Hyaluronic Acid as Adjunct to Scaling and Root Planing – A Brief Systematic Review

Structure of hyaluronan. (a) Chemical structure. (b) 3D model. (c) Hyaluronan is abundant, long, unsulfated glycosaminglycan (up to 25,000 sugars), synthesized in the extracellular matrix by an enzyme complex in the plasma membrane (Dahiya and Kamal 2013)

Structure of hyaluronan. (a) Chemical structure. (b) 3D model. (c) Hyaluronan is abundant, long, unsulfated glycosaminglycan (up to 25,000 sugars), synthesized in the extracellular matrix by an enzyme complex in the plasma membrane (Dahiya and Kamal 2013)

The American Academy of Periodontology features this month a paper by Eick et al. on hyaluronic acid (e.g. Gengigel, Merz Dental, Germany) as an adjunct after scaling and root planing. It might be interesting to search for comparable randomized clinical trials in order to get a clue as to whether application during and after phase (I) therapy (the hygienic phase) may in fact be recommended.

Hyaluronic acid is a linear polysaccharide of the extracellular matrix of several tissues including connective tissues of the periodontium. History, chemistry, origin in the body and its metabolism, and its unique physiochemical and biological properties have recently been reviewed by Dahiya and Kamal (2013).

Only papers written in English were sought using the focused question (PICO): “In patients with chronic periodontitis, does the adjunct application of hyarulonic acid during and after periodontal scaling and root planing lead to better results as regards periodontal probing parameters probing depth and/or clinical attachment loss than scaling and root planing alone.” Only studies of a minimum of 3 months duration were considered since at that time periodontal reevaluation maybe conducted and, if needed, further treatment planned.

As a rule, the list of items which outlined in the PRISMA statement was checked, i.e. preferred reporting items for systematic reviews and meta-analyses (PRISMA). A PubMed search using (“hyaluronic acid”[MeSH Terms] OR (“hyaluronic”[All Fields] AND “acid”[All Fields]) OR “hyaluronic acid”[All Fields]) AND (“periodontitis”[MeSH Terms] OR “periodontitis”[All Fields]) yields 34 papers. In total, five RCTs could be identified where adjunct hyaluronic acid was compared with scaling and root planing alone in patients with chronic periodontitis, Eick et al. (2013), Bevilacqua et al. (2012), Gontiya and Galgali (2012), Johannsen et al. (2009), and Xu et al. (2004). Note that the paper by Xu et al. (2004) had been republished in Chinese the same year. The pilot study by Pilloni et al. (2011) was not considered since only results of adjunct application of hyaluronic acid after toothbrushing were reported as compared to toothbrushing alone in patients with shallow pockets.

The remaining papers were read in full before certain data were extracted. Several of the papers contained issues which make proper interpretation of results problematic. While in the study by Bevilacqua et al. (2012) results revealed more reduction of pocket depth when a not further specified mixture of amino acids and sodium hyaluronate gel (Aminogam®) had been applied subgingivally after scaling and root planing of 2 pockets of at least 5 mm in each of 11 patient (average decreased from 6.14 mm at baseline to 4.64 mm at day 90) as compared to application of a placebo gel at 2 pockets in a different quadrant of the dentition (from 6.36 to 5.36 mm), authors mention that their statistical unit for hypothesis testing was the site, not the patient. While there are sophisticated statistical methods may be applied in order to properly consider the non-independence of the numerous observations  made in an oral cavity, such as generalized estimating equations or, more recently, multilevel modeling, just calculating standard errors (or, as has been done by the authors, confidence intervals) of estimates by disregarding the correlated structure of the data are inevitably be underestimated with severe consequences when testing hypotheses.

The study by Gontiya and Galgali (2012) presented with similar if not more problematic issues; for instance, improper site-specific analysis and  no specification of statistical tests. Moreover, the fact that variability measures are not specified makes including the study in a meta-analysis impossible. In general, while authors report more pronounced reduction of gingival inflammation in the group of test teeth having received 0.2% hyaluronic acid gel after scaling, pocket depth reduction and relatibve attachment level changes were similar in test and control groups.

