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Bisphosphonates in Periodontal Treatment:
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pyrig No Co t fo rP REVIEW ARTICLE ub lica tio n te ss e n c e A Review
Zahi Badrana/Michael Alexander Kraehenmannb/Jérôme Guicheuxc/ Assem Soueidana,c
Summary: Periodontitis is a multifactorial disease involving bacterial biofilms and the generation of an inflammatory response. The latter causes the major part of the periodontal tissue breakdown. Alveolar bone resorption is a major component of the periodontal destruction observed in periodontitis. Novel treatment modalities of periodontitis intend to control and modulate the host response to bacterial aggression. Drugs such as bisphosphonates (BPs) are proven antiresorptive agents that can potentially inhibit the alveolar bone resorption. This review describes the potential use of BPs in periodontal treatment and could be said that BPs have an in vitro and in vivo capability of reducing bone resorption. Only a few studies have been carried out on the improvement of clinical periodontal parameters after the administration of BPs. Therefore, the published data are not sufficient to establish an evidence-based relevance for the use of these drugs in the treatment of periodontal diseases. Key words: bisphosphonates, experimental periodontitis, host modulation, periodontal treatment Oral Health Prev Dent 2009; 7: 3–12.
eriodontitis encompasses multifactorial diseases involving bacterial biofilms and the generation of an inflammatory response (Loee et al, 1965). Under certain conditions (e.g. genetic predisposition) or environmental factors (e.g. tobacco smoking, diabetes mellitus or emotional stress), the pathogenic bacterial flora surpass the immune system defences (Fig 1) and this leads to periodontitis characterised mainly by alveolar bone resorption, attachment loss and the formation of periodontal pockets (Socransky and Haffajee, 1992). Our knowledge on the pathogenesis of periodontal diseases has grown considerably over the past
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Department of Periodontology – ERT 2004, School of Dental Surgery, University of Nantes, Nantes, France.
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Clinic for Preventive Dentistry, Periodontology and Cariology, Dental School, University of Zurich, Zurich, Switzerland.
c
Laboratoire d’Ingenierie Osteoarticulaire et Dentaire, LIOAD UMRS 791, School of Dental Surgery, University of Nantes, Nantes, France.
Correspondence: Michael Alexander Kraehenmann, Clinic for Preventive Dentistry, Periodontology and Cariology, University of Zurich, Plattenstr. 11, CH-8032 Zurich, Switzerland. Tel: +41 44 634 34 29. Fax: +41 44 634 43 08. Email: michael.kraehenmann@ zzmk.uzh.ch
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Submitted for publication: 13.11.07; accepted for publication: 16.01.08.
40 years since it was first reported that the biofilm plays a key role in the establishment and the progression of the disease by Loee and co-workers in their study ‘Experimental gingivitis in man’. The pathway of the disease is as follows: the presence of a pathogenic oral flora (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia or Actinobacillus actinomycetemcomitans) (Socransky et al, 1998) induces an inflammatory reaction leading to the secretion of the proinflammatory cytokines interleukin-1 beta (IL-1b), tumour necrosis factor-alpha (TNF-a), prostaglandin E2 (PGE2) and matrix metalloproteases (MMPs) by immune cells (leucocytes and macrophages) as well as gingival fibroblasts (Fig 2) (Page et al, 1997). Proinflammatory cytokines stimulate the osteoclast-mediated alveolar bone resorption as well as the apical migration of the junctional epithelium. The severity and the progression of the disease are modified for certain genetically susceptible individuals and/or for the presence of immunoderegulating risk factors such as stress, diabetes mellitus or usage of tobacco (Seymour et al, 1996). For these susceptible patients, the major part of periodontal destruction is due to the inflammatory response of the host. The prerequisite for a successful conventional periodontal treatment is the patient’s cooperation, 3
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Fig 1 Factors influencing the development of periodontal diseases. The increase of the bacterial load in comparison with the immune defence system leads to the establishment of periodontal disease in genetically susceptible individuals and/or in the exposed to risk factors such as tobacco smoking, stress or diseases that affect immunity.
