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The current model of disease patho-

genesis indicates that bacterial anti-

gens induce a host response associ-ated with deterioration of the

periodontal attachment appara-

tus.1,2 It is believed that components

of cell walls from gram-negative bac-

teria (eg, lipopolysaccharides)

induce cells such as monocytes and

macrophages to release cytokines.2

Cytokines are inflammatory media-

tors that can recruit other cells (eg,

fibroblasts) to produce inflammatory

agents such as prostaglandins andmatrix metalloproteinases (MMP).

Some prostaglandins (eg, PGE2) are

associated with alveolar bone

destruction, and a few MMPs (eg,

MMP-8 and MMP-9) are involved

with disease-induced collagen dis-

solution.2 Thus, it is recognized that

the host response can be both pro-

tective and destructive.3

During the 1980s, in vitro eval-

uations indicated that tetracyclinescould inhibit MMPs.4 Other in vivo

studies demonstrated that adminis-

tration of systemic doxycycline

results in decreased collagenase lev-

els in the gingival crevicular fluid

(GCF).5 In 1996, Crout et al6

Efficacy of Subantimicrobial-DoseDoxycycline in the Treatmentof Periodontal Diseases:A Critical Evaluation

Gary Greenstein, DDS, MS*

Controlled clinical trials that evaluate the benefits of adjunctive subantimicrobial-

dose doxycycline (SDD) with conventional therapy were selected for review. It

was deemed important to distinguish between statistically significant and clinical-

ly relevant results related to SDD use to help guide clinicians in selecting appro-

priate therapies. Several investigations demonstrated that SDD prescribed as an

adjunct to conventional therapy provides a statistically significant improvement

with respect to probing depth reduction, gain of clinical attachment, decreased

bleeding on probing, and reduced incidence of disease progression in patients

with chronic periodontitis. However, conflicting data were also noted in some

studies. Furthermore, it is suggested that the clinical relevance of improvements

obtained with SDD beyond those obtained with conventional therapy is debat-

able. Therefore, clinicians should interpret the data cautiously and differentiatebetween statistically significant and clinically relevant findings before altering

treatment regimens. (Int J Periodontics Restorative Dent 2004;24:528543.)

*Clinical Professor, Department of Periodontology, University of Medicine

and Dentistry of New Jersey, Newark.

Correspondence to: Dr Gary Greenstein, 900 West Main Street,

Freehold, New Jersey 07728. Fax: + 732 780-7798. e-mail:

[email protected]

The International Journal of Periodontics & Restorative Dentistry

528

COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC.

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Volume 24, Number 6, 2004

reported that oral administration of

low-dose doxycycline enhances the

gain of clinical attachment in the

absence of an antimicrobial effect.

More recently, a phase III clinical trialassessed the clinical efficacy of low-

dose doxycycline7; the drug (20 mg,

2 times a day) was referred to as sub-

antimicrobial-dose doxycycline

(SDD).7 Subsequently, the Food

and Drug Administration (FDA)

approved SDD (Periostat, Colla-

Genex) as an adjunct to scaling and

root planing in the treatment of

chronic periodontitis. Consequently,

the concept of modulating the hostresponse became a therapeutic

modality that could be employed by

clinicians. Host modulation therapy

is in an early stage of development;

however, it was deemed important

to distinguish between statistically

significant and clinically relevant find-

ings before clinicians alter treatment

regimens based on available data.

This commentary critically assesses

the data regarding the efficacy ofSDD to clarify its clinical utility.

Clinical study considerations

Regulatory agencies such as the

FDA require statistical evaluations

based on means of test and control

groups with respect to selected

parameters. Data from these groups

are compared to determine if thereis a statistically significant difference

between them. The term statisti-

cally significant denotes that the

detected difference between the

test and control groups did not usu-

ally occur by chance. However, the

term statistical significance should

not be interpreted to indicate that

the magnitude of the difference

between groups is large or impor-

tant.8,9

Furthermore, the mean valueused to calculate statistical signifi-

cance cannot be used to accurately

characterize expected clinical re-

sponses at individual sites because

the clinical outcomes could be more

or less than the mean results.

Clinical trials addressing the effi-

cacy of adjunctive SDD differed with

respect to investigatory protocols:

study populations, degree of dis-

ease severity, clinical procedures,study length, and duration of adjunc-

tive SDD therapy.6,7,1020 Some

salient features of evaluated studies

are listed in Table 1.

Diverse study protocols make it

difficult to compare results from dif-

ferent investigations. However,

trends concerning therapeutic effec-

tiveness can be identified; small

proof-of-principle studies (pilot stud-

ies) do not provide proof of thera-peutic efficacy,21 but rather evaluate

premises that need to be validated

in large clinical trials. Accordingly,

large investigations should be given

more credence when extrapolating

data to clinical practice. Currently,

only one large study (phase III clini-

cal trial) has addressed the efficacy of

SDD as an adjunct to scaling and

root planing,7 and another was

reported in abstract form.14 Thus,the phase III clinical trial is the focal

point of the following discussion.7

An additional large clinical trial used

supragingival scaling without root

planing and thus did not represent

routine therapy administered for the

management of chronic periodonti-

tis.13 Nevertheless, information

ascertained during that study pro-

vides additional evidence to support

the concept that SDD has a benefi-cial effect on periodontal status.