In the study by Johannsen et al. (2009), a suspicious sentence in the Materials and Methods section, ” All sites were included in the dataset” may suggest that authors used sites a statistical unit. A total of 12 patients with chronic periodontitis were treated by scaling and root planing. Test teeth (premolars and canines) in 2 random quadrants were subjected to adjunct application of 0.8% hyaluronic acid gel. No placebo was applied to contralateral control teeth. After 3 months, test teeth experienced 1 mm pocket depth reduction, on average, the respective reduction was 0.8 mm at control teeth. Clinical attachment levels did not change in either group.

The study by Xu et al. (2004) compared, in 20 patients with chronic periodontitis, frequent adjunct application of 0.8% hyaluronic acid (after scaling and at weekly intervals for altogether 7 applications) at molars and premolars with contralateral control teeth in a split mouth experimental design where only scaling and root planing was performed. In both groups, scaling and root planing was done at baseline and week 2, 4, and 6. The patient served as unit for statistical analyses. While probing parameters and signs of gingival inflammation improved significantly in both groups, any differences between groups were not significant. Neither were differences in the prevalence of certain periodontal organisms.

In the most recent study by Eick et al. (2013) 52 patients with chronic periodontitis were randomized. Test subjects received subgingival scaling and root in 2 sessions 24 h apart and adjunct subgingival application of 0.8% hyaluronic acid. In addition, patients were asked to apply 0.2% hyaluronic acid onto the gingival margin twice daily for 14 days. Full mouth scaling only was done in control subjects who were not provided with hyaluronic acid. No placebo was used. Patients and examiner were not blinded. Data of the remaining 34 subjects (17 in each group) were analyzed in a per protocol analysis. No adjustment for multiple hypothesis testing was done. So, as with most of the other studies, risk for bias was high. The patient served as unit for hypothesis testing. After 3 months, mean pocket depth reduction was greater in test subjects as was the decreased number of sites with a probing pocket depth of 5 mm or more. Differences in clinical attachment gain were not significant as were differences in sites bleeding on probing and sites covered by supragingival plaque.

A description of the studies can be seen in the Table.

Table

Despite the above mentioned problems with improper statistical analyses (standard errors of the mean and confidence intervals are underestimated if several sites within patients are erroneously considered as independent) and some need for imputation of missing estimates of standard deviations, a brief meta-analysis was done using MetaEasy. The program can manage a large array of different combinations of estimates and corresponding measures of variability, see Kontopantelis and Reeves (2009).  Click here for a pdf of the manual. Moreover, different methods to determine an overall effect are executed. Several statistics are given and a nice Forest plot is drawn.

The figure below displays the result for periodontal pocket depth (PPD). Data correspond to results obtained at 3 months post scaling and root planing. Note that in the paper by Eick et al. (2013) standard deviations for postoperative PPD for test and control patients were imputed and set to 0.3 mm.

Meta-analysis of four RCTs regarding mean PPD when scaling/root planing and topical  adjunct hyaloronic acid was compared with scaling and root planing alone

Meta-analysis of four RCTs regarding mean PPD when scaling/root planing and topical adjunct hyaloronic acid was compared with scaling and root planing alone

The results for clinical attachment level at 3 months are displayed in the figure below. Likewise, for the paper by Eick et al. (2013), standard deviations for test and control patients of 0.8 and 0.6 mm were imputed, respectively. The meta-analysis confirms a significant effect of adjunct hyaluronic acid as regards more favorable periodontal probing depth after scaling and root planing. More attachment gain is, on the other hand, not to be expected. One has to take into account, however, the very small net effects of parts of a mm which are hardly clinically relevant when considering application of this adjunct to scaling and root planing.

