In the downloadable file below from Dr. Reichel and the following information provided by Ludwick it would seem that we have a great deal  of the available information on ONJ on this site.

Larry Reichel, D.D.S has written a paper about Osteonecrosis of the Jaw (ONJ) for the benefit of those that visit this website. Since it comes from a retired Dentist it is very nicely done. He has surveyed about everything he could find on the problem and gave us a summary. He has referenced some 59 studies, papers, etc. that he researched and listed them for you. If you are taking Zometa, Aredia, Fosamax or Actonel or are considering using these drugs the reading of this paper and the link to the Power Point presentation is a MUST.

There is a link in the page to a file on the VA servers. In the DOC file you can click on the link and it will take you there. This is not possible in the PDF file. Therefore here is a clickable link to "Immediate Reconstruction of Mandibular Defects - Drug Induced Avascular Necrosis of Bone". Drug Induced Avascular Necrosis of Bone. This is a very large file and will take a very long, long time to load even with high speed internet connection.

This paper is copyrighted and can not be used without the express written permission of the author. It can be used for personal use and to share with your medical support staff. It may not be duplicated in any from, other than the above, and distributed or posted in any other location, website, mailing list, internet, etc.

Here are number of studies, etc. on bisphosphonates, their use and dangers when used to treat men with prostate cancer. Thanks to Ludwick for helping on this page. Some of may be part of the references in Dr. Reichel's file.

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Bisphosphonate-Induced Exposed Bone Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment

Robert E. Marx, DDS,* Yoh Sawatari, DDS, Michel Fortin, DMD, PhD, and Vishtasb Broumand, DMD, MD'

2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:1567 1575, 2005 See ABSTRACT at http://tinyurl.com/7sqd9. (DC NOTE: This is such an important paper that I have made the complete paper available by clicking on Bisphosphonate-Induced Exposed Bone Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment

RECOMMENDATIONS TO PREVENT BISPHOSPHONATE AVASCULAR NECROSIS (Part of the Study)

Before Initiating Bisphosphonate Therapy

As soon as the treating oncologist prescribes bisphosphonate therapy, the patient should be referred to an experienced dentist or oral and maxillofacial surgeon for an urgent examination. Close and ongoing communication between the 2 is crucial, and commencement of bisphosphonate therapy should be deferred until dental and oral surgical treatments have been completed. At the minimum, the dental examination should consist of clinical and panoramic radiographic examinations with individual periapical films where indicated. Dental treatment is aimed at eliminating infections and preventing the need for invasive dental procedures in the near and intermediate future. This may include tooth removal, periodontal surgery, root canal treatment, caries control, dental restorations, and dentures. These patients should not be considered as candidates for dental implants, which have no crevicular epithelial attachment and therefore would predispose the patients in this group to bone exposure (Fig 8). Impacted teeth that are completely covered by bone or soft tissue should be left undisturbed, but those with an oral communication are recommended to be removed and given a 1 month healing period. Similarly, small lingual mandibular tori do not require removal whereas large, multilobed mandibular tori or midline palatal tori with thin overlying mucosa are recommended to be removed 1 month before the initiation of bisphosphonate therapy. Prophylactic antibiotic coverage for noninvasive dental care is not required but is recommended for any invasive dental procedure, and for this penicillin remains the drug of choice. For individuals with a penicillin allergy, combination therapy using quinolones and metronidazole or erythromycin and metronidazole are good second choices and have proven efficacy in this group. Clindamycin alone is not recommended because of its lack of activity against actinomyces, Eikenella corrodens, and similar species that have been found to frequently colonize this exposed bone. As a general rule, if the patient requires only noninvasive dental care, such as dental cleanings (prophylaxis), fluoride carriers, dental restorations, dentures, and so forth, bisphosphonate therapy need not be delayed. If the patient requires invasive dental procedures such as tooth removals, periodontal surgery, or root canal therapy, commencement of bisphosphonate therapy should be deferred for 1 month to allow sufficient time for bone recovery and healing. Once the regimen of bisphosphonate therapy has begun, a surveillance schedule of once every 4 months is recommended.

