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Teriparatide Therapy for Bisphosphonate-Related Osteonecrosis of the Jaw Associated With Dental Implants Re-Mee Doh, DDS, PhD,* Hye-Jeong Park, DDS, MSD,† Yumie Rhee, MD, PhD,‡ Hyun Sil Kim, DDS, PhD,§ Jisun Huh, DDS, MSD,k and Wonse Park, DDS, PhD¶
isphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) was first reported by Marx,1 who described exposed necrotic bone in the maxillofacial region in a patient who had been exposed to intravenous BPs; many cases have been reported since then. Patients receiving high doses of intravenous BPs (zoledronate [Zometa] and pamidronate [Aredia]; Novartis Pharmaceutical, East Hanover, NJ) account for most BRONJ cases, although patients treated with a lower dose of the oral form (alendronate [Fosamax; Merck, Whitehouse Station, NJ], ibandronate [Bonviva; Roche, Basel, Switzerland], or risedronate [Actonel; Sanofi-Aventis, Paris, France]), most often for osteoporosis, have also been reported.2,3 Although the incidence of BRONJ
B
*Clinical Assistant Professor, Department of Advanced General Dentistry, Dankook University Dental Hospital, Cheonan, Korea. †Clinical Instructor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea. ‡Associate Professor, Department of Internal Medicine, Endocrine Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. §Associate Professor, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea. kPostgraduate Student, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea. ¶Associate Professor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea.
Reprint requests and correspondence to: Wonse Park, DDS, PhD, Department of Advanced General Dentistry, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea, Phone: +82-2-22288980, Fax: +82-2-22278906, E-mail: [email protected] ISSN 1056-6163/15/02402-222 Implant Dentistry Volume 24 Number 2 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/ID.0000000000000232
This report describes a case of teriparatide (TPTD) therapy for bisphosphonate (BP)-related osteonecrosis of the jaw induced after implant placement. A 75-year-old woman taking oral BP was referred with uncontrolled osteonecrosis of the mandible related to the implant placement. With conservative treatment, BP was suspended and daily subcutaneous injections of 20 mm/d TPTD were started. After 4 months of the therapy, fixture removal and sequestrectomy were performed. Histological analysis revealed necrotic lamellar bone and empty
osteocytic lacunae. In contrast, multiple irregular reversal lines of the lamellar bone and active osteoblasts were noted adjacent to the lesion. There was a significant increase in serum C-terminal telopeptide crosslink of type 1 collagen and serum osteocalcin after commencement of the therapy. After 7 months off therapy, the serum levels of the 2 markers remained at a high level compared with the baseline. (Implant Dent 2015;24:222–226) Key Words: BRONJ, teriparatide, parathyroid hormone, dental implant, CTX, osteocalcin
induced by oral BPs is low, it cannot be neglected because of the large population of patients who take oral BPs. Extraction is the most important dental treatment–associated risk factor for BRONJ, and a few cases of BRONJ that developed after implant placement have been reported recently.4–8 Treatment of BRONJ is quite challenging because the symptoms are not usually eliminated by conventional long-term palliative treatment; even after careful surgical treatment, healing of the hard and soft tissues is very poor and the disease frequently recurs. Parathyroid hormone (PTH) is an 84-amino acid peptide produced by parathyroid chief cells in response to
a decrease in plasma calcium. Teriparatide (TPTD) is a recombinant human PTH, which is the only anabolic agent that is currently approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis. TPTD was recently introduced as a treatment of BRONJ in several cases, but there are few publications on the topic, and the disease diagnosis and treatment sequence have yet to be clearly established. This report describes a case of TPTD therapy for the treatment of BRONJ induced after implant placement. Serial changes in markers of bone turnover (serum C-terminal telopeptide of type 1 collagen [s-CTX] and serum osteocalcin [s-OCN]) were recorded,
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015
Fig. 2. A, Necrotic bone and sequestrum were revealed after flap elevation. The sequestrum was located around the mandibular right first molar fixture. B, Fixture of the first molar (arrow), with surrounding dark red–colored necrotic bone and granulation tissue. C, Fixture of the second premolar (arrowhead), which was only partially involved in the lesion; however, the buccal and mesial parts of the fixture were surrounded by fresh bone.
