Hormone Agonist Therapy Disrupts Bone Density in Transgender Youth

Heidi Splete

September 20, 2021

The use of gonadotropin-releasing hormone agonists has a negative effect on bone mass in transgender youth, according to data from 172 individuals.

The onset of puberty and pubertal hormones contributes to the development of bone mass and body composition in adolescence, wrote Behdad Navabi, MD, and colleagues at Children's Hospital of Eastern Ontario, Canada. Although the safety and efficacy of gonadotropin-releasing hormone agonists (GnRHa) has been described in short-term studies of youth with gender dysphoria, concerns persist about suppression of bone mass accrual from extended use of GnRHas in this population, they noted.

In a study published in Pediatrics, the researchers reviewed data from 172 youth younger than 18 years of age who were treated with GNRHa and underwent at least one baseline dual-energy radiograph absorptiometry (DXA) measurement between January 2006 and April 2017 at a single center. The standard treatment protocol started with three doses of 7.5 mg leuprolide acetate, given intramuscularly every 4 weeks, followed by 11.25 mg intramuscularly every 12 weeks after puberty suppression was confirmed both clinically and biochemically. Areal bone mineral density (aBMD) measurement z scores were based on birth-assigned sex, age, and ethnicity, and assessed at baseline and every 12 months. In addition, volumetric bone mineral density was calculated as bone mineral apparent density (BMAD) at the lower spine, and the z score based on age-matched, birth-assigned gender BMAD.

Overall, 55.2% of the youth were vitamin D deficient or insufficient at baseline, but 87.3% were sufficient by the time of a third follow-up visit after treatment with 1,000-2,000 IU of vitamin D daily; no cases of vitamin D toxicity were reported.

At baseline, transgender females had lower z scores for the LS aBMD and BMAD compared to transgender males, reflecting a difference seen in previous studies of transgender youth and adult females, the researchers noted.

The researchers analyzed pre- and posttreatment DXA data in a subgroup of 36 transgender females and 80 transgender males to identify any changes associated with GnRHa. The average time between the DXA scans was 407 days. In this population, aBMD z scores at the lower lumbar spine (LS), left total hip (LTH), and total body less head (TBLH) decreased significantly from baseline in transgender males and females.

Among transgender males, LS bone mineral apparent density (BMAD) z scores also decreased significantly from baseline, but no such change occurred among transgender females. The most significant decrease in z scores occurred in the LS aBMD and BMAD of transgender males, with changes that reflect findings from previous studies and may be explained by decreased estrogen, the researchers wrote.

In terms of body composition, no significant changes occurred in body mass index z score from baseline to follow-up in transgender males or females, the researchers noted, and changes in both gynoid and android fat percentages were consistent with the individuals' affirmed genders. No vertebral fractures were detected.

However, GnRHa was significantly associated with a decrease in total body fat percentage and a decrease in lean body mass (LBM) in transgender females.

The study findings were limited by several factors, including the lack of consistent baseline physical activity records, and limited analysis at follow-up of the possible role of physical activity in bone health and body composition, the researchers noted. However, the results were strengthened by the relatively large study population with baseline assessments, and by the pre- and posttreatment analysis, they added.

"Evidence on GnRHa-associated changes in body composition and BMD will help health care professionals involved in the care of youth with GD [gender dysphoria] to counsel appropriately and optimize their bone health," the researchers said. "Given the absence of vertebral fractures detected in those with significant decreases in their LS z scores, the significance of BMD effects of GnRHa in transgender youth needs further study, as well as whether future spine radiographs are needed on the basis of BMD trajectory," they concluded.

Balance Bone Health Concerns With Potential Benefits

The effect of estrogen and testosterone on bone geometry in puberty varies, and the increase in the use of GnRHa as part of a multidisciplinary gender transition plan makes research on the skeletal impact of this therapy in transgender youth a top priority, Laura K. Bachrach, MD, of Stanford (Calif.) University, and Catherine M. Gordon of Harvard Medical School, Boston, wrote in an accompanying editorial.

The decrease in areal bone mineral density and in bone mineral apparent density (BMAD) z scores in the current study is not unexpected, but the key question is how much bone density recovers once the suppression therapy ends and transgender sex steroid use begins, they said. "Follow-up studies of young adults treated with GnRHa for precocious puberty in childhood are reassuring," they wrote. "It is premature, however, to extrapolate from these findings to transgender youth," because the impact of gender-affirming sex steroid therapy on the skeleton at older ages and stages of maturity are unclear, they emphasized.

In the absence of definitive answers, the editorial authors advised clinicians treating youth with gender dysphoria to provide a balanced view of the risks and benefits of hormone therapy, and encourage adequate intake of dietary vitamin D and calcium, along with weight-bearing physical activity, to promote general bone health. "Transgender teenagers and their parents should be reassured that some recovery from decreases in aBMD during pubertal suppression with GnRHa is likely," the authors noted. Bone health should be monitored throughout all stages of treatment in transgender youth, but concerns about transient bone loss should not discourage gender transition therapy, they emphasized. "In this patient group, providing a pause in pubertal development offers a life-changing and, for some, a life-saving intervention," they concluded.

Comparison to Cisgender Controls Would Add Value

"This study is important because one of the major side effects of GnRH agonists is decreased bone density, especially the longer that patients are on them," M. Brett Cooper, MD, of UT Southwestern Medical Center, said in an interview. The findings add to existing data to underscore the importance of screening for low bone density and low vitamin D levels, Cooper added.

Cooper said that he was not surprised by the study findings. "I think that this study supported what clinicians already knew, which is that GnRH agonists do potentially cause a decline in bone mineral density and thus, you need to support these patients as best you can with calcium, vitamin D, and weight-bearing exercise," he noted.

Cooper emphasized two main take-home points from the study. "First, clinicians who prescribe GnRH agonists need to ensure that they are checking bone density and vitamin D measurements, and then optimizing these appropriately," he said. "Second, when a bone density is found to be low or a vitamin level is low, clinicians need to ensure that they are monitored and treated appropriately." Clinicians need to use these data when deciding when to start gender-affirming hormones so their patients have the best chance to recover bone density, he added.

"I think one confounding factor on this study is the ranges they used for vitamin D deficiency," Cooper noted. "This study was done in Canada, and the scale used was in nmol/L, while most labs in the U.S. use ng/mL," he said. "Most pediatric and adolescent societies in the United States use < 20 ng/mL as an indicator of vitamin D deficient and between 20 and 29 ng/mL as insufficient," he explained, citing the position statement on recommended vitamin D intake for adolescents published by The Society for Adolescent Health and Medicine. In this study, the results converted to < 12 ng/mL as deficient and between 12 and 20 ng/mL as insufficient, respectively, on the U.S. scale, said Cooper.

"Therefore, I can see that there are cases where someone may have been labeled vitamin D insufficient in this study using their range, whereas in the U.S. these patients would be labeled as vitamin D deficient and treated with higher-dose supplementation," he said. In addition, individuals with levels between 20 ng/mL and 29 ng/mL in the U.S. would still be treated with vitamin D supplementation, "whereas in their study those individuals would have been labeled as normal," he noted.

As for future research, it would be useful to study whether bone mass in transgender young people differs from age- and gender-matched controls who are not gender diverse (cisgender), Cooper added. "It may be possible that the youth in this study are not different from their peers and maybe the GnRH agonist is not the culprit," he said.

The study received no outside funding. The researchers, editorial authors, and Cooper had no financial conflicts to disclose.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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