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Cited by 71Bone health and osteoporosis researchEstrogen and related hormone effectsSexual Differentiation and Disorders

Effects of Suppression of Estrogen Action by the P450 Aromatase Inhibitor Letrozole on Bone Mineral Density and Bone Turnover in Pubertal Boys

Wickman, Sanna, Kajantie, Eero, Dunkel, Leo·2003·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2002-021643
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Abstract

The essential role of estrogen (E) in regulation of developing peak bone mass in males was confirmed when young adult men were described who cannot respond to or produce E because of defective E receptor alpha or P-450 aromatase enzyme, respectively. These men had significantly reduced bone mineral density (BMD) despite normal or supranormal androgen concentrations, and E administration improved BMD in the men with aromatase deficiency, whereas testosterone (T) was ineffective. Because new P450 aromatase inhibitors may prove to be potential drugs in various growth disorders, the effect of suppression of E action on developing peak bone mass has to be closely evaluated. In this study, we explored the effects of suppression of E synthesis on bone metabolism in pubertal boys. A total of 23 boys with constitutional delay of puberty were randomized to receive T and placebo or T and a specific and potent P450 aromatase inhibitor, letrozole. We determined BMD in the lumbar spine and the femoral neck. Bone resorption was studied by measuring the serum concentration of cross-linked carboxyterminal telopeptide of type I collagen by two different methods (CTx and ICTP), and bone formation by determining the serum concentrations of carboxyterminal propeptide of type I procollagen (PICP), osteocalcin, and alkaline phosphatase. We demonstrated previously that, during treatment with T and placebo, the concentrations of androgens and E increased. During treatment with T and letrozole, the E concentrations remained at the pretreatment level, but the androgen concentrations increased; the increase in the T concentration was more than 5-fold higher than during treatment with T and placebo. We did not observe any significant differences in the changes in bone mineral content, BMD, or bone mineral apparent density, an estimate of true volumetric BMD, between the treated groups. Lumbar spine bone mineral apparent density increased in both treated groups; but in the T- plus letrozole-treated group, the increase was statistically significant only 6 months after discontinuation of letrozole treatment. All bone resorption and formation markers increased during treatment with T and placebo. During treatment with T plus letrozole, CTx, PICP, and osteocalcin remained unchanged, whereas ICTP and alkaline phosphatase increased. Thus, 1-yr treatment with this new P450 aromatase inhibitor in pubertal boys is unlikely to be associated with any major harmful effect on developing peak bone mass. However, to convincingly exclude such effects, particularly rare or minor ones, will require a study with a larger sample size; and thus, close follow-up of bone metabolism during treatment with P450 aromatase inhibitors is still warranted.

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  • Similar responses to placebo, tamoxifen and anastrozole were described in a number of observational studies.

    “This is in accordance with the data summarized in a recent review [68], describing similar responses to placebo, tamoxifen and anastrozole in a number of observational studies.”

    From Aromatase inhibitors in men: effects and therapeutic options (2011) · cites this paper as [68]

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Authors
Wickman, S., Kajantie, E., & Dunkel, L.
Affiliations
University of Helsinki (FI)
Corresponding author
Wickman, Sanna
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2003-08
Volume
88
Issue
8
Pages
3785-3793
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2002-021643
OpenAlex
W2169905015
Cited by
71
References
47
Citations by year
2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 1 · 2013: 4 · 2012: 1
FWCI
6.32
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
letrozole, aromatase inhibitors, estrogen suppression, peak bone mass, bone mineral density, bone turnover, pubertal boys, constitutional delay of growth and puberty, testosterone, bone resorption markers, bone formation markers, lumbar spine, femoral neck, bone mineral apparent density, osteocalcin, alkaline phosphatase, CTX, C-terminal telopeptide of type I collagen, PICP, androgens
MeSH terms
Letrozole, Adolescent, Bone and Bones, Bone Development, Child, Collagen, Enzyme Inhibitors, Estradiol, Estrogen Antagonists, Femur Neck, Humans, Insulin-Like Growth Factor I, Male, Nitriles, Puberty, Gonadal Steroid Hormones, Spine, Testosterone, Triazoles, Biomarkers, Bone Density, Insulin-Like Growth Factor Binding Protein 3, Aromatase Inhibitors

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