|Year : 2011 | Volume
| Issue : 2 | Page : 225-231
|Evaluation of the relative efficacy of an alloplast used alone and in conjunction with an osteoclast inhibitor in the treatment of human periodontal infrabony defects: A clinical and radiological study
Jyoti Gupta1, Amarjit Singh Gill2, Poonam Sikri3
1 Department of Periodontics, Dr. H. S. J. Institute of Dental Sciences and Research, Chandigarh, India
2 Department of Periodontics, Surendra Dental College and Research Institute, Sri Ganganagar, Rajasthan, India
3 Department of Periodontics, Seema Dental College, Rishikesh, Uttranchal, India
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|Date of Submission||21-Feb-2010|
|Date of Decision||11-Feb-2011|
|Date of Acceptance||14-Apr-2011|
|Date of Web Publication||27-Aug-2011|
| Abstract|| |
Background: Mucoperiosteal flap surgery stimulates varying amounts of alveolar bone loss due to accelerated osteoclastic activity [Regional Accelerated Phenomenon (RAP)]. Alendronate sodium inhibits osteoclastic activity and is thought to result in a net increase in osteoblastic activity. We undertook a preliminary study evaluating the effect of adjunctive use of topically delivered bisphosphonate alendronate (ALN) along with regenerative bone graft material in the treatment of periodontal infrabony defects.
Materials and Methods: Fifteen patients with two-walled or three-walled infrabony defects were selected. In each patient, the infrabony defect of one side of arch was designated as group A (control site) and received hydroxyapatite (HA) bone graft material, while the infrabony defect on the contralateral side of same arch was designated as group B (test site) and received HA + 200 μg drug solution of ALN.
Results: Both the groups exhibited a highly significant reduction in probing depth and gain in clinical attachment level and linear bone fill at the end of 24 weeks. Comparative evaluation between the study groups revealed a statistically nonsignificant reduction in probing depth (P=0.128 NS ) and mean gain in attachment level (P=0.218 NS ). However, there was a statistically significant gain in linear bone fill (P=0.040*) in group B as compared to group A.
Conclusions: The results suggest that use of ALN along with graft material led to enhanced linear bone fill at the surgical site. This research provides a clue that bone-targeting properties of bisphosphonates can be harnessed along with regenerative materials to potentiate osseous regeneration.
Keywords: Bisphosphonates, bone resorption, osteoclasts, regeneration, regional accelerated phenomenon
|How to cite this article:|
Gupta J, Gill AS, Sikri P. Evaluation of the relative efficacy of an alloplast used alone and in conjunction with an osteoclast inhibitor in the treatment of human periodontal infrabony defects: A clinical and radiological study. Indian J Dent Res 2011;22:225-31
A long-term goal in periodontal therapy is to regenerate the periodontium. Mucoperiosteal flaps are elevated to gain access to bone and root surfaces for debridement, pocket elimination, management of periodontal defects and for regenerative procedures. Various reports state that periodontal flap surgery results in varying amounts of alveolar crest loss  and interdental bone loss.  This bone loss may range from a minimum of 0.11 mm to a maximum of 3.1 mm with an average of 0.8 mm.  During this dissective procedure, the periosteum is usually separated from the alveolar bone, initiating a striking remodeling activity known as Regional Accelerated Phenomenon (RAP),  which hastens the healing process. The phenomenon , is a transient burst of localized remodeling activity following surgical wounding of cortical bone. It involves the recruitment of an increased number of osteoclasts and osteoblasts at the surgical site. The activation of RAP starts with accelerated resorptive activity by osteoclasts followed by the bone regeneration by osteoblasts.
