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Keywords:

  • yearly zoledronic acid;
  • osteoporosis;
  • tooth extraction;
  • dental implantation;
  • BRONJ

Abstract

  1. Top of page
  2. Abstract
  3. CASE 1
  4. CASE 2
  5. DISCUSSION
  6. REFERENCES

Background

Once-yearly zoledronic acid has been proven effective in the management of osteoporosis. Osteonecrosis of the jaws (ONJ) related to its use has not been reported since its approval in 2007.

Methods

Two women with osteoporosis/osteopenia developed ONJ after the second infusion of yearly zoledronic acid. They had no other systemic diseases and ONJ occurred after oral surgeries, which were performed about 2 months following drug administration.

Results

In 1 case osteonecrosis of the maxilla resolved after conservative therapy and sequestrectomy. In the other case bone necrosis developed on both sides of mandible, and the symptoms/signs of ONJ were partially responsive to conservative treatment.

Conclusions

ONJ related to yearly zoledronic acid is a severe complication that should not be ignored. To minimize the risk, we recommend preventive oral care before the start of therapy and avoiding dental invasive procedures within 3 months after drug administration. © 2011 Wiley Periodicals, Inc. Head Neck, 2013

Nowadays, oral bisphosphonates represent 1 of the most commonly prescribed drug classes for the treatment of postmenopausal osteoporosis. However, the gastrointestinal intolerance and the requirement of frequent drug administration result in poor compliance to oral bisphosphonates in many patients, thus compromising the therapeutic effectiveness. 1–4 On the other hand, parenteral administration of long-acting bisphosphonates such as the yearly infusion of zoledronic acid (Aclasta, Reclast; Norvatis Pharmaceuticals, East Hanover, NJ) was approved by the U.S. Food and Drug Administration in 2007 and 2009, respectively, for the treatment and prevention of osteoporosis in postmenopausal women. It may be a more attractive treatment option for some patients by avoiding the need of frequent dosing in oral bisphosphonate therapy. 5

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe complication, which occurs most frequently in patients on monthly intravenous (IV) zoledronic acid (Zometa; Norvatis Pharmaceuticals) or pamidronate (Aredia; Norvatis Pharmaceuticals) for malignant diseases. 6–8 However, reports of ONJ occurred in long-term users of oral alendronate (Fosamax; Merck, Whitehouse Station, NJ) for osteoporosis have also been published. 7, 9 Because of the minimal level of drug exposure, yearly zoledronic acid was thought to have a low risk of development of BRONJ. 5 In fact, jaw necrosis related to yearly zoledronic acid has not been reported since its approval for osteoporosis management in 2007. We report 2 cases of ONJ developed in postmenopausal women receiving annual infusion of zoledronic acid. Clinicians should be alert to the potential risk of this severe oral complication in patients using the new formulation of bisphosphonate.

CASE 1

  1. Top of page
  2. Abstract
  3. CASE 1
  4. CASE 2
  5. DISCUSSION
  6. REFERENCES

A 76-year-old woman visited our clinic on June 3, 2010, for the evaluation of an unhealed tooth extraction wound. She underwent extraction of the left maxillary lateral incisor, canine, and first premolar at a local dental clinic because of toothache on March 23, 2010. After the surgery, she experienced persistent pain, mucosal swelling, and sanguino-purulent discharge from the extraction wound. No significant improvement was noted after conservative therapy for >2 months.

She was diagnosed with osteoporosis, and yearly zoledronic acid (5 mg/100 mL, IV) was prescribed at an orthopedic clinic. The first injection was given in February 2009, and she received the second dose in February 2010. No other medication was used for the management of osteoporosis. Besides osteoporosis, she did not have other major systemic diseases or history of cancer.

Clinical examination revealed no facial swelling or skin erythema. She had good oral hygiene, but an unhealed extraction wound of left maxillary lateral incisor, canine, and first premolar was found. The wound was covered by purulent discharge and the surrounding gingiva was swollen and erythematous (Figure 1A). Sounding with a soft probe under local anesthesia could touch the bone of the sockets. An occlusal radiograph (Figure 1B) showed an osteolytic shadow in the socket walls. Laboratory data were largely within normal limits. The level of serum β C-terminal telopeptide of type I collagen (β-CTX) was 114 pg/mL.

