Bisphosphonates and Osteonecrosis of the Jaw

Web Sites

American Academy of Oral and Maxillofacial Surgeons
Home page of the American Academy of Oral and Maxillofacial Surgeons. Contains links to the AAOMS position paper (PDF, 277 KB) on BRONJ and related topics.

American Academy of Rheumatology
A "hotline" update from the American Academy of Rheumatology.

American Dental Association
An overview by the American Dental Association.

Bone Health Advisory Council
Brief description of ONJ, with links to in-depth articles, from the Bone Health Advisory Council.

National Osteoporosis Foundation
Information on osteonecrosis for patients.

World Health Organization
Technical report on the prevention and management of osteoporosis (PDF, 2.87 MB), WHO recommendations for the prevention of osteoporosis, and a compilation of evidence on osteoporosis screening (PDF, 382 KB) by WHO's Health Evidence Network.

Books

Alexander IM, Knight KA. 2006. 100 Questions & Answers on Osteoporosis and Osteopenia. Jones and Bartlett Publishers, Sudbury, MA.
Amazon

Siris ES, Roodman GD. 2003. Paget's Disease of Bone. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. American Society for Bone and Mineral Research, Washington, DC.
Amazon

Journal Articles

Graham Russell

Kavanagh KL, Guo K, Dunford JE, et al. 2006. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc. Natl. Acad. Sci. USA 103: 7829-7834. Full Text

Nancollas GH, Tang R, Phipps RJ, et al. 2006. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38: 617-627.

Russell RG. 2007. Bisphosphonates: mode of action and pharmacology. Pediatrics 119 Suppl 2: S150-162.

Russell RG. 2006. Ibandronate: pharmacology and preclinical studies. Bone 38 (4 Suppl 1): S7-S12.

Russell RG, Espina B, Hulley P. 2006. Bone biology and the pathogenesis of osteoporosis. Curr. Opin. Rheumatol. 18 Suppl. 1: S3-S10.

Michael Rogers

Coxon FP, Thompson K, Rogers MJ. 2006. Recent advances in understanding the mechanism of action of bisphosphonates. Curr. Opin. Pharmacol. 6: 307-312.

Lipton A, Berenson JR, Body JJ, et al. 2006. Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference. Clin. Cancer Res. 12: 6209s-6212s.

Roelofs AJ, Thompson K, Gordon S, Rogers MJ. 2006. Molecular mechanisms of action of bisphosphonates: current status. Clin. Cancer Res. 12: 6222s-6230s.

Rogers MJ. From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates. Calcif. Tissue Int. 75: 451-461.

Thompson K, Rogers MJ, Coxon FP, Crockett JC. 2006. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol. Pharmacol. 69: 1624-1632. Full Text

Robert Coleman

Body JJ, Diel IJ, Lichinitzer M, et al. 2004. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br. J. Cancer 90: 1133-1137.

Coleman RE. 2006. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 12(20 Pt 2): 6243s-6249s.

Coleman RE. 2001. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat. Rev. 27: 165-176.

Coleman RE. 1997. Skeletal complications of malignancy. Cancer 80: 1588-1594. Full Text

Coleman RE, Major P, Lipton A, et al. 2005. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J. Clin. Oncol. 23: 4925-4935. Full Text

Diel IJ, Solomeyer EF, Costa SD, et al. 1998. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 339: 357-363. Full Text

Kohno N, Aogi K, Minami H, et al. 2005. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J. Clin. Oncol. 23: 3314-3321. Full Text

Rosen LS, Gordon D, Kaminski M, et al. 2003. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98: 1735-1744.

Weinfurt KP, Castel LD, Li Y, et al. 2004. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med. Care 42: 164-175.

Eastell R, Barton I, Hannon RA, et al. 2003. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J. Bone Mineral Res. 18: 1051-1056.

Ethel Siris

Burge R, Dawson-Hughes B, Solomon DH, et al. 2007. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J. Bone Miner. Res. 22: 465-475.

Cooper C. 1997. The crippling consequences of fractures and their impact on quality of life. Am. J. Med. 103(2A): 12S-17S.

Cummings SR, Nevitt MC, Browner WS, et al. 1995. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N. Engl. J. Med. 332: 767-773.

Dennison E, Cooper C. 2000. Epidemiology of osteoporotic fractures. Horm Res. 54 suppl 1: 58-63.

Kanis JA, Johnell O, Oden A, et al. 2000. Long-term risk of osteoporotic fracture in Malmö. Osteoporos Int. 11: 669-674.

Siris ES, Chen YT, Abbott TA, et al. 2004. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch. Intern. Med. 164: 1108-1112. Full Text

Socrates Papapoulos

Black DM, Schwartz AV, Ensrud KE, et al.; FLEX Research Group. 2006. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296: 2927-2938. Full Text

Bone HG, Hosking D, Devogelaer JP, et al. 2004. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N. Eng. J. Med. 350: 11-21. Full Text

Cranney A, Guyatt G, Griffith L, et al; Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. 2002. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr. Rev. 23: 570-578. Full Text

Harris ST, Watts NB, Li Z, et al. 2004. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr. Med. Res. Opin. 20: 757-764.

Mellstrom DD, Sorensen OH, Goemaere S. 2004. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif. Tissue Int. 75: 462-468.

Marcus R, Wong M, Heath H, Stock JL. 2002. Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint. Endocr. Rev. 23: 16-37. Full Text

Recker R, Lappe J, Davies KM, Heaney R. 2004. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J. Bone Miner. Res. 19: 1628-1633.

Reginster J-Y, Adami S, Lakatos P, et al. 2006. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann. Rheum. Dis. 65: 654-661.

Rizzoli R, Greenspan SL, Bone G, et al. 2002. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J. Bone Miner. Res. 17: 1988&-1996.

Schnitzer T, Bone HG, Crepaldi G, et al. 2000. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging Clin. Exp. Res. 12: 1-12.

Stuart Silverman

Altman RD, Bloch DA, Hochberg MC, Murphy WA. 2000. Prevalence of pelvic Paget's disease of bone in the United States. J. Bone Miner. Res. 15: 461-465.

