Bisphosphonate therapy for bone loss in patients with osteoporosis and periodontal disease: clinical perspectives and review of the literature.

As the baby boomer generation in the United States ages, more patients are using bisphosphonates for systemic bone diseases like osteoporosis. Because of their ability to inhibit bone resorption and osteoclastic activity, bisphosphonates may also be beneficial in modulating host response for periodontal disease management. This literature review examines the mechanism of action for bisphosphonates and their uses in treating periodontal disease. The dental profession should continue to evaluate this class of drugs and to closely monitor patients who are on bisphosphonate therapy.     

Osteoporosis and osteopenia: implications for periodontal and implant therapy

How does low bone mineral density alter treatment decisions? Osteoporosis and osteopenia are major health care issues that may impact on periodontal and implant therapy. Because of the prevalence of osteoporosis, understanding its etiology and the current treatment regimens for patients with low bone mineral density is essential for dental professionals. Millions of patients are now taking medications for the treatment of osteoporosis, and periodontists should be aware of the many medication options that are prescribed. The most frequently prescribed drugs are the bisphosphonates. It is important to be aware that bisphosphonates are not all the same, and patient responses to treatment may vary depending on which bisphosphonates they are taking. Due to recent concerns about bisphosphonate‐induced osteonecrosis of the jaw, this paper provides guidance to help the clinician regarding decision‐making about preventive and interventional dental treatment when their patient has been prescribed a bisphosphonate. An understanding of current bisphosphonates, their uses, their structural differences and their intended actions helps to improve clinical decision‐making. Current knowledge regarding the effects of osteoporosis/osteopenia on periodontal diseases and alveolar bone loss is inconclusive. It is certainly clear that bisphosphonates are not indicated as an adjunctive treatment as part of periodontal therapy because of the risk of osteonecrosis. Regarding implant placement, there are no convincing data that dental implant placement is contraindicated in the osteoporotic patient. However, patients should understand the small risk of compromised bone healing following implant placement if the patient has been taking bisphosphonates. Due to the risks of osteonecrosis, dental clinicians should work closely with their medical colleagues prior to the physician prescribing oral bisphosphonates. Ideally, optimal periodontal and dental health should be established before the patient commences bisphosphonate therapy.     

双膦酸盐性颌骨坏死：病例报告及文献复习

双膦酸盐类药物临床用于治疗骨质疏松症、变形性骨炎和其他代谢性骨病、多发性骨髓瘤以及与肿瘤转移相关的骨骼疾病。该类药物通过抑制破骨细胞介导的骨吸收而产生临床治疗作用。然而,双膦酸盐类药物,尤其是静脉用双膦酸盐类药物有致颌骨骨坏死的危险。目前,国内尚未有该类药物致下颌骨坏死的报道。作者报告1例口服双膦酸盐类药物阿仑膦酸钠（Alendronate,商品名福善美,Fosamax）致下颌骨骨坏死病例,并结合文献对双膦酸盐性颌骨坏死的发病机制、临床表现及其预防和治疗进行讨论。     

Mediators of periodontal osseous destruction and remodeling: principles and implications for diagnosis and therapy

Osteoclastic bone resorption is a prominent feature of periodontal disease. Bone resorption via osteoclasts and bone formation via osteoblasts are coupled, and their dysregulation is associated with numerous diseases of the skeletal system. Recent developments in the area of mediators of osteoclastic differentiation have expanded our knowledge of the process of resorption and set the stage for new diagnostic and therapeutic modalities to treat situations of localized bone loss as in periodontal disease. This review describes the current state of knowledge of osteoclast differentiation and activity, mediators, and biochemical markers of bone resorption and their use and potential use in clinical periodontics. Finally, therapeutic strategies based on knowledge gained in the treatment of metabolic bone diseases and in periodontal clinical trials are discussed, and the potential for future strategies is proposed relative to their biologic basis. The intent is to update the field of periodontics on the current state of pathophysiology of the osteoclastic lesion and outline diagnostic and therapeutic strategies with a rational basis in the underlying biology.     

