A Strategy against the Osteonecrosis of the Jaw Associated with Nitrogen-Containing Bisphosphonates (N-BPs): Attempts to Replace N-BPs with the Non-N-BP Etidronate

Abstract

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) can occur when enhanced bone-resorptive diseases are treated with nitrogen-containing BPs (N-BPs). Having previously found, in mice, that the non-N-BP etidronate can (i) reduce the inflammatory/necrotic effects of N-BPs by inhibiting their intracellular entry and (ii) antagonize the binding of N-BPs to bone hydroxyapatite, we hypothesized that etidronate-replacement therapy (Eti-RT) might be useful for patients with, or at risk of, BRONJ. In the present study we examined this hypothesis. In each of 25 patients receiving N-BP treatment, the N-BP was discontinued when BRONJ was suspected and/or diagnosed. After consultation with the physician-in-charge and with the patient’s informed consent, Eti-RT was instituted in one group according to its standard oral prescription. We retrospectively compared this Eti-RT group (11 patients) with a non-Eti-RT group (14 patients). The Eti-RT group (6 oral N-BP patients and 5 intravenous N-BP patients) and the non-Eti-RT group (5 oral N-BP patients and 9 intravenous N-BP patients) were all stage 2–3 BRONJ. Both in oral and intravenous N-BP patients (particularly in the former patients), Eti-RT promoted or tended to promote the separation and removal of sequestra and thereby promoted the recovery of soft-tissues, allowing them to cover the exposed jawbone. These results suggest that Eti-RT may be an effective choice for BRONJ caused by either oral or intravenous N-BPs and for BRONJ prevention, while retaining a level of anti-bone-resorption. Eti-RT may also be effective at preventing BRONJ in N-BP-treated patients at risk of BRONJ. However, prospective trials are still required.

Bisphosphonates (BPs) are the most widely used drugs for enhanced bone-resorptive diseases, including osteoporosis and bone-metastatic cancers.¹⁾ BPs are bone-accumulating anti-bone-resorptive drugs, and there are many BPs and many preparations. Among the BPs, the nitrogen-containing BPs (N-BPs) have anti-bone-resorptive effects that are much more powerful than those of the non-nitrogen-containing BPs (non-N-BPs). However, cases of BP-related osteonecrosis of the jaw (BRONJ) have been increasing since this condition was first reported in 2003,¹⁾ and BRONJ has mostly been associated with the administration of N-BPs.^1,2) Actually, BRONJ occurs mostly in patients given intravenous N-BPs (patients with bone-metastatic tumors). However, oral N-BPs also cause BRONJ (mostly in patients with osteoporosis) though the incidence is much lower than with intravenous N-BPs.¹⁾ Notably, the ratio of the number of BRONJ cases in osteoporotic patients receiving oral N-BPs to that in patients receiving intravenous N-BPs is higher in Japan than in the U.S.A. and EU.³⁾

The mechanism underlying BRONJ is complicated, and there are few convincingly effective therapeutic methods.^1,4) BRONJ continues to progress even after a pause in the N-BP treatment, and sometimes appears long after discontinuation of N-BP therapy.¹⁾ Since N-BPs accumulate in the hydroxyapatite within bone, it is anticipated that more cases will come to light if N-BPs continue to be used as they are now. So, we urgently need effective strategies for the treatment and/or prevention of BRONJ.

