Janet S. Kinney

Teriparatide and osseous regeneration in the oral cavity

BACKGROUND Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. METHODS A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 μg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. RESULTS Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. CONCLUSIONS Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .).

Saliva as a diagnostic tool for periodontal disease: current state and future directions.

In periodontics and implant dentistry, traditional clinical criteria are often insufficient for determining sites of active disease, for monitoring quantitatively the response to therapy or for measuring the degree of susceptibility to future disease progression. Saliva as a mirror of oral and systemic health is a valuable source for clinically relevant information because it contains biomarkers specific for the unique physiological aspects of periodontal ⁄ peri-implant disease, and qualitative changes in the composition of these biomarkers could have diagnostic value by identifying patients with enhanced disease susceptibility, identifying sites with active disease, predicting sites that will have active disease in the future and ⁄ or serving as surrogate end points for monitoring the effectiveness of therapy. Although the diagnostic value of saliva has been recognized for some time (50, 51) and potential biomarkers of periodontal ⁄ periimplant disease have been identified in saliva (39, 67, 74), most work carried out to date has failed to provide reliable aids to the clinician. However, the availability of more sophisticated analytic techniques give cause for optimism that saliva will eventually become the tool needed for more precise treatment planning.

Oral Fluid–Based Biomarkers of Alveolar Bone Loss in Periodontitis

Abstract:  Periodontal disease is a bacteria‐induced chronic inflammatory disease affecting the soft and hard supporting structures encompassing the teeth. When left untreated, the ultimate outcome is alveolar bone loss and exfoliation of the involved teeth. Traditional periodontal diagnostic methods include assessment of clinical parameters and radiographs. Though efficient, these conventional techniques are inherently limited in that only a historical perspective, not current appraisal, of disease status can be determined. Advances in the use of oral fluids as possible biological samples for objective measures of current disease state, treatment monitoring, and prognostic indicators have boosted saliva and other oral‐based fluids to the forefront of technology. Oral fluids contain locally and systemically derived mediators of periodontal disease, including microbial, host‐response, and bone‐specific resorptive markers. Although most biomarkers in oral fluids represent inflammatory mediators, several specific collagen degradation and bone turnover‐related molecules have emerged as possible measures of periodontal disease activity. Pyridinoline cross‐linked carboxyterminal telopeptide (ICTP), for example, has been highly correlated with clinical features of the disease and decreases in response to intervention therapies, and has been shown to possess predictive properties for possible future disease activity. One foreseeable benefit of an oral fluid–based periodontal diagnostic would be identification of highly susceptible individuals prior to overt disease. Timely detection and diagnosis of disease may significantly affect the clinical management of periodontal patients by offering earlier, less invasive, and more cost‐effective treatment therapies.

Saliva/Pathogen Biomarker Signatures and Periodontal Disease Progression

The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 44 exhibiting PDP, while 39 demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 82% of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 78% of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0002). The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745).

The Impact of Vitamin D Status on Periodontal Surgery Outcomes

Vitamin D regulates calcium and immune function. While vitamin D deficiency has been associated with periodontitis, little information exists regarding its effect on wound healing and periodontal surgery outcomes. This longitudinal clinical trial assessed outcomes of periodontal surgery and teriparatide administration in vitamin-D-sufficient and -insufficient individuals. Forty individuals with severe chronic periodontitis received periodontal surgery, daily calcium and vitamin D supplements, and self-administered teriparatide or placebo for 6 wks to correspond with osseous healing time. Serum 25(OH)D was evaluated at baseline, 6 wks, and 6 mos post-surgery. Clinical and radiographic outcomes were evaluated over 1 yr. Placebo patients with baseline vitamin D deficiency [serum 25(OH)D, 16-19 ng/mL] had significantly less clinical attachment loss (CAL) gain (-0.43 mm vs. 0.92 mm, p < 0.01) and probing depth (PPD) reduction (0.43 mm vs. 1.83 mm, p < 0.01) than vitamin-D-sufficient individuals. Vitamin D levels had no significant impact on CAL and PPD improvements in teriparatide patients at 1 yr, but infrabony defect resolution was greater in teriparatide-treated vitamin-D-sufficient vs. -deficient individuals (2.05 mm vs. 0.87 mm, p = 0.03). Vitamin D deficiency at the time of periodontal surgery negatively affects treatment outcomes for up to 1 yr. Analysis of these data suggests that vitamin D status may be critical for post-surgical healing. (ClinicalTrials.gov number, CT00277706)

Serum Antibodies to Porphyromonas gingivalis Chaperone HtpG Predict Health in Periodontitis Susceptible Patients