Fig. 1. Serial changes in the bone around implants viewed on intraoral radiographs. A, First visit and (B) 3 and (C) 4 months after commencement of TPTD treatment. Over time, diffuse “moth-eaten” destructive lesions around the right lower molar fixtures became more distinct after PTH therapy, and the sequestrum became separated from the healthy bone.
and the histological features were analyzed.
CASE REPORT A 75-year-old woman was referred from a local dental clinic with a diagnosis of osteonecrosis of the mandible. The patient had been taking alendronate (Fosamax) for 2.5 years for the treatment of osteoporosis. She had hypertension and hypercholesterolemia that were being controlled. The patient had undergone removal and extraction of a 5-unit fixed dental prosthesis (FDP) on the mandibular right first premolar to third molar and 1 week later had received implant placement
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Fig. 4. Serial changes in serum C-terminal telopeptide of type I collagen (s-CTX) and serum osteocalcin (s-OCN). B, Baseline (starting point of BP suspension). The arrow indicates the starting and end points of TPTD therapy.
(4.0-mm diameter and 11.5-mm-long RBM surface; CMI implant, Neobiotech, Seoul, Korea) to the area of the missing first and second premolars and the first molar. The patient complained of pain after delivery of an implantsupported FDP (4 months after the first surgery). The dentist removed and replaced the fixture (same-sized fixture as in the first surgery) to the first premolar area and completed the prosthesis. However, the pain and pus discharge reemerged and persisted even after 10 months of conservative treatment. Clinical examination revealed no mobility, but the pocket depth was large and readily bled on probing around the right lower implant-supported FDP. A radiographic evaluation revealed diffuse osteolysis around the implant fixtures, and sclerotic bone and a thin sequestrum were noted (Fig. 1). After consideration of the patient’s history, and in consideration of the diagnosis of BRONJ, multidisciplinary care was instigated at the Department of Internal Medicine (Endocrine Division). Treatment Sequence
Fig. 3. Five months after open debridement of the lesion. A, Soft tissue healing is complete without bone exposure or fistula. B, Intraoral radiograph showing complete bone healing and some alveolar bone formation.
BP was suspended, and daily subcutaneous injections of 20 mm/d TPTD (Forteo; Eli Lilly, Indianapolis, IN) were commenced. Conservative treatment including chlorhexidine irrigation and administration of penicillin were
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Fig. 5. A and B, Pathologic findings of the right first molar (#46i) area and (C and D) pathologic findings of the right second premolar (#45i) area. A, Microscopic evaluation of #46i revealing the necrotic lamellar bone with bacterial colonies (arrows; hematoxylin and eosin [HE] stain, 3100). B, There are no osteocytes in the lacunae (HE stain, 3400). C, Microscopic appearance of #45i buccal showing multiple irregular reversal lines in the lamellar bone, indicating active bony remodeling (arrows; HE stain, 3100). D, Active osteoblasts synthesizing bone matrix are observed in the periphery (arrowheads; HE stain, 3400).
combined. During the therapy, the diffuse osteolytic lesion became distinct and the sequestrum became separated from the healthy bone, as evidenced on serial intraoral radiographic views (Fig. 1). After 4 months of TPTD therapy, the fixture was removed at the mandibular right second premolar and first molar, followed by sequestrectomy (Fig. 2). The TPTD therapy was terminated 6 months after the initial treatment, and periodic recall checks were scheduled for 1 week, 2 weeks, 1 month, 2 months, 3 months, and every 6 months thereafter. The last checkup was performed 20 months after the surgical treatment, at which point, the surgical wound was completely healed and radiography revealed stable alveolar bone conditions
with some bone deposition, the level of which was location dependent (Fig. 3). Effect of PTH on Bone Turnover Markers and Histological Evaluation of the Surgical Site
Levels of s-CTX and s-OCN were monitored at the first visit, at 0, 1, 3, 5, and 6 months of therapy, and at 7 months after cessation of the therapy (Fig. 4). There was slight increase in s-CTX and s-OCN after BP suspension and a rapid and significant increase in the 2 markers of bone turnover after the treatment started. The removed fixtures and tissues were examined histologically (Fig. 5), which revealed necrotic lamellar bone with bacterial colonies around the fixture
of the first molar. Empty osteocytic lacunae were observed that are typical of BRONJ specimens. The fixture of the second premolar area was also removed during surgery, although its buccal and mesial sides were well osseointegrated. The distal part of the fixture exhibited mature cortical bone with granulation tissue. In contrast to the area around the first molar, the microscopic appearance of the buccal-side lamellar bone exhibited multiple irregular reversal lines. Active osteoblasts synthesizing bone matrix were observed in the periphery at high magnification.