N-BPs, having entered cells, exhibit cytotoxicity in a variety of cell-types, irrespective of whether they are normal or tumor cells.⁵⁾ The cytotoxic effects of N-BPs on the soft-tissue cells surrounding jawbones within which N-BPs have accumulated have been suggested to be an important cause of BRONJ.^6–8) Indeed, N-BPs can be detected in the saliva of patients treated with N-BPs,⁹⁾ indicating that these drugs are released from the jawbones within which they had accumulated. Interestingly and importantly, few BRONJ cases have been reported in patients treated with the non-N-BP etidronate.¹⁰⁾ We previously reported that in mice: (i) etidronate, when co-administered with, or administered after, an N-BP, competes with the N-BP for binding to bone hydroxyapatite,^7,11) and (ii) etidronate can reduce the inflammatory and necrotic effects of N-BPs^7–11) by inhibiting their entry into soft-tissue cells.¹²⁾ These findings led us to expect that etidronate might to some extent eliminate N-BPs that had already accumulated within jawbones, and that etidronate might therefore be useful as a substitution drug in N-BP-treated patients at risk of BRONJ. Indeed, we previously reported the effectiveness of such etidronate-replacement therapy (Eti-RT) in two N-BP-treated patients with BRONJ.⁶⁾ Here, we report further evidence of such an effectiveness of Eti-RT, this time in a retrospective comparison of an Eti-RT group (6 oral N-BP patients and 5 intravenous N-BP patients) with a non-Eti-RT group (5 oral N-BP patients and 10 intravenous N-BP patients), all with stage 2–3 BRONJ. Etidronate is the one and only non-N-BP used in Japan.

MATERIALS AND METHODS

Ethics

This study complies with ethical principles cited by the World Medical Association Declaration of Helsinki (version 2008) and additional requirements. The design and procedures of this retrospective study were reviewed and approved by the Ethical Committee of the Institutional Review Board of Tohoku University School of Dentistry (receipt number 25-20). Informed consent was obtained from all individual participants included in the study. Moreover, the American Association of Oral and Maxillofacial Surgeons proposed a few years ago that if systemic conditions permit, drug discontinuation may be beneficial for BRONJ associated with either oral (for osteoporosis) or intravenous (for bone-metastatic tumors) N-BPs.⁴⁾ The use of Eti-RT in the present cancer patients is also supported by the suggestions in the literature that (i) bones are fertile ground for tumor growth and/or metastasis because bone-resorption leads to a release of factors for tumor growth,¹³⁾ and (ii) BPs exhibit anti-tumor effects through their anti-bone-resorptive effects.¹³⁾ Thus, an anti-tumor effect may persist during Eti-RT as a result of etidronate’s anti-bone-resorptive activity.

Patients, Diagnosis, and Etidronate Treatment

The study was retrospectively carried out with BRONJ patients who attended Tohoku University Hospital and related hospitals between 2006 and 2011. BRONJ was diagnosed according to the position papers issued by the American Association of Oral and Maxillofacial Surgeons.⁴⁾ We chose 25 patients with BRONJ (11 patients given oral N-BPs and 14 given intravenous N-BPs) at stage 2 or 3 (so as to exclude suspicious cases). After consultation with the physician-in-charge and with the patient’s informed consent, N-BP treatment was discontinued and Eti-RT was started (Eti-RT group). Oral etidronate (Didronel^®; Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan) (200 mg/d, equivalent to 800 µmol/d) was given according to the standard prescription (i.e., two weeks’ ingestion and three weeks’ rest). The data obtained from patients were compared between Eti-RT and non-Eti-RT groups. In the non-Eti-RT group (patients not consulted about, or not agreeable to, Eti-RT), N-BP treatment was discontinued soon after BRONJ was suspected and/or diagnosed. In all patients, irrespective of whether they were in the Eti-RT or non-Eti-RT group, conventional conservative care (antibiotics, analgesics, occasionally surgical intervention) was maintained.

RESULTS

BRONJ in BP-Treated Patients Who Visited Our Hospitals

The BP-treated patients examined in Tohoku University Hospital from 2005 to 2011 are summarized in Table 1. In total, 86 BP-treated patients were examined. Of these, 68 had received oral N-BPs while 18 had received intravenous N-BPs. Of the 86 patients, 37 were diagnosed as BRONJ. Of the 37 BRONJ patients, 22 had received oral N-BPs while 15 had received intravenous N-BPs, indicating that (i) 32% of the patients given oral BPs and 83% of those given intravenous BPs were diagnosed as BRONJ, and (ii) the percentage of BRONJ cases associated with oral N-BP use was 59%, while for intravenous N-BP use it was 41%. The latter result supports the previously reported indication that the percentage of BRONJ associated with oral N-BPs is greater in Japan than in the U.S.A. or EU.³⁾ It should also be noted that there was no patient with etidronate-associated BRONJ.

