Table 1. Adverse effects of bisphosphonate drugs in women with breast cancer.
| Outcome | Treatment | Odds ratio from network meta-analysis | No. studies forming basis of network meta-analysis odds ratio (total n) | Odds ratio from direct comparisons | Direct comparison studies (total n) | Number of women (out of 100) who would be expected to experience the outcome. Taking treatment: | ‘serious’ or Grade 3+ (absolute figures) | |
|---|---|---|---|---|---|---|---|---|
| NO | YES | |||||||
| ‘Influenza-like symptoms’ * | Any bisphosphonate | 16.09 (2.04,207.85) | 12 (9,968) | 22.18 (2.98, 164.89) | 7 (1,142) | 3 | 37 (7–88) | 5% (35/718) |
| Fever | Zoledronic acid | 5.2 (2.88,8.79) | 31 (25,388) | 4.06 (3.06–5.38) | 18 (10,581) | 1 | 6 (4–10) | 9% (82/933) |
| Pamidronate | 4.87 (1.9–12.62) | 31 (25,388) | 1.52 (0.47–4.92) | 2 (1,047) | 1 | 6 (2–14) | 100% (3/3) | |
| Chills | Zoledronic acid (no direct data for other drugs) | 15.19 (3.96,94.86) | 8 (10,368) | 8.55 (2.26, 32.32) | 7 (4,581) | 2 | 26 (8–68) | 1% (3/213) |
| Headache | Zoledronic acid | 1.48 (1.06, 2.25) | 28 (24,733) | 1.19 (1.02, 1.4) | 15 (9,354) | 24 | 32 (25–41) | 3% (36/1304) |
| Arthralgia/joint pain | Nitrogenous bisphosphonate | 1.54 (1.28, 1.86) | 31 (21,683) | 1.53 (1.29, 1.81) | 21 (7,376) | 17 | 24 (20–27) | 4% (189/5071) |
| Myalgia | Zoledronic acid | 2.36 (1.61, 3.6) | 23 (22,626) | 1.52 (1.31, 1.75) | 14 (8,158) | 3 | 8 (5–11) | 3% (47/1343) |
| * | Pamidronate | 2.32 (1.09, 5.21) | 23 (22,626) | 3 | 8 (4–16) | |||
| * | Oral ibandronate | 2.04 (1.13, 3.85) | 23 (22,626) | 1 (620) | 3 | 7 (4–12) | 6% (39/611) | |
| Stiffness* | Zoledronic acid (data not available for other drugs) | 2.76 (1.27, 5.83) | 3 (1,873) | 2.72 (1.46, 5.06) | 2 (971) | 2 | 4 (2–8) | 0% (0/37) |
| Hypertonia/muscle spasms | Zoledronic acid | 1.52 (0.93, 2.81) | 8 (4,613) | 1.53 (1.02, 2.3) | 7 (4,579) | 4 | 6 (4–11) | 14% (15/106) |
| Back pain | Nitrogenous bisphosphonate | 1.64 (1.08, 2.69) | 15 (12,076) | 1.54 (1, 2.37) | 9 (3,652) | 8 | 13 (9–19) | 3% (37/1247) |
| Increased bone pain in all patients | Any bisphosphonate | 1.79 (1.33, 2.49) | 31 (21,995) | 1.73 (1.47, 2.04) | 20 (10,646) | 11 | 19 (15–24) | 10% (352/3386) |
| Increased bone pain in patients with non-metastatic cancer | Any bisphosphonate | 1.53 (1.26,1.85) | 11 (5,984) | 11 | 16 (14–19) | |||
| Hypocalcaemia in all patients | Zoledronic acid | 7.28 (1.36,48.93) | 14 (16,853) | 7.07 (0.87, 57.56) | 5 (4,489) | 4 | 24 (6–68) | 3% (11/336) |
| Pamidronate | 3.18 (1.2, 8.64) | 14 (16,853) | 3.23 (1.45, 7.22) | 1 (294) | 4 | 12 (5–27) | ||
| Ibandronate | 6.15 (1.16,41.76) | 14 (16,853) | 2 (1,742) | 4 | 21 (5–64) | 2% (5/210) | ||
| Hypocalcaemia in patients with metastatic cancer | Any bisphosphonate | 2.14 (1.19,3.85) | 8 (2,689) | 4 | 9 (5–14) | |||
| Cardiac events (excluding congestive heart failure) | Nitrogenous bisphosphonate | 2.73 (1.33, 6.31) | 18 (20,236) | 2.51 (1.52, 4.17) | 11 (8,559) | 3 | 7 (4–15) | 62% (143/231) |
| Non-nitrogenous bisphosphonate (clodronate) | 4.35 (1.44, 13.6) | 18 (20,236) | 5.22 (0.25, 109.67) | 2 (3,517) | 3 | 11 (4–27) | 32% (21/65) | |
| Osteonecrosis of the jaw * | Nitrogenous bisphosphonate | 7.69 (2.31, 25.55) | 27 (26,018) 102 cases | |||||