DISCUSSION The treatment of BRONJ proposed by The American Association of Oral
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IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015 and Maxillofacial Surgeons includes patient education, antibacterial mouth rinse, antibiotic therapy, pain control, and surgical debridement/resection. However, even with long-term careful treatment, the symptoms barely subside, soft and hard tissue healing is usually poor, and the condition frequently recurs. These consequences are related to the pharmacodynamic character of BPs, whereby they exert their antiresorptive activity by suppressing osteoclast activity. Suppression of bone resorption allows closure of the existing skeletal remodeling space, further enhancing the increments in bone mineral density.9 However, its initial action is to inhibit bone resorption; it also rapidly inhibits bone formation, which is tightly coupled to resorption. Oversuppression of bone remodeling has a negative effect on bone area, especially at locations with a rapid remodeling rate, such as the jaw, causing BRONJ. In contrast to BPs, TPTD stimulates bone formation by increasing osteoblast number and activity, thus increasing both the bone remodeling rate and the amount of bone deposited in each remodeling cycle. This ultimately increases trabecular thickness, improves trabecular connectivity, and increases cortical thickness and bone size.9 TPTD has been approved by the US FDA for the treatment of osteoporosis in cases in which other treatments have failed or the patients have been intolerant of previous osteoporosis therapy and for glucocorticoid-induced osteoporosis. A few successful clinical cases of off-label use of TPTD for treating BRONJ have been reported2,8,10–14 (Readers should be aware that this is an off-label use of PTH. Off-label drug use is common. Most relevant is the use of bone morphogenic protein (BMP) mixed with other materials when grafting the maxillary sinus or other dentoalveolar defects). The anabolic effect of TPTD can be confirmed on radiographic images and by histological evaluation. In the present case, radiography performed at the initial visit revealed similar features of chronic osteomyelitis, with a patchy, ragged, and ill-defined radiolucency containing small radiopaque sequestra.
The surrounding bone exhibited an increased radiodensity compared with other areas. TPTD therapy resulted in the formation of a large sequestrum, demonstrating that the inflammation was localized and non-vital necrotic bone was separated from the adjacent healthy vital bone. The fixture in the first molar position that was fully involved in the lesion exhibited necrotic lamellar bone and empty osteocytic lacunae, which are distinct features of BRONJ. Interesting findings were obtained through histological evaluation around the fixture located in the second premolar site that partially (distal area) involved the lesion. The buccal area close to the lesion exhibited multiple irregular reversal lines and active osteoblasts forming bone matrix. This vigorous bone formation and resorption indicate that TPTD therapy activates bone remodeling toward bone formation. The effectiveness of TPTD therapy is usually evaluated by assessing the serum levels of markers of bone turnover, such as s-CTX (for osteoclast activity) and s-OCN (for osteoblast activity). In this study, there was a slight increase in s-CTX and s-OCN after suspension of BP and rapid and significant increases in these 2 bone markers after commencement of the treatment. After 7 months off therapy, serum levels of these 2 markers remained at a high level compared with the baseline. This finding concurs with Ohbayashi et al15 finding that TPTD primarily affects osteoblastic activity (bone formation) and secondarily osteoclastic activity (bone resorption) and that this effect persists over a long period. Kim et al16 conducted a retrospective longitudinal study comparing a nonTPTD and a TPTD therapy group to assess the utility of this drug for resolving BRONJ. They found that both s-CTX and s-OCN were increased until 1 month after suspending BP treatment but then decreased back to baseline levels; in other words, the BP-induced suppression of bone turnover rate did not recover. However, the bone markers continued to increase in the TPTD group after the end of the TPTD therapy. In another study, the reversal effects of TPTD on osteoporosis were tested in BP-pretreated and pretreatment-naive
