Impact of GH administration on skeletal endpoints in adults with overweight/obesity

in European Journal of Endocrinology
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  • 1 Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  • | 2 Harvard Medical School, Boston, Massachusetts, USA
  • | 3 Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA
  • | 4 Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence should be addressed to M S Haines; Email: mshaines@mgh.harvard.edu

*(L E Dichtel and M S Haines contributed equally to this work)

(M A Bredella and K K Miller contributed equally to this work as senior authors)

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Objective

Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity.

Design

An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation.

Methods

In this study, 77 adults (53% men), aged 18–65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ −1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed.

Results

Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline.

Conclusions

GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

 

     European Society of Endocrinology

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  • 1

    Evans AL, Paggiosi MA, Eastell R, Walsh JS. Bone density, microstructure and strength in obese and normal weight men and women in younger and older adulthood. Journal of Bone and Mineral Research 2015 30 920928. (https://doi.org/10.1002/jbmr.2407)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Janicka A, Wren TA, Sanchez MM, Dorey F, Kim PS, Mittelman SD, Gilsanz V. Fat mass is not beneficial to bone in adolescents and young adults. Journal of Clinical Endocrinology and Metabolism 2007 92 143147. (https://doi.org/10.1210/jc.2006-0794)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Harrington LM, Breggia A, Rosen CJ, Miller KK. Determinants of bone mineral density in obese premenopausal women. Bone 2011 48 748754. (https://doi.org/10.1016/j.bone.2010.12.011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Johansson H, Kanis JA, Oden A, McCloskey E, Chapurlat RD, Christiansen C, Cummings SR, Diez-Perez A, Eisman JA & Fujiwara S et al.A meta-analysis of the association of fracture risk and body mass index in women. Journal of Bone and Mineral Research 2014 29 223233. (https://doi.org/10.1002/jbmr.2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Compston JE, Watts NB, Chapurlat R, Cooper C, Boonen S, Greenspan S, Pfeilschifter J, Silverman S, Diez-Perez A & Lindsay R et al.Obesity is not protective against fracture in postmenopausal women: GLOW. American Journal of Medicine 2011 124 10431050. (https://doi.org/10.1016/j.amjmed.2011.06.013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Owusu W, Willett W, Ascherio A, Spiegelman D, Rimm E, Feskanich D, Colditz G. Body anthropometry and the risk of hip and wrist fractures in men: results from a prospective study. Obesity Research 1998 6 1219. (https://doi.org/10.1002/j.1550-8528.1998.tb00309.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Nielson CM, Marshall LM, Adams AL, LeBlanc ES, Cawthon PM, Ensrud K, Stefanick ML, Barrett-Connor E, Orwoll ES & Osteoporotic Fractures in Men Study Research Group. BMI and fracture risk in older men: the osteoporotic fractures in men study (MrOS). Journal of Bone and Mineral Research 2011 26 496502. (https://doi.org/10.1002/jbmr.235)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Mazziotti G, Bianchi A, Bonadonna S, Nuzzo M, Cimino V, Fusco A, De Marinis L, Giustina A. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. Journal of Bone and Mineral Research 2006 21 520528. (https://doi.org/10.1359/jbmr.060112)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. European Journal of Endocrinology 1997 137 240245. (https://doi.org/10.1530/eje.0.1370240)

    • Search Google Scholar
    • Export Citation
  • 10

    Wüster C, Abs R, Bengtsson BA, Bennmarker H, Feldt-Rasmussen U, Hernberg-Ståhl E, Monson JP, Westberg B, Wilton P & KIMS Study Group and the KIMS International Board. Pharmacia & Upjohn International Metabolic Database. The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. Journal of Bone and Mineral Research 2001 16 398405. (https://doi.org/10.1359/jbmr.2001.16.2.398)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Baum HB, Biller BM, Finkelstein JS, Cannistraro KB, Oppenhein DS, Schoenfeld DA, Michel TH, Wittink H, Klibanski A. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Annals of Internal Medicine 1996 125 883890. (https://doi.org/10.7326/0003-4819-125-11-199612010-00003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Barake M, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2014 99 852860. (https://doi.org/10.1210/jc.2013-3921)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Hansen TB, Brixen K, Vahl N, Jorgensen JO, Christiansen JS, Mosekilde L, Hagen C. Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 1996 81 33523359. (https://doi.org/10.1210/jcem.81.9.8784096)

