Local Drug Delivery of AlendronateGel for the Treatment of Patients WithChronic Periodontitis With DiabetesMellitus: A Double-Masked ControlledClinical TrialA. R. Pradeep,* Anuj Sharma,* Nishanth S. Rao,* Pavan Bajaj,* Savitha B. Naik,†

and Minal Kumari*

Background: Alendronate (ALN) increases alveolar bonedensity with systemic use and, has been found to increasebone formation on local delivery into the periodontal pocket.The purpose of the present study is to explore the efficacy of1% ALN gel as a local drug delivery system in adjunct to scalingand root planing (SRP) for the treatment of intrabony defectsin patients with chronic periodontitis (CP) with type 2 diabetes(DM) compared to a placebo gel.

Methods: Seventy intrabony defects were treated with either1% ALN or placebo gel. Clinical parameters were recorded atbaseline, 2 months, and 6 months. Radiographic parameterswere recorded at baseline and 6 months. Defect fill at baselineand 6 months was calculated on standardized radiographsusing image analysis software.

Results: Mean probing depth (PD) reduction and mean clin-ical attachment level (CAL) gain was greater in the ALN groupthan the placebo group at both 2 and 6 months. Furthermore,significantly greater mean percentage of bone fill was foundin the ALN group (44.2% – 11.78%) compared to the placebogroup (2.8% – 1.61%).

Conclusions: In patients with type 2 DM and CP, local deliv-ery of 1% ALN into periodontal pockets resulted in a significantincrease in the PD reduction, CAL gain, and improved bone fillcompared to placebo gel as an adjunct to SRP. Thus, ALN canbe used as an adjunct to SRP to provide a new dimension inthe periodontal therapy in the near future. J Periodontol2012;83:1322-1328.

KEY WORDS

Alendronate; bone regeneration; chronic periodontitis;diabetes mellitus; regeneration.

Periodontitis is a polymicrobial dis-ease, in which a complex microbialecology that matures in biofilms in

the subgingival sulcus triggers a chronicimmunoinflammatory lesion that destroyssoft and hard tissues of the periodon-tium.1,2 Diabetes mellitus (DM) is a meta-bolic disease that leads to abnormal fat,sugar, and protein metabolism and re-sultant hyperglycemia that can ulti-mately induce diverse multiple systempathologies. The relationship betweenperiodontitis and DM is widely ac-cepted.3-5 Several epidemiologic stud-ies6-9 have identified a greater incidenceof periodontitis and an increase in itsseverity in patients with DM.

The regeneration of injured or excisedbone tissue comprises a complex se-quence of events that begins with the re-cruitment, attachment, and proliferationof progenitor cells, followed by cell differ-entiation into appropriate phenotypesthat are capable of restoring the dam-aged tissue.10 Techniques for improvingbone regeneration have included the useof biologic mediators to improve thequantity and quality of the bone beingregenerated.11,12 One group of bonemetabolism mediators is the bisphos-phonates (BP), the carbon-substitutedpyrophosphate analogs that are potent

* Department of Periodontics, Government Dental College and Research Institute, Bangalore,Karnataka, India.

† Department of Endodontics and Conservative Dentistry, Government Dental College andResearch Institute.

doi: 10.1902/jop.2012.110292

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inhibitors of bone resorption and have been effec-tively used to control osteolysis or reduce bone lossin Paget disease, metastatic bone disease, hypercal-cemia of malignancy,13 and osteoporosis.14

Alendronate (ALN), an aminobisphosphonate, actsas a potent inhibitor of bone resorption. Previous stud-ies have demonstrated the effects of systemic ALN inhuman15-17 and animal models18-20 in decreasing lossand increasing density of alveolar bone. Additionalstudies21-25 have demonstrated that either systemicor topical application of ALN was highly effective inreducing alveolar bone resorption after mucoperios-teal flap surgery. Some reports26,27 have suggesteda possible association between the systemic use ofALN and avascular osteonecrosis of the jaw; there-fore, limitations exist in the systemic use of ALNfor the treatment of periodontal disease. In addition,various studies28,29 have proposed that periodontalsurgical procedures stimulate osteoclast activity withdifferent degrees of alveolar crest loss. Recently, ourstudies30,31 have shown that local delivery of 1%ALN into periodontal pockets stimulates a significantincrease in the probing depth (PD) reduction, clinicalattachment level (CAL) gain, and improved bone fillcompared to placebo gel an adjunct to scaling androot planing (SRP) in the treatment of chronic peri-odontitis (CP)30 and aggressive periodontitis31(AgP).However, no study has demonstrated the effect oflocally applied ALN in the treatment of patients withtype 2 DM with CP.

