Table 1.
Distribution of variables of 29 articles related to MRONJ included in this systematic review.
| Authors (Year) | Pts. under ART/AAT | Sex | Avg. Age in yr. (Range) | Indication for ART/AAT | Medication | Medication Use Time (Range) | Avg. Doses Number (Range) | Dosage Data | Cumulative Dose | Concomitant Medication |
|---|---|---|---|---|---|---|---|---|---|---|
| August et al. (2011) [35] | 19 | 12 (M) 7 (F) |
12.50 (1.10 to 23.10) | Malignant pathology | ZD | NDA | 7.47 (1 to 21) | <10 yr.: 4 mg q28 days approx. >10 yr.: 0.08–0.16 mg/kg q28 days approx. |
NDA | Vincristine, cyclophosphamide, doxorubicin, ifosfamide, etoposide, methotrexate, topotecan, temozolamide, gemcitabine, docetaxel, irinotecan, vinorelbine, busulfan, melfalan. |
| Bredell et al. (2017) [36] | 5 | 2 (M) 3 (F) |
18.00 (3.90 to 26.00) | CGCL | DS | NDA | 14.20 (12 to 15) | Case 1: 70–100 mg SC once a wk. for the first mo. and then once a mo. Rest of cases: 120 mg SC initial dose, 120 mg on the 8th day and 15th day. Then 120 mg q4 wk. |
NDA | Calcitonin, IFN alpha, vitamin D and calcium supplements, intralesional corticosteroids. |
| Brown et al. (2008) [37] | 42 | NDA | 8.25 | OI, MAS, osteoporosis, transverse myelitis | PD (n = 1) ZD (n = 4) PD + ZD (n = 37) |
6.50 | 29.60 | PD: 1 mg/kg/dose q2 mo. approx. ZD: 0.04–0.05 mg/kg/dose q4 mo. approx. |
PD: 19.8 mg/kg corresponds to an equivalent dose in adults of 1190 mg. ZD: 0.49 mg/kg corresponds to an equivalent adult dose of 29.4 mg. |
Corticosteroids in a single case. |
| Carpenter et al. (2007) [38] | 18 | 11 (M) 7 (F) |
11.30 (5.80 to 17.10) | Low BMD | PD. AL or ZD as alternatives |
0.96 | NDA | PD: 1 mg/kg q mo. | NDA | Growth hormone, sex hormones, prednisone, calcium and/or vitamin D supplements. |
| Chahine et al. (2008) [39] | 278 | 136 (M) 142 (F) |
14.70 (0.70 to 32.00) | OI, osteoporosis, fibrous/bone dysplasia, neuromuscular disorders, rheumatic disorders, Crohn’s disease | PD | 4.60 (0.00 to 112) |
NDA | <2 yr.: 0.5 mg/kg q day for 3 consecutive days q2 mo. 2–3 yr.: 0.75 mg/kg q day for 3 consecutive days q3 mo. >3 yr.: 1 mg/kg q day 3 consecutive days q4 mo. Maximum dose: 60 mg q day. Maximum infusion concentration: 0.1 mg/mL. Infusion administration duration: 3–4 h. |
9 mg/kg (total annual dose). Avg. cumulative dose before tooth extraction: 40 mg/kg (2.5 to 81 mg/kg) in pts. who underwent tooth extraction and had records of PD Tx. (n = 45) |
NDA |
| Feehan et al. (2018) [40] | 33 | 18 (M) 15 (F) |
9.00 | OI | PD or ZD | 7.00 (4 to 11.5) |
NDA | NDA | NDA | Antidepressants (n = 6), proton pump inhibitor (n = 2), pain relievers (n = 1). |
| Goldsby et al. (2013) [41] | 24 | 8 (M) 16 (F) |
13.50 (7.00 to 22.00). | Malignant pathology | ZD | 0.64 | 8.00 | Induction dose (wk. 1 to 12): 1.2 mg/m2 (max. 2 mg) (n = 6); 2.3 mg/m2 (max. 4 mg) (n = 6); 3.5 mg/m2 (max. 6 mg) (n = 6). According to tolerance, the dose levels were scaled. A fourth group (n = 6) was added at a dose of 2.3 mg/m2 (max. 4 mg) after determining the maximum tolerated dose, in order to help assess the post-induction feasibility of ZD. |
