Abstract
Objectives
The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health.
Methods
256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10 years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25 %/75 % interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate.
Results
The BHI standard deviation scores (SDS) were reduced (−0.97, −1.8/−0.3) as bone ages were retarded (−1.6 years, −2.31/−0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (−1.04, −1.85/−0.56; n=170) compared to non-GHD patients (−0.79, −1.56/−0.01; n=86; p=0.022). BHI SDS increased to −0.17 (−1/0.58) after 1 year of GH (T1, 0.5–1.49, p<0.001) and to −0.20 (−1/−0.50, p<0.001) after 5.3 years (T max, 3.45/7.25).
Conclusions
BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. LH, DC and MB planned the study, wrote study protocol, conducted study and collected data. LH evaluated the data, performed statistical analyses and created the graphs. LH, DC, MR, JPS and MB wrote the manuscript and interpreted the final results. All authors performed proof reading of the final version of this manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Competing interests: Authors state no competing of interest.
-
Informed consent: Not applicable. The Ethics Committee of University Hospital Heidelberg approved the study (S-029/2019) and decided that written consents of study participants were not required. The identification of personal information was not necessary for scientific reasons. All data were used pseudonymized.
-
Ethical approval: The Ethics Committee of University Hospital Heidelberg approved the study (S-029/2019). Written consents of study participants were not required. Study was conducted according to the recommendations of the Declaration of Helsinki.
-
Data availability: The data is available from the corresponding author (LH) upon reasonable request.
-
Definition of research data: Primary data.
References
1. Johannsson, G, Bidlingmaier, M, Biller, BMK, Boguszewski, M, Casanueva, FF, Chanson, P, et al.. Growth Hormone Research Society perspective on biomarkers of GH action in children and adults. Endocr Connect 2018;7:R126–34. https://doi.org/10.1530/ec-18-0047.Search in Google Scholar
2. Ohlsson, C, Bengtsson, BA, Isaksson, OG, Andreassen, TT, Slootweg, MC. Growth hormone and bone. Endocr Rev 1998;19:55–79. https://doi.org/10.1210/er.19.1.55.Search in Google Scholar
3. Mazziotti, G, Frara, S, Giustina, A. Pituitary diseases and bone. Endocr Rev 2018;39:440–88. https://doi.org/10.1210/er.2018-00005.Search in Google Scholar PubMed
4. Saggese, G, Baroncelli, GI, Bertelloni, S, Barsanti, S. The effect of long-term growth hormone (GH) treatment on bone mineral density in children with GH deficiency. Role of GH in the attainment of peak bone mass. J Clin Endocrinol Metab 1996;81:3077–83. https://doi.org/10.1210/jcem.81.8.8768878.Search in Google Scholar PubMed
5. Boot, AM, Engels, MA, Boerma, GJ, Krenning, EP, De Muinck Keizer-Schrama, SM. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab 1997;82:2423–8. https://doi.org/10.1210/jc.82.8.2423.Search in Google Scholar
6. Cowell, CT, Woodhead, HJ, Brody, J. Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency. Horm Res 2000;54(Suppl 1):44–51. https://doi.org/10.1159/000063447.Search in Google Scholar PubMed
7. Schweizer, R, Martin, DD, Schwarze, CP, Binder, G, Georgiadou, A, Ihle, J, et al.. Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling. J Clin Endocrinol Metab 2003;88:5266–72. https://doi.org/10.1210/jc.2003-030432.Search in Google Scholar PubMed
8. Lanes, R, Gunczler, P, Esaa, S, Weisinger, JR. The effect of short-and long-term growth hormone treatment on bone mineral density and bone metabolism of prepubertal children with idiopathic short stature: a 3-year study. Clin Endocrinol 2002;57:725–30. https://doi.org/10.1046/j.1365-2265.2002.01614.x.Search in Google Scholar PubMed
9. Arends, NJ, Boonstra, VH, Mulder, PG, Odink, RJ, Stokvis-Brantsma, WH, Rongen-Westerlaken, C, et al.. GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol 2003;59:779–87. https://doi.org/10.1046/j.1365-2265.2003.01905.x.Search in Google Scholar PubMed
