Athlete bone health and genetic factors -
Overall, women are more likely to experience osteoporosis than men. Trans people and others on hormone replacement therapies, or who have certain surgeries, may also be at risk of developing osteoporosis.
The National Institutes of Health report non-Hispanic white women and Asian women have the highest prevalence of osteoporosis. However, the authors found that Black people were found more likely to die from a hip fracture, have longer hospital stays, and be less mobile after discharge.
Most experts agree osteoporosis is under-diagnosed in the general population. And screenings are not accessed equally by all. For example, a study documented a 5 percent sample of Medicare beneficiaries 65 years or older. It reported percentages of people who received a DEXA scan between and Of those eligible, Due to prejudice and discrimination about perceived racial characteristics, certain people are treated differently and disadvantaged.
This can impact the ability to access and receive healthcare. Medications that may increase your risk of bone loss include:. Do not stop taking your medication without consulting them. Whether or not you have a genetic predisposition to osteoporosis, taking preventive measures can make all the difference.
A seemingly minor accident can lead to fractures if you have lost bone density. Knowing your risk factors for osteoporosis development can help you implement strategies to prevent falls and fractures, and preserve your overall quality of life.
Researchers are still studying genetic differences that could influence the way bones are formed and maintained, and how to preserve bone density in people who may be at risk for developing osteoporosis.
They may order testing to determine your current bone mass and develop a treatment and prevention plan. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. Learn seven common myths about osteoporosis and bone health, dispelled by bone health expert Dr.
Deborah Sellmeyer. Women going through menopause have a higher risk of developing osteoporosis. Learn how to slow it down and fortify your body against it.
Not getting enough calcium in your diet can lead to fragile, brittle bones that are more prone to fractures and disease. Find out which foods can help…. Vitamin D is important for optimal health, but many Americans are deficient. This article lets you know what dosage of vitamin D is best. Osteopaths and chiropractors are healthcare professionals who offer complementary forms of medicine.
While they treat similar conditions, their…. The prevalence of osteoporosis describes how common this condition is within specific groups.
It's most common in women over the age of A bone density scan helps your doctor know if your bones are healthy. Results are reported as Z-scores and T-scores. Z-scores are used for people…. While research on the benefits of tai chi for osteoporosis is promising, researchers note the need for more rigorous studies.
Here's what we know. Several doctors and other healthcare professionals can treat osteoporosis. The best option for you will depend largely on the underlying cause. A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect.
Is Osteoporosis Genetic? Risk Factors, Screening, and More. Medically reviewed by Angelica Balingit, MD — By Kristeen Cherney and Donald Collins on March 2, Some of these mutations have been shown to interfere with the DNA-binding activity of CBFA1, whereas others have been found to alter nuclear localization of the protein or to produce a mutant or truncated protein that is biologically inactive.
In addition to these rare mutations, various polymorphisms have been identified in CBFA1 and some of these have been associated with bone mass in population-based studies Vaughan et al. The best functional candidates lie within the Runx2 promoter Doecke et al. The polyalanine and polyglutamine repeats are of interest since they lie within one of the transactivation domains of Runx2.
Various polymorphic variations have been identified in this region, including an bp deletion that results in a polyalanine repeat of 11 residues 11 Ala compared with the more common repeat of 17 residues 17 Ala.
Various rare length variants within the polyglutamine repeat have also been identified, resulting in stretches of between 15 and 30 repeats. The strongest association with BMD has been observed with an anonymous polymorphism in the Ala repeat region Vaughan et al. It is currently unclear whether the length variants in the polyalanine and polyglutamine tracts have functional importance, but this is an area of ongoing investigation.
Mutations in Cathepsin K are responsible for the rare syndrome of Pycnodysostosis, which is a rare recessive bone dysplasia characterized by osteosclerosis and short stature Gelb et al.
Various disease-causing mutations have been identified that result in production of either a truncated or a nonfunctional protein. Studies of more common polymorphic variants of Cathepsin K in relation to BMD regulation in the normal population have so far yielded negative results Giraudeau et al.
The TCIRG1 gene encodes the APT6i subunit of the osteoclast-specific proton pump, and various inactivating mutations in TCIRGI have been described that are responsible for a subset of patients with recessive osteopetrosis Frattini et al. Recent work indicates that polymorphisms of TCIRG1 might also contribute to regulation of BMD in the normal population; a study by Frattini Sobacchi et al.
Functional studies need to be performed to identify the mechanisms that underlie this association, however, and to replicate the finding in other populations. The CLCN7 gene encodes a chloride channel that is highly expressed in osteoclasts and is essential for acidification of the resorption lacuna.
Homozygous inactivation mutations in CLCN7 cause a severe form of recessive osteopetrosis Kornak et al. Prompted by this observation, Pettersson et al. Further studies will be required to determine if this polymorphism is functionally important and to replicate the observation in other populations.
Vitamin D, through its principal bioactive form 1,dihydroxyvitamin D3[1, OH 2 D 3 ] plays a crucial role in bone metabolism. The action of 1, OH 2 D 3 is mediated through a specific hormone-receptor VDR that regulates gene expression by forming a heterodimer with retinoic X receptor RXR that binds to vitamin D response elements in target genes.
Mutations in VDR cause the syndrome of vitamin D-resistant rickets which is a recessive condition characterized by alopecia, hypocalcaemia, hypophosphatemia, and severe rickets, and is resistant to treatment with vitamin D and its active metabolites Kristjansson et al.
Targeted inactivation of the VDR gene in mice provides a phenocopy of the human syndrome Bouillon et al. It therefore appears that the bone defects that result from VDR deficiency are due to malabsorption of calcium and phosphate by the intestine rather than absence of 1, OH 2 D 3 signaling in bone cells.
A recent retrospective meta-analysis of association studies that genotyped the BsmI polymorphism concluded that there was evidence of an association between spine BMD and the BsmI polymorphism, equivalent to ~0. No association with femoral neck BMD was observed.
Another polymorphism affecting exon 2 of VDR has been described that creates an alternative translational start site, resulting in the production of two isoforms of the VDR protein, which differ in length by three amino acids Gross et al.
This has been associated with BMD in some, but not other, populations, and functional studies of this polymorphism have yielded inconclusive results Gross et al. A further polymorphism has been identified in the promoter of VDR at a binding site for the transcription factor Cdx-2, which has been associated with BMD in Japanese subjects and appears to be functional Arai et al.
This polymorphism has been associated with fracture in other populations, but not with BMD Fang et al. The most comprehensive study of VDR alleles in relation to osteoporosis-related phenotypes was that of Fang et al.
The data would be consistent with a model whereby the combination of risk haplotypes results in a lower VDR mRNA level due to decreased transcription and increased degradation. Interestingly, the risk alleles for fracture identified in this study were not associated with differences in BMD.
In view of this, the mechanism by which these polymorphisms predispose to fracture is unclear, although a possibility, alluded to by the authors, was through an effect on bone geometry. Although this was a large and well-conducted study, the risk estimates were modest, and if correction had been applied for all the combinations of haplotypes tested and their interactions , the results would not have been significant.
