Bone Quantitative Ultrasound

Bone quantitative ultrasound (QUS) is a non-invasive, non-ionizing technique used to assess bone properties related to strength and fracture risk. Unlike dual-energy X-ray absorptiometry (DXA), which primarily measures bone mineral density (BMD), QUS provides insights into bone microarchitecture, elasticity, and overall bone quality.^[1]Common QUS measurements include broadband ultrasound attenuation (BUA) and speed of sound (SOS), often performed at peripheral skeletal sites like the calcaneus (heel bone).^[1]These parameters are crucial for understanding bone health beyond just density.

Biological Basis

The biological basis of QUS lies in the interaction of ultrasound waves with bone tissue. As ultrasound waves pass through bone, their speed and attenuation are affected by the bone’s density, structure, and material properties. Speed of sound (SOS) reflects bone elasticity and density, while broadband ultrasound attenuation (BUA) is influenced by bone microarchitecture and the presence of trabecular bone.^[1]Together, these measurements provide an indication of bone strength and quality. Research indicates that bone phenotypes, including QUS measures, have significant heritability, ranging from 30% to 66%.^[1] This suggests a substantial genetic contribution to an individual’s QUS values. Genome-wide linkage analyses have, for instance, mapped quantitative ultrasound of the calcaneus to chromosome 1.^[2] highlighting specific genomic regions involved in this trait. Studies have also investigated the genetic and environmental factors influencing the relationship between QUS and BMD.^[3]

Clinical Relevance

Clinically, bone quantitative ultrasound is an important tool for fracture prediction and for monitoring osteoporosis treatment.^[1] Low BMD is a strong risk factor for fracture, but QUS offers additional, independent predictive value.^[1]For example, QUS of the calcaneus has been shown to be associated with hip fracture risk, largely independent of BMD.^[1]Its non-ionizing nature makes it a safe option for repeated measurements and screening in various populations. QUS can complement DXA in assessing overall fracture risk, providing a more comprehensive picture of bone health.

Social Importance

Osteoporosis is a significant public health concern, characterized by weakened bones and an increased risk of fractures.^[1] In the United States alone, over 1.5 million fractures occur annually, including a large number of hip and vertebral fractures.^[1]These fractures lead to substantial morbidity, mortality, and healthcare costs. By offering a readily accessible and non-invasive method for assessing bone strength, QUS plays a vital role in the early identification of individuals at risk for osteoporosis and fractures. This facilitates timely interventions, improves patient outcomes, and helps to alleviate the societal burden associated with osteoporotic fractures.

Methodological and Statistical Considerations

The generalizability of findings from bone quantitative ultrasound studies is inherently constrained by the characteristics of the cohorts involved. Initial genome-wide association studies (GWAS) often rely on samples of specific ancestries and sizes, such as the discovery phase with 1000 white U.S. subjects . Similarly,RSPO3, with its rs7741021 variant, functions as an R-spondin, a family of secreted proteins that amplify Wnt signaling. By enhancing this critical pathway, RSPO3significantly contributes to bone development and remodeling, where its variants may modulate the strength and quality of bone tissue.^[4] The ESR1 gene, along with the long non-coding RNA LNCAROD and CCDC170, also contributes to the genetic landscape of bone health.ESR1encodes Estrogen Receptor Alpha, a key protein that mediates the effects of estrogen, a hormone vital for maintaining bone density in both men and women. Variants likers2982552 and rs3020331 in ESR1are extensively studied for their impact on bone mineral density, osteoporosis risk, and bone turnover, which directly affects bone quality as assessed by quantitative ultrasound.^[4] LNCAROD(Long Non-Coding RNA Associated with Osteogenesis Differentiation) is involved in regulating gene expression critical for osteogenesis, the process of bone formation, and its variantsrs7902708 , rs6480949 , and rs11003050 could influence the differentiation and function of bone-forming cells. TheCCDC170 gene, including variants rs4869739 , rs1891002 , and rs66943969 , has been implicated in cell proliferation and differentiation pathways that may indirectly impact bone development and maintenance.^[4]Beyond direct signaling and hormonal regulation, genes involved in fundamental cellular processes also influence bone integrity. TheTMEM135 gene, with variants such as rs597319 , rs511755 , and rs533931 , encodes a transmembrane protein involved in mitochondrial function and autophagy, processes crucial for cellular energy metabolism and waste recycling. Optimal mitochondrial health is essential for the function and survival of osteocytes, the cells embedded within bone, thus impacting overall bone quality and strength.^[4] Similarly, SPTBN1 (Spectrin Beta, Non-Erythrocytic 1) encodes a cytoskeletal protein vital for maintaining cell structure and facilitating intracellular signaling. Variants like rs11898505 could affect the mechanical properties and signaling within bone cells, thereby influencing their ability to adapt to stress and maintain bone mass. TheGPATCH1 gene, harboring variants rs10416265 and rs58636263 , is involved in RNA processing, a foundational mechanism for gene expression, which could indirectly modulate the production of proteins essential for bone matrix formation and remodeling.^[4]These genetic variations collectively contribute to the diverse biological pathways that determine bone quantitative ultrasound measurements and susceptibility to skeletal conditions.