|How to cite this URL:|
Gupta J, Gill AS, Sikri P. Evaluation of the relative efficacy of an alloplast used alone and in conjunction with an osteoclast inhibitor in the treatment of human periodontal infrabony defects: A clinical and radiological study. Indian J Dent Res [serial online] 2011 [cited 2013 Jun 20];22:225-31. Available from: http://www.ijdr.in/text.asp?2011/22/2/225/84292
A class of recently developed drugs, bisphosphonates,  has been shown to be potent inhibitor of bone resorption. The high avidity of bisphosphonates for Ca 2+ ions is the basis of bone targeting property of these compounds. The ability to adsorb to bone mineral in vivo selectively delivers bisphosphonates to the sites of active bone remodeling, where they inhibit the bone resorption mediated by osteoclasts. This has made bisphosphonates the most important class of drugs used to treat diseases involving excessive osteoclastic activity, such as Paget's disease,  tumor associated bone disease  and postmenopausal osteoporosis. 
In earlier studies, it has been proved that bisphosphonate alendronate (ALN) is effective in reducing alveolar bone loss following periodontal surgery in rats. Topical application of sponge soaked in 10 μl of ALN solution at the time of surgery demonstrated marked reduction of bone resorption while maintaining the alveolar crest height  Aminobisphosphonate ALN given intravenously  significantly reduced alveolar bone resorption after mucoperiosteal flap surgery. It has also been reported that systemic treatment with ALN may be beneficial in preventing alveolar bone destruction associated with periodontal disease.  Furthermore, it has been shown that ALN increases early bone formation rate around dental implants. 
Taking a clue from the above observations it may appear logical to hypothesize that antiresorptive agents, bisphosphonates, if combined with bone regenerative material, may inhibit the surgery-induced RAP and hence can improve the performance of graft. Very small dose in the form of local drug delivery could be used to minimize any possible side defects of ALN. From this viewpoint, the present study was designed to evaluate the relative efficacy of the alloplast used alone and in conjunction with an osteoclast inhibitor in the treatment of human periodontal infrabony defects.
| Materials and Methods|| |
A controlled, single-blind study was designed with 15 patients (10 males and 5 females) in the age group of 30-50 years. Patients older than 50 years were not included in this study due to reported decreased regenerative potential in these patients.  The patients were selected from among those reporting at the Department of Periodontology, Government Dental College, Amritsar. The patients selected were suffering from chronic generalized periodontitis (based on criteria established by AAP, 1999),  having at least two or more bilateral two-walled or three-walled infrabony defects, with pocket depth ≥7 mm and radiographic evidence of infrabony (vertical) defect. The exclusion criteria for selection of the patients were as follows:
- Smokers and alcoholic patients
- Patients with any clinical signs and symptoms of trauma from occlusion
- Patients suffering from any systemic disease
- Patients with known history of allergy
Prior to surgery, all these patients received supragingival scaling and oral hygiene instructions. Patients were reviewed after a period of 2 weeks and evaluated for optimal oral hygiene. After an explanation of the proposed study criteria, including treatments, potential risks and benefits, a written informed consent was obtained using a consent form approved by institutional ethical committee at Punjab Government Dental College and Hospital, Amritsar. For each patient, two interproximal sites, one in each quadrant of the same arch, were selected based on periodontal pocket measuring about 5-7 mm and radiographic evidence of infrabony (vertical) defect. Sites were selected by simple random sampling technique and assigned as control site (group A) and test site (group B). In each patient, the infrabony defect of one side of arch was designated as group A and the infrabony defect of the contralateral side of the same arch was designated as group B. Group A was treated by the placement of hydroxyapatite (HA) alone and group B was treated by the placement of HA + ALN drug solution.
Clinical parameters assessed were probing depth and attachment level (to ascertain the clinical attachment loss). The clinical measurements were obtained by one examiner using Williams calibrated probe. Acrylic occlusal stents  were fabricated so that the measurements made post-surgically could be at the same position and angulation as those made pre-surgically. The stents were stored on the cast to minimize distortion.