application of oral hygiene (Axelsson and Lindhe, 1981) as well as the mechanical debridement of all tooth surfaces (scaling and root planing) (Lindhe and Nyman, 1985; Kalpidis and Ruben, 2002). The aimed outcome is the resolution or the reduction of inflammation, the prevention of further alveolar bone loss, the reduction of pocket depth with a gain of clinical attachment as well as the regeneration of alveolar bone in case of angular bony defects (Gilroy et al, 2004; Serhan, 2004; Kantarci et al, 2006). Another non-conventional treatment approach comprises controlling the host responses to
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pyrig No Co t fo rP ub lica tio bacterial aggression. Based on the assumption that n t the immune defence is not ‘perfect’ orenot of e ss efree c n profailures and can be deregulated, some authors posed the concept of ‘modulation of host response’ (Serhan, 2004) which is supposed to have fewer side effects as it is non-invasive and does not require complicated application methods compared with other armaments against infection (Pahlavan, 2000; McClung, 2006). One of these aforementioned ‘modulators of host response’ is the group of bisphosphonates (BPs) (Kornman, 1999; Reddy et al, 2003) that are synthetic chemical drugs used in the treatment of osteoporosis and other bone resorbing diseases (Dunstan et al, 2007). Systemically administrated, BPs have been used for more than 30 years in the treatment and prevention of osteoporosis (Silverman et al, 2007), and in the treatment of patients suffering from Paget’s disease (Pahlavan, 2000), malignant hypercalcaemia (Saunders et al, 2004) and bone metastasis (Heymann et al, 2004). The proven efficacy of BPs to inhibit the osteoclastic bone resorption has led to their use in the management of periodontal diseases as a host modulating factor in the perspective of preventing the alveolar bone loss (Parfitt, 1994). The aim of this study was to review the rationale of using BPs as alveolar bone resorption inhibitors and to summarise the current findings on these host modulating factors. In addition, the authors evaluate
Fig 2 Upregulation of local pro-inflammatory cytokine production. Bacterial lipopolysaccharides (LPSs) stimulate macrophages and polymorphonuclear leucocytes to secrete pro-inflammatory cytokines (IL-1b, TNF-a and PGE2). The local inflammatory reaction stimulates fibroblasts to secrete PGE2 and MMPs leading to the destruction of the periodontal tissues (data adapted from Page et al, 1997). 4
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Fig 3 Molecular structure of natural pyrophosphate and BP. The central carbon of BP confers stability to the molecule and prevents enzymatic acid hydrolysis from occurring.
if BPs play a key role as future therapeutic agents in the treatment of periodontal diseases. The search, up to and including April 2007, was limited to studies in English, using the electronic evidence source of the National Library of Medicine (Medline-Pubmed) using multiple combinations of the descriptors ‘bisphosphonates’, ‘periodontitis’, ‘periodontal disease’, ‘periodontal diseases’, ‘alveolar bone resorption’, ‘host modulation’ and ‘jaw necrosis’.
Bisphosphonates: Chemistry and Mode of Action BPs are synthetic molecules with a structure similar to inorganic pyrophosphates (Rogers et al, 2000) (Fig 3). Pyrophosphates are endogenous regulators of bone mineralisation, which can be found naturally in the blood serum, and they have the capacity to chelate calcium and to regulate the bone mineralisation process (Lin, 1996; Rodan, 1998). The biological inhibitory effects of BPs on osteoclast-mediated bone resorption were discovered in 1968 (Fleisch, 2002). BPs are resistant to enzymatic and chemical breakdown, and they present an affinity to the mineral phase of the bone due to their chelating properties for calcium (Rogers et al, 1999). They present a P–C–P molecular structure. There are three generations of BPs known to exist. The first generation has alkyl side chains (etidronate), the second generation includes amino-BPs with an amino-terminal side chain (alendronate) and the third generation (zoledronate) has a cyclic side chain (Fig 4). Bone is in a constant remodelling process characterised by alternate phases of resorption and formation of bony tissue (Teitelbaum and Bates, 1980; Parfitt, 1994). These two opposite phenomena are coupled and regulated locally by a complex signalling cascade of cytokines along with other molecules in a local spatial area called a bone multicellular unit. Any variation in the bone resorption process is compensated for by a similar variation of bone formation to maintain equilibrium in the total bone mass. In certain pathological conditions such as osteoporosis, Vol 7, No 1, 2009
Fig 4 Different types of BPs. The nature of the side chains (R1 and R2) determines the properties of each BP. The first generation of BPs has alkyl side chains (etidronate). The second generation included amino-BPs with an aminoterminal side chain (alendronate), and a cyclic side chain characterises the third-generation BPs (zoledronate).
