Periodontal disease -- the emergence of a risk for systemic conditions: pre-term low birth weight.

This paper addresses the problem of adverse pregnancy outcome in relation to periodontal disease. There is compelling evidence that a link exists between pre-term low birth weight (PLBW) and periodontitis. Although 25% to 50% of PLBW deliveries occur without any known aetiology, there is increasing evidence that infection may play a significant role in pre-term delivery. A model explaining the plausible relationship is proposed based upon the concept of infection leading to a cascade of inflammatory reactions associated with pre-term labour and periodontal disease. Current evidence has pointed to an interest in dental intervention studies to control periodontal disease as one of the potential strategies to reduce pre-term labour. This paper reviews the potential association between periodontal infection and adverse pregnancy outcomes.

Clinical relevance of adjunctive minocycline microspheres in patients with chronic periodontitis: secondary analysis of a phase 3 trial.

BACKGROUND: A recent Phase 3 trial demonstrated that adjunctive treatment with minocycline microspheres resulted in significant reductions in patient mean probing depths as compared to scaling and root planing (SRP) alone. The objective of the present study was to evaluate clinical relevance of these changes within the trial using proposed site-based criteria. METHODS: A total of 499 patients with moderate to advanced chronic periodontitis were enrolled in a multi-center trial and randomized to either: 1) SRP alone or 2) SRP plus minocycline microspheres. Subjects received complete probing examinations including the measurement of probing depths at baseline, and 1 and 3 months. Probing depth reductions were tabulated by treatment, examination time, and baseline depths, and inter-group differences were evaluated with logistic regression models for correlated data. RESULTS: Significantly more sites treated with adjunctive minocycline microspheres exhibited probing depths < 5 mm at 1 (P = 0.0009) and 3 (P = 0.01) months as compared to sites treated with SRP alone, both in the overall population and in smokers. In addition, significantly more sites decreased by 1, 2, or 3 mm in the adjunctive minocycline group than in the SRP alone group at 1 and 3 months, both overall as well as in smokers (P < 0.05). CONCLUSION: This secondary analysis indicates that treatment with SRP plus minocycline microspheres is consistently more effective than SRP alone in providing clinically relevant site-based responses in patients with chronic periodontitis.

Safety and clinical effects of topical histatin gels in humans with experimental gingivitis.

BACKGROUND: Our research group has recently reported that exogenously applied histatins can inhibit plaque accumulation and gingival inflammation in a preclinical canine model (Paquette et al. 1997). OBJECTIVES: The aims of the present double-blinded, randomized, controlled clinical trial were to evaluate the safety and toxicity of three histatin (P-113) concentrations in gel formulations, and to assess potential clinical benefit on the development of gingivitis (partial mouth design). MATERIAL AND METHODS: One hundred and six healthy subjects were recruited and brought to optimal gingival health (GI < 0.5) prior to treatment initiation. At baseline, eligible subjects were randomized for one of the following treatments: (1) placebo; (2) 0.0625% P-113; (3) 0.125% P-113; and (4) 0.375% P-113. Patients self-applied gels twice daily for 29 days to the maxillary right quadrant with the use of customized stents. In addition, patients deferred all oral hygiene procedures within this quadrant for the duration of the treatment period. Safety was assessed in terms of physical and oral examinations, clinical laboratory testing and recording of adverse events. Clinical indices were measured weekly and included gingival index (GI), plaque index (PI) and %BOP. RESULTS: All study formulations were well tolerated by patients, and no differences in adverse event occurrences were noted among treatment groups, including taste alteration or staining. For the intent-to-treat population, significantly smaller %BOP changes were noted in subjects treated with 0.0625, 0.125 and 0.375% P-113 gels (17.4, 18.18 and 17.9%, respectively) versus placebo (28.0%) (p < 0.05) at day 29. When groups were compared in terms of per cent responders (change in %BOP < 15 or < 20%), P-113 treatment groups exhibited a higher frequency of response, especially for the 0.0625 and 0.125% P-113 formulations (p < 0.05). Although no statistically significant intergroup differences were noted for changes in GI or PI among all subjects (intent-to-treat population), significantly smaller changes in PI at day 22 were observed among compliant individuals (defined as subjects using > 60% of the target gel mass) administering P-113 gels as compared with compliant placebo subjects (p < 0.05). CONCLUSIONS: These data indicate safety and tolerance of P-113 gels for topical oral use in human subjects. These data also suggest that P-113 gels administered twice daily may reduce experimental gingivitis as measured with bleeding on probing in humans.

Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial.

BACKGROUND: Periodontitis is an inflammatory condition of tooth-supporting tissues that is usually treated by mechanical removal of plaque and microorganisms that adhere to teeth. This treatment, known as scaling and root planing, is not optimally effective. Adjunctive therapy with locally delivered antimicrobials has resulted in improved clinical outcomes such as probing depth reduction. This article reports on the efficacy and safety of locally administered microencapsulated minocycline. METHODS: Seven hundred forty-eight (748) patients with moderate to advanced periodontitis were enrolled in a multi-center trial and randomized to 1 of 3 treatment arms: 1) scaling and root planing (SRP) alone; 2) SRP plus vehicle; or 3) SRP plus minocycline microspheres. The primary outcome measure was probing depth reduction at 9 months. Clinical assessments were performed at baseline and 1, 3, 6, and 9 months. RESULTS: Minocycline microspheres plus scaling and root planing provided substantially more probing depth reduction than either SRP alone or SRP plus vehicle. The difference reached statistical significance after the first month and was maintained throughout the trial. The improved outcome was observed to be independent of patients' smoking status, age, gender, or baseline disease level. There was no difference in the incidence of adverse effects among treatment groups. CONCLUSIONS: Scaling and root planing plus minocycline microspheres is more effective than scaling and root planing alone in reducing probing depths in periodontitis patients.

Pharmacodynamic effects of ketoprofen on crevicular fluid prostanoids in adult periodontitis.

The reported therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) in slowing periodontal disease progression appear intimately linked to the effective inhibition of local prostaglandin synthesis. This randomized, partially double-blind, controlled trial was conducted to evaluate the pharmacodynamic effects of the NSAID, ketoprofen (KTP), on gingival crevicular fluid (GCF) prostanoids. 42 subjects, ages 35-57 years, with moderate to advanced adult periodontitis were recruited and monitored for 22 days. On day 1, subjects were randomized for 1 of 5 treatments: i) 0.5% KTP gel; ii) 1.0% KTP gel; iii) 1.0% KTP alternate gel; iv) 2.0% KTP gel; v) 25 mg KTP capsule (positive control). Subjects applied 1 ml of gel topically to their gingiva or administered one capsule p.o., b.i.d. for 14.5 days. GCF samples were collected from posterior, interproximal sites on days 1 (pre-dosing; 1, 2, 3, 6 h), 8 (pre-dosing; 2 h), 15 (pre-dosing; 2 h) and 22 (post-treatment). GCF levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were determined using RIA, and expressed in ng/ml and % reduction from baseline (%Effect). Neither a significant difference among groups nor a dose response in % effect for either prostanoid was evident, both overall and among cohorts with elevated baseline mediator levels ([PGE2]>34 ng/ml; [LTB4]>300 ng/ml). When data were combined from all groups, significant (p<0.01) % reductions in GCF PGE2 were noted at 1 and 2 h post-dosing (29% and 24% respectively). In comparing topical versus systemic formulations, all topical formulations were as equipotent as systemic dosing in altering local prostaglandin levels despite lower KTP exposures with gel treatments. These data indicate that both topical and systemic KTP therapies pharmacodynamically reduce GCF PGE2 levels in adult periodontitis subjects, allowing for potential inhibition of disease progression.

Understanding the pathogenesis of periodontitis: a century of discovery.

The twentieth century was an especially notable time for research advances into the understanding of the aetiology and the pathogenesis of periodontitis. Beginning in 1900, using dark-field preparations, investigators began to implicate certain microorganisms, such as amoebae, as causing periodontitis. Today, using modern molecular techniques, we believe we have identified the primary causative agents of adult periodontitis. In 1900, histological sections of periodontal tissues at autopsy provided clues as to how periodontal pockets probably formed. Today there is a wealth of cellular and molecular data that suggest the actual pathways that the susceptible host uses to initiate periodontal tissue destruction. We now also appreciate that periodontitis may be a significant risk factor for systemic disease. A very exceptional 'century of discovery' into the nature of periodontal diseases should now lead to a new era of better diagnosis, prevention and treatment for this ubiquitous disease.

Modulation of host inflammatory mediators as a treatment strategy for periodontal diseases.