Table 1. BP-Treated Patients Examined in Our Hospital from 2005 to 2011

BP-Treated patients: total 86 (17m+69f)

oral BPs 68 (8m+60f)

intravenous BPs 18 (9m+9f)

BRONJ (including suspicious cases): 37 (7m+30f)

oral BPs 22————————22/68 (32%), 22/37 (59%)

alendronate 14, risedronate 5, both 1, not identified 2

intravenous BPs 15—————15/18 (83%), 15/37 (41%)

zoledronate 13, pamidronate 2

Diseases treated by BP therapy:

osteoporosis 21, cancer 14, fibrous dysplasia of bone 1, rheumatoid arthritis 1

Effects of Eti-RT on the BRONJ Associated with Use of Oral N-BPs for Osteoporosis (Table 2)

Table 2. Effects of Eti-RT on BRONJ Associated with Use of Oral N-BPs for Osteoporosis

Patient age, sex	N-BP and duration (months)	N-BP cessation and 1st examination dates (year–month)	Site and stage	Trigger	Separation of sequestrum#	Outcome and follow-up (months)
Non-Eti-RT
A 1. 72F*	Ris 36	08–09, 08–09	Lower, 2	Exodontia	**	Healed, 7
A 2. 74F	Ale 120	11–09, 11–09	Upper, 2	Exodontia	**	Healed, 10
A 3. 75F	Ale 38	07–02, 09–11	Lower, 2	Periodontitis	11	Healed, 36
A 4. 66F	Ale 36	10–02, 10–02	Lower, 2	Periodontitis	Not separated	Not improved, 10
A 5. 78F	Ale 72	06–11, 07–02	Lower, 2	Exodontia	6	Healed, 23
73±4	60±33					17±11
Eti-RT
A 6. 77F	Ris 56	07–06, 07–06	Lower, 2	Exodontia	3 (1)	Healed, 30
A 7. 65F*	Ale 24	09–09, 09–10	Lower, 2	Periodontitis	3 (2)	Healed, 17
A 8. 75F	Ale 68	12–07, 12–08	Upper, 2	Periodontitis	5 (5)	Healed, 8
A 9. 72F	Ale 24	10–12, 11–02	Upper, 2	Exodontia	9 (3)	Healed, 16
A10. 85F	Ris 8	14–04, 14–03	Upper, 2	Exodontia	4 (4)	Healed, 9
A11. 87F	Ale 72	12–08, 13–08	Lower, 3	Periodontitis	*	Healed, 8
77±7	42±24				4.8±2.2 (3.0±1.4)	15±8

^# Months after the first examination (and after the start of Eti-RT). * Risk factors for BRONJ were: Al had been given steroid therapy and A7 was suffering from uncontrolled diabetes. ** Sequestrum was separated at the first examination. Detailed progress of patient A6 has been reported previously (Yamaguchi et al.⁶⁾). Healed: mucosal healing and no inflammation.

There was no significant difference in the age of the patients or in the duration of N-BP therapy between the Eti-RT and non-Eti-RT groups. Exposed necrotic bone was healed (i.e., covered with soft tissues) in all patients of both groups, except one patient in the non-Eti-RT group. In most Eti-RT patients, pain and pus had disappeared within some weeks of the start of Eti-RT (data not shown), and bone sequestra could be removed within 3.0±1.4 months. Bone scintigraphy revealed shrinking of the inflammatory area, as previously reported.⁶⁾

Effects of Eti-RT on the BRONJ Associated with Use of Intravenous N-BPs for Cancer (Table 3)