Considering the above facts, the current study isdesigned as a single-center, randomized, controlledclinical trial to evaluate the efficacy of 1% ALN gelas local drug delivery in adjunct to SRP for the treat-ment of patients with type 2 DM with CP comparedwith placebo gel.

MATERIALS AND METHODS

Study PopulationIn this 6-month follow-up, longitudinal interventionalstudy, a total of 43 individuals (23 males and 20 fe-males; age range 30 to 50 years) with type 2 DMand CP were selected from the outpatient section ofthe Department of Periodontics, Government DentalCollege and Research Institute, Bangalore, India. Theresearch protocol was initially submitted to the Insti-tutional Ethical Committee and Review Board of theGovernment Dental College and Research Institute,Bangalore, India. After ethical approval, all individualswere verbally informed, and written informed consentwas obtained for participation in the study. The studywas conducted from November 2010 to April 2011.

Selection CriteriaPatients with well-controlled type 2 DM were se-lected and classified based on criteria of the American

Diabetic Association in 2011 and glycated hemoglo-bin levels (HbA1C).32 Patients with type 2 DM with PD‡5 mm or CAL ‡4 mm and vertical bone loss ‡3 mmon intraoral periapical radiographs with no historyof periodontal therapy or use of antibiotics in thepreceding 6 months were included. Individuals withknown systemic disease, known or suspected allergyto the ALN/BP group, those on systemic ALN/BPtherapy, individuals with AgP, use of tobacco in anyform, alcoholics, immunocompromised individuals,and pregnant or lactating females were excluded.

After enrollment by an examiner (ARP), partici-pants were randomly (by a computer-generated sys-tem) assigned to either the ALN (n = 37 sites in 21patients; 11 males and 10 females, aged 20 to 50years) or placebo group (n = 41 sites in 22 patients;12 males and 10 females, aged 20 to 50 years). Inthe ALN group, sites received 1% ALN gel (10 mg/mL)local drug delivery, whereas in the placebo group, siteswere treated with the placebo gel. Multiple sites in theposterior mandible and maxilla were treated in eachpatient. Participants were masked for allocation intothe ALN or placebo group. SRP was performed atbaseline until the root surface was considered smoothand clean by the operator (AS). No antibiotics or anti-inflammatory agents were prescribed after treatment.Clinical parameters, including modified sulcus bleedingindex33 (mSBI), full-mouthand site-specific plaque in-dex (PI),34 PD, and CAL were recorded at baseline(before SRP) and at 2 and 6 months. A custom-madeacrylic stent and a color-coded periodontal probe‡

were used to standardize the measurement of clinicalparameters. All pre- and post-treatment clinical pa-rameters were recorded by an examiner (ARP) whowas masked to the treatment received, whereas an-other clinician (AS) provided treatment to both groups.

Intra-Examiner CalibrationIntra-examiner calibration was achieved by examina-tion of 20 sites twice, 24 hours apart before beginningthe study. Calibration was accepted if measurementsat baseline and 24 hours were similar to 1 mm at the95% level.

Formulation of 1% ALN GelALN gel was prepared as described previously.23,30,31

Briefly, ALN§ was dissolved in the required amountof distilled water to achieve 1% ALN concentration.Weighed quantity of carbopol 934P (2% w/w) wastaken and added to the distilled water. The mixturewas stirred gradually and carbopol was allowed tosoak for 2 hours. One percent triethanolamine wasadded to neutralize the carbopol solution and to formthegel.ThepHwasadjusted to 6.8.Finally, the required

‡ PCP-UNC 15 color-coded periodontal probe, Hu-Friedy, Chicago, IL.§ Apex Healthcare, Ankleshwar, Gujarat, India.

