InTech uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Immunology, Allergology and Rheumatology » "Immunopathology and Immunomodulation", book edited by Krassimir Metodiev, ISBN 978-953-51-2210-4, Published: November 18, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 7

Biological Concepts on Bisphosphonate Treated Patients in the Context of Increasing Patient Life Quality and the Need for Oral Surgical Procedures

By Metodi Abadzhiev
DOI: 10.5772/61731

Article top

Overview

Normal osteoclast activity and osteoclasts death by bisphosphonate treatment (after R.E. Marx).
Figure 1. Normal osteoclast activity and osteoclasts death by bisphosphonate treatment (after R.E. Marx).
Scheme of bone metabolic unit (BMU) (after R.E. Marx).
Figure 2. Scheme of bone metabolic unit (BMU) (after R.E. Marx).
Basic molecular structure
Figure 3. Basic molecular structure
The way to bone fracture by solid bone tumors (after R.E. Marx).
Figure 4. The way to bone fracture by solid bone tumors (after R.E. Marx).
Prevention of bone resorption by bisphosphonate osteoclast inhibition (after R.E. Marx).
Figure 5. Prevention of bone resorption by bisphosphonate osteoclast inhibition (after R.E. Marx).
Basic X-ray
Figure 6. Basic X-ray
Intraoral situation after preliminary treatment
Figure 7. Intraoral situation after preliminary treatment
X-ray- before implant insertion
Figure 8. X-ray- before implant insertion
Minimal invasive insertion of the first implant
Figure 9. Minimal invasive insertion of the first implant
Implant insertion in second quadrant
Figure 10. Implant insertion in second quadrant
Implant insertion in lower jowjaw
Figure 11. Implant insertion in lower jowjaw
Activation of implant surface with PRGF
Figure 12. Activation of implant surface with PRGF
PRGF membrane for covering of the implants
Figure 13. PRGF membrane for covering of the implants
Pure ozone injected subcutaneously in the manipulation area
Figure 14. Pure ozone injected subcutaneously in the manipulation area
Usage of photodynamic therapy contributecontributes to cell destruction of the microorganisms and preventprevents complications and accelerateaccelerates wound healing
Figure 15. Usage of photodynamic therapy contributecontributes to cell destruction of the microorganisms and preventprevents complications and accelerateaccelerates wound healing
Photodynamic therapy with photodynamic intraoral tray
Figure 16. Photodynamic therapy with photodynamic intraoral tray
Minimal invasive extraction of 43- root separation
Figure 17. Minimal invasive extraction of 43- root separation
Minimal invasive extraction of 43
Figure 18. Minimal invasive extraction of 43
Granulation tissue ablation with Er:YagYAG laser
Figure 19. Granulation tissue ablation with Er:YagYAG laser
Palatal connective tissue graft
Figure 20. Palatal connective tissue graft
Palatal connective tissue graft in PRGF
Figure 21. Palatal connective tissue graft in PRGF
Bone graft material mixed with PRGF
Figure 22. Bone graft material mixed with PRGF
Bone graft material mixed with PRGF in postextractionpost-extraction socket
Figure 23. Bone graft material mixed with PRGF in postextractionpost-extraction socket
PRGF-clot cloth
Figure 24. PRGF-clot cloth
Covering of bone graft material with the PRGF clotcloth
Figure 25. Covering of bone graft material with the PRGF clotcloth
Suturing of the palatal connective tissue graft over the postextracted socetpost-extracted socket
Figure 26. Suturing of the palatal connective tissue graft over the postextracted socetpost-extracted socket
Soft healing process
Figure 27. Soft healing process
The end result
Figure 28. The end result
End result after treatment
Figure 29. End result after treatment
Initial X-ray
Figure 30. Initial X-ray
Intraoral view
Figure 31. Intraoral view
Intraoral view after bridge removal
Figure 32. Intraoral view after bridge removal
All implants, teeth and bridge after removal
Figure 33. All implants, teeth and bridge after removal
Granulation tissue ablation with Er:YagYAG laser
Figure 34. Granulation tissue ablation with Er:YagYAG laser
PRGF – cloth
Figure 35. PRGF – cloth
Covering with collagen sponge and suturing
Figure 36. Covering with collagen sponge and suturing
Day after surgery
Figure 37. Day after surgery
Ten days after surgery
Figure 38. Ten days after surgery
Three weeks after surgery
Figure 39. Three weeks after surgery
Intraoral view after implant insertion
Figure 40. Intraoral view after implant insertion
Intraoral view after suturing
Figure 41. Intraoral view after suturing
Two weeks after surgery
Figure 42. Two weeks after surgery
Panoramic X-ray after surgery
Figure 43. Panoramic X-ray after surgery
Four weeks after surgery
Figure 44. Four weeks after surgery
Intraoral view
Figure 45. Intraoral view
Postextracted sockets
Figure 46. Postextracted sockets
The extracted teeth
Figure 47. The extracted teeth
Granulation tissue ablation with Er:YagYAG laser
Figure 48. Granulation tissue ablation with Er:YagYAG laser
PRGF clotcloth
Figure 49. PRGF clotcloth
Covering with collagen sponge and suturing
Figure 50. Covering with collagen sponge and suturing
The immediate denture
Figure 51. The immediate denture
Three weeks after extraction
Figure 52. Three weeks after extraction

Biological Concepts on Bisphosphonate Treated Patients in the Context of Increasing Patient Life Quality and the Need for Oral Surgical Procedures

Metodi Abadzhiev1

1. Introduction

Since it was first identified in 2003, bisphosphonate-induced osteonecrosis has been under growing control by medical and dental specialist alike because it affects cancer patients receiving intra-venous bisphosphonate therapy and osteoporosis patients receiving oral bisphosphonate therapy.

It is of significant importance to introduce the mechanism of action of this type of medications, way of distribution and risk of complication during or after treatment with them. A strategy of preparation, medication support and techniques before, during and after dental surgery procedures and especially placement of dental implants must be clarified in order to avoid bisphosphonate-induced osteonecrosis.

2. Indications for bisphosphonates

Even though they were founded in the 18th century, their real clinical usage began only a hundred years ago with the synthesis of the first bisphosphonate (BP)–etidronate. The birthplace of these medicines is considered to be the scientific institute in Davos, Switzerland, where a team headed by Herbert Fleisch, Sylvia Bisaz, and Roman Muhlbauer proved the role of bisphosphonates in bone metabolism and their importance in bone disorders treatment in 1967.

media/image1.jpeg

Figure 1.

Normal osteoclast activity and osteoclasts death by bisphosphonate treatment (after R.E. Marx).

Data concerning pharmacokinetics of diphosphonates, later called bisphosphonates, were published for the first time in 1969. Forty-five years of experience, including researches, has significantly manifested the advantages and disadvantages of this drug group.

