Implementation of personalized medicine for fracture risk assessment in osteoporosis

Mori, Seijiro; Zhou, Heying

doi:10.1111/ggi.12721

Cited by 7 publications

(5 citation statements)

References 87 publications

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“…Taken together, this confirms that trabecular and cortical microtraits are differentially and independently modulated. These findings underscore the importance of precision phenotyping in mapping and in experimental precision medicine …”

Section: Discussionmentioning

confidence: 69%

“…These findings underscore the importance of precision phenotyping in mapping and in experimental precision medicine. (82,83) Advantages and limitations This is one of the first genetic studies of bone microarchitecture in mouse using μCT. Our method provides a precise way to quantify and image microarchitecture in trabecular and cortical bone compartments with a resolution of 10 microns or less.…”

Section: Site Specificitymentioning

confidence: 99%

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Genetic Dissection of Femoral and Tibial Microarchitecture

Huang

et al. 2019

JBMR Plus

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Our understanding of the genetic control of bone strength has relied mainly on estimates of bone mineral density. Here we have mapped genetic factors that influence femoral and tibial microarchitecture using high‐resolution x‐ray computed tomography (8‐μm isotropic voxels) across a family of 61 BXD strains of mice, roughly 10 isogenic cases per strain and balanced by sex. We computed heritabilities for 25 cortical and trabecular traits. Males and females have well‐matched heritabilities, ranging from 0.25 to 0.75. We mapped 16 genetic loci most of which were detected only in females. There is also a bias in favor of loci that control cortical rather than trabecular bone. To evaluate candidate genes, we combined well‐established gene ontologies with bone transcriptome data to compute bone‐enrichment scores for all protein‐coding genes. We aligned candidates with those of human genome‐wide association studies. A subset of 50 strong candidates fell into three categories: (1) experimentally validated genes already known to modulate bone function (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); (2) candidates without any experimentally validated function in bone (eg, Greb1, Ifi202b), but linked to skeletal phenotypes in human cohorts; and (3) candidates that have high bone‐enrichment scores, but for which there is not yet any functional link to bone biology or skeletal system disease (including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2). Our results highlight contrasting genetic architecture between sexes and among major bone compartments. The alignment of murine and human data facilitates function analysis and should prove of value for preclinical testing of molecular control of bone structure. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 69%

Section: Site Specificitymentioning

confidence: 99%

Genetic Dissection of Femoral and Tibial Microarchitecture

Huang

et al. 2019

JBMR Plus

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“…Taken together, this confirms that trabecular and cortical bone microtraits are differentially and independently modulated. These findings underscore the importance of precision phenotyping and in mapping and in precision medicine (117,118) .…”

Section: Site Specificitymentioning

confidence: 64%

Genetic dissection of femoral and tibial microarchitecture

Huang

et al. 2019

Preprint

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Our understanding of the genetic control of bone has relied almost exclusively on estimates of bone mineral density. In contrast, here we have used high-resolution x-ray tomography (8 µm isotropic voxels) to measure femoral and tibial components across a set of ~600 mice belonging to 60 diverse BXD strains of mice. We computed heritabilities of 25 cortical and trabecular compartments. Males and females have well matched trait heritabilities, ranging from 0.25 to 0.75. We mapped 16 QTLs that collectively cover ~8% of all protein-coding genes in mouse. A majority of loci are detected only in females, and there is also a bias in favor of QTLs for cortical traits. To efficiently evaluate candidate genes we developed a method that couples gene ontologies with expression data to compute boneenrichment scores for almost all protein-coding genes. We carefully collated and aligned murine candidates with recent human BMD genome-wide association results. We highlight a subset of 50 strong candidates that fall into three categories: 1. those linked to bone function that have already been experimentally validated (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); 2. candidates with putative bone function but not yet tested (e.g., Greb1, Ifi202b) but several of which have been linked to phenotypes in humans; and 3. candidates that have high bone-enrichment scores but for which there is not yet any specific link to bone biology or skeletal disease, including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2. Our results highlight contrasting genetic architecture between the sexes and among major bone compartments. The joint use and alignment of murine and human data should greatly facilitate function analysis and preclinical testing.

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“…Thus, it is suggested that medication selection would be on an individual basis. Personalized medicine that includes personalized genetic risk score and individualized environmental exposure may have a key role in pathophysiology of osteoporosis [ 98 ].…”

Section: Introductionmentioning

confidence: 99%

New horizons in treatment of osteoporosis

et al. 2017

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BackgroundPrevalence of osteoporosis is increasing both in developed and developing countries. Due to rapid growth in the burden and cost of osteoporosis, worldwide, it seems reasonable to focus on the reduction of fractures as the main goal of treatment. Although, efficient pharmacological agents are available for the treatment of osteoporosis, there still remains a need to more specific drugs with less adverse effects.Main bodyThis review article provides a brief update on the pathogenesis, presenting current pharmacological products approved by the US Food and Drug Administration (FDA) or Europe, and also newer therapeutic agents to treat osteoporosis according to the clinical trial data available at PubMed, UpToDate, International Osteoporosis Foundation (IOF), and clinical practice guidelines. As well, the effect of combination therapy and recommendations for future research will be further discussed.Short conclusionThe use of current antiresorptive and anabolic agents alone or in combinations for the treatment of osteoporosis entails several limitations. Mainly, their efficacy on non-vertebral fracture reduction is lower than that observed on vertebral fracture. In addition, they have potential adverse events on long time usage. Development of newer agents such as cathepsin k inhibitor and strontium ranelate not only have increased the available options for treating osteoporosis, but also have opened doors of opportunity to improvements in the effective treatment. However, the high cost of new agents have restricted their usage in selective patients who are at high risk of fracture or whom failed response to first line treatment options. Thus, personalized medicine should be considered for future evaluation of genetic risk score and also for environmental exposure assessment. In addition to permanent attention to early diagnosis of osteoporosis and understanding of the pathophysiology of osteoporosis for novel approach in drug discovery, there seems a need to more well-designed clinical trials with larger sample sizes and longer duration on current as well as on newer agents. Also, continuous research on plant-derived components as the source of discovering new agents, and conducting more clinical trials with combination of two or more synthetic drugs, plants, or drug-plant for the treatment of osteoporosis are recommended.Graphical AbstractSummary of treatment modalities for osteoporosis.

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Implementation of personalized medicine for fracture risk assessment in osteoporosis

Cited by 7 publications

References 87 publications

Genetic Dissection of Femoral and Tibial Microarchitecture

Genetic Dissection of Femoral and Tibial Microarchitecture

Genetic dissection of femoral and tibial microarchitecture

New horizons in treatment of osteoporosis

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