THE EFFICACY OF STRONTIUM RANELATE IN THE MANAGEMENT OF ALVEOLAR BONE LOSS (CLINICAL AND RADIOGRAPHIC STUDY)

Omar H. khashaba 1 , A. Nabil Nasser 2 and M. M. Bazed 3 . 1. Professor of Oral medicine and Pereiodontology, Department of Oral medicine and periodontology, Faculty of Oral and Dental Medicine, Mansuora university, Egypt. 2. B.D.S, Faculty of Oral and Dental Medicine, Mansuora university, Egypt. 3. Lecturer of Oral medicine and Pereiodontology, Department of Oral medicine and periodontology, Faculty of Oral and Dental Medicine, Mansuora university, Egypt. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

The uses ofperiodontal bone grafts are: reduction of probing depth , clinical attachment gain,bone fill of the osseous defect and regeneration of new bone 4 .Several methods ,materials and techniques have been used for bone grafting.Grafting material used for bone augmentation may be ;autogenous bone graft harvesting from one site to another within the same individual, allograft transferred between members of the same species, xenografts from different species, and alloplast which are synthetic in origin 5 . Allografts are osteoconductive and may be osteoinductive. Xenografts are osteoconductive but have a very slow resorption rate. The synthetic materials are inert with little osteoinductive activity 5 .
Recently a new material has been used for replacement of bone loss, this material is called stroniumranelate.Strontiumranelate is a used in the treatment of osteoporosis, Strontium ranelate is composed of two atoms of stable strontium (Sr) combined with ranelic acid, which acts as carrier , unlike any other drug, has a dual effect on bone remodelling, being able to stimulate bone formation by osteoblasts, a property shared with boneforming agents, and to inhibit bone resorption by osteoclasts, as do anti-resorptive agents 6,7 .
Strontium ranelate enhances the replication of pre-osteoblasts and increases collagen type I synthesis 8 . Strontium ranelate promotes bone nodule formation by increasing the differentiation from early progenitor cells to mature osteoblasts 9 .
There is growing evidence that strontium influences bone remodeling by affecting both bone resorption and bone formation. In vitro, strontium inhibits bone resorption 8 , and stimulates bone formation 10 . In vivo, the administration of strontium at low concentrations inhibits bone resorption 11,12 , and stimulates bone formation, as evaluated by bone histomorphometry in osteoporotic patients 13 .
It has been shown that strontium ranelate improves bone mass in an experimental model of osteopenia in rats. These histomorphometric data in estrogen-deficient rats suggest that strontium ranelate has an uncoupling effect between bone resorption and bone formation 14 .
Indeed, in vitro studies have shown that strontium ranelate inhibits osteoclast activity 15 , and stimulates osteoblast proliferation and collagen synthesis 10 . These findings raise the possibility that strontium ranelate may have beneficial effects on bone remodeling in large mammals by decreasing bone resorption while maintaining bone formation.

Materials and methods:-Patient selection:-
The present study was carried out on 20 patients , seeking a periodontal treatment at Department of Oral medicine and Periodontology, Faculty of Dentistry, Mansoura University.
Periodontal health state was assessed for each patient clinically and radiographically.

Inclusion criteria:-
The included patients in this study were:  Free from any systemic disease and no history of using systemic antibiotics in the last three months.  Dental history: No periodontal treatment for at least three months before starting the study.  Non-alcoholic.

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 Non-smoker.  Between 25 to 45 years in age Exclusion criteria:-The excluded patients from this study were: -Have systemic disease that may influence the severity or progression of periodontitis such as HIV infection or diabetes mellitus type 1 &2. -Receiving medications that may influence the periodontium (e.g., phenytoin, nifedipine, or non-steroidal antiinflammatory drugs) -Received systemic administration or local application of antibiotics within the previous 6 months -Pregnant or lactating female patients Study design:-A randomized split-mouth study was be used in all patients suffering from periodontal disease with alveolar bone loss. After scalling and root planning , a surgical flap (full thickness flap) was be done and a mix of strontium ranelate (Protelos 2gm) with sterile saline will be delivered in one side untill the bone defect is filled, and the other side was subjected only to scalling and root planning and depridemenet of granulation tissue.
Clinical measurements:-Proper case history was obtained from each patient taking into consideration the history of the present chief complain , onset and duration of the patients periodontal manifestations as well as any past dental treatment . Each patient was thoroughly examined clinically to assess the gingival tissue health in terms of color, size, texture and contour. Patients were evaluated at the baseline and after 2 ,6 , 8 and 12 weeks . Clinical evaluation was performed using the following clinical parameters:

