Atypical Femoral Fracture
Atypical femoral fracture (AFF) is a distinctive type of stress fracture that primarily affects the subtrochanteric region or femoral shaft. Unlike typical osteoporotic fractures, AFFs are characterized by a transverse or short oblique fracture pattern, often with a medial spike. While they are rare, they represent a significant clinical concern, particularly due to their association with long-term use of certain medications, such as bisphosphonates, which are commonly prescribed for osteoporosis. The underlying causes are multifactorial, involving a complex interplay of mechanical stress, bone material properties, bone geometry, and genetic predispositions.
Biological Basis
The biological underpinnings of atypical femoral fracture involve genetic factors that influence bone mineral density (BMD) and bone geometry, crucial determinants of bone strength. Low femoral neck bone mineral density (FN-BMD) is recognized as a strong causal factor for hip fractures. [1] Genome-wide association studies (GWAS) have identified numerous genetic loci associated with BMD and fracture risk. [2]
Specific genetic variants contribute to fracture susceptibility by affecting bone geometry and material properties. For instance, genetic variants in or near genes such as IRX1, ADAMTS16, FGFR4, NSD1, RAB24, LRP5, PPP6R3, and GAL have been associated with hip bone geometry parameters, including femoral neck length, narrowest width of the femoral neck, and femoral neck section modulus, which are all linked to fracture risk. [3] Bivariate genome-wide association analyses have further revealed genes with pleiotropic effects on femoral neck bone geometry. [4] Polymorphisms in genes like COL1A1, IGF1, TNFA, and ESR1 have been investigated for their associations with femoral neck geometry and fracture risk. [4]
Key genetic loci identified through meta-analyses include 56 loci associated with bone mineral density and 14 loci linked to fracture risk. [2] For example, rs7521902 and rs4792909 are secondary independent signals found to be associated with low-trauma fractures. [2] Whole-genome sequencing studies have also identified EN1 as a significant determinant of bone density and fracture. [5] Furthermore, research suggests the importance of pathways such as the EphrinA-EphR pathway for femoral neck bone geometry [4] and identifies candidate genes involved in monogenic syndromes with skeletal phenotypes or those acting as expression quantitative trait loci (eQTLs) within bone-active pathways. [2]
Clinical Relevance
Atypical femoral fractures hold significant clinical relevance, particularly in the context of osteoporosis management. Identifying individuals with a genetic predisposition to fractures, or those with specific at-risk bone geometries, could enable personalized treatment approaches and preventative strategies. This is critical for patients receiving long-term bisphosphonate therapy, where the risk of AFFs is increased. Clinical assessments for fracture risk often integrate factors such as age, sex, height, weight, and menopausal status. [5] Studies have also explored fracture risk in diverse populations, including African American women and childhood cancer survivors, highlighting the broad clinical implications of understanding fracture etiology across different demographic and medical backgrounds. [6] Enhanced understanding of the genetic factors influencing bone health can lead to improved diagnostic tools, risk stratification, and targeted interventions to mitigate the incidence of these severe fractures.
Social Importance
The social importance of addressing atypical femoral fractures is substantial due to their profound impact on public health and individual quality of life. Fractures, especially severe ones like hip fractures, are associated with considerable morbidity, a reduction in independence, and increased mortality rates, particularly among older adults. [1] By elucidating the genetic predispositions to AFFs, healthcare systems can implement more effective screening programs and preventive measures. This proactive approach can reduce the physical and psychological burden on affected individuals and their families, as well as alleviate the significant economic costs associated with fracture treatment, rehabilitation, and long-term care. Given the global demographic trend of an aging population and the widespread use of medications that influence bone metabolism, understanding and preventing AFFs is a crucial public health imperative.