Defining Quantitative Ultrasound and Its Parameters

Quantitative ultrasound (QUS) is a non-invasive technique utilized to assess various properties of bone, providing insights into skeletal health. This approach primarily involves transmitting and receiving ultrasonic waves through bone, with the calcaneus (heel bone) being a frequently measured site.^[1]Unlike methods that quantify bone mineral density, QUS evaluates the structural and material properties of bone by analyzing how ultrasound signals interact with the tissue. Key parameters derived from QUS include Broadband Ultrasound Attenuation (BUA) and Speed of Sound (SOS), which reflect different aspects of bone microarchitecture and elasticity.^[1]BUA, expressed in dB/MHz, measures the frequency-dependent reduction in ultrasound amplitude as it passes through bone, indicating aspects of bone density, architecture, and microstructure. Speed of Sound (SOS), measured in m/s, reflects the velocity at which the ultrasound wave travels through the bone, providing information related to bone elasticity and density.^[1]Together, these parameters offer a composite assessment of bone quality, complementing traditional bone mineral density measurements by capturing additional dimensions of bone strength. The terminology “QUS” serves as an overarching term for this approach, encompassing these specific ultrasonic indices.

Role in Osteoporosis Assessment and Fracture Risk

Quantitative ultrasound plays a significant role in the assessment of osteoporosis, a skeletal disorder characterized by compromised bone strength and increased fracture risk.^{[1], [5]}While dual-energy X-ray absorptiometry (DXA) of bone mineral density (BMD) is considered the gold standard for assessing fracture risk, QUS provides valuable, often independent, information.^[1]Studies have demonstrated that QUS of the calcaneus is associated with hip fracture risk, even largely independent of BMD, highlighting its utility as a complementary diagnostic and predictive tool.^[1]The clinical significance of QUS extends to monitoring osteoporosis treatment and identifying individuals at high risk for low-trauma fractures, particularly among the elderly.^{[1], [5]}Although specific diagnostic thresholds or cut-off values for QUS parameters are often contextual and may vary, its inclusion in bone health assessments offers a broader perspective on skeletal fragility. This allows for a more comprehensive evaluation beyond what BMD alone might provide, contributing to a more nuanced classification of fracture susceptibility.