Meta-analysis of four RCTs regarding mean CAL when scaling/root planing and topical  adjunct hyaloronic acid was compared with scaling and root planing alone

Meta-analysis of four RCTs regarding mean CAL when scaling/root planing and topical adjunct hyaloronic acid was compared with scaling and root planing alone

References

Bevilacqua L, Eriani J, Serroni I, Liani G, Borelli V, Castronovo G, DiLenarda R. Effectiveness of adjunct subgingival administration of amino acids and sodium hyaluronate gel on clinical and immunological parameters in the treatment of chronic periodontitis. Ann Stomatol (Roma) 2012; III(2): 75-81.

Dahiya P, Kamal R. Hyaluronic acid: a boon in periodontal therapy. N Am J Med Sci 2013; 5: 309-315.

Eick S, Renatus A, Heinicke M, Pfister W, Stratul SI, Jentsch H. Hyaluronic acid as an adjunct after scaling and root planing: a prospective randomized clinical trial. J Periodontol 2013; 84: 941-949.

Gontiya G, Galgali SR. Effect of hyaluronan on periodontitis: a clinical and histological study. J Indian Soc Periodontol 2012; 16: 184-192.

Johannsen A, Tellefsen M, Wikesjö U, Johannsen G. Local delivery of hyaluronan as an adjunct to scaling and root planing in the treatment of chronic periodontitis. J Periodontol 2009; 80: 1493-1497.

Kontopantelis E, Reeves D. MetaEasy: a meta-analysis add-in for Microsoft Excel. J Stat Software 2009 (April); 30(7)

Moher D, Liberati A, Tetzlaff J, Altman DG, and the PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Ann Int Med 2009; 151: 264-269.

Pilloni A, Annibali S, Dominici F, DiPaolo C, Papa M, Cassini MA, Polimeni A. Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters. A randomized-controlled clinical pilot study. Ann Stomatol (Roma) 2011; II(3-4): 3-9.

Xu Y, Höfling K, Fimmers R, Frentzen M, Jervoe-Storm PM. Clinical and microbiological effects of topical subgingival application of hyaluronic acid gel adjunctive to scaling and root planing in the treatment of chronic periodontitis. J Periodontol 2004; 75: 1114-1118.

12 July 2013 @ 6:56 pm.

Last modified July 13, 2013.

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2 comments

  1. Lynne Slim

    Thanks for your efforts in summarizing the evidence to date surrounding this topic. In the U.S. dental practices used to recommend Arestin or Atridox as an adjunct to SRP and some still do but I’ve noticed that it’s mostly used for localized pocketing. When these adjuncts first became available, unethical folks used these adjuncts as a ‘profit center’ for a dental practice and it was very upsetting to me because those of us who look at outcomes understood the benefit to be small in terms of clinical attachment gain with and without these adjuncts. Hopefully, the U.S. and European periodontal community will continue to grow in the area of EB clinical practice and start weighing the evidence and cost effectiveness of these adjuncts before jumping on board.

    Did you happen to read the Editorial entitled, “Periodontitis: Canary in the Coal Mine”?

    JADA 2013;144(7):764-766

    Wenche S. Borgnakke, Michael Glick and Robert J. Genco

    Like

    • Muller

      Here in Europe, Heraeus Kulzer have been quite aggressive in promoting a similar product, a 14% doxycycline gel, Ligosan. The claimed indication seems to be rather peri-implant diseases. Topical antibiotics in the treatment of periodontal disease is certainly an outdated concept based on the assumption of the 1980s of a “specific” infection which may differ from site to site. Benefits are not so clear, be it as an adjunct or sole therapy. A couple of parts of a millimeter more pocket depth reduction and gain of clinical attachment are not really clinically relevant. My main objection has been and still is the simple fact that the flora is not so different and periodontal organisms colonize wide areas of the oral cavity including mucosal surfaces.

      The above brief meta-analysis was mainly done for educational purposes. It should demonstrate that the focused dealing with a small problem may result, in one or two days, in some results which would allow a serious decision, well, against usage (despite promotion of the latest study by the AAP). The example can be used in lectures about evidence-based practice. I was also interested in trying out MetaEasy. It’s a nice add-in for Excel.

      As regards the editorial in JADA, it seems to be another attempt (such as the EFP Manifesto) to amplify a certain opinion by the authors.

      Like

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