Several other investigations that

address the clinical utility of adjunc-

tive SDD are included here; how-

ever, they should be considered

proof-of-principle studies because

they had small study popula-

tions.6,11,12,15,1720


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Response of clinical

parameters to SDD

The following discussion pertains to

patients with chronic periodontitis

without systemic modifying factors

(eg, diabetes, smoking) or groups

of individuals with other specific

identifying characteristics (eg, insti-

tutionalized elderly persons); these

subjects are addressed later.

Bleeding on probing

The phase III trial demonstrated that

after scaling and root planing with

and without adjunctive SDD (9-

month duration), the percentage of

sites initially 0 to 3 mm and 4 to 6

models when studying rheumatoid

arthritis. He found that doxycycline

is associated with less destruction ofcollagen and bone but does not

exhibit antiinflammatory proper-

ties.22 In contrast, two other studies

noted a statistically significant

decrease of bleeding on probing

after adjunctive use of SDD; how-

ever, the number of sites bleeding

on probing at the beginning or end

of these investigations was not pub-

lished.13,16

There are mixed results regard-ing the ability of adjunctive SDD to

enhance the effects of mechanical

instrumentation with respect to

reducing bleeding on probing. The

phase III clinical trial indicates that

when scaling and root planing with

mm that bled on probing was sta-

tistically significantly lower in the

groups administered SDD; however,no significant improvement was

reported at probing depths that

were initially 7 mm (Table 2).7 After

treatment with and without adjunc-

tive SDD, 64% of the initial 4- to

6-mm pockets and 75% of the

7-mm-deep sites still bled on prob-

ing.7 After therapy, the high preva-

lence of bleeding on provocation

may have been due to patients not

receiving maintenance during the 9-month monitoring period. Other

investigations report that SDD does

not significantly decrease bleeding

on probing.6,11,12 Greenwald22 also

noted a lack of an antiinflammatory

effect provided by SDD in animal

Table 1 Variations among studies addressing the efficacy of adjunctive subantimicrobial-dosedoxycycline (SDD)

Type of Duration

Study periodontitis Instrumentation of study (mo) Duration of SDD

Crout et al6 (n = 14) Chronic* None (at baseline) 6 2 mo on, 2 mo off, 2 mo on

Caton et al7 (n = 196) Chronic Root planing 9 9 mo

Novak et al11 (n = 20) Generalized severe Debridement! 8 6 mo

Golub et al12 (n = 66) Refractory* Scaling 9 36 wk (12 wk on,12 wk off,12 wk on)

Ciancio and Ashley13 (n = 437) Chronic Supragingival scaling 9 9 mo

Preshaw et al14# (n = 210) Chronic Root planing 9 9 mo

Gapski et al15 (n = 24) Chronic Access surgery 6 6 mo

Walker et al16 (n = 76) Chronic Root planing 9 9 mo

Pflug et al17# (n = 24) Chronic Root planing** 3 3 mo

Engebretson et al18# (n = 45) Chronic/diabetics Root planing 3 3 mo

Al-Ghazi et al19# (n = 20) Chronic/diabetics Root planing 3 3 mo

Mohammad et al20# (n = 24) Chronic/elderly Root planing 9 9 mo

*Elevated collagenase level used as selection criterion.30-min scaling and prophylaxis 4 wk prior to baseline recording.1 h per quadrant.Approximately half of the patients were smokers.!45 to 65 min of root debridement 7 times during study prior to final measurements.Supra- and subgingival scaling for 30 min.#Abstract.**Several systemic antibiotics used in conjunction with root planing.Data to date reported for 3 mo.





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and without adjunctive SDD are

compared, SDD results in a statisti-

cally significant decrease of bleeding

on probing at shallow and moder-

ately deep probing sites.7 However,

these improvements could be char-

acterized as defined but limited,

since they represented a small per-

centage of the total bleeding sites.

Furthermore, the inability of SDD toenhance the reduction of bleeding

on probing at deep sites beyond

that attained with scaling and root

planing,7,11 and its ineffectiveness to

decrease the overall prevalence of

bleeding on probing, casts doubt on

the clinical utility of employing SDD

to reduce gingival inflammation.7,11

Probing depth

Mean probing depth reductions

obtained with scaling and root plan-

ing and SDD (combined therapy)

versus root instrumentation alone

are presented in Table 3. There was

a statistically significantly better

result with combined therapy in the

phase III clinical trial at sites initially

0 to 3 mm, 4 to 6 mm, and 7 mm

deep.7 In all probing depth cate-

gories, the mean improvement with

combined therapy when compared

to scaling and root planing alone

was less than 0.5 mm.

The phase III clinical trial indi-cates that combined therapy re-

sults in more sites attaining a 2-

mm probing depth reduction than

with scaling and root planing alone

(29.9% vs 22.0%).7 However, these

data include all sites in the study

initially 4 mm deep and therefore

cannot be accurately extrapolated

to any one individual. On the other

hand, they do identify a trend for

improvement associated with SDDadministration. It should also be

noted that patients were not pro-

vided maintenance therapy.7 Thus,

differences reported between

treatment methods may not have

been detected if patients received

supportive therapy during the 9-

month evaluation period. Con-

versely, it is possible that if main-

tenance was performed, the results

could have been even better in the

group administered SDD.