NDA | Cisplatin, adriamycin, methotrexate, ifosfamide, etoposide, calcium and vitamin D supplements. |
| Idolazzi et al. (2017) [42] | 55 | 30 (M) 25 (F) |
12.60 (5.00 to 19.00) | OI | ND | 3.00 | 11.10 (3 to 13) | 2 mg/kg (max. 100 mg) q3 mo. for 3 yr. | NDA | Calcium and vitamin D supplements. |
| Ierardo et al. (2017) [43] | 20 | 12 (M) 8 (F) |
NDA (8.00 to 14.00) | OI | ND | NDA | NDA | Dose q3 mo. | NDA | NDA |
| Johannesen et al. (2009) [44] | 37 | 28 (M) 9 (F) |
10.80 (6.01 a 1550) | AFN | ZD | 1.18 | 6.70 | 1st dose: 0.0125 mg/kg. 2nd dose (at 6 wk.): 0.025 mg/kg. 3rd dose (12 wk. after the 1st dose): 0.025 mg/kg. Following dose: at 0.025 mg/kg 12 wk. apart. |
NDA | Calcium and vitamin D supplements. |
| Kumar et al. (2016) [45] | 26 | NDA | 7.00 (3.75 to 10.00) | OI | ZD | 3.00 (0.91 to 5.08) | 12,00 (3.66 to 20.3) | <1 yr.: 2 mg. >1 yr.: 4 mg q3 mo. |
48 mg/kg on avg. (16 to 80 mg/kg). | NDA |
| Li et al. (2011) [46] | 20 | 11 (M) 9 (F) |
10.60 | OI | IB | 2.00 | 8.00 | 2 mg q3 mo. | NDA | Calcium and vitamin D supplements. |
| Lindahl et al. (2016) [47] | 79 | 43 (M) 36 (F) |
6.75 (0.10 to 17.10). | OI | PD | 7.60 | NDA | Monthly infusion of 10 mg/m2 (1st 3 mo.), 20 mg/m2 (2nd 3 mo.), then 30 mg/m2. After 2 yr., the dose was adjusted in relation to the response (evaluated by bone densitometry, bone turnover markers in blood and urine, and regression of vertebral compression fractures). | NDA | Calcium and vitamin D supplements. |
| Maines et al. (2012) [48] | 102 | 47 (M) 55 (F) |
12.26 (3.10 to 23.40) | OI | ND | 6.81 (1.00 to 12.90) | NDA | Pts. who started treatment with less than 1 yr. (n = 15): Infusion 1 mg/kg/day for 2 consecutive days q3–4 mo. Rest of patients (n = 87): 2 mg/kg/dose in a single session q3–6 mo. |
Cumulative avg. dose: 1679 mg (144 to 5307 mg). Cumulative avg. dose (per kg): 50 mg/kg (10 to 100 mg/kg). | NDA |
| Malmgren et al. (2008) [49] | 64 | NDA | 8.10 (0.20 to 20.90). | OI | PD | 4.50 (0.50 to 12.50) | NDA | 1st 3 mo.: 10 mg/m2. 2nd 3 mo.: 20 mg/m2. Then: 30–40 mg/m2 in q mo. infusion. |
1623 mg/m2 on avg. (140–4020 mg/m2). | Steroids or cytostatics were never administered. |
| Milano et al. (2011) [50] | 1 | 1 (M) | 4.66 | OI | PD | NDA | 8.00 | Last dose before surgery: 60 mg. | NDA | Calcium and vitamin D supplements. |
| Moeini et al. (2013) [51] | 12 | 3 (M) 9 (F) |
13.00 (700 to 21.00) | Prostate thalassemia major | NDA | NDA | NDA | NDA | NDA | NDA |
| Naidu et al. (2014) [52] | 1 | 1 (F) | 9.00 | CGCL | DS | 1.50 | NDA | 120 mg q day for 28 days. Additionally, 2 loading doses were administered in 1mo. (8th and 15th day of Tx). | NDA | Calcium and vitamin D supplements. |
| Nasomyont et al. (2019) [53] | 123 | 69 (M) 54 (F) |
10.21 (0.01 to 20.60) | Osteoporosis | PD or ZD | NDA | 5.27 (1 to 48) | Individualized doses for each case. On avg. PD was administered: 9 mg/kg/yr. q2-4 mo. (Primary osteoporosis group). 4 mg/kg/yr. q3 mo. (secondary and glucocorticoid-induced osteoporosis groups). ZD: 0.1 mg/kg/year every 6 months. |
NDA | NDA |