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Figure 1. Case 1. (A) Purulent discharge and swollen gingiva around the tooth extraction wound on initial examination. (B) Occlusal radiograph showing osteolysis (arrows) in the socket walls. (C) Obvious sequestration (arrow) in the maxillary lesion shown on CT. (D) The sequestrum removed by surgery. (E) Histologic examination revealing necrotic bone with typical empty lacunae and numerous inflammatory cells. Note also the irregular peripheral resorption conspicuously absent of osteoclasts and osteoblasts (arrows) (hematoxylin–eosin stain, original magnification ×200). (F) Completely healed alveolar ridge 2 months after sequestrectomy.

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Under the diagnosis of BRONJ, 7, 10 conservative treatment including 0.12% chlorhexidine rinses, a 2-week course of amoxicillin 250 mg every 8 hours and acetaminophen 500 mg every 6 hours was given, but in vain. Further examination by CT revealed an area of bone destruction measuring about 2 × 2 cm in the alveolar process of the left maxilla. Sequestration was obvious but the nasal cavity and maxillary sinus were spared (Figure 1C).

On June 21, 2010, sequestrectomy and debridement were performed under local anesthesia. A sequestrum measuring 1.7 × 1.3 cm in size was removed (Figure 1D). Histologic study showed necrotic bone with typical empty lacunae and numerous inflammatory cells (Figure 1E). Postoperative recovery was good and wound healing was uneventful. Two months after the surgery, the alveolar ridge was completely epithelialized and there was no mucosal swelling, fistula formation, or bone exposure (Figure 1F).

CASE 2

  1. Top of page
  2. Abstract
  3. CASE 1
  4. CASE 2
  5. DISCUSSION
  6. REFERENCES

A 58-year-old woman was referred to our clinic on June 30, 2010, for the management of problematic intraoral wounds. Two months before her visit, she received dental implantation in bilateral mandibular posterior ridges. After the surgery, the wounds were persistently painful, frequently bled, and had fistulae with purulent discharge. She had a history of osteopenia and had been taking daily calcium supplement for 2 years. Other systemic diseases and history of malignancy were denied. In February 2009 IV infusion of zoledronic acid (5 mg/100 mL) was given for prevention of osteoporosis, and a second dose was administered in February 2010.

On clinical examination, good oral hygiene was noted but the mucosa overlying bilateral edentulous ridges in the mandible was swollen and erythematous. Bone exposure and purulent discharge were found on both sides, but the situation was more severe on the right (Figures 2A and 2B). The dental implants were exposed but not mobile. Dental periapical films showed bone resorption around the implant in the lower right premolar region, although peri-implant bone loss was not obvious in other locations (Figures 2C and 2D). Laboratory findings were largely normal. The level of serum β-CTX was 116 pg/mL.

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Figure 2. Case 2. (A) Swollen and erythematous mucosa with bone exposure and purulent discharge in the dental implantation area on right side of mandible. (B) Similar but less severe situation on the left. (C) Dental periapical film showing peri-implant bone resorption around the anterior implant on right side (arrows). (D) No obvious peri-implant bone loss on the left.

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Under the diagnosis of BRONJ, 7, 10 the patient was given a 2-week course of amoxicillin 250 mg every 8 hours and 0.12% chlorhexidine mouth rinses. In August 2010, the symptoms/signs of inflammation were completely resolved on the left side. The situation on the right side remained stationary and was under regular observation and treatment.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE 1
  4. CASE 2
  5. DISCUSSION
  6. REFERENCES

The efficacy and safety of yearly zoledronic acid for treatment of postmenopausal osteoporosis was mainly based on a large, randomized, prospective 3-year clinical trial (the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial [HORIZON-PFT]), in which 7714 patients with postmenopausal osteoporosis received yearly zoledronic acid or placebo at baseline, 12 months, and 24 months. The patients were followed until 36 months. No spontaneous reports of ONJ were received. 5 From a search of the trial database of adverse events, which was followed by expert adjudication, 2 cases of potential ONJ were identified, 1 in the placebo group and 1 in the zoledronic acid group. In both patients, delayed healing followed surgical manipulation, and both cases subsequently resolved with antibiotic therapy and debridement. 11 Although the results of the HORIZON-PFT study suggested a low risk of ONJ associated with yearly zoledronic acid treatment through 3 years, there are reasons to believe that the incidence of this complication was underestimated. Patients were recruited for the HORIZON-PFT study between February 2002 and June 2003. At that time ONJ was not a well-known adverse event associated with the use of bisphosphonates. As a matter of fact, the first cases of BRONJ were reported in the end of 2003. 12, 13 Therefore, it is highly possible that cases of BRONJ may have been missed because the diagnostic criteria were not known at the time the study was conducted. Another shortcoming of the study is that the adjudication committee evaluated the occurrence of ONJ based only on a retrospective review of adverse events reports. Standardized oral examination was not a part of the study and important clinical information may have been missed. 14