Data from a study by Preshaw et

al14 support the findings of Caton

et al.7 Preshaw et al14 report that

combined therapy results in a statis-tically significantly greater reduction

of probing depth than scaling and

root planing alone at sites initially 4

to 6 mm and 7 mm deep. The

mean probing depth reductions

beyond scaling and root planing

were 0.33 mm and 0.54 mm, respec-

tively, at sites initially 4 to 6 mm and

7 mm deep.

Novak et al11 compared the effi-

cacy of ultrasonic instrumentationwith and without SDD (prescribed

for 6 months) in a previously un-

treated population with generalized

chronic severe periodontitis. Patients

received root debridement sessions

4 weeks in a row (1 hour per session)

Table 2 Sites bleeding on probing (%) at completion of studies,grouped by initial probingdepth (mm)

Combined therapy* Scaling and root planing

Study 03 46 7 03 46 7 Statistical significance

Caton et al7 39 64 75 46 70 80

Novak et al11 41 53 60 37 44 50 Not reduced

Golub et al12 Numeric data not reported Not reduced

Ciancio and Ashley13 Numeric data not reported Reduced with SDD

Walker et al16 Numeric data not reported Reduced with SDD

Crout et al6 Numeric data not reported No reduction of GI!

*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant.Not statistically significant.Ultrasonic debridement used with combined therapy.!Gingival Index (GI) of 2 = bleeding on probing.





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and then at each recall visit after ini-

tial therapy at 1, 3, and 5.2 months,

for a total of seven sessions beforefinal measurements and mainte-

nance 8 months after study initia-

tion.11 Adjunctive SDD obtained a

statistically significantly greater prob-

ing depth reduction than root de-

bridement alone at sites initially 7

mm deep (3.02 mm vs 1.42 mm) but

did not provide any benefit beyond

root debridement alone at locations

with original probing depths of 0 to

3 mm or 4 to 6 mm.11An initial probing depth cate-

gory of 7 mm was used to delin-

eate data in these studies.7,11

Furthermore, only the amount of

improvement was reported, and the

initial or final mean probing depths

periodontitis. However, the limited

magnitude of change induced by

SDD may not provide a clinically rel-

evant benefit at any particular site.

This statement is made in light ofthe fact that individual therapists can

interpret clinical significance differ-

ently. Thus, it is important to con-

sider the severity of defects that

need to be treated and forecast

whether the benefits provided by

SDD will help achieve desired clini-

cal outcomes.

Clinical attachment level

The phase III clinical trial compares

the efficacy of root planing with and

without SDD and reports that com-

bined therapy results in a statistically

significantly greater gain of clinical

attachment than scaling and root

planing alone at sites initially 4 to 6

mm and 7 mm deep (Table 4).7

With regard to all levels of initial

probing depths, the mean differ-ences between test and control

groups were 0.4 mm. After com-

bined therapy, the number of sites

that attained 2-mm gain of clinical

attachment was greater than that

achieved with scaling and root plan-

ing alone (34.3% vs 30.7%; Table 5).7

The mean gain of clinical attach-

ment with respect to probing depth

reduction was larger than usually

reported in the literature in the testand control groups. The amount of

clinical attachment gain varies, but it

is often around half of the probing

depth reduction.23,24 In the phase III

trial, with and without SDD, the

amount of clinical attachment gain

in these categories in the test and

control groups were not included.

Therefore, it is unknown if a satis-factory endpoint was achieved.

There are additional conflicting data

within the literature concerning

probing depth reduction associated

with SDD administration. For in-

stance, other studies that address

the development of bacterial resis-

tance to antibiotics16 or disease pro-

gression12 do not report a statisti-

cally significantly greater probing

depth reduction when adjunctiveSDD is administered in conjunction

with root instrumentation.

Scaling and root planing plus

SDD may statistically significantly

enhance mean probing depth

reduction in patients with chronic

Table 3 Probing depth reduction (mm), grouped by initialprobing depth (mm)


Study 46 7 46 7

Caton et al7 0.95 1.68 0.69 1.20

Novak et al11 1.20 3.02 0.97 1.42

Preshaw et al14 1.29 2.31 0.96 1.77

Ciancio and Ashley13 0.71 1.39 0.46 0.96

Walker et al16 No significant differences (numeric data not reported)

Golub et al12 No significant differences (numeric data not reported)

Crout et al6 ! 1.80 ! 0.40

Specific patient populations

Gapski et al15# Access surgery + SDD = 3.3 vs access surgery 2.1 mm

Engebretson et al18** No significant differences (numeric data not reported)

Al-Ghazi et al19** 1.7-mm greater reduction with SDD

Mohammad et al20 1.64 4.34 0.69 0.70

*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant difference between test and control groups.Ultrasonic debridement used for combined therapy.Abstract.!Data not reported.Estimated from bar graph.#Data reported for sites initially 6 mm deep.**Diabetic patients.Institutionalized elderly patients.





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was similar to the probing depth

reduction.7 This could be due to

measurement error. Furthermore, it

is difficult to explain the finding that

the percentage of sites gaining

2or 3 mm of clinical attachment

was greater than the percentage of

sites manifesting 2- or 3-mm

probing depth reductions. It is not

possible to have more sites gaining

2 or 3 mm of clinical attachment

than sites demonstrating 2- or

3-mm probing depth reduction, un-

less the gingiva coronally migrated

and pocketing remained the same or

increased. These results may reflecta substantial amount of measure-

ment error and would affect other

calculations regarding the efficacy

of SDD (eg, gain of clinical attach-

ment, incidence of disease activity).