    • Search Google Scholar
    • Export Citation
  • 14

    Biller BM, Sesmilo G, Baum HB, Hayden D, Schoenfeld D, Klibanski A. Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency. Journal of Clinical Endocrinology and Metabolism 2000 85 970976. (https://doi.org/10.1210/jcem.85.3.6474)

    • Search Google Scholar
    • Export Citation
  • 15

    Franco C, Brandberg J, Lonn L, Andersson B, Bengtsson BA, Johannsson G. Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism 2005 90 14661474. (https://doi.org/10.1210/jc.2004-1657)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof K, Bjorntorp P, Sjostrom L, Bengtsson BA. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. Journal of Clinical Endocrinology and Metabolism 1997 82 727734. (https://doi.org/10.1210/jcem.82.3.3809)

    • Search Google Scholar
    • Export Citation
  • 17

    Utz AL, Yamamoto A, Sluss P, Breu J, Miller KK. Androgens may mediate a relative preservation of IGF-I levels in overweight and obese women despite reduced growth hormone secretion. Journal of Clinical Endocrinology and Metabolism 2008 93 40334040. (https://doi.org/10.1210/jc.2008-0930)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Colao A, Di Somma C, Savastano S, Rota F, Savanelli MC, Aimaretti G, Lombardi G. A reappraisal of diagnosing GH deficiency in adults: role of gender, age, waist circumference, and body mass index. Journal of Clinical Endocrinology and Metabolism 2009 94 44144422. (https://doi.org/10.1210/jc.2009-1134)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Haines MS, Dichtel LE, Santoso K, Torriani M, Miller KK, Bredella MA. Association between muscle mass and insulin sensitivity independent of detrimental adipose depots in young adults with overweight/obesity. International Journal of Obesity 2020 44 18511858. (https://doi.org/10.1038/s41366-020-0590-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Utz AL, Yamamoto A, Hemphill L, Miller KK. Growth hormone deficiency by growth hormone releasing hormone-arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women. Journal of Clinical Endocrinology and Metabolism 2008 93 25072514. (https://doi.org/10.1210/jc.2008-0169)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Whittaker LG, McNamara EA, Vath S, Shaw E, Malabanan AO, Parker RA, Rosen HN. Direct comparison of the precision of the new Hologic horizon model with the old discovery model. Journal of Clinical Densitometry 2018 21 524528. (https://doi.org/10.1016/j.jocd.2017.11.001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Nowitz M, Monahan P. Short term in vivo precision of whole body composition measurements on the Horizon A densitometer. Journal of Medical Imaging and Radiation Oncology 2018 62 179182. (https://doi.org/10.1111/1754-9485.12646)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Shepherd JA, Lu Y, Wilson K, Fuerst T, Genant H, Hangartner TN, Wilson C, Hans D, Leib ES & International Society for Clinical Densitometry Committee on Standards of Bone Measurement. Cross-calibration and minimum precision standards for dual-energy X-ray absorptiometry: the 2005 ISCD Official Positions. Journal of Clinical Densitometry 2006 9 3136. (https://doi.org/10.1016/j.jocd.2006.05.005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Kelly T Bone mineral density reference databases for American men and women. Journal of Bone and Mineral Research 1990 5 S249.

  • 25

    Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston Jr CC, Lindsay R. Updated data on proximal femur bone mineral levels of US adults. Osteoporosis International 1998 8 468489. (https://doi.org/10.1007/s001980050093)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston Jr CC, Lindsay RL. Proximal femur bone mineral levels of US adults. Osteoporosis International 1995 5 389409. (https://doi.org/10.1007/BF01622262)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Kelly TL, Wilson KE, Heymsfield SB. Dual energy X-ray absorptiometry body composition reference values from NHANES. PLoS ONE 2009 4 e7038. (https://doi.org/10.1371/journal.pone.0007038)