Paget’s disease or periodontitis, an imbalance in these processes takes place and the rate of the osteoclastic bone resorption exceeds the rate of bone formation (Blair and Athanasou, 2004). BPs inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalisation by bone-resorbing osteoclasts where they interfere with various intracellular biochemical processes (Russell, 2007).
The target: Osteoclast Osteoclasts (bone-resorbing cells) are different from haematopoietic stem cells (CFU-GM) in the presence of the receptor activator nuclear factor kappa B (NFjB) ligand (RANK-L) and macrophage colony stimulating factor (M-CSF) (Boyle et al, 2003). The fusion of osteoclastic precursor cells forms the mature multinucleated osteoclast, expressing tartrate-resistant acid phosphatase (TRAP), calcitonin receptors and membrane receptors, especially the avb3 integrins (Nesbitt et al, 1993). After adhering to the bone surface, the osteoclast develops a sealing zone (avb3 integrins and actin ring) and a ruffled border where protons (H+), cathepsin K and MMPs, respectively, are released to resorb the mineral part, as well as the organic matrix of the bone (Fig 5) (Bossard et al, 1996; Rousselle and Heymann, 2002; Boyle et al, 2003). 5
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Fig 5 After adhesion to the bone matrix, the osteoclast polarises and expresses a ruffled border. The resorption is caused by the release of hydrogen ions (H+) and hydrolytic enzymes (MMPs and cathepsin K) in the lacunae. Protons (H+) are formed at the intracellular level under the effect of carbonic anhydrase II (CAII). They are released in the resorption chamber by the proton pumps, specifically V-ATPase. A resorption lacuna is delimitated by an actin ring surrounded by integrins (avb3).
An overproduction of osteoclasts by the fusion of their precursors and/or their activation by pro-inflammatory cytokines (IL-1b, TNF-a and PGE2) (Heymann et al, 1998) is responsible for the bone loss occurring in periodontal diseases (Page et al, 1997). Therefore, the use of a drug that inhibits the osteoclast function and/or formation seems to be a promising issue in periodontal treatment, and consequently the attention was turned to anti-resorptive agents that have already been used for a long time in the medical management of excessive bone resorption (Tenenbaum et al, 2002).
Cellular effect of BPs After their systemic administration, BPs are adsorbed selectively on bone surfaces and are present in all areas of high bone resorption activity (Sato et al, 1991). Once released during the bone resorption activity, they are possibly endocytosed in the osteoclasts (Masarachia et al, 1996) and they interfere with various intracellular biochemical processes (Russell, 2007). • The non-nitrogen-containing BPs (clodronate and etidronate) can be metabolically incorporated into non-hydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes such as the osteoclast proton-pumping vacuolar ATPase (V-ATPase) (David et al, 1996), which plays a crucial role in the 6
bone resorption process by pumping protons in the resorption lacunae. • The more potent nitrogen-containing BPs (e.g. zoledronate and pamidronate) inhibit the key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thus, preventing the biosynthesis of isoprenoid compounds that are essential for the post-translational modification of small guanosine triphosphate (GTP)-binding proteins (prenylation). The latter causes the loss of the ruffled border as well as an alteration of the cell morphology, the integrin signalling or endosome trafficking (Rogers et al, 2000). The inhibition of protein prenylation and disruption of the function of these key regulatory proteins leads to the loss of osteoclastic activity (Luckman et al, 1998a, b; Fisher et al, 1999; Rogers et al, 1999). On the other hand, it was demonstrated that different groups of BPs have a potent capacity in inducing apoptosis of osteoclasts (Hughes et al, 1995) and in inhibiting the differentiation (Hughes et al, 1989) and maturation of osteoclasts (Shoji et al, 1995). In addition to all of the above-mentioned characteristics, it has been suggested that BPs may have an osteogenic action in vitro and in vivo by promoting the osteoblast differentiation and maturation (D’Aoust et al, 2000; Gun-Il Im et al, 2004). This is done by increasing the matrix formation Oral Health & Preventive Dentistry