Methodological and Statistical Constraints
Research into atypical femoral fracture is subject to various methodological and statistical constraints that can influence the interpretation of findings. While many studies involve large cohorts, limitations in sample size for specific outcomes or populations can reduce statistical power to detect subtle genetic effects or associations for less common fracture types [5]
Other variants are located within or near genes with established roles in cellular signaling and development. For instance, *rs11465606* is associated with _IL18R1_, a gene encoding a receptor for Interleukin-18, a cytokine that plays a role in inflammation and immune responses. Chronic inflammation is known to influence bone remodeling pathways, potentially leading to increased bone resorption and reduced bone formation, thereby contributing to weaker bones and a higher risk of fracture. The variant *rs145787127* is linked to _NTN1_ (Netrin-1), a protein important for cell guidance and migration during development, which also has roles in angiogenesis (blood vessel formation) and tissue repair, processes that are vital for bone healing and maintenance. Furthermore, *rs113093597* is associated with _LMX1A_, a transcription factor essential for the development of various tissues, including limbs and kidneys. Genetic changes in developmental genes can subtly alter skeletal formation or maintenance throughout life. Lastly, *rs12336042* is found near _TMEM38B_, a gene involved in regulating calcium release from the endoplasmic reticulum, a fundamental process for cellular signaling and proper function of bone cells. [1], [3] Variants also occur in genes related to metabolic processes and structural integrity. *rs73111385* is associated with _SNTN_ (Sarcospan), a protein primarily known for its role in muscle membrane stability and the dystrophin-glycoprotein complex. Given the direct mechanical interplay between muscle and bone, variations affecting muscle quality or function could indirectly influence skeletal loading and bone adaptation, potentially impacting susceptibility to stress fractures or atypical femoral fractures. The _PAH_ gene, associated with *rs147502517*, encodes phenylalanine hydroxylase, an enzyme critical for amino acid metabolism. While primarily linked to metabolic disorders like phenylketonuria, systemic metabolic imbalances can have profound effects on bone health, including bone mineral density and quality, making such variants relevant to overall skeletal resilience. [4], [7]
Causes of Atypical Femoral Fracture
Atypical femoral fractures (AFFs) arise from a complex interplay of genetic predispositions, environmental exposures, developmental influences, and various systemic health factors. Understanding these multifaceted causes is crucial for identifying individuals at risk and developing targeted prevention strategies.
Genetic Architecture of Femoral Strength
Genetic factors play a significant role in determining bone mineral density (BMD) and the structural integrity of the femur, thereby influencing fracture susceptibility. Genome-wide meta-analyses have identified numerous loci associated with BMD and fracture risk, including 56 BMD loci and 14 loci linked to fracture risk. [2] Specific genetic variants, such as rs7521902 and rs4792909, have been identified as independent signals associated with fracture risk. [2] Furthermore, studies have pinpointed genes like IRX1, ADAMTS16, FGFR4, NSD1, RAB24, LRP5, PPP6R3, and GAL as being in or near single nucleotide polymorphisms (SNPs) associated with hip bone geometry, which is a key determinant of bone strength. [3] The EphrinA-EphR pathway has also been implicated in femoral neck bone geometry, highlighting the importance of specific biological pathways in maintaining bone health. [4]
Beyond general bone density, particular gene polymorphisms have been directly associated with femoral neck geometry and fracture risk. For instance, variations in the COL1A1 and AHSG genes are linked to femoral neck bone geometric parameters, while an insulin-like growth factor I gene promoter polymorphism can influence hip bone geometry and the risk of non-vertebral fractures. [4] Polymorphisms in tumor necrosis factor-alpha and estrogen receptor alpha genes also demonstrate associations with bone strength phenotypes and the cross-sectional geometry of the femoral neck, respectively. [4] A genetically decreased femoral neck BMD (FN-BMD) is a strong causal factor for hip fractures, with a significant odds ratio per standard deviation decrease. [1] Novel genes such as MECOM have been identified as predisposing factors for osteoporotic fractures, and bivariate analyses suggest genes like SOX6 may influence both obesity and osteoporosis phenotypes in males, indicating pleiotropic effects on bone health. [6]
Environmental Modulators and Lifestyle Factors
Environmental and lifestyle factors significantly influence bone health and fracture risk, often modifying an individual's genetic predisposition. Age, height, and weight are fundamental physiological parameters that impact femoral bone geometry and are consistently adjusted for in bone-related genetic studies. [4] For example, femoral neck geometric parameters show differences based on age, sex, and race. [4] Lifestyle choices, such as alcohol consumption and the propensity for falls, are recognized as plausible causal risk factors for hip fractures, though their genetic instruments may be weak. [1]
Specific exposures and life events can also critically alter fracture risk. Childhood cancer survivors, for instance, exhibit sex- and therapy-specific fracture risks, pointing to the long-term effects of medical treatments. [8] Factors like premature menopause status are also considered relevant covariates in fracture risk assessments, underscoring the role of hormonal changes. [8] While direct dietary influences are not extensively detailed, the broader context of environmental exposures and their interaction with an individual's genetic makeup contributes to the overall risk profile for atypical femoral fractures.
