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State of the Art Review Bisphosphonates and Periodontics: Potential Applications for Regulation of Bone Mass in the Periodontium and Other Therapeutic/Diagnostic Uses* Howard C. Tenenbaum, Avi Shelemay, Bruno Girard, Ron Zohar, and Peter C. Fritz Bisphosphonates are widely utilized in the management of systemic metabolic bone disease due to their ability to inhibit bone resorption. Recently, new uses of this unique class of pharmacological agents have been suggested. Given their known affinity to bone and their ability to increase osteoblastic differentiation and inhibit osteoclast recruitment and activity, there exists a possible use for bisphosphonates in the diagnosis and management of periodontal diseases. These bone-specific properties could also provide an interesting management strategy to stimulate osteogenesis in conjunction with regenerative materials around osseous defects and may also result in the promotion of bone formation around endosseous implants. The objective of this article is to review the scientific evidence regarding the potential applications of bisphosphonate drugs in the therapeutic management of periodontal diseases. Moreover, the mechanism of action and the pharmacology of these drugs will be reviewed. Finally, the potential role of bisphosphonates regarding their potential to accelerate bone formation, in addition to their usual uses for inhibition of bone resorption, is discussed. J Periodontol 2002;73:813-822. KEY WORDS Bone regeneration; bisphosphonates; etidronate/ therapeutic use; osteoblasts; osteoclasts; periodontal diseases/prevention and control.

*University of Toronto, Faculty of Dentistry, Toronto, ON, Canada.

J Periodontol • July 2002

It is generally understood that successful management of periodontal disease and its sequelae should be focused on elimination of etiologic factors that are thought to play an important role in the initiation and progression of this group of diseases. Thus, a major focus of periodontal research has been directed towards the reduction and/or elimination of pathogenic bacteria that are thought to cause periodontitis.1 This has been accomplished in large part by the use of mechanical treatment approaches including the use of scaling and root planing, the use of home care measures, and finally, surgical intervention.2-4 In later years, other adjunctive approaches that aim to eradicate or drastically reduce bacterial contributions to periodontal disease initiation or progression have included pharmacological measures, which require the use of systemic5,6 as well as topical7 antimicrobial medications. In addition, there has been increasing evidence that other factors including smoking play an important role in disease prevalence, incidence, and severity;8,9 hence, there is an increasing emphasis on the development of smoking cessation programs. In large part, these measures have proven to be quite successful in that the majority of patients seem to benefit from treatment. These patients experience a cessation in disease progression that is further ensured by the initiation of recall or maintenance programs that require the use of ongoing mechanical debridement of roots and teeth.10 It should also be pointed out that the aforementioned approaches to therapy address issues pertaining to the progression of periodontitis and, in some cases, to prevention. Yet, even when periodontal diseases are controlled or “cured,” patients are often left with anatomical evidence of disease including lost bone and periodontal support for their remaining teeth. Therefore, even newer approaches are being developed to stimulate regeneration of lost periodontal tissues. These treatment options are still in their infancy but show promise nonetheless. Apart from therapy directed toward regeneration, it would appear that most treatments available today are directed toward elimination and/or reductions in exogenous factors that might cause and/or exacerbate periodontal diseases. However, there is an

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State of the Art Review increasing body of evidence suggesting that different approaches which involve modulation of the host might also be useful in the management of periodontitis and its sequelae. Specifically, we refer to modulation of host inflammatory responses11-14 (e.g., prostaglandin inhibition using non-steroidal antiinflammatories), regulation of destructive enzymes (e.g., inhibition of matrix metalloproteinases),15,16 and inhibition of alveolar bone resorption (e.g., osteoclast mediated). It is the purpose of this review to focus on the latter host-mediated phenomenon, alveolar bone resorption, with the use of bisphosphonates. In addition, we suggest that bisphosphonates might be used in areas pertaining to early diagnosis of periodontitis. Finally, we intend to show how bisphosphonates have the potential to actually stimulate new bone formation in the periodontium,17 both around teeth and in surgically created osseous defects such as those prepared for endosseous implants. The overall goals of this review are to discuss the class of drugs known collectively as bisphosphonates, their pharmacology, and putative mechanisms of action. We will then discuss their use or, at least, their potential for use in periodontics. Finally, we intend to demonstrate how a property of bisphosphonates thought to be a deleterious side effect, namely inhibition of mineralization, might be exploited to stimulate new bone in the periodontium and elsewhere. METHODS Scientific evidence was acquired from searches of all publication types in the 1970 to 2001 Medline database. Relevant articles in this topic area were identified by using MeSH headings including but not limited to such terms as “periodontitis” and “bisphosphonates,” and were limited to the English language. In addition to Medline searches, articles were identified manually by

