Treatment with the Oral Growth Hormone Secretagogue MK-677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males

Svensson, Johan; Ohlsson, Claes; Jansson, John‐Olov; Murphy, Gail; Wyss, Daniel F.; Krupa, David; Cerchio, K.; Polvino, William J.; Gertz, Barry J.; Baylink, David J.; Mohan, Subburaman; Bengtsson, Bengt‐Åke

doi:10.1359/jbmr.1998.13.7.1158

Cited by 36 publications

(18 citation statements)

References 70 publications

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“…In contrast, in men, IGFBP-5 increased similarly after GH and GH ϩ T. Prior studies (69) in GH-deficient adults revealed an initial increase in IGFBP-4 and -5 levels after GH administration followed by a later return in IGFBP-4 levels to normal. Similar temporally biphasic responses of IGFBP-4 have been reported after administration of GH to postmenopausal women (43) and of MK-677, an oral GH secretagogue, to young healthy obese men (66).…”

Section: Discussionsupporting

confidence: 79%

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Münzer¹,

Rosen²,

Harman³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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. Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men. Am J Physiol Endocrinol Metab 290: E1006 -E1013, 2006. First published January 3, 2006 doi:10.1152/ajpendo.00166.2005.-Circulating GH, IGF-I, IGFBP-3, and sex steroid concentrations decrease with age. GH or sex steroid treatment increases IGFBP-3, but little is known regarding the effects of these hormones on other IGFBPs. We assessed the effects of 26 wk of administration of GH, sex steroids, or GH ϩ sex steroids on AM levels of IGF-I, IGFBPs 1-5, insulin, glucose, and osteocalcin and 2-h urinary excretion of deoxypyridinolline (DPD) cross-links in 53 women and 71 men aged 65-88 yr. Before treatment, in women and men, IGF-I was directly related to IGFBP-3 (P Ͻ 0.001 and P Ͻ 0.0001) and IGFBP-1 to IGFBP-2 (P ϭ 0.0001). In women, IGFBP-1 was inversely related to insulin (P Ͻ 0.0005) and glucose (P Ͻ 0.005) and IGFBP-4 to osteocalcin (P Ͻ 0.01). IGFBP-4 and IGFBP-5 were not significantly related to DPD cross-links. GH and/or sex steroid increased IGF-I levels in both sexes, with higher concentrations in men (P Ͻ 0.001). In women, the IGF-I increment after GH was attenuated by hormone replacement therapy (HRT) coadministration (P Ͻ 0.05). Hormone administration also increased IGFBP-3. IGFBP-1 was unaffected by GH ϩ sex steroids, whereas GH decreased IGFBP-2 by 15% in men (P Ͻ 0.05). Hormone administration did not change IGFBP-4, whereas in men IGFBP-5 increased by 20% after GH (P Ͻ 0.05) and 56% after GH ϩ testosterone (P ϭ 0.0003). These data demonstrate sexually dimorphic IGFBP responses to GH. Additonally, HRT attenuated or prevented GH-mediated increases in IGF-I and IGFBP-3. Whether GH and/or sex steroid administration alters local tissue production of IGFBPs and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined. growth hormone; insulin-like growth factor-binding protein INSULIN-LIKE GROWTH FACTOR-BINDING PROTEINS (IGFBPs) are members of a structurally and genetically related superfamily of proteins that bind to insulin-like growth factors (IGFs) with high, but variable, affinities (34). In addition to their principal roles as modulators of endocrine, paracrine, and autocrine actions of IGFs, IGFBPs exert growth hormone (GH)-independent effects on various tissues in vivo and in vitro (38, 59). The detailed mechanisms of IGFBP synthesis and their metabolic activities remain incompletely understood. However, it has been reported (6, 64, 65) that circulating levels of IGFBP-1 are regulated by insulin and IGF-I. IGFBP-2 is also related to insulin levels (13), whereas increases in IGFBP-3 are closely correlated with those in IGF-I in response to GH in children (47) and adults (39) with GH deficiency (GHD). IGFBP-4 and -5 inhibit and stimulate, respectively, IGF-mediated effects on bone (53). How these important modulatory proteins are affected by aging and age-related changes in endocrine balance and the extent to which hormone replacement reverses such changes is incomplet...

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Section: Discussionsupporting

confidence: 79%

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Münzer¹,

Rosen²,

Harman³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…The gradual increase in ALP activity induced by HEXA and the difference between the ALP changes in the HEXA-treated vs control rats (þ 38% vs þ 1% respectively) at the end of the experiments would support this view. Accordingly, in a previous clinical study, the GHS MK677 induced a gradual, sustained increase of bone formation markers (22). In contrast to the present study, in a previous report we found HEXA ineffective in old dogs in modifying ALP activity (23).…”

Section: Discussioncontrasting

confidence: 99%

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

Sibilia

Villa

Lattuada

et al. 2002

European Journal of Endocrinology

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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.

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“…In a previous clinical study we found that a 2-month treatment with the GHS, MK-677, increases circulating markers of bone formation and resorption (Svensson et al 1998b). We have now shown that treatment of female rats with the GHSs ipamorelin and GHRP-6 for 3 months increased BMC as measured by DXA in vivo.…”

Section: Tablementioning

confidence: 52%

“…Little is known about the effects on bone of an increase in the amplitude of endogenous pulsatile GH secretion. We have recently shown that short-term treatment of obese men with the oral GHS, MK-677, increases circulating biochemical markers of bone formation and bone resorption (Svensson et al 1998b). The aim of the present study was to determine the effect of 12 weeks of treatment with the GHSs ipamorelin and GHRP-6 on bone mass in young adult female Sprague-Dawley rats.…”

Section: Introductionmentioning

confidence: 89%

The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats

Svensson

Lall²,

Dickson³

et al. 2000

Journal of Endocrinology

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Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0·5 mg/kg per day; n=7), GHRP-6 (0·5 mg/kg per day; n=8), GH (3·5 mg/kg per day; n=7), or vehicle administered continuously s.c. via osmotic minipumps for 12 weeks. The animals were followed in vivo by dual X-ray absorptiometry (DXA) measurements every 4th week. After the animals were killed, femurs were analysed in vitro by mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans. After this, excised femurs and vertebrae L6 were analysed by the use of Archimedes' principle and by determinations of ash weights. All treatments increased body weight and total tibial and vertebral BMC measured by DXA in vivo compared with vehicle-treated controls. However, total BMC corrected for the increase in body weight (total BMC:body weight ratio) was unaffected. Tibial area bone mineral density (BMD, BMC/area) was increased, but total and vertebral area BMDs were unchanged. The pQCT measurements in vitro revealed that the increase in the cortical BMC was due to an increased cross-sectional bone area, whereas the cortical volumetric BMD was unchanged. Femur and vertebra L6 volumes were increased but no effect was seen on the volumetric BMDs as measured by Archimedes' principle. Ash weight was increased by all treatments, but the mineral concentration was unchanged. We conclude that treatment of adult female rats with the GHSs ipamorelin and GHRP-6 increases BMC as measured by DXA in vivo. The results of in vitro measurements using pQCT and Archimedes' principle, in addition to ash weight determinations, show that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged.

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Treatment with the Oral Growth Hormone Secretagogue MK-677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males

Abstract: The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study.

Cited by 36 publications

References 70 publications

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

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

The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats

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