Inventing and developing bisphosphonates for treatment of different bone conditions is immense progress in solving fine mechanisms of bone formation and a significant development in medicine as a whole.

Bisphosphonates treatment indications are mainly for increasing bone density in osteoporosis patients (e.g. alendronate and rizedronate), and intravenous (IV) with mouth intake dosage for patients with primary or metastatic bone tumor (e.g. pamidronate and zoledronate). Intravenous intake is also recently tolerated in osteoporosis patients.

media/image2.jpeg

Figure 2.

Scheme of bone metabolic unit (BMU) (after R.E. Marx).

3. Pharmacokinetics of the bisphosphonates

Bisphosphonates are chemically stable analogs of non-organic pyrophosphates (PPi) related to skeleton mineralization. Their development is related to inventing inhibitors of calcification in order to resist hydrolysis with alkaline phosphatase. PPi and BPs could not only slow down bone growth but also destroy hydroxyapatite crystals. BPs are remarkably efficient inhibitors to bone resorption during experiments in vitro and in vivo. During the process of their clinical application in the 1990s, it became clear that in order to clarify the chemical and physical reactions, and explain the variety of their biological effects, it is necessary to study the cell to cell interactions. Bisphosphonates suppress bone resorption by selective absorption to mineralized bone surface where they counteract to osteoclasts.

media/fig3.png

Figure 3.

Basic molecular structure

Bisphosphonates couldcan be classified to at leastinto two groups with different molecular action mechanisms. The first one: is nitrogen free bisphosphonates (like etidronate and clodoronate) that interfere ATP-dependent intercellular ways. The second group is bisphosphonates with nitrogen, they that are more powerful (including pamidronate, alendronate, rizedronate, ibandronate, and zoledronate) they). They are metabolized differently, by inhibiting key enzymes of mevalonat/cholesterol biosynthetic way.

Precisely because of the obviously differentobvious biochemical and pharmacological differencedifferences and uneven intercellular interaction is important the division of, BPs in tohave been divided into separate groups and their specific usage according to a specific disease.

media/image4.jpeg

Figure 4.

The way to bone fracture by solid bone tumors (after R.E. Marx).

media/image5.jpeg

Figure 5.

Prevention of bone resorption by bisphosphonate osteoclast inhibition (after R.E. Marx).

They are incorporated in skeletal bone without being degraded. Bisphosphonates are attached to Ca2+ in areas with increased bone resorption and stay integrated in the bone for 10 to 40 years – alendronate. For example, alendronate’s half-life for example is 12 to 28 years. Once taken, BPs unlock cascade biochemical processes leading to loss of osteoclast ability to resorb bone or even to their apoptosis.

4. Bisphosphonate-induced osteonecrosis of the jaws

It is undoubtedly thatUndoubtedly, the intake increases the quality of life of the treated patients in general, but negative effecteffects should also be taken in tointo consideration. Stomach disorders, erosions of the esophagus, uveitis, flueflu-like conditions, muscle and joint pain, and severe necrosis in the maxillofacial area, known as BONJ – (bisphosphonate osteonecrosis of the jaw) could appear.

Recently inIn recent literature is found date for, a new type of complication associated with bisphosphonate intake –has been found, which is called avascular necrosis of the jaws. It is defined as necrosis associated with or without dental procedures, which could persist for more than 6-8 weeks with irresponsive to conservative treatment, found in patients without history of previous radiotherapy in the area affected but treated with nitrogen group bisphosphonates with nitrogen group, i.v. through IV for at least a year or per os for longer period, and associated with general condition withof bone resorption. Similar cases arewere published for the first time in 2003 by Marx with patients treated with pamidronate and zoledronate. Later, Carter and Gross, Ruggierro, Migliorati, and Wang reportalso reported similar cases. In 2005, Novartis (Aredia and Zometa48 producer) officially declaredeclared 475 cases of Bisphosphonate bisphosphonate-related osteonecrosis of the jaws. In nowadaysNowadays, the number of affected patients worldwide is unknown. Scientific literatures says the BONJ is from 1,.3% to 10%. More There are more than 5,.1 million patients are treated with bisphosphonates. More and more than 2 million acceptaccepted BPs as antimalignatanti-malignant therapy. The number of patients treated for osteoporosis with BPs is increasing rapidly. More than 10 million patients, mainly women in the USA has, have osteoporosis,. It and it is supposed that the number will increase to 12 million and 34. Thirty-four million patients older than 50 have decreased bone density and considered high risk for osteoporosis development. Oral BPs arewere prescribed to more than 70% of the patients diagnosed with osteoporosis in US during the USA in 2003- to 2006.((American association of Oral and Maxillofacial Surgeons)). More than 190 million prescriptions arewere issued in North America. In 2003 Alendronate, alendronate is 19th most prescribed medicine (17 million prescriptions) Risedronate), risedronate is 72nd (6 million prescriptions) zolendronate), while zoledronate is used from more than 300,000 sick people.

5. Pathophisiology of BONJ

Bisphosphonate-associated osteonecrosis of the jaws is a result of treatment with BPs, bone metabolism disorders and physiological micro damagemicrodamage of the jaws interferinginterfere their biomechanical properties. Oral cavity conditions, microtrauma, infections increase the efforts of the organism to bone recovery, exceeding the ability of the hipodynamic bone. Compared to all other bones maxilla and mandible are remodeled most frequently in the human body. This is the reason why BONJ is observed only in jaw-bones. Unlike to other bones in the human body, they are not enough protected enough. It is an important fact that only a thin mucosa and a periosteum are the only barriers protecting bone from injuries. From the other side teeth are prerequisite to easy microorganisms penetration and development of internal infections–caries and periodontal disease complications. It is interesting to mention that local factors like partial and full removable dentures are also factors that increase the risk of osteonecrosis. Smoking and continuous corticosteroid therapy are also risk factors.

According to Denn et al., all osteonecrosis cases describe todescribed in 2006 arewere associated with nitrogen containing bisphosphonates. In scientific literature, there is no single opinion which bisphosphonates exactly leads to more frequent BONJ development. The thought that Zoledroniczoledronic acid isis the most dangerous prevails. Most cases of BONJ are related with i.vIV intake.

In spite of the fact that for BONJ is has been here for a long period of time, factors that initiate the necrosis are still discussing.being discussed. It would be right to point out that for initiation of BONJ many factors are responsible with variable priority in different cases.