The gene encoding the α I chain of type I collagen COLIA1 is an important functional candidate for the pathogenesis of osteoporosis, since type I collagen is the major protein of bone and since mutations in this gene cause the syndrome of osteogenesis imperfecta—a rare disease characterized by increased bone fragility and reduced BMD Boyde et al.
Previous research identified associations between BMD and polymorphisms within the proximal promoter of COLIA1 Garcia-Giralt et al. Most research has focused on a polymorphism within intron 1, which is situated at a binding site for the transcription factor Sp1.
The COLIA1 Sp1-binding site polymorphism has been associated with various osteoporosis-related phenotypes, including bone density Grant et al. It is thought that the resulting imbalance between the COLIA1 and COLIA2 chains contributes to impairment of bone strength and reduced bone mass in carriers of the T allele by subtly affecting bone mineralization Stewart et al.
Retrospective meta-analyses of published studies have concluded that carriage of the T allele is associated with reduced BMD at the lumbar spine and femoral neck and with vertebral fractures Efstathiadou et al.
In the GENOMOS study, however, the BMD association was only observed for homozygotes for the T allele, in contrast to previous studies where heterozygotes also showed a reduction in BMD Mann and Ralston Interestingly, the association between COLIA1 alleles and vertebral fracture reported in GENOMOS and other studies was not fully explained on the basis of reduced bone density, implying that the Sp1 allele also acts as a marker for bone quality.
The promoter polymorphisms of COLIA1 are in strong linkage disequilibrium with the Sp1 polymorphism, and two studies have now suggested that an extended haplotype defined by the Sp1 polymorphism and other promoter polymorphism may exert stronger effects on BMD than the individual polymorphisms Garcia-Giralt et al.
The estrogen receptor α, encoded by the ESR1 gene, is another important functional candidate for the regulation of bone mass. A large number of investigators have looked for evidence of an association between ESR1 alleles and BMD, mostly focusing on two polymorphisms within intron 1 recognized by the XbaI and PvuII restriction enzymes, and on a TA repeat in the promoter.
Studies of ESR1 alleles in relation to BMD have yielded inconsistent results, possibly because most studies have been of small sample size and involved subjects of different ages, menopausal status, and ethnic backgrounds Ioannidis et al.
In this study, no association with BMD was observed, indicating that ESR1 influences fracture risk independent of an effect on BMD. The mechanism responsible for this observation remains unclear, but one possibility may be an effect on bone quality, since ESR1 alleles have been associated with ultrasound properties of bone and bone loss Albagha et al.
Previous studies have shown that the PvuII polymorphism lies within consensus recognition sites for the AP4 and Myb transcription factors; studies using promoter-reporter assays have shown that the PvuII polymorphism influences Myb-driven transcription in vitro Herrington et al.
These data are consistent with a direct functional effect of the PvuII and XbaI polymorphisms on ESR1 gene transcription, but it remains possible that the intron 1 polymorphisms are simply in linkage disequilibrium LD with causal polymorphisms elsewhere in the ESR1 gene.
Many advances have been made in understanding the role of genetic factors in osteoporosis since publication of the first paper in the field in that showed a strong association between VDR alleles and BMD Morrison et al. At this time it was believed that osteoporosis susceptibility would be determined by a few genes of major effect and that these would pave the way for specific targeted therapies and provide genetic markers to assess disease risk.
It has now become clear that osteoporosis susceptibility is mediated by a large number of genetic variants of modest effect size. Although there remains a prospect that genotyping for these variants could help assess the risk of osteoporosis, or complications such as fracture, it is likely that tens, or hundreds, of informative variants would have to be tested to be of real diagnostic value.
Since some of the genetic variants that predispose to osteoporosis seem to do so by mechanisms independent of BMD, it could be that these might be successfully combined with BMD measurements to improve risk assessment for complications of osteoporosis such as fragility fractures.
At the present time, many common polymorphic variants of candidate genes have been identified that contribute to osteoporosis susceptibility in specific studies. Relatively few candidate gene polymorphisms have been validated by large-scale studies, however, and much work remains to be done to identify genetic variants that are consistently associated with osteoporosis-related phenotypes and to determine whether they will represent useful diagnostic tools and molecular targets for therapeutic manipulation.
uk ; FAX View all Copyright © by Cold Spring Harbor Laboratory Press. Skip to main page content HOME ABOUT SUBMIT SUBSCRIBE ADVERTISE AUTHOR INFO ARCHIVE CONTACT HELP Search for Keyword: GO. Genetic regulation of bone mass and susceptibility to osteoporosis Stuart H.
Ralston 1 , 3 and Benoit de Crombrugghe 2 1 Rheumatic Diseases Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; 2 Department of Molecular Genetics, M.
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Figure 1. Figure 2. View this table: In this window In a new window. TABLE 1. Candidate genes for regulation of susceptibility to osteoporosis. Figure 3. Previous Section. Ai, M. Albagha, O. Altmuller, J. CrossRef Medline Web of Science Google Scholar.
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Athlere reprint requests yenetic John A. Eisman, Ph. John Muscle-building pre-workout. VDR gene polymorphisms Athlete bone health and genetic factors healrh phenotype. It is defined as the gradual reduction in bone strength with advancing age, particularly in women post menopause, such that bones fracture with minimal trauma 1 — 4. Although fractures of the hip, wrist, and spine are often focused upon, almost any bone can fracture 5 — Osteoporosis, characterized by deteriorated bone microarchitecture Atnlete low bone mineral factorx, is a chronic skeletal disease genetkc high worldwide prevalence. Osteoporosis Athlete bone health and genetic factors to aging is the most common form and causes significant morbidity and Maximizing energy levels with sports nutrition. Rare, monogenic forms Athlete bone health and genetic factors Pomegranate Varieties have their onset usually Allergen-friendly products childhood or young geneetic and have heqlth phenotypic features and fctors course depending on the underlying cause. The most Athlete bone health and genetic factors form is osteogenesis fadtors linked to mutations in COL1A1 and COL1A2the two genes encoding type I collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue.Risk of Athete fracture in later life relates to both age and Ketosis and Sleep Quality bone Mood stabilization effects but also to peak heaoth density achieved in early adulthood.