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searching and perusing bibliographies from appropriate sources. BISPHOSPHONATE STRUCTURE AND CLASSIFICATION Bisphosphonates are structurally similar to pyrophosphate, a normal product of human metabolism present in serum and urine that has calcium-chelating properties.18,19 Pyrophosphate modulates mineralization by binding to crystals of hydroxyapatite in vitro and in vivo, but is not a very stable molecule in vivo and undergoes rapid hydrolysis of its labile P-O-P bond as a result of pyrophosphatase and even alkaline phosphatase activity.20 If a carbon atom replaces the linking oxygen atom in the pyrophosphate molecule, a bisphosphonate is formed (Fig. 1). These analogs are

Figure 1. Bisphosphonates are structurally similar to the natural pyrophosphate. A. Retaining the calciumchelating properties of pyrophosphate but replacing the central unstable phosphoanhydride bond with a phosphoether bond (geminal carbon) makes the molecule resistant to hydrolysis under acidic conditions. Altering the structure of the 2 side chains (R1, R2) on the carbon atom will modify their biological activities. B. Affinity for calcium can be increased further if one of the side chains (R1) is a hydroxyl (-OH) or primary amino (-N2H) group. C. Increased potency could be achieved by increasing the length of the R2 side chain attached to the geminal carbon from a single methyl (-CH3) group (as in etidronate) to a longer alkyl chain, while retaining a hydroxyl (-OH) group in the R1 position to maximize the affinity for bone mineral.Tertiary nitrogen within a ring structure in the R2 side chain appears to be the most potent antiresorptive action in vivo.

Bisphosphonates and Periodontal Therapy

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State of the Art Review completely resistant to enzymatic (alkaline phosphatase, pyrophosphatase) hydrolysis and are extremely stable from a chemical perspective. Like pyrophosphate, bisphosphonates bind to the hydroxyapatite crystals of bone and prevent both their growth and dissolution. The binding to bone mineral is enhanced by including a hydroxyl group at R1 (Fig. 1). The R2 structure and 3-dimensional configuration determine the cellular effects of bisphosphonates, and their relative efficacies as inhibitors of bone resorption. Each bisphosphonate has its own activity profile, determined by its unique side chain. Substitution of different side chains for hydrogen at locations R1 and R2 changes the in vitro and in vivo potency and side effect profile of the compound. Alkyl side chains (e.g., etidronate) characterize first-generation bisphosphonates. Second-generation bisphosphonates include aminobisphosphonates with an amino-terminal group (e.g., alendronate and pamidronate). Third-generation bisphosphonates have cyclic side chains (e.g., risedronate). The antiresorptive properties of bisphosphonates increase approximately 10fold between drug generations. BISPHOSPHONATE MECHANISMS OF ACTION Classically, bisphosphonates are used to inhibit bone resorption and thus, it is not surprising that the majority of the literature regarding bisphosphonates is focused on their effects on osteoclasts. Several modes of action have been investigated including bisphosphonate-mediated inhibition of the development of osteoclasts, induction of osteoclastic apoptosis,21 reduction of activity,22 prevention of the development of osteoclasts from hematopoietic precursors,23 and stimulation of production of an osteoclast inhibitory factor.24 It has also been shown that the bisphosphonate alendronate caused a rise in intracellular calcium levels in an osteoclast-like cell line.25 This finding is of great interest since it could suggest the presence of a receptor for bisphosphonates on osteoclasts. Other researchers exposed several sarcoma cell lines to various second-generation bisphosphonates and observed a downregulation of bone resorption that correlated with inhibition of matrix metalloproteinases (MMPs).26 Moreover, it has been shown that low molecular weight bisphosphonates can be metabolized by mammalian cells.27 These observations have recently been corroborated, and it appears that non–nitrogen-containing bisphosphonates cause osteoclast apoptosis through activation of the capsase pathway.28 Conversely, more potent nitrogen-containing bisphosphonates are not metabolized25-31 and appear to affect protein prenylation in osteoclasts