Standardized and Exclusion Criteria in Research

In research settings, particularly in genetic studies, bone quantitative ultrasound and other bone health phenotypes undergo rigorous standardization and operational definitions to ensure data quality and comparability. For instance, QUS parameters, alongside BMD and hip geometry measures, are frequently analyzed as multivariable-adjusted residuals.^[1]This adjustment process accounts for influential covariates such as age, age squared, height, body mass index (BMI), smoking status, physical activity levels, and estrogen therapy, thereby isolating the specific trait being studied.^[1]Furthermore, precise exclusion criteria are applied in studies investigating bone mass and metabolism to minimize confounding environmental and therapeutic factors. Individuals with serious metabolic diseases (e.g., diabetes, hyper- or hypoparathyroidism, hyperthyroidism), other skeletal disorders (e.g., Paget disease, osteogenesis imperfecta, rheumatoid arthritis), or those chronically using drugs known to affect bone metabolism (e.g., hormone replacement therapy, corticosteroids, anticonvulsants) are typically excluded.^{[5], [6]}The exclusion of subjects taking anti-bone-resorptive or bone anabolic agents, such as bisphosphonates, further refines the study population, allowing for a clearer focus on genetic contributions to bone phenotypes.^[5]

Quantitative Ultrasound as an Imaging and Screening Tool

Bone quantitative ultrasound (QUS) serves as an important diagnostic tool for assessing bone strength, predicting fracture risk, and monitoring osteoporosis treatment. Specifically, broadband ultrasound attenuation (BUA) of the calcaneus is a commonly used QUS measure.^[1]While dual-energy X-ray absorptiometry (DXA) remains the gold standard for bone mineral density (BMD) assessment, QUS provides complementary information, showing an association with hip fracture largely independent of BMD.^[1]This independence highlights QUS’s unique clinical utility in providing insights into bone quality beyond density alone, thereby aiding in a more comprehensive evaluation of skeletal health.^[7]

Genetic Contributions to Bone Quantitative Ultrasound

Genetic factors significantly influence bone quantitative ultrasound measurements, with heritability estimates for bone phenotypes ranging between 30% and 66%.^[1] Studies on postmenopausal twins have demonstrated the heritability of calcaneal ultrasound, indicating a strong genetic predisposition.^[8] Genome-wide linkage analyses have mapped quantitative ultrasound of the calcaneus to chromosome 1, and specific genetic associations have been identified.^[2]For instance, single nucleotide polymorphisms (SNPs) in thePPARG gene, rs10510418 and rs2938392 , have been associated with both BMD and ultrasound measurements, while the IL1RL1gene on 2q12 has shown associations with various bone mass traits, including BUA.^[1] Despite these findings, replicating genetic results across different populations has presented challenges, and progress in identifying major genes for QUS has been modest, often due to the low power of linkage analyses to detect subtle genetic effects.^[1]

Clinical Context and Differentiating Factors

Integrating bone quantitative ultrasound into clinical practice requires consideration of its role alongside other diagnostic methods and clinical risk factors. QUS contributes to fracture prediction and osteoporosis treatment monitoring, offering valuable information that can be distinct from BMD measurements.^[1]For example, while low BMD is a strong risk factor, QUS of the calcaneus is associated with hip fracture risk largely independent of BMD, suggesting it captures different aspects of bone strength, such as bone geometry.^[1]The absence of widespread pleiotropic associations between BMD and hip geometry further supports the idea that these bone traits, including QUS, reflect distinct biological mechanisms influencing fracture risk. Therefore, QUS serves as an important adjunctive measure, helping clinicians to differentiate risk profiles and guide management strategies beyond what BMD alone can provide.^[1]

Bone Architecture and Mechanical Integrity

Bone is a complex, dynamic tissue that provides structural support, protects organs, and facilitates movement. Its mechanical integrity, crucial for resisting fractures, depends on both its mineral density and its intricate structural geometry.^[1]Quantitative ultrasound (QUS) measurements, such as broadband ultrasound attenuation (BUA) of the calcaneus, reflect these structural and material properties of bone, offering insights into bone quality beyond traditional bone mineral density (BMD) assessments.^[1]The calcaneus, along with the femoral neck, trochanter, and lumbar spine, are critical sites for evaluating bone health, as their specific architectural characteristics contribute differently to overall skeletal strength and fracture risk.^[1]These measurements provide valuable information about how well bone can absorb and transmit sound waves, which is influenced by factors like trabecular architecture and cortical thickness.