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| Bone Health Programs | Our Specialties | Boston Children's Hospital | Neugebauer J, Heilig J, Hosseinibarkooie S, Ross BC, Mendoza-Ferreira N, Nolte F, et al. Low bone-mineral density as predictor Kim originally approached his investigation as a way to help elite athletes or members of the military learn if they are at risk of bone injury during strenuous training. Effects of miRp in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. Poehlman ET, Tremblay A, Marcotte, Perusse L, Theriault G, Bouchard C. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. |
| Our Specialties | Overview | Osteoporosis is a condition that can cause weak bones that are more prone to fractures. It occurs when the body reabsorbs more bone tissue and produces less to replace it. This lowers the bone density and makes them more fragile. Many different factors — including genetics — can contribute to the development of osteoporosis. Read on to learn more about the influence of genetics on osteoporosis, as well as other potential causes and risk factors. Evidence notes that genetics play a role in the development of osteoporosis. For example, if a person has a family history of the condition, they are more likely to develop it themselves. Researchers have identified multiple genes that contribute to bone density and strength, which are key factors in the development of osteoporosis. One such variation is in the gene encoding the vitamin D receptor. This gene plays a role in regulating calcium absorption and bone mineralization. Alterations in this gene may relate to lower bone mineral density and an increased risk of fractures. Another gene — the COL1A1 gene — helps produce type I collagen, a major component of bone. A common variation in this gene can increase the risk of osteoporosis. However, it is important to note that having these gene variations does not mean that a person will necessarily develop osteoporosis. Osteoporosis is a multifactorial condition. This means there is a combination of causes and risk factors, some of which people cannot change. Some examples include :. The risk of osteoporosis increases with age, particularly in postmenopausal people. As individuals age, bone mass naturally decreases, making them more susceptible to bone loss and fractures. Biological females are at a higher risk of developing osteoporosis than biological males. This is because females generally have lower peak bone mass than men and also experience a significant decrease in estrogen levels during menopause, which accelerates bone loss. Low estrogen levels in biological females and low testosterone levels in biological males can contribute to bone loss and increase the risk of osteoporosis. Inadequate intake of calcium and vitamin D , which are essential for bone health, can lead to decreased bone density and increase the risk of osteoporosis. Lack of regular weight-bearing exercises , such as walking, running, or weightlifting, can contribute to weaker bones and a higher risk of osteoporosis. Physical activity helps stimulate bone formation and strengthen existing bone tissue. Smoking may increase the risk of osteoporosis. It reduces estrogen levels in biological females, affects calcium absorption, and impairs bone formation. Conditions such as rheumatoid arthritis , celiac disease , inflammatory bowel disease , and certain hormonal disorders can increase the risk of osteoporosis. Additionally, long-term use of certain medications, such as corticosteroids, can weaken bones and contribute to bone loss. Osteoporosis typically progresses without noticeable symptoms until a fracture occurs. Symptoms of spine fracture may include :. Living with osteoporosis means the affected bones may become fragile, leading to fractures occurring spontaneously or due to minor falls or typical stresses, such as coughing. According to the International Osteoporosis Foundation , diagnosis of osteoporosis will typically involve a bone mineral density BMD test. This test uses a dual-energy X-ray absorptiometry DEXA machine. A healthcare professional then compares the results with an average, typical year-old adult. To determine if the bone density is in the usual range, the BMD uses a T-score against the standard deviation. This is a term that calculates how much a result varies from the average. A T-score of Learn more about osteoporosis tests. The primary goal of treatment for osteoporosis is to prevent fractures, relieve pain, and improve overall bone health. Treatment will vary as a healthcare professional will tailor plans depending on individual circumstances. In combination with lifestyle recommendations such as gentle weight-bearing exercises, a balanced diet, and increasing calcium and vitamin D intake, a doctor may also recommend medication such as :. There are several measures a person can take to prevent osteoporosis. Clark GR, Duncan EL. The genetics of osteoporosis. Nielson CM, Liu CT, Smith AV, et al. Novel genetic variants associated with increased vertebral volumetric BMD, reduced vertebral fracture risk, and increased expression of SLC1A3 and EPHB2. J Bone Miner Res. Makitie RE, Contantiti A, Kampe A, et al. New insights Into monogenic causes of osteoporosis. Front Endocrinol Lausanne. Alswat KA. Gender disparities in osteoporosis. J Clin Med Res. Munoz-Garach A, Garcia-Fontana B, Munoz-Torres M. Nutrients and dietary patterns related to osteoporosis. Administration of Community Living. Combatting senior malnutrition. Al-Bashaireh AM, Haddad LG, Weaver M, Chenggou X, Kelly DL, Yoon S. The effect of tobacco smoking on bone mass: an overview of pathophysiologic mechanisms. National Institute on Alcohol Abuse and Alcoholism. Alcohol and other factors affecting osteoporosis risk in women. National Institutes of Health. What people recovering from alcoholism need to know about osteoporosis. Mirza F, Canalis E. Secondary osteoporosis, pathophysiology and management. Eur J Endocrinol. Zheng XY, Zhou A, Gao Y, et al. Racial differences and factors associated with low femoral neck bone mineral density: an analysis of NHANES — data. Arch Osteoporos. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Bone mass measurement: what the numbers mean. Preventive Services Task Force. Osteoporosis to prevent fractures: screening. National Institute on Aging. Lee J, Lee S, Jang S, Ryu OH. Age-related changes in the prevalence of osteoporosis according to gender and skeletal site: th Korea National Health and Nutrition Examination Survey Endocrinol Metab Seoul. Gallagher JC, Tella SR. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol. James Myhre is an American journalist and HIV educator. Use limited data to select advertising. Create profiles for personalised advertising. Use profiles to select personalised advertising. Create profiles to personalise content. Use profiles to select personalised content. Measure advertising performance. Measure content performance. Understand audiences through statistics or combinations of data from different sources. Develop and improve services. Use limited data to select content. List of Partners vendors. Medically reviewed by Anita C. Chandrasekaran, MD. Table of Contents View All. Table of Contents. Role of Genetics. Other Risk Factors. Prevention Tips. Frequently Asked Questions. An Overview of Osteoporosis. A Note on Gender and Sex Terminology Verywell Health acknowledges that sex and gender are related concepts , but they are not the same. Sex refers to biology: chromosomal makeup, hormones, and anatomy. People are most often assigned male or female at birth based on their external anatomy; some people do not fit into that sex binary and are intersex. Gender describes a person's internal sense of self as a woman, man, nonbinary person, or another gender, and the associated social and cultural ideas about roles, behaviors, expressions, and characteristics. Causes and Risk Factors of Osteoporosis. How Osteoporosis Self-Care Slows Bone Loss. Osteoporosis Gene Variants To date, no fewer than 71 genetic variants associated with osteoporosis have been found. Can Osteoporosis Be Reversed? Alcohol and Hormone Levels Chronic, heavy alcohol use can also reduce estrogen levels in females and testosterone levels in males, both of which contribute to bone mineral loss and impaired bone remodeling. Who Should Be Screened? How Osteoporosis Is Diagnosed. How to Cope and Live Well With Osteoporosis. How to Treat Osteoporosis. Frequently Asked Questions At what age does osteoporosis typically start? How quickly does osteoporosis progress? Learn More: Stages of Osteoporosis. What does osteoporosis feel like? Symptoms may include: Lower back pain due to collapsing vertebra Shooting leg pains due to a pinched spinal nerve Hip pain due to a weakened hip joint A stooped posture Bone fracture. Learn More: 9 Early Warning Signs of Osteoporosis. Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy. 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| Publication types | Health Conditions Health Products Discover Tools Connect. This gene plays a role in regulating calcium absorption and bone mineralization. deCODE-1 J Bone Miner Res 6 : — This test uses a dual-energy X-ray absorptiometry DEXA machine. |