through inhibition of the mevalonate pathway,32 which is involved in cholesterol synthesis. The findings described above clearly separate the less potent bisphosphonates from the more potent nitrogen-containing bisphosphonates with respect to the intrinsic ability to be metabolized, thus indicating that osteoclast activity is altered by bisphosphonates through a variety of mechanisms. It is evident that bisphosphonates may affect bone remodeling through direct action on osteoclasts. A more indirect mode of action suggests that osteoclast function can be altered by the production of an osteoclast inhibitory factor secreted by osteoblasts following exposure to bisphosphonates.24 In addition to their obvious effects on bone-resorbing cells, studies carried out in our laboratory clearly demonstrate that the bisphosphonate 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) has osteostimulative properties both in vitro and in vivo as demonstrated by HEBP-mediated increases in matrix formation and, on cessation of HEBP treatment, increased mineralized bone formation.33,34 These data also showed that HEBP treatment in vivo promotes osteoblastic differentiation in calvarial wounds,35 as well as a reversible stimulation of alveolar and calvarial bone width and reversible reductions in periodontal ligament space width.17 Other data show that abrogation of interleukin (IL)-6 production by bisphosphonates in human osteoblastic cells can occur, which could also affect osteoclastic activity.36 Furthermore, in regard to bisphosphonate action, it is known that bisphosphonates have a strong affinity to the surface of solid-phase calcium phosphate. This union culminates in the inhibition of hydroxyapatite aggregation, dissolution, and crystal formation, a key point that will be addressed below. Yet, the mechanisms of bisphosphonate action on bone resorption in vivo are likely not mediated by their physicochemical effects on crystal growth regulation.37 In fact, bisphosphonate effects on osteoclasts and other bone cells are probably more direct, and expressed at the molecular level as suggested in Table 1.38 Notably, bisphosphonates bound to bone mineral are released during bone resorption by osteoclasts. This could lead to a localized accumulation of bisphosphonate, which could directly perturb osteoclastic activity or indirectly target osteoblasts and macrophages, resulting in decreased osteoclastic chemotaxis and activity.39 BISPHOSPHONATES: USES IN BONE Bisphosphonates have been established as effective therapeutic agents for prevention and treatment of osteoporosis.37 In fact, etidronate and alendronate

Tenenbaum, Shelemay, Girard, Zohar, Fritz

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State of the Art Review of a wide variety of metabolic bone diseases includBisphosphonate Modulation of Bone Metabolism ing osteoporosis and Paget’s disease, as well as sequeTissue Level Cellular Level Molecular Level lae of malignancy including metastasis, and hyper↓ bone turnover due Inhibit mevalonate pathway (can result ↓ osteoclast recruitment to ↓ bone resorption in perturbed cell activity and induction calcemia.28,45-48 Such ↓ osteoclast recruitment of apoptosis) clinical uses are well estab↓ number of new bone lished and not the focus of ↑ osteoclast apoptosis multicellular units ↓ post-translational prenylation of this review. Instead, we GTP-binding proteins ↓ osteoclast adhesion Net positive whole body would like to draw attention bone balance to the potential uses of bis↓ depth of resorption phosphonates in the mansite agement of periodontal ↓ release of cytokines by disease-associated bone macrophages loss. This concept was ↑ osteoblast studied in animal models differentiation and of experimental periodonnumber titis in monkeys,47 where it was demonstrated that the have been approved in many countries and have been bisphosphonate alendronate, when administered intrashown to increase bone mass and reduce fracture venously biweekly at a concentration of 0.05 mg/kg, rates at the spine, hip, and other osseous sites in postcould retard bone loss around affected teeth in commenopausal women.40-42 Bisphosphonates are also parison to controls. Interestingly, although bone loss used in clinical settings for treatment of Paget’s diswas reduced with alendronate, periodontal pocketing ease and tumor-induced hypercalcemia. Similarly, was not. This suggests that although bone loss might they are used as inhibitors of osteoclast activity to be retarded, from a clinical perspective, the effects of alleviate bone pain that results from the release of biobisphosphonate treatment might be difficult to detect chemical mediators in metastatic bone disease. Furor appreciate. Another study showed that while a dose thermore, in addition to reducing bone pain, they can of 0.05 mg/kg of alendronate could inhibit bone loss, decrease hypercalcemia of malignancy, normalizing the higher dose (0.25 mg/kg) did not, which coincalcium concentrations within 48 hours of adminiscides with the finding that alendronate is released in tration and the subsequent risk of pathological or an acidic environment49 (inflamed periodontal pocktumor-related fractures in those patients. Treated ets) from hydroxyapatite and has locally cytotoxic patients exhibit reductions in collagen degradation effects to other stromal cells. In fact, another possiproducts in urine within a few weeks of beginning bisbility, especially in the case of the nitrogen-containphosphonate therapy. However, one of the potential ing bisphosphonates such as alendronate, suggests drawbacks is that these agents require chronic adminthat this class of bisphosphonate might upregulate istration over long periods to be effective in reducing inflammatory processes in vivo through stimulation fracture risks.43 Conversely, they increase bone mass of IL-1 and IL-6.50,51 This could suggest that in the due, in large measure, to their ability to inhibit bone periodontal pocket, higher doses of alendronate may resorption and to reduce activation frequency of bone augment the inflammatory host response. Studies remodeling units, but they also may enhance minerfocusing on local applications might be more sucalization.43 Contraindications may include sensitivity cessful in controlling the actual drug concentration to phosphates and gastrointestinal upset.44 and, hence, regulating or inhibiting alveolar bone resorption. BISPHOSPHONATES: USE IN DIAGNOSIS AND In fact, studies in our laboratory and elsewhere33,52 MANAGEMENT OF PERIODONTITIS have suggested that similar types of bisphosphonates Management of Periodontal Bone Loss can actually inhibit collagen production in bone and As noted above, there are potentially several uses for thus, perhaps, the findings reported by Brunsvold et bisphosphonates in the clinical setting. To reiterate, al.47 are not surprising. The latter study was carried these agents are currently being used in the treatment out largely at a radiographic level, while another hisTable 1.