Hosking D, Lyles K, Brown JP, et al. 2007. Long-term control of bone turnover in Paget's disease with zoledronic acid and risedronate. J. Bone Miner. Res. 22: 142-148.

Land C, Rauch F, Montpetit K, et al. 2006. Effect of intravenous pamidronate therapy on functional abilities and level of ambulation in children with osteogenesis imperfecta. J. Pediatr. 148: 456-460.

Langston AL, Ralston SH. 2004. Management of Paget's disease of bone. Rheumatology 43: 955-959. Full Text

Lyles KW, Siris ES, Singer FR, Meunier PJ. 2001. A clinical approach to diagnosis and management of Paget's disease of bone. J. Bone Miner. Res. 16: 1379-1387.

Rauch F, Cornibert S, Cheung M, Glorieux FH. 2007. Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta. Bone 40: 821-827. Epub 2007 Jan 12.

Reid IR, Miller P, Lyles K, et al. 2005. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N. Engl. J. Med. 353: 898-908. Full Text

Roodman GD, Windle JJ. 2005. Paget disease of bone. J. Clin. Invest. 115: 200-208. Full Text

Soininvaara TA, Jurvelin JS, Miettinen HJ, et al. 2002. Effect of alendronate on periprosthetic bone loss after total knee arthroplasty: a one-year, randomized, controlled trial of 19 patients. Calcif. Tissue Int. 71: 472-477.

Zeitlin L, Rauch F, Plotkin H, Glorieux FH. 2003. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics 111(5 Pt 1): 1030-1036. Full Text

Salvatore Ruggiero

Bilezikian JP. 2006. Osteonecrosis of the jaw—do bisphosphonates pose a risk? N. Engl. J. Med. 355: 2278-2281.

Ruggiero SL, Fantasia J, Carlson E. 2006. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 102: 433-441.

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. 2004. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J. Oral Maxillofac. Surg. 62: 527-534.

Ana Hoff

Ardine M, Generali D, Donadio M, et al. 2006. Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw? Ann. Oncol. 17: 1336-1337. Epub 2006 Mar 8.

Bamias A, Kastritis E, Bamia C, et al. 2005. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates:incidence and risk factors. J. Clin. Oncol. 23: 8580-8587. Full Text

Dimopoulos, MA, Kastritis E, Anagnostopoulos A, et al. 2006. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 91: 968-971. (PDF, 156 KB) Full Text

Delibasi T, Altundag K, Kanlioglu Y. 2006. Why osteonecrosis of the jaw after bisphosphonates treatment is more frequent in multiple myeloma than in solid tumors. J. Oral Maxillofac. Surg. 64: 995-996.

Khamaisi M, Regev E, Yarom N, et al. 2007. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J. Clin. Endocrinol. Metab. 92: 1172-1175. Epub 2006 Dec 19.

Pozzi S, Marcheselli R, Sacchi S, et al. 2007. Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk. Lymphoma 48: 56-64.

Sanna G, Preda L, Bruschini R, Cossu Rocca M, et al. 2006. Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer. Ann. Oncol. 17: 1512-1516.

Van Poznak C. 2006. The phenomenon of osteonecrosis of the jaw in patients with metastatic breast cancer. Cancer Invest. 24: 110-112.

Zervas K, Verrou E, Teleioudis Z, et al. 2006. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br. J. Haematol. 134: 620-623.

Regina Landesberg

Hansen T, Kunkel M, Weber A, James Kirkpatrick C. 2006. Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J. Oral Pathol. Med. 35: 155-160.

Landesberg R, Wilson T, Grbic JT. 2006. Bisphosphonate-associated osteonecrosis of the jaw: conclusions based on an analysis of case series. Dent. Today 25: 52, 54-57.

Leon Assael

Ficarra G, Beninati F, Rubino I, et al. 2005. Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J. Clin. Periodontol. 32: 1123-1128.

Marx RE, Sawatari Y, Forti M, Broumand V. 2005. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J. Oral Maxillofac. Surg. 63: 1567-1575.

Migliorati CA. Casiglia J, Epstein J, et al. 2005. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J. Am. Dent. Assoc. 136: 1658-1668. Full Text

Phal PM, Weissman J, Myall R, Assael L. 2007. Imaging findings of bisphosphonate Aassociated osteonecrosis of the jaws. Am. J. Radiol.; in press.

The skeletal system is a living organ that depends on a balance of bone resorption by osteoclasts and bone deposition by osteoblasts. When this balance is upset by diseases such as bone metastases and osteoporosis, bone resorption predominates and patients are vulnerable to fractures and other skeletal events. Bisphosphonates are a class of drugs used to prevent bone resorption by inhibiting osteoclast function. Most clinicians agree that bisphosphonates are effective drugs.

Should use of bisphosphonates for prevention of bone resorption be stopped, considering recent reports of its connection to risk of ONJ?

However, in 2001 reports of patients taking bisphosphonates (BPs) who had developed osteonecrosis of the jaw (ONJ) began to appear in the dental and oncology literature. The condition was characterized primarily by exposed bone in the jaw, swelling, and purulent discharge, but the usual treatments for osteomyelitis (the presumptive diagnosis) did not work. Most of the reported cases were in patients receiving intravenous BP therapy for metastatic bone disease from cancer, but some affected patients were taking oral BPs, primarily for the treatment of osteoporosis.

Much about the relationship between BPs and ONJ is unknown, including the mechanism by which ONJ is triggered. In addition, even the set of symptoms and signs that constitute ONJ are not fully defined. Clinically, perhaps the most important and controversial question is whether BP treatment ought to be stopped in certain patients or not used at all in view of ONJ as a possible complication. Does the benefit of stopping treatment outweigh the risks?

Held at the New York ACademy of Sciences on May 19, 2007, this multidisciplinary conference brought together basic scientists, dentists, oral surgeons, oncologists, internists, and others who see patients with the condition or who may be at risk for it. The speakers reviewed what is known about BP-related ONJ, proposed mechanisms, and strategies for prevention and treatment.

Organizers included John Bilezikian (Columbia University College of Physicians and Surgeons), John Grbic (Columbia University College of Dental Medicine), G. David Roodman (University of Pittsburgh Hillman Cancer Center), and Catherine Van Poznak (University of Michigan Comprehensive Cancer Center). A forthcoming volume of the Annals of the New York Academy of Sciences will also cover this subject.