| Is Osteoporosis Genetic? Risk Factors, Screening, and More | Most health data categorizes participants by their sex and gender assigned at birth. Overall, women are more likely to experience osteoporosis than men. Trans people and others on hormone replacement therapies, or who have certain surgeries, may also be at risk of developing osteoporosis. The National Institutes of Health report non-Hispanic white women and Asian women have the highest prevalence of osteoporosis. However, the authors found that Black people were found more likely to die from a hip fracture, have longer hospital stays, and be less mobile after discharge. Most experts agree osteoporosis is under-diagnosed in the general population. And screenings are not accessed equally by all. For example, a study documented a 5 percent sample of Medicare beneficiaries 65 years or older. It reported percentages of people who received a DEXA scan between and Of those eligible, Due to prejudice and discrimination about perceived racial characteristics, certain people are treated differently and disadvantaged. This can impact the ability to access and receive healthcare. Medications that may increase your risk of bone loss include:. Do not stop taking your medication without consulting them. Whether or not you have a genetic predisposition to osteoporosis, taking preventive measures can make all the difference. A seemingly minor accident can lead to fractures if you have lost bone density. Knowing your risk factors for osteoporosis development can help you implement strategies to prevent falls and fractures, and preserve your overall quality of life. Researchers are still studying genetic differences that could influence the way bones are formed and maintained, and how to preserve bone density in people who may be at risk for developing osteoporosis. They may order testing to determine your current bone mass and develop a treatment and prevention plan. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. Learn seven common myths about osteoporosis and bone health, dispelled by bone health expert Dr. Deborah Sellmeyer. Women going through menopause have a higher risk of developing osteoporosis. Learn how to slow it down and fortify your body against it. Not getting enough calcium in your diet can lead to fragile, brittle bones that are more prone to fractures and disease. Find out which foods can help…. Vitamin D is important for optimal health, but many Americans are deficient. This article lets you know what dosage of vitamin D is best. Osteopaths and chiropractors are healthcare professionals who offer complementary forms of medicine. Chronic illness in children can adversely impact bone health, growth, and development. A prolonged inflammatory state, altered hormonal balance, and potential side effects of medications can impede the body's ability to build and maintain strong bones. As a result, children with chronic illnesses may experience reduced bone density, increased susceptibility to fractures, and compromised growth potential. Multidisciplinary care — including close collaboration between pediatricians, endocrinologists, surgeons, and specialists in chronic conditions — is crucial to monitor and address skeletal health in these young patients. Early intervention strategies, such as nutritional optimization, physical therapy , and targeted medications, aim to mitigate the impact of chronic illness on skeletal fragility and provide children with the best possible foundation for a healthy and active life. Optimal bone health is paramount for student athletes. Good bone health can enhance performance and reduce the risk of injuries, and it lays the foundation for lifelong skeletal well-being. Recognizing the crucial role of bone health in both performance and long-term well-being, our initiatives provide tailored solutions for female athletes and all young sports enthusiasts. Similarly, the staff of our Sports Medicine Division extend their expertise to all young athletes, fostering peak performance and resilience through evidence-based practices. Breadcrumb Home Programs Bone Health Program Our Specialties. Our Specialties Overview. Metabolic bone diseases These are disorders that impact the structure and strength of bones due to abnormalities in mineralization of the skeleton. Metabolic bone diseases include: Hypoparathyroidism: A disorder characterized by abnormally low levels of parathyroid hormone PTH , leading to low blood calcium levels and potentially causing muscle cramps, weakness, and other symptoms. Hypophosphatasia: A genetic disorder characterized by low levels of an enzyme called alkaline phosphatase, leading to impaired bone mineralization and weak bones. It can be treated with alkaline phosphatase enzyme replacement, a medication called asfotase alfa. Hypophosphatemia: A condition marked by abnormally low levels of phosphate in the blood. The aim of the study was to summarize the current data of domestic and foreign literature on the factors affecting bone mineral density BMD in athletes, as well as to consider the key points of nutritional support necessary for the prevention and treatment of osteoporosis. Material and methods. The search was conducted using the Google Academy search engine and electronic databases PubMed, MEDLINE, EMBASE, Scopus, Web of Science, eLIBRARY for the period from to For the search, we used keywords and their combinations: "athletes", "osteoporosis", "stress fractures", "calcium" and "vitamin D". Results and discussion. Bone health is influenced by many factors, the most significant of which are lifestyle and the nature of a person's physical activity. Despite strong evidence for the benefits of exercise for bone health, there are sports that predispose to low BMD and increase the risk of osteoporosis. First of all, athletes involved in aerobic and aesthetic disciplines long-distance running, cycling, swimming, rhythmic gymnastics, dancing, etc. |
Athlete bone health and genetic factors -
The OPPS syndrome was found to be due to different homozygous missense, nonsense, and frameshift mutations throughout the gene Gong et al. Since these original reports, several additional missense mutations of LRP5 have been identified as a cause of HBM, and all of these cluster in or around the first β-propeller motif of LRP5 Van Wesenbeeck et al.
The mutations that cause OPPS produce a truncated or nonfunctional LRP5 protein Gong et al. Analysis of bone histomorphometry in LRP5 knockout mice has shown that the low bone mass is a consequence of decreased osteoblast proliferation and reduced bone matrix deposition rather than an effect of bone resorption Kato et al.
The GV mutation that was associated with HBM in the family studied by Johnson and colleagues Johnson et al. In these studies, mice were generated that expressed either wild-type human LRP5 or the GV mutant, and the mice that expressed the mutant had significantly higher BMD than wild type, despite the fact that levels of transgene expression were similar in both mouse strains.
Analysis of the skeletal phenotype in the GV transgenic mice showed that mineral apposition rate was increased and the rate of osteoblast apoptosis was reduced, whereas eroded surface reflecting bone resorption was unaffected. Functional analysis of the HBM-associated mutations of LRP5 has shown that the mutations probably cause activation of β-catenin signaling by inhibiting interactions between LRP5 and Dkk1.
An initial study by Boyden et al. Another study reached the same conclusion in showing that several HBM-associated mutants GV, GR, AT, AV, AT, TI, and DY were resistant to Dkk1 inhibition compared with wild-type LRP5, and had a lower affinity for Dkk1 binding Ai et al. There is evidence that more subtle variations in LRP5 could also underlie variations of BMD in the normal population.
Most of these studies have shown evidence of associations between LRP5 alleles and BMD and, interestingly, these associations have been particularly strong in men Ferrari et al. Although many variants have been studied, the most likely functional candidate is an alanine-to-valine amino acid substitution at position AV.
The mechanism by which this variant might affect LRP5 signaling has not been investigated, but evidence of an interaction between the LRP5 AV variant and a coding polymorphism of LRP6 V has also been gained in the Rotterdam study van Meurs et al.