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groups.17 The level of increased bone formation after 24 months of treatment was similar in patients who were either pretreatment-naive or had an initially low bone turnover because of previous BP therapy. These results suggest that PTH acts as a BP antagonist, recovering the previously irreversibly suppressed bone turnover cycle. Reconstruction of oral function in patients with BRONJ is both frustrating and challenging because of the remedial effect of BPs. Although implants can be removed and the wound ultimately heals, the long span of the edentulous space and severe vertical bone loss remain treated issues. In one case report, reconstruction was performed with implant FDPs after BRONJ treatment18; however, it is very risky to decide on a treatment in full knowledge of the residual effect of BPs. Removable prostheses are usually chosen to reconstruct these residual edentulous or bonereduced areas. If TPTD can alter (ie, recover) the BP-suppressed bone turnover rate, guided bone grafting or implant surgery could be considered after TPTD therapy. Although successful results have been reported with TPTD for the treatment of BRONJ, the safety and efficacy of this therapy remain under evaluated. In an animal study, TPTD therapy resulted in the development of osteosarcoma in rats treated for greater than 24 months. So far, there have been no case reports of humans developing osteosarcoma after receiving TPTD therapy within 18 months.19,20 According to the manufacturer’s instructions for this drug, the safety period for TPTD therapy is strictly limited to less than 2 years over an entire lifetime. Furthermore, this therapy is not recommended for patients with hypercalcemic disorder, osteosarcoma, metastatic bone disease, Paget disease of bone, pregnancy, or previous radiation therapy to the skeleton or to soft tissue in which a skeletal port is exposed. In addition, patients with severe renal or hepatic impairment should not receive TPTD therapy.2 There is a case report of a patient taking prednisone and rituximab for the treatment of rheumatoid arthritis who did not respond to TPTD therapy.21 This should be considered
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when deciding on the optimum therapy because it would be very frustrating for both the patient and the medical team if there is no symptom alleviation after applying the cost and effort of administering this drug. Other limitations to the use of TPTD for therapy are its storage and the need for daily administration; self-subcutaneous injections may be difficult for non-practitioners, and especially for elderly patients. Notwithstanding the aforementioned limitations, there is increasing interest in TPTD therapy for patients with BRONJ. The challenge of future research on this drug is to determine the duration of its treatment effect and to establish whether it results in full recovery of the patient’s bone remodeling ability, using methodical approaches and commencing with animal studies.
DISCLOSURE The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article.
ACKNOWLEDGMENTS This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A1009513).
REFERENCES 1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg. 2003;61:1115– 1117. 2. Lee JJ, Cheng SJ, Jeng JH, et al. Successful treatment of advanced
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bisphosphonate-related osteonecrosis of the mandible with adjunctive teriparatide therapy. Head Neck. 2011;33:1366– 1371. 3. Lerman MA, Xie W, Treister NS, et al. Conservative management of bisphosphonate-related osteonecrosis of the jaws: Staging and treatment outcomes. Oral Oncol. 2013;49:977–983. 4. Kwon JY, Kim CW, Lim YJ, et al. Three-dimensional accuracy of different correction methods for cast implant bars. J Adv Prosthodont. 2014;6:39–45. 5. Lopez-Cedrun JL, Sanroman JF, Garcia A, et al. Oral bisphosphonaterelated osteonecrosis of the jaws in dental implant patients: A case series. Br J Oral Maxillofac Surg. 2013;51:874–879. 