Calcium, Vitamin D and Exercise are the foundation for good bone health, though the Women's Health Initiative showed us that it is not enough alone to reduce fractures.1 Calcium (1200mg in supplements or the diet, split up several times a day), plus vitamin D (800 to 1000units a day, all at once if easier) as well as exercise (back extension strengthening, balance and core exercises, and of course, weight-bearing such as walking or jumping, if done safely) all help increase bone mineral density (BMD) and reduce the risk of both falls and fractures.
What we have learned in the last decade from osteoporosis clinical trials is that more vitamin D supplementation (at least 2000units a day) is needed for calcium absorption and fall prevention, which Drs. Bikle2 and Krohn 3 discuss in detail at this meeting, and FDA-approved osteoporotic medical therapy is important for fracture reduction.4,5
We will review data to try to answer the following questions. What fracture risk warrants initiating osteoporotic medical therapy? How long do we continue treatment? And, at what potential cost, both from an economic and safety standpoint, are we willing to take for fracture protection? 6,7,8
Fracture Risk increases with age and with each additional risk factor9 (ie. fracture after 50y/o or steroid use). The medications FDA-approved for osteoporosis all significantly increase BMD and reduce the risk of fracture, yet not to the same degree and few are studied head to head. The bisphosphonates are now the mainstay of osteoporosis therapy and include weekly oral Fosamax (alendronate), and Actonel (risedronate), as well as monthly oral and now also an intravenous injection every 3 months Boniva10,11 (ibandronate). The hormonal therapies include daily oral Evista (raloxifene, a selective estrogen receptor modulator), daily subcutaneous injections, Miacalcin (calcitonin hormone) and Forteo12,13 (teriparatide or parathyroid hormone), and of course estrogen14 yet more often used for menopausal symptoms given their potential cardiovascular and breast risks, which Dr. Walsh reviews at this meeting. 15
All of the above therapies, aside from Forteo, are anti-resorptive agents, reducing bone loss or resorption as well as bone formation, but with a 'positive' balance, BMD increases and fracture reduction is seen. Forteo does the 'opposite' as a bone forming agent and increases bone formation and bone loss or resorption, again due to a 'positive' balance, BMD increases and fractures are reduced.
We would like to have the most precise and accurate bone mineral density measurements which The International Society for Clinical Densitometry Credentialing & Accreditation programs provide for many BMD testing centers. More importantly, though, we need better means of quantifying bone strength, bone quality and differentiating specific fracture site protection in order to assess therapeutic efficacy and determine who warrants short vs. long term therapy.
Long-Term Therapy may make sense for patients at high risk for fracture, where continued medical therapy in low risk patients becomes a more difficult clinical decision. Osteoporossis trials with Fosamax have been as long as 10 years and with Actonel 7 years. Some of these studies have looked at the effects of stopping therapy.16,17,18 Safety of osteoporotic therapy specifically bisphosphonates have come into question recently with claims of 'over-treatment' and 'osteonecrosis of the jaw' (ONJ). These long-term treatment studies as well as the ONJ data will be reviewed, hopefully rebuilding our confidence in the safety and efficacy of our FDA-approved osteoporotic therapies.19,20
'Phossy-Jaw' was reported in the media as "Fosi-Jaw" implying a potential risk of Fosamax, yet in the 19th century high dose white phosphorus exposure in manufacturers of matches and explosives was thought to cause a osteochemonecrosis of the jaw. Hellstein et. al.21,22 suggested that ONJ may be similar to this possibly phosphorus-related 'phossy-jaw' seen years ago.
It is important to note that no cases of ONJ have been reported in an osteoporosis trial (human or animal), including long-term toxicity and carcinogenicity trials (over 120,000 person-years total). Nor has a case of ONJ been reported in the intravenous zoledronate (Reclast) multicenter osteoporosis trial, not yet completed. If there is a rare association between osteoporosis doses of bisphosphonates and ONJ it is estimated at 1 case or less per 100,000 patient years on medication, but the ONJ warning is now on all bisphosphonate labels.
The American College of Rheumatology provided a Summary in 2006 of 'ONJ and Bisphosphonates' through their 'Hotline' stating that 'Hotline' reflects the views of the authors and does not represent a position statement of the American College of Rheumatology, www.rheumatology.org. Other ONJ reviews can be found at www.ASBMR.org (American Society of Bone and Mineral Research), www.AACE.com (American Assoc. of Clinical Endocrinologists), www.nof.org (National Osteoporosis Foundation), www.ADA.org (American Dental Assoc.), and www.aaoms.org (American Assoc. of Oral and Maxillofacial Surgeons).
