Transgender Youth on Hormone Therapy Risk Substantial Bone Loss

Ted Bosworth

July 08, 2022

ATLANTA ― Among transgender youth who receive puberty-delaying or gender-affirming hormone therapy, bone mineral density (BMD) is lower relative to age-based norms, and this is true regardless of gender assignment at birth.

The problem worsens as the time during which these patients receive sex steroid hormones increases. So far, the "bone mineral density effects of these therapies are understudied," warned Natalie Nokoff, MD, who presented a cross-sectional study at ENDO 2022: The Endocrine Society Annual Meeting, which was held in Atlanta last month.

The study of bone density is part of a larger body of research being conducted by Nokoff and her co-investigators on the long-term health effects of gender-affirming therapy in children and adolescents. In one of several recent studies, transgender youths taking gonadotropin-releasing hormone (GnRH) agonists ― which effectively block puberty ― were shown to be at a greater risk of adverse changes in body composition and markers of cardiometabolic health than youths who were not taking them.

"We need more information on the optimal length of treatment with puberty-delaying medications before either discontinuation or introduction of gender-affirming hormones," said Nokoff, an assistant professor of pediatrics and endocrinology at the University of Colorado School of Medicine, Aurora.

In this study, 56 transgender youth underwent total body dual-energy x-ray absorptiometry (DEXA). The patients ranged in age from 10 years to almost 20 years. Just over half (53%) were assigned female sex at birth.

The mean Z scores, signifying deviation from age-matched norms, were lower regardless of current use or past use of GnRH agonists in both transgender males and transgender females, relative to age-matched norms.

Asked to comment, Michele A. O'Connell, MBBCh, Department of Endocrinology and Diabetes, Royal Children's Hospital, Victoria, Australia, said the risk of bone loss is real.

"Monitoring of bone health is recommended for all transgender-diverse adolescents treated with gonadotropin-releasing hormone agonists," said O'Connell. He referred to multiple guidelines, including those issued by the World Professional Association of Transgender Health in 2012 and those from the Endocrine Society that were issued in 2017.

Inverse Correlation Between Duration of GnRH Agonist Therapy and Z Scores

In Nokoff's study, for transgender males, the BMD Z score was reduced 0.2 relative to male norms and by 0.4 relative to female norms. For transgender females, the scores were reduced by 0.4 relative to male norms and by 0.2 relative to female norms.

Among transgender males who were taking testosterone and who had previously been exposed to GnRH agonists, the Z score was significantly lower than those taking testosterone alone (P = .004). There were no differences in Z score for transgender females taking estradiol alone relative to estradiol with current or past use of GnRH agonists.

There was a significant inverse correlation for duration of GnRH agonist therapy and Z scores for transgender females relative to male norms (P = .005) or female norms (P = .029). However, Z scores were unrelated to length of time receiving testosterone or estradiol therapy or to sex steroid concentrations.

The number of children and adolescents taking puberty-delaying or gender-affirming therapies is increasing. Although reliable data are limited, the exploration of gender identify appears to have become more common with the growing social acceptance of gender dysphoria. That term refers a sense of unease among individuals who feel that their biological sex does not match their gender identity, according to Nokoff.

"It is now estimated that 2% of youths identify as transgender," she said.

Findings from studies investigating the relationship between gender-affirming therapy and bone loss among adults have not been consistent. In a single-center study that followed 543 transgender men and 711 transgender women who had undergone DEXA scanning at baseline prior to starting hormone therapy, there did not appear to be any substantial negative effects on lumbar bone density over time (J Bone Min Res. 2018 Dec;34:447-54).

For adolescents, there is growing evidence of the risk of bone loss in relation to gender-affirming therapy, but there is limited agreement on clinical risks and how they can be avoided. Relevant variables include genetics and diet, as well as the types, doses, and length of time receiving gender-affirming therapy.

Monitor Bone in Transgender Youth; Use Vit D and Weight-Bearing Exercise

O'Connell is the first author of a recent summary of the pharmacologic management of trans and gender-diverse adolescents. That summary covered multiple topics in addition to risk of bone loss, including the impact on growth, cognition, and mental health (J Clin Endocrinol Metab. 2022 Jan;107:241-257).

Overall, she believes that bone health should be monitored for children receiving puberty-delaying or gender-affirming therapies but agrees with Nokoff that the clinical impact remains poorly defined.

"Long-term follow-up studies will be required to assess the impact, if any, on functional outcomes such as fracture risk," she reported. Still, she encouraged use of standard ways of improving bone health, including adequate vitamin D intake and weight-bearing exercise.

Nokoff and O'Connell have disclosed no relevant financial relationships.

ENDO 2022: The Endocrine Society Annual Meeting.

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