Identification of Hip BMD Loss and Fracture Risk Markers Through Population-Based Serum Proteomics.
Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ≥65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High-throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non-Hispanic white men using a multidimensional approach coupling liquid chromatography, ion-mobility separation, and mass spectrometry (LC-IMS-MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ≥0 g/cm2, n = 453); expected loss (estimated change 0 to 1 SD below the estimated mean change, -0.034 g/cm2for femoral neck, n = 1184); and accelerated loss (estimated change ≥1 SD below mean change, n = 237). Differential abundance values of 3946 peptides were summarized by meta-analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta-analytic standardized fold change at cutoffs of ≥1.1 or ≤0.9 (p < 0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction. © 2017 American Society for Bone and Mineral Research.
OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR, USA.|Bone and Mineral Unit, Oregon Health & Science University, Portland, OR, USA.
Carrie M
CM
Nielson
Biostatistics and Design Program, OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR, USA.
Jack
J
Wiedrick
Bone and Mineral Unit, Oregon Health & Science University, Portland, OR, USA.
Jian
J
Shen
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Jon
J
Jacobs
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Erin S
ES
Baker
Division of Biostatistics, Oregon Health & Science University, Portland, OR, USA.
Aaron
A
Baraff
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Paul
P
Piehowski
Research Service, Portland Veterans Affairs Medical Center, Portland, OR, USA.
Christine G
CG
Lee
Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA.
Arie
A
Baratt
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Vladislav
V
Petyuk
Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA.
Shannon
S
McWeeney
Division of Biostatistics, Oregon Health & Science University, Portland, OR, USA.
Jeong Youn
JY
Lim
Department of Medicine, University of California, San Francisco, CA, USA.
Douglas C
DC
Bauer
Department of Internal Medicine, University of California at Davis, Sacramento, CA, USA.
Nancy E
NE
Lane
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Peggy M
PM
Cawthon
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Richard D
RD
Smith
Biostatistics and Design Program, OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR, USA.
Jodi
J
Lapidus
Bone and Mineral Unit, Oregon Health & Science University, Portland, OR, USA.|Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Eric S
ES
Orwoll
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015519:Bone Density; D006615:Hip; D006620:Hip Fractures / Q000097:blood*; D006801:Humans; D008297:Male; D010024:Osteoporosis / Q000097:blood* / Q000473:pathology; D010455:Peptides / Q000097:blood*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics
D015415:Biomarkers; D010455:Peptides; D020543:Proteome
BIOCHEMICAL MARKERS OF BONE TURNOVER; GENERAL POPULATION STUDIES; OSTEOPOROSIS