Interactions between LRP5 and LRP6 as regulators of BMD have also been observed in preclinical studies where skeletal phenotyping of mice with targeted inactivation of both receptors revealed allele dose-dependent deficits in BMD and limb formation, suggesting functional redundancy between these two genes in bone and limb development Holmen et al.
In conclusion, the data so far indicate that genetic variation in LRP5 and possibly LRP6 plays an important role in regulation of bone mass and osteoporotic fractures in humans. Not only do rare mutations in the LRP5 gene play a major role in regulating BMD, but more subtle polymorphisms also seem to regulate BMD in the normal population.
Clearly, other components of this pathway—such as the Wnts, Dkks, Frizzled, Kremen, and Sfrps—now represent prime candidate genes for further study as potential genetic regulators of bone mass. Members of the TGF-β superfamily of related secreted polypeptides control critical cellular functions during embryonic development and also postnatally.
Most attention has focused on TGF-β1, which is encoded by the TGFB1 gene as a regulator of susceptibility to osteoporosis partly because it is particularly abundant in bone and has been shown to have effects on both osteoblast and osteoclast function in vitro Massagué and Chen The receptor system for TGFβ molecules consists of two different high-affinity receptors, each of which contains an extracellular ligand-binding domain, a trans-membrane domain, and an intracellular kinase domain.
Upon TGF-β binding, the type II receptor TBR II homodimer recruits a type I receptor TBR I homodimer to form a heterotetrameric receptor complex. Ligand binding to TBR II leads to phosphorylation of a glycine- and serine-rich domain in TBR I, which results in activation of signaling by this receptor.
TBR I then phosphorylates Smad2 and Smad3, two so-called regulatory Smads or R-Smads, each of of which forms a complex with a unique common Smad, Smad4. These complexes trans-locate to the nucleus where they interact with other transcription factors and also, in the case of Smad3, with specific DNA sequences to activate a variety of downstream target genes.
Inactivation of components of the TGF-β pathway frequently results in embryonic lethality, but TGF-β1-null mice develop generalized inflammation and decreased bone mass with a pronounced reduction of the number of osteoblasts Geiser et al.
In addition, Smad3-null mice show osteopenia, which is thought to be due to excessive late-phase osteoblast differentiation into osteocytes and concomitant apoptosis Borton et al.
Polymorphisms of the TGFB1 gene have been extensively studied in relation to osteoporosis. One of the earliest studies was that of Langdahl et al. Subsequent work by the same group evaluated the relationship between several polymorphisms in TGFB1 and osteoporosis in a case-control study and identified an association between a different polymorphism in intron 5 and BMD Langdahl et al.
Other research has focused on polymorphisms in the promoter and first exon of TGFB1 in relation to BMD. One of these polymorphisms a leucine-to-proline substitution at codon 10 has been associated with BMD in some populations Yamada et al. Although genetic association studies have yielded somewhat conflicting results, definitive evidence that genetic variation in TGFB1 regulates bone mass in humans comes from the observation that Camurati-Engelmann CED disease is caused by mutations in TGFB1 Janssens et al.
CED is a rare autosomal dominant genetic disorder characterized by hyperostosis and sclerosis, especially affecting the diaphysis of long bones.
Clinically, CED is characterized by radiological osteosclerosis, but affected patients also have increased markers of bone resorption, suggesting that bone resorption is elevated as well as bone formation Hernandez et al. The causal gene for CED was mapped to chromosome 19q13 by linkage analysis Ghadami et al.
Most causal mutations lie within a region of the gene that encodes the latency-associated peptide LAP , although two other mutations have been identified in the signal peptide region, including a duplication of three leucine residues at codon 12 and a tyrosine-to-histidine amino acid change at codon Following transcription and translation, the mature TGFβ1 peptide is cleaved from the LAP but is secreted from the cell in an inactive form as a dimer, which is bound noncovalently through disulfide bonds to LAP.
These molecules can also form a larger covalent complex with a latent TGF-β-binding protein LTBP. Activation of TGFβ1, which occurs outside the cell, can occur as the result of low pH or proteolytic activity and results in the release of the active TGFβ1 dimer from the LAP and other inhibitory molecules so that it can now directly interact with the TGFβ1 receptors Janssens et al.
Functional studies have shown that CED-causing mutations all act to increase SMAD-dependent TGFβ1 signaling, but by different mechanisms. Mutations in the LAP domain appear to inhibit formation of the disulfide bonds that link TGFβ1 to the LAP and cause increased release of biologically active TGFβ1.
However, the other mutations in the signal peptide region prevent TGFβ1 secretion and result in intracellular accumulation of TGF-β1 with stimulation of SMAD signaling by an intracrine mechanism that is poorly understood. BMPs are part of the TGFβ superfamily of molecules.
Signaling through BMP is regulated extracellularly by antagonists such as noggin and chordin De Robertis and Kuroda , and intracellularly by the Smad family of signaling proteins that act downstream from specific BMP receptors Cao and Chen BMPs are strong candidate genes for regulation of bone mass, and naturally occurring mutations in various components of the BMP pathway result in defects of limb formation Seemann et al.
Recent studies indicate that polymorphic variation in members of the BMP family may be involved in regulation of bone mass and susceptibility to osteoporosis. A linkage study in Icelanders identified a locus for regulation of BMD on chromosome 20p12 Styrkarsdottir et al.
A coding polymorphism was identified at codon 37 of the BMP2 protein, resulting in a substitution of alanine for a serine residue Ser37Ala that was overrepresented in Icelandic patients and in Danish patients with osteoporosis Styrkarsdottir et al.
The mechanisms by which this substitution affects BMP signaling to affect bone mass have not yet been investigated. Other workers have reported that common polymorphism, which causes an alanine-to-valine substitution at position in the BMP4 protein AlaVal , is associated with low BMD Ramesh et al.
These association studies raise the possibility that polymorphic variation in members of the BMP family may be involved in osteoporosis, but further work will be required to confirm these observations and to study the mechanism by which the coding variants so far identified affect bone cell function and modulate bone mass.
Sclerostin is a cysteine knot-containing protein that shares homology with the DAN family of BMP antagonists Winkler et al. Sclerostin was first identified as a regulator of bone mass by genetic mapping studies in the sclerosing bone dysplasias Sclerosteosis and van Buchem disease.
These are rare conditions with a similar phenotype that are inherited in an autosomal recessive manner. Both are characterized by progressive osteosclerosis mainly affecting the skull, mandible, and tubular bones of the extremities Beighton et al.
Sclerosteosis differs from van Buchem disease because it is more severe and is associated with hand malformations such as syndactyly, absent or dysplastic nails, and radial deviation of the terminal phalanges Balemans et al.
Both diseases were mapped to the same region of chromosome 17q in the late s Van Hul et al. Interestingly, mutation screening of SOST in patients with van Buchem disease showed no mutations, but a homozygous Kb deletion was identified 35 Kb downstream from SOST as the cause of this condition Balemans et al.
