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activity, which may have utility in reducing connective tissue break - down and augmenting healing responses following subgingival in - strumentation in periodontitis patients. Available evidence Eight placebo-controlled RCTs (14 publications, n = 610) reported on the systemic use of a sub-antimicrobial dose doxycycline (SDD) (up to 40 mg a day) in combination with subgingival instrumen - tation. Meta-analysis on PPD reduction (primary outcome) at 6 months post-subgingival instrumentation was performed in five RCTs ( n = 484). Risk of bias One study was considered to be at high risk of bias and the remain - ing studies presented some concerns in certain domains. Of the five studies included in meta-analysis, three declared industrial sponsor - ship, one was sponsored by the academic institution, and the fifth did not declare funding. Consistency The systematic review included data from eight RCTs, but meta- analysis was performed in five RCTs that stratified pockets into moderate (4–6 mm) versus deep (≥7 mm). The findings were con - sistent in all studies. The I 2 statistic was 0% (95% CI [0%; 64.1%]) for both moderate and deep pockets. Two out of five RCTs included did not report a power calculation. The strict experimental protocols employed by the five studies included in the meta-analysis limits the generalizability of the outcomes. Clinical relevance of outcomes and effect size Additional PPD reductions reported following the use of SDD were 0.22 mm at 6 months and 0.3 mm at 9 months in moder - ate depth pockets. The mean prediction interval ranged from 0.06 mm to 0.38 mm at 6 months and from 0.15 mm to 0.45 mm at 9 months. At deep sites, the additional PPD reductions were more clinically relevant, with 0.68 mm mean additional PPD reduc - tions at 6 months and 0.62 mm at 9 months. The mean prediction interval ranged from 0.34 mm to 1.02 mm at 6 months and from 0.28 mm to 0.96 mm at 9 months. Percentage of pocket closure was not reported. Balance of benefits and harm Most studies in the SDD category did not report any serious adverse events or patient dropouts that were directly attributed to the medi - cation. However, it is known that doxycycline may lead to elevations in liver enzymes, which was evident for some patients in the results of one RCT included in the systematic review (Caton et al., 2000, 2001). The sustainability of the benefits or adverse events beyond the study period is unknown. Ethical considerations Current health policies on antibiotic stewardship and related public health concerns surrounding increasing antibiotic resistance need
to be taken into account. The systemic effects of a drug taken over a 6- to 9-month period during the initial phase of subgingival instrumentation require careful consideration when extrapolat - ing outcomes from controlled research trials into general clinical practice.
Legal considerations SDD is not approved or available in some European countries.
Economic considerations There is a cost associated with the use of SDD that is borne by the patient.
Applicability SSD is mainly effective in deep sites (≥7 mm), although SDD is used as a systemic rather than a site-specific treatment. The clinical signif - icance in deep sites (0.68 mm at 6 months and 0.62 mm at 9 months) is small, given that re-treatment with non-surgical root debridement might yield additional PPD reductions, and local drug delivery sys - tems may yield similar effect sizes. Moreover, the five studies that did stratify results based upon pocket depth did not present an a priori statistical plan powered to stratify results in that manner. R2.9 | Does the adjunctive use of systemic/local bisphosphonates to subgingival instrumentation improve clinical outcomes? Evidence-based recommendation (2.9) We recommend not to use locally delivered bisphosphonate (BP) gels or systemic BPs as an adjunct to subgingival instrumentation. Supporting literature Donos et al. (2019) Quality of evidence Seven placebo-controlled RCTs ( n = 348), on local delivery of 1% alendronate gel (six studies) and 0.5% zolendronate gel (one study); two placebo-controlled RCTs ( n = 90) on systemic administration of BPs (alendronic acid and risedronate). Grade of recommendation Grade A—↓↓ Strength of consensus Strong consensus (0% of the group abstained due to potential CoI)
Background
Intervention Bisphosphonates (BPs) are a class of antiresorptive agents that act mainly by inhibiting osteoclast activity. BPs can also directly inhibit host degradative enzymes like matrix metalloproteinases released by osteoclasts and other cells of the periodontium. There is also evidence that BPs reduce osteoblast apoptosis, thus increasing bone density as an overall therapeutic outcome. It is therefore rational to speculate that BPs may benefit the management of inflammation- mediated alveolar bone resorption in periodontitis patients (Badran, Kraehenmann, Guicheux, & Soueidan, 2009).
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