Table 3.
Previous reports for medication-related osteonecrosis of the jaw (ONJ), cancer, and death. (A) Medication-Related Osteonecrosis of the Jaw (ONJ), (B) Cancer, (C) Death.
| A. Medication-Related Osteonecrosis of the Jaw (ONJ) | |||
|---|---|---|---|
| Study | Treatment | Total Number (Incidence) |
Follow Up |
| Watts, N. B. 2019 (7-Year FREEDOM extension) |
Denosumab (3 + 7 yrs) a Placebo (3 yrs)/Denosumab (7 yrs) |
2343 (7)
b 2207 (6) |
10 years 10 years |
| Kendler, D.L. 2018 | Teriparatide Risedronate (BP) |
680 (0) 680 (0) |
24 months 24 months |
| Saag, K.G. 2017 | Romosozumab (mAb) Alendronate (BP) |
2040 (0) 2014 (0) |
1 year 1 year |
| Cosman, F. 2016 | Romosozumab (mAb) Placebo Romosozumab to Denosumab c Placebo to Denosumab |
3581 (1) 3576 (0) 3581 (2) 3576 (1) |
12 months 12 months 24 months 24 months |
| Cummings, S.R. 2009 (FREEDOM study) |
Denosumab (mAb) Placebo |
3902 (0) 3906 (0) |
36 months 36 months |
| B. Cancer | |||
| Study | Intervention | Type of Cancers | Number of Events (Percentage of Events, %) |
| (Saag, K. G. et al. 2017) | SC 210mg Romosozumab QM for 12 M Oral 70 mg Alendronate QW for 12 M |
All cancers | Romosozumab group: 31 (1.5) Alendronate group: 28 (1.4) |
| (Cosman, F. et al. 2016) | SC 210 mg Romosozumab QM for 12 M Placebo |
All cancers | Romosozumab group: 59 (1.6) Placebo group: 69 (1.9) |
| (Palacios, S. et al. 2015) | Oral 20 mg Bazedoxifene daily for 7 yrs Placebo |
Breast cancer | Bazedoxifene group: 23 (0.6) Placebo group: 11 (0.6) |
| (LaCroix, A. Z. et al. 2010) | Oral 0.5 mg Lasofoxifene daily for 5 yrs Placebo |
Breast cancer | Lasofoxifene group: 5 (0.41) Placebo group: 24 (1.97) |
| (Christiansen, C. et al. 2010) | Oral 20 mg Bazedoxifene daily for 3 yrs Oral 60 mg Raloxifene daily for 3 yrs Placebo |
Breast cancer | Bazedoxifene group: 6 (0.3) Raloxifene group: 7 (0.4) Placebo group: 8 (0.4) |
| (Cummings, S. R. et al. 2009) | SC 60 mg Denosumab Q6 M for 36 M Placebo |
All cancers | Denosumab group: 187 (4.8) Placebo group: 166 (4.3) |
| (Martino, S. et al. 2005) | Oral 60 mg Raloxifene daily for 8 yrs Placebo |
All cancers (excluding non-melanoma skin cancer) | Raloxifene group: 156 (5.7) Placebo group: 110 (8.6) |
| (Barrett-Connor, E. et al. 2004) | Oral 60 or 120 mg Raloxifene daily for 4 yrs Placebo |
Invasive breast cancer, endometrial cancer | Invasive breast cancer Raloxifene group: 17 (0.1) Placebo group: 35 (0.4) Endometrial cancer Raloxifene group: 7 (0.04) Placebo group: 5 (0.06) |
| (Martino, S. et al. 2004) | Oral 60 mg Raloxifene daily for 8 yrs Placebo |
Breast cancers | Raloxifene group: 31 (0.9) Placebo group: 30 (1.8) |
| (Reginster, J. Y. et al. 2000) | Oral 5 mg Risedronate daily for 1 yr Placebo |
All cancers | Risedronate group: 19 (4.7) Placebo group: 17 (4.2) |
| C. Death | |||
| Study | Intervention | Reasons of Death | Number of Events (Percentage of Events, %) |
| (Kendler, D. L. et al. 2018) | SC 20 ug Teriparatide daily for 24 M Oral 35 mg Risedronate weekly for 24 M |
N/A (1) | Teriparatide group: 15 (2.2) Risedronate group: 7 (1.0) |