Preshaw et al14 support the find-

ings of Caton et al,7 indicating that

combined therapy results in a statis-

tically significant gain of clinical

attachment at sites initially 4 to 6

mm and 7 mm deep. The gain ofclinical attachment and probing

depth reduction were virtually the

same for patients with initial probing

depths of 4 to 6 mm. With respect to

7-mm pockets, patients treated

with and without SDD demonstrated

a gain of clinical attachment that

accounted for approximately 90%

of the probing depth reduction.

Novak et al11 found no statisti-

cally significant gain of clinicalattachment when combined therapy

was compared to root debridement

alone at sites initially 0 to 3 mm, 4 to

6 mm, and 7 mm deep. If a larger

number of patients were enrolled,

the clinical attachment gain after

Table 4 Gain of clinical attachment (mm),grouped by initialprobing depth (mm)


Study 46 7 46 7

Caton et al7 1.03 1.55 0.86 1.17

Novak et al11 0.56 1.78 1.00 1.24

Preshaw et al14 1.27 2.09 0.94 1.59

Ciancio and Ashley13 0.67 1.27 0.44 0.95

Walker et al16 No significant differences (numeric data not reported)

Golub et al12 No significant differences (numeric data not reported)

Crout et al6! 0.5-mm gain with SDD vs 0.2-mm loss with placeboSpecific patient populations

Gapski et al15 Access surgery + SDD = 1.8 vs access surgery 1.1 mm

Engebretson et al18# No significant differences (numeric data not reported)

Al-Ghazi et al19# 1.6-mm greater gain with SDD

Mohammad et al20** Data not reported

*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant difference between test and control groups.Ultrasonic debridement used for combined therapy.Abstract.!Data reported for all sites (5 selected sites per patient).Data reported for sites initially 6 mm deep.#Diabetic patients.**Institutionalized elderly patients.

Table 5 % of sites with increased clinical attachment related to% of sites with reduced probing depth*7

Procedure Probing depth reduction Clinical attachment gain

Combined 2 mm 29.9 (1,040/3,477) 34.3 (1,193/3,477)

3 mm 7.9 (275/3,477) 12.5 (435/3,477)

Scaling and root planing 2 mm 22.0 (755/3,435) 30.7 (1,054/3,435)

3 mm 4.7 (162/3,435) 10.0 (343/3,435)

*At sites initially 4 mm deep.Subantimicrobial-dose doxycycline (SDD) + root planing.





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adjunctive SDD might have been

statistically significant. At sites 7

mm deep in the test and control

groups, the amount of clinical attach-

ment gain was similar to the im-provement reported by Caton et al.7

However, in Novak et als study, this

represented around half the probing

depth reduction.

Several other studies report con-

flicting results. For example, when

Walker et al16 assessed the effect of

combined therapy on the microflora,

they also evaluated clinical alter-

ations at microbiologically moni-

tored sites. They found no statisti-cally significant gains of clinical

attachment at sites treated with or

without SDD. Similarly, a small study

that employed supra- and subgingi-

val scaling for 30 minutes per patient

reports that SDD does not result in a

statistically significant gain of clinical

attachment among patients with

sites demonstrating high collage-

nase levels.12 On the other hand,

Ciancio and Ashley13 demonstratedthat SDD used in conjunction with

supragingival scaling results in a sta-

tistically significantly greater gain of

clinical attachment than supragingi-

val scaling alone. There was a large

gain of clinical attachment related to

the size of the probing depth reduc-

tion in the test and control groups.13

Several clinical trials indicate that

when mechanical instrumentation

with and without SDD are compared,there is a statistically significantly

greater gain of clinical attachment

with SDD use.7,13,14 These mean

improvements are defined but lim-

ited in size ( 0.4 mm). Furthermore,

several investigations did not find

instrumentation without adjunctive

SDD.

From another perspective, the

number of 7-mm-deep sites that

need to be treated with adjunctiveSDD to avoid disease progression (

2-mm loss of clinical attachment) at

one additional 7-mm-deep site

can be calculated. This calculation is

referred to as the number needed to

treat (NNT) and is the inverse of the

difference between the proportion

of events in the test and control

groups (NNT = 1/Pc Pt).25 NNT

would be calculated as follows:

1/0.036 0.003 = 30 (95% confi-dence interval 21 to 58). Therefore,

on average, compared to scaling

and root planing alone, 30 7-mm

sites need to be treated with adjunc-

tive SDD to avoid disease progres-

sion at one additional 7-mm

pocket. Furthermore, clinicians are

faced with the dilemma of selecting

patients who would most likely ben-

efit from SDD use, as the difference

in disease progression between thetwo groups is small. On the other

hand, the number of deteriorating

sites is usually small during a study;

therefore, the difference in disease

activity recorded in the phase III trial

is proportionately large and clinically

relevant.7

Novak et al11 also report statis-

tically significantly less disease pro-

gression in patients administered

SDD. The proportion of sites ini-tially 7 mm deep manifesting dis-

ease progression (threshold = 4-

mm increase in probing depth)

among individuals administered

ultrasonic debridement and SDD

was 0.12%, versus 0.68% in patients

statistically significant gains of clini-

cal attachment after employing

SDD11,12,15,16; therefore, these data

need to be interpreted cautiously.