Subsequent work has shown that the deleted region contains highly conserved regulatory elements that play a key role in regulating SOST expression in bone Loots et al.
Although heterozygous carriers of SOST mutations are asymptomatic, they have significantly increased BMD, indicating that haploinsufficiency of SOST increases bone mass without apparently causing adverse effects Gardner et al.
Polymorphisms of SOST have also been associated with BMD in some population-based studies. In the Rotterdam study Uitterlinden et al. In another case-control study, SOST polymorphisms were not found to be associated with BMD Balemans et al.
In view of the structural similarity between SOST and other BMP antagonists, it was initially assumed that SOST regulates bone mass by affecting BMP signaling Winkler et al. In keeping with this view was the observation that Sclerostin binds to both BMP5 and BMP6, competes with BMP6 for binding to the type I BMP receptor, and antagonizes the effects of BMP6 on Smad signaling Winkler et al.
Transgenic mice that overexpress SOST are osteopenic and have reduced bone formation, consistent with a model whereby SOST negatively regulates osteoblast function Winkler et al. However, studies by van Bezooijen et al. The mechanisms by which SOST inhibits bone formation has been clarified by recent studies, which have shown that SOST directly interacts with LRP5 and LRP6 and antagonizes Wnt signaling both in vitro and in vivo Li et al.
However, other workers have proposed that the inhibitory effect of SOST on Wnt signaling is indirect and mediated through BMP production Winkler et al. While further studies will be required to clarify the mechanisms by which SOST affects bone formation, it seems possible that the increased bone mass that results from SOST deficiency is mediated, at least in part, through the LRP5—β-catenin pathway.
The CBFA1 gene also known as Runx2 plays an essential role in regulating osteoblast differentiation, since mice that are deficient in this transcription factor have complete absence of bone Komori et al. Moreover, mice with haploinsufficiency of CBFA1 phenocopy the human syndrome of cleidocranial dysplasia CCD , a skeletal disorder characterized by short stature, hypoplasia or aplasia of the clavicles, patent fontanelles, supernumerary teeth, and other defects in skeletal patterning and growth Otto et al.
The human syndrome of CCD is caused by various missense, nonsense, and frameshift mutations of CBFA1 Lee et al. Some of these mutations have been shown to interfere with the DNA-binding activity of CBFA1, whereas others have been found to alter nuclear localization of the protein or to produce a mutant or truncated protein that is biologically inactive.
In addition to these rare mutations, various polymorphisms have been identified in CBFA1 and some of these have been associated with bone mass in population-based studies Vaughan et al. The best functional candidates lie within the Runx2 promoter Doecke et al.
The polyalanine and polyglutamine repeats are of interest since they lie within one of the transactivation domains of Runx2. Various polymorphic variations have been identified in this region, including an bp deletion that results in a polyalanine repeat of 11 residues 11 Ala compared with the more common repeat of 17 residues 17 Ala.
Various rare length variants within the polyglutamine repeat have also been identified, resulting in stretches of between 15 and 30 repeats.
The strongest association with BMD has been observed with an anonymous polymorphism in the Ala repeat region Vaughan et al.
It is currently unclear whether the length variants in the polyalanine and polyglutamine tracts have functional importance, but this is an area of ongoing investigation. Mutations in Cathepsin K are responsible for the rare syndrome of Pycnodysostosis, which is a rare recessive bone dysplasia characterized by osteosclerosis and short stature Gelb et al.
Various disease-causing mutations have been identified that result in production of either a truncated or a nonfunctional protein.
Studies of more common polymorphic variants of Cathepsin K in relation to BMD regulation in the normal population have so far yielded negative results Giraudeau et al.
The TCIRG1 gene encodes the APT6i subunit of the osteoclast-specific proton pump, and various inactivating mutations in TCIRGI have been described that are responsible for a subset of patients with recessive osteopetrosis Frattini et al.
Recent work indicates that polymorphisms of TCIRG1 might also contribute to regulation of BMD in the normal population; a study by Frattini Sobacchi et al. Functional studies need to be performed to identify the mechanisms that underlie this association, however, and to replicate the finding in other populations.
The CLCN7 gene encodes a chloride channel that is highly expressed in osteoclasts and is essential for acidification of the resorption lacuna. Homozygous inactivation mutations in CLCN7 cause a severe form of recessive osteopetrosis Kornak et al.
Prompted by this observation, Pettersson et al. Further studies will be required to determine if this polymorphism is functionally important and to replicate the observation in other populations.
Vitamin D, through its principal bioactive form 1,dihydroxyvitamin D3[1, OH 2 D 3 ] plays a crucial role in bone metabolism. The action of 1, OH 2 D 3 is mediated through a specific hormone-receptor VDR that regulates gene expression by forming a heterodimer with retinoic X receptor RXR that binds to vitamin D response elements in target genes.
Mutations in VDR cause the syndrome of vitamin D-resistant rickets which is a recessive condition characterized by alopecia, hypocalcaemia, hypophosphatemia, and severe rickets, and is resistant to treatment with vitamin D and its active metabolites Kristjansson et al.
Targeted inactivation of the VDR gene in mice provides a phenocopy of the human syndrome Bouillon et al. It therefore appears that the bone defects that result from VDR deficiency are due to malabsorption of calcium and phosphate by the intestine rather than absence of 1, OH 2 D 3 signaling in bone cells.
A recent retrospective meta-analysis of association studies that genotyped the BsmI polymorphism concluded that there was evidence of an association between spine BMD and the BsmI polymorphism, equivalent to ~0. No association with femoral neck BMD was observed.
Another polymorphism affecting exon 2 of VDR has been described that creates an alternative translational start site, resulting in the production of two isoforms of the VDR protein, which differ in length by three amino acids Gross et al. This has been associated with BMD in some, but not other, populations, and functional studies of this polymorphism have yielded inconclusive results Gross et al.
A further polymorphism has been identified in the promoter of VDR at a binding site for the transcription factor Cdx-2, which has been associated with BMD in Japanese subjects and appears to be functional Arai et al.
This polymorphism has been associated with fracture in other populations, but not with BMD Fang et al. The most comprehensive study of VDR alleles in relation to osteoporosis-related phenotypes was that of Fang et al. The data would be consistent with a model whereby the combination of risk haplotypes results in a lower VDR mRNA level due to decreased transcription and increased degradation.
Interestingly, the risk alleles for fracture identified in this study were not associated with differences in BMD. In view of this, the mechanism by which these polymorphisms predispose to fracture is unclear, although a possibility, alluded to by the authors, was through an effect on bone geometry.
Although this was a large and well-conducted study, the risk estimates were modest, and if correction had been applied for all the combinations of haplotypes tested and their interactions , the results would not have been significant. The gene encoding the α I chain of type I collagen COLIA1 is an important functional candidate for the pathogenesis of osteoporosis, since type I collagen is the major protein of bone and since mutations in this gene cause the syndrome of osteogenesis imperfecta—a rare disease characterized by increased bone fragility and reduced BMD Boyde et al.