6. Park W, Kim NK, Kim MY, et al. Osteonecrosis of the jaw induced by oral administration of bisphosphonates in Asian population: Five cases. Osteoporos Int. 2010;21:527–533. 7. Sverzut CE, Sverzut AT, de Matos FP, et al. Mandibular bisphosphonaterelated osteonecrosis after dental implant rehabilitation: A case report. Implant Dent. 2012;21:449–453. 8. Tsai KY, Huang CS, Huang GM, et al. More on the resolution of bisphosphonateassociated osteonecrosis of the jaw. J Rheumatol. 2010;37:675; author reply 676. 9. Hodsman AB, Bauer DC, Dempster DW, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: A review of the evidence and suggested guidelines for its use. Endocr Rev. 2005; 26:688–703. 10. Cheung A, Seeman E. Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. N Engl J Med. 2010; 363:2473–2474. 11. Harper RP, Fung E. Resolution of bisphosphonate-associated osteonecrosis of the mandible: Possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg. 2007;65:573–580. 12. Kwon YD, Lee DW, Choi BJ, et al. Short-term teriparatide therapy as an adjunctive modality for bisphosphonate-
related osteonecrosis of the jaws. Osteoporos Int. 2012;23:2721–2725. 13. Lau AN, Adachi JD. Resolution of osteonecrosis of the jaw after teriparatide [recombinant human PTH-(1-34)] therapy. J Rheumatol. 2009;36:1835–1837. 14. Narongroeknawin P, Danila MI, Humphreys LG Jr, et al. Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: A review of the literature and a case report. Spec Care Dentist. 2010;30:77–82. 15. Ohbayashi Y, Miyake M, Sawai F, et al. Adjunct teriparatide therapy with monitoring of bone turnover markers and bone scintigraphy for bisphosphonaterelated osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013; 115:e31–e37. 16. Kim KM, Park W, Oh SY, et al. Distinctive role of 6-month teriparatide treatment on intractable bisphosphonaterelated osteonecrosis of the jaw. Osteoporos Int. 2014;25:1625–1632. 17. Stepan JJ, Burr DB, Li J, et al. Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis. Osteoporos Int. 2010;21:2027–2036. 18. Petropoulos VC, Balshi TJ, Wolfinger GJ, et al. Treatment of a Patient with Implant Failure and Jaw Osteonecrosis: Successful Retreatment Using Implants. J Oral Implantol. 2014; Mar 25 [Epub ahead of print]. 19. Lehman RA Jr, Dmitriev AE, Cardoso MJ, et al. Effect of teriparatide [rhPTH(1,34)] and calcitonin on intertransverse process fusion in a rabbit model. Spine (Phila Pa 1976). 2010;35:146–152. 20. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344: 1434–1441. 21. Narvaez J, Narvaez JA, GomezVaquero C, et al. Lack of response to teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw. Osteoporos Int. 2013;24:731–733.
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Teriparatide Therapy for Bisphosphonate-Related Osteonecrosis of the Jaw Associated With Dental Implants Re-Mee Doh, DDS, PhD,* Hye-Jeong Park, DDS, MSD,† Yumie Rhee, MD, PhD,‡ Hyun Sil Kim, DDS, PhD,§ Jisun Huh, DDS, MSD,k and Wonse Park, DDS, PhD¶
isphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) was first reported by Marx,1 who described exposed necrotic bone in the maxillofacial region in a patient who had been exposed to intravenous BPs; many cases have been reported since then. Patients receiving high doses of intravenous BPs (zoledronate [Zometa] and pamidronate [Aredia]; Novartis Pharmaceutical, East Hanover, NJ) account for most BRONJ cases, although patients treated with a lower dose of the oral form (alendronate [Fosamax; Merck, Whitehouse Station, NJ], ibandronate [Bonviva; Roche, Basel, Switzerland], or risedronate [Actonel; Sanofi-Aventis, Paris, France]), most often for osteoporosis, have also been reported.2,3 Although the incidence of BRONJ
B
*Clinical Assistant Professor, Department of Advanced General Dentistry, Dankook University Dental Hospital, Cheonan, Korea. †Clinical Instructor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea. ‡Associate Professor, Department of Internal Medicine, Endocrine Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. §Associate Professor, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea. kPostgraduate Student, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea. ¶Associate Professor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Korea.