Table 3. Effects of Eti-RT on BRONJ Associated with Use of Intravenous N-BPs for Cancer

Patient, age, sex	Disease	N-BP and duration (months)	N-BP cessation and 1st examination dates (year–month)	Site and stage	Trigger	Separation of sequestrum#	Outcome and follow-up (months)
Non-Eti-RT
B 1. 82M	Multiple myeloma	Zol 24	08–11, 08–10	Lower, 2	Exodontia	Not separated	Not improved, 20
B 2. 54F	Fibrous bone dysplasia	Pam 32	03–06, 05–04	Lower, 3	Periodontitis	Not separated	Improved, 71
B 3. 63F	Breast cancer	Pam 30	06–07, 06–04	Lower, 3	Exodontia	Not separated	Not improved, 5
B 4. 48M	Pharyngeal cancer	Zol 17	09–01, 08–08	Upper, 3 Lower, 3	Periodontitis	Not separated	Not improved, 6
B 5. 65F	Breast cancer	Zol 12	07–10, 08–09	Lower, 2	Exodontia	Not separated	Not improved, 2
B 6. 66M	Multiple myeloma	Zol 24	09–08, 09–11	Upper, 3	Exodontia	Not separated	Improved, 104
B 7. 76F	Breast cancer	Zol 22	09–03, 10–08	Lower, 3	Exodontia	Not separated	Worsened, 26
B 8. 68M	Kidney cancer	Zol 3	yesd) 11–08	Lower, 3	Periodontitis	Not separated	Not improved, 18
B 9. 84M	Breast and prostate cancer	Zol ?	yesd) 09–06	Lower, 3	Exodontia	Not separated	Not improved, 1
67±11		21±9a)					28±34
Eti-RT
B10. 65F	Breast cancer	Pam 11, Zol 10 Total 21	07–08, 08–05	Upper, 3	Exodontia	12 (11)	Healed, 16
B11. 74M	Multiple myeloma	Zol 58	10–06, 10–08	Upper, 3	Periodontitis	12 (7)	Improved, 2
B12. 80M	Prostate cancer	Pam 5, Inc 15, Zol 42 Total 62	11–06, 09–10	Upper, 3 Lower, 3	Periodontitis	Upper: 42 (*)Lower: 43 (1)	Improved, 78
B13. 81Mb)	Prostate cancer	Zol 6	12–05, 12–12	Lower, 3	Periodontitis	21 (15)	Improved, 24
B14. 77F	Breast cancer	Zol 33	11–04, 11–06	Lower, 3	Exodontia	13 (4)	Improved, 24
70±10		44±17c)				20.2±11.9 (7.6±5.0)	29±26

^# Months after the first examination (and after the start of Eti-RT). * Sequestrum was separated before Eti-RT. Healed: mucosal healing and no inflammation. Improved: reduced inflammation but with bone exposure. a) Patient B9 was removed. b) Given denosumab, too, after Zol. c) Patient B13 was removed. d) N-BP was stopped but the exact date could not be identified.

There was no significant difference between the two groups in the age of the patients, although two patients (B11, B12) in the Eti-RT group received N-BP therapy for much longer than any patients in the non-Eti-RT group. It is notable that (i) in the non-Eti-RT group, separation of sequestra occurred in none of the patients, there were only two improved patients, one patient worsened, and most patients were not improved, and (ii) in the Eti-RT group (all stage 3 BRONJ), sequestra were separated in all of the patients, inflammation was reduced in 4 of the 5 improved patients (although bone exposure remained), and one patient was healed (i.e., recovered from bone exposure).

The results in Tables 2 and 3 need supporting data from greater numbers of patients. Nevertheless, they are consistent with Eti-RT promoting the separation and removal of sequestra and thereby promoting the recovery of soft tissues, allowing them to cover the exposed jawbones. In addition, no notable side effects were observed during Eti-RT.