OnIn the first place, this is the inhibition of osteoclast activity and bone remodeling. But only this factor is not enough, because similar osteonecrosis would be observed in the other bones. Bacterial invasion with consequent inflammation is a factor that distinguish the condition in oral cavity compared to other body parts. The existence of various biofilm in oral cavity is dictated by different periodonatlperiodontal diseases, caries and its complications and periapical inflammation. This is a prerequisite for microorganism invasion to the left open bone left (after extraction, for example). In necroticNecrotic bone fragments after tooth extraction in BPs treated patients arehave isolated mainly Actinomyces species but also viruses and fungus. Angiogenesis suppression could also be initiator of jaw osteonecrosis. Medicines that disturb growth, migration, and differentiation of endothelial cells for new vessel formation playsplay an important role in avascular osteonecrosis. In addition to these basic factors to pathogenesis of medication-related osteonecrosis of the jaw (MRONJ could be added), microtrauma of the jaw during masticatory action and supposed harmful or acquired immune deficiency could also be added.

6. Prophylaxis and treatment of BONJ

In literature, there is no solidarity concerning bisphosphonate therapy suspension after the appearance of jaw-osteonecrosis. Marx suggests bisphosphonate therapy in onco-patients to be discussed with an oncologist in order to define positive effect/risk ratio, having in mind bisphosphonatebisphosphonate’s half-life (10 years).

In literature thereThere is prevalence of BONJ with prior dental procedures compared to the so called spontaneous osteonecrosis and 33%–86% of the BONJ in literature are described after different dental procedures.

Prevailing opinion is that with ageas one gets older the danger from bisphosphonate osteonecrosis increases withby 9%.

Behavior inof diagnosed osteonecrosis patients is dependent on the disease stage. It should be mentioned that American Association of Oral and Maxillofacial Surgeons proposeproposed a change in the disease nomenclature formfrom BONJ to Medicine medication-related osteonecrosis of the jaws (MRONJ). The reason is an increasing number of patients with osteonecrosis of the jaws have been diagnosed after other drug intake (denosumab). Due to this reason Hence, the AAOMS changeschanged the name, which was accepted in 2009, on. On their consensus conference in 2014, with a Position Paper and in addition to the new name accepts, they accepted new diagnostic and treatment strategies corresponding to the contemporary researches., as follows:

  1. I.v.IV bisphosphonates for treatment of primary bone tumors and bone metastasis, multiple myeloma, and severe osteoporosis but with lower dosage.

  2. Oral bisphosphonates mainly for osteoporosis and osteopenia treatment, as well as PagetPaget’s disease and osteogenesis imperfectimperfecta.

  3. DenozumabDenosumab–RANK ligand inhibitor–it inhibits bone resorption by inhibition of the function of osteoclasts and as an advantage could be mentioned that it is not connected to the bone so within 6 months after treatment the risk of complications is slightly noticeable.

  4. Antiangiogenetic medications–it is used in different tumor conditions and is useful due to the fact that preventsto prevent formation of new blood vessels. It connects to signal molecules responsible for blood vessels formation and interfereinterferes the angiogenesis signaling cascade.

According to AAOMSAAOMS’s Position Paper, it is possible to think about MRONJ if several characteristics are present:

  1. Antiresorptive or atiangiogenicantiangiogenic treatment conducted before or in the past.,

  2. Bone that is exposed in the maxillofacial region through intraoral or extraoral fistula(e) persisting for more than 8 weeks, and

  3. Lack of radiation therapy in the oro-facial region or metastatic disease to the jaws.

It should be mentioned that, according to the AAOMS, risk for osteonecrosis development in patients with bone tumors treated with zoledronate is 0% to 1%. It is similar in patients treated with denozumab.denosumab. A bit lower is the valuepercentage risk in patients treated with antiangiognetic drugs, like bevacizumab –, which is 0.2%. The risk for patients with osteoporosis treated with denozumabdenosumab and zoledoronate is 0.04%. It should be noted that with increasingthe longer the period of time for treatment is increasingthe higher the risk for jaw osteonecrosis form, from 0.5% for one year of treatment to 1.1% for three year years of treatment. After all it is a matter ofThese are based on retrospective studies of treated patients, which who have not been treated surgically in the oral cavity but has develophave developed spontaneous osteonecrosis. As aA trigger factor could be underlined tooth or even multiple teeth extraction and placement of dental implants. In differentDifferent retrospective studies are shown showed that 1.6% to 14.8% of patients treated i.v.through IV with BPs for longer than a year period of time and have developed osteonecrosis developed after tooth extraction. According to a research done by Carlos Pigrau – –Serralach et al since 2014, BONJ reachescases have reached 30.2% Viridance since 2014. Viridans group Streptococcistreptococci are isolated in 83.3% formfrom the cases and AcctinomycesActinomyces spp in 39.0% from all bone histological samples.

According to other studies, between 52% and 61% from all cases described of osteonecrosis of patientscases treated with bisphosphonates are triggered after surgical treatment – –a percentage that is extremely high. Retrospective research done by Kunchur R,., Need A,., Hughes T,., et al. in 2009, says stated that from0.5% out of 194 patients treated with oral bisphosphonates have developed osteonecrosis occurrence is 0.5% after tooth extraction. They assumeassumed that dental implant placement iswas with similar biological load as tooth extraction. Moreover, Donggeol Lee reportsreported that 77 patients treated with bisphosphonate undergounderwent implantology treatment, with 78 placed implants with 97.4% success equal to success in normal conditions. Sebastien Hoefert and Harald Eufinger report i.v.reported IV and per os antibiotic treatment in bisphosphonate treated patients before surgical treatment.

In 2009, P. Pechalova, A. Bakardjiev, B. Vladimirov, E. Poryazova, I. Angelova, and A. Jeleva publishpublished a case of a patient with bisphosphonate osteonecrosis of the mandible of a patient after consistent oral intake of 14 month consistent intake for fourteen months of FosamaxR (alendronate) (70mg per week dosage, taken once a week) and BonvivaR (ibadronate) (150mg month dosage, taken once a month) on the occasion ofdue to severe osteoporosis with pathological fractures of vertebras. The oddly think in the case published is bone sequester covered entirely with mucosa. Without fistula..

A group formfrom ITI (Bornstein, Cionca, Momblli)), based on a vast literature in 2009 differentiate, differentiated the surgeon behavior in patients with oral and i.v.IV bisphosphonate intake. They assumeassumed that, in addition to the way of intake there is, the duration of intake played an important role of the duration.. They saysaid that patients with osteoporosis/osteopenia take much lower dosage of bisphosphonate compared to cancer patients and, thus, the accumulation of the medicine should be several years. This is enough to conclude that In conclusion, patients who underwent oral surgical procedures are withhave significantly lower risk of necrosis in these patientscompared to those who had IV bisphosphonate intake.

Similar conclusions are were made by our team on the basis of 3 treatedthree patients in 3 yearswho underwent treatment for the period of three years. One of the patients were onhad an oral intake of bisphosphonates, one i.v.had IV, and one on DenozumabeDenosumabe (subcutaneоus) As part of our). Our entire biological concept treatment include includes preliminary antibiotic treatment, irrigation with chlorxeidine solutions, general and local ozone therapy, hyperbaric chamber, PRGF usage, Er;Yag:YAG laser, photodynamic therapy, and minimally invasive surgical techniques.