Previous research identified associations between BMD and polymorphisms within the proximal promoter of COLIA1 Garcia-Giralt et al.
Most research has focused on a polymorphism within intron 1, which is situated at a binding site for the transcription factor Sp1. The COLIA1 Sp1-binding site polymorphism has been associated with various osteoporosis-related phenotypes, including bone density Grant et al.
It is thought that the resulting imbalance between the COLIA1 and COLIA2 chains contributes to impairment of bone strength and reduced bone mass in carriers of the T allele by subtly affecting bone mineralization Stewart et al.
Retrospective meta-analyses of published studies have concluded that carriage of the T allele is associated with reduced BMD at the lumbar spine and femoral neck and with vertebral fractures Efstathiadou et al.
In the GENOMOS study, however, the BMD association was only observed for homozygotes for the T allele, in contrast to previous studies where heterozygotes also showed a reduction in BMD Mann and Ralston Interestingly, the association between COLIA1 alleles and vertebral fracture reported in GENOMOS and other studies was not fully explained on the basis of reduced bone density, implying that the Sp1 allele also acts as a marker for bone quality.
The promoter polymorphisms of COLIA1 are in strong linkage disequilibrium with the Sp1 polymorphism, and two studies have now suggested that an extended haplotype defined by the Sp1 polymorphism and other promoter polymorphism may exert stronger effects on BMD than the individual polymorphisms Garcia-Giralt et al.
The estrogen receptor α, encoded by the ESR1 gene, is another important functional candidate for the regulation of bone mass. A large number of investigators have looked for evidence of an association between ESR1 alleles and BMD, mostly focusing on two polymorphisms within intron 1 recognized by the XbaI and PvuII restriction enzymes, and on a TA repeat in the promoter.
Studies of ESR1 alleles in relation to BMD have yielded inconsistent results, possibly because most studies have been of small sample size and involved subjects of different ages, menopausal status, and ethnic backgrounds Ioannidis et al.
In this study, no association with BMD was observed, indicating that ESR1 influences fracture risk independent of an effect on BMD. The mechanism responsible for this observation remains unclear, but one possibility may be an effect on bone quality, since ESR1 alleles have been associated with ultrasound properties of bone and bone loss Albagha et al.
Previous studies have shown that the PvuII polymorphism lies within consensus recognition sites for the AP4 and Myb transcription factors; studies using promoter-reporter assays have shown that the PvuII polymorphism influences Myb-driven transcription in vitro Herrington et al.
These data are consistent with a direct functional effect of the PvuII and XbaI polymorphisms on ESR1 gene transcription, but it remains possible that the intron 1 polymorphisms are simply in linkage disequilibrium LD with causal polymorphisms elsewhere in the ESR1 gene.
Many advances have been made in understanding the role of genetic factors in osteoporosis since publication of the first paper in the field in that showed a strong association between VDR alleles and BMD Morrison et al.
At this time it was believed that osteoporosis susceptibility would be determined by a few genes of major effect and that these would pave the way for specific targeted therapies and provide genetic markers to assess disease risk.
It has now become clear that osteoporosis susceptibility is mediated by a large number of genetic variants of modest effect size. Although there remains a prospect that genotyping for these variants could help assess the risk of osteoporosis, or complications such as fracture, it is likely that tens, or hundreds, of informative variants would have to be tested to be of real diagnostic value.
Since some of the genetic variants that predispose to osteoporosis seem to do so by mechanisms independent of BMD, it could be that these might be successfully combined with BMD measurements to improve risk assessment for complications of osteoporosis such as fragility fractures.
At the present time, many common polymorphic variants of candidate genes have been identified that contribute to osteoporosis susceptibility in specific studies.
Relatively few candidate gene polymorphisms have been validated by large-scale studies, however, and much work remains to be done to identify genetic variants that are consistently associated with osteoporosis-related phenotypes and to determine whether they will represent useful diagnostic tools and molecular targets for therapeutic manipulation.
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Chandrasekaran, MD. Table of Contents View All. Table of Contents. Role of Genetics. Other Risk Factors. Consequently, research in osteoporosis genetics has moved to the more powerful and comprehensive approach of genome-wide association studies to make progress.
Several groups worldwide are currently performing genome-wide association studies in osteoporosis, mostly studying general population cohorts, particularly focusing on BMD. An early screen from the Framingham study [ 51 ] lacked sufficient marker density and statistical power, and no findings of genome-wide significance were reported.
Two recent studies, examining larger cohorts and using denser marker sets, have been more successful. deCODE Genetics [ 52 ] studied 5, men and women from the general population, initially testing more than , single nucleotide polymorphisms SNPs , and then following up 74 SNPs in a further cohort of 7, Icelandic, Australian, and Danish individuals.
Five regions were identified that achieved genome-wide significance for association with BMD. In two cases, these SNPs were in genes that are known to be involved in bone development or turnover, including RANKL encoding receptor activator of nuclear factor-κ and its antagonist OPG encoding osteoprotegerin.
Two novel regions included an area on chromosome 1p36 close to the gene ZBTB40 encoding zinc finger and ETB domain containing 40 and, somewhat surprisingly, the major histocompatibility complex.
Significant association was also seen near to ESR1 encoding estrogen receptor-α , a gene previously associated with low BMD. However, all bar one of the associated markers lie not in ESR1 itself but in an open reading frame gene C6orf97 , which is currently of unknown expression and function.
This may prove to be the primary associated gene. Notable results were also seen for SNPs in a number of other candidate genes previously studied in osteoporosis, although not achieving genome-wide significance in this study.
These included SNPs in SOST , in the glucocorticoid receptor gene NR3C1 in the top BMD-associated SNPs overall , and in the vitamin D receptor gene and LRP5 in the top 1, SNPs. It is therefore likely that other true osteoporosis-associated SNPs will be identified among these less strongly associated markers.
The study also investigated association with fracture, in a cohort including a total of 4, fracture cases and 36, control individuals [ 52 ].
Thus, no gene was identified to have significant association with fracture but not with BMD. This lends support to the approach of studying BMD as the primary phenotype. One further point to note illustrates the importance of adequately powered studies of sufficient marker density.
ESR1 variants associated with BMD were not associated with fracture; this is in disagreement with a prospective meta-analysis of 18, individuals performed by the GENOMOS consortium [ 53 ], which identified association with fracture but not BMD.
The meta-analysis studied two intronic SNPs in ESR1 , neither of which exhibited any association in the deCODE study. The effect size of the fracture associated variants in the deCODE study [ 52 ] was small, with risk ratios ranging between 1. Individually, they are not of great use in prediction of fracture risk, which will probably require computation of risk from combinations of markers.
The current capacity of these tests to predict fracture is illustrated in Figure 1. Using the findings from the discovery component of the study, we calculated the posterior probability of a fracture for allele carriers of the five SNPs most strongly associated with fracture assuming a dominant model, Hardy-Weinberg equilibrium, and no interaction between markers [that their effects are additive].