10. Lem, AJ, van der Kaay, DC, Hokken-Koelega, AC. Bone mineral density and body composition in short children born SGA during growth hormone and gonadotropin releasing hormone analog treatment. J Clin Endocrinol Metab 2013;98:77–86. https://doi.org/10.1210/jc.2012-2492.Search in Google Scholar PubMed
11. Schweizer, R, Martin, DD, Haase, M, Roth, J, Trebar, B, Binder, G, et al.. Similar effects of long-term exogenous growth hormone (GH) on bone and muscle parameters: a pQCT study of GH-deficient and small-for-gestational-age (SGA) children. Bone 2007;41:875–81. https://doi.org/10.1016/j.bone.2007.06.028.Search in Google Scholar PubMed
12. Dunger, D, Darendeliler, F, Kandemir, N, Harris, M, Rabbani, A, Kappelgaard, AM. What is the evidence for beneficial effects of growth hormone treatment beyond height in short children born small for gestational age? A review of published literature. J Pediatr Endocrinol Metab 2020;33:53–70. https://doi.org/10.1515/jpem-2019-0098.Search in Google Scholar PubMed
13. Stagi, S, Iurato, C, Lapi, E, Cavalli, L, Brandi, ML, de Martino, M. Bone status in genetic syndromes: a review. Hormones 2015;14:19–31. https://doi.org/10.1007/bf03401378.Search in Google Scholar PubMed
14. Faienza, MF, Ventura, A, Colucci, S, Cavallo, L, Grano, M, Brunetti, G. Bone fragility in Turner syndrome: mechanisms and prevention strategies. Front Endocrinol 2016;7:34. https://doi.org/10.3389/fendo.2016.00034.Search in Google Scholar PubMed PubMed Central
15. Sas, TC, de Muinck Keizer-Schrama, SM, Stijnen, T, van Teunenbroek, A, van Leeuwen, WJ, Asarfi, A, et al.. Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner’s syndrome participating in a randomized dose-response study. Pediatr Res 2001;50:417–22. https://doi.org/10.1203/00006450-200109000-00019.Search in Google Scholar PubMed
16. Cleemann, L, Hjerrild, BE, Lauridsen, AL, Heickendorff, L, Christiansen, JS, Mosekilde, L, et al.. Long-term hormone replacement therapy preserves bone mineral density in Turner syndrome. Eur J Endocrinol 2009;161:251–7. https://doi.org/10.1530/eje-09-0020.Search in Google Scholar
17. Schweizer, R, Mayer, J, Binder, G. Normal bone density but altered geometry in girls with Turner syndrome. J Pediatr Endocrinol Metab 2023;36:270–7. https://doi.org/10.1515/jpem-2022-0516.Search in Google Scholar PubMed
18. Thodberg, HH, van Rijn, RR, Tanaka, T, Martin, DD, Kreiborg, S. A paediatric bone index derived by automated radiogrammetry. Osteoporos Int 2010;21:1391–400. https://doi.org/10.1007/s00198-009-1085-9.Search in Google Scholar PubMed PubMed Central
19. Schündeln, MM, Marschke, L, Bauer, JJ, Hauffa, PK, Schweiger, B, Führer-Sakel, D, et al.. A piece of the puzzle: the bone health index of the BoneXpert software reflects cortical bone mineral density in pediatric and adolescent patients. PLoS One 2016;11:e0151936. https://doi.org/10.1371/journal.pone.0151936.Search in Google Scholar PubMed PubMed Central
20. Shalof, H, Dimitri, P, Shuweihdi, F, Offiah, AC. Which skeletal imaging modality is best for assessing bone health in children and young adults compared to DXA? A systematic review and meta-analysis. Bone 2021;150:116013. https://doi.org/10.1016/j.bone.2021.116013.Search in Google Scholar PubMed
21. Reinken, L, van Oost, G. [Longitudinal physical development of healthy children 0 to 18 years of age. Body length/height, body weight and growth velocity]. Klin Pädiatr 1992;204:129–33. https://doi.org/10.1055/s-2007-1025337.Search in Google Scholar PubMed
22. Kromeyer-Hauschild, K, Wabitsch, M, Kunze, D, Geller, F, Geiß, HC, Hesse, V, et al.. Perzentile für den Body-mass-Index für das Kindes-und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 2001;149:807–18. https://doi.org/10.1007/s001120170107.Search in Google Scholar
23. Voigt, M, Fusch, C, Olbertz, D, Hartmann, K, Rochow, N, Renken, C, et al.. Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland. Geburtshilfe Frauenheilkd 2006;66:956–70. https://doi.org/10.1055/s-2006-924458.Search in Google Scholar