Case Example-1 (A7 in Table 2)

This lady’s medical history included slowly progressing type-I diabetes mellitus and bronchial asthma. She received several kinds of antimicrobials, but her BRONJ symptoms did not improve. Within two months of the start of the first Eti-RT, separation of sequestrum was observed, and so extraction of lower molar teeth (6, 7) and sequestrectomy could be performed without expansion of her BRONJ and bone exposure. Within a month after the start of the second Eti-RT, another lower molar tooth (5) could also be safely extracted. Within one year of the start of Eti-RT, her BRONJ was healed (i.e., closure of exposed bone and no sign of inflammation), and she was able to restart N-BP therapy for osteoporosis.

Case Example-2 (B10 in Table 3)

At the first visit, this lady’s upper jawbone was exposed. She had been given two kinds of intravenous N-BP for a total of 21 months. Within 3 months of the start of Eti-RT, the expansion of the bone exposure had ceased. Ten months later, separation of the sequestrum was observed and sequestrectomy could be performed. Within a month of this sequestrectomy, the previously exposed bone had acquired a soft-tissues covering and there was no sign of inflammation.

DISCUSSION

The precise incidence, clinical backgrounds, and pathogenesis of BRONJ remain unclear, and appropriate strategies for its prevention and treatment have not yet been established.^1,4) Although a strategy involving drug discontinuation for a period has been proposed for patients treated with either oral or intravenous N-BPs,^1,4) the best strategy would be aimed at preventing or reducing the side effects of N-BPs while retaining a certain level of anti-bone-resorptive effect.

The mechanism underlying the inflammatory/necrotic effects of N-BPs may be complicated and the following factors have been reported to be relevant to BRONJ. (i) N-BPs inhibit farnesyl pyrophosphate synthase in the mevalonate pathway during cholesterol synthesis, leading to cytotoxicity, including apoptosis, and reduced prenylation of proteins.^17,14) Thus, N-BPs are by themselves inflammatory and necrotic, and they directly injure soft-tissue cells.^8,15,16) (ii) BPs (both N-BPs, non-N-BPs) accumulate within bone after repeated administration, especially within inflamed bones.⁶⁾ (iii) N-BPs are released from injured jawbones since N-BPs are detectable in the saliva of N-BP-treated patients with, or at risk of, BRONJ.⁹⁾ (iv) As shown in Tables 2 and 3, exodontia and/or periodontitis have been suggested as triggering or exacerbating factors.

It should be noted that such cytotoxic effects of N-BPs are initiated by their entry into soft-tissue cells,¹²⁾ and that there are few reports of inflammatory/necrotic side effects in patients treated with non-N-BPs.¹⁰⁾ Indeed, the non-N-BPs etidronate and clodronate almost completely lack inflammatory and necrotic effects in mice,^7,16) and they are hardly retained at all within soft-tissues in mice after intravenous injection.¹⁷⁾ On the contrary, they antagonize the entry of N-BPs into soft-tissues.^12,16,18) Hence, etidronate and clodronate can reduce or prevent the inflammatory/necrotic effects of N-BPs, whether these occur following administration of N-BPs or their release from sites that have already accumulated them.^7,12,16,18) Thus, in contrast to the complicated mechanism underlying BRONJ itself, the mechanism by which etidronate can protect against BRONJ may be quite simple. The present results may support the proposed mechanism underlying Eti-RT shown in Fig. 1.

Fig. 1. Effects of Eti-RT

(A) Bone-accumulated N-BPs enter osteoclasts during bone-resorption (i.e., under strong acidic conditions) and kill the osteoclasts, resulting in reduced bone-resorption and release of N-BPs from the dead osteoclasts. (B) Etidronate inhibits the accumulation of N-BPs when given together with an N-BP. (C) Etidronate, when given after N-BP therapy, eliminates jawbone-accumulated N-BPs. (D) Etidronate inhibits entry of N-BPs (whether administered or released from bone) into soft-tissue cells around jawbones. (E) Etidronate accumulates in bones, enters osteoclasts, and exhibits cytotoxicity, resulting in reduced bone-resorption. Thus, etidronate can maintain a certain level of anti-bone-resorptive effect during Eti-RT while preventing entry of N-BPs into soft-tissue cells around jawbones. By so doing, Eti-RT can reduce cytotoxic effects of N-BPs and prevent BRONJ.