John P. Bilezikian introduced the conference, which was divided into two sessions. The first session, which Bilezikian also chaired, reviewed the basic science of BPs, the use of BPs in diseases other than osteoporosis, and the initial case reports of BP-related ONJ. Speakers in the second session, chaired by Ira Lamster (Columbia University College of Dental Medicine) summarized the epidemiology and prevalence of ONJ, reviewed current research in the area, and discussed the management of the condition and how it might be prevented.

Highlights included:

BPs and bone cancer

• The chemical composition of the bisphosphonates is a PCP backbone with nitrogenous or nonnitrogenous sidechains.
• Each BP has a distinct profile, but all work by inhibiting bone resorption through bone mineral affinity and enzyme inhibition.
• Simple BPs help create a toxic metabolite within the osteoclast that causes the osteoclast to undergo cell suicide.
• Nitrogen-containing BPs inhibit FPPS, an enzyme in the mevalonate (cholesterol) pathway.
• BPs can reduce skeletal morbidity by 30%–50% in metastatic bone disease. Zoledronic acid is the most reliable agent here.

BP treatment of nonmalignant diseases

• For patients at risk of fracture from osteoporosis, the benefits of treatment greatly outweigh the risk of ONJ.
• The usual dose of BPs is 10 times lower for osteoporosis than the dose used for metastatic bone disease.
• BPs are part of standard treatment in Paget's disease.
• BPs should be used with caution in osteogenesis imperfecta.
• BPs may have a role in procedures where bone implants are used.

Overview of ONJ: initial descriptions and case reports

• Patients with ONJ usually present with a nonhealing extraction socket, exposed jawbone with localized swelling, and purulent discharge.
• Almost all ONJ patients who haven't received radiotherapy to the head or neck are taking BPs, either as intravenous monthly infusions or as oral agents.
• New cases of BP-related ONJ seem to occur preferentially in patients with breast cancer or multiple myeloma.
• Major risk factors for the development of ONJ are longer duration of exposure to BPs, cumulate dosage of BPs, treatment with zoledronic acid rather than other BPs, and dental procedures.
• A German ONJ registry set up in 2004 now contains data on 600 patients.
• ONJ in the German patients with osteoporosis is extremely rare.
• Analysis of ONJ treatments in Germany shows no difference between conservative therapy and surgical intervention, or a combination of both.

ONJ in the lab and the clinic

• BP-associated ONJ probably results from multiple factors, including trauma and hygiene.
• ONJ may represent an alteration in normal wound healing.
• The current generally accepted case definition of BP-associated ONJ includes current or previous treatment with a BP; exposed, necrotic bone in the maxillofacial region that has lasted for more than eight weeks; and no history of radiation therapy to the jaws.
• A staging system for BP-associated ONJ has been developed:
  • Stage 1: patients asymptomatic with no evidence of infection, but with exposed or necrotic bone.
  • Stage 2: patients have exposed or necrotic bone, along with pain and clinical evidence of infection.
  • Stage 3 includes all the elements of stages 1 and 2, and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border.
  
  
• Patients can improve outcomes by regular brushing and flossing, and dental checkups; ensuring denture fit; not smoking; and maintaining salivation and hydration.

Faith McLellan, PhD, is North American senior editor at The Lancet.

How do bisphosphonates work?

Graham Russell of the Oxford University Institute of Musculoskeletal Sciences introduced one of the major drug classes used to inhibit bone loss. Bisphosphonates (BPs) are stable analogs of inorganic pyrophosphate that come in two forms: the simple nonnitrogen-containing BPs are called clodronate (Bonefos, Bayer Schering Pharma) and etidronate (Didronel, Proctor & Gamble). The nitrogen-containing compounds are known as pamidronate (Aredia, Novartis), alendronate (Fosamax, Merck), risedronate (Actonel, Proctor & Gamble/sanofi-aventis), zoledronate (Zometa, Novartis), and ibandronate (Boniva, Roche Therapeutics). Their chemical structures have a common phosphate-carbon-phosphate (PCP) backbone. But each drug has a distinct profile, with varying pharmacological potencies and important clinical differences.

Russell and Michael Rogers of the University of Aberdeen noted that the simple and nitrogen-containing BPs have different mechanisms of action. The simple BPs act through the formation of a cytotoxic metabolite within the osteoclast that closely resembles ATP. This toxic analog cannot be broken down and causes the osteoclasts to undergo apoptosis (cell suicide).

BPs prevent protein prenylation, which is required for cell function.

The newer nitrogen-containing BPs inhibit farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate (cholesterol) pathway whose crystal structure was recently elucidated, allowing researchers to observe the interaction of the drug with the enzyme. Inhibition of this enzyme prevents the synthesis of the lipid tags that are attached to some proteins to direct them to the right place within the cell, a process known as protein prenylation. Small GTPases, which are important for regulating the activity of the osteoclast, are one class of proteins that do not function properly without prenylation. Thus, the inhibition of protein prenylation in osteoclasts explains the antiresorptive effects of nitrogen-containing bisphosphonates. The effect is not unique to osteoclasts though; for example, BPs cause the same effect in other cell types, such as tumor cells.

However, BPs would be devastating if they were readily taken up by all cell types. They specifically target the skeleton by virtue of their ability to bind to calcium ions and thus attach to mineralizing and resorbing surfaces of bone. According to Russell, about one-third of their activity is explained by their bone mineral affinity and their ability to inhibit the dissolution of calcium phosphate crystals; the rest results from enzyme inhibition. He noted that the different BPs have different mineral binding affinities, which influences both their potency and their duration of action.

The BPs in bone are taken up by resorbing osteoclasts, which sit on the bone surface, chewing away a resorption cavity and absorbing materials through endocytosis at a specialized membrane called the ruffled border. Then, because they acidify the bone surface, osteoclasts in turn release the BP.

The end—and desired—result in the osteoclast, as demonstrated in vitro, is thus a disrupted cytoskeleton, loss of the ruffled border, and cell death by apoptosis. The relevance of these effects on other cell types such as osteoblasts and endothelial cells, which have been described from in vitro studies, still remains to be determined.