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pyrig No Co t fo r P et al Badran ub lica tio Table 1 BPs in the treatment of experimental periodontitis in animals. All studies found an inhibitory effect on alveolar t ess c e n bone resorption en
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Administration
Effect on bone resorption
Effect on periodontal healing
Goya et al (2006)
Olpadronate
Topical
Buduneli et al (2005) Menezes et al (2005)
Alendronate Alendronate
IV SA SC SA
# ABR # OC maturation and number # ABR # ABR
Buduneli et al (2004)
Alendronate
IV SA
# ABR
Duarte et al (2004) Tani-Ishii et al (2003)
Alendronate Icadronate
SC SA Oral SA
# ABR # ABR
Mitsuta et al (2002)
Chlodronate
Alencar et al (2002)
Chlodronate
Topical (subperiosteal palatal area) SC SA
Shibutani et al (2001)
Pamidronate
IM SA
# ABR # OC maturation and numbers # ABR # OC numbers # ABR " Bone density
# Periodontal ligament destruction " Serum osteocalcin # PMN # Bacteria # Inflammatory mediators ND # PMN migration # Periodontal ligament destruction ND
O’Uchi et al (1998) Shoji et al (1995)
YM175 Risedronate
Oral SA IV SA
Reddy et al (1995)
Alendronate
Oral SA
Weinreb et al (1994) Brunsvold et al (1992)
Alendronate Alendronate
IV SA IV SA
# # # # "
ABR ABR OC maturation ABR Bone mass
# ABR # ABR " Bone density
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# PMN ND
# Gingival index ND No effect on clinical parameters (inflammation or plaque) ND No effect on clinical parameters
ABR: alveolar bone resorption; IM: intramuscular; IV: intravenous; ND: not determined; OC: osteoclast; PMN: polymorphonuclear leucocytes; SA: systemic administration; SC: subcutaneous.
(Tenenbaum et al, 1992) and collagen synthesis (Guenther et al, 1981).
BISPHOSPHONATES IN PERIODONTAL THERAPY Systemic administration Animal studies (Table 1) One major research focus of BPs in periodontal therapy is the determination of their effect on bone resorption along with the clinical parameters in experimental animal models. After the induction of periodontitis (by ligatures or LPS), BPs were Vol 7, No 1, 2009
administrated systemically (orally or intravenously) as adjuvants to the conventional periodontal therapy (mechanical subgingival debridement [test group] versus conventional treatment only [control group]). Even though there is a difficulty in comparing data from various publications because different families and doses of administrated BPs were included, almost all studies have shown an obvious benefit of BPs as adjuvants to the mechanical periodontal treatment that resulted in reduced alveolar bone resorption following systemic administration (Shibutani et al, 2001; Duarte et al, 2004; Buduneli et al, 2005) together with clinical and/or histological benefits in the resolution of inflammation in periodontal tissues (O’Uchi et al, 1998; Alencar et al, 7
Effect on bone resorption
Lane et al (2005)
Alendronate or Risedronate
Oral SA
Takaishi et al (2003)
Etidronate
Oral SA
No effect on periodontal bone mass " ABD
El-Shinnawi and El-Tantawy (2003) Takaishi et al (2001)
Alendronate
Oral SA
" ABD
Etidronate
Oral SA
" ABD
Rocha et al (2001)
Alendronate
Oral SA
# ABR
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Administration
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Table 2 BPs in the treatment of patients suffering from periodontitis. Except one study, BP alveolar bone density or decreased alveolar bone resorption
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pyrig No Co t fo rP ub lica t treatment increased ion te ss e n c e Effect on periodontal healing # PD # BOP # CAL # PD # Tooth mobility No effect on clinical parameters # PD # Tooth mobility Improvement in clinical parameters
ABD: alveolar bone density; ABR: alveolar bone resorption; BOP: bleeding on probing; CAL: clinical attachment loss; OC: osteoclast; PD: pocket depth; SA: systemic administration.