Radiographic assessment was made to measure the amount of linear bone fill by using intraoral periapical films (size 32Χ41 mm) (E speed plus). Radiographically, the infrabony defect depth was ascertained by using a standardized radiographic technique and by measuring from a fixed reference point (the adjacent cuspal tip) to the most apical point of the base of the defect. To ascertain the depth, an X-ray grid mount [Grid Mount manufactured by HagerWerken, marketed by Tracom Services (P) Ltd., New Delhi, India] was used with millimeter markings on it for accurate measurements.
- Synthetic HA (OsteoGen® ) [OsteoGen (HA RESORB), Impladent Ltd., Holliswood, NY, USA].
- Alendronate sodium 10 mg tablets (Alenost-10)® (ALENOST-10, Macleods Pharmaceuticals Ltd., Kachigam, Daman, India).
Preparation of drug solution
To prepare 200 μg of the drug solution,  two tablets of 10 mg each were crushed and dissolved in 1 ml of normal saline. 10 μl of this solution was measured with a fixed value pipette (Accumax, Fine Care Corporation, Ahmedabad, India), which was equivalent to a drug concentration of 200 μg. This was then smeared over the HA graft placed inside the infrabony defect.
The patients were premedicated using 10 mg diazepam and 0.3 mg glycopyrrolate intramuscularly, 45 min prior to the surgical procedure.
Envelope flaps were reflected following anesthesia (2% lidocaine + 1:200,000 adrenaline) so as to debride the infrabony defects prior to the regenerative procedure. After the placement of HA, either alone [Figure 1] or in combination with ALN drug solution [Figure 2], the flaps were repositioned and approximated with interrupted sutures, using 3-0 black braided silk.
|Figure 1: Infrabony defect of a patient being treated with the placement of HA bone graft material (group A)|
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|Figure 2: Infrabony defect of the patient being treated with the placement of HA bone graft material loaded with 200 μg of alendronate drug solution (group B)|
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Antibiotic therapy (amoxicillin 250 mg + cloxacillin 250 mg + lactobacillus 60 million spores) for 8 days, along with an anti-inflammatory agent for 3 days, was prescribed postoperatively. The patients were asked to follow the dietary instructions strictly and perform adequate plaque control by rinsing with 10 ml of 0.2% chlorhexidine gluconate twice daily for 2 weeks postoperatively. Sutures were removed 1 week after surgery, and postoperative assessments of the clinical and radiographic parameters were done at 12 and 24 weeks [Figure 3] and [Figure 4].
|Figure 3: (Top) Radiograph of a patient showing infrabony defect depth preoperatively (group A). (Bottom) Radiograph of the patient showing the infrabony defect depth at 24 weeks postoperatively (group A)|
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|Figure 4: (Top) Radiograph of a patient showing infrabony defect depth preoperatively (group B). (Bottom) Radiograph of the patient showing the infrabony defect depth at 24 weeks postoperatively (group B)|
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| Results|| |
All the subjects tolerated the surgical procedures well, experienced no postoperative complications, compiled with the study protocol, and completed the 24-week follow-up. The postoperative assessments for the parameters were done at 12 and at 24 weeks. There were no drop-outs during the assessment period. The observations recorded were subjected to statistical analysis. No difference in results was found between male and female patients. Similarly, with regard to age, periodontal regenerative potential was found to be the same in all patients (30-50 years).
The mean values of probing depth [Table 1], clinical attachment level [Table 2], and infrabony defect depth [Table 3] at three points in time were evaluated. The efficacy of the two treatment modalities at 12 and 24 weeks postoperatively was evaluated using the paired Student's t-test since the observations at the two points in time were expected to be closely related to each other. The two groups, group A (HA) and group B (HA + ALN), were then comparatively evaluated over the three time intervals, using independent Student's t-test.
|Table 1: Probing depth of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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|Table 2: Clinical attachment loss of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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|Table 3: Infrabony defect depth of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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On analyzing the clinical criteria of reduction in probing depth of the two groups, it was seen that there had been a significant reduction in probing depth with HA loaded with ALN at all the three points in time. HA used alone provided a significant reduction in probing depth at 12 and 24 weeks postoperatively and a nonsignificant reduction in probing depth between 12 and 24 weeks postoperatively [Table 4].