Rationale for bisphosphonate use in cancer

Whatever the mechanism of action, BPs have become part of the oncologist's arsenal against the devastating effects of bone metastases. Metastatic bone disease is common, and some cancers, such as prostate, lung, thyroid, bladder, melanoma, and kidney, are well known to have a predilection for metastasizing to bone, said Robert Coleman of the University of Sheffield Weston Park Hospital. Bone metastases are also highly prevalent in breast cancer, as the median survival rate, about three years, is longer than for other cancers.

Bone metastases cause pain as well as structural complications, such as fracture and spinal cord compression, and metabolic complications, such as hypercalcemia. Every year about one-third of patients with bone metastases require a course of radiotherapy for pain or structural damage to the skeleton. The frequency of skeletal complications from bone metastases varies by the type of primary cancer. For example, patients with breast cancer are more likely than those with prostate cancer to experience fractures.

Increased bone resorption is the hallmark of metastatic bone disease. Rapid bone turnover and increased osteoclast activity provide the rationale for the use of BPs across all tumors that spread to bone. Tumor cells cannot destroy bone by themselves; they require the application of osteoclasts and osteoblasts. When tumor cells get to the bone through the bone marrow circulation, they secrete cytokines and growth factors, some of which will interact with osteoclasts. Bone resorption sets up a fertile environment that allows the tumor cells to stay there and aggressively proliferate. This is the so-called "vicious cycle" hypothesis of osteolytic metastases.

Goals of treatment and evidence

Bone metastases cannot be cured, and treatments are palliative. BPs are usually combined with several other therapies to treat the condition. The aims of treatment with BPs are to maintain normal bone health, prevent skeletal morbidity, relieve bone pain, prevent and treat hypercalcemia, maintain quality of life, preserve functional independence, and normalize rate of bone resorption.

With all of the BPs out there, which ones work best?

BPs may provide long-term relief of bone pain, and they have been shown to improve patients' quality of life. But with all of the BPs out there, which ones work best? The drugs approved for the treatment of specific cancers vary between the U.S. and Europe, with more BPs available in Europe for the treatment of breast cancer and myeloma. And, Coleman stressed, the studies of which compounds to use are often driven by economics, not necessarily by science, making comparisons difficult.

But some information is available. In breast cancer specifically, a 2005 Cochrane systematic review showed that all BPs are active in the prevention of skeletal complications, but the newer and intravenous agents may be somewhat more active. BPs can reduce skeletal morbidity by about 33%–50%.

Across a range of solid tumors, zoledronic acid, one of the newest and most potent BPs, has been shown to reduce the risk of skeletal-related events. When zoledronic acid was compared with pamidronate in breast cancer and multiple myeloma, there was a statistical advantage in favor of zoledronic acid. One might have expected a greater difference in clinical activity between these two drugs, as their potencies are very different, but this was not shown.

When to administer and how much?

Bisphosphonate treatment in metastatic bone disease is more intensive than in benign bone disease; that is, it is given more frequently. A question now being researched is whether treatment should move from its current fixed monthly schedule to one that is directed by bone markers.

Another current research question, said Coleman, is whether BPs can prevent metastases in early cancer. Two studies of oral clodronate in early breast cancer have shown encouraging results. Clodronate delayed bone metastases and increased overall survival in both trials, and increased disease-free survival in one trial. A third, smaller trial did not show any treatment effect.

Another breast-cancer trial (the AZURE trial), which compares standard adjuvant therapy with standard therapy plus zoledronic acid, has finished recruiting subjects, but no efficacy endpoints are available yet. Zoledronic acid was well tolerated with no increase in chemotherapy related side-effects. To date, with a median follow-up of 18 months, 8 cases of ONJ have occurred in 1700 patients.

Bisphosphonates are an effective intervention to prevent cancer treatment-induced bone loss.

Bone loss following a chemotherapy-induced menopause or the use of androgen deprivation therapy in men with prostate cancer, or aromatase inhibitors in postmenopausal women with breast cancer, occurs at rates two to five times greater than in the normal population. This may lead to osteoporosis and fragility fractures as cancer patients live longer and are increasingly exposed to long term endocrine treatments. The bisphosphonates are an effective intervention to prevent this cancer treatment-induced bone loss.

Coleman concluded that BPs can markedly reduce skeletal morbidity in metastatic bone disease by 30%–50%, with zoledronic acid being most reliable. Both early and long-term treatments are indicated. On the horizon, there is a potential role for bone-targeted therapies to prevent bone metastases, and new agents are challenging the role of BPs.

Osteoporosis: definition, pathogenesis, prevalence

Osteoporosis is the other main target of bisphosphonate drugs. Ethel Siris of Columbia University Medical Center, New York-Presbyterian Hospital emphasized the need to effectively treat osteoporosis, as it is a widespread and costly disease with profound effects on patients' quality of life. The National Institutes of Health (NIH) defines osteoporosis as "a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture." Bone strength is defined as bone quantity (bone mineral density) plus bone quality (microarchitecture).

Some of the factors that predispose a person to fracture are low peak bone mass or increased bone loss, heredity, menopause, and age. All of these combine to reduce bone quantity and quality.

Osteoporosis affects 200 million women worldwide.

Worldwide, osteoporosis affects one-third of women aged 60 to 70, and two-thirds of women 80 and older, for a prevalence of 200 million women. The prevalence of osteoporosis and low bone mass is predicted to rise, reaching 3.25 million in Asia alone by the year 2050.

In the United States, 8 million women and 2 million men over age 50 have osteoporosis, said Siris. An additional 34 million have low bone mass. The lifetime fracture risk for people over 50 is quite high: 1 in 2 for women and 1 in 4 for men, with the most common single site of fracture being the spine, and the most medically serious site being the hip. Osteoporotic fractures in women are more common than myocardial infarction, stroke, and breast cancer combined.

Sequelae of osteoporotic fractures

Fractures are expensive, with direct costs ranging from $12.2 billion to $17.9 billion in 2002. Indirect costs, including lost productivity and family care, add billions to those amounts.

