Bone effects of hexarelin, a GH-releasing peptide, in female rats: influence of estrogen milieu

Abstract

Objective: The present study was performed to evaluate the potential influence of the estrogen milieu in modulating the effects of GH/IGF stimulation by a GH-releasing peptide, hexarelin (HEXA), on bone metabolism and mineral density in middle-aged female rats. Methods: HEXA was administered for 60 days (50 mg/kg s.c. twice a day) to intact and ovariectomized (OVX) 11-month-old female rats and changes in bone parameters were evaluated with respect to those of the same rats under baseline conditions and with those of control rats (intact and OVX) administered isovolumetric amounts of physiological saline. Serum total alkaline phosphatase (ALP) and urinary deoxypyridinoline (Dpd) were measured before and at various times during HEXA treatment. Bone mineral content (BMC) and density of lumbar vertebrae and femoral mid-diaphyses were measured by dual energy X-ray absorptiometry before and after treatment. In all groups, serum IGF-I levels were determined before and during treatment and the GH secretory response to HEXA was assessed at the end of the experiment. Results: In intact rats, HEXA did not modify Dpd urinary excretion, induced a trend toward an increase of serum ALP activity and significantly increased BMC (þ6.5%) and bone area (+4.1%) only at lumbar vertebrae. In OVX rats, HEXA did not modify the OVX-induced increase in bone turnover markers (Dpd and ALP) and did not affect the OVX-induced vertebral bone loss, but significantly increased BMC (þ7.2%) and bone area (þ 5.3%) at femoral mid-diaphyses. HEXA significantly increased serum IGF-I levels at day 14, but not at day 60, in both intact and OVX rats, whereas the GH secretory response to HEXA was higher in the former than in the latter. Conclusions: Overall, the present data demonstrate that chronic HEXA treatment increases BMC and bone area at lumbar vertebrae in intact rats and at femoral diaphyses in OVX rats. The different sensitivity to HEXA of the skeletal districts examined is related to the estrogen milieu and may reflect a complex interplay between estrogens and GH/IGF function.

Bone health-promoting bioactive peptides

“…Kim et al () also discovered BFP‐2 corresponding to residues 140–154 of immature BMP‐7 and demonstrated its strong osteogenic activity and bone formation in vitro and in vivo. Other bioactive peptides with bone health activity, including calcinonin gene‐related peptide (CGRP), hexarelin, thrombin‐related peptide (TP508), osteogenic growth peptide (OGP), and calcitonin receptor fragment peptide (CRFP), were also investigated in vitro and in vivo (Komatsu, Hadjiargyrou, Udin, Trasolini, & Pentyala, ; Li, Ryaby, Carney, & Wang, ; Sibilia et al, ; Valentijn et al, ; Zhao et al, ). Osteogenic peptides with in vitro and in vivo activity are summarized in Table .…”

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

“…( 80 ) Moreover, a long‐acting GH secretagogue, hexarelin, prevents bone loss in the setting of androgen deficiency; however, after estrogen deficiency, efficacy of this compound seemed to be restricted to specific bone compartments in rats. ( 81 , 82 ) In a ghrelin knockout model, there was no effect on bone size, BMD, or fat deposition in 8‐week‐old mice. ( 83 ) In children, ghrelin secretion is not suppressed in response to diet, and thus, it is possible that skeletal effects of ghrelin are masked during growth, and a bone phenotype may only become apparent during aging.…”

Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts

“…In vivo studies showed that intraperitoneal [ 5 ] as well as central administration [ 12 ] of ghrelin increases bone mineral density and mass through a mechanism independent of GH-IGF1 axis and appetite regulation, respectively. Consistently, synthetic GH secretagogues increase bone mineral density [ 13 ] and prevent gonadectomy-induced bone loss in the rat [ 14 , 15 ]. Data from clinical studies are limited but indicate a positive association between circulating ghrelin levels and bone mineral density in women [ 16 , 17 ] and elderly men [ 18 ].…”