Studies ranging from preclinical animal models to human clinical trials support the basic hypothesis that the inhibition of local arachidonic acid metabolites with nonsteroidal anti-inflammatory drugs slows periodontal disease progression. Data on modulation of other host mediators such as cytokines and NO remain restricted to laboratory or preclinical investigations, but appear promising. It is unlikely that such agents, following regulatory approval, will be used ubiquitously in patient populations, but rather may be targeted for at-risk patients. In the emerging field of periodontal medicine, patient cohorts are currently being identified with genetically based inflammatory mediator hyper-responses (48, 49, 68, 115). Such cohorts who respond to the endotoxin challenge posed by periodontitis with a robust release of cytokines or prostaglandins may benefit most in terms of slowing periodontitis progression and potentially improving systemic susceptibility (3, 67).

A radiographic evaluation of bone healing around submerged and non-submerged dental implants in beagle dogs.

BACKGROUND: The rehabilitation of the oral cavity with dental implants has become a predictable treatment modality. However, there have been only a few direct comparisons evaluating the submerged and nonsubmerged placement techniques. The purpose of this study was to characterize radiographic peri-implant bone changes following the insertion of submerged and nonsubmerged implants in the beagle dog. METHODS: At the end of the extraction healing phase, 19 submerged and 19 nonsubmerged implants were randomly placed in a split-mouth study design and observed over an 18-week period. For submerged implants, a second stage surgery and transmucosal abutment attachment was performed at week 12. Standardized dental radiographs taken at baseline, week 12, and week 18 were used to measure peri-implant bone changes. The radiographs were analyzed with a simple computer assisted method. RESULTS: A total of 43 standardized radiographs were exposed to evaluate the 38 implants. During the study period, all submerged and nonsubmerged implants demonstrated peri-implant bone loss. At baseline, both submerged and nonsubmerged implants had similar bone levels (P > or = 0.05). When the mean peri-implant bone levels for submerged and nonsubmerged implants were compared from baseline to week 12, nonsubmerged implants had a significantly greater amount and rate of bone resorption than submerged implants (P < or = 0.05). Following week 12, the initially submerged implant had a significantly higher rate and amount of peri-implant bone loss than the nonsubmerged implants (P < or = 0.05). However, by the end of the study period, week 18, both submerged and nonsubmerged implants had comparable bone levels (P > or = 0.05). CONCLUSIONS: The study indicates that, although the temporal patterns of peri-implant bone resorption differed, there were no differences between submerged and nonsubmerged implants in the overall amount and rate of peri-implant bone loss.

Periodontitis-atherosclerosis syndrome: an expanded model of pathogenesis.

The early reports of a linkage between periodontitis and atherosclerosis have garnered further support by additional data generated by several investigative teams in many different countries. The evidence continues to suggest that periodontitis may be an important risk factor or risk indicator for cardiovascular pathology for some individuals. The term periodontitis-atherosclerosis syndrome (PAS) is proposed as a new diagnostic term to describe this condition in these individuals. Current evidence, albeit preliminary in nature, which describes a cluster of clinical signs and symptoms that are associated with this condition, is presented. It is clear that this syndrome will require considerable study and refinement before a definitive diagnosis and treatment plan can be formulated. Potential mechanisms by which systemic inflammation and infectious challenge of periodontal origin may serve as a potential modifier of cardiovascular disease are discussed in the context of a detailed working model of pathogenesis. This hypothetical model embraces many cellular and molecular components of atherogenesis and thromboembolic diseases from the perspective of periodontitis pathogenesis. Many aspects of the hypothetical model remain unproved; however, it is our opinion that only through the clarification of the mechanisms of pathogenesis can we ultimately construct a knowledge framework for accurate diagnoses and successful therapies. The concept of diagnosing and treating a periodontal patient to minimize the deleterious effects of this chronic infectious and inflammatory condition on the cardiovascular system represents an unprecedented challenge to our profession.

The concept of "risk" and the emerging discipline of periodontal medicine.