| (Koh, J. M. et al. 2016) | SC 60 mg Denosumab Q6 M for 6 M Placebo |
Traumatic subdural hemorrhage due to motorcycle accident | Denosumab group: 1 (1) Placebo group: 0 (0) |
| (Cosman, F. et al. 2016) | SC 210 mg Romosozumab QM for 12 M Placebo |
Romosozumab: 17 from Cardiovascular causes Placebo: 15 from Cardiovascular causes |
Romosozumab group: 23 (0.6) Placebo group: 29 (0.8) |
| (Miller, P. D. et al. 2016) | SC 80 ug Abaloparatide daily for 1 yr SC 20 ug Teriparatide daily for 1 yr Placebo |
Abaloparatide: sepsis, bronchiectasis, ischemic heart disease Teriparatide: pancreatic cancer, general health deterioration, cardiorespiratory arrest Placebo: bowel cancer, intestinal obstruction, myocardial infarction, dissecting aneurysm of the aorta, sudden death |
Abaloparatide group: 3 (0.4) Teriparatide group: 3 (0.4) Placebo group: 5 (0.6) |
| (Palacios, S. et al. 2015) | Oral 20 mg Bazedoxifene daily for 7 yrs Placebo |
N/A (2) | Bazedoxifene group: 52 (1.4) Placebo group: 18 (1.0) |
| (Cummings, S. R. et al. 2010) | Oral 0.25 mg Lasofoxifene daily for 5 yrs Placebo |
Lasofoxifene: 34 from cancers Placebo: 20 from cancers |
Lasofoxifene group: 90 (3.2) Placebo group: 65 (2.3) |
| (Cummings, S. R. et al. 2009) | SC 60 mg Denosumab Q6 M for 36 M Placebo |
N/A | Denosumab group: 70 (1.8) Placebo group: 90 (2.3) |
| (Black, D. M. et al. 2007) | IV (15 min) 5 mg Zoldronic acid yearly for 3 yrs Placebo |
Zoldronic acid: 20 from stroke; 39 from cardiovascular causes Placebo: 11 from stroke; 33 from cardiovascular causes |
Zoldronic acid group: 130 (3.4) Placebo group: 112 (2.9) |
| (Martino, S. et al. 2005) | Oral 60 mg Raloxifene daily for 8 yrs Placebo |
N/A | Raloxifene group: 47 (1.7) Placebo group: 29 (2.3) |
| (Boonen, S. et al. 2004) | Oral 5 mg Risedronate daily for 3 yrs Placebo |
N/A | Risedronate group: 40 (5.7) Placebo group: 49 (7.1) |
a Ten-year treatment with denosumab in long-term group compared with three-year placebo and subsequently seven-year denosumab in crossover patients. b There were no reported cases of ONJ in the 3-year FREEDOM study. During the FREEDOM extension, there were 7 in long-term patients and 6 in crossover patients. c During open-label period, each patient was administrated denosumab subcutaneously every 6 months for additional 12 months. (1) The author considered that all deaths were unrelated to study drug. (2) The reasons of death were not defined in the 7-year dataset. However, previous 5-year follow-up study from de Villers, T. J. et al. 2011 summarized that 7 patients died from cardiovascular causes, 9 from oncology, 6 from others, 2 from unknown reason in Bazedoxifene group; while in placebo group, 6 died from cardiovascular causes, 5 from oncology, 1 from other, and 1 from unknown reason. Abbreviation: BP, bisphosphate; mAb, monoclonal antibody; Yr, year; SC: subcutaneously; QM: once a month; QW: once a week; Q6 M: every 6 months; yr: year; N/A, not available; SC, subcutaneously; QM, once a month; Q6 M, every 6 months; IV, intravenously.