Cellular and Molecular Regulation of Bone Homeostasis

Bone health is maintained through a finely tuned balance of bone formation by osteoblasts and bone resorption by osteoclasts, a process known as remodeling. This intricate cellular activity is regulated by numerous molecular pathways, involving critical proteins, enzymes, receptors, and hormones. For instance,Osteocalcin, a non-collagenous protein synthesized by osteoblasts, plays a key role in bone mineralization, with its function being dependent on vitamin K-mediated carboxylation.^[9] Signaling pathways involving genes like PPARG and ANKHhave been implicated in influencing bone mineral density and femoral neck section modulus, respectively, highlighting their roles in cellular differentiation and extracellular matrix regulation.^[1] Furthermore, zinc finger transcription factors are essential regulatory elements that modulate gene expression patterns critical for proper skeletal development.^[10]

Genetic Influences on Bone Traits

Genetic factors significantly contribute to the normal variation in bone mass, density, and geometry, with studies demonstrating the heritability of traits like bone mineral density, calcaneal ultrasound, and hip axis length.^{[1], [8]}Specific genetic variations, or single nucleotide polymorphisms (SNPs), within genes such asPPARG (rs10510418 and rs2938392 ) have been associated with both BMD and ultrasound parameters, suggesting a shared genetic architecture for these bone characteristics.^[1] Similarly, variants in ANKH (rs2454873 and rs379016 ) are linked to femoral neck section modulus, indicating gene-specific roles in bone geometry.^[1] The gene IL1RL1on chromosome 2q12 has shown associations with multiple bone mass traits, including BMD and BUA, whileCDH9 and DCC have exhibited sex-specific associations with BMD phenotypes, particularly in women.^[1]These findings underscore the complex polygenic nature of bone traits and the presence of sex-specific quantitative trait loci that contribute to bone structure.^[11]

Pathophysiology of Bone Disorders

Disruptions in the tightly regulated bone remodeling process and genetic predispositions can lead to pathophysiological conditions such as osteoporosis, a skeletal disorder characterized by compromised bone strength and an increased risk of fractures.^[1]While low bone mineral density is a primary risk factor, other measurements like quantitative ultrasound and bone geometry are crucial for a comprehensive assessment of fracture risk and for monitoring treatment efficacy.^[1]For instance, QUS of the calcaneus is independently associated with hip fracture, demonstrating its utility beyond BMD.^[1]Therapeutic interventions, including hormone replacement, alendronate, raloxifene, and teriparatide, aim to restore bone homeostasis by influencing bone structural geometry and density, thereby mitigating the risk of debilitating fractures.^{[12], [13]}

Genetic and Transcriptional Regulation of Bone Structure

Bone quantitative ultrasound (QUS) traits are significantly influenced by a complex interplay of genetic factors that regulate bone structure and density. Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with QUS, bone mineral density (BMD), and bone geometry, suggesting a genetic architecture underlying these skeletal properties. These genetic variations can impact the expression of genes crucial for skeletal development and maintenance, often through modulating the activity of transcription factors. For instance, zinc finger transcription factors are known to play a vital role in orchestrating gene expression patterns essential for proper skeletal development.^{[1], [10]}The identification of quantitative trait loci (QTL), such as those mapped to chromosome 1 for calcaneal QUS, further underscores the localized genetic control over specific bone characteristics.^[2]This genetic regulation extends to distinct phenotypic outcomes, as SNPs significant for one bone geometric phenotype often do not overlap with those for others, implying specialized genetic pathways for different aspects of bone morphology.^[1]

Cellular Signaling and Remodeling Dynamics

The dynamic maintenance of bone, which underpins its quantitative ultrasound properties, is governed by intricate cellular signaling pathways that coordinate bone remodeling. This process involves a precise balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, initiated by the activation of specific receptors on cell surfaces. Upon receptor binding, intracellular signaling cascades are triggered, propagating signals that ultimately regulate gene expression and cellular functions within bone cells. These signaling networks are characterized by extensive pathway crosstalk and feedback loops, allowing bone cells to respond adaptively to diverse stimuli, including mechanical forces and systemic hormones. This integrated cellular communication ensures the continuous renewal and repair of bone tissue, directly influencing its structural integrity and material properties as assessed by QUS.^[1]

