Fibrosis markers, hip fracture risk, and bone density in older adults.
We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome.


BACKGROUND
TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels.


METHODS
Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures).


RESULTS
Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women.


CONCLUSIONS
TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.
Kaiser Permanente of Georgia, Division of Endocrinology and the Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA. joshua.barzilay@kp.org.|, 3650 Steve Reynolds Blvd, Duluth, GA, 30096, USA. joshua.barzilay@kp.org.
J I
JI
Barzilay
Department of Biostatistics, University of Washington, Seattle, WA, USA.
P
P
Bůžková
Department of Medicine and the Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
J R
JR
Kizer
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
L
L
Djoussé
Division of Nephrology, University of California San Diego, San Diego VA Healthcare System, San Diego, CA, USA.
J H
JH
Ix
Geriatric Research Education and Clinical Center, Veterans Affair Medical Center, Minneapolis, MN, USA.
H A
HA
Fink
New York Academy of Sciences, New York, NY, USA.
D S
DS
Siscovick
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
J A
JA
Cauley
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
K J
KJ
Mukamal
D015502:Absorptiometry, Photon / Q000379:methods; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology*; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D006620:Hip Fractures / Q000097:blood* / Q000503:physiopathology; D006801:Humans; D008297:Male; D058866:Osteoporotic Fractures / Q000097:blood* / Q000503:physiopathology; D010446:Peptide Fragments / Q000097:blood*; D011347:Procollagen / Q000097:blood*; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D016212:Transforming Growth Factor beta / Q000097:blood*
D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; D016212:Transforming Growth Factor beta; C041876:procollagen Type III-N-terminal peptide; D002097:C-Reactive Protein
Bone mineral density; Hip fracture; PIIINP; TGF-β