7. Conclusions

During an surgical, respectively a surgery, such as implantology treatment, especially in bisphosphonate treated patients it is vital antibiotics preparation and is vital for the primary healing process to be guaranteed, especially in bisphosphonate treated patients. Usage of Clindamycin as osteotopicosteotropic antibiotics is a gold standard assuring lackto ensure absence of post-operation infection and prevention of complications. LackThe absence of dehiscence assureensures us smooth osteointegration process and lack of bone lose. That is whyFor this purpose, the common requirements for soft tissue management, include suitable implantology system, proper operation technique, atraumatic preparation, and last but not least proper suturing materials and technique. Implantology has extra sources like PRP, PRF,, PRGF, which could be applied with great success if it’s needed. The high concentration of platelets rich in growth factors (PRGF) in the operation field contributecontributes to a light and with lack of troublestrouble-free post-operative process, guaranteeing perfect conditions for the osteointegration process. In cases of post-operative complications MethronidazoleMetronidazole is a matter of choice.

8. Clinical cases

8.1. Case 1

The patient has arrived at our clinic for the first time in 2009 with pain syndrome, periodontal abscess in the 47, 44, 31, 32, 41, and 42 area due to periodontitis developed formfrom the plaque with periodontal pockets form 6from 6mm to 8mm.,combined with chronic occlusal trauma from iatrogenic sharp edges of metal-ceramic constructions made years ago (X-ray, Fig. 1). Based on the anamnesis, a treatment with medicines was found–6 months treatment with Bonviva medicine–3mg once a month parenteral, associated with diagnosed osteopenia in 2007 with quantitative osteometry over tibia bone with T-score 2,9. It was considered that due to the short-term treatment with the bisphosphonate medicine and the 5five-year period after it by keepingto keep certain protocol for preparation and implantation, an implantology treatment could be initiated. A multiple extraction of 47, 44, 42, 41, 31, and 32 was undertaken after antibiotic protection, initial ultrasonic and sand-blasting therapy divided in tointo several appointments, high-intensity and low intensity laser therapy, local and general ozone therapy and hyperbaric therapy. Extraction sockets were filled with PRGF and sutured with PTFE. As an additional prophylaxis measure from bisphosphonates induced osteonecrosis, photodynamic therapy was used. The healing process was without any complications.

The treatment plane includesplan included the entire sanitation of the mouth, periodontal and endodontic preparation, and placement of 11 pieces titanium screwed implants. After uncovering of the implants, tooth 43 was planplanned for extraction despite the exact root-canal treatment, due theto long term prognosis and high risk of root fracture. TillUntil that time, this particular tooth was used for temporary fixed construction abutment. Because of the short clinical crowns, crown-lengthening was planplanned and performed with Er:YAG laser, based on the preliminary analysis of the size and shape of future prosthetic crowns and attached gingiva available. X-ray surgical guide was made, along with a prototype of the future prosthetic constructions, and was used for the CT. Due to the fact of previous bisphosphonate usage, a certain surgical protocol was used again including: antibiotic prophylaxis, high-intensity and low intensity laser therapy, local and general ozone therapy, hyperbaric therapy, PRGF, precise soft-tissue management and photodynamic therapy. One implant was placed in 15 area. Due to the lack of complications it was proceeded to, the placement of the rest of the planned implants proceeded. Bone type was D4 for the maxilla and D3 for the mandible. Bone spreaders were used for bone condensation. The primary stability of the implants was 15 up to 30 N/cm. Osteotomic implant beds were shaped by the usage of the existing surgical guide. Existing bone doesdid not demandeddemand additional augmentative procedures. Suture material was 4/0 PTFE. On the both jaws, fixed long-term temporary constructions waswere provided. After longer than usual period of waiting (more than ana year)), implants were uncovered by half-thickness flaps moved apically. All 11 implants were osteointegrated. After open-tray, impression technique with transfers zirconium abutments with titanium base were made. CAD-CAM zirconium constructions were madmade directly on the same model. In the frontal area constructions were made by blend-ceramic and distally full anatomy zirconium.

Complete functional rehabilitation of the masticatory apparatus was achieved. Aesthetic demands of the patient was covered completely.

media/image6.jpeg

Figure 6.

Basic X-ray

media/image7.jpeg

Figure 7.

Intraoral situation after preliminary treatment

media/image8.jpeg

Figure 8.

X-ray- before implant insertion

media/image9.jpeg

Figure 9.

Minimal invasive insertion of the first implant

After preliminary treatment, the patient receivereceived one implnantimplant in the area of the second upper right premolar (15) accompanied with clindamycin prophylaxis, PRGF activation of the implant surface and covered by PRFG fibrin membrane, combined with postimplantationpost implantation photodynamic therapy using PhotoSan® for 4 minutes, two timetimes a day tilluntil the suture removal, and ozone therapy in the first three days combined with hyperbaric-chambers.

media/image10.jpg

Figure 10.

Implant insertion in second quadrant

media/image11.jpeg

Figure 11.

Implant insertion in lower jowjaw

media/image12.jpeg

Figure 12.

Activation of implant surface with PRGF

media/image13.jpeg

Figure 13.

PRGF membrane for covering of the implants

The high concentration of platelets rich in growth factors (PRGF) in the operation field contributecontributes to a light and with lack of troubles trouble-free post-operative process, guaranteeing perfect conditions for the osteointegration process.

The process of tissue repair iswas based on a complex cascade of biological events controlled by a long list of biologically active growth factors and proteins. The spatial and temporal action of this family of mediators on the tissue-damaged area regulates the mechanisms and phases that govern tissue repair and regeneration

media/image14.png

Figure 14.

Pure ozone injected subcutaneously in the manipulation area

Another method used in our biological concept is ozone therapy. There are several known actions of ozone onin the human body, such as anti-microbial, immunostimulating, antihipoxyc, analgesic, detoxicating, bioenergetics and biosynthetic (activation of the metabolism of carbohydrates, proteins and lipids)), etc. Ozone is a relatively rare and unstable molecule composed of three oxygen atoms O3. The normal oxygen molecule has two oxygen atoms O2. Stratospheric ozone is important in the earth system because it absorbs ultraviolet radiation from the sun, protecting life on earth. The beneficial biological effects of ozone, is its anti-microbialantimicrobial activity. How we can derive ozon?the ozone? Using a simple electric arc, we can produce ozone. In case, for example, of bone regeneration, for example, the purpose of ozone using ozone is the initial local growth factor expression and stimulatetion stimulate the migration of osteoprogenitor cells to the wound site and subsequentlyand subsequently, in a controlled fashion, to direct their differentiation to the osteogenic cell line. Throughout this process, another set of factors will regulate the dynamic equilibrium between cell inhibition and proliferation, as well as angiogenesis and extracellular matrix formation. Ozone-generator can introduce pure ozone in saline. Ozone infusion is also precious for the fact that it generates a therapeutic effect on faster post op wound healing and preliminary preparation of the patient by avoiding further complications and assuring on 99% smooth primary closure. Anti-microbial effect of ozone asis a result of its action on cells by damaging its cytoplasmatic membrane due to ozonolysis of dual bonds and also ozone-induced modification of intercellular contents because of secondary oxidants effects. This action is non-specific and selective to microbial cells, it does not dameagedamage human cells because of their major antioxidative ability. Ozone is very efficient in antibiotics resistant strains. Its anti-microbial activity increases in liquid environment of acidic pH. In viral infections, the ozone action lies in the intolerance of infected cells to peroxides and change of activity of reverse transcriptase, which takes part in synthesis of viral proteins.

media/image15.png

Figure 15.

