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An evidence-based review on host modulatory agents in treatment of peri-implant disease

 Department of Periodontology, K M Shah Dental College and Hospital, Sumandeep Vidyapeeth, Deemed to be University, Vadodara, Gujarat, India

Date of Submission26-Oct-2021
Date of Acceptance31-May-2022
Date of Web Publication23-Sep-2022

Correspondence Address:
Jasuma Rai,
Department of Periodontology, K M Shah Dental College and Hospital, Sumandeep Vidyapeeth, Deemed to be University, Piparia, Waghodia, Vadodara - 391 760, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_153_21


Antimicrobials have traditionally been the only chemotherapeutic option for treating periodontitis and peri-implant disorders. With a growing understanding of the host–pathogen interactions in periodontal pathogenesis, novel therapeutic options for periodontitis and peri-implant disorders are developed by focusing on the host response with host-modulating drugs. When employed as host-modifying agents, a variety of sub-antimicrobial dose doxycycline (SDD), bisphosphonates and non-steroidal anti-inflammatory drugs were found to be successful in both experimental animal research and human trials. The current state and future prospects of host modulatory agents used to treat peri-implant disease are discussed in this evidence-based review.

Keywords: Bisphosphonates, melatonin, peri-implantitis, probiotics, sub-antimicrobial dose doxycycline

How to cite this URL:
Andharia M, Rai J, Shah M, Sonavane P. An evidence-based review on host modulatory agents in treatment of peri-implant disease. Adv Hum Biol [Epub ahead of print] [cited 2023 Feb 9]. Available from: https://www.aihbonline.com/preprintarticle.asp?id=356795

  Introduction Top

Dental implants became a recognised therapy in dentistry in order to restore lost teeth in diverse clinical scenarios.[1] Peri-implant inflammations have become more common in recent decades, and these are one of the most common problems affecting both the surrounding soft and hard tissues and potentially leading to implant loss. Hence, prevention, as well as management of peri-implant diseases, is most important. Techniques for the prevention and management of peri-implant diseases should be included in current rehabilitation concepts in dentistry.[2],[3] Peri-implant mucositis and peri-implantitis are the two types of peri-implant illnesses. Peri implants are 'an inflammatory lesion of the mucosa that affects the supporting bone and causes osseointegration loss'. Mucositis is 'a reversible inflammatory lesion limited to the surrounding mucosa of an implant'.[4]

Several modes have been labelled to deal with peri-implantitis, which comprises non-surgical and surgical therapies. Non-surgical treatment choices embrace scaling and polishing, use of antimicrobials, lasers, occlusal therapy and photodynamic therapy. Surgically comprises flap, respective or regenerative procedures. Host modulatory therapy (HMT) has grown an enormous trend in the conduction of peri-implantitis adjunctively to scaling and polishing.[5]

HMT is a therapeutic approach aimed at reducing tissue damage and stabilising or even regenerating the periodontium by upregulating protective or regenerative responses while altering or downregulating destructive elements of the host response. The goal is to re-establish equilibrium between destructive enzymes and pro-inflammatory mediators, as well as enzyme inhibitors and anti-inflammatory mediators. They can be used as a supplement to scaling and root planing and can be given locally or systemically.[6]

HMT has been presented as a method to stop the deterioration of periodontal tissue. Arachidonic acid metabolites, excessive synthesis of matrix metalloproteinases (MMPs), regulation of bone metabolism and regulation of immunological and inflammatory responses are elements of disease aetiology that have been considered for modulation. Bisphosphonates, non-steroidal anti-inflammatory drugs (NSAIDs), sub-antimicrobial dose doxycycline (SDD) and locally derived agents such as growth factor (GF), Enamel Matrix Derivative” (EMD), tetracyclines and bone morphogenetic proteins (BMPs), amongst others, have all been used to treat peri-implantitis.[7]

Host response modulation has fewer side effects, is non-invasive and does not require a complex administration procedure as compared to other modalities used to treat the periodontal infection.[8],[9] This evidence-based review climaxes the present and forthcoming scenario of many host modulatory therapeutic agents for the treatment of peri-implantitis, used as an adjunct to the traditional periodontal remedies.