Dental clinicians intuitively weigh patient risks for developing disease and use that information for making treatment decisions and recommendations. Periodontitis, for instance, is one oral disease with documented risk factors including smoking, specific plaque bacteria and diabetes mellitus. While this link between systemic disease and periodontitis was thought to be unidirectional, mounting evidence in the last decade suggests that the relationship may be bi-directional. Cross sectional and case control studies indicate that periodontitis may confer two and seven-fold elevations in risk for cardiovascular disease and premature low birth weight respectively. While these early studies indicate potential associations between oral and systemic health, they support the central hypothesis that periodontitis triggers both local and systemic host inflammatory responses. Consequently, a new discipline, periodontal medicine, has emerged in dentistry which seeks to further define these interrelationships through scientific inquiry. Ultimately, this new knowledge may prove useful in intervention strategies to reduce patient risks and prevent systemic disease outcomes. This manuscript clarifies the concept of risk, traces the emergence of periodontal medicine and serves as a resource for the oral health professional in assessing and utilizing the current evidence on periodontal-systemic disease connections.

Pharmacokinetic and safety evaluations of ketoprofen gels in subjects with adult periodontitis.

This clinical trial used a randomized, partially double-blind, controlled parallel design to evaluate the pharmacokinetics and safety of the NSAID, ketoprofen (KTP), in gel formulations. Forty-two subjects, ages 35 to 57 years, with generalized, moderate to advanced adult periodontitis were recruited and randomized to one of 5 treatments over a 14 1/2-day treatment period: (1) 0.5% KTP gel; (2) 1.0% KTP gel; (3) 1.0% KTP alternate gel; (4) 2.0% KTP gel; and (5) 25 mg KTP capsule (positive control). Plasma samples were obtained on days 1 (pre-dosing, 0.5, 1, 2, 3, 6 hr), 8 (pre-dosing, 2 hr), 15 (pre-dosing, 2 hr), and 22 (7 days post-treatment). Plasma KTP concentrations were determined by means of high-performance liquid chromatography. Significant differences in mean area under the plasma concentration vs. time curve (AUC(0-infinity)) among the groups were detected (p < 0.001), with the 25 mg p.o. capsule exhibiting the largest value (5054 ng-hr/mL), the 2.0% gel exhibiting an intermediate value (2244 ng-hr/mL), the 1.0% gels exhibiting lower but comparable values (1516 for the alternate formulation vs. 1461 ng-hr/mL), and the 0.5% gel showing the lowest value (736 ng-hr/mL). Significant differences in dose- and weight-adjusted maximum plasma concentration (Cmax/dose/kg) were detected overall such that the 25 mg p.o. capsule demonstrated higher values as compared with the 4 gel formulations (p = 0.001). The 5 treatments exhibited similar mean times of maximum plasma concentration (tmax) values ranging from 0.6 to 1 hr. Systemic exposures relative to dose and body weight were lower for the gel formulations than for the capsule. The relative systemic bioavailability of the gels compared with peroral administration ranged from 54% to 69%.

Enantiospecific inhibition of ligature-induced periodontitis in beagles with topical (S)-ketoprofen.

Systemic and topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce periodontal disease progression in both animal models and human subjects. Our present research focuses on single enantiomers of these agents to examine whether enantiospecific therapy will be efficacious in slowing periodontitis. The purpose of this study was to evaluate the inhibitory effects of (S)-ketoprofen on experimentally induced alveolar bone loss in beagle dogs. 16, 18-month-old, female beagles were brought to optimal periodontal health over a 2-week pretreatment period. Experimental periodontitis was then induced by placing silk ligatures around premolar and molar teeth and by instituting a soft, plaque-promoting diet. At baseline, animals were randomized to 1 of 4 groups, consisting of 2x daily administration of (1) placebo dentifrice, (2) 0.3% (S)-ketoprofen dentifrice, (3) 3.0% (S)-ketoprofen dentifrice, or (4) 10.0 mg (S)-ketoprofen capsules (p.o.) over a 60 day treatment period. Standardized, periapical radiographs exposed at days 1 and 60 were analyzed by computer-assisted digital radiography in order to assess the rate of alveolar bone loss. Secondary outcomes included technetium 99m-tin-diphosphonate (99mTc-Sn-MDP) uptake and the gingival index. At baseline, no differences were observed among the groups for linear bone height or 99mTc-Sn-MDP uptake ratios. From days 1 to 60, cohorts differed significantly in terms of bone loss rates (p < 0.001). In particular, beagles treated with systemic or topical (S)-ketoprofen (0.3% or 3.0% dentifrices) exhibited significantly lower mean rates of bone loss compared to placebo treated beagles (p < 0.05). Group differences in mean radiopharmaceutical uptake ratio changes approached significance (ANOVA, p = 0.07), where animals treated with topical 0.3% (S)-ketoprofen demonstrated a reduction and other groups demonstrated elevations over the 60-day dosing period. Treatment cohorts did differ significantly with respect to changes in mean gingival indices (p < 0.05). Animals treated with 0.3% or 3.0% (S)-ketoprofen dentifrice exhibited significantly reduced elevations in gingival index scores as compared to placebo treated animals. These data provide evidence that enantiospecific therapy with (S)-ketoprofen, topically or systemically delivered, may alter the progression of periodontal disease in the beagle dog model.