Usage of photodynamic therapy contributecontributes to cell destruction of the microorganisms and preventprevents complications and accelerateaccelerates wound healing

media/image16.jpeg

Figure 16.

Photodynamic therapy with photodynamic intraoral tray

media/image17.jpeg

Figure 17.

Minimal invasive extraction of 43- root separation

media/image18.jpeg

Figure 18.

Minimal invasive extraction of 43

media/image19.jpeg

Figure 19.

Granulation tissue ablation with Er:YagYAG laser

media/image20.jpeg

Figure 20.

Palatal connective tissue graft

media/image21.jpeg

Figure 21.

Palatal connective tissue graft in PRGF

media/image22.jpeg

Figure 22.

Bone graft material mixed with PRGF

media/image23.jpeg

Figure 23.

Bone graft material mixed with PRGF in postextractionpost-extraction socket

media/image24.jpeg

Figure 24.

PRGF-clot cloth

media/image25.jpeg

Figure 25.

Covering of bone graft material with the PRGF clotcloth

media/image26.jpeg

Figure 26.

Suturing of the palatal connective tissue graft over the postextracted socetpost-extracted socket

media/image27.jpeg

Figure 27.

Soft healing process

media/image28.png

Figure 28.

The end result

media/image29.jpeg

Figure 29.

End result after treatment

8.2. Case 2

A female patient, 57 years old, S. H. in good general good health, non-smoker, was received at the clinic with complainscomplaints of mobility of the entire upper jaw prosthetic fixed construction, accompanied with pain and inability to eat, dating back to 3 months earlier. Clinical exam findfound out significant mobility (4th degree by Miller) of metal-ceramic fixed one-piece bridge prosthetic construction of the upper jaw. (Fig. 2). On the X-ray (Fig.1), 4 screwing dental implants arewere observed, “Tramonte design” and 4four residual roots were in terminal stage. There iswas a significant bone resorption around the implants visible on the x-ray (proven lack of osteointegration.). From the patient histori ispatient’s history, it was known that these implants arewere placed 5five years ago. AnA year later, patient beginsbegan treatment with Fozamax per os once a week withfor the duration 2of two years because of osteoporosis diagnosediagnosis (T-scorscore-2.9%).

media/image30.jpeg

Figure 30.

Initial X-ray

media/image31.jpeg

Figure 31.

Intraoral view

After initial periodontal therapy, with ultrasonic device and highintensityhigh intensity laser, under antibiotic cover (clindamycin 600mg. /./8h per os), 2two times hyperbaric chamber before and three times after the dental procedures, saline enriched with ozone 9nine times and three were locally applied subcutaneously, photodynamic therapy tilluntil the 10th den after the dental procedure of removing all residual roots and implants. In the extraction sockets were placed PRGF cloth, collagen sponge and the wound were sutured. Post-operative period was smooth without any pain or complications. The patientspatient was given an immediate fabricated total removable dentures.

media/image32.jpeg

Figure 32.

Intraoral view after bridge removal

media/image33.jpeg

Figure 33.

All implants, teeth and bridge after removal

media/image34.jpeg

Figure 34.

Granulation tissue ablation with Er:YagYAG laser

media/image35.jpeg

Figure 35.

PRGF – cloth

media/image36.jpeg

Figure 36.

Covering with collagen sponge and suturing

media/image37.jpeg

Figure 37.

Day after surgery

media/image38.jpeg

Figure 38.

Ten days after surgery

media/image39.jpeg

Figure 39.

Three weeks after surgery

media/image40.jpeg

Figure 40.

Intraoral view after implant insertion

media/image41.jpeg

Figure 41.

Intraoral view after suturing

media/image42.jpeg

Figure 42.

Two weeks after surgery

media/image43.jpeg

Figure 43.

Panoramic X-ray after surgery

media/image44.jpeg

Figure 44.

Four weeks after surgery

8.3. Case 3

A female patient, 54 years old, in good general health condition, smoker (over 10 cigarettes per day), was received at the clinic with complainscomplaints from fixed prosthetic construction mobility on the upper jaw, poor aesthetics, and inability to eat normally. X-ray proves anand aggressive periodntoalperiodontal disease with more than 9-10mm910mm bone resorption of interdental bone. PatientPatient’s history sayssaid that she is was on Denosumabdenosumab (subcutaneously every 6 months) during for the last 3three years –in treatment for osteoporosis diagnose. The treatment plan was similar with case N2 and the healing process went smoothsmoothly.

media/image45.png

Figure 45.

Intraoral view

media/image46.png

Figure 46.

Postextracted sockets

media/image47.png

Figure 47.

The extracted teeth

media/image48.png

Figure 48.

Granulation tissue ablation with Er:YagYAG laser

media/image49.png

Figure 49.

PRGF clotcloth

media/image50.png

Figure 50.

Covering with collagen sponge and suturing

media/image51.png

Figure 51.

The immediate denture

media/image52.png

Figure 52.

Three weeks after extraction

*All case-pictures are Dr. Abadzhiev’s private practice patiens.

media/image53.png

Table 1.

Usage and dosage of the bisphosphonates

After R.E. Marx

MRONJ† Staging Treatment Strategies‡
At risk category No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates⋅ No treatment indicated
⋅ Patient education
Stage 0 No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms⋅ Systemic management, including the use of pain medication and antibiotics
Stage 1 Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection⋅ Antibacterial mouth rinse
⋅ Clinical follow-up on a quarterly basis
⋅ Patient education and review of indications for continued bisphosphonate therapy
Stage 2 Exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and ery- themaerythema in the region of the exposed bone with or without purulent drainage⋅ Symptomatic treatment with oral antibiotics
⋅ Oral antibacterial mouth rinse
⋅ Pain control
⋅ Debridement to relieve soft tissue irritation and infection control
Stage 3 Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the fol- lowingfollowing: exposed and necrotic bone extending beyond the region of alveolar bone,(, (i.e.,. inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor⋅ Antibacterial mouth rinse
⋅ Antibiotic therapy and pain control
⋅ Surgical debridement/resection for longer term palliation of infection and pain

Table 2.