  Search Strategy Top

The research articles were searched from January 2016 to September 2021 in PubMed, the EBSCO database and the Google Scholar search engine. Because, in the present review, the authors want to include recent randomised controlled trials and current publications on HMA. Keywords such as 'host modulatory agent treatment and/or therapy of peri-implant disorders' were used to conduct a systematic search for relevant papers, and each modulatory agent was separately searched. After a comprehensive examination of the literature, the historical data were incorporated. In addition, all relevant papers' reference lists were examined; titles and abstracts were initially screened, and only full-text articles were included.

  Classification Top

It is classified as:

According to the mode of administration

  1. Systemically administered agents

    • NSAIDs
    • Bisphosphonates
    • SDD.[10]

  2. Locally administered agents

    • Topical NSAIDs
    • Enamel matrix proteins
    • GFs
    • BMP

    • Tetracyclines.

Classification of host modulation therapeutics

  1. Modulation of immune response

    1. Pro-inflammatory cytokine inhibition
    2. Modulation of MMP activities.

  2. Modulation of arachidonic acid metabolites

    1. NSAIDs
    2. Lipoxins, resolvins and protectins.

  3. Modulation of bone remodelling

    1. Anti-inflammatory agents
    2. Bisphosphonates
    3. Chemically modified tetracyclines (CMTs)
    4. Hormonal replacement therapy for post-menopause women.

  4. Host modulation by promoting periodontal regeneration
  5. Modulation of nitric oxide synthase (NOS) activity
  6. Modulation of cell signalling pathways in periodontal diseases
  7. Recombinant anti-inflammatory cytokine administration.[11]

  A Brief History Top

Mombelli et al. were the first to coin the term 'peri-implantitis'.[12] The surprising anti-collagenolytic and non-antibiotic characteristics of tetracyclines led to the first tradition of the phrase 'host modulation' as a potential treatment method for periodontal disease.[13] For the last several decades, physicians have used the idea of host response modulation in the treatment of chronic illnesses, including osteoporosis and rheumatoid arthritis.[14] However, in the 1970s, Max Goodson and Paul Goldhaber tried to relate arachidonic acid metabolites to bone loss in periodontitis as major inflammatory mediators.[15]

The idea of host modulation in dentistry was introduced by William and Golub in 1990. The compelling data from animal and human evidence propose that pharmacologic drugs that regulate host responses are considered to have a role in the aetiology of periodontal damage and may decrease periodontal disease progression [Figure 1].[15] The evidence of host modulatory agents in the treatment of peri-implant diseases is described in [Table 1].
Figure 1: Action of Host Modulation Agent

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Table 1: Randomised controlled trials as therapeutics in peri-implant disease

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Tetracycline, synthetic tetracyclines and chemically modified tetracyclines

Tetracycline is a broad-spectrum antibiotic used to treat a variety of infections. They offer excellent antibacterial defence locally for periodontal pathogens on the non-vascular wall of the periodontal pocket due to their high concentration and release in gingival crevicular fluid (GCF).[23] Tetracycline has the property of inhibition of MMPs, due to which it has an anti-collagenase effect. Calcium- and zinc-dependent endopeptidases are known as MMPs. It also scavenges and limits the synthesis of oxygen metabolites (e.g., hypochlorous acid) by polymorphonuclear (PMN) leucocytes, reducing inflammatory reactions in the host and preventing the breakdown of endogenous MMP inhibitors. Tetracyclines' direct suppression of MMPs and anti-inflammatory impact through hypochlorous acid blocking both limit the activation of latent pro-MMPs, lowering tissue degradation even more. MMPs produced from osteoclasts and osteoblasts are also inhibited, resulting in less alveolar bone resorption.[24],[25],[26]