Specific fracture sites result in various morbidities. Vertebral fractures cause back pain, loss of height, physical deformity, reduced pulmonary function, and diminished quality of life. Hip fractures are particularly devastating, with a 20% risk of death after one year, a 30% risk of permanent disability, and an 80% risk of inability to carry out one independent activity of daily living. The rates of survival after hip fracture are much lower than the expected survival rates in the general population.

Diagnosis and management

The diagnosis of osteoporosis, ranging from normal to osteopenia to osteoporosis or severe osteoporosis, is based on measurement of bone mineral density and the resulting T-score, which is a comparison of the person's BMD with that of a "young normal person." The T-score definition was developed by the World Health Organization in 1994, but there were no specific recommendations for when to treat. Bone density testing is an excellent measure of risk of future fracture, but the T-score must be combined with clinical risk factors to optimize risk assessment.

For patients at risk of fracture, the benefits of treatment greatly outweigh the risk of ONJ, said Siris.

A variety of factors add to the risk of fracture, including age, family history, health conditions such as rheumatoid arthritis, body mass index, and previous low-trauma fracture after age 45, use of glucocorticoids, smoking, and high alcohol consumption. A new WHO and National Osteoporosis Foundation algorithm for absolute fracture probability will combine T-score at the hip with a set of clinical risk factors (especially age) to determine fracture probability over 10 years in an individual patient. Decisions on when to treat after determining fracture probability will be made country by country, based on available resources and considerations of cost-effectiveness.

For patients at risk of fracture, the benefits of treatment greatly outweigh the risk of ONJ, said Siris. In patients for whom BPs are appropriate, more data are needed to determine optimal duration of treatment and the cumulative amount of drug that is both safe and effective.

Treatment of osteoporosis

FDA-approved treatment options include antiresorptive agents and anabolic agents. The antiresorptives, all of which reduce the risk of vertebral fracture, include estrogen, which prevents bone loss; the BPs, alendronate, risedronate, and ibandronate; the selective estrogen receptor modulator raloxifene; and the hormone calcitonin. Alendronate also has been shown to reduce risk of hip fracture, and risedronate has been shown to reduce the risk of nonvertebral fractures. Teriparatide is an anabolic agent that reduces both vertebral and nonvertebral fracture risk.

Treatment for osteoporosis is also supplemented by general measures, including correction of deficiencies in vitamin D and calcium, said Socrates Papapoulos of the University of Leiden. Interventions are both pharmacologic and nonpharmacologic.

Papapoulos stressed that bisphosphonates are the most widely used treatment for osteoporosis, and he discussed some features of the disease that are counteracted by the drugs. Patients with osteoporosis have three to four times the rate of bone remodeling than normal, and more bone is lost at each remodelling cycle. This has an adverse effect on the bone microstructure, leading to loss of trabeculae, the bony spicules that form a meshwork filled with bone marrow. Ultimately, the result is weaker bone that is prone to fracture.

BPs are used in the treatment of osteoporosis because, as Russell and Rogers explained, they inhibit bone resorption and turnover. BP treatment is associated with increases in BMD and maintenance of the bone microstructure, and a decrease in cortical porosity. All BPs show a consistent effect in the reduction of vertebral fractures, reiterated Papapoulos.

The usual dose of BPs is 10 times lower for osteoporosis than the dose used for metastatic bone disease, which may explain why most cases of ONJ are found in patients with the latter.

Evidence base for efficacy and dosing schedule of BPs

Papapoulos presented the results of a meta-analysis in Endocrine Reviews in 2002 that examined the relationship between BPs and the risk of nonvertebral fracture. Alendronate reduced the risk of fracture by 13%–49%, depending on the dose, and risedronate reduced risk by 27%, he said.

Bisphosphonates are usually given to osteoporosis patients for many years. The FLEX study (Fracture Intervention Trial Long-term Extension) compared the effects of discontinuing alendronate treatment after 5 years versus continuing for 10 years. Women on the shorter duration of treatment showed a modest decline in BMD but had no higher fracture risk than those who continued alendronate for 10 years. The treatment carried no deleterious effects. Giving alendronate for osteoporosis for 10 years does not lead to a cumulative effect on bone turnover, said Papapoulos.

Risedronate and alendronate, given once weekly, for the equivalent of seven daily doses, has the exact same effect as daily administration.

Because daily use of BPs is very efficacious, but not very convenient, a weekly regimen of BP has been developed. Risedronate and alendronate, given once weekly, for the equivalent of seven daily doses, has the exact same effect as daily administration. Weekly dosing of alendronate increased BMD, and there was no fluctuation from day to day. The results remained the same after one to two years of treatment.

What happens when a drug-free interval is extended during BP administration? Intermittent administration for long-term intervals causes great fluctuation in bone resorption and is not associated with antifracture efficacy. Simple math doesn't work here; the dose must be increased to compensate for fluctuation in drug levels between doses. All BPs reduce fracture when given at the right dose and interval, and if the right dose is given, more extended drug-free intervals can be entertained. But safety and tolerability must always be considered, cautioned Papapoulos.

Bisphosphonate use in Paget's disease

Stuart Silverman of Cedars-Sinai Medical Center in Los Angeles discussed the largely positive effects of bisphosphonates in a number of other bone disorders. Paget's disease is the second most common metabolic bone disease after osteoporosis, affecting about one million persons over the age of 65 in the U.S. The incidence increases markedly with age; the disease rarely occurs in persons younger than 40. This chronic, progressive skeletal disorder is characterized by an increased size and number of osteoclasts. The disease carries a risk of significant complications, including osteoarthritis, fractures, neurological complications, hearing loss, and osteosarcoma.

The goals of treatment are to normalize the rate of bone turnover, relieve symptoms, and reduce vascularity in surgical pagetic sites. Management of the disease usually consists of nitrogen-containing BPs (the gold standard therapy), pain relievers (NSAIDs, COX-2 inhibitors, analgesics, opioids), and surgery. BPs are used both orally and intravenously in differing doses and for differing durations, up to six months. Intravenous zoledronic acid has been shown to create an earlier and more rapid response than oral risedronate, as measured by alkaline phosphatase levels.

Bisphosphonate use in osteogenesis imperfecta

Osteogenesis imperfecta (OI) occurs mainly in children. There are seven types of this genetic disorder, which affects collagen. OI is a disease of the osteoblast, causing a disorganized matrix and a high bone turnover rate. The disease results in deformities, pain, and decreased ability to walk.

