Osteoporosis risk factors: prevention and detection through clinical and genetic monitoring

Abstracts

A osteoporose é uma doença sistêmica caracterizada pela baixa massa óssea e deterioração da micro arquitetura do tecido ósseo. Consequentemente existe um aumento na fragilidade do osso e suscetibilidade à fratura, que é considerada o efeito clínico mais importante deste processo. Muitos estudos que se utilizam de modelos em gêmeos ou pais e seus descendentes têm confirmado o papel da herança genética no pico de massa óssea, na verdade o maior fator de risco da fratura. Neste artigo de revisão, são enfocados os prováveis genes envolvidos no processo de osteoporose, ressaltando a importância das interações entre gene- gene e gene-ambiente. Concernente à influência isolada do ambiente, são abordados os hábitos relacionados ao estilo de vida, à nutrição e ao tabagismo envolvidos no aparecimento dessa doença. Durante os próximos anos, o conhecimento baseado na genética molecular elucidará o processo osteoporótico. Do mesmo modo, os estudos clínicos se expandirão, visando contribuir para a detecção precoce da doença, permitindo assim a aplicação de medidas preventivas e terapêuticas adequadas.

Osteoporose; Aspectos genéticos; Prevenção; Detecção

ARTIGO DE REVISÃO

Osteoporosis risk factors: prevention and detection through clinical and genetic monitoring

Nívea Dulce Tedeschi Conforti Froes^I; Edgard dos Santos Pereira^II; Wilson Fábio Negrelli^III

^IMaster and PhD in Genetics by Universidade Estadual Paulista, UNESP; Post-Doc by Texas University, Preventive Medicine Department, Galveston, USA

^IIChairman, Faculdade de Medicina Unisa; Co-ordinator of Medical Residency from Hospital de Vila Penteado

^IIIOrthopedist and Traumatologist. Spine Surgery Group Co-ordinator from Hospital de Vila Penteado

^{Correspondence}

SUMMARY

Osteoporosis is a systemic disorder characterized by low bone mass and microarchitectural deterioration of bone tissue. Consequently, there is an increase in bone fragility and susceptibility to fracture, which is considered the most important clinical outcome of this process. Several studies using twins or parents- offspring models have confirmed the strong heritability of peak bone mass, in fact, the major risk factor of fracture. In this review article, we focused on the candidate genes involved in osteoporosis, pointing out the importance of the interaction between gene-gene and gene-environment. Concerning the environmental influence itself, we approach about life style, nutrition and smoke habit related with the disease onset. During the coming years, knowledge on the genetic molecular basis will elucidate the osteoporosis process. At the same way, clinical studies will expand in order to contribute to early detection of the disease, thus allowing application of adequate preventive and therapeutic measures.

Key words: Osteoporosis. Genetic aspects. Prevention. Detection

REVIEW ARTICLE

Osteoporosis is a metabolic disease characterized by low bone mass and deterioration of bone tissue, which leads to impaired skeletal strength and increased susceptibility to fracture. Familial studies have suggested osteoporosis as a genetic disease with involvement of different genes and the majority (85%) of bone mass variation is under genetic control⁽⁶²⁾.

Bone mass means the difference between maximum mineral density content acquired during growth and the consequent loss verified during senility period. Those changes occur during bone remodeling process as a result of re-absorption cells (osteoclasts) and forming cells (osteoblasts) disequilibrium that remove and replace bone packages in discrete points of the skeletal. According of this, it can be noticed that the bone is an alive tissue, its matrix and mineral supplements are remodeling constantly along the mechanical stress lines⁽⁴⁰⁾.

Osteoporosis is a silent disease that progresses without any outward sign, sometimes for decades. It affects thousands of people and for this reason it has been considered a world health problem that hampers the quality of life, mainly in elderly people.

Nowadays, the costs related to osteoporosis have been considered as the major concern for the authorities in developed countries. In the United States, the treatment cost is beyond U$10 billion annually. There are more than 25 million affected people, 12% males and 40% females⁽¹³⁾. It has been estimated that bone loss reaches more than 220 million people, which represent ¼ world population⁽⁴⁹⁾.

