The incidence of MRONJ development in patients with osteoporosis treated with DNO is very low (ranging from 0.15% to less than 0.001% person-years of exposure) [20]. The minimal and average numbers of low doses of DNO till MRONJ development are 4 and 8, respectively [12]. There are, however, exceptions to the rule. For example, Hoefert et al. reported MRONJ stage III of the maxilla after 3 low doses of DNO at 6-month intervals in a 58 years old female [17]. Tofé et al. [21] reported the mean treatment time till MRONJ development with DNO to be 30.8 ± 3.9 months for low doses of DNO.
The number of DNO doses to MRONJ development in patients with osteoporosis is lower in patients previously treated by BP [22] and it is suggested that patients transitioning from BP to DNO are at higher risk of developing MRONJ [10]. However, the issue remains controversial as they were not confirmed by other studies. For example, Jung et al. did not observe any difference in MRONJ occurrence between patients treated with DNO only or with BP-DNO sequential therapy [23]. Similarly to Jung et al., a recent study by Miller et al. [24] showed that none of the 1413 patients in the cohort transitioning from BP to DNO suffered from MRONJ. The controversy goes even further – Pautke et al. [25] reported that MRONJ developed significantly earlier in DNO-only treated patients than in BP or BP-DNO patients and that the success rate of treatment was lower in the BP group than in the DNO or BP-DNO group. The length of the “drug holiday” between BP and DNO doesn´t seem to have a significant impact on MRONJ occurrence, either (or at least not if it's shorter than 1 year) [10].
A literature search for original articles, case reports, and case series with MRONJ development after a single low dose of DNO was conducted in PubMed and Scopus. The following combination of keywords was used for search: osteonecrosis AND jaw AND denosumab. Only reports on patients with osteoporosis who, besides other medication, received just a single low dose of DNO, were included in this review, see Table 2. In total, 9 articles with 11 cases with MRONJ were included. Except for 3 patients, all of them were taking some kind of medication possibly predisposing to MRONJ (BP/statins/romosozumab). However, only limited information was available for some of these cases and in most of them, we cannot be sure if all risk factors have been duly reported in the respective papers.
Table 2
Literature review of medication-related osteonecrosis of the jaw (MRONJ) triggered by a single low-dose of DNO (60 mg) in patients with osteoporosis
Case | Age | Sex | ARD before DNO | Other medication | Medical history | Initiating factor | MRONJ location | MRONJ stage | MRONJ onset | Symptoms | Reference |
1. | 75 | Female | Alendronate 70 mg/week for more than 3 years | N/A | Unclassified inflammatory bowel disease, previous glucocorticoid therapy, impaired renal function, chronic anemia, heterozygous b-thalassemia, mild to moderate iron overload | None | Mandible | N/A | 2 months after administration of DNO | MRONJ right lower jaw | [62] |
2. | 58 | Male | No | Calcium (1 g/24 h) and vitamin D (800 IU/1 h), simvastatin | Myocardial infarctions (twice), hypertension | Dental extraction | Mandible | N/A | 5 months after DNO administration, 1 month after extraction | Pain, bone exposure | [43] |
3. | 84 | Female | No | None | Hypertension | Placement of dental implants | Mandible | N/A | 3 weeks after the placement of dental implants and approximately 23 weeks after DNO administration | Pain, bone exposure, peri-implant suppuration | [63] |
4. | 65 | Female | Risedronate for a total of 4 years followed by annual zoledronic acid injections for a period of two years with the last dose being roughly 1 year prior to the extraction | N/A | Hypertension, gastroesophageal reflux disease, iron deficiency anemia, and rheumatoid arthritis | Dental extraction | Mandible, ulceration of the soft palate | N/A | 3 weeks after extraction and 4 weeks after DNO administration | Cutaneous fistula in the left submandibular region, spontaneous necrosis of the right side of the soft palate, ultimately developed acute respiratory distress syndrome | [64] |
5. | 78 | Female | Ibandronate for 43 months | N/A | N/A | Dental extraction | Mandible | Stage I | N/A | Bone exposure | [65] |
6. | 77 | Female | Risedronate for 84 months | N/A | N/A | Dental extraction | Mandible | Stage I | N/A | Bone exposure | [65] |
7. | N/A | N/A | Romosozumab for 12 months | N/A | N/A | Dental extraction | N/A | N/A | N/A, DNO administered 1 month after extraction | N/A | [15] |
8. | 81 | N/A | Alendronate for 55 months | N/A | N/A | None | Mandible | N/A | N/A | N/A | [22] |
9. | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | [22] |