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amount of methyl paraben (0.1%) and propyl paraben(0.05%) were dissolved in ethanol and added to the gel.The placebo gel was prepared by the same procedurewithout adding active ingredient (ALN), maintainingsame physical properties such as color and taste.

Local Drug DeliveryFor standardization, 10-mL prepared ALN gel(10 mg/mL) was injected into the periodontalpockets with intrabony defects (IBDs) using a syringewith a blunt cannula. Patients were instructed to re-frain from chewing hard or sticky foods, forcefullybrushing the treated sites, or using any interdentalaids for 2 months. Adverse effects were recorded at re-call visits and supragingival deposits were removed.

Radiographic Assessment of IBDsThe depth of bone fill was evaluated at baseline and6 months using an image analyzer.i IBD was mea-sured on the radiograph by measuring the vertical dis-tance from the crest of the alveolar bone to the base ofthe defect. Individually customized bite blocks anda parallel-angle technique were used to obtain filmsas reproducible as possible. All radiographs werereviewed in a single reference center by a masked

evaluator (NR). For assessment,radiographs were scanned witha scanner¶ of 6400 dots per inchby an evaluator (PB) who wasmasked to surgical procedure per-formed in participants. The radio-graphic IBD depth was measuredby a computer-aided software pro-gram# as used previously.30,31,35

Primary and SecondaryOutcome MeasuresThe primary outcome of the studywas complete bone defect fill. Thesecondary outcomes were PD,CAL, mSBI, and PI.

Statistical AnalysesPower analysis calculations wereperformed before the study wasinitiated. To achieve 90% powerand detect mean differences ofthe clinical parameters betweengroups, 30 sites in each groupwere required. Categorical vari-able (site-specific PI) was expressedas percentage and continuous var-iable (full-mouth PI, mSBI, PD,CAL, and IBD depth) as mean –SD. Site-specific PI was comparedby using the x2 test or a Fisherexact test when the expected fre-quency was <5. Normality as-

sumption was tested using Shapiro-Wilk W test.Between-treatment group comparison was per-formed using Student t test, if continuous variable fol-lowing a normal distribution. Statistical significancewas defined as P <0.05. Statistical analysis was per-formed with statistical software.**

RESULTS

Forty-one participants (multiple sites per participant)of 43 completed the study (Fig. 1). Two participants,one in each of the ALN and placebo groups failed tofollow up. All participants tolerated the drug well with-out any complications or adverse reactions to thedrug. Soft tissues healed within normal limits, andno significant visual differences were noted.

Both groups showed improvement in site-specificPI score, but there was no statistically significant dif-ference between the groups at 6 months; however,

Figure 1.Study flowchart.

i Scion Corporation, Frederick, MD.¶ Perfection V700, Epson, Bangalore, India.# Scion Corporation.** SPSS v.15, IBM, Chicago, IL.

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at 2 months, there was significant difference betweenthe groups, with more improvement in the placebogroup (P <0.05) (Table 1). Improvement in full-mouthPI score was significantly greater in the ALN groupcompared to the placebo group at 6 months (Table 2).

mSBI in both groups showed no difference at base-line, but it was significantly decreased in the ALNgroup compared to the placebo group at 2 and 6months (P <0.05) (Table 2).

Mean baseline data in both groups are shown inTable 3. There were no differences between groupsin PD and CAL at baseline and significant PD reduc-tion and CAL gain at 2 and 6 months in ALN groupas compared to placebo group at P <0.05 (Tables 4and 5).

The radiographic parameter IBD showed statisti-cally significant mean reduction of 2.44 – 0.92 mmin the ALN group compared to the placebo group(0.14 – 0.07 mm) (Table 5). The ALN group sites pre-sented with a significantly greater vertical defect fill

(44.2% – 11.78%) than the placebo sites (2.8% –1.61%) at 6 months (Table 5).

DISCUSSION

The current study evaluates the clinical efficacy of1% ALN gel as an adjunct to SRP for the treatmentof IBD in patients with type 2 DM with CP and showedsignificant radiographic bone fill and improvement inclinical parameters compared to placebo gel.