|Table 4: Reduction in probing depth of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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Regarding gain in attachment level, in both the groups, there has been a significant gain in the clinical attachment level at the end of 12 and 24 weeks but a nonsignificant gain in clinical attachment level between 12 and 24 weeks [Table 5].
|Table 5: Gain in clinical attachment level of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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The linear bone fill level for both the groups was statistically significant at all the three points of time [Table 6].
|Table 6: Linear bone fill of group A (hydroxyapatite bone graft) and group B (hydroxyapatite bone graft loaded with osteoclast inhibitor) (in mm) |
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On comparative evaluation between the two groups, the results indicate that HA loaded with ALN exhibited greater mean reduction in probing depth for the entire study period, but the difference was statistically nonsignificant (P=0.128) [Table 7]. Though the mean gain in clinical attachment level of group A (control site) was higher than that of group B (test side), the difference was statistically nonsignificant (P=0.218) [Table 8].
|Table 7: Comparative reduction in probing depth between group A (hydroxyapatite bone graft alone) and group B (hydroxyapatite bone graft loaded with alendronate) |
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|Table 8: Comparative reduction in probing depth between group A (hydroxyapatite bone graft alone) and group B (hydroxyapatite bone graft loaded with alendronate) |
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HA loaded with ALN provided greater linear bone fill than HA used alone over the entire span of the study, with statistically significant linear bone fill between 12 and 24 weeks postoperatively (P=0.040) [Table 9].
|Table 9: Comparative linear bone fill between group A (hydroxyapatite bone graft alone) and group B (hydroxyapatite bone graft loaded with alendronate) |
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| Discussion|| |
Periodontal regeneration is now a major challenge in periodontal research and practice. It involves the use of regenerative materials to restore the defects produced by disease process. Among alloplasts, synthetic HA has been extensively used for alveolar ridge augmentation, , craniofacial reconstruction,  bone graft substitute in orthognathic surgery,  maxillary sinus upliftment procedures,  and around metal implants for their fixation directly to the surrounding bone. HA has a great potential as a regenerative material when used in the treatment of periodontal infrabony defects. 
However, the occurrence of resorptive phase due to RAP following mucoperiosteal flap surgeries has been a cause of concern. The increased osteoclastic activity at the surgical site with the already compromised bone support further deteriorates the supporting structures. It is conceptualized here that an agent that could suppress or inhibit the activity of osteoclasts could be effective in preventing crestal resorption after mucoperiosteal flap surgeries. Bisphosphonates have been shown to be potent inhibitors of bone resorption due to their anti-osteoclastic action.
Because of the high affinity of bisphosphonates for HA bone mineral, these drugs are targeted to areas of bone turnover and are specifically concentrated at the site of osteoclastic bone resorption. Therefore, the most likely route by which bisphosphonates could inhibit bone resorption is by a direct effect on resorbing osteoclasts, though the fine mechanism/mechanisms by which bisphosphonates act on bone are not very clear. There may be an indirect effect on secretion of osteoclast activating factor by osteoblasts.  The direct effect on osteoclasts includes cytotoxic or metabolic injury of mature osteoclasts,  inhibition of osteoclast attachment to bone,  inhibition of osteoclast differentiation or recruitment,  and interference with osteoclast structural features necessary for bone resorption. 
The proposed mode of action of nitrogen-containing bisphosphonates is as follows. After administration, bisphosphonates bind to the bone mineral. During the initiation of resorptive process by osteoclasts, bisphosphonates are released due to highly acidic local environment. These are then taken up by osteoclasts. Inside the osteoclasts, they inhibit the enzyme(s) of the mevalonate pathway. This biosynthetic pathway is responsible for the production of cholesterol and isoprenoid lipids such as isopentyl diphosphate (IPP), farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are important substrates for the post-translational lipid modification (prenylation) of small GTPases such as Ras, Rho and
Rac.  These are important signaling proteins that regulate a variety of cell processes important for osteoclast function, including control of cell morphology, membrane ruffling and apoptosis.  Prenylation is required for the correct functioning of these proteins.