In addition to antibiotics, analgesics, and conventional surgical intervention, several strategies against BRONJ have been proposed.^19–24) The studies cited for (i) to (iv) in Table 4 are all case reports and have not been confirmed. In contrast, the effectiveness of teriparatide therapy (v) has been reported repeatedly. Although the case reports mostly lack controls, Kim et al., by comparing a non-treated group, observed that teriparatide was significantly beneficial, and suggested that the serum vitamin D concentration is important if such a beneficial effect is to be obtained.²³⁾ However, it should be noted that teriparatide must be given subcutaneously by the patients themselves (it cannot be given orally), and moreover that it cannot be employed in BRONJ patients with bone-metastatic cancers, because of its tumorigenic property, a contraindication in such patients. The effectiveness of platelet-rich-plasma therapy [strategy (vi)] has also been repeatedly reported, and Pelaz et al. noted that this method produced better results than teriparatide therapy.²⁴⁾

Table 4. Previously Proposed Strategies against BRONJ

Method	References*
(i) Fluorescence-guided curettage of necrotic bones	19
(ii) Low intensity laser therapy	20
(iii) Local flaps using pedicled buccal fat pad	21
(iv) Hyperbaric oxygen therapy	22
(v) Teriparatide therapy	23
(vi) Application of autologous platelet-rich-plasma on the surface of live bones after sequestrectomy	24
(vii) Etidronate-replacement therapy	6

* Recent typical references.

The anti-bone-resorptive effect of etidronate, the only non-N-BP approved in Japan, is much less powerful than those of N-BPs. Consequently, the clinical dose of etidronate (200–1000 mg) is markedly greater than those of N-BPs (1–45 mg). That being so, it might be expected that clinically, Eti-RT will achieve a level of anti-bone-resorption roughly comparable to that achieved with a given N-BP (although the possibility of it being at a somewhat lower level than that achieved with the N-BP cannot be ruled out). From this viewpoint, Eti-RT may be superior to a drug holiday or drug discontinuation. By comparison with other strategies (Table 4), Eti-RT would be simple, economic, and capable of being applied to cancer patients, too. More importantly, Eti-RT could be used to prevent BRONJ, because etidronate has the ability to eliminate N-BPs that have already accumulated within jawbones, making it feasible to resume N-BP therapy after Eti-RT. It should also be noted that taking a tablet of etidronate is straightforward (between meals once a day), while taking tablets of N-BPs is quite complicated, and can be troublesome for aged or bedridden patients (once a day upon getting up, ingested with 180 mL or more water, not lying down for at least 30 min, and not ingesting anything other than water). A further encouragement for us to employ Eti-RT is that etidronate exhibits an analgesic effect that is more potent than those of N-BPs, and this effect is independent of its anti-bone-resorptive effect.^25,26) Prospective, randomized, controlled trials will be needed for further evaluation of the efficacy of Eti-RT, although it is hard to collect a large enough number of patients for such studies.

