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A “Point-by-Point” Statement on Periodontal Host-Modulation Therapy: Safety First!


July 3, 2018
by Lorne M. Golub, DMD, MSc, DSc (H), Cert. Perio, MD (honorary), FNAI; Ying Gu, DDS, PhD, Cert. AEGD; Howard Tenenbaum, DDS, Dip. Perio, PhD, FRCD(C); Michael B. Goldberg, MSc., DDS, Dip. Perio; Timo Sorsa, DDS, PhD, Dipl. Perio

Introduction
Over the past several decades, dentistry has come to realize that:

(a) Periodontitis is the most common progressive, chronic inflammatory disease known to mankind – more common than rheumatoid arthritis, chronic inflammatory bowel disease, chronic inflammatory skin disease, etc., and

(b) although the dental plaque, i.e., the oral microbial biofilm (and its metabolic products), initiates inflammation in the gingival tissues, it is the patient’s reaction, called the “Host-Response”, to these bacterial insults that mediates soft and hard tissue breakdown; and it is this tissue destruction (largely mediated by host-derived proteolytic enzymes called the matrix metalloproteinases or MMPs) that produces the clinical “picture” of increased pocket depth, clinical attachment loss, alveolar bone loss, and ultimately, tooth loss (Fig. 1).

Fig. 1
Clinical outcomes of the healthy (resolved) and abnormal (chronic & prolonged) inflammatory response.

Fig. 2
Health Canada approved non-antibiotic doxycycline formulation, as adjunctive treatment in the management of chronic periodontitis.

This recognition of the over-arching importance of the host-response has led to new clinical strategies of periodontal disease management, beyond reduction of the bacterial “burden”. This novel therapeutic strategy, now called “Host-Modulation Therapy,”1-4 has raised new issues which are addressed in the “Commentary” below.

Commentary
The following “points” highlight the safety and efficacy of the only U.S., Canadian, and European-government approved Periodontal Host-Modulator, MMP-Inhibitor medication, Periostat (subantimicrobial-dose doxycycline or SDD):

Point #1. Numerous peer-reviewed scientific double-blind, placebo-controlled clinical trials, in the U.S. and other countries, have repeatedly-and without exception-demonstrated that Periostat is safe and effective.1-6

The mechanism? The active-ingredient, “NON-antibiotic dose doxycycline” (or SDD), by its novel action as an MMP-I (MMP-I, Matrix Metalloproteinase-Inhibitor), inhibits the pathologically-excessive, but NOT the physiologic, degradation of collagen and other connective tissue constituents.4-6 These constituents form the matrix of all soft and hard tissues of the periodontium – the gingiva, the periodontal ligament, and the alveolar bone.

Point #2. A major example: A National Institutes of Health (NIH, Bethesda, Maryland)-funded, double-blind randomized clinical study (involving two U.S. universities) on 126 post-menopausal women with periodontitis, found:

(A) That a two-year regimen of Periostat produced significant improvements, compared to “look-alike” placebo capsules, in reducing periodontal breakdown assessed by calibrated clinical, radiographic, and biomarker measurements. Note: all patients, whether on test-medication or on placebo capsules, received non-surgical periodontal maintenance therapy every three to four months paid by the grant; and

(B) That this two-year daily regimen was as SAFE (No adverse events, or AEs) as placebo capsules, based on approved criteria.7-9 Moreover, based on beneficial effects on collagen in general – in addition to reduction of inflammation – an improvement in facial skin in these post-menopausal women7, 10 (and other patients in other studies11) was also seen in this collagen-rich tissue.

Point #3. Another example, this time in a medical study: A professor of Rheumatology at a major U.S. medical school reported that, in a double-blind clinical study on arthritic patients, those patients administered Periostat for two years showed NO evidence of side-effects, compared to those patients administered placebo capsules for two years.12 In contrast, those arthritic patients administered a much higher, antibiotic-dose doxycycline DID develop side effects [Note: that all patients in this study were on methotrexate, a standard treatment for rheumatoid arthritis; also of interest, both NON-antibiotic dose, and much higher, antibiotic-dose doxycycline demonstrated evidence of similar efficacy in these arthritic patients].12

Point #4. In contrast to Periostat, another category of MMP-Is, (which are chemically different from the novel NON-antibiotic dose doxycycline/Periostat), namely hydroxamic acid peptides which are designed to potently bind zinc in order to maximize the inhibition of MMP enzyme activity, DID produce significant side-effects, i.e., musculo-skeletal dysfunction. As a result, this product was canceled and its development stopped.13, 14

Fig. 3
Sub-antimicrobial dose doxycycline (Periostat) produces blood levels which are substantially below the minimum required for antibiotic activity. However, current systemic blood levels of “antimicrobial-dose” doxycycline are even higher, e.g., 2,000-5,000 ng/mL, not 1,200 ng/mL, since the standard antibiotic dose is currently 100 mg once or twice a day, not 50 mg. Thus, the “gap” between the high blood levels of doxycycline produced by current antibiotic doses, and the low blood levels produced by Periostat, are even greater.

Table 1
Side effects of Periostat were similar to Placebo (reference: Periostat Product Monograph). A similar safety profile was described in a double-blind clinical trial on 126 post-menopausal women, testing safety and efficacy of Periostat versus Placebo capsules administered for 2-years (see reference # 8). In that study, the only AE that was SIGNIFICANTLY affected was “dermatologic”, which was actually IMPROVED in those women treated with Periostat.

The explanation? The strategy of this failed product, as well as similar other failed strategies in the MMP-I field, was to excessively block MMP activity! They did not sufficiently appreciate the physiologic necessity of a low-level of MMP activity for normal connective tissue (collagen) health, and that excessively inhibiting these enzymes would be detrimental and produce side-effects.