2002; Tani-Ishii et al, 2003; Menezes et al, 2005). BPs seem to have an inhibitory effect on inflammatory mediators and MMPs, especially when combined with doxycyclines (Buduneli et al, 2004, 2007). In some studies, it was shown that groups treated with BPs showed a reduced alveolar bone resorption (Weinreb et al, 1994) with no significant improvement with regard to the clinical status except for the reduction in pocket depth (Brunsvold et al, 1992; Reddy et al, 1995). On the other hand, some authors observed an increased periodontal destruction and inflammation when high doses of BPs were administrated in the test group (Weinreb et al, 1994). The explanation might be that high doses of BPs (above all aminoBPs) (Yamaguchi et al, 2000) stimulate the local release of pro-inflammatory cytokines such as IL-1b and IL-6 in the periodontal tissues (Adami et al, 1987), and hence prevent the periodontal woundhealing process. It has also been suggested that nitrogen-containing classes of BPs (e.g. alendronate) could reduce the collagen production and thus, by this process, block the reconstitution of the extracellular matrix of injured periodontal tissues. Another potential use of BPs in the periodontal tissue regeneration is the administration of first-generation BPs, to temporarily inhibit the mineralisation of the newly formed bone matrix and by this, to promote the secretion of osteoid that will be mineralised after cessation of the BPs therapy (Tenenbaum et al, 2002). The aim of this procedure (i.e. osteoacceleration) is to enhance osteogenesis. The most
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suitable BP for the osteoacceleration phenomenon is etidronate (Tenenbaum et al, 1992; Goziotis et al, 1995). A recent finding is that a new BP (TRK-530) showed anti-inflammatory properties in addition to the established bone-resorption inhibition; these properties seem to be effective in the prevention of not only alveolar bone loss but also of periodontal tissue destruction in mice (Takeyamaa et al, 2006).
Human studies With regard to human trials (see Table 2), the existing literature demonstrate a further benefit of the systemic administration of BPs in addition to mechanical debridement compared with mechanical debridement alone. This benefit is mainly the reduction of alveolar bone loss and the preservation of the alveolar bone height. On the subject of the clinical parameters, some trials failed to show a significant improvement (El-Shinnawi and El-Tantawy, 2003), whereas other studies reported that BPs supported (in addition to inhibiting alveolar bone loss) the periodontal healing, in particular, the reduction of probing pocket depth and tooth mobility (Rocha et al, 2001; Takaishi et al, 2001, 2003; Lane et al, 2005).
Topical administration Mucoperiostal flap elevations in periodontal and oral surgery lead to alveolar bone resorption (Lekovic
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Recently, avascular osteonecrosis of the jaw (AONJ) has been observed after the intravenous administration of BPs, especially the nitrogen-containing zoledronate and pamidronate (Marx, 2003; Migliorati, 2003; Soileau, 2006). In some cases, this was also observed after oral administration of BPs (Farrugia et al, 2006). For this reason, it was suggested that BPs may have anti-angiogenic properties (Wood et al, 2002). It should be noted that in most cases, the patients under BP therapy exhibited signs of AONJ after oral surgery or a dental extraction (Pastor Zuazaga et al, 2006; Soileau, 2006). A significant association was found between a radiographically widened periodontal space in the furcation areas of molars and the BP-induced osteonecrosis (Marx et al, 2005). The incidence of AONJ is not exactly known. An Australian survey estimated that the risk for AONJ following dental extraction was 1/1000 in the case of osteoporotic patients receiving BP treatment (Mavrokokki et al, 2007), and a German study found that the incidence of AONJ was less than 1/100,000 for the non-oncology treatment with BPs (Felsenberg et al, 2006). Recent histological findings suggest that the avascular necrosis of the jaws associated with BPs is due to sequester formation and is initiated by the passage of oral microorganisms into bone tissues (Hoefert et al, 2006). Clinical signs of AONJ are: exposed bone in the
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et al, 1998). The inhibition of this inevitable bone loss has been the subject of numerous studies on the rational use of local application of BPs either in the surgical area or distantly in the cheek (Yaffe et al, 1997, 1999; Binderman et al, 2000). The drug-delivery system used was a gelatin sponge soaked in BPs and placed directly in contact with the bone or indirectly in the submucosa of the cheek. All studies showed a significant inhibition of bone resorption after surgery. The local administration of BPs in an experimental periodontitis in rats prevented the alveolar bone resorption initiated by the disease (Mitsuta et al, 2002; Goya et al, 2006). Another approach for the topical administration of BPs was the use of synthetic bone substitutes as a drug-delivery system with incorporated BPs. This approach of controlled local delivery of BPs combines the osteoconductive property of the calcium phosphate biomaterials and the osteoclast inhibitory action (Denissen et al, 1994, 1997; Josse et al, 2005).