Developmental Trajectories and Gene-Environment Dynamics
The interaction between an individual's genetic makeup and their environment, particularly during developmental stages, can profoundly shape bone health and influence the risk of atypical femoral fractures. Early life influences, though not explicitly detailed as epigenetic factors in the provided studies, are implicitly captured by the long-term effects of certain exposures. For example, childhood cancer survivors who received specific treatments, such as corticosteroids, intravenous (IV) or intrathecal (IT) methotrexate doses, and maximum tumor doses from radiotherapy to major body regions, show altered fracture risk. [8] These therapeutic exposures represent significant environmental triggers that interact with an individual's genetic background to modulate bone integrity over time.
This gene-environment dynamic highlights how a genetic predisposition to weaker bone structure can be exacerbated or mitigated by external factors throughout life. The observed sex- and therapy-specific fracture risk effects in childhood cancer survivors are a clear example of this interaction, where the genetic susceptibility of the individual is influenced by the specific medical interventions received. [8] Such interactions underscore that fracture risk is not solely determined by inherited traits but is also a consequence of the ongoing dialogue between genes and the environment, influencing bone development and remodeling.
Systemic Health and Therapeutic Agents
Atypical femoral fractures can also be influenced by broader systemic health conditions and the long-term use of certain medications. Several comorbidities have been identified as plausible causal risk factors for hip fractures, including Alzheimer’s disease, coronary heart disease, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and type 2 diabetes. [1] These conditions can impact bone metabolism, overall physical activity, or increase the risk of falls, thereby indirectly contributing to the likelihood of fracture.
Furthermore, pharmacological interventions, particularly those used for chronic conditions or intensive therapies, can have significant adverse effects on bone health. For instance, exposure to corticosteroids and various doses of methotrexate (intravenous and intrathecal) have been identified as treatments relevant to fracture risk, particularly in vulnerable populations such as childhood cancer survivors. [8] These medications can interfere with bone formation, increase bone resorption, or alter nutrient absorption, leading to compromised bone strength. Age-related changes are also a primary determinant of fracture risk, with studies consistently adjusting for age due to its profound impact on bone mineral density and geometry. [4]
Genetic Determinants of Femoral Bone Geometry and Density
Atypical femoral fractures are underpinned by complex genetic pathways that dictate bone structure and strength. Specific genes play crucial roles in shaping femoral neck bone geometry, including length, narrowest width, and section modulus, which are critical indicators of fracture resistance . [3], [4] Genes such as LRP5, PPP6R3, IRX1, ADAMTS16, RUNX1, FGFR4, NSD1, and RAB24 have been identified through genome-wide association studies for their influence on hip bone geometry. [3] Additionally, genetic variants in COL1A1 and EN1 are directly associated with femoral neck geometry and overall bone density, respectively, highlighting their fundamental roles in bone matrix composition and skeletal development . [5], [9], [10]
The regulation of these genes involves intricate molecular mechanisms. Epigenomic analyses, such as ATAC-seq on mouse embryonic proximal femora, have identified putative regulatory variants that influence proximal femur geometry, suggesting that non-coding regions play a significant role in gene expression relevant to bone structure. [3] Furthermore, expression quantitative trait loci (eQTLs) and genetically predicted gene expression (GPGE) offer insights into how genetic variants impact gene expression levels, which in turn affect bone phenotypes and fracture risk . [2], [6] These regulatory layers, including transcription factor regulation, orchestrate the precise development and maintenance of bone architecture, influencing its susceptibility to atypical fractures.