    • Search Google Scholar
    • Export Citation
  • 28

    Bligh M, Bidaut L, White RA, Murphy Jr WA, Stevens DM, Cody DD. Helical multidetector row quantitative computed tomography (QCT) precision. Academic Radiology 2009 16 150159. (https://doi.org/10.1016/j.acra.2008.08.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Khoo BC, Brown K, Cann C, Zhu K, Henzell S, Low V, Gustafsson S, Price RI, Prince RL. Comparison of QCT-derived and DXA-derived areal bone mineral density and T scores. Osteoporosis International 2009 20 15391545. (https://doi.org/10.1007/s00198-008-0820-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Lang TF, Li J, Harris ST, Genant HK. Assessment of vertebral bone mineral density using volumetric quantitative CT. Journal of Computer Assisted Tomography 1999 23 130137. (https://doi.org/10.1097/00004728-199901000-00027)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. Journal of Clinical Endocrinology and Metabolism 2005 90 65086515. (https://doi.org/10.1210/jc.2005-1258)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Pistoia W, van Rietbergen B, Laib A, Ruegsegger P. High-resolution three-dimensional-pQCT images can be an adequate basis for in-vivo microFE analysis of bone. Journal of Biomechanical Engineering 2001 123 176183. (https://doi.org/10.1115/1.1352734)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    The Prevention and Treatment of Missing Data in Clinical Trials, Panel on Handling Missing Data in Clinical Trials. Washington, DC: The National Academie Press. (available at: www.nap.edu)

    • Search Google Scholar
    • Export Citation
  • 34

    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III ). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002 106 31433421. (https://doi.org/10.1161/circ.106.25.3143)

    • Search Google Scholar
    • Export Citation
  • 35

    Bredella MA, Gerweck AV, Barber LA, Breggia A, Rosen CJ, Torriani M, Miller KK. Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women. Bone 2014 62 2935. (https://doi.org/10.1016/j.bone.2014.01.022)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Gillberg P, Mallmin H, Petren-Mallmin M, Ljunghall S, Nilsson AG. Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. Journal of Clinical Endocrinology and Metabolism 2002 87 49004906. (https://doi.org/10.1210/jc.2002-020231)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Saaf M, Hilding A, Thoren M, Troell S, Hall K. Growth hormone treatment of osteoporotic postmenopausal women – a one-year placebo-controlled study. European Journal of Endocrinology 1999 140 390399. (https://doi.org/10.1530/eje.0.1400390)

    • Search Google Scholar
    • Export Citation
  • 38

    Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial. Journal of Bone and Mineral Research 2003 18 393405. (https://doi.org/10.1359/jbmr.2003.18.3.393)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    Krantz E, Trimpou P, Landin-Wilhelmsen K. Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study. Journal of Clinical Endocrinology and Metabolism 2015 100 32513259. (https://doi.org/10.1210/jc.2015-1757)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Klefter O, Feldt-Rasmussen U. Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis. European Journal of Endocrinology 2009 161 213221. (https://doi.org/10.1530/EJE-09-0160)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Bredella MA, Gerweck AV, Lin E, Landa MG, Torriani M, Schoenfeld DA, Hemphill LC, Miller KK. Effects of GH on body composition and cardiovascular risk markers in young men with abdominal obesity. Journal of Clinical Endocrinology and Metabolism 2013 98 38643872. (https://doi.org/10.1210/jc.2013-2063)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Bredella MA, Lin E, Brick DJ, Gerweck AV, Harrington LM, Torriani M, Thomas BJ, Schoenfeld DA, Breggia A & Rosen CJ et al.Effects of GH in women with abdominal adiposity: a 6-month randomized, double-blind, placebo-controlled trial. European Journal of Endocrinology 2012 166 601611. (https://doi.org/10.1530/EJE-11-1068)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Dichtel LE, Yuen KC, Bredella MA, Gerweck AV, Russell BM, Riccio AD, Gurel MH, Sluss PM, Biller BM, Miller KK. Overweight/obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 2014 99 47124719. (https://doi.org/10.1210/jc.2014-2830)

    • Crossref
    • Search Google Scholar
    • Export Citation