.68). Glucagon-like peptide 1 was associated with reduced osteoporosis risk in the crude logistic regression analysis [OR (95% CI) = 0.724 (0.53-0.97), p = 0.031] and adjusted analysis [OR = 0.603 (0.38-0.94), p = 0.027]. We found no association of glucagon-like peptide 2, or dipeptidyl-peptidase 4 activity with osteoporosis. Postprandial glucagon-like peptide 1 levels are related to osteoporosis and osteoporosis risk in non-diabetic postmenopausal women. Further studies are required to verify these findings.

Topics: Absorptiometry, Photon; Bone Density; Case-Control Studies; Dipeptidyl Peptidase 4; Eating; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Middle Aged; Osteoporosis, Postmenopausal; Postprandial Period