The use of bisphosphonates in children: review of the literature and guidelines for dental management

Bisphosphonates are inhibitors of osteoclastic bone resorption with therapeutic benefit in a variety of bone disorders in both adults and children. While these agents have been routinely used in adults for the past three decades, their more recent introduction into paediatric medicine means there is a paucity of data on long‐term safety and effects on dental development. There is uncertainty regarding the dental management of children treated with bisphosphonates, particularly when invasive dental procedures, such as extractions and oral surgical procedures, are required. There are limited data with which to make recommendations about the dental management of patients treated with bisphosphonates, and there are no published recommendations that specifically address paediatric patients. This paper aims to outline paediatric uses and adverse effects of bisphosphonates and present recommendations on the dental management of children receiving bisphosphonates.     

Tetracyclines in the management of periodontal diseases

Abstract Periodontal diseases essentially comprise a group of oral infections whose primary aetiological factor is dental plaque. Removal of the cause (and its effects) is the primary aim of both non-surgical and surgical treatment regimens, although the infective nature of the diseases has led to the widespread use of antimicrobials as an adjunct to mechanical debridement. The tetracyclines are primarily bacteriostatic agents that are effective against many Gram-negative species including putative periodontopathogens such as Actinobacillus actinomycetemcomitans (A.a.). The proven efficacy of this group of drugs in the management of periodontal diseases may be related not only to their antibacterial actions, but to a number of additional properties that have been recently identified. These include collagenase inhibition, anti-inflammatory actions, inhibition of bone resorption and their ability to promote the attachment of fibroblasts to root surfaces. Consequently, tetracyclines have also been used as an adjunct to bone grafting in periodontal defects, and as agents for “conditioning” root surfaces to enhance the regeneration of periodontal tissues. When tetracyclines are taken orally, consideration must be given both to the potential unwanted effects and to interactions with other drugs that are taken concurrently. Such problems are minimised however, when the drugs are incorporated into controlled, slow-release formulations which are currently being researched and marketed for intra-oral use.     

The role of histopathology in the diagnosis and prognosis of periodontal diseases

The histological evaluation of surgical biopsies from affected tissues is a standard way of assessing pathological change and determining treatment in many diseases. In most forms of periodontal disease, however, this approach finds limited application. Here, we review what uses the histopathological approach has in the study and evaluation of the periodontal diseases. Current understanding of the changes in epithelial anatomy during pocket formation, the cellular composition and dynamics of the inflammatory infiltrate and the mechanisms of bone resorption and repair are reviewed from the perspective of the information available from microscopical investigation, including the uses and potential application of modern immunocytochemical methods to these questions. The usefulness of histological study of biopsy material is reassessed in the light of advances made in immunohistochemical techniques and their application to gingival inflammatory infiltrates and epithelia. Such techniques offer immediately valuable research opportunities with potential for diagnostic applications, noteably the recognition of phases of destructive activity and their differentiation from periods of effective host defence.     

Phytochemicals That Stimulate Osteoblastic Differentiation and Bone Formation

Some bone diseases, such as osteoporosis and periodontitis, result from an imbalance in bone remodeling characterized by excessive bone resorption relative to bone formation. Two different pharmacological approaches can be used to treat such diseases: anti-resorptioe agents that inhibit osteoclastic bone resorption, and anabolic agents that stimulate osteoblastic bone formation. Anti-resorptioe agents, such as bisphosphonates and calcitonin, are currently available for the treatment of osteoporosis ; however, these anti-resorptioe agents are unlikely to have an anabolic effect, and the need for anabolic agents aimed at increasing bone mass has recently been a matter for concern. Natural compounds could provide the basis for developing anabolic agents. A wide variety of natural compounds has recently been found to stimulate osteoblastic bone formation. This review describes the effects of natural compounds on osteoblast proliferation, differentiation, and bone formation in vitro and in vivo.     

双磷酸盐类药物用于牙周炎治疗的研究进展

牙周炎是一种由致病菌引起的炎症破坏性疾病，可造成包括牙槽骨吸收在内的一系列牙周组织破坏。双磷酸盐类（BPs）药物具有调节骨吸收、潜在性促进骨形成的作用；在对动物实验性牙周炎的治疗中表现出抗炎和阻断骨吸收的作用；并已逐渐应用于人牙周炎的辅助性治疗。本文就BPs对牙槽骨代谢调节的机制和牙周炎治疗应用方面的新进展作一综述。     

Advantages and disadvantages of the use of bisphosphonates in oral and maxillofacial surgery

Bisphosphonates are a class of drugs of proven efficacy in the prevention and treatment of various bone diseases, affecting bone turnover by decreasing bone resorption by different mechanisms. In recent years, this class of drugs has become the target of numerous studies in relation to oral and maxillofacial surgery. The aim of this paper is to review the literature on the effects of bisphosphonates in this context, especially in the development of osteonecrosis and as adjuvant in implant placement, osteogenic distraction and bone grafting surgery.     