Doxycycline and minocycline are synthetic tetracyclines with the ability to inhibit collagenase enzymes. However, doxycycline has received a lot of interest and investigation since it has the most effective anti-collagenase effects at a considerably lower inhibitory concentration than minocycline and tetracycline.[25] Doxycycline is also more effective at blocking PMN-type collagenases (MMP-8) than fibroblast-type collagenases (MMP-1), ensuring that regular tissue turnover is not hampered.[15]

CMT is an example of a pharmacological class that has been considered a possible. Tetracyclines' antibacterial and anti-collagenase capabilities were discovered by Golub et al. in different portions of four-ringed structures. They changed the structure of tetracyclines, resulting in the formation of CMTs. Several CMTs have been produced since then. CMT-1, CMT-3 and CMT-8 have all been studied for periodontal purposes.[26] It is used to treat peri-implantitis by inhibiting MMPs, inducible NOS, pro-inflammatory cytokines and bone resorption, as well as improving the adhesion of fibroblasts and connective tissues to the tooth surface.[27] Unlike traditional tetracyclines, CMTs do not induce gastrointestinal problems, and their therapeutic effects can be attained with less frequent dosing.

Sub-antimicrobial dose doxycycline

Collagenase's enzymes are effectively reduced by tetracycline and its synthetic family members. However, due to severe effects on the gastrointestinal system, cutaneous, hepatic and renal organs, as well as the establishment of resistant strains, longstanding usage is not suggested. SDD was introduced in 1998 for host modulation therapy to overcome this problem.[28] Periostat® was the brand name given to it when it was initially introduced (CollaGenex Pharmaceuticals Inc., Newtown, PA, USA). As an addition to root surface instrumentation, a 20-mg dose of doxycycline hyclate is administered twice a day for 3–9 months.[29],[30]

When taken in dosages of 50–100 mg/day for its antibacterial activity, SDD exhibited better and expected therapeutic results deprived of the appearance of side effects or any variations in subgingival microbiota. SDD has a substantially lower doxycycline serum concentration of 0.7–0.8 g/dL, whereas its antimicrobial dosage serum concentration is 3–4 g/dL.[31],[32]

SDD remedy has also been verified to improve long-term glycaemic control markers in diabetic patients. SDD and SRP have been revealed to enhance alveolar bone height and density in females with osteoporosis, as well as clinical attachment gains and not at all attachment loss in a variety of sites across extended periods of time when compared to SRP alone.[33] Rash, dyspepsia, headache and diarrhoea are all common side effects of SDD.[31]

Research shows that using a custom-formed medical device (Perio Tray) to deliver hydrogen peroxide gel (1.7%) (Perio Gel), with or without doxycycline, modifies the micro-environment of the gingival sulcus and tissues surrounding the teeth, resulting in reduced bleeding on probing, tissue inflammation and lessened pocket depth.[34] Doxycycline boosts osteoblastic activity, and hydrogen peroxide gel inhibits osteoclasts by hyperbaric oxygen production.[35],[36] Preceding research on natural teeth utilising this subgingival delivery approach boosted oxygen saturation to 5.7 X, which is comparable to hyperbaric oxygen, and the medicaments are administered up to 9-mm subgingival and sustained for over 15 min.[37]

  Non-steroidal Anti-inflammatory Drugs Top

In response to lipopolysaccharide, NSAIDs decrease the synthesis of prostaglandins, particularly prostaglandin E2, which is formed by a range of periodontal resident and invading cell types (including fibroblast, macrophages, neutrophils and epithelial cells). Because it upregulates osteoclastic bone resorption, prostaglandin E2 is a significant inflammatory mediator in periodontal disease.[38],[39]

In patients with gingivitis, periodontitis and peri-implantitis, raised amounts of PGE2 and other arachidonic acid metabolites have been seen in GCF and periodontal tissues. PGE2 concentrations in the crevicular fluid are also much higher in patients who are progressing through the disease. Inhibition of enzymes responsible for the production of these harmful compounds is one potential method for modulating the host response. Flurbiprofen, naproxen and indomethacin are three NSAIDs currently under investigation. Because NSAIDs are lipophilic and are absorbed into gingival tissues, they can be used topically.[40]