Metabolic Pathways and Matrix Maturation

The material properties of bone, critical for its quantitative ultrasound characteristics, are profoundly shaped by various metabolic pathways that govern the composition and quality of the extracellular matrix. These pathways encompass the biosynthesis of key components such as collagen and non-collagenous proteins, alongside the intricate processes of mineral deposition. A prime example of a metabolic regulator with significant impact on bone quality is vitamin K, which is essential for the post-translational carboxylation of bone matrix proteins. Specifically, vitamin K mediates the gamma-carboxylation of osteocalcin, a process vital for its ability to bind calcium ions and integrate effectively into the mineralized matrix.^[9]Any dysregulation in vitamin K status can lead to the production of undercarboxylated osteocalcin, thereby compromising the structural integrity and mechanical strength of the bone matrix.

Integrated Systems Biology of Bone Strength

Bone quantitative ultrasound provides a holistic measure of bone strength, reflecting emergent properties that arise from the systems-level integration of numerous genetic, cellular, and metabolic pathways. The overall bone architecture, density, and material quality, as captured by QUS parameters, are the result of hierarchical regulation where local cellular interactions are meticulously coordinated by systemic factors. For instance, studies have identified sex-specific quantitative trait loci that contribute to normal variation in bone structure at sites like the proximal femur, illustrating how complex regulatory layers can influence bone geometry and density differently between individuals.^[11]This extensive network of interacting pathways ultimately determines bone’s overall resistance to fracture. Consequently, QUS is recognized as an important and largely independent predictor of fracture risk, providing insights beyond traditional bone mineral density measurements by integrating multiple aspects of bone quality.^{[1], [3]}

Fracture Risk Prediction and Clinical Utility

Quantitative ultrasound (QUS) measurements, particularly broadband ultrasound attenuation (BUA) of the calcaneus, serve as an important tool for assessing fracture risk. Studies have demonstrated QUS’s association with hip fracture, notably showing this association to be largely independent of bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA).^[3] This independence suggests that QUS provides complementary information to standard BMD, enhancing the comprehensive evaluation of an individual’s susceptibility to fractures.^[1] The utility of ultrasound for risk assessment has been recognized, highlighting a need for defining clear strategies for its optimal clinical integration.^[7]The application of QUS in clinical settings extends beyond simple diagnosis, contributing to a more nuanced understanding of an individual’s bone strength. By offering an alternative or supplementary measure to DXA, QUS can aid in identifying individuals at high risk for osteoporotic fractures, even in cases where BMD values may not be severely compromised.^[8] This diagnostic utility helps clinicians make informed decisions regarding patient management, potentially guiding early interventions and preventative strategies.

Monitoring Bone Health and Treatment Response

Quantitative ultrasound plays a valuable role in monitoring the effectiveness of osteoporosis treatments and tracking disease progression over time. As an assessment tool, QUS can provide insights into changes in bone strength, which is crucial for evaluating patient response to therapeutic interventions.^[8]This monitoring capability allows healthcare providers to adjust treatment regimens as needed, optimizing long-term patient outcomes and ensuring the most appropriate care for individuals with osteoporosis.

The ability of QUS to track changes in bone health without the use of ionizing radiation makes it a potentially attractive option for serial measurements. While research indicates its utility in monitoring, further strategies are needed to fully define how ultrasound can best be integrated into routine follow-up protocols.^[7]Such integration could facilitate more dynamic and personalized management plans, contributing to improved patient care and sustained bone health.