WHILE RECEIVING BISPHOSPHONATE THERAPY Oncologists should consider referring all patients already receiving IV bisphosphonates to a dentist or oral and maxillofacial surgeon for an examination and a surveillance schedule. The dental team should carefully evaluate the oral cavity for exposed bone in the areas most commonly affected, such as the posterior lingual area of the mandible, and for radiographic evidence of osteolysis, osteosclerosis, widened periodontal membrane spaces, and furcation involvements. A dental cleaning and fluoride carriers should be considered, and tooth removal should be avoided if at all possible. If the tooth is nonrestorable because of caries, root canal treatment and amputation of the crown is a better option than removing the tooth. Similarly, teeth that demonstrate 1 or 2 mobility should be splinted rather than removed. If the mobility is 3 or more or is associated with a periodontal abscess, there is a strong possibility that osteonecrosis is already present and the abscess and/or granulation tissue is merely covering exposed bone. In these situations, removing the tooth and providing antibiotic treatment, as described in the previous section, is the only recourse. Elective surgery within the jaws, such as removal of third molar teeth or tori, periodontal surgery, or placement of dental implants, is strongly discouraged at this time. Denture wearing is acceptable, but the prosthesis should be examined for areas of excessive pressure or friction and given a soft reline if needed.

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Oncologist 2000;5(6):463-70 Related Articles, Books, LinkOut

Management of bone metastases.

Coleman RE

Yorkshire Cancer Research Department of Clinical Oncology, Cancer Research Center, Weston Park Hospital, Sheffield, England.

[Medline record in process]

Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signaling mechanisms involved in cancer-induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and its use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.

PMID: 11110597, UI: 20562996

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Cancer 2000 Jun 15;88(12 Suppl):3047-53 Related Articles, Books, LinkOut

Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton.

Papapoulos SE, Hamdy NA, van der Pluijm G

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, The Netherlands.

BACKGROUND: Prostate carcinoma metastasizes frequently to the skeleton, causing significant morbidity, particularly severe bone pain. Metastatic lesions typically are osteosclerotic, but there is experimental, histologic, and biochemical evidence of increased bone resorption. Furthermore, bone resorption rates appear to correlate with bone pain. These observations provide the rationale for the use of bisphosphonates in the management of patients with prostate carcinoma and skeletal metastases. METHODS: The authors reviewed the literature and current findings on the use of biphosphonates in the management of patients with prostate carcinoma metastatic to the skeleton. RESULTS: Compared with the large number of studies with bisphosphonates in predominantly osteolytic bone disease, there have been relatively few (mostly uncontrolled) studies in patients with prostate carcinoma. Apart from the lack of appropriate experimental models, the osteoblastic nature of the metastases and the low incidence of objectively assessed endpoints of treatment (e.g., hypercalcemia, pathologic fractures) have delayed developments. Available data, however, strongly suggest that potent bisphosphonates are efficacious in reducing skeletal morbidity in patients with prostate carcinoma. CONCLUSIONS: For the optimal management of patients with skeletal metastases from prostate carcinoma with bisphosphonates their mode of administration, the dose and duration of treatment need to be evaluated. Better understanding of the cellular and molecular mechanisms underlying bone metastases can lead to the design of improved treatment protocols with potent bisphosphonates.

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Cancer 2000 Jun 15;88(12 Suppl):2989-94 Related Articles, Books, LinkOut

The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma.

Carlin BI, Andriole GL

Division of Urology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

BACKGROUND: Prostate carcinoma poses a significant public health problem. Although a minority of men with newly diagnosed prostate carcinoma manifest bone metastases or skeletal abnormalities, a significant proportion of men will develop these complications over the course of their lives. Patients at highest risk for bone metastases include those with high grade, high stage neoplasms, those who fail primary curative therapies such as radical prostatectomy or radiation therapy, and those who develop biochemical recurrence after hormonal therapy. METHODS: The relative risks and prognostic factors for bone metastases in each of these settings will be reviewed. RESULTS: In comparison with men without prostate carcinoma, benign skeletal complications (osteopenia and fractures) occur at significantly increased rates among men with untreated prostate carcinoma. Moreover, the incidence rate of these conditions increases dramatically among those men who are receiving endocrine therapy. The duration and intensity of the endocrine therapy may be associated with the incidence rate and severity of skeletal complications. CONCLUSIONS: Given the significant incidence rate and quality of life implications of skeletal complications and bone metastases, there is an urgent need to identify effective preventive therapies and treatments. Bisphosphonates may have a role in preventing osteopenia and, potentially, bone metastases among men with prostate carcinoma.