  Bisphosphonates Top

Bisphosphonates were first used to treat osteoporosis and osteolytic tumours in 1990. They are the second class of medications being studied for their ability to prevent bone resorption and control bone loss. Paget's disease, hypercalcaemia and osteoporosis are the most common conditions treated with them. These are pyrophosphate analogues that are non-biodegradable and have a robust attraction for calcium phosphate crystals, inhibiting osteoclast function. Bisphosphonates are fixed to the bone and assembled there, where they stay for months. They bound osteoclast adhesion to the bone, encourage osteoclast death and stop bone marrow precursor cells from converting into osteoclasts, all of which contribute to declined bone resorption and improved bone mass. These chemicals also seem to conquer matrix metalloproteinase action through a cation-chelating mechanism.[41]

Several case reports of avascular necrosis of the jaws, particularly the mandible, stated that following bisphosphonate medication, there was an increased risk of bone necrosis following dental extractions. Bisphosphonate-associated osteonecrosis is a major and life-threatening consequence of bisphosphonate therapy. When compared to high-dose intravenous bisphosphonate medication, the incidence of osteonecrosis of the jaws is substantially lower with oral bisphosphonate therapy.[42]

  Probiotics Top

Lilly and Stillwell defined probiotics in 1965 as 'substances produced by bacteria that encourage the growth of other microbes'.[43],[44] These bacteria are easily available to the general public, as they can be found in everyday items (most notably fermented milk), food supplements in soft beverages and tablet formulae.[45]

Their effects can be shown in changes in bacterial colonisation, oral biofilm modification, reduction in pathogenic microorganism and cytokine inflammatory levels and upgrading in clinical periodontal symptoms. However, the success of the treatment is dependent on the microbial concentration, the bacterial strain used, the ailment being treated and the number of species involved.[46],[47],[48],[49],[50] Probiotics suppresses the periodontal pathogens by creating antimicrobial defence chemicals (such as bacteriocins, lactic acid and hydrogen peroxide) and decreases the pH of the oral cavity, ultimately preventing the formation of organised bacterial plaque and thereby preventing oral illnesses.[43],[51],[52] Lactobacillus and bifidobacteria are two well-known probiotics that can modify the composition of the oral microbiota while also employing anti-inflammatory and antibacterial effects.[43],[44],[51]

When compared to mechanical debridement alone, Flichy-Fernández et al. (2015) found a significant reduction in clinical parameters (plaque index, pocket probing depth, modified gingival index and peri-implant crevicular fluid volume) and immunological parameters (interleukin 6 [IL-6] and IL-8) with mechanical debridement and probiotics.[53] While using probiotics as a treatment of choice in peri-implantitis, Galofré et al. found improvement in inflammatory parameters with significant reductions in and peri-implantitis, bleeding on probing at the implant level and probing pocket depth at the implant level.[54]

  Statins Top

Statins were developed as a means of lowering cholesterol by inhibiting a liver enzyme (HMG-CoA reductase).[55] Statins have non-cholesterol dependent, pleiotropic impact, which includes anti-inflammatory, vascular cytoprotection, antioxidant, anti-thrombotic, immunomodulatory and osteomodulatory capabilities. The most fundamental mechanism of statin suppression of bone resorption is inhibition of the enzyme HMG-CoA reductase and subsequent blocking of the mevalonate pathway. Bone resorption occurs when the making of isoprenoids is interrupted, ensuing in failure of vesicular fusion and the formation of ruffled borders on osteoclasts, both of which are required for bone resorption to occur. Statins are thought to endorse bone formation by promoting the synthesis of BMP-2, which has been associated with bone and periodontal healing.[18],[56]

Simvastatin is thought to have significant antioxidant and anti-inflammatory properties, inhibiting macrophage IL-6 production, reduction in plasma levels of inflammatory markers like C-reactive protein and inhibiting nicotinamide adenine dinucleotide phosphate oxidase. Statins affect the immune system by adhering to leucocytes and obstructing them from assigning to intercellular adhesion molecule-1, which inhibits leucocyte adherence and extravasation.[57] Statin therapy lessens GCF levels of MMPs, IL-1β and tumour necrosis factor-α in periodontal patients, modulating the host response. Many of the host tissues are destroyed as a result of these pro-inflammatory mediators.[18]

