Journal Facts

Journal
BoneKEy Knowledge Environment
ISSN
1940-8692
Volume
8
Year
2011

Article Facts

Title
Bisphosphonates in periodontitis: Friend or foe?
DOI
10.1138/20110508
Authors

Serge Ferrari
Nicolas Bonnet
Philippe Lesclous

Online Date
04/00/2011

Article Links

IBMS BoneKEy | Commentary

Bisphosphonates in periodontitis: Friend or foe?

Serge Ferrari
Nicolas Bonnet
Philippe Lesclous


DOI:10.1138/20110508

Commentary on: Aghaloo TL, Kang B, Sung EC, Shoff M, Ronconi M, Gotcher JE, Bezouglaia O, Dry SM, Tetradis S. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res. 2011 Feb 23. [Epub ahead of print]

Periodontal disease (PD) refers to the common inflammatory disorders of tissues surrounding and supporting the teeth: inflammation of the gingival tissue leading to gingivitis, and of the periodontal ligament and alveolar bone leading to periodontitis. PD is caused by pathogenic local microflora, as opposed to invasion by pathogenic microorganisms. Consecutive inflammation that extends deep into the tissues causes loss of supporting connective tissue and alveolar bone, resulting in loosening of the teeth in susceptible hosts (). Periodontitis is a common problem as it is estimated that 48.2% of the U.S. population aged ≥ 30 years is affected, with up to 20% of subjects showing severe attachment loss in the NHANES III survey (). Moreover, PD has been associated with osteoporosis (). A few small but controlled, sometimes randomized, studies have suggested that bisphosphonates (BPs), particularly alendronate and risedronate, may reduce the radiological and/or clinical signs of PD, including alveolar bone loss, gingival index and bleeding (). A larger, 2-year, randomized controlled trial of weekly alendronate (70 mg) in 355 men and women showed no significant effect of alendronate on alveolar bone loss (alveolar crestal height) overall, but a preservation in a subgroup of subjects with low mandibular bone mineral density (BMD) at baseline (). Moreover, only 30 teeth were lost in the alendronate group, vs. 52 in the placebo group. The rate of overall and specifically oral/dental adverse events did not differ between treated and placebo groups. Osteonecrosis of the jaw (ONJ) did not occur, which is not surprising considering the limited number of relatively low risk subjects, i.e., not cancer patients, included in this study. On another side, patients with a history of inflammatory dental diseases, i.e., PD and dental abscesses, may be at increased risk for developing ONJ when receiving BPs (). The clinical benefits of BPs in periodontitis are supported by a number of experimental data in animals, which are summarized below. In this context, a recent experimental model published by Aghaloo et al. () showing bone lesions consistent with ONJ in rats receiving zoledronate raises questions regarding the benefit/risk of BP administration in periodontitis.

Experimental periodontitis

The rice rat was the first model, reported in the mid-fifties, to investigate the development of PD (). In 1981, Gotcher and Jee reported the detailed mandibular bone histology of the rice rat administered a high sucrose diet for 18 weeks (). Their work demonstrated an early and heavy infiltration of the epithelium by inflammatory cells (PMNs and lymphocytes), followed by a marked increase of osteoclasts and loss of alveolar bone. This inflammation results from an infectious gingivitis by enterococci, as previously shown by the periodontal response to antibiotic therapy (). Some animals showed a total destruction of the periodontium and only small spicules (fragments) of alveolar bone were left at 18 weeks, in which the bone surface appeared “quiescent” whereas other bone spicules contained some osteoclasts. In addition, there were large vascular spaces and a marked proliferation of fibroblasts, while the overall number of osteoblasts was unchanged at any time point (). This experiment demonstrated, therefore, that severe periodontitis, that is, local infection and inflammation, could lead to the destruction of alveolar bone with the appearance of small necrotic bone remnants.

In parallel, these authors treated a group of rice rats with clodronate, an early generation non-nitrogen-containing BP, at doses from 0.1 to 10 mg/kg/d for up to 18 weeks (). The amount of alveolar bone was increased by the higher doses of clodronate, and the vascular spaces were reduced. Osteoblast numbers were also reduced in the treated animals. Trabeculae of alveolar bone lined with epithelial cells and heavily infiltrated by PMNs were observed protruding into the oral cavity. Portions of alveolar crestal bone exposed to the oral cavity and devoid of bone cells as well as scalopped spicules were also observed. The authors concluded that the main effect of clodronate in this experiment was to increase bone mass in the interdental alveolar space, but also that inhibition of bone remodeling delayed the removal of necrotic bone remnants.

Similarly, in a rat model in which inflammatory periodontitis was created by placing an elastic ring around the neck of the right mandibular first molar, short term (7 days) injections of risedronate (0.8 to 3.2 μmol/kg/d) prevented the resorption of alveolar bone and the loss of bone mineral content in a dose-dependent manner (). The authors reported the presence of large, “frustrated” osteoclasts detached from the bone surface, but no differences in the degree of inflammation compared to controls, nor the presence of necrotic bone. It is unclear whether or not the investigators looked specifically for exposed bone in the oral cavity. Effects of alendronate on the preservation of alveolar bone were also shown in a cynomolgus monkey periodontitis model after both tooth ligature and bacterial inoculations ().