Incidence of diseaseprogression

Several investigations indicate that

SDD in conjunction with conven-

tional therapy decreases the number

of sites experiencing disease pro-

gression.7,11,12 When Caton et al7

compared the incidence of clinical

attachment loss ( 2 mm) in groupsthat underwent scaling and root

planing with and without SDD, they

noted that at pockets initially 7

mm deep, the number of sites man-

ifesting loss of clinical attachment

was statistically significantly lower in

individuals who received combined

therapy (0.3% vs 3.6% of the treated

sites). However, at initial probing

depths of 0 to 3 mm or 4 to 6 mm,

the incidence of disease progres-sion was not significantly lower after

combined therapy. At sites 7 mm

deep, the relative percentage of

benefit with regard to inhibiting

more deterioration after using SDD

can be calculated: 3.6% 0.3%/3.6%

= 92% less disease progression with

combined therapy. However, the rel-

ative importance of this calculation

can be misleading: After scaling and

root planing, at locations initially 7 mm deep, 96.4% of the sites did

not experience 2-mm loss of clin-

ical attachment. Thus, the issue of

the value of treating all patients with

SDD arises, as most deep pockets

responded favorably to mechanical





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who underwent only root debride-

ment. Clinicians need to interpret a

difference of 0.56% less disease

progression with respect to its clin-

ical relevance.Golub et al12 evaluated the effi-

cacy of SDD to inhibit disease pro-

gression at sites in patients with ele-

vated collagenase levels. All

individuals underwent 30 minutes of

supra- and subgingival instrumenta-

tion. Then, half of the patients were

administered a variety of SDD regi-

mens for different periods. Patients

treated with SDD (20 mg, 2 times a

day for 12 weeks on, 12 weeks off,and 12 weeks on) experienced less

disease progression than individu-

als who were only mechanically

instrumented. The loss of clinical

attachment with regard to this spe-

cific therapeutic regimen in the test

and control groups was, respectively,

0.3 mm and 0.8 mm. The finding of

clinical attachment loss in both

groups after subgingival instrumen-

tation differs from that usually foundin the literature. Most studies that

employ root planing report a gain

of clinical attachment.7,11,14,15,24

Patients with elevated collagenase

levels may represent a group of indi-

viduals who are refractory to con-

ventional therapy, or the 30 minutes

allocated for supra- and subgingival

instrumentation may have been in-

sufficient.

Clinicians need to decide if thereported improvements in inhibiting

disease progression warrant SDD

administration. This decision is com-

plicated by the fact that on a yearly

basis, disease progression only

occurs in a small percentage of

patients with periodontitis.2628

Furthermore, calculation of the

mean number of sites experiencing

disease activity in a group of patients

is misleading because a large per-centage of the sites experiencing

loss of clinical attachment are usually

found in a small percentage of the

patients. Thus, using mean data from

study populations to help decide

which patients to treat can result in

an erroneous basis for therapy.

Accordingly, clinicians need to try to

determine who will most benefit

from adjunctive therapy based on

history of disease occurrence, sever-ity of the periodontal problem, med-

ical history, and a variety of other

factors that can be used conceptu-

ally to construct a patient risk profile.

Utility of SDD as an adjunct

to periodontal surgery

Gapski et al15 address the efficacy of

access flap surgery with and with-out supplemental SDD for 6 months

among individuals (n = 24) previ-

ously unresponsive to scaling and

root planing. They note that individ-

uals administered SDD demon-

strated a statistically significantly

greater probing depth reduction at

sites initially 6 mm deep (3.3 mm

vs 2.1 mm); however, there was no

statistically significantly greater gain

of clinical attachment (1.8 mm vs 1.1mm). The latter result may be due to

the small study population. SDD

administration also resulted in a

greater reduction of levels of ICTP (a

carboxyterminal fragment of type 1

collagen, which is a marker for bone

resorption).

With respect to these data, sev-

eral issues need to be discussed.

This was a proof-of-principle study

with a small study population. Theterm access surgery was used

instead of pocket elimination or

regenerative surgeries; thus, the

results are specific for a particular

surgical technique. Larger study

populations and additional investi-

gations are needed to assess the

adjunctive use of SDD before any

judgment can be rendered with

regard to its ability to improve sur-

gical results.





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levels (7.6% to 6.3%). There was no

change in HbA1c levels in the

groups administered antimicrobial-

dose doxycycline (7.6% to 7.8%) or

the placebo (8.2% to 8.3%).Another study compared the

efficacy of scaling and root planing

with and without SDD (n = 20)

among individuals with generalized

periodontitis who were either type 1

or 2 diabetics.19 In the group admin-

istered SDD for 3 months, there was

a statistically significant benefit in

diabetics with regard to reduction

of probing depth (2.21 mm vs 0.43

mm) and gain of clinical attachment(2.21 mm vs 0.48 mm). Furthermore,

there was a decrease in HbA1c asso-

ciated with use of SDD. This proof-

of-principle study demonstrated the

potential benefit of using SDD in a

diabetic population; however, addi-

tional studies in larger diabetic pop-

ulations are needed to verify these

results.