Reprint requests and correspondence to: Wonse Park, DDS, PhD, Department of Advanced General Dentistry, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea, Phone: +82-2-22288980, Fax: +82-2-22278906, E-mail: [email protected] ISSN 1056-6163/15/02402-222 Implant Dentistry Volume 24 Number 2 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/ID.0000000000000232
This report describes a case of teriparatide (TPTD) therapy for bisphosphonate (BP)-related osteonecrosis of the jaw induced after implant placement. A 75-year-old woman taking oral BP was referred with uncontrolled osteonecrosis of the mandible related to the implant placement. With conservative treatment, BP was suspended and daily subcutaneous injections of 20 mm/d TPTD were started. After 4 months of the therapy, fixture removal and sequestrectomy were performed. Histological analysis revealed necrotic lamellar bone and empty
osteocytic lacunae. In contrast, multiple irregular reversal lines of the lamellar bone and active osteoblasts were noted adjacent to the lesion. There was a significant increase in serum C-terminal telopeptide crosslink of type 1 collagen and serum osteocalcin after commencement of the therapy. After 7 months off therapy, the serum levels of the 2 markers remained at a high level compared with the baseline. (Implant Dent 2015;24:222–226) Key Words: BRONJ, teriparatide, parathyroid hormone, dental implant, CTX, osteocalcin
induced by oral BPs is low, it cannot be neglected because of the large population of patients who take oral BPs. Extraction is the most important dental treatment–associated risk factor for BRONJ, and a few cases of BRONJ that developed after implant placement have been reported recently.4–8 Treatment of BRONJ is quite challenging because the symptoms are not usually eliminated by conventional long-term palliative treatment; even after careful surgical treatment, healing of the hard and soft tissues is very poor and the disease frequently recurs. Parathyroid hormone (PTH) is an 84-amino acid peptide produced by parathyroid chief cells in response to
a decrease in plasma calcium. Teriparatide (TPTD) is a recombinant human PTH, which is the only anabolic agent that is currently approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis. TPTD was recently introduced as a treatment of BRONJ in several cases, but there are few publications on the topic, and the disease diagnosis and treatment sequence have yet to be clearly established. This report describes a case of TPTD therapy for the treatment of BRONJ induced after implant placement. Serial changes in markers of bone turnover (serum C-terminal telopeptide of type 1 collagen [s-CTX] and serum osteocalcin [s-OCN]) were recorded,
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015
Fig. 2. A, Necrotic bone and sequestrum were revealed after flap elevation. The sequestrum was located around the mandibular right first molar fixture. B, Fixture of the first molar (arrow), with surrounding dark red–colored necrotic bone and granulation tissue. C, Fixture of the second premolar (arrowhead), which was only partially involved in the lesion; however, the buccal and mesial parts of the fixture were surrounded by fresh bone.
Fig. 1. Serial changes in the bone around implants viewed on intraoral radiographs. A, First visit and (B) 3 and (C) 4 months after commencement of TPTD treatment. Over time, diffuse “moth-eaten” destructive lesions around the right lower molar fixtures became more distinct after PTH therapy, and the sequestrum became separated from the healthy bone.
and the histological features were analyzed.
CASE REPORT A 75-year-old woman was referred from a local dental clinic with a diagnosis of osteonecrosis of the mandible. The patient had been taking alendronate (Fosamax) for 2.5 years for the treatment of osteoporosis. She had hypertension and hypercholesterolemia that were being controlled. The patient had undergone removal and extraction of a 5-unit fixed dental prosthesis (FDP) on the mandibular right first premolar to third molar and 1 week later had received implant placement
223
Fig. 4. Serial changes in serum C-terminal telopeptide of type I collagen (s-CTX) and serum osteocalcin (s-OCN). B, Baseline (starting point of BP suspension). The arrow indicates the starting and end points of TPTD therapy.
(4.0-mm diameter and 11.5-mm-long RBM surface; CMI implant, Neobiotech, Seoul, Korea) to the area of the missing first and second premolars and the first molar. The patient complained of pain after delivery of an implantsupported FDP (4 months after the first surgery). The dentist removed and replaced the fixture (same-sized fixture as in the first surgery) to the first premolar area and completed the prosthesis. However, the pain and pus discharge reemerged and persisted even after 10 months of conservative treatment. Clinical examination revealed no mobility, but the pocket depth was large and readily bled on probing around the right lower implant-supported FDP. A radiographic evaluation revealed diffuse osteolysis around the implant fixtures, and sclerotic bone and a thin sequestrum were noted (Fig. 1). After consideration of the patient’s history, and in consideration of the diagnosis of BRONJ, multidisciplinary care was instigated at the Department of Internal Medicine (Endocrine Division). Treatment Sequence
Fig. 3. Five months after open debridement of the lesion. A, Soft tissue healing is complete without bone exposure or fistula. B, Intraoral radiograph showing complete bone healing and some alveolar bone formation.