Fracture is considered the most important clinical feature in osteoporosis. Its repair involves complex physiological steps with the coordinated participation of different cells⁽¹⁸⁾. Lately, the molecular genetics became a powerful tool for medical research⁽⁴⁴⁾, enabling to identify important mechanisms involved in fracture healing that occurs at molecular level, through new methodologies⁽²⁶⁾.

The genetic role in osteoporosis has been considered as a clear process involving density modulation and shape and size of the bone⁽¹⁵⁾. The skeletal fragility is determined by bone micro-structure and mass. The bone mass pick is the main issue for quantification of risk fracture⁽⁵¹⁾ and allelic variations in the vitamin D receptor gene (VDR) has been related as responsible for calcium metabolism with subsequent effects on bone density and size^{(12,20,48,55,62)}. Individuals bearing unfavorable genotypes with the presence of mutation at specific sites of VDR gene, present higher fractures incidence and prevalence, besides bone mass loss^(5,23,24). Nevertheless, contradictory data have been presented⁽⁶³⁾ that did not find association between VDR mutation and osteoporosis risk in Afro- American women. According of this, the theory that it has to be considered the ethnic differences is reinforced, once the genetic inheritance is preponderant regarding the development of the disease. Furthermore, it has also to be considered the gene-age⁽²¹⁾, gene-gene⁽²⁰⁾ and gene-environmental interactions⁽¹⁹⁾.

Recently, it was emphasized the interaction between the VDR and estrogen receptor gene (ER) in bone density⁽¹²⁾ which corroborates with the hypothesis that the better is the understanding of the disease, the better is the treatment focusing bone mass preservation. The estrogen influences on bone metabolism and developing and this effect depends on nuclear receptor⁽⁴⁷⁾. Caucasian American women that are ER mutant present significant low mineral density compared to those who have normal genotypes⁽⁶³⁾. Moreover, the genetic variation at the locus, singly and in relation to the Vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others⁽⁴⁾. There is a potential physiologic link between the ER and vitamin D. The vitamin D is among the hormones that regulate P450 aromatase and this enzyme, which modulates availability of estrogen to its receptor, is expressed in osteoblasts.

One of the hormones involved in bone metabolism is calcitonin, a polypeptide hormone secreted by parafollicular cells of the thyroid gland, able to inhibit osteoclastic bone resorption and to stimulate urinary calcium excretion. The role of the gene encoding for a peptide hormone receptor (CTR) was evaluated⁽⁴¹⁾ in BMD determination in a population of Italian postmenopausal women. They found that genotype Tt was the most frequently represented in both osteoporotic and normal women. Women with tt genotype showed a lower spinal BMD in comparison with those the Tt genotype. Otherwise, no significant variations of BMD among the genotypes were observed in the femoral neck BMD. This observation is in agreement with a stronger genetic influence on bone mass at sites with higher proportions of trabecular bone and with a genetic specificity for anatomical sites. Polymorphic forms of CTR may underlie individual differences in susceptibility to bone mass loss and to responsiveness to treatment regimens.

According to this, the CTR gene becomes a new candidate in the scenario of genes influencing BMD determinations.

The collagen type 1 is the most abundant bone extra-cellular protein, moreover is essential for skeletal strength and also associated with bone mass and fracture predisposition. It contains a polymorphic site named Sp1, recessive mutations are related with fracture prone⁽³⁷⁾. This suggests that COL1A1- Sp1 polymorphic locus could be related to the quality of collagen in the skeleton. Altogether, these results suggest that COL1A1 gene may be implicated in the determination of bone mass or strength. Significant differences on genotypic distribution were encountered in osteoporotic patients when compared with control people, therefore the study of this polymorphism can contribute for clinical identification of at risk individuals, both males and females.

Another candidate gene is the apolipoprotein E (APOE) that acts as a ligand for low density lipoprotein receptors and facilitates intro-vascular transport of lipids and vitamin K, a co-factor for the g- carboxiglutamin formation of many bone matrix proteins⁽⁷⁾. One possible explanation for the APOE gene and fracture occurrence is that it can interfere in vitamin K absorption^(30,31). As already known, vitamin K modulates the gama-carboxilation of glutamine residues in most bone proteins, mainly osteocalcin, therefore, high decarboxilated osteocalcin and low concentrations of vitamin K are associated to low mineral density and consequently to a higher fracture risks. Recently⁽⁷⁾, it was reported that women bearing at least a mutant allele of APOE gene are under a elevated risk of hip and wrist fractures, data confirmed by others.