Plaque index 98 (PI):-
This index was used to assess the thickness of plaque at the gingival area of the tooth .The evaluation or scoring was done on selected teeth (upper right 6, upper right 2, upper left 4, lower left 6, lower left 2, lower right 4) .The surfaces examined were the four gingival areas of the tooth: the distofacial, facial, mesiofacial and lingual/palatal surface. Mouth mirror, light source, periodontal probe and air drying of the teeth and gingival were used in the scoring of this index Scoring criteria: 0-No plaque 1-A film of plaque adhering to the free gingival margin and adjacent area of the tooth .The plaque was recognized only by running a probe across the tooth surface 2-moderate accumulation of soft deposits within the gingival margin and/or adjacent tooth surface that could be seen by naked eye 3-Abundance of soft matter within the gingival pocket and /or on the gingival margin and adjacent tooth surface Gingival index 99 (GI):-This index will be used to assess the severity of gingivitis and its location in four possible areas .The severity of gingivitis will scored on all surfaces of selected teeth (upper right 6, upper right 2, upper left 4, lower left 6, lower left 2, and lower right 4).
The surfaces will be examined are the four gingival areas of the tooth: the distofacial papilla, facial margin, mesiofacial papilla and entire lingual gingival margin .A periodontal probe will be used for recording the scores Scoring criteria: 0-No inflammation / normal 1-Mild inflammation / slight color change and edema, no bleeding elicited on probing 2-Moderate inflammation, redness, edema, bleeding on probing 3-Severe inflammation, marked redness and edema, ulceration, spontaneous bleeding For each index, the score of the tooth will be obtained by adding the four scores per tooth and dividing it by four .The index score for the person will be obtained by adding the index scores per tooth and dividing it by the number of teeth examined. 53 bleeding on probing index 100 (BOP):-This index was used to assess both immediate evaluation of the patient's gingival condition and his motivation, based upon the actual bleeding tendency of the gingival papillae. A periodontal probe is inserted into the gingival sulcus at the base of the papilla on the mesial aspect, and then moved coronally to the papilla tip. This is repeated on the distal aspect of the papilla. The intensity of any bleeding is recorded as: 0-no bleeding; 1-A single discreet bleeding point; 2-Several isolated bleeding points or a single line of blood appears; 3-The interdental triangle fills with blood shortly after probing; 4-Profuse bleeding occurs after probing; blood flows immediately into the marginal sulcus.

Probing Pocket Depth 101 (PPD):-
The evaluation was performed for teeth by Michigan (O) probe with Williams marking at (1, 2, 3, 5,7,8,9 and 10). Probing pocket depth (PPD) will be measured from gingival margin to the base of the pocket at six points (mesiobuccal, mid-buccal, distobuccal, mesiolingual, mid-lingual, distolingual) around each tooth. The mean probing depth will be obtained by all the measurements around the tooth and dividing by six. The mean probing depth of the patient will be obtained by totaling the mean probing depth of each tooth examined and dividing by the number of the teeth examined .

Radioghraphic examination:-
Bone level for the tooth which was indicated in the surgery was measured by digital panoramic x-rays through image analysis programme as follow: Treatment procedures:-At the baseline, digital panoramic radiograph were be taken to access alveolar bone lost then all patients were be subjected to a full mouth supra and sub gingival scaling and root planning as basic full mouth treatment , using ultrasonic and hand instruments under local anesthesia Fig(2) , one week later : Following adequate local anesthesia, buccal and lingual intrasulcular incisions were made using Bard-Parker blade no.15 Fig(3), and a full 55 thickness flap was reflected to expose the intrabony defects with care to preserve the interdental papilla Fig(4). After debridement of the osseous defects, the root surfaces were thoroughly scaled and root planed With Gracey curettes.   56 then strontium ranelate (Protelos 2gm) Fig(5) , mixed with 4-6 drops of sterile saline to make putty form Fig(6), then carried by a spoon like an instrument to be placed into the defect site untill filled Fig(7), and condensed gently with a sterile smooth amalgam condenser. suturing is done by 0.3 of non resropable suture Fig(8).
The other side was be subjected only to SRP and depridement of granulation tissue.
The patients will be informed about oral hygiene instructions and motivation. After one week the stitches were be removed Patients were recalled for follow up and rescoring of all indices after 2 , 6 and 8 weeks , and a digital panoramic radiographs were be taken again after 12 weeks for radiographic assesement.  Numerical data were summarized using means and standard deviations. Paired t test was done to assess the effect of treatment on different variables. Repeated measure analysis of variance was done to assess changes overtime in each side followed by pairwise comparisons by paired t test. Analysis was repeated by nonparametric methods to ensure robustness of results but presentation was done by parametric method only. All p-values are two-sided. P-values < 0.05 were considered significant.