BP was suspended, and daily subcutaneous injections of 20 mm/d TPTD (Forteo; Eli Lilly, Indianapolis, IN) were commenced. Conservative treatment including chlorhexidine irrigation and administration of penicillin were
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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Fig. 5. A and B, Pathologic findings of the right first molar (#46i) area and (C and D) pathologic findings of the right second premolar (#45i) area. A, Microscopic evaluation of #46i revealing the necrotic lamellar bone with bacterial colonies (arrows; hematoxylin and eosin [HE] stain, 3100). B, There are no osteocytes in the lacunae (HE stain, 3400). C, Microscopic appearance of #45i buccal showing multiple irregular reversal lines in the lamellar bone, indicating active bony remodeling (arrows; HE stain, 3100). D, Active osteoblasts synthesizing bone matrix are observed in the periphery (arrowheads; HE stain, 3400).
combined. During the therapy, the diffuse osteolytic lesion became distinct and the sequestrum became separated from the healthy bone, as evidenced on serial intraoral radiographic views (Fig. 1). After 4 months of TPTD therapy, the fixture was removed at the mandibular right second premolar and first molar, followed by sequestrectomy (Fig. 2). The TPTD therapy was terminated 6 months after the initial treatment, and periodic recall checks were scheduled for 1 week, 2 weeks, 1 month, 2 months, 3 months, and every 6 months thereafter. The last checkup was performed 20 months after the surgical treatment, at which point, the surgical wound was completely healed and radiography revealed stable alveolar bone conditions
with some bone deposition, the level of which was location dependent (Fig. 3). Effect of PTH on Bone Turnover Markers and Histological Evaluation of the Surgical Site
Levels of s-CTX and s-OCN were monitored at the first visit, at 0, 1, 3, 5, and 6 months of therapy, and at 7 months after cessation of the therapy (Fig. 4). There was slight increase in s-CTX and s-OCN after BP suspension and a rapid and significant increase in the 2 markers of bone turnover after the treatment started. The removed fixtures and tissues were examined histologically (Fig. 5), which revealed necrotic lamellar bone with bacterial colonies around the fixture
of the first molar. Empty osteocytic lacunae were observed that are typical of BRONJ specimens. The fixture of the second premolar area was also removed during surgery, although its buccal and mesial sides were well osseointegrated. The distal part of the fixture exhibited mature cortical bone with granulation tissue. In contrast to the area around the first molar, the microscopic appearance of the buccal-side lamellar bone exhibited multiple irregular reversal lines. Active osteoblasts synthesizing bone matrix were observed in the periphery at high magnification.
DISCUSSION The treatment of BRONJ proposed by The American Association of Oral
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IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015 and Maxillofacial Surgeons includes patient education, antibacterial mouth rinse, antibiotic therapy, pain control, and surgical debridement/resection. However, even with long-term careful treatment, the symptoms barely subside, soft and hard tissue healing is usually poor, and the condition frequently recurs. These consequences are related to the pharmacodynamic character of BPs, whereby they exert their antiresorptive activity by suppressing osteoclast activity. Suppression of bone resorption allows closure of the existing skeletal remodeling space, further enhancing the increments in bone mineral density.9 However, its initial action is to inhibit bone resorption; it also rapidly inhibits bone formation, which is tightly coupled to resorption. Oversuppression of bone remodeling has a negative effect on bone area, especially at locations with a rapid remodeling rate, such as the jaw, causing BRONJ. In contrast to BPs, TPTD stimulates bone formation by increasing osteoblast number and activity, thus increasing both the bone remodeling rate and the amount of bone deposited in each remodeling cycle. This ultimately increases trabecular thickness, improves trabecular connectivity, and increases cortical thickness and bone size.9 TPTD has been approved by the US FDA for the treatment of osteoporosis in cases in which other treatments have failed or the patients have been intolerant of previous osteoporosis therapy and for glucocorticoid-induced osteoporosis. A few successful clinical cases of off-label use of TPTD for treating BRONJ have been reported2,8,10–14 (Readers should be aware that this is an off-label use of PTH. Off-label drug use is common. Most relevant is the use of bone morphogenic protein (BMP) mixed with other materials when grafting the maxillary sinus or other dentoalveolar defects). The anabolic effect of TPTD can be confirmed on radiographic images and by histological evaluation. In the present case, radiography performed at the initial visit revealed similar features of chronic osteomyelitis, with a patchy, ragged, and ill-defined radiolucency containing small radiopaque sequestra.
