Identification of Risk Factors for Bisphosphonate-Associated Atypical Femoral Fractures and Osteonecrosis of the Jaw in a Pharmacovigilance Database

Medication-related osteonecrosis of the jaw (MRONJ) is associated with many drugs, including bisphosphonates (BPs). BPs are associated with atypical femoral fractures and osteonecrosis of the external auditory canal. Thus, many drugs are reported to cause adverse effects on bone. This study aimed to investigate the effects of drugs and patient backgrounds regarding osteonecrosis-related side effects, including MRONJ. This study used a large voluntary reporting database, namely, the Japanese Adverse Drug Event Report database. First, we searched for risk factors related to MRONJ using volcano plots and logistic regression analysis. Next, we searched for bone-necrosis-related side effects using principal component and cluster analysis. Factors that were significantly associated with MRONJ included eight types of BPs and denosumab, prednisolone, sunitinib, eldecalcitol, raloxifene, letrozole, doxifluridine, exemestane, radium chloride, medroxyprogesterone, female, elderly, and short stature. Furthermore, antiresorptive agents (i.e., BPs and denosumab) tended to induce MRONJ and atypical femoral fractures by affecting osteoclasts. We believe these findings will help medical personnel manage the side effects of many medications.

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Evaluation of the nature and etiologies of risk factors for diaphyseal atypical femoral fractures

Medical Principles and Practice ◽

10.1159/000517484 ◽

2021 ◽

Author(s):

Hiroyuki Tsuchie ◽

Naohisa Miyakoshi ◽

Yuji Kasukawa ◽

Koji Nozaka ◽

Kimio Saito ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analyses ◽

Femoral Fractures ◽

Japanese Patients ◽

High Serum ◽

Control Group ◽

Atypical Femoral Fractures ◽

Factors Affecting ◽

Lateral Curvature ◽

Low Serum

Objectives: Differences in the mechanisms of subtrochanteric and diaphyseal atypical femoral fractures (AFFs) have been speculated in studies that have analyzed differences in the patients’ backgrounds. However, the etiologies of each type of AFF have not been investigated in detail. Therefore, this study aimed to investigate the nature and etiologies of the risk factors for diaphyseal AFFs. Materials and Methods: Eighty consecutive Japanese patients with 91 diaphyseal AFFs (the AFF group) and 110 age-matched female patients with osteoporosis (the non-AFF control group) were included. Their clinical data were compared and the factors affecting AFFs were investigated. Furthermore, the etiologies of the risk factors for diaphyseal AFFs were examined. Results: Multivariate analysis revealed that femoral serrated changes, bisphosphonate or denosumab usage, and lateral and anterior femoral curvatures were the risk factors for diaphyseal AFFs (p<0.0011, p=0.0137, and p<0.0001, respectively). Multivariate analyses also revealed that serrated changes and low serum 25(OH)D levels affected the lateral curvature (p=0.0088 and 0.0205, respectively), while serrated changes affected the anterior curvature (p=0.0006); each significantly affected the femoral curvature. In addition, a high serum calcium (Ca) level, lateral femoral curvature, and anterior femoral curvature were the predictors of serrated changes (p=0.0146, 0.0002, and 0.0098, respectively). Conclusion: The risk factors for diaphyseal AFFs were bone resorption inhibitor usage, a strong femoral curvature, and serrated changes. A low serum 25(OH)D level and serrated changes are the risk factors for lateral curvature, while a high serum Ca level is a risk factor for serrated changes.

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Medication-Induced Musculoskeletal Changes

Musculoskeletal Imaging Volume 2 ◽

10.1093/med/9780190938178.003.0118 ◽

2019 ◽

pp. 322-326

Author(s):

Winnie A. Mar

Keyword(s):

Musculoskeletal System ◽

Gold Standard ◽

Imaging Modality ◽

Femoral Fractures ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy ◽

Atypical Femoral Fractures ◽

Osteoblastic Activity ◽

Induced Changes

Chapter 117 discusses common medication-induced changes of the musculoskeletal system. The effect of corticosteroids on the musculoskeletal system, including osteoporosis and osteonecrosis, is discussed. Corticosteroids decrease osteoblastic activity, stimulate bone resorption, and decrease intestinal absorption of calcium. Complications of bisphosphonate therapy such as atypical femoral fractures and osteonecrosis of the jaw are reviewed. Myopathies and tendon pathologies are briefly discussed, as well as bony changes potentially seen with long-term voriconazole treatment. For osteoporosis, DXA scan is the gold standard, whereas radiography is usually the first imaging modality performed in patients on voriconazole therapy who present with pain.

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Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy

Bone ◽

10.1016/j.bone.2013.07.010 ◽

2013 ◽

Vol 56 (2) ◽

pp. 426-431 ◽

Cited By ~ 29

Author(s):

Paola Franceschetti ◽

Marta Bondanelli ◽

Gaetano Caruso ◽

Maria Rosaria Ambrosio ◽

Vincenzo Lorusso ◽

...

Keyword(s):

Risk Factors ◽

Femoral Fractures ◽

Bisphosphonate Therapy ◽

Atypical Femoral Fractures ◽

Oral Bisphosphonate

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Comment on Compston: Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Osteoporosis International ◽

10.1007/s00198-012-1905-1 ◽

2012 ◽

Vol 23 (12) ◽

pp. 2901-2902 ◽

Cited By ~ 3

Author(s):

K. Michaëlsson ◽

J. Schilcher ◽

P. Aspenberg

Keyword(s):

Femoral Fractures ◽

Osteonecrosis Of The Jaw ◽

Atypical Femoral Fractures

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Do bisphosphonate-related atypical femoral fractures and osteonecrosis of the jaw affect the same group of patients? A pilot study

Orthopedic Reviews ◽

10.4081/or.2014.5067 ◽

2014 ◽

Vol 6 (1) ◽

Cited By ~ 1

Author(s):

Haitham Afif ◽

Sebastian Mukka ◽

Göran Sjödén ◽

Arkan S. Sayed-Noor

Keyword(s):

Clinical Practice ◽

Pilot Study ◽

Femoral Fractures ◽

Osteonecrosis Of The Jaw ◽

Simultaneous Occurrence ◽

Limited Sample ◽

Atypical Femoral Fractures ◽

Limited Sample Size ◽

Dental Records

Bisphosphonates (BPs) are commonly used drugs in clinical practice. In this pilot study, we investigated whether bisphosphonate-related atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) occurred simultaneously in the same group of patients. Six ONJ patients were examined by an orthopedic surgeon and 5 AFF patients were examined by a dentist to look for manifestations of simultaneous occurrence of AFF in ONJ patients and <em>vice versa</em>. The required radiological investigations and previous medical and dental records were available. No simultaneous occurrence of AFF and ONJ was found in the examined patients. In this pilot study with limited sample size, no manifestations of simultaneous occurrence of AFF and ONJ were found. This could be an indication that these complications have different pathophysiologies and affect different subgroups of patients on long-term BP treatment.

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