Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database
Abstract
:1. Introduction
2. Results
2.1. Construction of Data Analysis Tables
2.2. Sites of Drug-Induced Fractures
2.3. Association between Patient Characteristics and Drug-Induced Fractures
2.4. Association between Drug Use and Drug-Induced Fractures
2.5. Independent Risk Factors for Drug-Induced Fracture by Multiple Logistic Regression Analysis
2.6. Association between Drug Use and the Drug-Induced Fracture Site by Principal Component Analysis
3. Discussion
3.1. Drug-Induced Fracture Sites
3.2. Risk Factors for Drug-Induced Fractures
3.3. Association between Drug Use and the Drug-Induced Fracture Site
3.4. Limitations
4. Materials and Methods
4.1. JADER Database and the Selection of Data for Analysis
4.2. Association between Patient Characteristics and Drug-Induced Fracture by Single Regression Analysis
4.3. Association between Drug Use and Drug-Induced Fractures by Single Regression Analysis
4.4. Associated between Patient Characteristics and Drug-Induced Fracture by Multiple Logistic Regression Analysis
4.5. Association between Drug Use and Drug-Induced Fracture Site by Principal Component Analysis
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Adverse Event | Reporting Times | Reporting Ratio (%) |
---|---|---|
Atypical femur fracture | 1653 | 17.3% |
Fracture | 1550 | 16.3% |
Femur fracture | 1366 | 14.3% |
Spinal compression fracture | 1059 | 11.1% |
Femoral neck fracture | 619 | 6.5% |
Compression fracture | 355 | 3.7% |
Rib fracture | 261 | 2.7% |
Lumbar vertebral fracture | 217 | 2.3% |
Humerus fracture | 199 | 2.1% |
Pelvic fracture | 197 | 2.1% |
Spinal fracture | 142 | 1.5% |
Pathological fracture | 129 | 1.4% |
Radius fracture | 128 | 1.3% |
Foot fracture | 113 | 1.2% |
Atypical fracture | 111 | 1.2% |
Upper limb fracture | 106 | 1.1% |
Jaw fracture | 92 | 1.0% |
Osteoporotic fracture | 79 | 0.8% |
Lower limb fracture | 76 | 0.8% |
Tibia fracture | 76 | 0.8% |
Cervical vertebral fracture | 74 | 0.8% |
Ulna fracture | 74 | 0.8% |
Clavicle fracture | 67 | 0.7% |
Ankle fracture | 67 | 0.7% |
Thoracic vertebral fracture | 66 | 0.7% |
Hip fracture | 64 | 0.7% |
Facial bones fracture | 60 | 0.6% |
Multiple fractures | 55 | 0.6% |
Hand fracture | 50 | 0.5% |
Wrist fracture | 37 | 0.4% |
Skull fracture | 37 | 0.4% |
Stress fracture | 36 | 0.4% |
Patella fracture | 36 | 0.4% |
Scapula fracture | 28 | 0.3% |
Fibula fracture | 28 | 0.3% |
Traumatic fracture | 27 | 0.3% |
Ilium fracture | 26 | 0.3% |
Sternal fracture | 22 | 0.2% |
Fractured sacrum | 18 | 0.2% |
Avulsion fracture | 16 | 0.2% |
Skull fractured base | 14 | 0.1% |
Comminuted fracture | 13 | 0.1% |
Fracture delayed union | 12 | 0.1% |
Forearm fracture | 11 | 0.1% |
Fracture nonunion | 9 | 0.1% |
Fracture pain | 8 | 0.1% |
Limb fracture | 8 | 0.1% |
Complicated fracture | 8 | 0.1% |
Open reduction of fracture | 6 | 0.1% |
Periprosthetic fracture | 6 | 0.1% |
Lisfranc fracture | 5 | 0.1% |
Internal fixation of fracture | 4 | <0.1% |
Open fracture | 3 | <0.1% |
Fractured coccyx | 3 | <0.1% |
Acetabulum fracture | 2 | <0.1% |
Epiphyseal fracture | 1 | <0.1% |
Sacroiliac fracture | 1 | <0.1% |
Fractured skull depressed | 1 | <0.1% |
Patient Characteristics | Drug-Induced Fracture (9531) | Non–Drug-Induced Fracture (1,675,323) | p-Value |