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State of the Art Review tological study investigated the potential for bisphosphonate-mediated reduction in bone loss associated with experimental periodontitis.53 These studies also seemed to confirm that 0.05 mg/kg of alendronate could inhibit bone loss in ligature-induced periodontitis. These authors suggested that from the perspective of osteoclast inhibition, bisphosphonates might prove useful from a clinical perspective to inhibit bone loss in humans with periodontitis. Of course, the previous investigation utilized experimentally induced periodontitis in the monkey, so there were questions as to whether the bisphosphonate drugs would be useful in naturally occurring periodontitis. This was demonstrated in the beagle dog, an animal that naturally develops periodontitis.54 In this model, the dogs received a weekly oral dose of 3.0 mg/kg alendronate. However, the results were not quite as robust, demonstrating only trends in reduction of bone loss in alendronate-treated dogs. Similar to previous findings, though, the investigators did show that there were no differences in signs of inflammation or pocketing, but there were still increases in bone mineral density. One possible reason for the somewhat less robust response could be related to the use of naturally occurring disease, but it is also possible that the different dose of alendronate (3.0 mg/kg) could have had a paradoxically reduced effect as predicted in previous investigations suggesting an optimal dose in the 0.05 mg/kg range (in monkeys).53 In addition, although periodontitis occurs naturally in the beagle dog, the investigators magnified disease activity by the use of ligatures; thus, it is possible that a more aggressive disease was present than in the monkey model. Interestingly though, after ligature removal, the alendronate-treated animals actually regained bone while the controls did not, further suggesting the potentially beneficial effects of bisphosphonate drugs in treating periodontitis. In addition to the potentially useful effects of the bisphosphonates in preventing periodontitis-associated bone loss, other studies have focused on the potential effects of bisphosphonates in relation to regional accelerated phenomenon (RAP).55 This phenomenon was noted, or at least findings relating to this were observed, as early as 1962.56,57 In fact, it was shown that the bisphosphonate alendronate could inhibit bone resorption induced as a result of flap elevation and attendant RAP.58 Notably, these investigators suggested initially that topical administration of a bisphosphonate was ineffective in preventing flap-induced bone resorption,58 while intravenous administration was quite effective. However, in later studies, this same group demonstrated that topical


