Osteoporosis represents a major public health problem in the United States. Osteoporosis is associated with decreased systemic bone mineral density (BMD), an increased incidence of vertebrae, wrist and hip fractures, and tooth loss. The dominant pathogenic factor for osteoporosis in postmenopausal women is estrogen (E2) deficiency. In longitudinal NIH-supported clinical trials, we have shown accelerated alveolar crestal bone height and density loss in postmenopausal, E2- deficient women with a periodontitis history relative to E2-sufficient women, and in osteoporotic/osteopenic women versus women with normal lumbar spine BMD. Because of this relationship between E2- deficiency, osteoporosis and oral bone loss, it is desirable to test therapeutic strategies to mitigate alveolar bone loss in postmenopausal women. A recent discovery by Dr. Golub (Co-PI) showed that tetracyclines, including low-dose doxycycline (LDD), by virtue of a non- antimicrobial property, can: a) inhibit host-derived, tissue-destructive matrix metalloproteinases (MMPs), including collagenases, involved in bone resorption; and b) stimulate osteoblast activity and bone formation. These biological properties make tetracyclines compelling candidates for use in postmenopausal women with periodontitis. Therefore, the objective of this research is to investigate the therapeutic potential of LDD in postmenopausal osteopenia and periodontitis, diseases characterized by excess collagen breakdown and bone resorption. The hypothesis of this proposal is that LDD (compared to placebo) can improve radiographic, clinical and biochemical parameters of periodontitis in E2-deficient, osteopenic postmenopausal women with periodontitis. Accordingly, the specific aim of this proposal is to use a 2- year double-blind, placebo-controlled trial of E2-deficient women to determine the effect of LDD on: a) alveolar bone crestal and subcrestal density (measured by computer-assisted densitometric image analysis) and linear alveolar crestal bone height; b) clinical periodontal measurements such as probing depth and relative clinical attachment level; and c) gingival crevicular fluid markers of bone turnover (e.g., C- terminal telopeptide pyridinoline crosslinks [ICTP, a collagen breakdown fragment]). As a secondary aim, the study will evaluate the effect of LDD on systemic bone mineral density at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry (DEXA) and the effect of LDD on serum and urine biochemical markers of bone turnover.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE012872-02S1
Application #
6599596
Study Section
Special Emphasis Panel (ZDE1 (57))
Program Officer
Mowery, Richard L
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$4,116
Indirect Cost
Name
University of Nebraska Medical Center
Department
Surgery
Type
Schools of Dentistry
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Bright, R; Thiele, G M; Manavis, J et al. (2018) Gingival tissue, an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins. J Periodontal Res 53:139-143
Schwenzer, Anja; Quirke, Anne-Marie; Marzeda, Anna M et al. (2017) Association of Distinct Fine Specificities of Anti-Citrullinated Peptide Antibodies With Elevated Immune Responses to Prevotella intermedia in a Subgroup of Patients With Rheumatoid Arthritis and Periodontitis. Arthritis Rheumatol 69:2303-2313
Payne, Jeffrey B; Nummikoski, Pirkka V; Thompson, David M et al. (2013) The association between clinical and radiographic periodontitis measurements during periodontal maintenance. J Periodontol 84:1382-90
Salminen, Aino; Pussinen, Pirkko J; Payne, Jeffrey B et al. (2013) Subantimicrobial-dose doxycycline treatment increases serum cholesterol efflux capacity from macrophages. Inflamm Res 62:711-20
Gu, Ying; Walker, Clay; Ryan, Maria E et al. (2012) Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine. J Oral Microbiol 4:
Payne, J B; Stoner, J A; Lee, H-M et al. (2011) Serum bone biomarkers and oral/systemic bone loss in humans. J Dent Res 90:747-51
Payne, Jeffrey B; Golub, Lorne M (2011) Using tetracyclines to treat osteoporotic/osteopenic bone loss: from the basic science laboratory to the clinic. Pharmacol Res 63:121-9
Payne, Jeffrey B; Golub, Lorne M; Stoner, Julie A et al. (2011) The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. J Am Dent Assoc 142:262-73
Bretz, Walter A (2011) Low-dose doxycycline plus additional therapies may lower systemic inflammation in postmenopausal women with periodontitis. J Evid Based Dent Pract 11:194-5
Gu, Ying; Lee, Hsi-Ming; Simon, Sanford R et al. (2011) Chemically modified tetracycline-3 (CMT-3): a novel inhibitor of the serine proteinase, elastase. Pharmacol Res 64:595-601

Showing the most recent 10 out of 19 publications