24. Tanner, JM, Goldstein, H, Whitehouse, RH. Standards for children’s height at ages 2–9 years allowing for heights of parents. Arch Dis Child 1970;45:755–62. https://doi.org/10.1136/adc.45.244.755.Search in Google Scholar PubMed PubMed Central
25. Thodberg, HH, Kreiborg, S, Juul, A, Pedersen, KD. The BoneXpert method for automated determination of skeletal maturity. IEEE Trans Med Imag 2009;28:52–66. https://doi.org/10.1109/tmi.2008.926067.Search in Google Scholar
26. Blum, WF, Schweizer, R. Insulin-like growth factors and their binding proteins. Ranke, MB, editor. Basel: Karger; 2003:166–99 pp.10.1159/000073550Search in Google Scholar
27. Högler, W, Shaw, N. Childhood growth hormone deficiency, bone density, structures and fractures: scrutinizing the evidence. Clin Endocrinol 2010;72:281–9. https://doi.org/10.1111/j.1365-2265.2009.03686.x.Search in Google Scholar PubMed
28. Improda, N, Capalbo, D, Esposito, A, Salerno, M. Muscle and skeletal health in children and adolescents with GH deficiency. Best Pract Res Clin Endocrinol Metabol 2016;30:771–83. https://doi.org/10.1016/j.beem.2016.11.012.Search in Google Scholar PubMed
29. Lalayiannis, AD, Fewtrell, M, Biassoni, L, Silva, S, Goodman, N, Shroff, R, et al.. Studying bone mineral density in young people: the complexity of choosing a pQCT reference database. Bone 2021;143:115713. https://doi.org/10.1016/j.bone.2020.115713.Search in Google Scholar PubMed
30. Ashby, RL, Ward, KA, Roberts, SA, Edwards, L, Mughal, MZ, Adams, JE. A referenc1e database for the Stratec XCT-2000 peripheral quantitative computed tomography (pQCT) scanner in healthy children and young adults aged 6–19 years. Osteoporos Int 2009;20:1337–46. https://doi.org/10.1007/s00198-008-0800-2.Search in Google Scholar PubMed
31. Exton-Smith, AN, Millard, PH, Payne, PR, Wheeler, EF. Method for measuring quantity of bone. Lancet 1969;2:1153–4. https://doi.org/10.1016/s0140-6736(69)92482-9.Search in Google Scholar PubMed
32. Bettendorf, M, Graf, K, Nelle, M, Heinrich, UE, Tröger, J. Metacarpal index in short stature before and during growth hormone treatment. Arch Dis Child 1998;79:165–8. https://doi.org/10.1136/adc.79.2.165.Search in Google Scholar PubMed PubMed Central
33. Bouillon, R, Koledova, E, Bezlepkina, O, Nijs, J, Shavrikhova, E, Nagaeva, E, et al.. Bone status and fracture prevalence in Russian adults with childhood-onset growth hormone deficiency. J Clin Endocrinol Metab 2004;89:4993–8. https://doi.org/10.1210/jc.2004-0054.Search in Google Scholar PubMed
34. Soucek, O, Lebl, J, Zapletalova, J, Novotna, D, Plasilova, I, Kolouskova, S, et al.. Bone geometry and volumetric bone density at the radius in patients with isolated SHOX deficiency. Exp Clin Endocrinol Diabetes 2013;121:109–14. https://doi.org/10.1055/s-0032-1333260.Search in Google Scholar PubMed
35. Rubin, K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics 1998;102:481–5. https://doi.org/10.1542/peds.102.s3.481.Search in Google Scholar
36. Balasuriya, CND, Evensen, KAI, Mosti, MP, Brubakk, AM, Jacobsen, GW, Indredavik, MS, et al.. Peak bone mass and bone microarchitecture in adults born with low birth weight preterm or at term: a cohort study. J Clin Endocrinol Metab 2017;102:2491–500. https://doi.org/10.1210/jc.2016-3827.Search in Google Scholar PubMed
37. Baroncelli, GI, Bertelloni, S, Sodini, F, Saggese, G. Lumbar bone mineral density at final height and prevalence of fractures in treated children with GH deficiency. J Clin Endocrinol Metab 2002;87:3624–31. https://doi.org/10.1210/jcem.87.8.8754.Search in Google Scholar PubMed
38. Kraus, R, Schneidmüller, D, Röder, C. Häufigkeit von Frakturen der langen Röhrenknochen im Wachstumsalter. Dtsch Arztebl International 2005;102:A-838.Search in Google Scholar
39. Bachrach, LK. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metabol 2001;12:22–8. https://doi.org/10.1016/s1043-2760(00)00336-2.Search in Google Scholar PubMed
© 2023 Walter de Gruyter GmbH, Berlin/Boston