administration using a somewhat different local administration vehicle could, in fact, inhibit flapinduced bone loss.59,60 Taken together, it would appear that there may be a potentially important role for bisphosphonates in the prevention of periodontitis- or flap-associated bone loss that occurs in the periodontium. Diagnosis of Periodontal Bone Loss Although it would seem that the most important clinical use for bisphosphonates would be related to inhibition of bone loss, their affinity for newly mineralizing bone or actively remodeling bone makes these drugs ideal for diagnostic purposes as well, when combined with radiolabels, a field known as nuclear medicine. Indeed, there are a number of investigations suggesting that radiolabeled bisphosphonate can be used to detect periodontal bone loss61-65 in animal models. This has also been demonstrated in human periodontitis.66-68 Further studies also demonstrated that radiolabeled bisphosphonates can be used to detect changes of metabolic activity at skeletal sites,69 bone loss associated with periodontal disease, and cessation of bone loss following treatment with the anti-inflammatory flurbiprofen in both animals70 and humans.71 These findings suggested it is conceivable that early intervention or more aggressive therapy can be initiated if and when radiolabeled bisphosphonate uptake demonstrated with nuclear scanning indicates that bone loss is occurring. Given the above, it would appear that in the area of periodontology, bisphosphonates might have potential usefulness not only for treatment or prevention of bone loss associated with periodontitis but also possibly as aids in diagnosis and early intervention. That being said, the diagnostic use of bisphosphonates probably has not come into routine use for reasons related to cost, accessibility, and full-body irradiation that would occur since these agents have to be administered intravenously. Nonetheless, it seems that there is a strong rationale for using bisphosphonates therapeutically for prevention of bone loss observed in patients with periodontitis. THE POTENTIAL ROLE OF ETIDRONATE FOR STIMULATION OF BONE FORMATION Inverse Relationship Between Mineralization and Bone Matrix Formation To this point, we have discussed the use of bisphosphonates with respect to their known affinity to mineralizing bone (hence, their diagnostic use) as well as their ability to inhibit bone resorption (hence, the potential clinical utility for prevention of periodonti-


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State of the Art Review tis-associated bone loss). Yet, another effect of most bisphosphonates is their ability to inhibit mineralization. All bisphosphonates have this ability, but these drugs have been engineered so as to magnify their anti-resorptive effects, meaning that the newer drugs can be used in doses that are low enough so as to not inhibit bone mineralization.72,73 Indeed, at first glance, it would seem most logical to minimize the potential inhibitory effects that the bisphosphonates have on mineralization. Yet, our laboratory has described what appears to be an inverse relationship between osteoid matrix formation and mineralization. Using an in vitro periosteal model system in which bone formation has been shown to occur,74 our laboratory has demonstrated consistently that when mineralization is stimulated, bone matrix formation is inhibited.75,76 These findings led us to speculate that intentional but reversible inhibition of mineralization might actually be used to accelerate bone formation (osteoacceleration).

mineralization to occur, thus leading to increased bone formation. On the basis of these in vitro studies, it was concluded that etidronate was in fact capable of inhibiting mineralization reversibly, consequently stimulating osteoid formation, and that upon removal of etidronate from the culture media, mineralization ensued with a net increase in total bone volume that was also more densely mineralized than the controls.33,34,79 Interestingly, this effect was detected in another investigation using an in vivo ankylosis model system, but the phenomenon described here was not apparently recognized.80 Further studies in our laboratories have demonstrated this phenomenon in vivo using 2 different wound healing models: a periodontal wound healing system,17 and a calvarial wound healing model.34,35 In the latter study, direct stimulation of bone matrix formation was demonstrated during etidronate treatment, as well as virtually complete mineralization of new bone matrix, once etidronate treatment (15 mg/kg) was stopped. Given the above, it would then appear that bisphosphonates and etidronate in particular might not only be useful for prevention of osteoclast-mediated bone loss but also, under the appropriate conditions, for stimulation of bone formation. In fact, ongoing investigations in our laboratories (with thanks to Drs. Douglas Deporter and Robert Pilliar) have suggested that etidronate might be used to stimulate bone matrix growth into a porous-coated titanium endosseous implant system (Fig. 2).