Elderly people

Mohammad et al20 address the util-

ity of SDD in a geriatric institutional-

ized population (n = 24) in a 9-month

study. A standardized episode of

root planing was administered. The

authors report a significant improve-

ment in individuals administered

SDD in conjunction with scaling and

root planing with respect to probingdepth reduction in the test and con-

trol groups: 4.34 mm versus 0.7 mm

at sites initially 7 mm and 1.64

mm versus 0.69 mm at sites initially

4 to 6 mm. The benefit obtained at

the deep sites is unusually large, and

Use of SDD in specific

study populations

Smokers

Preshaw et al29 recently reanalyzed

their data on the effect of scaling

and root planing with and without

SDD in smokers and nonsmokers (n

= 210; 67 smokers). Adjunctive SDD

provided a statistically significant

benefit in both smokers and non-

smokers. Among smokers, when

adjunctive therapy with SDD was

compared to a placebo, the in-

creased probing depth reduction atsites initially 4 to 6 mm and 7 mm

deep were as follows: 1.19 mm ver-

sus 0.93 mm and 2.25 mm versus

1.89 mm. The increased gains of

clinical attachment at sites initially 4

to 6 mm and 7 mm deep were

1.19 mm versus 0.85 mm and 2.02

mm versus 1.88 mm. There was no

statistically significant difference

between results in smokers and non-

smokers administered SDD.

Diabetics

Engebretson et al18 compare the


with and without SDD or antimicro-

bial-dose doxycycline in 45 individ-

uals who had untreated periodonti-

tis and type 2 diabetes. After 3

months of SDD administration, therewas no statistically significant

improvement in monitored clinical

parameters. However, individuals

administered SDD did demonstrate

a statistically significant reduction of

glycosylated hemoglobin (HbA1c)





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537


additional investigations are needed

to verify the benefit of SDD admin-

istration in elderly people.

Other SDD considerations

Comparison to other treatmentmethods

Ideally, the efficacy of therapeutic

methods should only be compared

if they were assessed in a controlled

clinical trial. However, it is reason-

able to evaluate results from other

studies and judge whether treat-ment methods routinely provided

desired clinical outcomes. This is

rational, as it is not possible to con-

duct clinical trials to compare the

efficacy of procedures (eg, scaling

and root planing plus SDD) to all

other types of therapies. For exam-

ple, Table 6 lists the results of several

treatments. It appears that at prob-

ing depths 7 mm, scaling and root

planing plus adjunctive SDD,7 scal-ing and root planing alone,24 tetra-

cycline fibers and scaling and root

planing,30 minocycline polymer plus

scaling and root planing,31 metron-

idazole plus scaling and root plan-

ing,32,33 and irrigation with povidone

iodine via an ultrasonic device34 all

produce probing depth reductions

1.6 mm. Similarly, amoxicillin used

in conjunction with scaling and root

planing35 and repeated scaling androot planing produce mean probing

depth reductions 1.6 mm when all

probing sites are pooled.3638

A recent clinical trial compared

the utility of scaling and root planing

alone, and scaling and root planing

Table 6 Representative results of different therapies (mm)

Probing depth Clinical

Procedure reduction attachment gain

SDD + SC/RP7

*Pockets 46 mm 1.03 0.95

Pockets 7 mm 1.68 1.55

SC/RP24

Pockets 46 mm 1.29 0.55


Repeated SC/RP36 3.2

Repeated SC/RP37 2.2

Local drug delivery

Tetracycline fibers + SC/RP30



Minocycline microspheres + SC/RP31

Pockets 5 mm 1.32

Pockets 6 mm 1.46 Pockets 7 mm 1.99

Povidone iodine + ultrasonic debridement34

Pockets 7 mm 3.0

Systemic antibiotics

Metronidazole + SC/RP32

Pockets 46 mm 1.22 0.79


Metronidazole + SC/RP33

Pockets 46 mm 0.75 0.40


Amoxicillin + SC/RP35 2.5 2.0

*Periostat.

Actisite, Alza.Arestin, Orapharma.All probing sites.SDD = subantimicrobial-dose doxycycline; SC/RP = scaling and root planing.





11/16

538


plus azithromycin (500 mg for 3

days), metronidazole (250 mg, 3

times a day for 14 days), or SDD (20

mg, 2 times a day for 3 months).17

There were no significant differencesbetween treated groups with respect

to complete-mouth mean probing

depth reduction or gain of clinical

attachment (Table 7). At pockets ini-

tially 6 mm, the best results were

obtained with metronidazole.17

Thus, prior to selecting a treat-

ment method, clinicians should con-

sider a variety of treatment modali-

ties, taking into consideration a

patients past medical and dentalhistories. For patients who do not

respond to conventional treatment,

it may be more expedient and less

costly to prescribe an adjunctive sys-

temic or locally delivered antibiotic

to determine if a desired outcome

could be achieved prior to adminis-

tering SDD for several months.

Conceptually, if the bacterial chal-

lenge can be diminished, it may be

possible to avoid the need to pre-scribe a drug to alter the host re-

sponse.

Development of resistantstrains of bacteria

Several investigations that assessed

the effect of SDD on the microflora

demonstrate that the drug did not

alter the proportions of bacteria orinduce drug resistance among

patients who used it for 9 consecu-

tive months.7,16,39 However, no data

are available to determine if multi-

ple applications of SDD or pro-

longed use past 9 months result in

Table 8 % of strains susceptible to various concentrations ofdoxycycline:Common anaerobic bacteria44

No. of 0.5 g/mL 1.0 g/mLOrganism strains concentration* concentration*

Gram positive

Peptostreptococcus 59 45 45

Streptococcus 10 70 90

Clostridium perfringens 8 67 67

Actinomyces 16 63 69

Gram negative

Cocci 26 58 69

Fusobacterium 34 94 94

Prevotella melaninogenica 67 75 78

Other Bacteriodes 72 33 35

*Inhibitory concentration of doxycycline.

