Abstract
Teriparatide is a synthetic polypeptide hormone that contains the 1–34 amino acid fragment of the recombinant human parathyroid hormone that stimulates bone formation. Currently, it is approved only for the treatment of osteoporosis. The outcomes of daily teriparatide injections for the treatment of bisphosphonate-related osteonecrosis of the jaw in 10 patients are reported here. Two of the 10 cases dropped out due to adverse events. Of the remaining eight cases, seven exhibited clinical improvement of the jaw-related symptoms of osteonecrosis and progression of the sequestration, while one case did not show improvement of the symptoms. Administration of teriparatide in patients with osteonecrosis of the jaw promotes bone formation and subsequent sequestration over a short period of time. These results suggest that adjunctive teriparatide therapy is a viable and effective option for treating osteonecrosis of the jaw.
Bisphosphonates (BPs) are first-line therapeutic drugs used in the treatment of osteoporosis , in addition to being used for bone diseases such as Paget’s disease, bone metastases, and multiple myeloma . BPs inhibit the bone resorption by osteoclasts and may have an effect on osteoblasts. Since these drugs are structurally similar to pyrophosphate, they have a high affinity for bone and thus most likely remain in the bone for many years. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) was first reported by Marx in 2003 . Many cases have since been reported and therefore BRONJ is no longer considered to be a rare disease clinically. BRONJ typically appears as an intraoral lesion with areas of exposed necrotic bone, with smooth or ragged borders, sometimes with an associated extraoral or intraoral fistula . Painful ulcers may be present in the soft tissues adjacent to the ragged bony margins of the lesion. The biggest issue with this disease is that it is highly intractable.
Although many studies have been reported and recommendations proposed regarding diagnostics, therapeutics, and prophylaxis, clear standards have yet to be established.
Teriparatide (Forteo; Eli Lilly, Indianapolis, IN, USA), a synthetic polypeptide hormone that contains the 1–34 amino acid fragment of recombinant human parathyroid hormone (PTH), is a bone anabolic agent indicated for the treatment of osteoporosis. It is used for the treatment of both men and postmenopausal women with osteoporosis, for osteoporosis that occurs after several months of administration of glucocorticoid medicines, such as prednisone, and for patients who are at high risk of broken bones or fractures. Daily teriparatide administration first stimulates new bone formation, which is followed by bone remodelling and increases in bone mineral density (BMD). Physiological effects include the stimulation of bone formation due to an effect on the osteoblasts, an increase in renal tubular re-absorption of calcium and the excretion of phosphate, and an indirect increase in the intestinal absorption of calcium via an effect on 1,25-dihydroxyvitamin D production . Daily subcutaneous self-injection and weekly subcutaneous injection formulas of teriparatide are available as anabolic agents in Japan. The development of these injection formulas is expected to lead to new treatment choices for patients with osteoporosis at high risk of fracture.
In 2007, Harper and Fung reported cases in which teriparatide therapy was used successfully to treat BRONJ . Several subsequent studies also demonstrated that teriparatide was effective in the treatment of BRONJ . However, due to the limited numbers of cases seen clinically, new treatment strategies for BRONJ have yet to be established. Therefore, a clinical study designed to accumulate a larger number of cases administered teriparatide in order to examine and prove the effectiveness of the drug in the treatment of BRONJ was conducted. Information on BRONJ cases that were followed continuously through the use of imaging studies and measurements of bone turnover markers is reported here. Factors affecting the healing of BRONJ in patients who received teriparatide therapy are also reported.
Materials and methods
This study was approved by the clinical ethics committee of the study university hospital in Nagasaki, Japan. After obtaining written informed consent from each patient, the study was carried out in the department of regenerative oral surgery and department of endocrinology and metabolism at the university hospital. Between October 2012 and May 2015, this study enrolled 10 patients diagnosed with stage 2 or 3 BRONJ. The classification of BRONJ stage was based on the American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper 2009 . Patients with hypercalcaemia, metastatic bone tumours, or primary malignant bone tumours were excluded.
All patients received a daily subcutaneous injection of 20 μg teriparatide. During the study, patient medical records were reviewed, and all patients underwent physical evaluations and interviews. The clinical findings evaluated included pain, pus discharge, exposure of necrotic bone in the oral cavity, and desensitization. C-terminal telopeptide of type 1 collagen (CTX), which is a biochemical marker of bone resorption, and bone-specific alkaline phosphatase (BAP), which is a bone formation marker, were measured at the initiation of the study and at 3 or more months after the administration of teriparatide. Treatment outcomes, changes in biochemical markers, and radiographic imaging findings were assessed. Daily mouth rinses with chlorhexidine were continued during the course of the teriparatide therapy. Oral antibiotics were administered when acute inflammation findings were observed, and a sequestrectomy was performed when sequestration was recognized.