Staging and Treatment Strategies

Position Paper of American Association of Oral and Maxillofacial Surgeons (2014)

References

1 - Alberto Bedogni, Stefano Fadele, Georgio Bedogni, Matteo Scoletta, Gianfranco Favia, Giordana Bettini, Olga Di Feda, Giacomo Oleri, Stephen Porter, M. Petrizzi, P. Arduino, S. DAmatoDamato, C. Ungari, P-L Fung Polly, G. Saia, et al. Standing of Osteonecrosisosteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease. British J Oral Maxillofac Surg, 52(7):603–608, 2014.
2 - Raj B. Lotwala, Geoffrey M. Greenlee, Susan M. Ott, Stanton H. Hall, Greg J. Huang. Bisphosphonates as a risk factor for adverse orthodontic outcomes; a retrospective cohort study Original Research Article. American J Orthodontics and Dentofacial Orthopedics, 142(5):625–634, e3, 2012.
3 - Ines Losada, Leonardo Sartoni, Elena di Gianantonio, Margherita Zen, Maurizio Clementi, Andrea Doria. Bisphosphonates in Patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age? Review Article Autoimmunity Reviews, 9(8):547–552, 2010.
4 - Carlos Pigrau–Serrallach, Evelyn Carbal–Galeano, Benito Almirante-Gragera, Roger Sorde–Masip, Dolors Rodrigues–Pardo, Nuria Fernandez–Hidalgo, Niaves Larossa, Soccoro Bescos–Atin, Albert Pahissa–Berga. Long–term follow-up of jaw osteomyelitis associated with Bisphosphonatebisphosphonate use in a tertiary-care center. originalOriginal Research Article Entermadades infecciosas y Microbiologia Clinica, 32(1):128–22, 2014.
5 - Atalay B, Yalcin S, Emes Y, et al: Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci 26:815, 2011.
6 - Ayllon J, Launay-Vacher V, Medioni J, et al: Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann Oncol 20:600, 2009.
7 - Ali-Erdem M, Burak-Cankaya A, Cemil-Isler S, et al: Extraction socket healing in rats treated with bisphosphonate: animal model for bisphosphonate related osteonecrosis of jaws in multiple myeloma patients. Med Oral Patol Oral Cir Bucal 16:e879, 2011.
8 - Aguirre JI, Akhter MP, Kimmel DB, et al: Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res 27:2130, 2012.
9 - Aghaloo TL, Felsenfeld AL, Tetradis S: Osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg 68:959, 2010.
10 - Abu-Id MH, Warnke PH, Gottschalk J, et al: “Bis-phossy jaws” -high and low risk factors for bisphosphonate-induced osteonecro-sis of the jaw. J Craniomaxillofac Surg 36:95, 2008.
11 - Aghaloo TL, Kang B, Sung EC, et al: Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res 26:1871, 2011.
12 - Allen MR, Burr DB: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 67:61, 2009.
13 - Allen MR, Burr DB: Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 66:987, 2008.
14 - Aapro M, Saad F, Costa L: Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases. Oncologist 15:1147, 2010.
15 - Bagan JV, Jimenez Y, Gomez D, et al: Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol 44:1088, 2008.
16 - Black DM, Reid IR, Boonen S, et al: The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:243, 2012.
17 - Bedogni A, Fusco V, Agrillo A, et al: Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis 18:621, 2012.
18 - Balmor GR, Yarom N, Weitzen R: Drug-induced palate osteonecrosis following nasal surgery. Isr Med Assoc J 14:193, 2012.
19 - Bonacina R, Mariani U, Villa F, et al: Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients. J Can Dent Assoc 77:b147, 2011.
20 - Badros A, Weikel D, Salama A, et al: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945, 2006.
21 - Brown JJ, Ramalingam L, Zacharin MR: Bisphosphonate-associated osteonecrosis of the jaw: does it occur in children? Clin Endocrinol (Oxf) 68:863, 2008.
22 - Bozas G, Roy A, Ramasamy V, et al: Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib. Onkologie 33:321, 2010.
23 - Boonyapakorn T, Schirmer I, Reichart PA, et al: Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44:857, 2008.
24 - Bi Y, Gao Y, Ehirchiou D, et al: Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol 177:280, 2010.
25 - Briefing Information for the September 9, 2011 Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Septemer 9, 2011;
26 - http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm270957.htm. Accessed April 7, 2014.
27 - Bashutski JD, Eber RM, Kinney JS, et al: Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363:2396, 2010.
28 - Brunello A, Saia G, Bedogni A, et al: Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44:173, 2009.
29 - Bagan, J.V., Jimenez, Y., Murillo, J., Jaw osteonecrosis associated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions — Study of 20 cases, Oral Oncol, 42: 327–329, 2011.
30 - Background Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. United States. Food and Drug Administration. September 9, 2011;
31 - Baron R, Ferrari S, Russell RG: Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677, 2011.
32 - Beuselinck B, Wolter P, Karadimou A, et al: Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer 107:1665, 2012.
33 - Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:85, 2009.
34 - Christodoulou C, Pervena A, Klouvas G, et al: Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 76:209, 2009.
35 - Cummings SR, San Martin J, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756, 2009.
36 - Carlson ER, Fleisher KE, Ruggiero SL: Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications. J Oral Maxillofac Surg 71:2077, 2013.
37 - Coleman R, Woodward E, Brown J, et al: Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat 127:429, 2011.
38 - Dickinson M, Prince HM, Kirsa S, et al: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 39:304, 2009.
39 - Damm DD, Jones DM: Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen Dent 61:33, 2013.
40 - Engroff SL, Kim DD: Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction? J Oral Maxillofac Surg 65:2374, 2007.
41 - Endodontic Implications of Bisphosphonate-Associated Osteonecrosis of the Jaws. Chicago, IL: American Association of Endodontists; 2010:4.
42 - Epstein MS, Epstein JB, Ephros HD: The effects of osteoclast modifiers on the oral cavity: a review for prescribers. Curr Opin Support Palliat Care 6:337, 2012.
43 - Eckardt AM, Lemound J, Lindhorst D, et al: Surgical management of bisphosphonate-related osteonecrosis of the jaw in oncologic patients: a challenging problem. Anticancer Res 31:2313, 2011.
44 - Edwards BJ, Hellstein JW, Jacobsen PL, et al: Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 139:1674, 2008.
45 - Fleissig Y, Regev E, Lehman H: Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 113:e1, 2012.
46 - Ferrari S, Bianchi B, Savi A, et al: Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 66:999, 2008
47 - Fedele S, S. Porter, F. Daiuto, N. Donos, H. Ireland, S. Humphries. P1.41. the GEN-VA-BO study (GENetic VAriants in Bisphosphonate–related Ostenecrosis of the jaws). A cooperation proposal. Oral Oncology Supplement, vol. 3. Issue 1. July 2009, p. 136.
48 - Ferlito S, Puzzo S, Palermo F, et al: Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg 50:425, 2012.