Effects of antiresorptive medications on tooth root formation and tooth eruption in paediatric patients

Tooth eruption is a pivotal milestone for children's growth and development. This process involves with the formation of the tooth root, the periodontal ligament (PDL) and the alveolar bone, as the tooth crown penetrates the bone and gingiva to enter the oral cavity. This review aims to outline current knowledge of the adverse dental effects of antiresorptive medications. Recently, paediatric indications for antiresorptive medications, such as bisphosphonates (BPs), have emerged, and these agents are increasingly used in children and adolescents to cure pathological bone resorption associated with bone diseases and cancers. Since tooth eruption is accompanied by osteoclastic bone resorption, it is expected that the administration of antiresorptive medications during this period affects tooth development. Indeed, several articles studying human patient cohorts and animal models report the dental defects associated with the use of these antiresorptive medications. This review shows the summary of the possible factors related to tooth eruption and introduces the future research direction to understand the mechanisms underlying the dental defects caused by antiresorptive medications.     

非甾体抗炎药物在牙周炎治疗中应用研究进展

牙周炎是发生在牙周组织的慢性感染性疾病,其主要临床表现为牙龈红肿出血、牙周袋形成、牙齿松动及牙槽骨吸收,是引起成年人牙齿丧失的主要原因之一。近年来,随着对牙周炎发病机制的深入研究发现,前列腺素是牙槽骨吸收强有力的刺激因子,使骨细胞发生破骨性吸收。同时,药物研究发现,非甾体抗炎药物(non-steroidal anti-inflammatory drugs,NSAIDs)能够抑制环氧酶,减少前列腺素的合成,从而产生抗炎、镇痛和成骨效果。因此,在临床上NSAIDs对牙周炎的治疗效果研究成为热点。文章就NSAIDs在牙周炎治疗中应用的研究进展做一综述。     

Role of epigenetics in alveolar bone resorption and regeneration around periodontal and peri‐implant tissues

Periodontitis and peri‐implantitis are multifactorial diseases characterized by alveolar bone destruction mediated by the host response to a microbial challenge. Alveolar bone resorption mediated by epigenetics could be one of the mechanisms responsible for this destruction of alveolar bone. The relationship between epigenetic modifications and bone metabolism has been thoroughly investigated in bone remodeling, cancer, and rheumatoid arthritis, but evidence is low regarding the relationship between epigenetic modifications and alveolar bone loss related to periodontal and peri‐implant diseases. Therefore, we conducted a review of the pertinent literature based on a priori‐formulated focused questions and a screening strategy, in an attempt to comprehend the role of different epigenetic mechanisms in alveolar bone loss and to determine the current state with respect to their possible therapeutic applications in regenerative medicine. The review showed that the roles of DNA methylation, histone modifications, and non‐coding RNAs in bone loss have been investigated. The results indicate that epigenetic mechanisms can participate in periodontal and peri‐implant alveolar bone breakdown, suggesting their potential as therapeutic targets in alveolar bone regeneration. However, there is still only preliminary information regarding the possible therapeutic utility of these epigenetic mechanisms, suggesting a need for basic and translational research to assess the potential of such mechanisms in promoting alveolar bone regeneration.     