Genetic Influences and Phenotypic Associations

Research, including genome-wide association studies, has revealed significant genetic contributions to bone phenotypes, including quantitative ultrasound measures like broadband ultrasound attenuation (BUA).^[1]Heritability estimates for bone phenotypes, encompassing QUS, range from 30% to 66%, underscoring a substantial genetic component.^[1] For instance, a phenotypic subgroup combining BMD and BUA was associated with the IL1RL1gene on chromosome 2q12, suggesting shared genetic influences on these bone mass traits.^[1]Further genetic associations have been identified, such as specific single nucleotide polymorphisms (SNPs) in thePPARG gene (rs10510418 and rs2938392 ), which are linked to both BMD and ultrasound measures.^[1]These findings highlight overlapping genetic pathways that influence various aspects of bone health, contributing to our understanding of the complex etiology of osteoporosis. Identifying such molecular profiles through genetic screening could eventually lead to more personalized prevention and management strategies for bone disorders, allowing for the stratification of individuals based on their genetic risk.^[1]

Key Variants

RS ID	Gene	Related Traits
rs2908007	CPED1 - WNT16	bone quantitative ultrasound bone tissue density velocity of sound heel bone mineral density bone fracture
rs3779381	WNT16	spine bone mineral density femoral neck bone mineral density bone quantitative ultrasound heel bone mineral density ischemic cardiomyopathy
rs7741021	RSPO3	heel bone mineral density bone quantitative ultrasound bone tissue density velocity of sound bone fracture
rs597319 rs511755 rs533931	TMEM135	bone quantitative ultrasound velocity of sound heel bone mineral density
rs10416265 rs58636263	GPATCH1	bone quantitative ultrasound velocity of sound heel bone mineral density spine bone mineral density
rs11898505	SPTBN1	bone tissue density bone quantitative ultrasound velocity of sound alkaline phosphatase spine bone mineral density
rs4869739 rs1891002 rs66943969	CCDC170	velocity of sound bone quantitative ultrasound heel bone mineral density
rs2982552	ESR1	bone quantitative ultrasound heel bone mineral density
rs3020331	ESR1	bone quantitative ultrasound velocity of sound heel bone mineral density bone tissue density
rs7902708 rs6480949 rs11003050	LNCAROD	bone quantitative ultrasound velocity of sound heel bone mineral density

Frequently Asked Questions About Bone Quantitative Ultrasound

These questions address the most important and specific aspects of bone quantitative ultrasound based on current genetic research.

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1. My mom has weak bones; will I get them too?

Yes, bone strength, as measured by QUS, has a significant genetic component, with heritability ranging from 30% to 66%. This means you can inherit a predisposition for certain bone properties from your parents, influencing your own bone health. However, lifestyle factors also play an important role.

2. Why do my siblings have stronger bones than me?

Even with shared genetics, individual QUS values can vary. While bone health has a strong genetic basis, inherited predispositions can manifest differently, and environmental factors like diet, exercise, and other lifestyle choices also influence bone development and strength. It’s a complex interplay of many factors.

3. Can my diet or exercise really beat bad bone genes?

While genetics contribute significantly to bone strength, it’s a polygenic trait with a substantial environmental component. This means that even if you have a genetic predisposition for weaker bones, a healthy diet and regular exercise can positively influence your bone quality and help mitigate genetic risks. Specific genes likeADAMTS18 and TGFBR3 explain only a small fraction of the total variation.

4. Does my non-European background affect my bone strength risk?

Yes, research shows that genetic contributions to bone mass can differ between various populations, like Caucasians and Chinese. Many studies have focused primarily on people of European descent, so genetic associations identified may not be universally applicable or have different effects in your specific ethnic group. Expanding research to diverse ancestries is crucial.

5. Are bone tests less accurate for people like me, if I’m not white?

The accuracy of QUS measurements themselves isn’t necessarily less, but the interpretationof genetic risk factors for bone health can be less complete if your ethnic group is underrepresented in research. Genetic associations, such as those involvingADAMTS18 and TGFBR3, might not fully capture the genetic landscape in diverse populations, meaning your personal genetic risk profile might be less understood.