Inhibition of experimental gingivitis in beagle dogs with topical salivary histatins.

Histatins, histidine-rich proteins found within parotid and submandibular secretions, are a novel class of endogenous peptides with antimicrobial properties. This masked, randomized, placebo-controlled preclinical investigation examined the effect of 3 topical histatins on the development of plaque and gingivitis in beagle dogs. 16, female, 1-year-old beagles were brought to optimal gingival health by mechanical scaling and polishing followed by rigorous daily tooth brushing. At the conclusion of this pretreatment period, dogs were randomly divided into 4 groups for the application of test formulations, and were placed on a plaque-promoting diet. Test agents included 3 synthetic salivary histatins (histatin 5, P-113 and P-113D) which were incorporated in hydroxypropyl methylcellulose gel at a concentration of 0.125%, and a placebo, or negative control, which was the gel vehicle alone. Throughout the 10-week treatment period, test formulations (2.0 ml) were applied 2 x daily to all premolar teeth using a Monojet syringe. Plaque formation and gingival inflammation were assessed using the plaque (PI) and gingival (GI) indices on days 0, 7, 14, 21, 28, 42, 56 and 70. Furthermore, bleeding to probing was recorded as a percent of sites (%BOP) and according to the modified sulcus bleeding index (mSBI). Comparisons among groups and between group pairs (active versus placebo) were made with Kruskal-Wallis tests with the average of data over the interval, days 14-42, being the primary focus of the analysis. From baseline to day 7, all groups expressed similar indices. Thereafter, overall significant differences among the groups were noted at day 42 for PI, at days 21, 28, 42 and 70 for GI, and at days 14 and 28 for %BOP (p < 0.05). In particular, beagles treated with P-113 demonstrated significantly lower PI scores at day 42 (p < 0.05), significantly lower GI scores from days 21 through 42 (p < 0.05), and significantly lower %BOP scores at days 14 and 28 (p < 0.05) compared to beagles treated with placebo. Beagles treated with P-113D exhibited significantly lower GI at day 42 compared to the placebo (p < 0.05). For the primary analysis conducted over the midtreatment interval (days 14-42), significant differences were detected for all parameters except mSBI (p < 0.05). Accordingly, significantly lower PI scores were found for P-113, lower GI scores for P-113 and P-113D, and lower %BOP for P-113 and P-113D compared to placebo (p < 0.05). These data indicate that in the beagle model, salivary histatins, P-113 and P-113D, topically applied, can significantly reduce clinical signs of plaque formation and gingival inflammation.

Design principles and statistical considerations in periodontal clinical trials.

Although clinical trials are a small subset of conducted biomedical research, they have become powerful investigational tools for the evaluation and approval of new treatments by clinician groups and regulatory agencies like the US Food and Drug Administration. To impact the delivery of care, trials in general must meet three criteria: clarity, comparability, and generalizability. Accordingly, trials can offer meaningful data if they have procedures which are well defined and subjects who represent a reasonably homogeneous population. The evaluation of periodontitis interventions presents several challenges due to the disease's heterogeneity and its irregular, episodic pattern; nevertheless, the intent of these novel interventions is to prevent, diagnose, inhibit, or reverse periodontal disease progression. Careful consideration of the trial's objectives should dictate clinical endpoints (primary and surrogate), comparison groups (placebo, standard therapy, test therapy), and equivalence versus superiority as the basis for conclusions. Several design elements such as control population specification, randomization, masking, sample size calculation, and standardization of procedures for patient care and assessment can decrease potential bias and variability. In both parallel and paired (split-mouth) design trials, multiplicities of endpoints, treatments, and subgroups require strategies which address the broader scope of chance findings without excessive loss of study power. Also, the longitudinal assessment of multiple periodontal sites within patients produces correlated data structures for which analytic methods need to account for the appropriate sampling unit. With these design and analytic elements, clinical trials can provide important evidence to investigators, patients, and governmental agencies for the introduction of novel interventions in periodontal practice.

