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Bone mineral density in individuals treated with puberty suppression caught up with pretreatment levels in most cases after long-term use of gender-affirming hormones (GAH), according to a single-center cohort study.

Among 75 participants diagnosed with gender dysphoria who used puberty suppression before age 18 and then received at least 9 years of GAH, bone mineral density z scores recovered all except for those at the lumbar spine in persons assigned male at birth.

The exception might have been due to low estradiol concentrations, reported Maria Anna Theodora Catharina van der Loos, MD, of Amsterdam University Medical Center in the Netherlands, and colleagues in .

"While treatment with puberty suppression for adolescents diagnosed with gender dysphoria has become controversial, especially because of questions about the long-term safety, we present evidence that [gonadotropin-releasing hormone agonist] treatment is generally safe regarding bone health," van der Loos told MedPage Today in an email.

"It's an important finding that in most individuals this approach is safe regarding bone health," van der Loos added. "However, in participants assigned male at birth extra attention should be paid because the lumbar spine does not catch up with pretreatment levels."

Use of gonadotropin-releasing hormone (GnRH) agonists is relatively new in the treatment of transgender adolescents, van der Loos and colleagues wrote. "Around the year 2000, treatment with GnRH agonists was introduced as a means of puberty suspension to lighten the burden of undesired physical changes while extending the time for exploration of treatment wishes with subsequent GAH."

There have been concerns about possibly increased risk of osteoporosis and associated increased fracture risk if these individuals achieve lower peak bone mass, the group pointed out.

To complete their study, van der Loos and colleagues targeted a follow-up duration of 15 years. Participants were selected from a database containing all individuals visiting a gender identity clinic at an academic hospital in the Netherlands from 1972 through the end of 2018.

Of the 75 participants in the study, 50 were assigned female at birth, and 25 were assigned male.

The median age at follow-up was 28.2 years. Median duration of GAH treatment was 11.9 years among those assigned female at birth and 11.6 years in those assigned male.

Among participants assigned female at birth, their individual bone mineral density increased over time at all three regions of interest: the lumbar spine, the total hip, and the femoral neck. Z scores in comparison to population means decreased following initiation of GnRH agonist treatment. However, during GAH treatment, z scores increased, resulting in similar scores to those at the start of GnRH agonist treatment.

Following long-term GAH, mean bone mineral density z score was 0.20 for the lumbar spine (change from start of GnRH agonist 0.09, 95% CI -0.09 to 0.27), 0.07 for the total hip (0.10, 95% CI -0.06 to 0.26), and -0.19 for the femoral neck (-0.20, 95% CI -0.26 to 0.06).

At follow-up, there was no association of estradiol, testosterone, or vitamin D concentrations or duration of mono GnRH agonist treatment with z scores at any of the regions. Luteinizing hormone (LH) was negatively associated with the lumbar spine z score, while BMI was positively associated with z scores at the total hip and femoral neck, but not at the lumbar spine.

Among individuals assigned male at birth, bone mineral density remained stable during GnRH agonist treatment but increased during GAH. Z scores were already below zero at the start of a GnRH agonist and further decreased during this treatment.

During GAH treatment, their mean lumbar spine z score (-1.34) remained stable, resulting in a decreased z score at follow-up (-0.87, 95% CI -1.15 to -0.59) compared with that at the start of GnRH agonist treatment. The mean z scores at the total hip (-0.66) and femoral neck (-0.54) increased during GAH treatment, while the z scores at follow-up were not different compared with those from the start of GnRH treatment (total hip: -0.12, 95% CI -0.31 to 0.07; femoral neck: 0.01, 95% CI -0.20 to 0.22).

At follow up, z scores were greater with increasing estradiol concentrations; however, the score differences were not significant. LH, vitamin D concentrations, and the duration of mono GnRH agonist treatment were not associated with z scores.

Furthermore, similar to participants assigned female at birth, a positive association was found between BMI and z scores at the total hip and at the femoral neck, but not at the lumbar spine. And because testosterone was low in all participants assigned male at birth at follow-up, this analysis was omitted.

Limitations of the study included that, overall, 19% of eligible participants could not be reached for the study, and another 21% did not provide informed consent for a variety of reasons. Also, data were not available for all participants at every time point, and participants were not able to be stratified for puberty stage at the start of GnRH agonist treatment.

"In future studies, it would be informative to assess the association between estradiol and bone mineral density in a larger study population," van der Loos told MedPage Today. "Additionally, the natural course of bone mineral density development in transgender people should be studied," as z scores prior to initiation of GnRH agonist treatment were already decreased in individuals assigned male at birth.

"This would help clarify to what extent the finding that follow-up measurements did not catch up with pretreatment levels at the lumbar spine can be attributed to the hormonal treatment and to what extent to other factors," said van der Loos.

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