---|---|---|---|
Sex # (male; female) | 2530; 6533 (9063) | 837,777; 785,685 (1,623,462) | <0.001 ### |
Age † | 69.1 ± 17.4 (8239) | 59.5 ± 21.5 (1,565,208) | <0.001 *** |
Height (cm) † | 154.0 ± 12.6 (2369) | 157.2 ± 18.3 (703,033) | <0.001 *** |
Weight (kg) † | 52.1 ± 13.7 (2721) | 54.5 ± 16.3 (821,264) | <0.001 *** |
BMI † | 22.2 ± 4.5 (2286) | 21.9 ± 4.5 (680,578) | 0.010 ** |
Risk Factor | Drug Class | Odds Ratio | 95% Confidence Interval | p-Value |
---|---|---|---|---|
etidronic acid | drugs affecting bone structure and mineralization | 189.01 | 73.21–487.95 | <0.001 ** |
trientine | other alimentary tract and metabolism products | 164.48 | 19.57–1382.36 | <0.001 ** |
dolutegravir | direct acting antivirals | 151.14 | 63.90–357.50 | <0.001 ** |
abacavir | direct acting antivirals | 123.71 | 37.41–409.03 | <0.001 ** |
prednisolone sodium phosphate | corticosteroids | 106.92 | 12.67–902.28 | <0.001 ** |
alendronic acid | drugs affecting bone structure and mineralization | 78.13 | 66.18–92.25 | <0.001 ** |
adefovir dipivoxil | direct acting antivirals | 71.83 | 51.25–100.68 | <0.001 ** |
laninamivir | direct acting antivirals | 63.91 | 33.37–122.41 | <0.001 ** |
abacavir sulfate and lamivudine | direct acting antivirals | 60.8 | 18.93–195.25 | <0.001 ** |
minodronic acid hydrate | drugs affecting bone structure and mineralization | 59.15 | 44.62–78.41 | <0.001 ** |
risedronic acid | drugs affecting bone structure and mineralization | 59.14 | 46.46–75.29 | <0.001 ** |
radium (223Ra) dichloride | other therapeutic radiopharmaceuticals | 53.77 | 31.62–91.44 | <0.001 ** |
cepharanthine | isoquinoline alkaloids | 51.53 | 12.01–221.06 | <0.001 ** |
tetrabenazine | other nervous system drugs | 45.02 | 21.90–92.55 | <0.001 ** |
denosumab | drugs affecting bone structure and mineralization | 44.12 | 35.96–54.14 | <0.001 ** |
L-aspartate potassium | potassium | 40.9 | 17.75–94.25 | <0.001 ** |
nafarelin | hypothalamic hormones | 36.81 | 4.90–276.58 | 0.001 * |
ropinirole | dopaminergic agents | 33.28 | 14.49–76.42 | <0.001 ** |
lamivudine | direct acting antivirals | 33.03 | 18.86–57.86 | <0.001 ** |
ibandronic acid | drugs affecting bone structure and mineralization | 32.76 | 20.59–52.12 | <0.001 ** |
clostridium butyricum | antidiarrheal microorganisms | 30.21 | 14.05–64.95 | <0.001 ** |
interferon beta-1a | immunostimulants | 30.19 | 4.07–224.02 | 0.001 * |
anastrozole | hormone antagonists and related agents | 29.22 | 17.50–48.77 | <0.001 ** |
trelagliptin succinate | blood glucose lowering drugs, excl. insulins | 28.21 | 12.31–64.64 | <0.001 ** |
incadronate disodium hydrate | drugs affecting bone structure and mineralization | 27.8 | 6.63–116.61 | <0.001 ** |
emtricitabine and tenofovir disoproxil | direct acting antivirals | 26.95 | 3.68–197.42 | 0.001 * |
teneligliptin and canagliflozin | blood glucose lowering drugs, excl. insulins | 26.36 | 8.25–84.31 | <0.001 ** |
tafamidis | other nervous system drugs | 24.85 | 7.84–78.76 | <0.001 ** |
methylphenidate | psychostimulants, agents used for adhd and nootropics | 23.69 | 7.48–74.98 | <0.001 ** |
zoledronic acid | drugs affecting bone structure and mineralization | 23.67 | 18.27–30.67 | <0.001 ** |