Acknowledgments

We are grateful to the following physicians for their cooperation with this study: Dr. Takashi Kudo (Japan Community Health Care Organization Sendai Hospital), Dr. Syotaro Tani (Tani Orthopedic Clinic), Dr. Masamichi Tadokoro (Tadokoro Heart Clinic), Dr. Tamotsu Saito (Mono Family Clinic), Dr. Hiroji Akimoto (Akimoto Clinic), Dr. Katsuyuki Utsunomiya (Mishuku Hospital), and Dr. Kuninari Itoh (Itoh Orthopedic Clinic). We are grateful to Dr. Satoru Okada and Mr. Hikari Suzuki (Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai) for collecting and analyzing data, to Dr. Hiromi Funayama (Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama) for providing basic information relevant to this study, to Dr. Shiro Mori (Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai) and Dr. Hiroshi Nagasaka (Department of Oral Surgery, National Hospital Organization, Sendai Medical Center, Sendai) for instructive suggestions. We are also grateful to Dr. Robert Timms (Birmingham, U.K.) for editing the manuscript. This work was supported by Grants from the Japan Society for the Promotion of Science (21390529 for Y.E., 24659835 for Y.E., 24592978 for K.Y., and 25861910 for T.O.).

Conflict of Interest

Yasuo Endo received a scholarship from Sumitomo Dainippon Pharma Co., Ltd. (Osaka, Japan).