Further along these lines, one of the authors has carried out studies focused on MMP-inhibition for prevention of cardiac failure following myocardial infarction (MI) in a rat model.15 It was demonstrated clearly that when MMP activities were abolished or blocked almost completely, post-MI cardiac failure worsened significantly compared to control (no inhibition of MMPs).

However, when MMP activities were downregulated to essentially normal or constitutive levels, there was a 50% reduction in post MI development of heart failure. Similar conclusions were reached from a double-blind placebo-controlled clinical trial on humans with severe coronary vascular disease, “acute coronary syndromes”; those patients on Periostat for six months showed significant reductions systemically in CVD biomarkers.16 This underscores the ideas outlined above indicating that host modulation therapy should focus on normalization of MMP activities and not complete inhibition.5,6

The authors of the above “summary statement” have published extensively on collagen and MMP biology, and have discussed the clinical rationale for Periostat based on this novel drug’s function as a MILD MMP-inhibitor; their publications, and those by others, have contrasted the desirable safety record of Periostat to the problematic record of excessively-potent MMP-Is.5,6,10,13-15 OH

Oral Health welcomes this original article.

Disclaimer
Dr. Golub and Tenenbaum have served as consultants to Oral Science, Ltd., Quebec, which is the distributor of Periostat in Canada.

References

  1. Gu Y, Walker C, Ryan ME, Payne JB, Golub LM. Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine. J Oral Microbiol. 2012;4. doi: 10.3402/jom.v4i0.19227.
  2. Preshaw PM. Host response modulation in periodontics. Periodontol 2000. 2008;48:92-110.
  3. Giannobile WV. Host-response therapeutics for periodontal diseases. J Periodontol. 2008 Aug;79(8 Suppl):1592-600.
  4. Walker SG and Golub LM. Host modulation therapy for periodontal diseases: subantimicrobial-dose doxycycline, medical as well as dental benefits. Oral Health 2012 (Oct.): 24-35.
  5. Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, Golub LM, Brown DL, Mäntylä P. Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann Med. 2006;38(5):306-21.
  6. Sorsa T, Golub LM. Is the excessive inhibition of matrix metalloproteinases (MMPs) by potent synthetic MMP inhibitors (MMPIs) desirable in periodontitis and other inflammatory diseases? That is: ‘Leaky’ MMPIs vs excessively efficient drugs. Oral Dis. 2005 Nov;11(6):408-9.
  7. Payne JB, Golub LM. Using tetracyclines to treat osteoporotic/ osteopenic bone loss: from the basic science laboratory to the clinic. Pharmacol Res. 2011 Feb;63(2):121-9. doi: 10.1016/j.phrs.2010.10.006.
  8. Payne JB, Stoner JA, Nummikoski PV, Reinhardt RA, Goren AD, Wolff MS, Lee HM, Lynch JC, Valente R, Golub LM. Subantimicrobial dose doxycycline effects on alveolar bone loss in post-menopausal women. J Clin Periodontol. 2007 Sep;34(9):776-87.
  9. Walker C, Puumala S, Golub LM, Stoner JA, Reinhardt RA, Lee HM, Payne JB. Subantimicrobial dose doxycycline effects on osteopenic bone loss: microbiologic results. J Periodontol. 2007 Aug;78(8):1590-601.
  10. Golub LM. Introduction and background. Pharmacol Res. 2011 Feb;63(2):99-101. doi: 10.1016/j.phrs.2010.10.003.
  11. Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res. 2011 Feb;63(2):130-45. doi: 10.1016/j.phrs.2010.10.007.
  12. O’Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, Blakely KM, Hausch R, Leff RD. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum. 2006 Feb;54(2):621-7.
  13. Gomis-Rüth FX. Third time lucky? Getting a grip on matrix metalloproteinases. J Biol Chem. 2017 Oct 27;292(43):17975-17976. doi: 10.1074/jbc.H117.806075.
  14. Scannevin RH, Alexander R, Haarlander TM, Burke SL, Singer M, Huo C, Zhang YM, Maguire D, Spurlino J, Deckman I, Carroll KI, Lewandowski F, Devine E, Dzordzorme K, Tounge B, Milligan C, Bayoumy S, Williams R, Schalk-Hihi C, Leonard K, Jackson P, Todd M, Kuo LC, Rhodes KJ. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. J Biol Chem. 2017 Oct 27;292(43):17963-17974. doi: 10.1074/jbc.M117.806075.
  15. Tenenbaum HC. MMPs: A noveltarget for regulation of cardiovascular disease. Presented at Josephtal Hospital/Toronto Science Forum, Eilat, Israel, 2014 (October).
  16. Brown DL, Desai K, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):733-8.

About the Authors
   Lorne M. Golub, DMD, MSc, Cert. Perio., MD (honorary), FNAI SUNY Distinguished Professor, Department of Oral Biology & Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY.

 

Ying Gu, DDS, PhD, Cert. AEGD, Associate Professor, Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY.

 

 

Howard Tenenbaum, DDS, Dip. Perio., PhD, FRCD(C), Professor of Periodontology, Faculty of Dentistry, Dentist-in-Chief, Department of Dentistry, Sinai Health System, University of Toronto, Toronto, ON.

Michael B. Goldberg, M.Sc., DDS, Dip. Perio.Associate Professor, Faculty of Dentistry Head, Division of Periodontology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

 

Timo Sorsa, DDS, PhD, Dipl Perio, Professor of Periodontology, Chief Physician, Department of Oral and Maxillofacial Diseases, Biomedicum 1, FIN-00014 University of Helsinki, Helsinki, Finland and Karolinska Institutet, Stockholm, Sweden.