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Results:-Effect of treatment on pocket depth:-Comparing 2 sides :Mean Pocket depth before treatment was 3.1±0.4on side A(applied side) and 3.1± 0.4 on side B(control side) (p=0.743). Mean pocket depth level were comparable in both sides before treatment and all over time periods.

Discussion:-
There is growing evidence that strontium influences bone remodeling by affecting both bone resorption and bone formation. In vitro, strontium inhibits bone resorption 8 , and stimulates bone formation 10 .
In vivo, the administration of strontium at low concentrations inhibits bone resorption 11,12 , and stimulates bone formation, as evaluated by bone histomorphometry in osteoporotic patients 13 .
Studies on healthy animals confirm that strontium ranelate improves bone microarchitecture at both trabecular and cortical levels and preserves the structure of bone matrix crystals without affecting the mineralization process. These changes can possibly be attributed to the improvement in the biomechanical properties of bone 17 .
Therefore, the present study was designed to evaluate and asses the clinical efficacy of strontium ranelate (Protoles) when used as adjunct to scaling and root planning (SRP) in patients with bone loss due to periodontal disease. Also, comparing these results with conventional mechanical debridement alone in the same patients but on the other side of mouth (split mouth techneque)having also bone defect.
Subjects with an age range of 25 to 45 years were recruited in the study. Subjects had no periodontal treatment for at least three months before starting the study.
Subjects were excluded : subjects with a history of local and/or systemic antibiotic therapy within the last six months before baseline examination , Have systemic disease that may influence the severity or progression of periodontitis such as HIV infection or diabetes mellitus type 1 &2.
In this study, subjects were evaluated clinically at the baseline, 2 ,6 and 8 weeks after treatment using different clinical parameters as ; plaque index, gingival index, bleeding index, probing pocket depth .Furthermore the operative sites were also evaluated radiographicaly at the baseline and after 12 weeks .
The clinical results of the current study showed greater improvement in all clinical parameters especially those of the applied side comparing to control side.
Clinical results of probing depth revealed that; there was more improvement in the scores in the applied side than the control side and it was statistically significant.
Clinical results of plaque index (PI) of both groups revealed that; there was no statistically significant difference between mean change percent of applied and control sides.
Clinical results of gingival index (GI) revealed that;there was no statistically significant difference between mean change percent of applied and control sides.
Both the plaque and gingival indices remained satisfactory during the entire studying period, suggesting patients complied with oral hygiene instructions. The reduction in plaque and gingival scores could be due to SRP and proper oral hygiene maintains.
Clinical results of bleeding index revealed that ;there was no statistically significant difference between mean change percent of applied and control sides.
Study carried by J. BUEHLER,1 P. CHAPPUIS,2 J. L. SAFFAR,3 Y. TSOUDEROS,4 and A. VIGNERY, 2001 18 ,showed that 6 months treatment with strontiumranelate (adminsterated orally by gavage) significantly reduces the indices of bone resorptionwhile maintaining those of bone formation in alveolar bone in normal adult monkeys.

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The same study has revealed that strontiumranelate could decrease the number of osteoclasts ,suggesting that bone resorption was reduced. Other results obtained in vitro suggest that the inhibitory effect of strontium ranelate on bone resorptionis related to a direct effecton osteoclast activity 19 .
Another study carried by Pierre J. Marie and Monique Hott, et al,1985 20 ,showed that oral Stroniumranelate supplementation at the dose of 0.27% was shown to be effective in stimulating bone formation and bone density when administered for nine weeks in rats.
Low doses of Sr supplementation in drinking water were previously shown to increase parameters of bone format ion in rats, and this effect resulted in a 10% increase in the trabecular calcified bone volume 21 . It also revealed that short-term treatment with oral Srtransiently reduces the osteoclasticactivity and that longer term Sr supplementation induces asignificant stimulation of bone formation and a positive trabecular bone balance 21 .
According to sudy carried by Marie PJ, Chabot G, Glorieux FH et al ,1985 22 , Stimulation of bone formation has also recently been documented in humans treated for six months with Sr at low dosage level." In their study both static and dynamic parameters of bone formation wereincreased, but the relative short period of treatment did not allow a significant increase in the trabecular bone volume.

Conclusion:-
In the present study the clinical and radiographic results obviously showed statistically significant and provides evidence that strontium ranelate can be succesfully used for management of alveolar bone loss assiociated with periodontal diseases.