10. | 59 | Female | No | Acetylsalicylic acid (100 mg/24 h); atorvastatin (20 mg/ 24 h); hydrochlorothiazide (25 mg/24 h); 1 syringe/183 days), calciferol (25.000 UI/2.5 ml/ twice a week) | Poliomyelitis, meningitis, hypothyroidism due to hemithyreoidectomy due to microcalcifications, breast cancer, and received chemotherapy with partial removal of the breast, scoliosis, hypocalcemia, bronchial asthma, C5-C6 disc protrusion, microcytic anemia, right, carpal tunnel inversion, two strokes, heavy smoker | Dental extraction | Mandible | Stage II | 4 months after extraction, 3 months after DNO administration | Pain, bone exposur, with mucosa ulceration | [42] |
11. | 54 | Female | No | N/A | N/A | Dental extraction | Mandible | Stage II | 4 months after extraction | MRONJ on the lingual side of the mandible | [23] |
12. | 83 | Female | Aledronate 70 mg/week for 3 years | Rosuvastatin (10 mg/24h) for 7 years, acetylsalicylic acid/glycine (100 mg/50 mg/24h), bisoprolol (2.5 mg/24h), micronised purified flavonoid fraction (500 mg/24 h), pramipexole (0.18 mg/12 h), glycopyrronium + indacaterol (85 mg/43 mg/24 h), pantoprazole (40 mg/24 h), benfotiamine + pyridoxine + cyanocobalamin (40 mg/90 mg/0.25 ug/12 h), calcium + vitamin D3 (500 mg/800 IU/24 h) | Chronic obstructive pulmonary disease, radical resection of adenocarcinoma of the left pulmonary lobe (T1N0M0) with dissection of the lymph nodes without any adjuvant therapy, phlebothrombosis of the right lower limb, percutaneous coronary intervention with the insertion of a coronary stent was conducted due to ST elevation myocardial infarction, total hip replacement of the left hip, Parkinson’s disease, epilepsy (without any recent paroxysms). | Most likely trauma caused by dentures | Maxilla | Stage III | 3 months after DNO application | Bone exposure | Current study |
* one year “drug holiday” between risedronate and denosumab |
N/A, non-applicable/specified, or unknown |
DNO, denosumab |
ARD, antiresorptive drug |
Our patient received only a single low dose of DNO and developed MRONJ within just 3 months. It must be taken into account that previously, she had been taking statins for 7 years and BP for nearly 3 years in the past. Although BP treatment had been terminated approximately 1.5 years before she received the single dose of DNO, the half-life for alendronate is, due to its irreversible binding to the bone, several years [12]. Hence, it is plausible that MRONJ developed on the basis of a combined effect of BP and DNO. Of the other contributing factors that may possibly play a role in the initiation of MRONJ development in our patient, the long-term therapy by rosuvastatin may be considered.
Rosuvastatin represents the latest inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase introduced into clinical practice for hypercholesterolemia treatment, and is considered very safe [26]. It is worth mentioning the case presented by Aghaloo and Tetradis, where MRONJ stage III developed spontaneously without any surgical intervention or other local irritating factors; however, rosuvastatin was in the pharmacological history of the case described in their report (unfortunately, dosage and duration of therapy are not properly described in the publication) [27]. Hypothetically, there may be an interaction or relationship between DNO and hydrophilic statins (rosuvastatin, pravastatin) supporting MRONJ development, as indicated in a very recent cohort study [28].
Statins are discussed in relation to MRONJ etiopathogenesis [19] mainly because of their influence on bone metabolism [29, 30]. Simvastatin, due to its protective effects on osteoblasts by acting on the mevalonate pathway and inhibiting osteoclastogenesis by blocking the RANKL pathway, is now considered to be a potential drug for treating patients with osteoporosis [31]. Furthermore, statins are regarded as promising agents that could be used in treating some oncologic patients. It was shown that targeting the mevalonate pathway with the combination of BP and statins can lead to more effective treatment of breast cancer [32, 33]. Moreover, rhabdomyolysis, a known adverse effect of statins [34] can be potentiated by DNO [35], with rapid onset seen even after a single dose of DNO [36]. As for oral manifestations of adverse effects related to statins, several cases of mucosal ulcers were described [37]. Xerostomia, which is described in patients using statins, could be one of the underlying reasons [38, 39]. This is similar to patients with Sjogren´s syndrome, who typically suffer from dry mouth and often develop ulcers [40, 41]. Therefore, the effect of some statins in relation to MRONJ can be two-fold. By damaging the mucosa, statins enable the oral bacteria to invade the bone and the combination with its direct involvement in bone metabolism (the inhibition of osteoclastic differentiation and activity) can potentiate the negative effect.
Furthermore, this significant impact of statins is supported by several reported cases of statin-induced MRONJ in patients without ARD therapy (see the overview of such reports in Table 3). Also, two cases from Table 2 had statin treatment before the DNO application [42, 43].