Receptor-Mediated Signaling in Bone Remodeling
Bone remodeling, a continuous process of bone formation and resorption, is tightly controlled by various receptor-mediated signaling pathways. The EphrinA-EphR pathway, for instance, has been identified as important for femoral neck bone geometry. [11] Its activation initiates intracellular signaling cascades that mediate cell-cell communication, differentiation, and migration of osteoblasts and osteoclasts, thereby regulating bone turnover and structural integrity. Disruptions in this pathway can lead to imbalances in bone remodeling, potentially contributing to weakened bone structure.
Other critical signaling molecules and their receptors also play pivotal roles in maintaining bone homeostasis. Polymorphisms within the promoter region of the Insulin-like Growth Factor I (IGF-I) gene have been linked to hip bone geometry and the risk of nonvertebral fractures [10] indicating its involvement in growth factor-mediated bone cell proliferation and matrix synthesis. Similarly, variants in the Tumor Necrosis Factor-alpha (TNF-α) gene are associated with bone strength phenotypes and fracture risk [12] reflecting its role in inflammatory responses and bone resorption. Furthermore, polymorphisms in the Estrogen receptor alpha (ERα) gene are associated with the cross-sectional geometry of the femoral neck, underscoring the profound influence of hormonal signaling on bone architecture and density. [13]
Metabolic and Hormonal Regulation of Bone Homeostasis
Metabolic pathways and hormonal regulation exert significant control over bone health and fracture susceptibility. The nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is central to lipid and glucose metabolism, and its disruption has been shown to increase the risk of osteonecrosis. [14] This highlights a mechanistic link between systemic metabolic regulation and localized bone pathology, suggesting that metabolic imbalances can compromise bone integrity. The SOX6 gene further exemplifies this metabolic connection, exhibiting pleiotropic effects that influence both obesity and osteoporosis phenotypes [4] demonstrating how shared genetic and metabolic pathways can impact multiple physiological systems, including the skeleton.
Hormonal influences are equally crucial for bone development and maintenance. Age at menarche, which correlates with the duration and exposure to sex steroids, is significantly associated with femoral neck bone geometry . [4], [15] Sex steroids play a vital role in bone structural adaptation to mechanical loading and overall bone mass acquisition during growth and maintenance throughout adulthood. [4] Therefore, variations in hormonal profiles and their regulatory mechanisms can alter bone density and geometry, ultimately affecting fracture risk. These complex interactions underscore how metabolic flux control and endocrine signals are integrated at a systems level to modulate bone composition and resilience.
Systems-Level Dysregulation and Atypical Fracture Pathogenesis
Atypical femoral fractures (AFFs), particularly those associated with bisphosphonate use, represent a significant clinical challenge stemming from complex systems-level dysregulation rather than a single molecular defect. [16] Genetically decreased femoral neck bone mineral density (FN-BMD) has been causally linked to an increased risk of hip fractures [1] illustrating how genetic predispositions can manifest as an emergent property of fragility at the whole bone level. This causal relationship highlights the importance of integrating genetic susceptibility with environmental and pharmacological factors to understand fracture pathogenesis.
Pathway crosstalk and network interactions are critical in the development of AFFs. The identification of the MECOM gene as a novel predisposing factor for osteoporotic fracture further emphasizes the intricate genetic network contributing to skeletal resilience. [6] The concept of "bone active pathways," where multiple candidate genes contribute to overall bone health, suggests that AFFs may arise from a confluence of subtle dysregulations across several interacting molecular pathways. [2] These include altered energy metabolism, compromised biosynthesis, and impaired catabolism, leading to a breakdown in compensatory mechanisms. Understanding this hierarchical regulation and the broader biological significance of pathway dysregulation is crucial for identifying effective therapeutic targets and developing strategies to mitigate atypical fracture risk.
