Subantimicrobial-dose doxycycline modulates gingival crevicular fluid biomarkers of periodontitis in postmenopausal osteopenic women.
BACKGROUND
We recently demonstrated that a 2-year subantimicrobial-dose doxycycline (SDD) regimen (double-masked, placebo-controlled clinical trial) in postmenopausal (PM) women exhibiting mild systemic bone loss (osteopenia) and local bone loss (periodontitis) reduced the progression of periodontal attachment loss (intent-to-treat analysis) and the severity of gingival inflammation and alveolar bone loss (subgroups) without producing antibiotic side effects. We now describe SDD effects on biomarkers of collagen degradation and bone resorption in the gingival crevicular fluid (GCF) of the same vulnerable subjects.


METHODS
GCF was collected from SDD- and placebo-treated PM subjects (n=64 each) at the baseline and 1- and 2-year appointments; the volume was determined; and the samples were analyzed for collagenase activity (using a synthetic peptide as substrate), relative levels of three genetically distinct collagenases (Western blot), a type-1 collagen breakdown product/bone resorption marker (a carboxyterminal telopeptide cross-link fragment of type I collagen [ICTP]; radioimmunoassay), and interleukin-1beta (enzyme-linked immunosorbent assay). Statistical analyses were performed using generalized estimating equations; primary analyses were intent-to-treat.


RESULTS
Collagenase activity was significantly reduced by SDD treatment relative to placebo based on intent-to-treat (P=0.01). ICTP showed a similar pattern of change during SDD treatment, and GCF collagenase activity and ICTP were positively correlated at all time periods (P<0.001). Matrix metalloproteinase (MMP)-8 accounted for approximately 80% of total collagenase in GCF, with much less MMP-1 and -13, and SDD reduced the odds of elevated MMP-8 by 60% compared to placebo (P=0.006).


CONCLUSIONS
These observations support the therapeutic potential of long-term SDD therapy to reduce periodontal collagen breakdown and alveolar bone resorption in PM women; effects on serum biomarkers of systemic bone loss in these subjects are being analyzed.
Golub
Lorne M
LM
Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA. lorne.golub@stonybrook.edu
Lee
Hsi Ming
HM
Stoner
Julie A
JA
Sorsa
Timo
T
Reinhardt
Richard A
RA
Wolff
Mark S
MS
Ryan
Maria E
ME
Nummikoski
Pirkka V
PV
Payne
Jeffrey B
JB
D000368:Aged; D016301:Alveolar Bone Loss / Q000201:enzymology / Q000517:prevention & control; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000032:analysis; D001851:Bone Diseases, Metabolic / Q000150:complications* / Q000201:enzymology; D003094:Collagen / Q000032:analysis / Q000187:drug effects; D024042:Collagen Type I; D017364:Collagenases / Q000032:analysis / Q000187:drug effects*; D004311:Double-Blind Method; D004318:Doxycycline / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D005883:Gingival Crevicular Fluid / Q000737:chemistry / Q000187:drug effects*; D005891:Gingivitis / Q000517:prevention & control; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000187:drug effects; D053509:Matrix Metalloproteinase 13 / Q000032:analysis / Q000187:drug effects; D020784:Matrix Metalloproteinase 8 / Q000032:analysis / Q000187:drug effects; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis / Q000187:drug effects; D010455:Peptides; D017622:Periodontal Attachment Loss / Q000517:prevention & control; D010518:Periodontitis / Q000188:drug therapy* / Q000201:enzymology; D010919:Placebos; D017698:Postmenopause; D011347:Procollagen / Q000032:analysis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D024042:Collagen Type I; D053583:Interleukin-1beta; D010446:Peptide Fragments; D010455:Peptides; D010919:Placebos; D011347:Procollagen; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020784:Matrix Metalloproteinase 8; D020781:Matrix Metalloproteinase 1; D004318:Doxycycline