This combination was associated with a likelihood ratio of fracture of 2. With increasing numbers of markers available, better predictive performance will be possible, although larger combinations of markers will be relevant to smaller numbers of people.
How such genetic tests interact with traditional osteoporosis risk factors such as BMD has yet to be established. Fracture risk given genetic marker findings. Presented is the post-test probability of fracture given the pre-test risk and findings at five most strongly fracture-associated SNPs in deCODE osteoporosis genome-wide association study [ 52 ].
SNP, single nucleotide polymorphism. Two genes reached genome-wide significance, namely LRP5 and OPG. These studies illustrate the massive sample sizes required to identify osteoporosis genes, particularly if fracture is used as the study end-point.
Studies of younger fracture cohorts are likely to be more fruitful, given the greater heritability suggested for hip fracture in younger cases, but these will be harder to recruit, because most fractures occur in older age cohorts. The small effect size seen with the fracture-associated variants indicates that future studies will need to be adequately powered to detect variants with odds ratios lower than those observed here, and will thus need to be extremely large.
For example, assuming an equal number of cases and controls, an SNP with minor allele frequency of 0. The genetic assumptions underlying this calculation are actually optimistic. Much larger numbers will be required if the associated variants are less common, if the mapping SNP and fracture-associated SNP have different allele frequencies, or if gene-gene interactions are involved.
In reality, the numbers required will be beyond the reach of individual studies, and large consortia and meta-analytical methods will be required to achieve adequate power.
The genetics community is well aware of this, and the recently established European Union funded 'Genetic Factors in Osteoporosis' GEFOS consortium has rapidly established itself as the central organization for such efforts worldwide. There is little doubt that genome-wide association studies will identify more genes that are involved in bone fragility than those that have been reported so far.
Genome-wide association analysis in unselected populations has proven to be a powerful method with which to identify common genes of moderate effect size. The studies performed to date are not sufficiently powered to identify genes of smaller population effect, and may not identify some forms of human genetic variation that are likely to influence bone fragility.
No single approach is likely to identify all bone fragility genes, and a variety of different methods are either being developed or are in use to tackle the problem. The usual mantra for complex diseases is that larger studies are needed and are likely to make many further contributions to what we know.
Size isn't everything, however; it is equally likely that more efficient study designs of selected cohorts aimed at maximizing the power to detect association will make further significant discoveries, and at considerably lower genotyping cost than simply increasing the sample size.
In particular, cohorts recruited to minimize genetic heterogeneity are likely to be valuable. The genetic control over skeletal development is known to vary between sites and sexes, and it is likely that genes make different contributions at different ages.
Thus, cohorts recruited to investigate osteoporosis genetics focusing on a particular site, age, and sex are likely to have greater power to identify genes than studies of cohorts recruited unselected from the general population. Our group recently demonstrated this with a proof-of-principle study [ 45 ], which easily confirmed the known association of LRP5 with BMD in a cohort of just postmenopausal women selected for extreme BMD at the hip.
Meta-analysis may also produce findings that individual screens have missed. Although in the past competition between groups hindered data sharing for meta-analysis, there is a solid recognition among osteoporosis researchers that collaboration and open data sharing will be essential both for gene discovery and for replication.
Genetics research is technology driven. Genome-wide association analysis was made possible by chip-based SNP genotyping technology. A further genetics revolution is being brought about by the development of next-generation sequencers capable of producing up to 20 gigabases per run, which has reignited interest in monogenic diseases.
It is likely that in a high proportion of individuals with extreme phenotypes such as extreme high or low BMD in humans a monogenic — usually rare — mutation underlies their extreme phenotype, as has been demonstrated, for example, with osteogenesis imperfecta type 1 and Marfan's syndrome. When there were not enough family members to help localize the gene by traditional linkage methods, or the individual did not fit a known syndrome that would allow population studies to be conducted, the mutations in these cases could not be identified.
With the new sequencing capacity it will be possible to sequence extremely large proportions of the genome such as, for example, all exons in a single sequencing run.
Such cases may be studied again, and it is highly likely that new disease genes affecting bone fragility will be identified, not just of relevance to these extreme phenotypes but also to control of BMD in the general population.
Two further influences on human variation that have yet to be addressed significantly in osteoporosis include copy number variation CNV and gene-gene interaction.
CNV is known to be common throughout the genome and is likely to influence gene expression. High-throughput, accurate genotyping methods for CNV are still in development, but array-based methods show promise.
Gene-gene interaction is known from mouse models to influence skeletal development significantly [ 55 ] and is thus likely also to contribute to human skeletal development.
All genome-wide association studies to date have been single-marker studies, but it is likely that once sufficient cases have been screened, more complex genetic models will be tested.
Mouse genetics to date has contributed much to what we know about the genetic epidemiology of bone fragility and associated phenotypes, such as BMD and bone microarchitecture. Hypothesis-free gene mapping of bone fragility genes has made slow progress though.
Congenic approaches, investigating the genetic causes of differences in bone parameters between inbred mouse strains, has yielded some success in the identification of Alox12 , implicating the lipoxygenase system in osteoporosis [ 56 ]. However, the inbred nature of the mice restricts the mapping resolution that can be obtained, and most established linkages with bone parameters have not resulted in identification of the causative gene.
An alternate approach is ENU mutagenesis, in which male mice are treated with the alkylating agent ethinyl-nitrosourea, causing point mutations in sperm DNA. Offspring of these mice carry these mutations. By screening thousands of offspring of mutagenized mice, mice with phenotypes generally caused by monogenic point mutations caused by the ENU can be identified.
These monogenic variants are much easier to map than congenic genes, and because the mutations concerned are not as severe as knock-out or knock-in methods, the models are more physiological.
This approach is being used by a number of groups worldwide to create new mouse models of osteoporosis. This is a time of great excitement in the world of genetics generally, and in osteoporosis genetics specifically.
The publication of the Wellcome Trust Case Control Consortium less than 12 months ago at the time of writing [ 57 ] was not only an enormous leap forward in identifying that genes that underlie complex genetic disorders such as inflammatory bowel disease, ankylosing spondylitis, and type 1 diabetes.
It also provided proof that the approach adopted was going to work for other complex quantitative traits such as osteoporosis. The success of early genome-wide association studies in osteoporosis supports this position.
Already, these studies have identified novel pathways that contribute to control of BMD and bone fragility with possible therapeutic targets. The possibility of genetic prognostic tests, adding to existing predictive information from BMD, is likely to become a reality within the next decade.
Hopefully, the frustrations of the past few decades have taught the genetics community that careful phenotyping, sophisticated study design, adequately powered cohorts, and collaboration are key elements to successful gene identification.
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Athldte is a common disease with a genegic genetic component characterized aand Athlete bone health and genetic factors bone tactors and increased Black pepper extract for brain health of fragility fractures. Twin bpne family studies have shown that the heritability of bone mineral density BMD hezlth other determinants of fracture Improve your metabolism naturally as ultrasound properties of bone, skeletal geometry, and bone turnover—is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population.
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