Bone Mineral Density in Women with Functional Hypothalamic Amenorrhea: A Systematic Review and Meta-Analysis.
6 affiliations
- 1Department of Obstetrics and Gynecology, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan.
- 2Department of Obstetrics and Gynecology No. 2, Astana Medical University, Astana 010000, Kazakhstan.
- 3Department of Health Policy and Management, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan.
- 4Board for Clinical Work, Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty 050020, Kazakhstan.
- 5Department of Propedeutics of Internal Diseases, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan.
- 6Department of Surgical Diseases, Kazakhstani Medical University "KSPH", Almaty 050060, Kazakhstan.
Abstract
This study aims to quantitatively evaluate bone mineral density (BMD) in women with functional hypothalamic amenorrhea (FHA), determine differences across skeletal sites, and summarise current evidence on the diagnosis and management of impaired bone health in this population. Methods: A systematic search of comparative studies evaluating BMD by dual-energy X-ray absorptiometry (DXA) in women with FHA or anorexia nervosa (AN) and healthy eumenorrhoeic controls was performed. Eleven studies met the eligibility criteria, five of which were included in the meta-analysis. The quantitative synthesis comprised 14 group comparisons, with lumbar spine and hip BMD analysed separately. Effect sizes were pooled using Hedges' g with 95% confidence intervals (CI) under a random-effects model. Sensitivity analyses using REML estimation with Hartung-Knapp adjustment and leave-one-out analyses were performed to assess the robustness of the pooled estimates. Results: The narrative synthesis of 11 studies generally showed lower BMD in women with FHA or AN compared with healthy controls. In the meta-analysis, among women with FHA, hip BMD was significantly lower than in healthy controls (Hedges' g = -0.60; 95% CI -1.13 to -0.06; p = 0.030; I² = 63%), while a moderate reduction was observed at the lumbar spine (Hedges' g = -0.68; 95% CI -1.48 to 0.13; p = 0.101; I² = 83%). In women with AN, substantial reductions were observed at both the lumbar spine (Hedges' g = -1.66; 95% CI -2.28 to -1.04; p < 0.001; I² = 71%) and the hip (Hedges' g = -1.37; 95% CI -2.33 to -0.42; p = 0.005; I² = 89%). The lumbar spine reduction in AN remained statistically significant across sensitivity and leave-one-out analyses and was the most robust finding, whereas the statistical significance of hip BMD estimates in both FHA and AN and of lumbar spine BMD in FHA was sensitive to the analytical approach or exclusion of individual studies. The systematic review demonstrated that DXA with interpretation based on Z-scores remains the preferred method for skeletal assessment in premenopausal women with FHA. Bone health assessment is recommended after ≥6 months of amenorrhea or earlier in women with severe energy deficiency or a history of fractures. Restoration of energy availability, weight gain, and recovery of menstrual function remain the cornerstone of treatment. When amenorrhea persists and low BMD is confirmed, physiological transdermal 17β-estradiol combined with cyclic progesterone is the preferred hormonal therapy, whereas combined oral contraceptives, bisphosphonates, and denosumab are not recommended for routine management. Conclusions: Functional hypothalamic amenorrhea is associated with reduced BMD, with substantially greater skeletal deficits observed in the AN subgroup. These findings support early assessment of bone health and timely correction of low energy availability in women with FHA. The considerable between-study heterogeneity and sensitivity of some pooled estimates highlight the need for larger prospective studies using standardized diagnostic criteria and uniform skeletal outcome measures.
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BibTeX
@article{sultanova2026bone,
title = {{Bone Mineral Density in Women with Functional Hypothalamic Amenorrhea: A Systematic Review and Meta-Analysis.}},
author = {Zhanat Sultanova and Saule Issenova and Yelena Dissyukeyeva and Saule Nukusheva and Aliya Aimbetova and Kulman Nyssanbayeva and Rassul Dyussenov and Fatima Kassymbekova},
journal = {Medical sciences (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/medsci14060615},
url = {https://europepmc.org/article/MED/42930534},
note = {CC BY},
}
RIS
TY - JOUR
TI - Bone Mineral Density in Women with Functional Hypothalamic Amenorrhea: A Systematic Review and Meta-Analysis.
AU - Zhanat Sultanova
AU - Saule Issenova
AU - Yelena Dissyukeyeva
AU - Saule Nukusheva
AU - Aliya Aimbetova
AU - Kulman Nyssanbayeva
AU - Rassul Dyussenov
AU - Fatima Kassymbekova
PY - 2026
DA - 2026/09/29
JO - Medical sciences (Basel, Switzerland)
DO - 10.3390/medsci14060615
UR - https://europepmc.org/article/MED/42930534
AB - This study aims to quantitatively evaluate bone mineral density (BMD) in women with functional hypothalamic amenorrhea (FHA), determine differences across skeletal sites, and summarise current evidence on the diagnosis and management of impaired bone health in this population. Methods: A systematic search of comparative studies evaluating BMD by dual-energy X-ray absorptiometry (DXA) in women with FHA or anorexia nervosa (AN) and healthy eumenorrhoeic controls was performed. Eleven studies met the eligibility criteria, five of which were included in the meta-analysis. The quantitative synthesis comprised 14 group comparisons, with lumbar spine and hip BMD analysed separately. Effect sizes were pooled using Hedges' g with 95% confidence intervals (CI) under a random-effects model. Sensitivity analyses using REML estimation with Hartung-Knapp adjustment and leave-one-out analyses were performed to assess the robustness of the pooled estimates. Results: The narrative synthesis of 11 studies generally showed lower BMD in women with FHA or AN compared with healthy controls. In the meta-analysis, among women with FHA, hip BMD was significantly lower than in healthy controls (Hedges' g = -0.60; 95% CI -1.13 to -0.06; p = 0.030; I² = 63%), while a moderate reduction was observed at the lumbar spine (Hedges' g = -0.68; 95% CI -1.48 to 0.13; p = 0.101; I² = 83%). In women with AN, substantial reductions were observed at both the lumbar spine (Hedges' g = -1.66; 95% CI -2.28 to -1.04; p < 0.001; I² = 71%) and the hip (Hedges' g = -1.37; 95% CI -2.33 to -0.42; p = 0.005; I² = 89%). The lumbar spine reduction in AN remained statistically significant across sensitivity and leave-one-out analyses and was the most robust finding, whereas the statistical significance of hip BMD estimates in both FHA and AN and of lumbar spine BMD in FHA was sensitive to the analytical approach or exclusion of individual studies. The systematic review demonstrated that DXA with interpretation based on Z-scores remains the preferred method for skeletal assessment in premenopausal women with FHA. Bone health assessment is recommended after ≥6 months of amenorrhea or earlier in women with severe energy deficiency or a history of fractures. Restoration of energy availability, weight gain, and recovery of menstrual function remain the cornerstone of treatment. When amenorrhea persists and low BMD is confirmed, physiological transdermal 17β-estradiol combined with cyclic progesterone is the preferred hormonal therapy, whereas combined oral contraceptives, bisphosphonates, and denosumab are not recommended for routine management. Conclusions: Functional hypothalamic amenorrhea is associated with reduced BMD, with substantially greater skeletal deficits observed in the AN subgroup. These findings support early assessment of bone health and timely correction of low energy availability in women with FHA. The considerable between-study heterogeneity and sensitivity of some pooled estimates highlight the need for larger prospective studies using standardized diagnostic criteria and uniform skeletal outcome measures.
SN - 2076-3271
ER -