romosozumab | drugs affecting bone structure and mineralization | 23.64 | 12.80–43.66 | <0.001 ** |
ritonavir | direct acting antivirals | 22.23 | 3.05–161.95 | 0.002 * |
calcium L-aspartate hydrate | calcium | 20.87 | 7.60–57.35 | <0.001 ** |
somatropin | anterior pituitary lobe hormones and analogues | 19.05 | 8.40–43.20 | <0.001 ** |
pamidronic acid | drugs affecting bone structure and mineralization | 18.98 | 10.05–35.85 | <0.001 ** |
etelcalcetide | anti-parathyroid agents | 18.95 | 6.98–51.44 | <0.001 ** |
exemestane | hormone antagonists and related agents | 16.66 | 7.80–35.57 | <0.001 ** |
memantine | anti-dementia drugs | 16.11 | 9.55–27.17 | <0.001 ** |
rasagiline | dopaminergic agents | 15.96 | 5.86–43.44 | <0.001 ** |
leuprorelin | hormones and related agents | 14.94 | 9.43–23.67 | <0.001 ** |
certolizumab pegol | immunosuppressants | 14.42 | 7.12–29.23 | <0.001 ** |
tofacitinib | immunosuppressants | 14.09 | 10.43–19.04 | <0.001 ** |
abiraterone | hormone antagonists and related agents | 14.05 | 7.68–25.71 | <0.001 ** |
tenofovir alafenamide | direct acting antivirals | 13.95 | 3.43–56.67 | <0.001 ** |
perampanel | antiepileptics | 13.87 | 3.41–56.45 | <0.001 ** |
methylprednisolone | corticosteroids | 13.55 | 8.83–20.80 | <0.001 ** |
teriparatide | parathyroid hormones and analogues | 13.36 | 5.90–30.25 | <0.001 ** |
goserelin | hormones and related agents | 13.22 | 5.88–29.75 | <0.001 ** |
paliperidone | antipsychotics | 12.61 | 4.67–34.01 | <0.001 ** |
entacapone | dopaminergic agents | 12.6 | 4.00–39.70 | <0.001 ** |
letrozole | hormone antagonists and related agents | 12.43 | 6.38–24.23 | <0.001 ** |
tramadol | opioids | 12.29 | 6.32–23.91 | <0.001 ** |
raloxifene | other sex hormones and modulators of the genital system | 11.99 | 6.71–21.41 | <0.001 ** |
eszopiclone | hypnotics and sedatives | 11.07 | 2.72–45.00 | 0.001 * |
istradefylline | other antiparkinson drugs | 11 | 2.70–44.75 | 0.001 * |
fluticasone furoate and vilanterol trifenatate | adrenergics, inhalants | 10.56 | 1.46–76.28 | 0.019 * |
zopiclone | hypnotics and sedatives | 10.17 | 4.52–22.87 | <0.001 ** |
aripiprazole hydrate | antipsychotics | 9.89 | 2.44–40.08 | 0.001 * |
suvorexant | hypnotics and sedatives | 9.75 | 4.01–23.69 | <0.001 ** |
hydrocortisone | corticosteroids | 8.79 | 2.17–35.60 | 0.002 * |
levodopa and benserazide hydrochloride | dopaminergic agents | 8.51 | 2.71–26.72 | <0.001 ** |
pioglitazone | blood glucose lowering drugs, excl. insulins | 8.43 | 5.19–13.70 | <0.001 ** |
rotigotine | dopaminergic agents | 8.34 | 1.15–60.30 | <0.001 ** |
alogliptin | blood glucose lowering drugs, excl. insulins | 8.13 | 3.84–17.22 | <0.001 ** |
golimumab | immunosuppressants | 8.09 | 4.75–13.78 | <0.001 ** |
prednisolone | corticosteroids | 8.08 | 6.73–9.70 | <0.001 ** |
pramipexole | dopaminergic agents | 7.93 | 3.27–19.23 | <0.001 ** |
enzalutamide | hormone antagonists and related agents | 7.64 | 3.78–15.42 | <0.001 ** |
teriparatide acetate | parathyroid hormones and analogues | 7.64 | 4.18–13.96 | <0.001 ** |
cinacalcet | anti-parathyroid agents | 6.9 | 2.20–21.63 | 0.001 * |
buprenorphine | opioids | 6.83 | 1.69–27.64 | 0.007 * |
salmeterol xinafoate and fluticasone propionate | corticosteroids | 6.64 | 1.65–26.78 | 0.008 * |