REFERENCES

• 1) Fliefel R, Tröltzsch M, Kühnisch J, Ehrenfeld M, Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int. J. Oral Maxillofac. Surg., 44, 568–585 (2015).
• 2) Pazianas M. Osteonecrosis of the jaw and the role of macrophages. J. Natl. Cancer Inst., 103, 232–240 (2011).
• 3) Urade M, Tanaka N, Furusawa K, Shimada J, Shibata T, Kirita T, Yamamoto T, Ikebe T, Kitagawa Y, Fukuta J. Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan. J. Oral Maxillofac. Surg., 69, e364–e371 (2011).
• 4) AAOMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J. Oral Maxillofac. Surg., 65, 369–376 (2007).
• 5) Tanaka Y, Nagai Y, Dohdoh M, Oizumi T, Ohki A, Kuroishi T, Sugawara S, Endo Y. In vitro cytotoxicity of zoledronate (nitrogen-containing bisphosphonate: NBP) and/or etidronate (non-NBP) in tumor cells and periodontal cells. Arch. Oral Biol., 58, 628–637 (2013).
• 6) Yamaguchi K, Oizumi T, Funayama H, Kawamura H, Sugawara S, Endo Y. Osteonecrosis of the jawbones in 2 osteoporosis patients treated with a nitrogen-containing bisphosphonate: osteonecrosis reduction replacing NBP with non-NBP (etidronate) and rationale. J. Oral Maxillofac. Surg., 68, 889–897 (2010).
• 7) Oizumi T, Funayama H, Yamaguchi K, Yokoyama M, Takahashi H, Yamamoto M, Kuroishi T, Kumamoto H, Sasaki K, Kawamura H, Sugawara S, Endo Y. Inhibition of necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their elimination from bone by etidronate (a non-NBP): a proposal for possible utilization of etidronate as a substitution drug for NBPs. J. Oral Maxillofac. Surg., 68, 1043–1054 (2010).
• 8) Cornish J, Bava U, Callon KE, Bai J, Naot D, Reid IR. Bone-bound bisphosphonate inhibits growth of adjacent non-bone cells. Bone, 49, 710–716 (2011).
• 9) Scheper MA, Badros A, Salama AR, Warburton G, Cullen KJ, Weikel DS, Meiller TF. A novel bioassay model to determine clinically significant bisphosphonate levels. Support. Care Cancer, 17, 1553–1557 (2009).
• 10) Crépin S, Laroche M-L, Sarry B, Merle L. Osteonecrosis of the jaw induced by clodronate, an alkylbisphosphonate: case report and literature review. Eur. J. Clin. Pharmacol., 66, 547–554 (2010).
• 11) Funayama H, Ohsako M, Monma Y, Mayanagi H, Sugawara S, Endo Y. Inhibition of inflammatory and bone–resorption–inhibitory effects of alendronate by etidronate. Calcif. Tissue Int., 76, 448–457 (2005).
• 12) Okada S, Kiyama T, Sato E, Tanaka Y, Oizumi T, Kuroishi T, Takahashi T, Sasaki K, Sugawara S, Endo Y. Inhibition of phosphate transporters ameliorates the inflammatory and necrotic side effects of the nitrogen-containing bisphosphonate zoledronate in mice. Tohoku J. Exp. Med., 231, 145–158 (2013).
• 13) Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer, 2, 584–593 (2002).
• 14) Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J. Biochemical and cellular mechanisms of action of bisphosphonates. Bone, 49, 34–41 (2011).
• 15) Endo Y, Nakamura M, Kikuchi T, Shinoda H, Takeda Y, Nitta Y, Kumagai K. Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine-synthesis and increase macrophages, granulocytes, and osteoclasts in vivo. Calcif. Tissue Int., 52, 248–254 (1993).
• 16) Oizumi T, Yamaguchi Y, Funayama H, Kuroishi T, Kawamura H, Sugawara S, Endo Y. Necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their inhibition by clodronate (a non-NBP) in mice: potential for utilization of clodronate as a combination drug with an NBP. Basic Clin. Pharmacol. Toxicol., 104, 384–392 (2009).
• 17) Mönkkönen J, Koponen H-M, Ylitalo P. Comparison of the distribution of three bisphosphonates in mice. Pharmacol. Toxicol., 66, 294–298 (1990).
• 18) Kiyama T, Tsuchiya M, Okada S, Oizumi T, Yamaguchi K, Sasaki K, Sugawara S, Endo Y. Phosphonocarboxylates can protect mice against the inflammatory and necrotic side effects of nitrogen-containing bisphosphonates by inhibiting their entry into cells via phosphate transporters. Biol. Pharm. Bull., 39, 712–720 (2016).
• 19) Pautke C, Bauer F, Otto S, Tischer T, Steiner T, Weitz J, Kreutzer K, Hohlweg-Majert B, Wolff KD, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum SR, Kolk A. Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaw: first clinical results of a prospective pilot study. J. Oral Maxillofac. Surg., 69, 84–91 (2011).
• 20) Vescovi P, Meleti M, Merigo E, Manfredi M, Fornaini C, Guidotti R, Nammour S. Case series of 589 tooth extractions in patients under bisphosphonates therapy. Proposal of a clinical protocol supported by Nd:YAG low-level laser therapy. Med. Oral Patol. Oral Cir. Bucal, 18, e680–e685 (2013).
• 21) Gallego L, Junquera L, Pelaz A, Hernando J, Megias J. The use of pedicled buccal fat pad combined with sequestrectomy in bisphosphonate-related osteonecrosis of the maxilla. Med. Oral Patol. Oral Cir. Bucal, 17, e236–e241 (2012).
• 22) Freiberger JJ, Padilla-Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, Moon RE, Piantadosi CA. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J. Oral Maxillofac. Surg., 70, 1573–1583 (2012).
• 23) Kim KM, Park W, Oh SY, Kim H-J, Nam W, Lim S-K, Rhee Y, Cha IH. Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw. Osteoporos. Int., 25, 1625–1632 (2014).
• 24) Pelaz A, Junquera L, Gallego L, Garcia-Consuegra L, Junquera S, Gómez C. Alternative treatments for oral bisphosphonate-related osteonecrosis of the jaws: a pilot study comparing fibrin rich in growth factors and teriparatide. Med. Oral Patol. Oral Cir. Bucal, 19, e320–e326 (2014).
• 25) Fujita T, Ohue M, Fujii Y, Miyauchi A, Takagi Y. Comparison of the analgesic effects of bisphosphonates: etidronate, alendronate and risedronate by electroalgometry utilizing the fall of skin impedance. J. Bone Miner. Metab., 27, 234–239 (2009).
• 26) Kim S, Seiryu M, Okada S, Kuroishi T, Takano-Yamamoto T, Sugawara S, Endo Y. Analgesic effects of the non-nitrogen-containing bisphosphonates etidronate and clodronate, independent of anti-resorptive effects on bone. Eur. J. Pharmacol., 699, 14–22 (2013).