Pharmacogenetics of Atypical Femoral Fracture
Atypical femoral fractures, while multifactorial in etiology, are increasingly recognized to have a significant pharmacogenetic component, influencing both an individual's susceptibility and their response to therapeutic interventions. Understanding these genetic predispositions can guide personalized treatment strategies and mitigate adverse drug reactions.
Genetic Influences on Drug Metabolism and Bone Toxicity
Variants in genes encoding drug-metabolizing enzymes can significantly alter an individual's susceptibility to drug-induced bone adverse effects, including osteonecrosis. For instance, polymorphisms in alcohol metabolizing enzyme genes have been linked to an increased risk of avascular necrosis of the hip joint in alcoholic individuals, particularly within specific populations. [17] This highlights how genetic differences in metabolic pathways can lead to altered drug pharmacokinetics, resulting in higher systemic exposure to toxic metabolites or parent compounds that adversely affect bone health. Similarly, glucocorticoids, widely used medications, are a known risk factor for osteonecrosis, with studies identifying genetic risk factors for glucocorticoid-associated osteonecrosis in patients treated for acute lymphoblastic leukemia. [18] These genetic variations may affect how glucocorticoids are processed or how bone cells respond to their presence, leading to impaired bone repair or increased cell death.
The impact of drug exposure on bone health can also be profoundly modified by genetic factors influencing the body's response to specific therapies. For example, chemotherapy regimens, including corticosteroids and methotrexate, have been shown to modify fracture risk in childhood cancer survivors in a sex- and therapy-specific manner, suggesting underlying genetic susceptibilities influence treatment outcomes. [8] While the precise metabolic pathways for all these drugs in relation to bone are complex, the overall pharmacodynamic effect, where genetic variants alter the cellular and tissue response to a drug, is critical. The disruption in peroxisome proliferator-activated receptor-γ (PPARG) has been linked to increased osteonecrosis risk through both genetic variance and pharmacologic modulation, suggesting that drugs interacting with this pathway could have varied effects based on an individual's PPARG genotype. [14]
Polymorphisms Affecting Drug Targets and Bone Integrity
Genetic variations in drug target genes or genes critical for bone homeostasis play a crucial role in determining an individual's baseline bone integrity and their response to bone-modifying agents. Polymorphisms in genes such as COL1A1 (collagen type I alpha 1), ESR1 (estrogen receptor alpha), IGF-1 (insulin-like growth factor I), and TNF-alpha (tumor necrosis factor-alpha) have been associated with variations in femoral neck bone geometry and the risk of nonvertebral fracture. [4] These genes encode proteins that are fundamental to bone matrix formation, bone cell signaling, and inflammatory responses, all of which can be modulated by therapeutic agents. For instance, ESR1 variants could alter the efficacy of estrogen-based therapies or selective estrogen receptor modulators (SERMs) in maintaining bone mineral density and preventing fractures.
Furthermore, several genes identified through genome-wide association studies (GWAS) are directly involved in bone development, metabolism, or structural integrity and may represent potential drug targets or modifiers of therapeutic response. Loci near genes like IRX1, ADAMTS16, FGFR4, NSD1, RAB24, LRP5, PPP6R3, and GAL have been associated with hip bone geometry and fracture risk. [3] Variations in genes like LRP5 (low-density lipoprotein receptor-related protein 5), a key regulator of bone mass, could influence the effectiveness of drugs that target the Wnt/β-catenin signaling pathway. Similarly, the MECOM gene has been identified as a novel predisposing factor for osteoporotic fracture, indicating its potential role as a therapeutic target or a marker for personalized fracture risk assessment. [6] These genetic variants influence the pharmacodynamic profile of numerous bone-active drugs, dictating individual responses to anti-resorptive or anabolic treatments.