Osteoacceleration With Etidronate Given the above, a pharmacological agent with the potential to reversibly inhibit mineralization of bone was required. It seemed that one of the first-generation bisphosphonates, etidronate, might be useful in this regard if utilized in a pulsatile fashion in a dose high enough to inhibit mineralization without being toxic. In fact, such an approach (pulsatile dosing) had already been described for treatment of osteoporosis,77,78 although the notion of intentional inhibition of mineralization had not been elucidated. Thus, etidronate has been demonstrated to inhibit bone resorption but at a dose that is also quite close to that required to inhibit mineralization. Further investigations in our laboratory were carried out to determine whether etidronate might be used in a high-dose pulsatile fashion to stimulate Figure 2. A porous-coated dental implant was placed in the distal femur of mature male New Zealand mineralized bone formation. rabbits.The histologic view (×10 magnification) of specimens harvested after 6 days of healing The rationale for this was that if demonstrated very little implant-bone contact and bone ingrowth in control animals (A). Rabbits mineralization of bone could be treated with HEBP (s.c. injections) demonstrated abundant amounts of newly formed osteoid that inhibited temporarily with etidhad formed adjacent to and deep within the porous-coated layer (B), and even mineralized bone ronate, matrix formation might ingrowth (C) after 6 days of healing.This level of bone/osteoid ingrowth is not routinely observed in control animals at this time point.The osteoid (O) has grown up to and within the titanium be increased. Once the “excess” spheres/porous coating (TP), and can be seen deep within the TP layer (arrow heads) in B and C. matrix was formed, it was posHowever, in A, bone (B) is closely adapted to the TP layer but has not grown deeply into the layer tulated that removal of the (arrows). etidronate would then allow

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State of the Art Review POTENTIAL MECHANISMS UNDERLYING HEBP-INDUCED STIMULATION OF BONE FORMATION The mechanisms by which mineralization and osteoid formation are coupled in physiological and pathological processes are poorly understood, in part, due to the challenges of appropriately modeling these processes in vitro. In vitro osteogenic model systems enable mechanistic studies of matrix formation and mineralization and, potentially, identification of the genes that regulate coupling. In these systems, induction of mineralization with organic phosphate down-

regulates bone matrix formation, while inhibition of mineralization causes increased bone matrix formation.33 Breakdown products of the organic phosphates, phosphoethanolamine (PEA) or pyridoxal phosphate (PLP), could regulate or even stimulate mineralization as they might be metabolized intracellularly by osteoblasts following alkaline phosphatase-mediated hydrolysis. We suggest that ethanolamine, pyridoxal, or glycerol (all breakdown products of alkaline phosphatase-mediated hydrolysis of organic phosphates) perturb gene expression in osteoblastic cells. Using the chicken periosteal osteogenesis model as well as

Figure 3. Organic phosphates such as phosphoethanolamine, pyridoxal phosphate, or ß-glycerophosphate (the latter being in vitro only) are thought to induce mineralization partly through release of inorganic phosphate following their hydrolysis by alkaline phosphatase. However, release of inorganic phosphate, which would theoretically be utilized for hydroxyapatite formation, probably does not explain the complete phenomenon.This model suggests that the breakdown products (ethanolamine, pyridoxal, or glycerol) derived from alkaline phosphatase-mediated hydrolysis of organic phosphates are rephosphorylated on entering the cell (they cannot enter the cell in their phosphorylated forms). Once in the cell and rephosphorylated, they could conceivably regulate a variety of intracellular processes including synthesis of collagen (downregulation) and non-collagenous proteins (upregulation). It is also hypothesized that HEBP, which is known to inhibit alkaline phosphatase, will therefore inhibit alkaline phosphatase-mediated breakdown of the organic phosphates. Since the phosphorylated molecules cannot traverse the cell membrane, their downstream effects on collagen and non-collagenous protein synthesis would be inhibited. As indicated in the text, preliminary experimental data show that ethanolamine alone can stimulate mineralization and downregulate collagen synthesis in vitro as would be expected on the basis of this model. This hypothetical mechanism could explain how HEBP may stimulate matrix formation while concurrently inhibiting mineralization.



