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. 2024 Sep 6:22:101802.
doi: 10.1016/j.bonr.2024.101802. eCollection 2024 Sep.

Delineating the relationship between circulating osteoprotegerin and bone health in women with a pathogenic variant in BRCA1: A cross-sectional analysis

Aghaghia Mokhber  1   2 , Elizabeth Hall  3 , Aleksandra Uzelac  3 , Leonardo Salmena  4 , Angela Cheung  5 , Jan Lubinski  6 , Steven A Narod  1   7 , Joanne Kotsopoulos  1   7
Affiliations

Delineating the relationship between circulating osteoprotegerin and bone health in women with a pathogenic variant in BRCA1: A cross-sectional analysis

Aghaghia Mokhber et al. Bone Rep. .

Abstract

Purpose: Osteoprotegerin (OPG) plays an important role in the inhibition of osteoclast formation and bone resorption. Studies have reported lower OPG levels among women with a pathogenic variant (mutation) in the BRCA1 gene, and thus, may be at greater risk for skeletal bone loss. Thus, we investigated the association between circulating OPG and two validated markers of bone health: 1) bone fracture risk score (FRAX) and 2) bone mineral density (BMD), among BRCA mutation carriers.

Methods: Women with a blood sample and clinical data were included in this analysis. An enzyme-linked immunosorbent assay (ELISA) was used to quantify serum OPG (pg/mL) and the 10-year risk of major osteoporotic fracture (FRAXmajor) and hip fracture (FRAXhip) (%) was estimated using a web-based algorithm. For a subset of women, lumbar spine BMD was previously assessed by dual x-ray absorptiometry (DXA)(T-score). A Mann-Whitney U test was used to evaluate the association between OPG and FRAX score, while linear regression was used to assess the association of OPG and BMD.

Results: Among 701 women with a BRCA1 mutation, there was a significant (and unexpected) positive association between OPG levels and FRAX score (FRAXmajor: 2.12 (low OPG) vs. 2.53 (high OPG) P < 0.0001; FRAXhip: 0.27 (low OPG) vs. 0.44 (high OPG) P < 0.0001). In a subset with BMD measurement (n = 50), low serum OPG was associated with a significantly lower BMD T-score (-1.069 vs. -0.318; P = 0.04).

Conclusion: Our findings suggest that women with inherently lower OPG may be at risk of lower BMD, the gold standard marker of bone disease. Due to the young age of our cohort, on-going studies are warranted to re-evaluate the association between OPG and FRAX in BRCA mutation carriers.

Keywords: BRCA mutation carriers; Bone mineral density; FRAX; Osteoprotegerin (OPG).

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Conflict of interest statement

All the authors named on this paper declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors have seen and approved the final version of the manuscript being submitted. They warrant that the article is the authors' original work, has not received prior publication and is not under consideration for publication elsewhere.

Figures

Fig. 1
Fig. 1
Distribution of FRAX scores by serum OPG levels in BRCA1 mutation carriers. a. FRAXmajora (%) and b. FRAXhipb (%) among all women; c. FRAXmajora (%) and d. FRAXhipb (%) among premenopausal women; e. FRAXmajora (%) and f. FRAXhipb (%) among postmenopausal womenc aFRAXmajor = 10-year risk of developing major osteoporotic fracture (%) bFRAXhip = 10-year risk of developing hip fracture (%) cP-value and ρ-coefficient were calculated using Spearman's Rank Correlation.
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