Personalized Risk Stratification and Therapeutic Guidance
Integrating pharmacogenetic insights into clinical practice offers a pathway to more personalized and effective management of atypical femoral fractures. Identifying genetic predispositions, such as those related to glucocorticoid-induced osteonecrosis or alcohol metabolism, allows for proactive risk stratification and tailored preventative strategies. [18] For patients at high genetic risk, alternative therapies could be considered, or more intensive monitoring for bone adverse effects could be implemented. This personalized approach extends to drug selection, where knowledge of genetic variants in drug targets like PPARG or ESR1 can guide the choice of medication to optimize efficacy and minimize adverse reactions, as seen with Stanozolol therapy for idiopathic osteonecrosis. [14]
The concept of genetically predicted gene expression (GPGE) offers a powerful tool for personalized prescribing, suggesting that genetic variants influencing gene expression levels can predict fracture risk and potentially guide treatment decisions. [6] This approach moves beyond single SNP associations to consider the functional impact of genetic variation on gene activity, providing a more comprehensive understanding of individual susceptibility. While specific clinical guidelines for atypical femoral fracture based on pharmacogenetic profiles are still evolving, the evidence supports a future where genetic testing will inform dosing recommendations, drug selection, and overall treatment planning to enhance patient safety and therapeutic outcomes for this complex condition.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs7729897 | RNU7-156P - MIR5197 | atypical femoral fracture |
| rs11465606 | IL18R1 | atypical femoral fracture |
| rs145787127 | NTN1 | atypical femoral fracture |
| rs144094653 | RNA5SP359 - TUBB8P5 | atypical femoral fracture |
| rs73111385 | SNTN | atypical femoral fracture |
| rs113093597 | RNU6-755P - LMX1A | atypical femoral fracture |
| rs191328328 | HAND2-AS1 | atypical femoral fracture |
| rs12336042 | TMEM38B | atypical femoral fracture |
| rs147502517 | PAH | serum alanine aminotransferase amount atypical femoral fracture |
| rs72698961 | TCL1A - TUNAR | atypical femoral fracture |
Frequently Asked Questions About Atypical Femoral Fracture
These questions address the most important and specific aspects of atypical femoral fracture based on current genetic research.
1. I take bone medication; am I at higher risk for this fracture?
Yes, long-term use of certain medications, particularly bisphosphonates, is a known factor that increases your risk for atypical femoral fractures. Understanding your genetic predisposition and bone geometry can help tailor preventative strategies while you are on these important treatments.
2. My mom broke her hip easily. Will I too?
Your family history can play a role, as genetic factors influence bone mineral density and bone geometry, both crucial for bone strength. Genes like COL1A1 or LRP5 are examples that have been studied for their association with bone strength and fracture risk.
3. Can exercising the wrong way cause these unusual fractures?
Atypical femoral fractures are a type of stress fracture, meaning mechanical stress is a factor. While the article focuses on genetics and medication, your bone's unique geometry, which is influenced by genes like IRX1 or FGFR4, might make it more susceptible to certain types of stress.
4. Why do my bones seem weaker than my friends' even if we're similar?
It's possible your genetics contribute to differences in your bone mineral density and bone geometry, making your bones inherently less strong. Genome-wide studies have identified numerous genetic loci, including EN1, that are significant determinants of bone density and fracture risk.
5. Does my ethnic background affect my risk for these fractures?
Yes, research suggests that fracture risk can vary across diverse populations, including African American women, indicating that your ethnic background may influence your specific genetic risk factors for fractures. This highlights the importance of personalized risk assessment.
6. Is there a test to see if I'm prone to these specific breaks?
While not routinely available as a single test, understanding your genetic predispositions and bone geometry could enable more personalized risk assessment. Scientists are identifying specific genetic variants and pathways, like the EphrinA-EphR pathway, that influence hip bone geometry and fracture risk.
