Impact of ovarian insufficiency on bone health in childhood cancer survivors: Two cases

Authors: HE, CARA - Baylor College Of Medicine; LEE, DANIELLE - Children'S Nutrition Research Center (CNRC); FOSTER, KAYLA - Baylor College Of Medicine; GORDON, CATHERINE - Children'S Nutrition Research Center (CNRC)

Submitted to: Bone
Publication Type: Other
Publication Acceptance Date: 10/8/2023
Publication Date: 10/14/2023
Citation: He, C.Y., Lee, D.J., Foster, K.L., Gordon, C.M. 2023. Impact of ovarian insufficiency on bone health in childhood cancer survivors: Two cases. Bone. 178:Article 116930. https://doi.org/10.1016/j.bone.2023.116930.
DOI: https://doi.org/10.1016/j.bone.2023.116930

Interpretive Summary: Adolescent girls who undergo cancer treatments, like chemotherapy and radiation, may face long-term consequences such as premature ovarian insufficiency (POI), which is defined as the loss of ovarian activity in adolescents and women under the age of 40. POI often presents clinically with signs of estrogen deficiency. In particular, estrogen, which is produced by the ovaries, plays a crucial role in maintaining bone health, and its deficiency may lead to low bone density and/or heighten risk of fracture and other skeletal issues. In a recent case report, two adolescent female childhood cancer survivors with POI were studied with a focus on various aspects of their bone health, including bone mineral density and bone strength. The findings revealed that both girls exhibited significantly lower bone density compared to norms for their age, displaying compromised bone health. Even after adjusting for shorter stature, their bone density levels improved, but still were not normalized. Detailed scans further revealed weakened bone structure and strength. Of note, while both patients presented with similar symptoms of estrogen deficiency, they had different cancer diagnoses and received different location, duration, and types of cancer treatment. As a result, the underlying cause of their POI differed: direct injury to the ovaries vs. additional injury to estrogen regulation systems within the brain. This study underscores the important distinction between these two cases, despite their similar clinical presentations, and how medical management differs. More generally, the study highlights the importance of monitoring bone health in adolescent girls with POI. Early detection allows for timely intervention, such as hormone replacement therapy, which can significantly improve bone health during critical periods of development.

Technical Abstract: To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI). Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician. Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<- 2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised. Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass.