Recognition and support are growing for the estimated 0.7% of American teenagers who identify as transgender or gender fluid.1 Many children’s hospitals now offer multidisciplinary care to patients to assist them in transitioning from their designated sex at birth (natal sex or sex assigned at birth) to their affirmed gender. Therapy can begin in early puberty with suppression of sex steroid hormone production followed by supplementation with sex steroids appropriate for their gender identity. The duration of pubertal suppression with gonadotropin hormone releasing hormone agonists (GnRHa) varies but can be as long as 4 years for younger patients who must wait until age 16 to consent for receipt of gender-affirming sex steroid replacement. Much remains unknown about how these manipulations in sex steroids will impact bone geometry, turnover, mass, and strength, all of which contribute to peak bone mass and strength in early adulthood.
Peak bone mass and strength attained by early adulthood reflects the culmination of genetic and modifiable influences on bone density and microstructure.2 Sex steroids have differing effects on bone geometry during puberty, with testosterone fostering apposition of bone on the outer cortical surface and estrogen modifying the internal, endocortical area of bone.3 Research into the skeletal effects of hormone therapy for transgender youth is a high priority. The treatment protocols provide a valuable opportunity to distinguish the relative influence of sex steroids versus genetic preprogramming in determining bone development. Beyond the academic questions to be addressed, the onus is on providers to determine if their patients will sustain any adverse effects with respect to their long-term bone health. The influence of this treatment on the skeleton can be assessed noninvasively with dual energy radiograph absorptiometry (DXA), standard or high-resolution peripheral computed tomography, and/or MRI. These tools provide surrogate measures of bone strength that remain imperfect predictors of fracture in children and young adults.
In this issue of Pediatrics, Navabi et al report on areal bone mineral density (aBMD) and bone mineral apparent density (BMAD), the latter an estimate of volumetric bone mineral density measured by DXA in transgender youth.4 They compare findings before pubertal suppression and after a nearly a year of GnRHa therapy before initiation of gender-affirming sex steroids. At baseline, transfemale individuals had lower aBMD SD (z scores) when compared with normative data from healthy male individuals matched by age and ethnicity, as has been reported previously.5,6 At follow-up, spine and total hip aBMD z scores decreased significantly in both transmale and transfemale individuals; spine BMAD z scores decreased significantly only in transfemale indiviuals. Body composition changed as well, with increased fat mass and decreased lean body mass in transgender female youth. In their discussion, the authors emphasize that 55.2% of the transgender youth studied had vitamin D insufficiency or deficiency and urge attention to ensuring adequate calcium and vitamin D supplementation.
Other investigators have similarly observed bone health risk factors in teenagers seeking transgender therapy including low serum vitamin D concentrations or low dietary calcium intake. Researchers in several studies have also observed the pattern of lower BMD z scores in transgender female compared with transmale individuals before pubertal suppression therapy.5,6 This finding has been attributed to differences in lifestyle between transfemale and natal male individuals, including lower physical activity and higher intake of fast food. Although it is speculative, young transgender youth may worry about teasing by peers while engaging in sports, thereby discouraging them from these activities in a school or community setting. Alternatively, biological factors during intrauterine or early skeletal development could influence both skeletal development and gender identity.
The decrease in aBMD and BMAD z scores reported by Navabi et al during pubertal suppression with GnRHa therapy is not unexpected given the important influence sex hormones for bone acquisition. The magnitude of these skeletal effects is likely greater in later puberty (when sex steroids are high); 90.7% of the subjects were in late puberty (Tanner 4–5) when pubertal suppression therapy was initiated. A key question is how much recovery in bone density occurs once GnRHa therapy is stopped and transgender sex steroids are initiated. Follow-up studies of young adults treated with GnRHa for precocious puberty in childhood are reassuring. Peak bone mass is normal in these individuals, indicating that any transient decrease in bone mineral acquisition is fully reversible.7 It is premature, however, to extrapolate from these findings to transgender youth. The skeletal effects of pubertal suppression at a later age and stage of maturity and therapy with exogenous gender-affirming sex steroid therapy may not be similar.
Given the measurable contribution of bone geometry to bone strength, it is important to examine the effects of gender-affirming therapy on this parameter, as well. Van der Loos et al studied changes in bone geometry using hip structural analysis from DXA-derived images of the proximal femur.8 Measurements were taken at the start of GnRHa therapy, at the initiation of gender-affirming hormones, and after 2 years of supplementation. The outcome measures were subperiosteal width and endocortical diameter that are regulated by testosterone and estrogen, respectively. The study revealed that hip geometry was altered only in subjects who started GnRHa therapy during early puberty. Transgender male and female youth who began pubertal suppression in mid to late puberty had hip structural analysis parameters comparable to those for natal female and male individuals, respectively. These findings suggest that there is a critical window during which sex steroid manipulation could alter some aspects of bone development.
Additional research into the skeletal effects of hormone therapy for transgender youth is needed. To what extent is the skeleton “preprogrammed” by genetic factors, and how much can bone geometry, mass, and body composition be altered by therapy with transgender hormones? Researchers to date have found that transgender individuals have lower aBMD than natal male individuals even after affirming hormone is provided.5,9–10 The clinical impact of this observation remains uncertain because measurements of bone density or geometry using DXA or peripheral quantitative computed tomography are surrogate measures of bone strength. The most important outcome indicator of bone health at any age is the frequency of low-impact bone fractures. The study by Navabi et al and other studies to date reveal no evidence of increased fracture risk in transgender youth who are undergoing pubertal blockade. Whether there will be an increase in lifetime bone fragility is unknown.
Until there are more definitive answers, practitioners treating youth with gender dysphoria must provide a balanced view of the risks and benefits of hormonal therapy. General bone health measures should be encouraged including ensuring adequate vitamin D and calcium intake in the diet, and participation in weight-bearing activity. Provision of calcium and vitamin D is important for transgender youth as for all children and adolescents, but this alone is unlikely to counter the bone loss due to blockade of sex steroid secretion. A variety of physical activities should be discussed, including those that can be pursued as a solo pursuit for youth preferring to socially isolate. Transgender teenagers and their parents should be reassured that some recovery from decreases in aBMD during pubertal suppression with GnRHa is likely. Whether all skeletal parameters in transwomen will be identical to those of individuals assigned male at birth is unknown, as is whether those of transmen will be identical to those of individuals assigned female at birth. Further investigations will shed valuable light on the biological determinants of skeletal development and the potential risks of hormonal therapy for transgender adolescents.
Until more is known, bone health should be monitored throughout all stages of treatment in transgender youth, especially during pubertal blockade. A recent clinical guideline from the Endocrine Society recommends considering BMD screening by DXA every 1 to 2 years in young patients receiving GnRHa therapy, during subsequent gender-affirming hormones, and always in the setting of other risk factors for osteoporosis.11 Understanding the effects of blocking sex steroid secretion on the growing skeleton will provide important information to both pediatric and adult clinicians who care for these patients. Concern about transient bone loss should not discourage this therapy. What is certain is that rates of anxiety, depression, and suicide are strikingly higher among transgender youth, and GnRHa therapy offers hope to these patients. In this patient group, providing a pause in pubertal development offers a life-changing and, for some, a life-saving intervention.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-039339.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.