| Periodontal disease * | Zoledronic acid (other drugs, with more evidence, not significant) | 10.2 (1.14,1322.28) | 2 (1803) only 16 events | 15.34 (0.87, 269.36) | 1 (903) | 14% (1/7) | ||
| Nausea * | Any bisphosphonate | 1.33 (1.11, 1.63) | 38 (25,049) | 1.21 (1.08, 1.35) | 27 (13,928) | 34 | 41 (37–46) | 9% (323/3579) |
| Abdominal pain | Any bisphosphonate | 1.51 (1.1, 2.11) | 24 (19,808) | 1.51 (1.13, 2.02) | 17 (10,165) | 13 | 19 (14–24) | 10% (122/1277) |
| Diarrhoea | Oral clodronate (also possibly true for others taken orally) | 1.81 (1.35, 2.74) | 27 (23,194) | 3.34 (1.18, 9.45) | 4 (4,759) | 11 | 18 (14–25) | 8% (49/591) |
| Vomiting | Clodronate | 1.67 (1.18, 2.92) | 22 (19,059) | 2 (1,242) | 19 | 28 (22–41) | 3% (9/312) | |
| Hepatotoxicity * | Oral ibandronate | 3.39 (1.13,11.73) | 10 (11,040) | 4.27 (1.28, 14.22) | 1 (2,800) | 26 | 55 (29–81) | 0% |
| Clodronate | 1.46 (0.78–2.59) | 10 (11,040) | 1.69 (1.05–2.71) | 3 (4,586) | 26 | 34 (22–48) | 15% (14/95) | |
| Dysgeusia | Zoledronic acid (evidence suggestive for others too) | 8.53 (1.25,119.8) | 4 (8,354) | 10.1 (1.17, 87.24) | 1 (301) | 0 | 1 (0–11) | |
| Neurosensory problems | Any bisphosphonate | 1.29 (1.05, 1.66) | 17 (19,922) | 1.23 (1.05, 1.45) | 13 (12,821) | 10 | 12(10–15) | 3% (52/1509) |
| Thromboembolic events | Zoledronic acid | 2.74 (0.98, 7.65) | 9 (14,865) | 3.18 (1.34, 7.51) | 2 | 5(2–14) | 72% (28/39) | |
| Ibandronate | 13.33 (2.43,73.09) | 2 (5,971) | 2 | 22 (5–60) | 91% (10/11) | |||
| * | Clodronate | 7.27 (1.41,33.44) | 12 (14,86) | 1 (3,235) | 2 | 13 (3–40) | 100% (27/27) | |
| Fatigue in all patients | Any bisphosphonate | 1.28 (1.06, 1.65) | 34 (25,914) | 1.13 (1.02, 1.26) | 23 (14,490) | 10 | 13 (11–16) | 5% (247/4607) |
| Fatigue in patients with metastatic cancer | Any bisphosphonate | 1.69 (1.24,2.29) | 5 (1,556) | 10 | 16 (12–21) | |||
| Infection * | Ibandronate (oral) | 22 (23,314) | 2.24 (1.18, 4.22) | |||||
| Additional findings from analysis of only 24 trials with the most comprehensive reporting of adverse events | ||||||||
| Neutropaenia | Nitrogenous bisphosphonate | 2.33 (1, 5.43) | 2.04 (0.7, 5.93) | 4 | 9 (4–19) | 5% (8/166) | ||
| Skin disorder | Any bisphosphonate | 1.48 (0.87, 2.44) | 1.61 (1.03, 2.48) | 5 | 7 (4–11) | 3% (37/1142) | ||
Adverse events (and treatments) for which either the direct comparison or the selected network meta-analysis model produced a practically and statistically significant treatment effect, defined as an odds ratio with a posterior median of 1.5 or greater and lower 95% credible limit greater than 1, or a risk difference with posterior median 0.02 or greater and a positive lower 95% credible limit. The odds ratio is the ratio of the odds of the event between the treatment group (as defined in the table) and an “observation only” control group.
* Finding not upheld when analysis run on only 24 trials with comprehensive adverse event reporting (reporting threshold <5% of patients suffering the event).
Colours represent subjective quality of evidence (green = highest, yellow = lower, red = lowest, based on replicability of results between full dataset and comprehensive reporting subset, subgroup analyses, and number of patients included in direct comparison trials).