|"Bisphosphonate-Associated Osteonecrosis of the Jaw"
Hotline Authors: Bart L. Clarke, MD, Metabolic Bone Disease Core Group, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Medicine, Rochester, MN; Sree Koka, DDS, PhD, Department of Dental Specialties, Mayo Clinic and Mayo Foundation, Rochester, MN. Hotline Editors: A. Kavanaugh, MD; E. L. Matteson, MD, MPH. Disclosures: Dr. Clarke: Consultant for Merck, and Confidentiality Agreement with Amgen. Dr. Koka: Nothing to disclose. Dr. Kavanaugh: Nothing to disclose. Dr. Matteson: Drug trials, and/or consultant, and/or confidential agreements and/or study and/or educational grants from Genentech, Amgen, Centocor, Biogen-Idec, Abbott, Wyeth, Regeneron, Takeda, Glaxo-Smith-Klein, Hoffmann-LaRoche, Human Genome Sciences, Immunex, Protein Design Laboratories, Nastech, Pharmacia & Upjohn, Schering.
Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) has recently been recognized as an uncommon but severe adverse event associated with oral or intravenous bisphosphonate therapy in humans. Letters, case reports, and small case series published in the oncology, dental, and maxillofacial surgery literature since September 2003 describe ONJ as typically causing jaw pain, more often in the mandible than the maxilla, with associated exposed bone.23-26
How common is ONJ? In a systematic review of 368 cases of bisphosphonate-associated ONJ published between 1966 and January 31, 2006, Woo et al.27 found most cases (94%) occurred in patients treated with intravenous bisphosphonates with 65% of cases affected the mandible, 26% the maxilla, and 9% both mandible and maxilla. About 2/3 of the lesions were painful at diagnosis, with the remaining one-third painless, and 60% of cases occurred in women. Multifocal or bilateral involvement was more common in the maxilla than the mandible, with most lesions occurring on the posterior lingual mandible near the mylohyoid ridge. 60% occurred after oral surgery for dental extraction or other dentoalveolar surgery, whereas the remainder occurred spontaneously, some in patients wearing dentures.
Most (85%) cases had multiple myeloma or breast cancer metastatic to the skeleton. Patients receiving intravenous bisphosphonates for cancer were most often treated with one or more of the potent nitrogen-containing intravenous bisphosphonates, i.e., zoledronic acid or pamidronate, typically once a month for several years. Some patients developed ONJ within 4 months of starting therapy, but the median duration of therapy before diagnosis ranged from 22 to 39 months, with the mean duration ranging from 9 to 14 months. The highest risk of ONJ appears to be associated with frequent, typically monthly, infusions of intravenous zoledronic acid, which has been widely used in patients with myeloma, breast cancer, and prostate cancer in recent years.
What is the clinical presentation of ONJ? ONJ typically appears as an intra-oral lesion with areas of exposed yellow-white hard bone with smooth or ragged borders, sometimes with associated extra-oral or intra-oral sinus tracts.28 Painful ulcers may be present in the soft tissues adjacent to the ragged bony margins of the lesion. Dental x-rays may be unremarkable in early cases, but advanced cases demonstrate poorly defined areas of moth-eaten radiolucencies, with or without radio-opaque bone sequestra. Pathological jaw fractures have occurred in some cases. In its most severe form, ONJ may cause loss of a significant part of the mandible or maxilla.
What are the risk factors for ONJ? The main risk factors identified to date include cancer, frequent infusions of IV nitrogen-containing bisphosphonates, and dentoalveolar trauma. 29 Risk factors have not been identified in patients receiving oral bisphosphonates for postmenopausal osteoporosis without cancer due to the very small number of published cases.
What about ONJ in patients without cancer, including rheumatic diseases? Although under-reporting is always a potential consideration in pharmacovigilance data, the total number of cases of non-cancer patients with ONJ associated with oral bisphosphonate therapy reported among several million estimated patients who have been exposed to these drugs over the last 20 years appears small. To date, fewer than 20 cases of ONJ have been reported in the medical literature among patients without cancer treated with oral bisphosphonates. The risk of development of ONJ in patients with Paget's disease of bone treated with oral or intravenous bisphosphonates is not known, with only 3 cases reported in this review. None of the reported cases describe bisphosphonate related ONJ in women or men treated with glucocorticoid therapy for rheumatologic disease. The overall risk of ONJ in these patients appears low, but not well quantified.
Which type of bisphosphonate causes ONJ? Most cases of ONJ reported have occurred with intravenous zoledronic acid and pamidronate. The risk of development of ONJ in postmenopausal osteoporotic patients treated with oral bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva) is not known, as only a small number of cases have been reported. Most of these cases are associated with alendronate therapy, likely due to its wider use than other oral bisphosphonates.
The review by Woo et al.27 reported only 15 patients treated for osteoporosis without cancer with any bisphosphonate. Of the 368 total cases of ONJ reported, 18 were associated with oral alendronate, and of these, 15 occurred without exposure to intravenous or other oral bisphosphonates. Thirteen of the alendronate-treated cases occurred in patients treated for osteoporosis without cancer. One case of ONJ was associated with oral risedronate, and one case with oral ibandronate, both in patients treated for osteoporosis without cancer.
