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Low Serum Levels of DKK2 Predict Incident Low-Impact Fracture in Older Women
Ana M Rodrigues1,2,3, Mónica Eusébio4, Ana B Rodrigues2
1CEDOC EpiDoc Unit-Epidemiology of Chronic Diseases Nova Medical School Universidade Nova de Lisboa Lisboa Portugal.
Abstract:
There are currently no robust noninvasive markers of fragility fractures. Secreted frizzled related protein-1 (sFRP-1), dickkopf-related protein 1 (DKK1) and DKK2, and sclerostin (SOST) inhibit Wnt signaling and interfere with osteoblast-mediated bone formation. We evaluated associations of serum levels of sFRP-1, DKK1, DKK2, and SOST with incident low-impact fracture and BMD in 828 women aged ≥65 years from EpiDoC, a longitudinal population-based cohort. A structured questionnaire during a baseline clinical appointment assessed prevalent fragility fractures and clinical risk factors (CRFs) for fracture. Blood was collected to measure serum levels of bone turnover markers and Wnt regulators. Lumbar spine and hip BMD were determined by DXA scanning. Follow-up assessment was performed through a phone interview; incident fragility fracture was defined by any new self-reported low-impact fracture. Multivariate Cox proportional hazard models were used to analyze fracture risk adjusted for CRFs and BMD. During a mean follow-up of 2.3 ± 1.0 years, 62 low-impact fractures were sustained in 58 women. A low serum DKK2 level (per 1 SD decrease) was associated with a 1.5-fold increase in fracture risk independently of BMD and CRFs. Women in the two lowest DKK2 quartiles had a fracture incidence rate of 32 per 1000 person-years, whereas women in the two highest quartiles had 14 fragility fractures per 1000 person-years. A high serum sFRP1 level was associated with a 1.6-fold increase in fracture risk adjusted for CRFs, but not independently of BMD. Serum levels of SOST (r = 0.191; p = 0.0025) and DKK1(r = -0.1725; p = 0.011) were correlated with hip BMD, but not with incident fragility fracture. These results indicate that serum DKK2 and sFRP1 may predict low-impact fracture. The low number of incident fractures recorded is a limitation and serum levels of Wnt regulators should be further studied in other populations as potential noninvasive markers of fragility fractures. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Insights
Low serum dickkopf-related protein 2 (DKK2) levels may predict fragility fractures in older women. Higher levels of secreted frizzled related protein-1 (sFRP1) also indicated increased fracture risk, independent of bone density.
Area of Science:
- Biochemistry and Molecular Biology
- Gerontology and Geriatric Medicine
- Orthopedics and Sports Medicine
Background:
- Fragility fractures pose a significant health burden, particularly in older adults.
- Current noninvasive markers for predicting fragility fractures are limited.
- Wnt signaling pathway regulators, including sFRP-1, DKK1, DKK2, and SOST, play crucial roles in bone metabolism.
Purpose of the Study:
- To investigate the association between serum levels of Wnt signaling regulators (sFRP-1, DKK1, DKK2, SOST) and the risk of incident low-impact fractures in older women.
- To determine if these serum markers could serve as noninvasive predictors of fragility fractures, independent of bone mineral density (BMD) and clinical risk factors (CRFs).
Main Methods:
- A longitudinal population-based cohort study (EpiDoC) involving 828 women aged ≥65 years.
- Baseline assessment included questionnaires for prevalent fractures and CRFs, serum collection for Wnt regulators and bone turnover markers, and DXA scans for BMD.
- Follow-up via phone interview to ascertain incident low-impact fractures; Cox proportional hazard models were used for risk analysis.
Main Results:
- A low serum dickkopf-related protein 2 (DKK2) level was associated with a 1.5-fold increased risk of incident fracture, independent of BMD and CRFs.
- Women in the lowest DKK2 quartiles exhibited a higher fracture incidence rate (32 per 1000 person-years) compared to those in the highest quartiles (14 per 1000 person-years).
- High serum secreted frizzled related protein-1 (sFRP1) was linked to increased fracture risk adjusted for CRFs, but this association was not independent of BMD.
- Serum sclerostin (SOST) and dickkopf-related protein 1 (DKK1) levels correlated with hip BMD but not with incident fractures.
Conclusions:
- Serum levels of DKK2 and sFRP1 show potential as noninvasive predictors of low-impact fractures in older women.
- DKK2 appears to be a more robust predictor, offering risk assessment independent of BMD and CRFs.
- Further validation in larger, diverse populations is warranted to establish these Wnt regulators as reliable biomarkers for fragility fracture risk.
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