Table 3
Literature review of cases with medication-related osteonecrosis of the jaws (MRONJ) on statin therapy, who are not users of antiresorptive drugs
Case | Age | Sex | Statin | Other medication | Medical history | Triggering factor | MRONJ Location | MRONJ stage | Symptoms | Therapy | Duration for healing | Reference |
1 | 53 | Male | Atorvastatin 80 mg | N/A | * | Dental extraction | Mandible | N/A | Pain, bone exposure | Surgical debridement and primary wound closure | 4 months | [66] |
2 | 71 | Female | Atorvastatin 10 mg | N/A | * | Dental extraction | Maxilla | N/A | Pain, bone exposure | Surgical debridement and primary wound closure | 4 months | [66] |
3 | 61 | Male | Atorvastatin 10 mg | N/A | * | Dental extraction | Mandible | N/A | Pain, bone exposure | Surgical debridement and primary wound closure | 4 months | [66] |
4 | 48 | Female | Simvastatin 40 mg, received for 10 years | N/A | N/A | Dental extraction | Mandible | N/A | Pain, Swelling, Purulent drainage | Surgical debridement, application of platelet-rich fibrin, primary wound closure. | N/A | [67] |
5 | N/A | N/A | Simvastatin 40 mg, received for more than 20 years | N/A | N/A | Oral surgery | Maxilla | N/A | Bone exposure | Debridement, antibiotic therapy | N/A | [68] |
6 | N/A | N/A | Simvastatin 40 mg, received for more than 20 years | N/A | N/A | Oral surgery | Maxilla | N/A | Bone exposure | Debridement, antibiotic therapy | N/A | [68] |
7 | 70 | Female | Rosuvastatin | Amitriptyline, celecoxib, fluticasone, hydrochlorthiazide, loratadine, andtemporarily amoxicillin | Osteoarthritis of the hip, previously received local hip steroid injections | None | Maxilla | III | Bleeding | Local rinsing with chlorhexidine | 6 months | [27] |
* In the article by Nordi and Ghazali two of three patients reported diabetes mellitus, not specified which ones [66]. |
N/A, non-applicable/specified, or unknown |
On the other hand, short-term use of statins was shown to have many beneficial effects on oral health [44], including aiding the healing of the extraction socket [45]. In fact, fluvastatin and atorvastatin have therapeutic effects on MRONJ and/or can act protectively [46, 47, 48, 49]. This is in line with the decreased risk of osteonecrosis of the femoral head when glucocorticoids are combined with statins [50]. This ambivalent feature of statins could be explained by their pleiotropic effect that can, for example, depend on its dose: lower doses promote angiogenesis, while higher doses inhibit it [51]. This seems to be plausible, since the cases of statin-induced MRONJ reported prolonged therapy, usually with higher doses of statins (see Table 3). Moreover, patients on long-term statin therapy often suffered from oral ulcers, which spontaneously healed after statin cessation [37]. In our case, the patient also used rosuvastatin for several years, although in low doses.
It is not clear whether any of the other co-administered drugs can increase the risk of MRONJ, the involvement of acetylsalicylic acid (ASA) and glycopyrronium cannot be excluded. ASA is known as an irreversible nonselective cyclooxygenase inhibitor with a dose-dependent effect. In our case, low-dose ASA was administered for secondary prevention of myocardial infarction. Recently, it was shown that ASA or its metabolites are able to reduce angiogenesis in multiple types of cancer [52]. The mechanisms of the antiangiogenic effect of ASA are explained through inhibition of matrix metalloproteinases [53], influence on platelet activity [54], or effects of cyclooxygenases on endothelial cells [55]. Most of the abovementioned effects of ASA are dose-dependent and low-dose ASA is, therefore, obviously not the main cause of MRONJ in our case. On the other hand, ASA can present an important piece in the puzzle of the total risk of MRONJ development. Glycopyrrolate, a peripheral competitive muscarinic receptor antagonist, should be also evaluated as an agent that shouldn't be omitted with respect to the risk of MRONJ. The decreased activity of salivary glands and xerostomia are some of the side effects of this drug.
Besides medication history, the higher age of the patient was the only other possible systemic risk factor to consider. The oncological status is not of particular interest, since the adenocarcinoma of the pulmonary globe was treated only surgically with complete remission. Regarding the local factors, dentures could be a causative factor; however, the patient did not report any significant problems with the dentures or any problems in the oral cavity prior to DNO application. On the other hand, we have to take into account that she did not visit her dentist for 3 years before the application of DNO, so discrepancies in the alignment of the denture with the alveolar process cannot be ruled out. In the case of BP-induced MRONJ, the study of Hasegawa et al. [56] revealed that the duration to the onset of MRONJ was significantly shorter in patients with dentures than in those not wearing dentures. Given the high frequency of trauma caused by poorly fitting dentures [57, 58, 59, 60], it is not surprising that dentures are considered to be a very important, if not the most important, risk factor for MRONJ development [56, 61]. Hence, it is critical to regularly follow up the patients with dentures who are treated with DNO and all precautions should be made to prevent any trauma of the mucosa.
Altogether, the combination of the synergistic effect of BP-DNO and long-term rosuvastatin therapy on bone metabolism with a possible contribution of inappropriate denture adjustment, ASA, and glycopyrronium could be the most probable explanation for the rapid development of severe MRONJ in our patient. However, given that MRONJ developed just after the administration of a single low dose of DNO, this seems to have been the triggering agent. This suggests that patients at high risk of MRONJ should be carefully evaluated before DNO administration.