Comparative analysis of the effects of a novel vacuolar adenosine 5'-triphosphatase inhibitor, FR202126, and doxycycline on bone loss caused by experimental periodontitis in rats

BACKGROUND: Doxycycline is reported to inhibit alveolar bone destruction by blocking matrix metalloproteinases (MMPs). Nevertheless, MMPs are not involved in osteoclastic bone resorption; osteoclasts directly resorb bone. An acidic microenvironment, which is formed by vacuolar adenosine 5'-triphosphatase (V-ATPase) expressed in the plasma membranes of osteoclasts, is indispensable for osteoclastic bone resorption. In the present study, we investigated the potential role of the acidic environment on periodontal bone destruction using a novel and specific V-ATPase inhibitor, FR202126, which we compared to doxycycline. METHODS: Inhibitory activity against in vitro bone resorption was examined by measuring the Ca2+ release from murine calvariae cultured for 6 days, which were treated with interleukin-1 (IL-1), IL-6, or parathyroid hormone. Experimental periodontitis was induced by a ligature wire tied around the contact between the first and second maxillary molars of male Wistar rats. FR202126 and doxycycline were administered orally once daily for 6 days. Seven days after tying, the maxillae were dissected and mesiodistal longitudinal paraffin sections, including interdental alveolar bone, were processed for histopathologic analysis. RESULTS: FR202126 inhibited bone resorption almost completely in calvaria cultures induced by three stimulators, whereas doxycycline was unable to prevent in vitro bone resorption. Oral administration of FR202126 significantly prevented alveolar bone loss in experimental periodontitis. However, doxycycline did not inhibit alveolar bone destruction. CONCLUSION: These results suggest that an acidic microenvironment plays a more important role than MMPs in periodontal alveolar bone destruction and that V-ATPase inhibitors may offer a new approach to the treatment of periodontal disease.     

抑制核因子-κB受体活化因子及其配体通路治疗牙周炎的研究进展

核因子-κB受体活化因子(RANK)及其配体(RANKL)在牙周炎患者的牙槽骨吸收中具有重要的作用,抑制RANKL/RANK通路,可有效抑制破骨细胞的分化和激活,从而抑制牙槽骨的吸收。骨保护蛋白(OPG)可和RANKL结合,干扰RANKL和RANK的结合,从而防止骨组织的过度破坏。本文就RANKL/RANK/OPG轴、RANKL/RANK/OPG与牙周炎、抑制RANKL/RANK通路治疗牙周炎的可行性等研究进展作一综述。     

抑制核因子-κB受体活化因子及其配体通路治疗牙周炎的研究进展

核因子-κB受体活化因子（RANK）及其配体（RANKL）在牙周炎患者的牙槽骨吸收中具有重要的作用,抑制RANKL／RANK通路,可有效抑制破骨细胞的分化和激活,从而抑制牙槽骨的吸收。骨保护蛋白（OPG）和RANKL结合,干扰RANKL和RANK的结合,从而防止骨组织的过度破坏。本文就RANKL／RANK／OPG轴、RANKL／RANK／OPG与牙周炎、抑制RANKL／RANK通路治疗牙周炎的可行性等研究进展作一综述。     

The Light and Dark Side of Bisphosphonates

Bisphosphonates are stable compounds of pyrophosphoric acid that inhibit hydroxyapatite formation. This class of chemical was first investigated in the 1960s for use in the treatment of disorders of bone metabolism. Bisphosphonates have been developed for clinical use since then, and, currently, the third, nitrogen-containing, generation of bisphosphonates is widely used for the treatment of various bone diseases, including osteoporosis and bone metastases in cancer. However, despite the therapeutic benefits, the emergence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a growing and significant problem in a subset of patients receiving these drugs. In this review, we introduce the benefits and risks of bisphosphonates, "the light and dark side" so to speak, to facilitate a full understanding of these compounds.     

The pathogenesis, oral manifestations, and implications for dentistry of metabolic bone disease.

Metabolic bone diseases often result in striking oral manifestations that can lead to a diagnosis of the underlying systemic condition. Numerous studies suggest that subclinical derangements in calcium homeostasis and bone metabolism may also contribute to alveolar ridge resorption and periodontal bone loss in predisposed individuals. The significance of this spectrum of diseases and their overall impact on oral health and dental management are likely to increase as the elderly segment of the population increases in the coming decades.     

Resorbing potential of different connective tissue types

Pieces of dentin were implanted into five different connective tissues in rats and examined with scanning electron microscopy after observation periods of up to 2 weeks. Dentin-oclast-like cells, apparently involved in resorption of the implants, were only seen associated with periosteum and periodontal membrane. These findings indicate that the resorbing potential of connective tissues is related to their ability to induce bone formation.