Table 7 Results of four periodontal therapies after 3 months17

Duration Mean probing depth

of reduction (clinical attachment

Procedure n administration level gain), in mm

SC/RP 6 Initial 0.42 (0.22)

SC/RP + azithromycin 6 3 d 0.32 (0.06)

SC/RP + metronidazole 5 14 d 0.42 (0.36)

SC/RP + SDD 8 3 mo 0.34 (0.23)

SC/RP = scaling and root planing;SDD = subantimicrobial-dose doxycycline.





12/16

development of antibiotic-resistant

bacterial strains. Administration of

20 mg of SDD (2 times a day) pro-

vides a serum level of doxycycline of

around 0.6 to 0.8 g/mL.16

How-ever, the exact concentration of

doxycycline in the GCF is unclear.

Sakellari et al40 suggest that it would

be around 70% of the serum level.

However, others report that the level

of tetracyclines in GCF is higher than

the serum level.4143 At present, the

amount of doxycycline in the GCF

after ingestion of 20-mg SDD (2

times a day) is unresolved. A con-

centration of 1 g/mL of doxycy-cline is considered a therapeutic

dose to kill bacteria.16 Thus, SDD

provides a subantimicrobial dose

and obtains an improved clinical

result by inhibiting certain MMPs. It

should be noted that the expected

serum level of doxycycline (0.6 to

0.8 g/mL) is greater than the con-

centration needed to kill many

microorganisms in vitro (Table 8)44;

it cannot be assumed that the levelof doxycycline delivered with SDD

did not destroy any bacteria.

Duration of therapy

Several clinical trials administered

SDD for 9 months.7,13,14,16 In the

phase III clinical trial, which lasted 9

months, Caton et al7 achieved

around 90% of the final clinical resultswithin 3 months. This seems reason-

able, as others indicate that SDD (2

times a day) needs to be adminis-

tered for 12 consecutive weeks to

maximally lower collagenase levels

(47% reduction).12 The duration for

which adjunctive SDD needs to be

administered to obtain optimal

results is unknown. It appears that 3

months of adjunctive SDD achieves

most of the therapys potential ben-efits in patients with chronic peri-

odontitis. However, prolonged drug

use (eg, 9 months) may improve the

results.

Areas for further research

Studies are underway to explore the

potential benefits of host modula-

tion among several patient popula-tions (eg, immunocompromised

people, smokers, individuals under-

going orthodontic movement). Host

modulation with SDD also is being

tested as an adjunct to surgical and

nonsurgical therapy. It would also

be enlightening if additional com-

parative studies were conducted to

determine if conventional therapy

plus systemic antibiotics delivered

for 1 week provides a result similar to6 to 9 months of adjunctive SDD.

Numerous other issues need eluci-

dation (eg, effect of SDD on all the

MMPs, precise relationship between

select MMPs and clinical periodon-

tal status, effect of SDD applications

on the microflora when it is admin-

istered several times for a few

months each time, long-term bene-

fits of using SDD).

539

Volume 24, Number 6, 2004COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC.




13/16

Conclusion

Modulation of the host response

with SDD as an adjunct to mechani-

cal instrumentation has scientificmerit, and there appear to be no

adverse side-effects. This concept is

supported by the finding that SDD

provides statistically significant

improvements beyond scaling and

root planing among patients with

chronic periodontitis.7,14 However,

clinicians need to cautiously inter-

pret the clinical relevance of statisti-

cally significant findings, as it is

debatable whether the magnitudeof SDDs improvements beyond scal-

ing and root planing is clinically rel-

evant in all patients. With respect to

its use as an adjunct to ultrasonic

debridement11 or surgical therapy,15

or in particular treatment popula-

tions (eg, diabetics, institutionalized

elderly persons),1820 there is too lit-

tle information to render judgment.

At present, therapists must decide

on an individual basis if they think apatient will benefit from SDD admin-

istration based on medical and den-

tal histories.

Consideration should also be

given to other treatment modalities

that may produce similar therapeu-

tic outcomes more quickly and less

expensively than host modulation

with SDD for several months. Ulti-

mately, clinicians need to employ

treatments that provide desired clin-ical outcomes. In this respect, it is

important to focus on the fact that

periodontitis is an infectious disease;

therefore, reduction of the bacterial

challenge may preclude the need to

modify the host response. Eventually,

it may be determined that patients

who develop recurrent or refractory

chronic or aggressive periodontitis,

smokers, and systemically compro-

mised individuals may benefit fromadjunctive SDD therapy. However,

these scenarios need to be validated

in controlled clinical trials.

Addendum

Since the acceptance of this manu-

script, a systematic review and sev-

eral studies regarding the ability of

SDD to enhance periodontal therapywere published.