Based on data from previous case report studies, the estimated incidence of ONJ in patients with cancer who are receiving monthly injection of zoledronic acid ranged from 0.8% to 10%, 15 at least 100-fold higher than that in the osteoporosis population treated with weekly oral alendronate. 16–18 In addition, it was thought that the incidence of BRONJ increased significantly when duration of drug use was more than 9.4 months and 3 years, respectively, for Zometa and alendronate users. 9, 19 With a lower cumulated dose, the absence of concomitant cytotoxic therapy and better immunological competence compared with that of patients with cancer, the occurrence of ONJ in patients with osteoporosis receiving yearly zoledronic acid is possibly rarer and later than that among the monthly users. The incidence rate of ONJ related to yearly zoledronic acid remains to be determined. However, our 2 cases of ONJ that occurred after the second dose of annual zoledronic acid should remind clinicians not to neglect the possibility of this severe complication.

Previous studies found that invasive dental procedure is an important contributing factor to the occurrence of BRONJ. 20 In our patients and the case reported in the HORIZON-PFT study, surgical manipulation is also considered a major trigger of jaw necrosis. However, the ONJ patient in the HORIZON-PFT study had poorly controlled type 2 diabetes with end-stage organ complications, 11 which may create further challenges to her immune status and wound-healing capacity. In contrast, there were no comorbidities in our cases, which demonstrated that invasive dental procedure indeed played an important role in the development of BRONJ.

Recently, it was proposed that the levels of serum β-CTX, a marker of bone turnover activity, may predict the subsequent risk of developing BRONJ after oral surgery for patients taking oral bisphosphonates. 21 Marx et al 9 reported a mean β-CTX level of 238 ± 144 pg/mL among 215 oral bisphosphonate users without BRONJ, in contrast to a level of 72.9 ± 25.6 pg/mL in a sample of 17 subjects who had BRONJ after exposure to oral bisphosphonates. 21 In addition, β-CTX levels increased 26 pg/mL per month after discontinuation of the oral bisphosphonate over a 6-month period. 21 Although there are no data available to suggest whether discontinuation of bisphosphonate reduces the risk of ONJ for patients requiring dental procedures, considering the change in serum β-CTX associated with bisphosphonate treatment, Marx et al recommended discontinuation of oral bisphosphonate for at least 3 months prior to oral surgery. 9 In the case of annual zoledronic acid, the time elapsed between drug administration and elective oral surgery should be considered since the drug was injected only once a year.

In our 2 patients, ONJ occurred after invasive procedures performed about 2 months following the injection of zoledronic acid. This fact implied that oral surgery close to the time of drug administration poses a higher risk of ONJ. In agreement with this suggestion, it has been shown that serum β-CTX was reduced by about 80% at month 1 following the first injection of zoledronic acid and increased thereafter, but remained within the premenopausal reference range. 22, 23 After a second infusion at month 12, serum β-CTX decreased significantly within 3 months and then gradually increased again. 23 In a study on risk factors associated with BRONJ, Marx et al 9 suggested that serum β-CTX values < 100 pg/mL represented a high risk and values between 100 and 150 pg/mL denoted a moderate risk. In our patients, the levels of serum β-CTX were relatively low (114 and 116 pg/mL) 4 months after the injection of zoledronic acid, and it is highly possible that serum β-CTX levels were even lower during the time of oral surgery. Our cases demonstrated that in patients receiving yearly zoledronic acid, a low level of serum β-CTX shortly after drug infusion may be associated with a higher risk of developing ONJ. To minimize the risk of ONJ, we suggest that it is better to avoid oral surgical procedures within 3 months after the administration of annual zoledronic acid.

The use of once-yearly injections of zoledronic acid is intended to replace oral bisphosphonates in the treatment of postmenopausal osteoporosis, for its convenience and possibly lower risk of ONJ. In view of the possible increase in its use in the future, the present report of ONJ cases is an alert to dentists and physicians who prescribe this medication for postmenopausal osteoporosis. Preventive oral care before the start of therapy is recommended and dental invasive procedures shortly after drug, administration should be avoided. Both the physicians and dentists should carefully monitor the oral conditions for all patients throughout yearly zoledronic acid therapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE 1
  4. CASE 2
  5. DISCUSSION
  6. REFERENCES
  • 1
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