Results
Table 1 shows the clinical findings and outcomes of the 10 patients enrolled. All of the patients were female, with seven classified as stage 2 and three as stage 3. Age ranged from 63 to 91 years, with an average age of 79.1 years. All patients took oral BPs (alendronate, four patients; risedronate, two patients; minodronate, one patient; alendronate and minodronate, one patient; alendronate and risedronate, one patient; minodronate and an unidentified BP, one patient). The duration of BP intake ranged from 9 to 108 months, with an average of 51.4 months. BP intake was stopped in all patients prior to the administration of teriparatide.
| Patient | Age, years | Gender | BPs | Duration of BP therapy, months | ONJ location | Stage | Trigger | Risk factors | Duration up to sequestrectomy, months Anaesthesia |
Duration of teriparatide therapy, months | Clinical outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 82 | Female | Alendronate | 42 | Maxilla Mandible |
2 | Tooth extractions | Diabetes Prednisone |
7 General anaesthetic |
11 | Healed |
| 2 | 91 | Female | Alendronate | 21 | Mandible | 3 | Periodontitis | Prednisone | – | 4 | Healed |
| 3 | 68 | Female | Risedronate | 24 | Mandible | 3 | Tooth extractions | Prednisone | 7 General anaesthetic |
12 | No effect |
| 4 | 78 | Female | Alendronate | 52 | Maxilla | 2 | Tooth extractions | None | 4 | 15 | Healed |
| Minodronate | 16 | Local anaesthetic | |||||||||
| 5 | 82 | Female | Unidentified | 48 | Mandible | 2 | Tooth extractions | None | 2 | 9 | Healed |
| Minodronate | 8 | General anaesthetic | |||||||||
| 6 | 63 | Female | Risedronate | 9 | Mandible | 2 | Periodontitis | Diabetes Prednisone |
4 General anaesthetic |
24 | Healed |
| 7 | 78 | Female | Alendronate | 60 | Mandible | 3 | Tooth extractions | None | – | 9 | Healed |
| 8 | 78 | Female | Alendronate | 108 | Mandible | 2 | Tooth extractions | Diabetes Prednisone |
3 days | Adverse events, dropped out | |
| 9 | 84 | Female | Minodronate | 36 | Mandible | 2 | Periodontitis | None | 0 Local anaesthetic |
15 | Healed |
| 10 | 87 | Female | Alendronate Risedronate |
90 | Mandible | 2 | Periodontitis | None | 7 days | Adverse events, dropped out |
The mandible was the most common location of the osteonecrosis of the jaw in eight patients. The osteonecrosis was found in the maxilla in one patient and in both the maxilla and mandible in one patient. Tooth extractions were the most frequent trigger for BRONJ, with six patients affected after the extraction procedure. In four patients, the trigger was associated with the development of periodontitis. Five patients were taking corticosteroids, while three had diabetes, both of which are thought to be risk factors for BRONJ ( Table 1 ).
Adverse events required the discontinuation of the teriparatide therapy in two out of the 10 cases; these patients dropped out of the study. Patient 8 had facial and lower limb oedema, nausea, and vomiting starting 3 days after the initiation of teriparatide therapy, while patient 10 developed strong arthralgia in her knee, or developed strong arthralgia in her knees, at 1 week after administration. No adverse events were seen in any of the other eight cases assessed in this study. The duration of teriparatide therapy ranged from 4 to 24 months (average 12.4 months). The administration of teriparatide therapy resulted in a complete recovery in seven cases (patients 1, 2, 4, 5, 6, 7, and 9), with all exhibiting coverage of the exposed bone by mucosa. Five stage 2 cases (patients 1, 4, 5, 6, and 9) underwent a sequestrectomy at between 0 and 7 months of teriparatide administration. In these five cases, sequestrum separation progressed and was accompanied by surrounding bone formation. Two stage 3 cases (patients 3 and 7) only healed after curettage of the extraction socket under local anaesthesia. In these cases, small pieces of sequestrum were discharged during continuous local irrigation, and the bone was covered with mucosa. However, patient 3 still had an intraoral fistula and did not show any progression of the sequestrum separation, even though her severe symptoms, which included local pain, disappeared during the 1 year of teriparatide administration. Dual-energy X-ray absorptiometry (DXA) scanning and bone turnover markers also revealed that this patient did not show any improvement in the bone mineral quantity in either the spine or femoral areas. Therefore, it was decided to cease the teriparatide therapy in this patient.
Figure 1 shows the changes in markers of bone turnover. BAP, a bone formation marker, showed a tendency to increase after the administration of teriparatide, although the difference was not statistically significant. Although the BAP in patients 5 and 6 increased significantly to levels higher than the normal range (3.8–22.6 μg/l), the various levels observed in the other cases were within the normal range. CTX, a bone resorption marker, showed tendencies similar to BAP, and exhibited no statistically significant difference. With the exception of one case (patient 4), the CTX values increased to levels outside the normal range (0.03–0.26 ng/ml).
The details of two representative patients who underwent a typical course of teriparatide therapy are presented below.
Case 1 (patient 2)
A 91-year-old Japanese woman with a 21-month history of alendronate therapy was referred for the treatment of a fistula on her right mandible ( Fig. 2 a). She was diagnosed with stage 3 BRONJ. Her systemic diseases included osteoporosis and rheumatoid arthritis, and she was taking oral methotrexate and prednisone in addition to the BP. Marginal periodontitis of her right mandibular molar region was considered to be the trigger of the BRONJ. At her first visit, there was high mobility of the right mandibular first molar, with the root almost completely exposed. Although computed tomography (CT) images revealed bone sclerosis and bone resorption at the lower border of the mandible, there was no obvious sequestrum separation ( Fig. 2 b and c). She underwent extraction of her right mandibular first molar at 1 month after the initiation of teriparatide therapy. After extraction and closure of the fistula on the right mandible, pus discharge from the extraction socket was observed; the sequestrum could be palpated and was subsequently excreted ( Fig. 2 d). During the course of the teriparatide therapy, the patient continued to gargle and use chlorhexidine for local irrigation. At 2 months of therapy, significant new bone formation was observed on X-ray imaging ( Fig. 2 e and g). The mucosal coverage was completed and the intra–extraoral fistula had completely closed after 4 months ( Fig. 2 f).