Treatment with pamidronate has been shown to increase bone mineral density and content, and to change bone shape. Pamidronate also reduces the rate of fractures, increases children's growth (measured by height/growth curves), and increases mobility. Treatment benefits are mostly realized in the first three to four years of treatment. Because of the known side effects—suppression of bone remodeling, accumulation of growth plate cartilage, and respiratory distress—Silverman noted that it is prudent to limit the use of BPs to moderate and severe cases.

Periprosthetic bone mineral density loss

Periprosthetic bone mineral density (BMD) loss occurs after a prosthesis has been inserted into a weight-bearing bone, thereby altering its mechanical loading properties, and increasing bone remodeling. Bone may decrease by as much as 44% around a prosthesis. Randomized controlled trials have shown that alendronate preserves periprosthetic BMD in total knee arthroplasty and in total hip replacement, said Silverman.

On the horizon

Bisphosphonate treatment is currently being investigated for a number of other bone conditions. For example, the cement around a titanium implant, such as a dental implant, is likely to fail over time. In order to create osseous integration of the implant, it must be polished, pitted, or coated with hydroxyapatite. In animal models, BPs have been added to the hydroxyapatite coating, which resulted in a 50% increase in peri-implant bone. The data on the effects of BPs on dental implants and periodontal disease in humans are limited.

Because bisphosphonates inhibit osteoclasts, clinicians are hoping they might help in fracture healing and bone degeneration. Currently, there is anecdotal evidence only, in three cases, that zoledronic acid helps remodel bone when delayed union occurs after fracture. No randomized controlled trials have been conducted. Similarly, preclinical studies in animal models suggest that BPs may have a positive effect on osteonecrosis of the hip, a condition in which vascular supply to the bone is interrupted, resulting in bone weakening and joint collapse. Randomized controlled trials in humans are needed, concluded Silverman.

History of the phenomenon

Like many drugs, bisphosphonates can have negative effects as well as positive ones, and oral surgeon Salvatore Ruggiero of Long Island Jewish Medical Center (LIJMC) was one of the first to discover the adverse effects. In 2001, a woman with end-stage breast cancer was referred to Ruggiero with a large area of exposed bone in the posterior maxilla, or upper jaw. Ruggiero performed surgery to remove the area, and the patient improved. Within four months, however, she had the same problem on the opposite side of her jaw. This was Ruggiero's first case of a disease he characterized as bisphosphonate-related osteonecrosis of the jaw (ONJ).

ONJ patients got worse with the traditional treatment for osteomyelitis.

Other cases appeared, all in patients with metastatic bone disease who presented with exposed alveolar bone or who were referred for management of "refractory osteomyelitis." Osteomyelitis of the jaw is a well-described and treatable condition, but these patients got worse with the traditional treatment.

The patients were receiving various therapeutic regimens, and none had a history of radiation to the head and neck, although surgically ONJ looks very much like osteoradionecrosis. All of the patients reported that they were receiving monthly infusions of either pamidronate or zolendronate.

From February 2001 to February 2007, 186 cases of ONJ, diagnosed by biopsy or clinical examination, were seen at LIJMC. The uniform clinical presentation was a nonhealing extraction socket, exposed jawbone with localized swelling and purulent discharge. No tumors were found at the sites. Oral surgeons were dismayed to find that debridement and antibiotics were ineffective.

Patient characteristics

Ruggiero began to collect information about the patients to get a better understanding of the basis for the disease. More than 75% of the LIJMC patients were women, with a mean age of 66 years. Eighty-seven percent of the patients had had previous dental trauma, some sort of extraction, implant, or dental procedure that injured the bone and required remodeling. Their primary diagnoses, in order of frequency, were multiple myeloma, breast cancer, and osteoporosis; the rest were classified as "other." In 70% of the cases, the site of necrosis was the mandible, or lower jaw, and the rest were in the maxilla.

In keeping with Ruggiero's early observations, most affected patients were receiving monthly intravenous infusions of zolendronate or pamidronate; 19% were on oral agents. Patients on oral agents had a longer duration of exposure to the drugs than those on intravenous drugs.

Patients who did not have a history of cancer, but presented with ONJ, were usually taking oral BPs, mainly alendronate, for osteoporosis. Some osteoporosis patients were also receiving steroids, and these patients developed ONJ after a shorter exposure to the drugs than patients taking BPs alone. After reviewing their data, Ruggiero and his colleagues came to the conclusion that the cases of osteonecrosis of the jaw were related to bisphosphonate treatment.

Definition and prevalence of ONJ

To determine the extent of BP-related ONJ, members of the American Association of Oral and Maxillofacial Surgeons (AAOMS) were surveyed by email. Thirty percent of the active membership responded, for a total of 1771 respondents. The participants agreed on the following definition of BP-related ONJ:

• history of treatment with BPs
• no history of radiotherapy to the maxillofacial region
• exposed bone in the maxillofacial area that occurred either spontaneously or after dental trauma
• no evidence of any healing for more than 8 weeks after some type of appropriate care

By April 2006, 4737 patients had been identified by this survey, a significant number, and the problem is likely to keep growing, said Ruggiero.

Ruggiero noted that there is very little literature to date on BP-related ONJ, and he initially had difficulty getting his findings accepted by clinical journals. But, by 2005, case reports began to appear in the oncology literature. Position statements have been issued, such as the one published in the Journal of Clinical Oncology Practice in 2005. The most prescriptive guidelines are found on the AAOMS website. The American Dental Association also has recommendations for the assessment of ONJ, which largely parallel the AAOMS guidelines.

Ruggiero emphasized the importance of the position statement by the American Association of Endodontists (AAE) because it reassured endodontists that peforming nonsurgical endodontic therapy on BP patients was safe. Ruggiero thus outlined one of the big problems facing patients receiving bisphosphonates. Many dentists are wary of treating them for fear of triggering BP-ONJ, and at the same time, the doctors who prescribe the drugs are wary of stopping BP therapy.