A phase I/II clinical trial to evaluate a combination of recombinant human platelet-derived growth factor-BB and recombinant human insulin-like growth factor-I in patients with periodontal disease.

The primary objective of this study was to assess the safety of recombinant human (rh) platelet-derived growth factor-BB (PDGF-BB) and (rh) insulin-like growth factor-I (IGF-I) when applied to periodontal osseous defects in humans; a secondary objective was to begin to accrue data on the therapeutic dose of these growth factors (GFs) required to stimulate periodontal regeneration. Thirty-eight human subjects possessing bilateral osseous periodontal lesions were assigned to one of two treatment groups in a split-mouth design. Following full-thickness flap reflection, test sites received local application of the therapeutic drug delivered in coded syringes by a "masked" investigator. Two dose levels were tested, 50 micrograms/ml each of rhPDGF-BB and rhIGF-I in a gel vehicle (LD-PDGF/IGF-I) and 150 micrograms/ml each of rhPDGF-BB and rhIGF-I plus vehicle (HD-PDGF/IGF-I). Control treatment consisted of either conventional periodontal flap surgery or surgery plus vehicle. Safety analyses included physical examination, hematology, serum chemistry, urinalysis, antibody titers, and radiographic evaluation of bony changes. The primary therapeutic assessment was bone fill measured at re-entry 6 to 9 months after treatment. No local or systemic safety issues were found as a result of GF administration. No patients developed antibodies to the rhGF proteins. In subjects treated with LD-PDGF/IGF-I, there were no enhancements in periodontal regeneration compared to controls. However, in patients treated with HD-PDGF/IGF-I, statistically significant increases in alveolar bone formation were noted as measured by surgical re-entry 9 months following drug delivery (P < 0.05). This corresponded to an increase of 2.08 mm of new vertical bone height and 42.3% osseous defect fill in the HD-PDGF/IGF-I subjects versus only 0.75 mm and 18.5% gains in new bone height and osseous fill, respectively, in the controls. Furcation lesions, although limited in number, responded most favorably to treatment, with 2.8 mm horizontal osseous fill. The results from this study suggest that the local application of rhPDGF-BB and rhIGF-I to periodontal lesions is safe at the dose levels studied. LD-PDGF/IGF-I did not elicit increased defect fill compared to the control; however, HD-PDGF/IGF-I resulted in a significant promotion in bone regeneration. Additional studies are warranted to more fully characterize the effects of PDGF/IGF-I on periodontal regeneration in humans.

Comparison of healed tissues adjacent to submerged and non-submerged unloaded titanium dental implants. A histometric study in beagle dogs.

This study involved histometry of the healed tissues around submerged and nonsubmerged dental implants in beagle dogs. In a split-mouth design, 19 submerged and 19 nonsubmerged commercially pure titanium implants, titanium plasma-sprayed in the bone anchoring part and smooth in the transmucosal portion, were placed in the mandibles of 6 dogs. Oral hygiene was performed 3 times weekly. After 3 months of healing, transmucosal abutments were inserted in the submerged implants. Six weeks after second stage surgery, the dogs were sacrificed and specimens obtained and processed for histology and histometry. Using a light microscope and a digitizing pad, the distance from implant top to mucosa border (DIM), the extent of epithelial downgrowth (ED), the attachment level, (AL), the length of connective tissue contact (CTC) and the distance of the first coronal alveolar bone contact from the implant top (DIB) were measured at the mesial and distal aspects. Means +/- standard deviations for submerged and nonsubmerged implants were calculated, with the dog being the unit of measure. No statistically significant differences between submerged and nonsubmerged implants were found for DIM, CTC and DIB. However, significant differences were observed for ED and AL. This study in beagle dogs indicates that the apical extension of the peri-implant epithelium is significantly greater and the attachment level significantly lower adjacent to submerged implants with second-stage transmucosal abutments than in nonsubmerged, one-stage implants.

Crevicular fluid osteocalcin and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) as markers of rapid bone turnover in periodontitis. A pilot study in beagle dogs.

