Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women

TY - JOUR

T1 - Disassociation of bone resorption and formation by GLP-2

T2 - a 14-day study in healthy postmenopausal women

AU - Henriksen, Dennis B

AU - Alexandersen, Peter

AU - Hartmann, Bolette

AU - Adrian, Charlotte L

AU - Byrjalsen, Inger

AU - Bone, Henry G

AU - Holst, Jens Juul

AU - Christiansen, Claus

PY - 2007/3

Y1 - 2007/3

N2 - 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.

AB - 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.

KW - Aged

KW - Area Under Curve

KW - Bone Resorption

KW - Calcium

KW - Collagen Type I

KW - Creatinine

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Female

KW - Glucagon-Like Peptide 2

KW - Humans

KW - Injections, Subcutaneous

KW - Osteocalcin

KW - Osteogenesis

KW - Osteoporosis, Postmenopausal

KW - Peptide Fragments

KW - Peptides

KW - Phosphates

KW - Premenopause

KW - Procollagen

U2 - 10.1016/j.bone.2006.09.025

DO - 10.1016/j.bone.2006.09.025

M3 - Journal article

C2 - 17081815

SN - 8756-3282

VL - 40

SP - 723

EP - 729

JO - Bone

JF - Bone

IS - 3

ER -