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Osteoporosis Genetic Testing, OsteoGenomiX®

Genetic testing of osteoporosis with Diagnostiki Athinon’s OsteoGenomiX® is an important laboratory effort to identify individuals at increased risk of developing osteoporosis.

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Osteoporosis is a progressive systemic bone disease characterized by a decrease in density and disruption in the micro-architecture of bone tissue. It is accompanied by reduced bone strength and high risk of fractures. Osteoporosis is the leading cause of disability in the elderly and femoral neck  (hip), accompanied by high mortality. According to WHO, about 35% of fractures in women (and 20% of fractures in men) are related to osteoporosis.

Identifying high-risk groups, early detection of reduced bone mass density (BMD) and prevention of osteoporosis all contribute to reducing the risk of fractures and disability. However, in most cases, the diagnosis of osteoporosis is often made after the onset of fractures.

Among all cases of osteoporosis, primary osteoporosis (mainly postmenopausal osteoporosis) accounts for about 85% of all cases. The deficiency of sex hormones observed in postmenopausal women, especially estrogens, is a significant risk factor. In addition to gender and age of women, there are other risk factors for osteoporosis: Caucasian race, low weight, high height (over 172 cm for women and 183 cm for men), and very thin body type (ectomorphic body type). The deficiency of 25-hydroxy vitamin D3 is a significant risk factor for osteoporosis.

A strained family history (presence of relatives with osteoporosis) often indicates the risk of osteoporosis and fragility fractures, especially hip and vertebral fractures. The high importance of the genetic background in the pathogenesis of the disease occurs in 45-70% of cases. Bone density characteristics are inherited from parents to children.

In some cases, despite the presence of normal bone density, there may be disturbances in the micro-architecture of the bones leading to increased fragility. This condition can lead to an underestimation of the risk of osteoporosis and dangerous fractures. In this regard, more and more attention is being paid to the detection of gene polymorphisms (SNPs) associated with osteoporosis.

Osteoporosis gene network

One of the most well-known genes associated with osteoporosis is the vitamin D receptor gene (VDR gene). Vitamin D receptor is an intracellular receptor for vitamin D3. This receptor can alter the expression of genes involved in calcium homeostasis, which can lead to reduced bone density in both children and young girls and postmenopausal women. It is also associated with low bone density in men.

Estrogens and estrogen receptors, the most important of which is the estrogen receptor alpha (ESR1), play an important role in bone tissue metabolism. Estrogen receptors are found in both osteoclasts and osteoblasts. Estrogens inhibit bone resorption by reducing the amount, activity, and lifespan of osteoclasts. Estrogen deficiency or polymorphism of the estrogen receptor gene leads to a disorder of bone remodeling dominated by bone resorption over the formation of new bone.

The enzyme aromatase (CYP19A1) plays an important role in estrogen synthesis and osteoporosis. Catalyzes the conversion of testosterone to estrogen. Aromatase levels have been shown to affect the condition of the cancellous bone (spine), while the difference in the number of estrogen receptors affects the condition of mainly the cortical bone (femoral neck).

RANK / RANKL / OPG system imbalance is a powerful factor leading to the development of postmenopausal osteoporosis due to estrogen deficiency. The degree of bone remodeling is controlled by the balance between the expression of osteoprotegerin (OPG) and the expression of the receptor activator nuclear factor kappa-B ligand (RANKL). When the balance shifts to the OPG, bone resorption is inhibited, and new bone formation dominates. In case the effect of RANKL prevails, bone resorption prevails.

The production of certain cytokines promotes osteoclastogenesis and inhibits osteoclast apoptosis. One of the major cytokines (protein products of the cells of the immune system) that affects bone metabolism is interleukin-6 (IL-6) in the gene of which there are protective polymorphisms that reduce the risk of bone resorption and appearance. osteoporosis in postmenopausal women.

The estrogen-independent phase of bone tissue metabolism is activated by LRP5 (a low-density lipoprotein receptor-related protein 5), which stimulates the proliferation and differentiation of osteoblasts and osteoclasts. Mutations and polymorphisms of this gene are independent risk factors for fractures and do not depend on bone density, age, or sex.

Disorder in the structure of collagen is one of the causes of fractures in postmenopausal osteoporosis which is also associated with bone density. Thanks to collagen, bone tissue combine hardness and durability with elasticity and flexibility, while polymorphisms in the regulatory region of the COL1A1 gene (collagen type I, alpha 1) encoding the alpha-1 chain lead to disruption of bone collagen structure and increases the risk of osteoporosis.

It is important to know that the same parameter can have different effects on men and women.

The existence of genetic risk factors is the basis for genetic analysis. The complete evaluation of the genetic and non-genetic factors allows the most accurate assessment of the risk of osteoporosis and the prognosis of the disease, as well as the individual choice of preventive and/or therapeutic measures.

In addition to genetic risk factors, non-genetic or epigenetic factors play an important role in the development of the disease:

  • Non-modifiable factors
    • Low bone density
    • Female gender
    • Age over 65 years
    • Caucasian race
    • Family history (osteoporosis or fragility fractures over the age of 50)
    • Hypogonadism
    • The systematic intake of glucocorticoids for more than 3 months
    • History of fractures
    • Prolonged immobilization
  • Modifiable factors
    • BMI <18.5 kg / m2 or body weight <57 kg
    • Smoking
    • Absence of physical activity
    • Insufficient calcium intake
    • Vitamin D deficiency (also caused by lack of sun exposure)
    • Alcohol abuse
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