The objective of this study was to correlate the levels of 2 putative markers of bone metabolism, namely osteocalcin and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), to the progression of experimental alveolar bone loss in the beagle dog. 36 control sites and 36 experimental sites in 2 beagle dogs were assessed longitudinally at 2-week intervals for gingival crevicular fluid (GCF) osteocalcin and ICTP levels during a 6-month observation period. Analysis of osteocalcin and ICTP in GCF was performed by RIA. During the study, bone-seeking radiopharmaceutical uptake (BSRU) of 99mTc-MDP was assessed monthly; standardized radiographs were taken at 2-week intervals. The results showed osteocalcin and ICTP levels in GCF increased significantly (p < 0.05) by 2 weeks following initiation of disease. This increase preceded significant increases in BSRU by 2 weeks and radiographic evidence of bone loss by 4 weeks. BSRU was significantly elevated (p < 0.05) at experimental sites as compared to controls at 4 and 8 weeks post-disease initiation. Osteocalcin in GCF peaked 8 and 10 weeks after ligature placement in experimental sites at levels nearly 10-fold greater than contralateral paired control sites. ICTP levels in GCF remained elevated throughout the entire disease progression phase. Following the removal of ligatures, both GCF osteocalcin and ICTP levels dropped precipitously approaching control values. Osteocalcin revealed overall a positive predictive value (PPV) and negative predictive value (NPV) for future bone loss during disease progression of 0.87 and 0.34, respectively, while ICTP showed both high PPV and NPV of 0.87 and 0.91 respectively. Results from this study in the dog model indicate that osteocalcin and especially ICTP relate to indices of active periodontal bony destruction and suggest that these molecules may serve as predictive markers for future alveolar bone loss.

Inhibition of peri-implant bone loss with the nonsteroidal anti-inflammatory drug flurbiprofen in beagle dogs. A preliminary study.

There is increasing interest in how pathways of tissue destruction around dental implants are similar as for teeth and how these pathways can be modulated to slow loss of supporting bone. The purposes of this study were to develop a short-term animal model to study the effect of the nonsteroidal anti-inflammatory drug flurbiprofen, on slowing the rate of induced peri-implant bone resorption. A total of 20 cylindrical titanium implants were placed in 2 beagle dogs using a low-trauma surgical technique. During the 3-month healing period without functional loading of the implants, daily oral hygiene was performed to maintain a Gingival Index of 0 to 0.5. At completion of the healing period, a baseline evaluation was performed which included the uptake of the bone-seeking radiopharmaceutical (BSRU) 99mtechnetium-tin-diphosphonate (99mTc-Sn-MDP) in peri-implant bone and standardized radiographs. Peri-implantitis was induced with 4-0 silk ligatures, cessation of oral hygiene and soft diet. One beagle was given 0.02 mg/kg of flurbiprofen by mouth; the other received a placebo. BSRU and radiographic height of bone were remeasured to calculate the rate of bone loss during the 60-day treatment period. The percent rate of bone loss during the study period was calculated from the radiographs using a computer-assisted method. The radiopharmaceutical uptake for the flurbiprofen-treated implants remained unchanged. However, BSRU for placebo-treated implants was significantly increased from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials and the evaluation of new periodontitis therapies.

A number of new periodontitis therapies have recently emerged for either inhibiting disease progression or regenerating lost tissues. As basic research continues to define specific bacteria and host response mechanisms involved in periodontitis, the development of new treatment strategies will continue to expand. This surge in biotechnology along with a tightening of federal regulations has prompted intense interest in clinical trials for testing new periodontitis therapies. A clinical trial is a scientific experiment involving human subjects in which treatment is initiated specifically for evaluation. The overall goal of any clinical trial is to minimize bias and variability. Studying periodontitis in clinical trials presents three problems related to this goal. Periodontitis is a heterogeneous disease grouping, the course of disease is often irregular, and conventional assessment instruments are associated with high error thresholds. Several methods can be used to minimize bias and variability when planning periodontitis trials. These include experimental design selection; inclusion and exclusion criteria; randomization of treatment and blinding; and standardization of treatment, follow-up, and assessment procedures. In addition, recently developed automated periodontal probes and computer-assisted radiography show promise in accurately detecting subtle changes in periodontal support. With improved planning, conduct, and reporting of periodontal clinical trials, investigators can facilitate the transfer of information to clinicians, who can decide on the utility of these new therapies for their periodontitis patients.