Background Chaperones are ubiquitous conserved proteins critical in stabilization of new proteins, repair/removal of defective proteins and immunodominant antigens in innate and adaptive immunity. Periodontal disease is a chronic inflammatory infection associated with infection by Porphyromonas gingivalis that culminates in the destruction of the supporting structures of the teeth. We previously reported studies of serum antibodies reactive with the human chaperone Hsp90 in gingivitis, a reversible form of gingival disease confined to the oral soft tissues. In those studies, antibodies were at their highest levels in subjects with the best oral health. We hypothesized that antibodies to the HSP90 homologue of P. gingivalis (HtpG) might be associated with protection/resistance against destructive periodontitis. Methodology/Principal Findings ELISA assays using cloned HtpG and peptide antigens confirmed gingivitis subjects colonized with P. gingivalis had higher serum levels of anti-HtpG and, concomitantly, lower levels of attachment loss. Additionally, serum antibody levels to P. gingivalis HtpG protein were higher in healthy subjects compared to patients with either chronic or aggressive periodontitis. We found a negative association between tooth attachment loss and anti-P. gingivalis HtpG (p = 0.043) but not anti-Fusobacterium nucleatum (an oral opportunistic commensal) HtpG levels. Furthermore, response to periodontal therapy was more successful in subjects having higher levels of anti-P. gingivalis HtpG before treatment (p = 0.018). There was no similar relationship to anti-F. nucleatum HtpG levels. Similar results were obtained when these experiments were repeated with a synthetic peptide of a region of P. gingivalis HtpG. Conclusions/Significance Our results suggest: 1) anti-P. gingivalis HtpG antibodies are protective and therefore predict health periodontitis-susceptable patients; 2) may augment the host defence to periodontitis and 3) a unique peptide of P. gingivalis HtpG offers significant potential as an effective diagnostic target and vaccine candidate. These results are compatible with a novel immune control mechanism unrelated to direct binding of bacteria.

Personalized medicine: an update of salivary biomarkers for periodontal diseases

This article provides an up-to-date review of the more robust salivary biomarkers, as well as of panels of combinatorial markers and periodontal pathogens, that reveal high sensitivity and specificity for enhancing clinical decision-making in periodontal disease progression, risk and diagnosis. Periodontal diseases are complex and require an inflammatory response to bacterial pathogens in a susceptible host to stimulate tissue destruction. When used alone, traditional clinical assessments provide a diagnosis of periodontitis only after the biologic onset of the disease process, and are unable to substantiate disease activity or future risk. New technologies are becoming available that are capable of measuring combinations of inflammatory cytokines and proteinases for rapid chair-side testing. Utilizing saliva to identify and measure specific phenotypes and host-derived mediators will allow highly individualized diagnosis, prognosis and treatments for periodontal diseases. This personalized medicine approach will strengthen the power of the clinical oral examination and medical history assessments, providing patients with evidence-based, targeted risk care.

Immunoglobulin G (IgG) Class, but Not IgA or IgM, Antibodies to Peptides of the Porphyromonas gingivalis Chaperone HtpG Predict Health in Subjects with Periodontitis by a Fluorescence Enzyme-Linked Immunosorbent Assay

ABSTRACT Chaperones are molecules found in all cells and are critical in stabilization of synthesized proteins, in repair/removal of defective proteins, and as immunodominant antigens in innate and adaptive immunity. Subjects with gingivitis colonized by the oral pathogen Porphyromonas gingivalis previously demonstrated levels of anti-human chaperone Hsp90 that were highest in individuals with the best oral health. We hypothesized that similar antibodies to pathogen chaperones might be protective in periodontitis. This study examined the relationship between antibodies to P. gingivalis HtpG and clinical statuses of healthy and periodontitis-susceptible subjects. We measured the humoral responses (immunoglobulin G [IgG], IgA, and IgM) to peptides of a unique insert (P18) found in Bacteroidaceae HtpG by using a high-throughput, quantitative fluorescence enzyme-linked immunosorbent assay. Indeed, higher levels of IgG class anti-P. gingivalis HtpG P18 peptide (P < 0.05) and P18α, consisting of the N-terminal 16 amino acids of P18 (P < 0.05), were associated with better oral health; these results were opposite of those found with anti-P. gingivalis whole-cell antibodies and levels of the bacterium in the subgingival biofilm. When we examined the same sera for IgA and IgM class antibodies, we found no significant relationship to subject clinical status. The relationship between anti-P18 levels and clinical populations and individual subjects was found to be improved when we normalized the anti-P18α values to those for anti-P18γ (the central 16 amino acids of P18). That same ratio correlated with the improvement in tissue attachment gain after treatment (P < 0.05). We suggest that anti-P. gingivalis HtpG P18α antibodies are protective in periodontal disease and may have prognostic value for guidance of individual patient treatment.