To the best of our knowledge, there have been nostudies reporting the use of 1% ALN gel as local drug de-livery in the treatment of patients with type 2 DM withCP. Therefore, a direct comparison with other studiesis not possible. Rocha et al.36 used systemic ALN for6 months in the treatment of periodontitis patients withtype 2 DM and reported significant improvement inthe healing response compared to the placebo group.Comparing change in clinical and differences in radio-graphic parameters to the previous study,36 improve-ment in clinical parameters was greater in the current

Table 1.

Site-Specific PI in ALN and Placebo Groups at Baseline, 2 and 6 Months

Baseline 2 Months 6 Months

Plaque

Scores

ALN Group

n (%)

Placebo Group

n (%)

ALN Group

n (%)

Placebo Group

n (%)

ALN Group

n (%)

Placebo Group

n (%)

0 0 (0) 0 (0) 24 (70.6) 26 (72.2) 27 (79.4) 31 (86.1)

1 11 (32.4) 11 (30.6) 10 (29.4) 10 (27.8) 7 (20.6) 5 (13.9)

2 14 (41.2) 14 (38.9) 0 (0) 0 (0) 0 (0) 0 (0)

3 9 (26.5) 11 (30.6) 0 (0) 0 (0) 0 (0) 0 (0)

P value† 0.143 0.023* 0.553

* Statistically significant at P <0.05.† x2 test.

Table 2.

Full-Mouth PI and mSBI for ALN and Placebo Groups at Baseline, 2 and 6 Months

Baseline (mean – SD) 2 Months (mean – SD) 6 Months (mean – SD)

Parameter ALN Group Placebo Group ALN Group Placebo Group ALN Group Placebo Group

Full-mouth plaque score 1.70 – 0.36 1.63 – 0.39 0.96 – 0.42 1.03 – 0.52 0.48 – 0.29 0.48 – 0.24t value† 0.661 0.427 0.001P value 0.419 0.515 0.982

mSBI 2.77 – 0.59 2.71 – 0.62 0.99 – 0.37 1.34 – 0.91 0.89 – 0.94 1.57 – 0.80t value† 0.124 19.806 10.845P value 0.726 <0.001* 0.002*

* Statistically significant at P <0.05.† t test.

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study. The PD reduction was greater (4.56 – 1.73 mm)than that achieved by systemic ALN therapy (1.29 –0.69 mm)36 at 6 months, and CAL gain was greater(3.59 – 1.21 mm) than systemic ALN therapy (1.31 –0.64 mm) at 6 months.36

Comparing changes in clinical and radiographicparameters with our previous studies,30,31 improve-ment in clinical parameters in the current study wasgreater than in individuals with AgP31 but less thanin the individuals with CP,30 whereas greater radio-graphic bone fill in individuals with CP in our previousstudy,30 but less than in the individuals with AgP31

was found in the current study. The PD reduction wasgreater in individuals with CP (4.48 – 1.27 mm) 30

and individuals with AgP (3.88 – 1.39 mm) 31 at 6months. Similarly, CAL gain was less than individualswith CP (4.03 – 0.84 mm) 30 but greater compared toindividuals with AgP (3.27 – 1.11 mm) 31 at 6 months.Conversely, percentage change in bone fill in the cur-rent study was nearly equal (44.2% – 11.78%) to indi-viduals with AgP (46.1% – 9.48%)31 and greater thanindividuals with CP (40.4% – 11.7%).30

Previous studies21-25 have reported that ALN washighly effective in reducing alveolar bone resorptionafter mucoperiosteal flap surgery when given as asystemic or topical application. In this study, we finda significant decrease in clinical parameters mSBI,PI, and PD, with significant gain in CAL as reportedpreviously.21-25 In contrast, Brunsvold et al.37 didnot observe an effect on PD measurements of peri-odontitis in a monkey model treated with systemicALN. The lack of an effect was explained by shortduration (16 weeks) of treatment. In the current studypercentage of IBD fill in the ALN group was 44.2% –11.78% compared to 2.8% – 1.61% in the placebogroup at 6 months. This is in accordance with a studyin which Reddy et al.23 reported bone fill of 42.85%.This suggests the same percentage of bone fill canbe obtained whether ALN is delivered subgingivally,as in the current study, or topically applied after muco-periosteal flap elevation.23 Considering this, it can beproposed that direct subgingivally injected ALN willbe a better approach for periodontal regeneration ofbony defects in patients with CP compared to topicalapplication because it does not require the additionalstep of mucoperiosteal flap elevation and bone loss.