In beagle dogs in which naturally-occurring periodontitis was exacerbated by silk ligature of the study teeth, oral alendronate (3 mg/kg/d) for 6 months preserved jaw bone mass compared to placebo (as evaluated by digital image analysis of oral radiographs), and had no effect on clinical parameters of gingival inflammation or plaque (). Moreover, intramuscular pamidronate (0.6 mg/kg every 3 days for 3 months) inhibited alveolar bone resorption in experimentally-induced peri-implantitis in beagle dogs (). In contrast, after administering a “clinical dose” (0.2 mg/kg/d) or a high dose (1 mg/kg/d) of alendronate for 3 years, Allen and Burr noted areas of necrotic alveolar bone, as assessed by the absence of basic fuchsin staining, in 3 and 4, respectively, out of 12 dogs in each treatment group, vs. none in the control group (). The absence of staining in this case represents a disruption of the canalicular network, i.e., an indirect sign of osteocyte apoptosis. The authors found no sign of avascular necrosis, as vessels were always present, and no animals with exposed bone in the oral cavity. As concluded properly by the authors, the areas of dead bone matrix are not necessarily caused by the BP, but could be explained by naturally dead (old) bone remaining rather than being removed since bone remodeling is low with BP treatment. To support the latter conclusion, areas of dead bone were also found in the ribs (). Moreover, in a separate study with zoledronic acid (0.06 mg/kg/month) for 6 months, no animals showed evidence of necrosis based on fuchsin staining (). However, at this early six-month time point, on lactate dehydrogenase staining the number of necrotic osteocytes was higher in the zoledronic acid group than in either the alendronate or control groups.

The rat model recently published by Aghaloo et al. also induced severe PD by wire ligature placement around the crown of the right maxillary first molar (). Consistent with the other studies, ligature placement induced significant alveolar bone loss, which was attenuated by zoledronic acid treatment (66 μg/kg three times per week for 3 weeks prior to intraoral procedures). Zoledronate also significantly reduced the distance between the cementoenamel junction (CEJ) and the alveolar bone crest (ABC). However, osteonecrosis was observed associated with ligature-induced periodontitis in 47% of the zoledronate group and 5% of controls. This was seen as sequestration and extensive periosteal alveolar bone on μCT in the ligated site of BP-treated animals. Histologic examination confirmed these findings, including observation of necrotic bone with diffuse loss of osteocytes (of which apoptosis was increased as evaluated by TUNEL) and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and exposure to the oral cavity in 21% vs. 0% of zoledronate and control groups, respectively. The authors propose a mechanism by which non-resorbed alveolar bone under the effects of BPs remains in the vicinity of the inflammatory and infected nidus, in which a toxic environment of osteonecrosis can develop.

A mouse genetic model of PD has been reported recently, i.e., the periostin-deficient mouse (). Periostin is an extracellular matrix protein, synthesized by osteoblasts/osteocytes, that is linked to type I collagen in the periodontal ligament, where it regulates fibrillogenesis and consequently the biomechanical properties of fibrous connective tissues around the tooth. Its expression is increased in the periodontal ligament upon mechanical loading and is essential for the integrity and function of this ligament during occlusal loading. Periostin-deficient mice show severe alterations in tooth (incisor) eruption, resulting from a failure to digest collagen fibers in the shear zone of the periodontal ligament (). As a consequence, the enamel and dentin of the incisors are compressed and disorganized, and these mice develop severe periodontitis, with loss of alveolar bone. The severity of periodontitis, however, can be moderated with age and a soft diet. These mice also have osteopenia and a reduced response to mechanical loading (), thereby representing a unique model of osteoporosis and PD, as often seen in aging humans. Repeated administration of high-dose zoledronate (100 μg/kg/week, equivalent to 6-times the monthly dose in cancer patients, i.e., 4 mg) for 3 months in periostin-deficient mice improved basal BV/TV in the mandible and trabecular BV/TV in long bones, without significant changes in alveolar BV/TV nor in the distance between enamel-cement and alveolar bone (DEA), an index of apparent bone in the oral cavity (). Moreover, histological analysis based on standard HE and toluidine blue stainings provided no signs of worsening inflammation nor necrotic bone in the zoledronate group, despite some increase in the number of empty osteocytic lacunae.

Discussion

The rat experiment reported by Aghaloo et al. is the first to indicate that BP administration in periodontitis could lead specifically to ONJ. Through infection and inflammation, severe periodontitis causes alveolar bone loss and can also lead to bone matrix necrosis. In the presence of infectious/inflammatory sockets and in the absence of bone remodeling, necrotic bone remnants could therefore develop and persist, eventually protruding into the oral cavity. This was suggested from the early studies with clodronate in the rice rat, and is consistent with the interpretation of their own data by Aghaloo et al. Nevertheless, it remains unclear why these rats developed lesions compatible with ONJ, i.e., exposed bone in the oral cavity, while in the mouse genetic periodontitis model (periostin-deficient mice), as well as in beagle dogs, this was not the case. Besides obvious species and sex differences, contrasting results could be explained by the higher cumulative dose of zoledronate administered over a short period of time in the Aghaloo et al. study, which is equivalent to the human monthly 4-mg dose given 9 times over the course of 3 weeks in these rats. It could also be due to the aggressive periodontitis induced by the tooth wire ligature, whereas inflammation does not appear to be so severe with cotton or silk ligature generally used in the recent periodontal literature (), as well as in the periostin-deficient mouse.

Thus far, the animal models showing necrotic bone lesions compatible with ONJ upon BP administration were based on multiple and traumatic molar tooth extractions, causing tooth fragments and tissue ulcerations in the jaw (). In some experiments, high-dose dexamethasone was administered concomitantly (). The limitations of the Sonis et al. study () have been commented upon previously in BoneKEy () and there is no proof thus far that BPs, or any anti-resorptive, directly cause bone necrosis in the mandible/maxilla in humans (). Utilizing pharmacological agents at clinically-relevant doses and dosing schedules will be important to strengthen the validity of the models. Equally important will be to perform time-dependent dynamic histomorphometry analyses of the mandibular/maxillar bones in order to evaluate the relationship between bone remodeling and the development, or persistence, of osteonecrotic fragments.

Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.