Epidemiology of ONJ

Ira Lamster of Columbia University College of Dental Medicine introduced many of the questions epidemiologists are trying to answer about bisphosphonates and osteonecrosis of the jaw. They ranged from the most basic, such as agreeing on a definition of the disease, to the more complex—determining the incidence, pathophysiology, and risk factors for ONJ.

Ana Hoff of the Fleury Institute in Brazil presented a review of the worldwide literature on the still-emerging picture of ONJ. She noted that before recent reports of BP-related ONJ began appearing, osteonecrosis of the jaw had been previously described primarily in patients with head and neck tumors who had been treated with radiotherapy. The MD Anderson Cancer Center in Houston, where Hoff was formerly a researcher, has had considerable experience with patients whose ONJ was preceded by radiotherapy.

After excluding head and neck cancer patients, the frequency of cancer patients with ONJ ranged from 0.6% to 9.9%.

But beginning in 2003, reports, mainly from the U.S. and Europe, of ONJ in patients without head and neck cancer, began to appear. The frequency of ONJ ranged from 0.6% to 9.9% in patients with cancers that included multiple myeloma, breast cancer, and prostate cancer. Higher frequencies were found in patients from Greece.

Studies of ONJ cases reported in the literature revealed risk factors similar to those noted by Ruggiero: length of treatment with intravenous BPs, dental procedures, and use of zoledronic acid, with ONJ occurring earlier in patients treated with zoledronic acid compared with those on other BPs. A study from the University of Maryland, added length of time since diagnosis of the cancer as an additional risk factor, a finding corroborated by an MD Anderson Cancer Center study.

A study from Greece demonstrated no association of ONJ with gender, cancer staging, number of bone lesions, or presence of anemia. In addition, the MD Anderson Cancer Center study found no differences in patient age and no important association with glucocorticoids.

Other potential risk factors for ONJ have been suggested. These include secondary hyperparathyroidism and diabetes mellitus. According to the MD Anderson study, ONJ is seen more often in patients with breast cancer and multiple myeloma, a phenomenon that may be dose-related.

German case registry

When a new disease appears in the clinic, the main thing doctors and scientists need is information. Dieter Felsenberg of the Free University of Berlin in Germany discussed an ONJ registry that was set up in Berlin in December 2004. The registry was created for several reasons: to document cases of ONJ; to collect and disseminate fundamental data that could be used to determine the etiology and pathogenesis of ONJ; to make recommendations for treatment and prevention; to create a forum for interdisciplinary discussion and consultation; and to provide educational materials. At present, 3–4 cases are added each week; the current total is about 600. The registry collects as much information as possible about each case.

The definition of ONJ used for the registry is similar to that of AAOMS: local infection of the bone and/or stomatitis and delayed healing (> 6–8 weeks) after oral intervention. Bone may or may not be exposed, and patients may or may not have used BPs.

Patient characteristics

Most patients in the registry have cancer: 319 compared with 8 patients with osteoporosis alone. Fourteen out of 26 patients with osteoporosis also have cancer. In total, 1.9% of all patients in the registry have been diagnosed with osteoporosis. Felsenberg stressed the importance of determining whether patients reported as having osteoporosis are in fact cancer patients who also have osteoporosis, because the cancer patients are treated with much higher levels of BPs.

Eighty-five percent of the German patients developed ONJ within the first four years of treatment with BPs. There is no increase in ONJ cases beyond that time. Most patients had a history of tooth extraction. Other dental procedures associated with ONJ included periodontal procedures, root canal, osteotomy, and implants.

The registry has shown no difference in outcomes between conservative treatment, surgery, or a combination of conservative treatment plus surgery. There is a low frequency of completely successful outcomes with any of the treatments.

What can we conclude from the registry data?

ONJ in patients with osteoporosis alone is extremely rare. Of 743,700 patients on BP therapy yearly in Germany, only 8 developed ONJ, or 1 in 93,000 patients. Patients with cancer are at higher risk for developing ONJ. No specific recommendations for treatment can be construed from this database.

Suppression of bone repair by BPs may cause ONJ after dental work.

The etiology of ONJ continues to be elusive. Felsenberg's hypothesis is that BPs used in high doses or for long periods lead to severe reductions in bone metabolism, and suppression of osteoclasts and macrophages. Angiogenesis is also suppressed and apoptosis of osteocytes increases. All of these factors inhibit the repair of bone that is required following dental treatments such as tooth extraction. BPs may also cause immunological barriers to be breached, he said.

The basic trio of proximate causes includes immune modulation, dental intervention or inflammation, and repeated high doses of intravenous BPs, Felsenberg concluded.

Theories of ONJ etiology

Regina Landesberg of Columbia University College of Dental Medicine presented several possible mechanisms of the etiology of ONJ, cautioning that these explanations are speculative, with little available data at present. She noted that no differences are seen in the histological appearance of osteomyelitis, osteonecrosis resulting from radiation therapy, and osteonecrosis associated with BPs. Similarly, when 8 cases of ONJ were compared with 10 cases of infected osteoradionecrosis, Actinomyces, an opportunistic bacterial pathogen, was seen in all cases. The only distinguishing factor was that areas of necrosis in ONJ were diffuse and patchy, while necrosis was larger and less diffuse in infected osteoradionecrosis.

Why is BP-associated osteonecrosis seen only in the jaws?

Why is BP-associated osteonecrosis seen only in the jaws? Landesberg said that it will take several years to get to the bottom of this "burning question" and others about ONJ. She noted that the process of wound healing in the oral cavity after tooth extraction differs from fracture healing at other sites in that no cartilage is involved. In addition, the oral cavity is exposed to the germ-laden environment, which presents a huge challenge that most fracture sites don't face. With respect to the specific effects of BPs, studies of oral keratinocytes and alveolar bone cell cultures have shown that these cells are quite sensitive to the effects of pamidronate. Thus, the function of these cells requires further examination.

One theory of the mechanism of ONJ is that trauma is the initiating event. But it is not clear what happens next: Does the lesion begin from the "outside in" (a breach of the mucosa into the bone), or does it begin in the bone and progress outward?