How do bisphosphonates cause ONJ? There is no established pathophysiological mechanism by which oral or intravenous bisphosphonates may cause ONJ, although it is hypothesized that suppressed bone turnover caused by potent bisphosphonate therapy leads to accumulation of microdamage, which may eventually lead to microfractures.30,31 Trauma or infection increase demand for bone microdamage repair, which might lead to localized osteonecrosis, although it is not yet clear how exactly this might occur. The antiangiogenic properties of some bisphosphonates32 and other medications and comorbidities may increase the risk of persistence and progression of ONJ.
How can ONJ be prevented? No randomized clinical trials have been published describing either prevention or treatment of ONJ. The American Academy of Oral Medicine (AAOM) guidelines29 call for prevention of ONJ in patients requiring therapy with bisphosphonates by conducting a dental examination and completing any traumatic treatment, such as dental extractions, before starting oral or intravenous bisphosphonate therapy, and avoiding dental trauma in patients who have begun such therapy. Woo et al.33 advised treating active oral infections and obtaining routine dental care before starting nitrogen-containing bisphosphonate therapy, using the least traumatic surgical approach when tooth extraction or other dental surgery is required, and avoiding wide excision of dead bone in patients with ONJ.
How can ONJ be treated? Once ONJ develops, there is no current recognized effective therapy. Dental specialists typically recommend supportive management, with withdrawal of bisphosphonate therapy, avoidance of further dentoalveolar trauma, appropriate use of oral antibiotic rinses, and allowing time for healing. Further aggressive surgery to debride dead bone may exacerbate the condition, but dental gingival flap placement may help stimulate healing.
For established ONJ, Marx et al.26 recommended systemic and topical antibiotic therapy with oral penicillin VK or amoxicillin, concurrent with use of chlorhexidine gluconate 0.12% oral rinses. The authors reported that this palliative regimen is over 90% effective in controlling pain in patients with ONJ, but resolution of lesions did not occur with this regimen. A surgical approach to treat ONJ lesions by means of pedicled flaps may be helpful.34
Current Clinical Practice Until more clinical data become available, it is reasonable to continue oral or intravenous bisphosphonate therapy in patients with appropriate indications, unless ONJ develops. The decision to continue to treat cancer patients with frequent infusions of potent intravenous bisphosphonates should be discussed with each patient's oncologist. Patients contemplating starting therapy with oral or intravenous bisphosphonate therapy for prevention or treatment of postmenopausal or glucocorticoid-induced osteoporosis should be informed of the rare risk of ONJ with oral or infrequent intravenous doses of bisphosphonates. Patients should be informed that caries and periodontal disease may increase the risk of ONJ in patients taking bisphosphonates. Dental examination and treatment should be completed either prior to or as early as possible after beginning bisphosphonate therapy.
Bottom Line: Bisphosphonates (BPs) and ONJ
Fracture risk increases with age and risk factors. The optimal duration of medical therapy for postmenopausal women and men with osteoporosis is uncertain, but calcium and vitamin D supplementation as well as exercise to maintain strength and balance are recommended lifelong. We hope that the long awaited 'Absolute Fracture Risk Assessment', once clinically available, will provide us with easier answers to 'When do we start medical therapy for osteoporosis?' and, 'When, if ever do we stop medical therapy for osteoporosis?' Those patients with a high risk for bone loss and fracture need to be identified earlier, treated more aggressively and watched for 'silent' signs of fracture (VFA- vertebral fracture assessment on the BMD DXA machines or by x-ray).
In addition to fracture history, other secondary causes of bone loss which increase risk warrant our special attention. An evaluation to rule out secondary causes should be considered in patients with very low BMD (Z-score -1.0 or lower) or with new fractures.
We continue to question our inability (~18%) to provide Post-Fracture Care as well as we do Post-MI and Post-Stroke Care, and the poor compliance of patients to lifestyle changes and medications despite strong encouragement from providers.
The Medicare cuts in BMD reimbursement will have both positive and negative effects on these goals, but no doubt, many BMD centers will close their doors not able to pay their overhead, and quality BMD DXA testing will be more difficult to find for our patients. For more information regarding this legislation see 'Update on the Deficit Reduction Act of 2005 (DRA) and Its Potential Effect on DXA Imaging' at http://www.iscd.org/visitors/positions/LegislativeAlert.cfm. More advanced bone quality testing (ie. DXA Hip Structure Analysis, micro-MRI, nano-CT) will hopefully be clinically available in the near future, yet will surely be very expensive.
Lastly, exciting new osteoporosis therapies are on the horizon which will give us more choices for treatment and create more questions as to length of treatment and safety.
ACR References for "ONJ & Bisphosphonates"