pyrig No Co t fo r P et al Badran ub lic maxillofacial region, sequestrated bone fragments,atio te Predis- n defective soft tissue healing and severe pain. ss e n c e posing risk factors for the AONJ are the intravenous long-term administration of BPs, dental surgery procedures, anatomical variations (palatal and lingual tori) as well as dental and periodontal infections. Other suggested risk factors are poor oral hygiene, tobacco smoking, diabetes and other bone diseases (e.g. osteoporosis and osteopaenia) (AAOMS Position Paper, 2007; Lam et al, 2007). The best approach to prevent AONJ is a ‘preventive’ approach for those patients at risk. Prerequisites for starting treatment with BPs are dental scanning and good oral hygiene, and also includes the treatment of all potential infection sites (Lam et al, 2007). An interdisciplinary approach must be taken by the treating physician and the most conservative surgical approach possible should be used in patients under treatment with BPs undergoing dental surgeries. The clinician should also decide if an interruption of the BP administration can be done for a short period of time (Marx et al, 2005). Adverse reactions such as allergy to phosphates or gastrointestinal intolerance were documented (Twiss et al, 2001). Also, the second-generation BP, aledronate, may cause oesophageal and stomach ulcers (Parfitt and Driman, 2007).
CONCLUSIONS Based on the present knowledge of BPs, the use of BPs in periodontal research shows a promising method of managing periodontal diseases by modifying the host response. Published studies tend to demonstrate that BPs prevent or at least reduce the alveolar bone loss in comparison with control subjects. Even though animal and human studies have shown a significant improvement in periodontal treatment outcome using BPs, there is a lack of data determining the optimal prescription concentration and formulation. In addition, by changing the prescribed family of BP molecule, a variation in the effects of the periodontal healing can be observed. In particular, the new BP, TRK-530, seems to be promising as it combines anti-inflammatory and bone-resorption-inhibitory properties. The recent published data on AONJ could lead us to the question about the rationality of using BPs in periodontal treatment considering the risk/benefit ratio of such therapeutic treatment. Nevertheless,
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1. AAOMS Position Paper. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonaterelated osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65(3):369–376. 2. Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, Salvagno G et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987;41(6): 326–331. 3. Alencar VB, Bezerra MM, Lima V, Abreu AL, Brito GA, Rocha FA et al. Disodium chlodronate prevents bone resorption in experimental periodontitis in rats. J Periodontol 2002; 73(3):251–256. 4. Axelsson P, Lindhe J. Effect of controlled oral hygiene procedures on caries and periodontal disease in adults. Results after 6 years. J Clin Periodontol 1981;8(3): 239–248. 5. Binderman I, Adut M, Yaffe A. Effectiveness of local delivery of alendronate in reducing alveolar bone loss following periodontal surgery in rats. J Periodontol 2000; 71(8):1236–1240. 6. Blair HC, Athanasou NA. Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 2004;19(1):189–199. 7. Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 1996;271(21): 12517–12524.