  Resolvins Top

The resolution of inflammation is a critical module of inflammatory responses. Formerly, it was assumed that after the preliminary stimulus was removed, inflammatory processes would gradually and passively subside. Resolved inflammation is a meticulous process which includes cessation of leucocyte infiltration by pro-resolving mediators and reduction in vascular permeability, which help in the informal removal of leucocytes by means of apoptosis and exclusion of necrotic and bacterial tissue.[58]

Inflammation must be resolved. If not, tissue harm may result from ongoing chronic inflammatory responses. Molecules that 'turn off' inflammation could be appealing in the treatment of inflammatory conditions, including periodontitis and peri-implant diseases, and could potentially offer advantages over anti-inflammatory medicines with considerable side effects. Resolvins, protectins and lipoxins are a group of agents that have been studied in this area. The discovery of these molecules, which indicate the end of an acute inflammatory event, could expand our treatment choices for chronic inflammatory illnesses. The lipoxins are made up of arachidonic acid, while the maresins, protectins and resolvins are made up of omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid, which may be found in fish oil.[59]

  Future Advances Top

Growth factors

Enamel matrix derivative (EMD) and platelet-derivative factors such as platelet-rich fibrin and plasma rich in GFs are two types of GFs used in regenerative dentistry to improve clinical outcomes.[60],[61] They include and activate bioactive substances such as platelet-derived GF, vascular endothelial GF, transforming GF-beta and BMP. The release of these GFs is proposed to activate cells locally for a brief time period, increasing proliferation and differentiation, as well as regeneration.[62],[63] It also has antibacterial features, which may be beneficial given that peri-implant illnesses are caused by bacteria. GF s may also help with implant-related outcomes such as alveolar ridge maintenance and implant stability.[64],[65],[66]

  Enamel Matrix Derivatives Top

EMD is a pure acid extract of porcine enamel proteins.[67],[68] A family of hydrophobic proteins, which encompasses 95% of amelogenins and it plays a role in the regulation of osteoblast and fibroblast. These proteins are certainly present during the development of the tooth's attachment apparatus and have been publicised to stimulate periodontal ligament regeneration responses. Although the mechanisms are unknown, it is known that when amelogenins are applied to a conditioned root surface, they precipitate to form an insoluble extracellular matrix with a high affinity for hydroxyapatite and collagen, which can interact with the surrounding cells and recruit periodontal regeneration.[69]

  Melatonin Top

Melatonin (n-acetyl-5-methoxytryptamine) is a hormone that is produced by the pineal gland, retina, bone marrow, gastrointestinal tract and immune system, amongst other organs. Its chief job is to keep the circadian rhythm (day–night cycles) patterned. By scavenging free radicals and interacting with the cell membrane and intracellular proteins, it has anti-toxin, anti-inflammatory and immunomodulatory properties. It can arrive in the oral cavity by diffusing into saliva from the bloodstream. Because the widely held melatonin is devoted to serum albumin, the total of melatonin found in saliva is about one-third of that found in the blood. The presence of MT1 receptors on both healthy and malignant oral mucosal cells advocates that melatonin could be cast off as an anti-inflammatory or anti-tumour drug in the mouth.[70] It primarily serves two functions: first, it has the ability to scavenge free radicals, so exerting antioxidative action, and second, it has a cell-protective impact in inflammatory circumstances.[71]

  Conclusion Top

Host modulatory agents definitely help in halting the progress of peri-implant disease and have shown promising results in clinical, radiographic and microbial Outcomes. HMTs were used as the treatment option in the non-surgical arena, but as research development has increased, they have been included in surgical therapies as well. The highest level of evidence needs to be procured on low dose aspirin, flurbiprofen, statins and herbal alternatives as they have shown positive outcome in the treatment of periodontitis.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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