bazedoxifene | other sex hormones and modulators of the genital system | 6.57 | 2.09–20.62 | 0.001 * |
betamethasone | corticosteroids | 6.46 | 2.67–15.64 | <0.001 ** |
ledipasvir acetonate and sofosbuvir | direct acting antivirals | 6.41 | 2.86–14.40 | <0.001 ** |
eldecalcitol | vitamin a and d, incl. combinations of the two | 6.39 | 3.67–11.12 | <0.001 ** |
galantamine | anti-dementia drugs | 6.36 | 2.83–14.31 | <0.001 ** |
alprazolam | anxiolytics | 6.24 | 2.32–16.76 | <0.001 ** |
rivastigmine | anti-dementia drugs | 5.86 | 2.17–15.77 | 0.001 * |
zolpidem | hypnotics and sedatives | 5.85 | 3.02–11.31 | <0.001 ** |
urapidil | antiadrenergic agents, peripherally acting | 5.74 | 0.80–41.38 | 0.083 |
brotizolam | hypnotics and sedatives | 5.67 | 2.68–11.97 | <0.001 ** |
pregabalin | antiepileptics | 5.55 | 3.85–8.00 | <0.001 ** |
sofosbuvir | direct acting antivirals | 5 | 2.06–12.09 | <0.001 ** |
carbidopa hydrate and levodopa | dopaminergic agents | 4.29 | 1.38–13.41 | 0.012 * |
donepezil | anti-dementia drugs | 4.15 | 1.96–8.77 | <0.001 ** |
tramadol hydrochloride and acetaminophen | opioids | 3.85 | 1.59–9.31 | 0.003 * |
mirogabalin besylate | other analgesics and antipyretics | 3.77 | 0.53–27.07 | 0.187 |
darbepoetin alfa | other antianemic preparations | 3.75 | 1.40–10.04 | 0.009 * |
alfacalcidol | vitamin a and d, incl. combinations of the two | 3.48 | 1.30–9.34 | 0.013 * |
duloxetine | antidepressants | 3.09 | 1.28–7.47 | 0.012 * |
tocilizumab | immunosuppressants | 3.06 | 1.77–5.30 | <0.001 ** |
methoxy polyethylene glycol-epoetin beta | other antianemic preparations | 2.73 | 0.68–10.98 | 0.157 |
clozapine | antipsychotics | 2.34 | 0.58–9.41 | 0.23 |
ramelteon | hypnotics and sedatives | 2.32 | 0.32–16.57 | 0.402 |
aliskiren | other agents acting on the renin-angiotensin system | 2.28 | 0.32–16.31 | 0.41 |
paliperidone palmitate | antipsychotics | 2.27 | 0.32–16.17 | 0.414 |
abatacept | immunosuppressants | 2.25 | 0.72–7.02 | 0.161 |
quetiapine | antipsychotics | 1.89 | 0.61–5.87 | 0.274 |
mirabegron | urologicals | 1.64 | 0.23–11.72 | 0.62 |
etanercept | immunosuppressants | 1.56 | 0.74–3.29 | 0.24 |
ixazomib | other antineoplastic agents | 1.18 | 0.29–4.72 | 0.818 |
female | ― | 2.05 | 1.86–2.26 | <0.001 ** |
Unit Odds Ratio | ||||
Risk Factor | Odds Ratio | 95% Confidence Interval | p-Value | |
age | ― | 1.02 | 1.01–1.02 | <0.001 ** |
BMI | ― | 1.02 | 1.01–1.03 | <0.001 ** |
Range Odds Ratio | ||||
Risk Factor | Odds Ratio | 95% Confidence Interval | p-Value | |
age | ― | 5.59 | 4.21–7.43 | <0.001 ** |
BMI | ― | 5.49 | 2.64–11.45 | <0.001 ** |
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Toriumi, S.; Kobayashi, A.; Sueki, H.; Yamamoto, M.; Uesawa, Y. Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database. Pharmaceuticals 2021, 14, 1299. https://doi.org/10.3390/ph14121299
Toriumi S, Kobayashi A, Sueki H, Yamamoto M, Uesawa Y. Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database. Pharmaceuticals. 2021; 14(12):1299. https://doi.org/10.3390/ph14121299
Chicago/Turabian StyleToriumi, Shinya, Akinobu Kobayashi, Hitoshi Sueki, Munehiro Yamamoto, and Yoshihiro Uesawa. 2021. "Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database" Pharmaceuticals 14, no. 12: 1299. https://doi.org/10.3390/ph14121299