The surrounding bone exhibited an increased radiodensity compared with other areas. TPTD therapy resulted in the formation of a large sequestrum, demonstrating that the inflammation was localized and non-vital necrotic bone was separated from the adjacent healthy vital bone. The fixture in the first molar position that was fully involved in the lesion exhibited necrotic lamellar bone and empty osteocytic lacunae, which are distinct features of BRONJ. Interesting findings were obtained through histological evaluation around the fixture located in the second premolar site that partially (distal area) involved the lesion. The buccal area close to the lesion exhibited multiple irregular reversal lines and active osteoblasts forming bone matrix. This vigorous bone formation and resorption indicate that TPTD therapy activates bone remodeling toward bone formation. The effectiveness of TPTD therapy is usually evaluated by assessing the serum levels of markers of bone turnover, such as s-CTX (for osteoclast activity) and s-OCN (for osteoblast activity). In this study, there was a slight increase in s-CTX and s-OCN after suspension of BP and rapid and significant increases in these 2 bone markers after commencement of the treatment. After 7 months off therapy, serum levels of these 2 markers remained at a high level compared with the baseline. This finding concurs with Ohbayashi et al15 finding that TPTD primarily affects osteoblastic activity (bone formation) and secondarily osteoclastic activity (bone resorption) and that this effect persists over a long period. Kim et al16 conducted a retrospective longitudinal study comparing a nonTPTD and a TPTD therapy group to assess the utility of this drug for resolving BRONJ. They found that both s-CTX and s-OCN were increased until 1 month after suspending BP treatment but then decreased back to baseline levels; in other words, the BP-induced suppression of bone turnover rate did not recover. However, the bone markers continued to increase in the TPTD group after the end of the TPTD therapy. In another study, the reversal effects of TPTD on osteoporosis were tested in BP-pretreated and pretreatment-naive
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groups.17 The level of increased bone formation after 24 months of treatment was similar in patients who were either pretreatment-naive or had an initially low bone turnover because of previous BP therapy. These results suggest that PTH acts as a BP antagonist, recovering the previously irreversibly suppressed bone turnover cycle. Reconstruction of oral function in patients with BRONJ is both frustrating and challenging because of the remedial effect of BPs. Although implants can be removed and the wound ultimately heals, the long span of the edentulous space and severe vertical bone loss remain treated issues. In one case report, reconstruction was performed with implant FDPs after BRONJ treatment18; however, it is very risky to decide on a treatment in full knowledge of the residual effect of BPs. Removable prostheses are usually chosen to reconstruct these residual edentulous or bonereduced areas. If TPTD can alter (ie, recover) the BP-suppressed bone turnover rate, guided bone grafting or implant surgery could be considered after TPTD therapy. Although successful results have been reported with TPTD for the treatment of BRONJ, the safety and efficacy of this therapy remain under evaluated. In an animal study, TPTD therapy resulted in the development of osteosarcoma in rats treated for greater than 24 months. So far, there have been no case reports of humans developing osteosarcoma after receiving TPTD therapy within 18 months.19,20 According to the manufacturer’s instructions for this drug, the safety period for TPTD therapy is strictly limited to less than 2 years over an entire lifetime. Furthermore, this therapy is not recommended for patients with hypercalcemic disorder, osteosarcoma, metastatic bone disease, Paget disease of bone, pregnancy, or previous radiation therapy to the skeleton or to soft tissue in which a skeletal port is exposed. In addition, patients with severe renal or hepatic impairment should not receive TPTD therapy.2 There is a case report of a patient taking prednisone and rituximab for the treatment of rheumatoid arthritis who did not respond to TPTD therapy.21 This should be considered
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TERIPARATIDE THERAPY
FOR
BRONJ DOH
when deciding on the optimum therapy because it would be very frustrating for both the patient and the medical team if there is no symptom alleviation after applying the cost and effort of administering this drug. Other limitations to the use of TPTD for therapy are its storage and the need for daily administration; self-subcutaneous injections may be difficult for non-practitioners, and especially for elderly patients. Notwithstanding the aforementioned limitations, there is increasing interest in TPTD therapy for patients with BRONJ. The challenge of future research on this drug is to determine the duration of its treatment effect and to establish whether it results in full recovery of the patient’s bone remodeling ability, using methodical approaches and commencing with animal studies.
DISCLOSURE The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article.
ACKNOWLEDGMENTS This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A1009513).
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