A systematic review discusses

host modulation using adjunctive

SDD in the treatment of chronic peri-

odontitis.45 A meta-analysis indicated

that when mechanical instrumenta-

tion with and without adjunctive SDD

are compared, patients administered

SDD experience a statistically signif-

icantly greater probing depth reduc-

tion and gain of clinical attachment.Increased probing depth reductions

associated with SDD use at sites ini-

tially 4 to 6 mm and 7 mm deep

were, respectively, 0.448 mm and

0.481 mm. Increased gains of clinical

attachment with SDD at pockets ini-

tially 4 to 6 mm and 7 mm deep

were, respectively, 0.442 mm and

0.452 mm. The meta-analysis pro-

vides a relative measure of improve-

ment, as the normalized effect is themean difference between monitored

groups divided by the standard devi-

ation of the difference; thus, the real

mean is adjusted by the variability of

the studies. A consensus report

attached to that article concludes

that there is evidence to support

the use of SDD as an adjunct to

mechanical instrumentation in the

treatment of chronic periodontitis,

and the clinicians decision to useSDD therapy remains a matter of

individual clinical judgment, based

on the phase of treatment and the

patients status and preferences.45

Emingil et al46 compared the


with and without adjunctive SDD (3-

month drug regimen). The study

lasted 12 months and included 30

patients with chronic periodontitis. It

assessed both clinical parametersand the GCF level of MMP-8. In the

group administered SDD, the final

complete-mouth mean probing

depth was statistically significantly

lower than in the group not admin-

istered SDD (reduced from 3.62 to

2.03 mm vs 3.97 to 2.65 mm).

Similarly, the final Gingival Index was

lower among patients provided SDD

(1.74 to 0.46 vs 1.91 to 0.86). The

gain of clinical attachment was notstatistically significantly different

between treatment groups. The

GCF level of MMP-8 among patients

given SDD was lower at 3 months

(50% less) and 6 months (70% less);

however, at 12 months, there was

no difference between treatment

groups. The authors conclude that

their data provide additional infor-

mation about the usefulness of SDD

therapy and that the greatest bene-fits occur at about 9 months.

Choi et al47 also compared the


with and without adjunctive SDD

(the drug was administered for 120

days). Clinical parameters (probing

540

The International Journal of Periodontics & Restorative DentistryCOPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC.




14/16

depth, clinical attachment level, and

bleeding on probing) and the effect

of SDD on GCF levels of MMP-8,

MMP-9, tissue inhibitor of MMPs

(TIMP)-1, and interleukin (IL)-6 wereevaluated every 30 days. Thirty-two

patients with incipient to moderate

periodontitis were included in the

study. Patients administered SDD

demonstrated a statistically signifi-

cantly smaller final probing depth

than individuals who underwent scal-

ing and root planing alone (5.4 to 3.8

mm vs 5.5 to 4.4 mm). Associated

with SDD use was also less clinical

attachment loss (6.4 to 4.2 mm vs 6.1to 5.5 mm) and a reduced bleeding

index (1.0 to 0.3 vs 1.2 to 0.5).

Patients receiving SDD demon-

strated statistically significantly

decreased levels of MMP-8 (407.1 to

63.8 ng/mL vs 378.7 to 168.1

ng/mL). However, for TIMP-1, MMP-

9, and IL-6, there were no differences

between treatment groups. The

investigators conclude that im-

proved clinical parameters reflectbetter control of MMP-8 levels.

Lee et al48 compared the effi-

cacy of low-dose flurbiprofen (LDF),

SDD, and a combination of the two

drugs to determine their effect on

MMPs and endogenous protease

inhibitors among patients under-

going mucoperiosteal flap surgery.

Nineteen patients with chronic peri-

odontitis were divided into three

groups, and the drugs were admin-istered for 3 weeks. Gingival tissues

were biopsied before and after

drug therapy. Gingival Index and

probing depth were not affected

by a 3-week drug regimen. Longer-

term drug regimens may induce

azithromycin, metronidazole, SDD,

and scaling and root planing groups

were 5.9%, 3.8%, 2.1%, and 1.7%,

respectively (statistically signifi-

cantly different). The proportions ofsites that lost 2 mm of attach-

ment for the same therapies were

0.6%, 0.4%, 0.9%, and 0.9%,

respectively. Those authors con-

clude that patients receiving azith-

romycin or metronidazole showed

the greatest proportion of sites

gaining 2 mm of clinical attach-

ment and the smallest number of

sites losing 2 mm of clinical

attachment.

improved clinical parameters. With

regard to inhibition of MMPs and

neutral proteases, LDF had no

effect on collagenase, gelatinase, or

elastase activities in the GCF. SDDcaused a 23% to 30% reduction in

neutral proteases, whereas a com-

bination of SDD and LDF produced

the greatest reduction (43% to

75%). This is the first study to de-

monstrate that a combination of

drugs may have a synergistic effect.

The mechanism for this synergistic

activity and its long-term effects are

unknown.

Periodontal diseases may addto the inflammatory burden of an

individual, which may have systemic

consequences. A 6-month study that

included 50 patients indicated that

SDD administration results in a sta-

tistically significant decrease in lev-

els of C-reactive protein, MMP-9,

and IL-6 among patients with acute

coronary syndromes (eg, myocardial

infarction, unstable angina).49 These

results suggest that SDD may reducesystemic markers of inflammation

and possibly the risk of myocardial

infarction. Additional studies are

needed to corroborate these pre-

liminary findings.

Pflug et al50 recently compared

the efficacy of scaling and root plan-

ing alone (n = 17) with scaling and

root planing plus systemically deliv-

ered azithromycin (500 mg a day

for 3 days; n = 15), metronidazole(250 mg, 3 times a day for 14 days;

n = 16), or SDD (20 mg, 2 times a

day for 3 months; n = 9) among

patients with chronic periodontitis.

The proportions of sites gaining

2 mm of clinical attachment in the

541

Volume 24, Number 6, 2004COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC.




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