The current study shows that this technique ofsubgingivally delivering ALN directly into pockets ofpatients with type 2 DM with CP as the local drugdelivery system offers the advantages of high concen-trations at the target site with reduced dosage, fewerapplications, and high patient acceptability.38 Com-pared to a systemic regimen, local delivery may offerimportant benefits in terms of adverse reaction and pa-tient compliance as reported in other studies.30,31,39

The current study reports the presence of bone fill af-ter 6 months from baseline, whereas ALN was found ingingival crevicular fluid samples only at 1 month andwas absent at 2 months as reported previously (ALN

Table 3.

Baseline Clinical Parameters

Parameter ALN Group Placebo Group

Fasting plasma glucose (mg/dL) 146.52 – 16.22 148.44 – 12.16

HbA1C (%) 6.85 – 0.23 6.77 – 0.19

PD (mm) 8.41 – 2.41 8.31 – 1.80

CAL (mm) 6.24 – 1.65 6.53 – 1.87

IBD depth (mm) 5.40 – 1.19 5.36 – 1.34

Table 4.

PD, CAL, and IBD Depth in ALN and Placebo Groups at Baseline, 2 and 6 Months

Parameter ALN Group (mean – SD) Placebo Group (mean – SD) t Value† P Value

PD (mm)Baseline 8.41 – 2.41 8.31 – 1.80 0.04 0.8352 Months 5.91 – 1.82 6.92 – 1.78 5.47 0.022*6 Months 3.85 – 1.89 5.94 – 1.77 22.80 <0.001*

CAL (mm)Baseline 6.24 – 1.65 6.53 – 1.87 0.48 0.4922 Months 3.82 – 2.08 5.83 – 1.95 17.41 <0.001*6 Months 2.65 – 1.45 4.92 – 1.93 30.55 <0.001*

IBD depth (mm)Baseline 5.40 – 1.19 5.36 – 1.34 0.02 0.8816 Months 2.97 – 0.69 5.22 – 1.35 76.05 <0.001*

* Statistically significant at P <0.05.† t test.

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concentration in gingival crevicular fluid samples wereassessed by high-performance liquid chromatographyinourpreviousstudy).30 Thiscanbeexplainedbyreleaseof BP from bounded bone mineral during bone resorp-tion by osteoclasts. This could lead to a localizedaccumulation of BP, which could directly disturb osteo-clasticactivityor indirectly targetosteoblastsandmacro-phages, resulting in decreased osteoclastic chemotaxisand activity.40 Carbopol was used as the vehicle prepar-ing the ALN gel in the current study, which is consideredto provide intimate contact and prolong the time adosage remains in the periodontal pocket, by meansof specific interfacial forces in a process commonly re-ferred toasmucoadhesion,after localdrugdelivery.41-43

CONCLUSIONS

This clinical trial demonstrates that local delivery of1% ALN into periodontal pockets of patients with type2 DM and CP stimulated a significant increase in thePD reduction, CAL gain, and improved bone fill com-pared to placebogelan adjunct toSRP.Thiscanprovidea new direction in the field of periodontal regenerationin this special group of patients who are greater riskfor periodontal destruction. However, long-term, mul-ticenter randomized, controlled clinical trials will be re-quired to know its clinical, histologic, and radiographiceffects on bone regeneration in patients with DM.

ACKNOWLEDGMENTS

The authors thank Apex Healthcare, Ankleshwar,Gujarat, India, for providing the alendronate. The au-thors also thank Dr. Sarasija Suresh (Professorand Head) and Mr. Nagraj Patro (PhD student),Department of Pharmaceutics, Al-Ameen College of

Pharmacy, Bangalore, India, for assistance with prepar-ing alendronate and placebo gels. The authors also ex-press their thanks to Mr. P. S. Jagannatha, Rajajinagar,Bangalore, for statistical analyses. The authors reportno conflicts of interest related to this study.

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Correspondence: A.R. Pradeep, Department of Periodon-tics, Government Dental College and Research Institute,Bangalore 560002, Karnataka, India. Fax: 080-26703176;e-mail: periodonticsgdcri@gmail.com.

Submitted May 13, 2011; accepted for publication December16, 2011.

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