Publication Types: Review Review, tutorial

PMID: 10898342, UI: 20354707

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Cancer 2000 Jun;88(S12):2989-2994 Related Articles, Books, LinkOut

The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma.

Carlin BI, Andriole GL

Division of Urology, Washington University School of Medicine, St. Louis, Missouri.

[Record supplied by publisher]

BACKGROUND: Prostate carcinoma poses a significant public health problem. Although a minority of men with newly diagnosed prostate carcinoma manifest bone metastases or skeletal abnormalities, a significant proportion of men will develop these complications over the course of their lives. Patients at highest risk for bone metastases include those with high grade, high stage neoplasms, those who fail primary curative therapies such as radical prostatectomy or radiation therapy, and those who develop biochemical recurrence after hormonal therapy. METHODS: The relative risks and prognostic factors for bone metastases in each of these settings will be reviewed. RESULTS: In comparison with men without prostate carcinoma, benign skeletal complications (osteopenia and fractures) occur at significantly increased rates among men with untreated prostate carcinoma. Moreover, the incidence rate of these conditions increases dramatically among those men who are receiving endocrine therapy. The duration and intensity of the endocrine therapy may be associated with the incidence rate and severity of skeletal complications. CONCLUSIONS: Given the significant incidence rate and quality of life implications of skeletal complications and bone metastases, there is an urgent need to identify effective preventive therapies and treatments. Bisphosphonates may have a role in preventing osteopenia and, potentially, bone metastases among men with prostate carcinoma. Copyright 2000 American Cancer Society.

PMID: 10871517

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Cancer Res 2000 Jun 1;60(11):2949-54 Related Articles, Books, LinkOut

Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases.

Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P

Institut National de la Sante et de la Recherche Medicale Research Unit 403, Faculte de Medecine Laennec, Lyon, France.

The molecular mechanisms by which tumor cells metastasize to bone are likely to involve invasion, cell adhesion to bone, and the release of soluble mediators from tumor cells that stimulate osteoclast-mediated bone resorption. Bisphosphonates (BPs) are powerful inhibitors of the osteoclast activity and are, therefore, used in the treatment of patients with osteolytic metastases. However, an added beneficial effect of BPs may be direct antitumor activity. We previously reported that BPs inhibit breast and prostate carcinoma cell adhesion to bone (Boissier et al., Cancer Res., 57: 3890-3894, 1997). Here, we provided evidence that BP pretreatment of breast and prostate carcinoma cells inhibited tumor cell invasion in a dose-dependent manner. The order of potency for four BPs in inhibiting tumor cell invasion was: zoledronate > ibandronate > NE-10244 (active pyridinium analogue of risedronate) > clodronate. In addition, NE-58051 (the inactive pyridylpropylidene analogue of risedronate) had no inhibitory effect, whereas NE-10790 (a phosphonocarboxylate analogue of risedronate in which one of the phosphonate groups is substituted by a carboxyl group) inhibited tumor cell invasion to an extent similar to that observed with NE-10244, indicating that the inhibitory activity of BPs on tumor cells involved the R2 chain of the molecule. BPs did not induce apoptosis in tumor cells, nor did they inhibit tumor cell migration at concentrations that did inhibit tumor cell invasion. However, although BPs did not interfere with the production of matrix metalloproteinases (MMPs) by tumor cells, they inhibited their proteolytic activity. The inhibitory effect of BPs on MMP activity was completely reversed in the presence of an excess of zinc. In addition, NE-10790 did not inhibit MMP activity, suggesting that phosphonate groups of BPs are responsible for the chelation of zinc and the subsequent inhibition of MMP activity. In conclusion, our results provide evidence for a direct cellular effect of BPs in preventing tumor cell invasion and an inhibitory effect of BPs on the proteolytic activity of MMPs through zinc chelation. These results suggest, therefore, that BPs may be useful agents for the prophylactic treatment of patients with cancers that are known to preferentially metastasize to bone.

PMID: 10850442, UI: 20306615

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