| Ngan et al. (2013) [54] | 1 | 1 (F) | 12.00 | OI | PD | NDA | NDA | 1 mg/kg/dose q3 mo. | NDA | Calcium and vitamin D supplements. |
| Okawa et al. (2017) [55] | 31 | NDA | NDA | OI | NDA | NDA | NDA | NDA | NDA | NDA |
| Piperno-Neumann et al. (2018) [56] | 110 | NDA | NDA | Malignant pathology | ZD | 0.83 | 10.00 | >25 yr.: 10 monthly doses of 4 mg. 18–25 yr.: 10 monthly doses of 0.05 mg/kg for the first two cycles and 4mg for the remaining 8 cycles. Children <18 yr.: 10 monthly doses of 0.05 mg/kg in all cycles without exceeding 4 mg. |
NDA | Calcium and vitamin D supplements. Chemotherapy regimens with: Methotrexate, etoposide, ifosfamide, cisplatin, doxorubicin. |
| Putman et al. (2018) [57] | 14 | NDA | 14.70 (4.00 to 20.00) | Low BMD | AL (n = 12) y PD (n = 2) | 1.90 (AL group) | NDA | AL: 35 mg po once a wk. (n = 12). PD: (single dose IV) (n = 2). |
NDA | Vitamin D supplements, glucocorticoids. |
| Schwartz et al. (2008) [58] | 13 | 9 (M) 4 (F) |
9.10 (2 to 17.41) | OI | NDA | 4.56 | NDA | NDA | NDA | NDA |
| Simm et al. (2011) [59] | 20 | 9 (M) 11 (F) |
9.60 (3.30 to 16.50) | Osteoporosis | ZD | 1.70 (0.50 to 2.00) | NDA | 1st dose: 0.0125 mg/kg. 2nd dose: (at 12 wk.): 0.025 mg/kg. Following dose: (12 wk. after the previous dose): 0.025 mg/kg. |
0.1 mg/kg per year on avg. | Calcium and vitamin D supplements. |
| Tessaris et al. (2016) [60] | 13 | 6 (M) 7 (F) |
20.30 (7.00 to 27.00) | Fibrous dysplasia, MAS. | PD | 2.50 | NDA | 1 mg/kg/day for 3 consecutive days (1 daily infusion) repeating at intervals of 4–6 mo. | NDA | NDA |
| Uday et al. (2018) [61] | 2 | 1 (M) 1 (F) |
14.85 (14.00 to 15.70) | CGCL | DS | 2.45 | 32.00 (18.00 to 46.00) | 120 mg on days 1, 8, 15, and 28. Then q4 wk. (2.1 and 2.6 mg/kg/dose, respectively). | 5520 and 2160 mg, respectively. | Corticosteroids, chemotherapy, and bisphosphonates were not administered to patients. |
| Vuorimies et al. (2011) [62] | 17 | 8 (M) 9 (F) | 10.10 (1.50 to 16.80) | OI | ZD | 1.90 (1.00 to 3.20) | NDA | 1 infusion q6 mo. at a dose of 0.05 mg/kg (maximum 4.0 mg daily). | NDA | Calcium and vitamin D supplements. |
| Wagner et al. (2011) [63] | 12 | 9 (M) 3 (F) |
10.84 (2.20 to 14.50) | Osteoporosis | PD | 1.00 | 4.16 (1.00 to 21.00) | Protocol of 1 or 3 days depending on the healthcare center. 1st day: 1 mg/kg (max. 30mg). 2nd day: (according to serum calcium) >2.2 mmol/L: 1 mg/kg (maximum 60 mg). Between 2 and 2.2 mmol/L: 0.5 mg/kg (maximum 30 mg). <2 mmol/L: no more infusions. It is repeated q3 mo. |
NDA | Calcium and Vitamin D supplements, acetaminophen, codeine and morphine. |
AAT: antiangiogenic; AFN: avascular femoral necrosis; AL: alendronate; approx.: approximate; ART: antiresorptive; Avg.: average; BMD: bone mineral density; CGCL: central giant-cell lesion; DS: denosumab; F: female; IB: ibandronate; IV: intravenous; M: male; MAS: McCune-Albright syndrome; max.: maximum; mo.: month(s); ND: neridronate; NDA: No data available; OI: osteogenesis imperfecta; PD: pamidronate; po: per os (by mouth); pts.: patient(s); q: every; SC: subcutaneous; tx.: treatment; wk.: week(s); yr.: year(s); ZD: zoledronate.