6. Could this new bone test predict if I’ll break a bone soon?

Yes, quantitative ultrasound is an important tool for fracture prediction. It offers additional, independent predictive value beyond just bone mineral density (BMD) measured by DXA, providing insights into bone microarchitecture and elasticity. For example, QUS of the calcaneus has been shown to be associated with hip fracture risk.

7. Why would I need this bone test if my old X-ray was fine?

This test provides different information than a standard X-ray or even a DXA scan. While DXA primarily measures bone mineral density, QUS assesses bone microarchitecture and elasticity, giving a more comprehensive picture of overall bone quality and strength. It can reveal risks not captured by density alone.

8. Does my age mean my bones are definitely getting weaker?

While bone strength can naturally decline with age, your individual trajectory is influenced by a complex interplay of genetic and environmental factors. Bone QUS measures have significant heritability, meaning some individuals are genetically predisposed to maintain better bone quality longer, alongside their lifestyle choices.

9. Why do some people always have strong bones no matter what?

A substantial part of bone strength is genetically determined, with heritability for QUS measures ranging from 30% to 66%. This means some individuals inherit a genetic makeup that predisposes them to naturally stronger bones, even if their lifestyle isn’t perfectly optimized. It’s a complex trait influenced by many genes.

10. Is this test safe for me to do many times?

Yes, bone quantitative ultrasound is a non-invasive and non-ionizing technique. This means it doesn’t use radiation, making it a safe option for repeated measurements and routine screening without concerns about radiation exposure.

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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

[1] Kiel DP, et al. “Genome-wide association with bone mass and geometry in the Framingham Heart Study.”BMC Med Genet, vol. 8, 2007, p. 57.

[2] Karasik, D, Myers RH, Hannan MT, et al. “Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis.”Osteoporosis International, vol. 13, no. 10, 2002, pp. 796-802.

[3] Howard, G. M. et al. “Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study.”Journal of Bone and Mineral Research, vol. 13, no. 8, 1998, pp. 1318-1327.

[4] O’Donnell CJ et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.” BMC Med Genet 2007.

[5] Liu, Y. Z., et al. “Powerful bivariate genome-wide association analyses suggest the SOX6gene influencing both obesity and osteoporosis phenotypes in males.”PLoS One, vol. 4, no. 8, 2009, p. e6827.

[6] Lu, S., et al. “Bivariate genome-wide association analyses identified genetic pleiotropic effects for bone mineral density and alcohol drinking in Caucasians.”Journal of Bone and Mineral Metabolism, 2018.

[7] Gluer, CC, and D Hans. “How to use ultrasound for risk assessment: a need for defining strategies.” Osteoporosis International, vol. 9, no. 3, 1999, pp. 193-195.

[8] Arden, N. K. et al. “The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins.”Journal of Bone and Mineral Research, vol. 11, no. 4, 1996, pp. 530-534.

[9] Gundberg, C. M., et al. “Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin.”J Clin Endocrinol Metab, vol. 83, 1998, pp. 3258-3266. PMID: 9768687.

[10] Ganss, B., and A. Jheon. “Zinc finger transcription factors in skeletal development.” Crit Rev Oral Biol Med, vol. 15, 2004, pp. 282-297. PMID: 15470266.

[11] Peacock, M., et al. “Sex-specific quantitative trait loci contribute to normal variation in bone structure at the proximal femur in men.”Bone, vol. 37, no. 4, 2005, pp. 467-473. PMID: 16112521.

[12] Uusi-Rasi, K., et al. “Effects of teriparatide [rhPTH (1–34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women.” Bone, vol. 36, no. 6, 2005, pp. 948-958. PMID: 15894172.

[13] Uusi-Rasi, K., et al. “Structural effects of raloxifene on the proximal femur: results from the multiple outcomes of raloxifene evaluation trial.” Osteoporos Int, vol. 17, no. 4, 2006, pp. 575-586. PMID: 16400494.