49 - Fehm T, Felsenberg D, Krimmel M, et al: Bisphosphonate-associated osteonecrosis of the jaw in breast cancer patients: recommendations for prevention and treatment. Breast 18:213, 2009.
50 - Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:96, 2009.
51 - Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813, 2011.
52 - Fleisher KE, Welch G, Kottal S, et al: Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:509, 2010.
53 - Freiberger JJ, Padilla-Burgos R, McGraw T, et al: What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral Maxillofac Surg 70:1573, 2012.
54 - Fehm T, Beck V, Banys M, et al: Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 112:605, 2009.
55 - Fedele S, Porter SR, D'Aiuto F, et al: Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060, 2010.
56 - Guarneri V, Miles D, Robert N, et al: Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 122:181, 2010.
57 - Gerard DA, Carlson ER, Gotcher JE, et al: Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein. J Oral Maxillofac Surg 72:61, 2014.
58 - Grbic JT, Black DM, Lyles KW, et al: The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc 141:1365, 2010.
59 - Graziani F, Vescovi P, Campisi G, et al: Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases. J Oral Maxillofac Surg 70:2501, 2012.
60 - Henry DH, Costa L, Goldwasser F, et al: Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125, 2011.
61 - Hellstein JW, Adler RA, Edwards B, et al: Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 142:1243, 2011.
62 - Hoff AO, Toth BB, Altundag K, et al: Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826, 2008.
63 - Hoefert S, Eufinger H: Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:463, 2010.
64 - Hokugo A, Christensen R, Chung EM, et al: Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats. J Bone Miner Res 25:1337, 2010.
65 - Hinchy NV, Jayaprakash V, Rossitto RA, et al: Osteonecrosis of the jaw-prevention and treatment strategies for oral health professionals. Oral Oncol 49:878, 2013.
66 - John W. Hellstein, Robert A. Adier, Beatrice Edwards, Peter L. Jacobsen, John R. Kalman, Sreenivas Koka, Cesar A. Migliorati, Helen Ristic. Managing the care of patients receiving antiresorptive for prevention and treatment of osteoporosis: Executive summery of recommendations from the American Dental Association Council on Scientific Affairs. J American Dent Assoc, vol. 142, issue 11, Nov.2011, p. 1243–1251.
67 - Khan AA, Sandor GK, Dore E, et al: Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:478, 2009.
68 - Kim I, Ki H, Lee W, et al: The effect of systemically administered bisphosphonates on bony healing after tooth extraction and osseointegration of dental implants in the rabbit maxilla. Int J Oral Maxillofac Implants 28:1194, 2013.
69 - Katz J, Gong Y, Salmasinia D, et al: Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw. Int J Oral Maxillofac Surg 40:605, 2011.
70 - Koch FP, Walter C, Hansen T, et al: Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 15:63, 2011.
71 - Kos M, Junka A, Smutnicka D, et al: Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg 71:1010, 2013.
72 - Kumar SK, Gorur A, Schaudinn C, et al: The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy. Curr Osteoporos Rep 8:40, 2010.
73 - Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology Kang B, Cheong S, Chaichanasakul T, et al: Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. J Bone Miner Res 28:1631, 2013.
74 - .Kwon YD, Kim DY, Ohe JY, et al: Correlation between serum C-terminal cross-linking telopeptide of type I collagen and staging of oral bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:2644, 2009.
75 - Kyrgidis A, Vahtsevanos K, Koloutsos G, et al: Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 26:4634, 2008.
76 - Kim HK: Introduction to osteonecrosis of the femoral head (OFH) and osteonecrosis of the jaw (ONJ). J Musculoskelet Neuronal Interact 7:350, 2007.
77 - Kikuiri T, Kim I, Yamaza T, et al: Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res 25:1668, 2010.
78 - Kunchur R, Need A, Hughes T, et al: Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167, 2009.
79 - Kuroshima S, Kovacic BL, Kozloff KM, et al: Intra-oral PTH administration promotes tooth extraction socket healing. J Dent Res 92:553, 2013.
80 - Khan AA, Morrison A, Hanley DA, et al: International Consensus on Diagnosis and Management of Osteonecrosis of the Jaw. 2013:22.
81 - Lacey DL, Boyle WJ, Simonet WS, et al: Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11:401, 2012.
82 - Lee CY, David T, Nishime M: Use of platelet-rich plasma in the management of oral biphosphonate-associated osteonecrosis of the jaw: a report of 2 cases. J Oral Implantol 33:371, 2007.
83 - Lane, N., Armitage, G.C., Loomer, P., Bisphosphonate therapy improves the outcome of conventional periodontal treatment: Results of a 12-month, randomized, placebo-controlled study J Periodontol, 2005: 76, 1113-1122.
84 - Lopez-Jornet P, Camacho-Alonso F, Martinez-Canovas A, et al: Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws. J Oral Maxillofac Surg 69:2488, 2011.
85 - Lo JC, O'Ryan F, Yang J, et al: Oral health considerations in older women receiving oral bisphosphonate therapy. J Am Geriatr Soc 59:916, 2011.
86 - Lehrer S, Montazem A, Ramanathan L, et al: Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106:389, 2008.
87 - Landesberg R, Woo V, Cremers S, et al: Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann N Y Acad Sci 1218:62, 2011.
88 - Landesberg R, Cozin M, Cremers S, et al: Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66:839, 2008.
89 - Lo JC, O'Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243, 2010.
90 - Lipton A, Fizazi K, Stopeck AT, et al: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082, 2012.
91 - Marini F, Tonelli P, Cavalli L, et al: Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Front Biosci (Elite Ed) 3:364, 2011.
92 - Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115, 2003.
93 - Marx RE, Oral and Intravenous Bisphosphonata-Indiced Osteonecrosis of the Jaws. History, Etiology, Prevention and treatment, second edition, Quintessence, 2011
94 - Mehrotra B, Fantasia J, Ruggiero SL: Outcomes of bisphosphonate related osteonecrosis of the jaw. Importance of staging and management. A large single institution update. J Clin Oncol 26:20526, 2008.
95 - Marcelo Cunio Fonseca, Gabriela Tannus Branco de Araujo, Helder Etto, Alexandre Schiola, Natalia Santoni, Marko Machado. Economic Evalution of Clodronate and Zolesronatw in Patients Diagnosed with Metastatic Bone Disease From the Perspective of Public and III-rd Party Payors in Brazil. Clinical Therapeutics, 33 (11), 1769-1780, e2.
96 - Mucke T, Koschinski J, Deppe H, et al: Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol 137:907, 2011.
97 - Marx RE, Cillo JE, Jr., Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397, 2007.
98 - Mozzati M, Arata V, Gallesio G: Tooth extraction in patients on zoledronic acid therapy. Oral Oncol 48:817, 2012.
99 - Mauri D, Valachis A, Polyzos IP, et al: Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 116:433, 2009.