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the occurrence of AONJ is limited and the risk that it represents seems to be small in comparison with the overall health benefits for patients treated with BPs. In particular a favourable oral health status before BPs prescription is crucial to minimise the risk of AONJ (Sambrook et al, 2006). A simple way to avoid the side effects could be topical use of BPs with a drug-delivery system. This seems to be a promising therapeutic option and can inhibit post-surgical bone resorption. The use of a biomaterial as a carrier or a controlled drug-delivery system is an innovation and part of a new generation biomaterials acquiring a functional role in addition to their principal use as osteoconductive scaffolds for bone regeneration (Guicheux et al, 2005). However, the benefit of inhibiting or slowing down the bone resorption after implantation of a biomaterial into bone could be questionable. In fact, with this approach the synthetic material will remain in contact with the bone for a longer period of time and therefore the bone-regeneration process will be slowed down. Based on this mini-review of the literature, it can be concluded that there is still a need to develop more clinical studies to support the use of BPs for the reinforcement of the periodontal therapeutic armada. In brief, there is insufficient evidence to suggest the integration of these drugs in the routine periodontal prescription and tissue engineering procedures.
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pyrig No Co t fo rP ub lica 8. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation tio n and activation. Nature 2003;423(6937):337–342. te ss e n c eTB, 9. Brunsvold MA, Chaves ES, Kornman KS, Aufdemorte Wood R. Effects of a bisphosphonate on experimental periodontitis in monkeys. J Periodontol 1992;63(10): 825–830. 10. Buduneli E, Buduneli N, Vardar-Sengul S, Kardesler L, Atilla G, Lappin D et al. Systemic low-dose doxycycline and alendronate administration and serum interleukin-1 beta, osteocalcin, and C-reactive protein levels in rats. J Periodontol 2005;76(11):1927–1933. 11. Buduneli E, Vardar-Sengul S, Buduneli N, Atilla G, Wahlgren J, Sorsa T. Matrix metalloproteinases, tissue inhibitor of matrix metalloproteinase-1, and laminin-5 gamma2 chain immunolocalization in gingival tissue of endotoxin-induced periodontitis in rats: effects of lowdose doxycycline and alendronate. J Periodontol 2007; 78(1):127–134. 12. Buduneli E, Vardar S, Buduneli N, Berdeli AH, Turkoglu O, Baskesen A et al. Effects of combined systemic administration of low-dose doxycycline and alendronate on endotoxin-induced periodontitis in rats. J Periodontol 2004;75(11):1516–1523. 13. D’Aoust P, McCulloch CA, Tenenbaum HC, Lekic PC. Etidronate (HEBP) promotes osteoblast differentiation and wound closure in rat calvaria. Cell Tissue Res 2000; 302(3):353–363. 14. David P, Nguyen H, Barbier A, Baron R. The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H(+)-ATPase. J Bone Miner Res 1996;11(10): 1498–1507. 15. Denissen H, van Beek E, Lowik C, Papapoulos S, van den Hooff A. Ceramic hydroxyapatite implants for the release of bisphosphonate. Bone Miner 1994;25(2):123–134. 16. Denissen H, van Beek E, Martinetti R, Klein C, van der Zee E, Ravaglioli A. Net-shaped hydroxyapatite implants for release of agents modulating periodontal-like tissues. J Periodontal Res 1997;32(1 Pt 1):40–46. 17. Duarte PM, de Assis DR, Casati MZ, Sallum AW, Sallum EA, Nociti FH Jr. Alendronate may protect against increased periodontitis-related bone loss in estrogen-deficient rats. J Periodontol 2004;75(9):1196–1202. 18. Dunstan CR, Felsenberg D, Seibel MJ. Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 2007;4(1):42–55. 19. El-Shinnawi UM, El-Tantawy SI. The effect of alendronate sodium on alveolar bone loss in periodontitis (clinical trial). J Int Acad Periodontol 2003;5(1):5–10. 20. Farrugia MC, Summerlin DJ, Krowiak E, Huntley T, Freeman S, Borrowdale R et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 2006;116(1):115–120. 21. Felsenberg D, Hoffmeister B, Michael Amling M. Bisphosphonattherapie assoziierte. Kiefernekrosen. Deutsches Arzteblatt 2006;46:A3078–A3080. 22. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 1999;96(1):133–138. 23. Fleisch H. Development of bisphosphonates. Breast Cancer Res 2002;4(1):30–34. 24. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov 2004;3(5):401–416.
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