Normal wound healing in the oral cavity after a trauma, such as tooth extraction, progresses as follows: the area where the tooth was extracted fills up with a blood clot. All healing takes place at the base of the alveolar socket, where granulation tissue is formulated. After about one week, connective tissue and bone have been formed at the base of socket. After 40 days, the socket is about 50% filled in with bone, and there is complete closure of the epithelium overlying the socket. Landesberg speculated that following the trauma of tooth extraction, there is a breach of the mucosa and the lesion progresses inward.

Other potential mechanisms

Unlike Felsenberg, Landesberg thinks BP-associated ONJ is not likely to result from a decrease in angiogenesis. It may however, be related to the immunosuppression that occurs in various disease and conditions, she said. Diabetes, for example, is associated with delays in wound healing, microvascular ischemia, endothelial cell dysfunction, and decreased bone turnover—all of which might contribute to an increased susceptibility to ONJ. Limited evidence, in 31 patients with ONJ, revealed 18 cases of diabetes mellitus (58%) compared with only 4 cases of diabetes in 33 controls (12%).

A pilot study is investigating risk factors and biomarkers that would predict which patients will develop ONJ.

Landesberg and colleagues are now undertaking a pilot study of BPs and oral complications of cancer chemotherapy. The study, funded by a grant from the National Institutes of Health, aims to identify risk factors and biomarkers that would predict which patients will develop ONJ, and to collect incidence data by prospectively following a group of 400 breast cancer patients (prospective cohort) and in a case-control study of 40 ONJ patients. Copious amounts of data will be collected.

Landesberg concluded that ONJ likely has a multifactorial etiology, with trauma as the initiating event. She hypothesized that the resulting lesion starts from the mucosal side and spreads into the bone. ONJ thus may represent an alteration in normal wound healing.

Clinical presentation

Leon Assael of the Oregon Health & Sciences University discussed the prevention and management of bisphosphonate-associated osteonecrosis of the jaw. The usual clinical presentation has changed somewhat since the initial cases reported by Ruggiero, in which most patients had a history of multiple myeloma, said Assael. Now more patients are being seen with prostate and renal cell carcinoma.

Assael showed radiographs and MRI scans of several patients with ONJ. Case series have led the AAOMS to develop a staging system for ONJ:

• Stage 1 patients are asymptomatic, with no evidence of infection, but who have exposed or necrotic bone;
• Stage 2 patients have exposed or necrotic bone, along with pain and clinical evidence of infection;
• Stage 3 includes all the elements of stages 1 and 2, and, in addition, one of more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border.

The concept of ONJ development as a process has led to the question of whether there is a prodrome for BP-related ONJ (BRONJ). Patients have been seen with non-specific clinical findings that may be an early indication of a BP effect on bone. Assael proposes calling this effect "bisphosphonate disease of the jaws (BDJ)."

Dental therapy and prevention

Clinical guidance for treatment of patients on BPs with ONJ includes consideration of the BP dose the patient has received (the mean time to induction of ONJ for patients on oral BPs is more than 2.5 years). Oral health should be optimized by performing only necessary, not discretionary, invasive treatments (curettage is probably acceptable, but osseous surgery should be performed only with caution). Bone graft therapy that relies on phase 2 healing or bone remodelling should not be performed.

Patients with signs and symptoms of the BRONJ prodrome may not inevitably go on to develop ONJ, if prevention and mitigation strategies are employed. Furthermore, BRONJ is not a sign of more serious illness, such as recurrent tumor. In fact, the vast majority of patients with BRONJ can live pain-free with exposed bone.

BP "drug holidays" might be a mitigating strategy.

Current ideas about prevention methods are based upon the postulated pathophysiology of BRONJ. If the BP level in new bone is a key etiologic factor, it would follow that BP "drug holidays" might be a mitigating strategy. No available data suggest that discontinuation of BPs reduces the risk for ONJ, but there are some data to suggest that patients with BRONJ who are given drug holidays may have better outcomes.

Only the dose of BP necessary for the clinical indication should be used, as cumulative dose/exposure does matter. If bacteria play a role in ONJ development, systemic antibiotics can be used. Periodontitis should be treated and caries controlled. Implicated cofactors, which include smoking, anemia, steroids, and chronic obstructive pulmonary disease, should be treated or eliminated. Dental intervention should be limited to non-invasive or minimally invasive procedures.

Serum C-terminal telopeptide (CTX), a bone turnover marker, has been proposed as part of a prevention strategy. CTX may in fact help assess the risk of BRONJ, predict response to treatment, and guide decisions about possible surgical intervention.

Management strategies

The overall objectives of BRONJ treatment are to eliminate pain, control infection, and minimize the progression or occurrence of bone necrosis. Assael's personal recommendations for management include ongoing use of 0.12% chlorhexidine on the toothbrush and at the brush site. When pain or cellulitis are present, antibiotics should be given. Patients who are immunocompromised should also have staph coverage.

Other possible strategies include hyperbaric oxygen, parathyroid hormone administration, switching to raloxifene for patients with osteoporosis alone, and, for patients with severe stage 3 disease, resection and fibula vascularised tissue transfer.

Preoperative assessment of the patient is key.

BPs clearly have important positive effects when used correctly for appropriate indications. However, nearly 3000 cases of ONJ on patients receiving BPs have been reported to the FDA, with the risk in patients with multiple myeloma perhaps reaching 10% of more. These numbers are likely to increase as more and more patients start taking BPs. In about one-third of cases, tooth extraction appears to be the precipitating event, so good dental hygiene and avoidance of extraction when possible are important prevention strategies. Preoperative assessment of the patient is key; only physicians and dentists experienced in treating ONJ should manage these patients.

Are current definitions of ONJ adequate?

What is the true incidence of ONJ?

What is the pathophysiology of ONJ?

Are there risk factors for ONJ that have not yet been described?

Is ONJ a phase in the development of osteomyelitis?

Why does ONJ appear to be preferentially associated with certain types of cancer but not others?

Should BP treatment in metastatic bone disease move away from a fixed monthly treatment schedule to a bone-marker-directed schedule?

Can BPs prevent metastases in early cancer?

What is the risk-benefit ratio associated with the overall use of BPs?

Do the benefits of drug holidays (stopping BPs in order to perform a dental intervention) outweigh the risks of stopping treatment?

As BPs are beginning to be used for many nonbone diseases, for example, to prevent vascular calcification, will the incidence of ONJ increase?