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State of the Art Review other models of osteogenesis, we have shown that organic phosphate treatment not only induces physiological mineralization of osteoid formed in vitro, but also downregulates collagen formation. Hence, it stood to reason that intentional but transient inhibition of mineralization using a pulse chase approach should actually stimulate mineralized bone formation.33 Preliminary findings show that pyridoxine, which like pyridoxal is a dephosphorylated breakdown product (both being dietary forms of vitamin B6) (unpublished data) of PLP, dramatically stimulates mineralization in vitro (see diagram regarding putative mechanisms, Fig. 3) and, on its own, inhibits collagen synthesis. In Figure 3, we outline a possible mechanism whereby HEBP and other factors might play a role. As explained in this figure, HEBP might, in addition to its ability to directly inhibit hydroxyapatite formation, interfere with alkaline phosphatase-mediated hydrolysis of organic phosphates, which otherwise would have mediated downstream effects on bone formation including upregulation of the synthesis of putative nucleators of mineralization such as bone sialoprotein, and downregulation of collagen synthesis. The details of this proposed mechanism are outlined in more detail in Figure 3. CONCLUSION Bisphosphonates represent a class of pharmacological agents that have potentially important applications in periodontics and the treatment of metabolic bone diseases. It is also conceivable that in the future, not only will such drugs be used to prevent bone loss observed in periodontal diseases and even around implants, but also to possibly stimulate new bone formation. Thus, bisphosphonates could be used in conjunction with regenerative therapies, and even for stimulation of bone growth into and around endosseous implants as shown in Figure 2. Whether early or later biomechanical advantages or disadvantages exist vis-a-vis implant retention remains to be seen. For example, the early osteoid phase of healing would likely reduce initial implant stability, while over the longer term, increased bone ingrowth could lead to greater implant stability and retention success. In any case, it would appear that bisphosphonate use in periodontics, both from a diagnostic and therapeutic perspective, provides a potentially exciting avenue for future exploration. ACKNOWLEDGMENTS The authors gratefully acknowledge the help of Mrs. Caroline Chu, who assisted in the preparation of this

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manuscript. The authors also thank Dr. Douglas Deporter, Dr. Robert Pilliar, and Ms. Nancy Valiquette, who provided the histological slides in Figure 2. REFERENCES 1. Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: Current concepts. J Periodontol 1992;63(Suppl.):322-331. 2. Isidor F, Karring T. Long-term effect of surgical and non-surgical periodontal treatment. A 5-year clinical study. J Periodont Res 1986;21:462-472. 3. Lindhe J, Westfelt E, Nyman S, Socransky SS, Haffajee AD. Long-term effect on surgical/non-surgical treatment of periodontal disease. J Clin Periodontol 1984;11: 448-458. 4. Berglundh T, Krok L, Liljenberg B, Westfelt E, Serino G, Lindhe J. The use of metronidazole and amoxicillin in the treatment of advanced periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol 1998;25:354-362. 5. Lopez NJ, Gamonal JA, Martinez B. Repeated metronidazole and amoxicillin treatment of periodontitis. A follow-up study. J Periodontol 2000;71:79-89. 6. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, Smith RA. Metronidazole in periodontitis: Reduced need for surgery. J Clin Periodontol 1992;19:103-112. 7. Jeffcoat MK, Bray KS, Ciancio SG, et al. Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improves attachment level compared with scaling and root planing alone. J Periodontol 1998;69:989-997. 8. Albandar JM, Streckfus CF, Adesanya MR, Winn DM. Cigar, pipe, and cigarette smoking as risk factors for periodontal disease and tooth loss. J Periodontol 2000; 71:1874-1881. 9. Haber J, Wattles J, Crowley M, Mandell R, Joshipura K, Kent RL. Evidence for cigarette smoking as a major risk factor for periodontitis. J Periodontol 1993;64:16-23. 10. Axelsson P, Lindhe J. The significance of maintenance care in the treatment of periodontal disease. J Clin Periodontol 1981;8:281-294. 11. Paquette DW, Williams RC. Modulation of host inflammatory mediators as a treatment strategy for periodontal diseases. Periodontol 2000 2000;24:239-252. 12. Feldman RS, Szeto B, Chauncey HH, Goldhaber P. Non-steroidal anti-inflammatory drugs in the reduction of human alveolar bone loss. J Clin Periodontol 1983; 10:131-136. 13. Jeffcoat MK, Williams RC, Wechter HG, et al. Flurbiprofen treatment of periodontal disease in beagles. J Periodont Res 1986;21:624-633. 14. Jeffcoat MK, Williams RC, Reddy S, English R, Goldhaber P. Flurbiprofen treatment of human periodontitis: Effect on alveolar bone height and metabolism. J Periodont Res 1988;23:381-385. 15. Ryan ME, Golub LM. Modulation of matrix metalloproteinase activities in periodontitis as a treatment strategy. Periodontol 2000 2000;24:226-238. 16. McCulloch CA, Birek P, Overall C, Aitken S, Lee W, Kulkarni G. Randomized controlled trials of doxycycline in the prevention of recurrent periodontitis in highrisk patients: Antimicrobial activity and collagenase


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Correspondence: Dr. H. C. Tenenbaum, Biological & Diagnostic Sciences, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON M5G 1G6. E-mail: howard. [email protected]. Accepted for publication February 8, 2002.
