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Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients
Wei Zhou1, Jeroen Gj van Rooij1, Denise M van de Laarschot1
1Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Abstract:
Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Insights
Atypical femur fractures (AFFs) are linked to monogenic bone disorders, especially in patients showing symptoms. Genetic testing revealed pathogenic variants in 15% of AFF patients, highlighting the need for clinical evaluation.
Area of Science:
- Genetics
- Orthopedics
- Endocrinology
Background:
- Atypical femur fractures (AFFs) are rare but associated with bisphosphonate use.
- AFFs have also been observed in patients with monogenic bone disorders, independent of bisphosphonate treatment.
- The precise link between AFFs and monogenic bone disorders remains unclear.
Purpose of the Study:
- To investigate the prevalence of monogenic bone disorders in a cohort of Dutch patients diagnosed with AFFs.
- To identify genetic underpinnings contributing to AFFs in this cohort.
Main Methods:
- Recruitment of AFF patients from two Dutch specialist bone centers.
- Review of medical records for clinical indicators of monogenic bone disorders.
- Whole-exome sequencing of 37 candidate genes and analysis of copy number variations.
- Classification of genetic variants using ACMG guidelines.
Main Results:
- The cohort included 60 AFF patients; 95% had used bisphosphonates.
- Fifteen percent (15%) of AFF patients exhibited clinical features suggestive of monogenic bone disorders.
- Eight patients (54% of those with clinical suspicion) carried pathogenic variants in genes like PLS3, COL1A2, LRP5, or ALPL.
- Overall, 15% of the AFF cohort had a pathogenic variant, including one with a TENT5A deletion.
Conclusions:
- A significant association exists between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, especially in symptomatic individuals.
- Genetic testing in AFF patients with clinical suspicion yields a high rate of pathogenic variants, underscoring the importance of thorough clinical assessment.
- While bisphosphonate use's role is uncertain, these findings are crucial for managing patients with AFFs.
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