Inhibition of the mevalonate pathway by nitrogen-containing bisphosphonates and thus interference with generation of GGPP results in loss of prenylation of these GTP binding proteins. This results in disruption of actin cytoskeleton and loss of ruffled border formation, both of which are essential for the bone resorbing activity of osteoclasts, resulting in osteoclast inactivation and finally leading to inhibition of bone resorption. ,
The bisphosphonate used in this study was ALN (Alenost-10® ). It is a potent nitrogen-containing bisphosphonate. Synthetic HA used in the present study was OsteoGen® , which is a synthetic, granular, osteoconductive and non-ceramic crystalline form of HA, resembling the natural bone components. The particle size of OsteoGen® is 300-400 μm, which is considered optimum for periodontal applications. , Our approach was to combine the favorable properties of HA with the bone modulating properties of bisphosphonates. The present study investigated the effect of topically delivered bisphosphonate ALN at the surgical site along with synthetic HA.
On analyzing the results, the difference in the mean reduction in probing depth (higher for group B) and the mean gain in clinical attachment level (higher for group A) between the two groups was statistically nonsignificant. It implies that these clinical parameters have not been significantly affected by the adjunctive use of ALN.
These results are similar with those reported in the earlier studies,  evaluating the effect of ALN on experimental periodontitis in monkeys and showing that there were no significant differences in the signs of inflammation or pocketing with the use of ALN. The method employed was intravenous bi-weekly administration of ALN at a concentration of 0.05 mg/kg without incorporating any surgical or non-surgical therapy.
Regarding linear bone fill, group B revealed a greater mean linear bone fill than group A for the entire study period, with a statistically significant difference between 12 and 24 weeks.
The results of the study show evidence of aminobispho-sphonates potentiating osseous regeneration by virtue of their osteoclast inhibitory activity, following mucoperiosteal flap surgery. Previous studies have demonstrated significant effect of aminobisphosphonates in preventing alveolar bone resorption. In 1995, Reddy et al.  also evaluated ALN for inhibition of alveolar bone loss in naturally occurring periodontitis. The results demonstrated that though there were no differences in signs of inflammation or pocketing, there was still an increase in bone mineral density. Meraw et al.  conducted a study to evaluate the effect of local delivery of ALN on bone regeneration within peri-implant defects. The results indicated that ALN increases the amount of peripheral peri-implant bone. Kaynak et al.  in their study concluded that local application of aminobisphosphonate ALN could be used as an adjunct in reducing bone resorption following surgery.
The investigators of the above-reviewed literature agreed that bisphosphonates could reduce the bone loss associated with periodontitis and can play an important role as an adjunct to the conventional periodontal surgical and regenerative procedures by preventing RAP-induced bone resorption as well as augmenting bone formation. The present study has relevant clinical significance, implying that topical delivery of ALN along with the bone regenerative material may achieve new dimensions in periodontal regenerative therapy. In conclusion, we emphasize that the data generated from the study were derived from a 24-week observation period, which is probably a short time interval when one considers the long-term success of regenerative procedures. Long-term studies with a larger sample size are required to evaluate whether or not the results obtained in the present study are sustainable over a long period of time.
| Acknowledgments|| |
We express our sincere thanks to Dr. AS Sethi, Professor, Punjab School of Economics, Guru Nanak Dev University, Amritsar, for his help with the statistical analysis and interpretation of data; Dr. Rashi Chaturvedi for her help in preparation of the manuscript; and Vikram Rajput and Sunil Rajput for their technical support.
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Department of Periodontics, Dr. H. S. J. Institute of Dental Sciences and Research, Chandigarh
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]
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