100 - Migliorati CA, Saunders D, Conlon MS, et al: Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144:406, 2013.
101 - Malden N, Lopes V: An epidemiological study of alendronate-related osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence. J Bone Miner Metab 30:171, 2012.
102 - Marx R: Oral and Intravenous Bisphosphonate Induced Osteonecrosis of the Jaws: History, etiology, prevention, and treatment. 2nd ed. Hanover Park, IL: Quintessence Publishing Co; 2011.
103 - Marx, R.E., Sawatari, Y., Fortin, M., Broumand, V., Bisphosphonate-induced exposed bone (osteonerosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment (2005) J Oral Maxillofac Surg, 63, pp. 1567-1575;
104 - Mortensen M, Lawson W, Montazem A: Osteonecrosis of the jaw associated with bisphosphonate use: Presentation of seven cases and literature review. Laryngoscope 117:30, 2007.
105 - Nicoletti P, Cartsos VM, Palaska PK, et al: Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3. Oncologist 17:279, 2012.
106 - Nicolatou-Galitis O, Migkou M, Psyrri A, et al: Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol 113:234, 2012.
107 - O'Ryan FS, Khoury S, Liao W, et al: Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg 67:1363, 2009.
108 - Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol, 2013.
109 - Patel V, McLeod NM, Rogers SN, et al: Bisphosphonate osteonecrosis of the jaw—a literature review of UK policies versus international policies on bisphosphonates, risk factors and prevention. Br J Oral Maxillofac Surg 49:251, 2011.
110 - Papapoulos S, Chapurlat R, Libanati C, et al: Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 27:694, 2012.
111 - Rosen LS, Gordon D, Tchekmedyian NS, et al: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 100:2613, 2004.
112 - Ruggiero, S., Gralow, J., Marx, R.E., Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer (2006) J Oncol Prac, 2, pp. 7-14;
113 - Ruggiero SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. J Oral Maxillofac Surg 67:2, 2009.
114 - Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433, 2006.
115 - Ripamonti CI, Maniezzo M, Campa T, et al: Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20:137, 2009.
116 - Roelofs AJ, Thompson K, Gordon S, et al: Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s, 2006.
117 - Reid IR, Cornish J: Epidemiology and pathogenesis of osteonecrosis of the jaw. Nat Rev Rheumatol 8:90, 2012.
118 - Reid IR, Bolland MJ, Grey AB: Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318, 2007.
119 - Shannon J, Shannon J, Modelevsky S, et al: Bisphosphonates and osteonecrosis of the jaw. J Am Geriatr Soc 59:2350, 2011.
120 - Saad F, Brown JE, Van Poznak C, et al: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23:1341, 2012.
121 - Saussez S, Javadian R, Hupin C, et al: Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 119:323, 2009.
122 - Savoidelli C, F. le Page, J. Santini, G. Scortecci, G. Odin. Osteonecrose maxillaire sous Bisphosphonateset implants dentaires. Revue de Stomatologie et de Chirurgie Maxillo-faciale, vol. 108, issue 8, Dec. 2007, P. 555-558.
123 - Sedghizadeh PP, Kumar SK, Gorur A, et al: Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 66:767, 2008.
124 - Seth R, Futran ND, Alam DS, et al: Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 120:2165, 2010.
125 - Sinningen K, Tsourdi E, Rauner M, et al: Skeletal and extraskeletal actions of denosumab. Endocrine 42:52, 2012.
126 - Sedghizadeh PP, Kumar SK, Gorur A, et al: Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J Am Dent Assoc 140:1259, 2009.
127 - Scoletta M, Arduino PG, Reggio L, et al: Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study. Photomed Laser Surg 28:179, 2010.
128 - Scoletta M, Arata V, Arduino PG, et al: Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 71:994, 2013.
129 - Scoletta M, Arduino PG, Dalmasso P, et al: Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:46, 2010.
130 - Smidt-Hansen T, Folkmar TB, Fode K, et al: Combination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 71:1532, 2013.
131 - Scagliotti GV, Hirsh V, Siena S, et al: Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7:1823, 2012.
132 - Soydan SS, Uckan S: Management of bisphosphonate-related osteonecrosis of the jaw with a platelet-rich fibrin membrane: technical report. J Oral Maxillofac Surg 72:322, 2014.
133 - Schubert M, Klatte I, Linek W, et al: The Saxon bisphosphonate register — therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol 48:349, 2012.
134 - Stopeck A, Body JJ, Fujiwara Y, et al: Denosumab versus zolendronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Supplements [EJC supplements] 7:2, 2009.
135 - Sedghizadeh PP, Yooseph S, Fadrosh DW, et al: Metagenomic investigation of microbes and viruses in patients with jaw osteonecrosis associated with bisphosphonate therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 114:764, 2012.
136 - Sivolella S, Lumachi F, Stellini E, et al: Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res 33:1793, 2013.
137 - Stockmann P, Vairaktaris E, Wehrhan F, et al: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer 18:449, 2010.
138 - Stanton DC, Balasanian E: Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical cases. J Oral Maxillofac Surg 67:943, 2009.
139 - Tsao C, Darby I, Ebeling PR, et al: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 71:1360, 2013.
140 - United States. Food and Drug Administration. Sutent (sunitinib malate) capsules Safety Information. http://www.fda.gov/safety/ medwatch/safetyinformation/ucm224050.htm. Accessed March 13, 2014.
141 - United States. Food and Drug Administration. Office of Drug Safety. Postmarketing Safety Review. Bisphosphonates. http://www. fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDATab3.pdf Accessed February 10, 2014.
142 - United States. Food and Drug Administration. Avastin (bevacizumab) Safety Information. http://www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm275758.htm Accessed March 13, 2014.
143 - Vescovi P, Merigo E, Meleti M, et al: Bisphosphonates-related osteonecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. J Oral Pathol Med 41:214, 2012.
144 - Vahtsevanos K, Kyrgidis A, Verrou E, et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356, 2009.
145 - Van den Wyngaert T, Claeys T, Huizing MT, et al: Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol 20:331, 2009.
146 - Vandone AM, Donadio M, Mozzati M, et al: Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol 23:193, 2012.
147 - Wanger G, Gorby Y, El-Naggar MY, et al: Electrically conductive bacterial nanowires in bisphosphonate-related osteonecrosis of the jaw biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol 115:71, 2013.
148 - Walter C, Al-Nawas B, du Bois A, et al: Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer 115:1631, 2009.
149 - Yamazaki T, Yamori M, Ishizaki T, et al: Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg 41:1397, 2012.
150 - Yamashita J, McCauley LK: Antiresorptives and osteonecrosis of the jaw. J Evid Based Dent Pract 12:233, 2012.