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Teriparatide for Bone Loss in the Jaw - Editorial
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NEJM, October 16, 2010 (10.1056/NEJMe1010459)
Andrew Grey, M.D.
From the Department of Medicine, University of Auckland, Auckland, New
Zealand.
Teriparatide, which consists of the N-terminal 34 amino acids of parathyroid hormone, has been in clinical use for the treatment of osteoporosis for almost a decade, ever since clinical trials showed that among patients with severe osteoporosis who were treated with teriparatide, the relative risks of vertebral and nonvertebral fractures were reduced by 65% and 53%, respectively.1 Currently, treatment with teriparatide is limited to 2 years because of evidence from a preclinical study that the risk of osteosarcoma might be increased during long-term exposure.2 Unlike bisphosphonates, the current first-line agents for the prevention of fractures, which act primarily by inhibiting bone resorption, teriparatide increases bone density and strength primarily by stimulating osteoblastic bone formation. Thus, teriparatide stimulates bone remodeling, whereas bisphosphonates decrease it.
Because teriparatide is a medication that exerts anabolic effects on bone, it has been suggested that this drug might be beneficial in situations in which stimulation of bone repair is desired. Evidence from preclinical studies suggests that teriparatide promotes the repair of experimentally induced fractures, including those in the mandible,3 but data from humans are limited and inconclusive,4 and trials involving patients in whom fractures have not healed or healing is delayed have not yet been conducted. This issue of the Journal includes an article describing the effects of teriparatide in patients with periodontitis5 and a letter describing its effects in a patient with osteonecrosis of the jaw.6 Both of the diseases described in these reports are characterized by bone loss in the jaw.
Periodontitis is a common inflammatory condition of the oral cavity.7 In the majority of patients, appropriate dental care and attention to oral hygiene, including smoking cessation, are sufficient to prevent serious complications. However, severe disease develops in some persons and is characterized by chronic suppurative inflammation and loss of periodontal attachment and alveolar bone, leading to tooth loss.7 Bashutski and colleagues randomly assigned 40 patients with severe periodontitis to daily teriparatide or placebo for 6 weeks after surgical treatment.5 Treatment with teriparatide was associated with greater radiographic resolution of alveolar bone loss and more marked improvements in clinical measures of disease activity during 1 year of follow-up.
This small trial provides preliminary evidence that an agent that stimulates bone formation might confer additional benefit over that achieved with standard care in patients with severe periodontitis. However, many questions remain. How durable is the effect of teriparatide? What is the optimal dosing regimen? Does teriparatide alter important end points such as tooth loss or the need for further operative intervention? Do antiresorptive agents, which cost considerably less than teriparatide, confer similar benefits? A striking histologic feature of the inflammatory infiltrate in severe periodontitis is the presence of large numbers of bone-resorbing osteoclasts.7 There is some evidence suggesting that there is a benefit to giving bisphosphonates to people with periodontitis who are receiving nonsurgical treatment.8 Larger and longer trials than the study by Bashutski et al., as well as trials comparing different regimens, are required to answer these questions and to evaluate the safety of various interventions for the treatment of periodontitis.
Osteonecrosis of the jaw is also an inflammatory disease, which is defined by the presence of exposed bone in the mouth that fails to heal after appropriate intervention over a period of 6 or 8 weeks.9 It occurs in approximately 5% of patients with cancer who are treated with high doses of potent antiresorptive agents - either bisphosphonates or denosumab - for the prevention or palliation of skeletal metastases9,10 but occurs at very low rates (current estimated incidence, 1 case per 100,000) among patients who take conventional doses of bisphosphonates for the treatment of nonmalignant skeletal disease.9 The pathogenesis of osteonecrosis of the jaw is uncertain, but its occurrence during treatment with high doses of each of two drugs that potently decrease bone turnover suggests that aggressive reduction of bone remodeling and a consequent impairment in the ability to repair bone damaged by oral trauma, such as dental extraction, are likely to be important factors, with secondary infection perpetuating the disorder. The condition can be severe and debilitating. Cheung and Seeman report the case of an elderly woman, who had taken alendronate for 10 years for the treatment of glucocorticoid-induced osteoporosis, who presented with osteonecrosis of the jaw. The condition failed to respond to standard therapy,6 which typically includes cautious dŽbridement, the use of antiseptic mouthwashes, and treatment with antibiotics. After treatment with teriparatide for 8 weeks, the osteonecrosis of the jaw was healed, and there was impressive resolution of the mandibular osseous defect.
There are other reports of similar efficacy of teriparatide in the management of severe osteonecrosis of the jaw that was resistant to conventional therapy.11 Since teriparatide activates bone remodeling, these reports provide indirect evidence that suppressed bone remodeling plays a role in the pathogenesis of osteonecrosis of the jaw. They also suggest that there may be a therapeutic role for teriparatide in the management of severe osteonecrosis of the jaw in patients with nonmalignant skeletal disease.
Cheung and Seeman argue that a controlled trial would be helpful in investigating the efficacy of teriparatide in patients with osteonecrosis of the jaw. In reality, the incidence of the disorder among patients with nonmalignant skeletal disease is so low, at least currently, that performing such a trial would be difficult, if not impossible, in that population. Clinicians faced with managing cases of severe osteonecrosis of the jaw in patients who do not have cancer must rely on observational data and clinical judgment, including careful discussion with their patients about the uncertainties regarding optimal management. A similar caveat applies to the investigation of teriparatide for the treatment of atypical femoral fractures that occur at very low rates in patients receiving long-term bisphosphonate therapy.12
It would be more practical to conduct clinical trials of teriparatide in patients with cancer, in whom the incidence of osteonecrosis of the jaw is much higher. Such trials would need to be carefully configured, however, since currently, teriparatide is not recommended for patients with metastatic cancer because of concerns that the increase in bone remodeling that it promotes might also increase the risk of the development or exacerbation of skeletal metastases - concerns that have resulted in the Food and Drug Administration mandating a black-box warning on the teriparatide label. Whether a treatment period of only several weeks, as was effective in the case reported by Cheung and Seeman, is safe in a patient with skeletal metastases is not known. Until trials addressing this issue are conducted or data on safety are available, clinicians treating patients with cancer in whom osteonecrosis of the jaw develops should continue to provide optimal dental and supportive care according to published guidelines.13 Because the risk of osteonecrosis of the jaw appears to be strongly influenced by the dose of the antiresorptive treatment, the results of trials in progress investigating the efficacy of doses of antiresorptive agents that are lower than those currently prescribed for the prevention of cancer-related skeletal events will be of considerable importance to patients with cancer and the clinicians who care for them.
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