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Gender dysphoria in children: puberty blockers study draws further criticism

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5647 (Published 20 September 2019) Cite this as: BMJ 2019;366:l5647

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Close examination of existing studies indicates that use of puberty blockers in transgender young people commonly results in loss of bone mineral density

Writing in this journal, Cohen and Barnes clearly articulate the ongoing debate in relation to the effects of puberty blockers (Gonadotrophin Releasing Hormone agonists; GnRHa) on bone density in trans and gender diverse (TGD) young people. In particular, contention remains as to whether GnRHa causes slow accrual relative to pubertal controls, static accrual or bone loss.
Contributing to this confusion is that bone mineral density (BMD) in adolescents is typically reported as a Z-score that is adjusted for sex, height and age (height-for-age Z, HAZ) and based on normative population data (1, 2).

Significant reductions in HAZ during GnRHa treatment have been widely reported (3-7), and generally interpreted as poor accrual relative to pubertal population norms (3). However, HAZ scores decline with slow relative accrual, static accrual and actual BMD loss, and cannot distinguish between any of these different scenarios. Thus, we would argue that HAZ scores have limited utility in assessing an adolescent undergoing pubertal suppression.

In contrast, measurement of absolute BMD allows for determination of positive, negative and static changes over time. However, previous studies looking at the effects of GnRHa have focused on mean changes in absolute BMD when interpreting their cohort data (4, 5, 7), an approach that fails to adequately represent the range of changes to BMD within a cohort. For example, Vlot et al. reported no statistically significant declines in mean BMD during GnRHa treatment, apart from in a subset of older, transmale adolescents. Close examination of individual data (Figures 4 & 5 in their paper) reveals that 63% (20/32) of adolescents lost absolute BMD at the hip and 48% (10/21) at the lumbar spine in the remaining subsets, despite mean differences in these groups failing to reach statistical significance (5). In this way, the impact of GnRHa on BMD among any given group of adolescents appears heterogeneous, and many actually lose BMD. Any loss of BMD in adolescence is abnormal and attaining adequate peak bone mass (PBM) in adulthood – which should be the primary clinical focus for clinicians managing bone health in GnRHa-treated TGD adolescents – becomes increasingly unlikely if adolescents lose BMD during pubertal suppression.

Looking ahead, it will therefore be important to determine whether there are particular risk factors that make an individual more likely to lose bone density during treatment with GnRHa. In this regard, it is important to note that the determinants of PBM in this context will include not only non-modifiable factors such as genetics – which in general accounts for 60-80% of variance in a given individual’s BMD (8) – but also potentially modifiable factors such as: 1) absolute BMD at baseline, 2) timing of GnRHa commencement/cessation, 3) timing of gender-affirming hormone (GAH) commencement (which should stimulate BMD accrual), 4) rates of BMD accrual (or loss) during GnRHa and GAH treatment, 5) vitamin D and calcium status, 6) exercise, and 7) body composition. In this way, each individual undergoing GnRHa treatment will likely have a variable risk profile for low PBM depending on these factors. For example, adolescents beginning GnRHa later in puberty with high absolute BMD may be able to tolerate some BMD losses and still achieve adequate PBM, whereas others with low baseline BMD may not.

Until we elucidate the role of these different factors on PBM, it will be difficult to optimise the bone health of TGD young people receiving GnRHa. Efforts could begin by determining typical BMD accrual rates during GnRHa and GAH treatment and the role of modifiable risk factors in influencing these rates. To this end, international, multi-centre collaborative studies may be necessary to develop normative datasets and achieve meaningful results.

In the meantime, whilst some have suggested less frequent surveillance of BMD during GnRHa treatment is warranted – after being reassured by stable mean BMD values over time (7) – we would argue that greater vigilance is needed to detect those patients who are actually losing absolute BMD, so that appropriate action can be taken to optimise their PBM. After all, clinicians have a duty of care to ensure bone health is maximised in all TGD adolescents receiving GnRHa.

References
1. Gordon CM, Bachrach LK, Carpenter TO, et al. Dual Energy X-ray Absorptiometry Interpretation and Reporting in Children and Adolescents: The 2007 ISCD Pediatric Official Positions. Journal of Clinical Densitometry 2008;11(1):43-58. doi: https://doi.org/10.1016/j.jocd.2007.12.005
2. Zemel BS, Kalkwarf HJ, Gilsanz V, et al. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 2011;96(10):3160-9. doi: 10.1210/jc.2011-1111 [published Online First: 2011/09/16]
3. Chew D, Anderson J, Williams K, et al. Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review. Pediatrics 2018;141(4):e20173742. doi: 10.1542/peds.2017-3742
4. Klink D, Caris M, Heijboer A, et al. Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria. J Clin Endocrinol Metab 2015;100(2):E270-5. doi: 10.1210/jc.2014-2439 [published Online First: 2014/11/27]
5. Vlot MC, Klink DT, den Heijer M, et al. Effect of pubertal suppression and cross-sex hormone therapy on bone turnover markers and bone mineral apparent density (BMAD) in transgender adolescents. Bone 2017;95:11-19. doi: 10.1016/j.bone.2016.11.008 [published Online First: 2016/11/16]
6. Waal H, Cohen-Kettenis P. Clinical Management of Gender Identity Disorder in Adolescents: A Protocol on Psychological and Paediatric Endocrinology Aspects2006.
7. Joseph T, Ting J, Butler G. The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort. J Pediatr Endocrinol Metab 2019 doi: 10.1515/jpem-2019-0046 [published Online First: 2019/09/01]
8. Brown LB, Streeten EA, Shapiro JR, et al. Genetic and environmental influences on bone mineral density in pre- and post-menopausal women. Osteoporos Int 2005;16(12):1849-56. doi: 10.1007/s00198-005-1948-7 [published Online First: 2005/07/05]

Competing interests: No competing interests

03 October 2019
Grant M Ferguson
Adolescent Medicine Fellow
Dr Peter Simm, Dr Michele O’Connell and Dr Ken Pang
The Royal Children's Hospital,
50 Flemington Rd, Parkville, Victoria, Australia, 3052