7. Can I do anything daily to prevent these unusual fractures?
Understanding your genetic predisposition and bone geometry can help. While the article doesn't detail specific daily actions, knowing your risk allows doctors to personalize treatment and prevention, especially if you're on medications like bisphosphonates.
8. I'm getting older; do my genes make these fractures more likely?
As you age, your risk for fractures generally increases, and your genetic makeup can influence how your bones respond over time. Genetic variants associated with bone mineral density and geometry, such as those near ADAMTS16 or NSD1, contribute to your overall fracture susceptibility throughout life.
9. Why do some people get these rare fractures, but others don't?
It's a complex interplay of factors, but genetics play a significant role in determining individual susceptibility. Specific genetic variants affect bone material properties and geometry, making some people more prone to these distinctive stress fractures than others, even under similar conditions.
10. Does my bone shape make me more likely to get an atypical fracture?
Yes, absolutely. Your hip bone geometry, including factors like femoral neck length and narrowest width, is strongly linked to fracture risk. Genetic variants in genes like RAB24 or GAL have been specifically associated with these crucial bone geometry parameters.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
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[3] Hsu YH, et al. "Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry." J Bone Miner Res, 2019.
[4] Ran S, et al. "Bivariate genome-wide association analyses identified genes with pleiotropic effects for femoral neck bone geometry and age at menarche." PLoS One, 2013.
[5] Zheng HF, et al. "Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture." Nature, 2015.
[6] Taylor, K. C., et al. "A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women." Bone Rep, vol. 6, 2017, pp. 147–154.
[7] Styrkarsdottir U, et al. "GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures." Nat Commun, 2019.
[8] Im, C et al. "Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors." J Bone Miner Res, vol. 36, no. 4, 2021, pp. 696-708.
[9] Jiang, H., Lei, S. F., Xiao, S. M., Chen, Y., Sun, X., et al. "Association and linkage analysis of COL1A1 and AHSG gene polymorphisms with femoral neck bone geometric parameters in both Caucasian and Chinese nuclear families." Acta Pharmacol Sin, vol. 28, no. 3, 2007, pp. 375–381.
[10] Rivadeneira, F., Houwing-Duistermaat, J. J., Beck, T. J., Janssen, J. A., Hofman, A., et al. "The influence of an insulin-like growth factor I gene promoter polymorphism on hip bone geometry and the risk of nonvertebral fracture in the elderly: the Rotterdam Study." J Bone Miner Res, vol. 19, no. 8, 2004, pp. 1280–1290.
[11] Chen, Y., Xiong, D. H., Guo, Y. F., Pan, F., Zhou, Q., et al. "Pathway-based genome-wide association analysis identified the importance of EphrinA-EphR pathway for femoral neck bone geometry." Bone, vol. 46, no. 1, 2010, pp. 129–136.
[12] Moffett, S. P., Zmuda, J. M., Oakley, J. I., Beck, T. J., Cauley, J. A., et al. "Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women." J Clin Endocrinol Metab, vol. 90, no. 6, 2005, pp. 3491–3497.
[13] Xiong, D. H., Liu, Y. Z., Peng, Y. L., Zhao, L. J., Deng, H. W. "Association analysis of estrogen receptor alpha gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families." Osteoporos Int, vol. 16, no. 12, 2005, pp. 2113–2120.
[14] Wyles, C. C., et al. "CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor-γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation." Clin Orthop Relat Res, vol. 477, no. 8, 2019, pp. 1775-1785.
[15] Onland-Moret, N. C., Peeters, P. H., van Gils, C. H., Clavel-Chapelon, F., Key, T., et al. "Age at menarche in relation to adult height: The EPIC study." Am J Epidemiol, vol. 162, 2005, pp. 623–632.
[16] Kharazmi, M., et al. "A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture." Calcif Tissue Int, vol. 105, no. 1, 2019, pp. 10-18.
[17] Chao, YC et al. "Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver." Alcohol Alcohol, 2003.
[18] Karol, SE et al. "Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia." Blood, 2015.