There is no doubt about genetic involvement on bone modulation, shape and size. No matter the age or life period, the genetic inheritance plays a important role in those processes although there is an interaction between genes and environmental factors, such as diet and life style⁽¹⁵⁾ which interfere in the penetrance of the gene⁽⁵⁴⁾. According to that, beyond descriptive population studies, there is an increased interest concerning the role of individual or population variability in the disease susceptibility⁽¹⁾. Thereby, to decode the genetic basis of response variability to environmental xenobiotic can answer questions such as why certain groups present higher incidence of an specific disease. In the same manner, it would constitute a strong tool focusing on prevention of a ill condition.

Among the available biomarkers for biological system researches, the effect markers indicate the presence of diseases or its precursors and susceptibility markers indicate biological individual differences capable to affect the response of an organism to environment agents⁽⁹⁾. Those markers constitute unique tolls to be adopted as prevention strategies^(35,60). Besides, the genetic markers will be utilized in a close future not only in epidemiologic studies and in clinical practices, as well.

Among the environmental factors involved in osteoporotic process, the nutrition, mainly related with protein intake, dairy products and vegetables are referred to enhance bone mass formation^(3,50,52). The calcium and vitamin K supplements during childhood seem to contribute with bone health⁽⁶¹⁾. Retrospective studies in adults suggest that the calcium intake during the first phase of development are associated with the occurrence of risk fracture and osteoporosis onset in elderly phase^(56,59). However, it is important to consider that the absorption capacity varies depending on genetic individual constitution⁽⁴²⁾.

The caffeine and alcohol intake along with the smoke habit seem to decrease bone density^(33,58). Most likely, caffeine effect is associated with the increase of calcium excretion. Overall, daily intake of more than two cups is moderately associated with the increase of fracture risk⁽³⁴⁾. These data are not corroborated by other authors that affirm there is no consistence between caffeine intake, risk fracture and osteoporosis development^(10,39).

Concerning smoke habit and alcohol intake there is less inconsistency, once cigarette smoke is considered as a moderate risk factor for osteoporosis⁽⁵⁷⁾. The chemical cigarette components, including nicotine, acting as a depressor of osteoblast cell activity, both directly or by hormonal pathway^(29,36). An average bone mineral density of 5 to 10% deficit and a detrimental effect as well are reported in smoke people⁽³⁸⁾, reason why the cigarette is related with an increase risk of fractures⁽²⁸⁾ and as a bone loss inducer, both in males and females. These consequences are probably due to the cigarette anti-estrogenic effect which reduces estradiol level and the increase of sexual hormone globulin ligand^(11,14,27). It has to be point out that the deleterious cigarette effects are not restricted to elderly people, once there⁽⁴⁶⁾ is data reporting bone mass loss in young and health men, considered heavy smokers (more than 21 cigarettes/day).

Concerning alcohol intake it seems to have a direct effect on osteoblast cells which determines a decrease in osteocalcin levels during the early stages and hystomorphometric changes in further stages. Besides the decreasing effect in bone formation, it is also reported an re-absorption increase^(17,32). In chronic alcoholic people, the seric levels of vitamin D and its metabolites diminish, independently of any hepatic anomaly. The alcoholic consuming that exceeds 200 ml weekly may interfere in estrogenic levels which can be associated with osteoporosis onset⁽²²⁾.

The physical activity has been pointed as a contributor factor that promotes bone mass increase, consequently reducing the fracture risk⁽²⁵⁾. The specific benefits of a regular exercise program include the weight control, the increase of lipid blood profile and micro-nutrients ingestion^(45,53). The physical activity is counseled since childhood, because this is the period when the bone mass is formed⁽⁶⁾. At the same time, physical over-activity during youth has to be avoided due to hormonal imbalance verified in young athletes⁽²⁾.

According to the present information it seems evident that knowing the molecular physiologic effect of the involved genes in osteoporosis will certainly lead to better understanding of the disease, making the diagnosis easier and mainly helping in the identification and detection of at risk groups, propitiating a specific management of individual treatment as well, by enabling the selection of therapeutic more appropriated options⁽¹⁶⁾.

The use of molecular markers allied to clinical follow up are the precise tool in the ethiology understanding and the risk factors detection as well. This kind of monitoring performs a preventive approach which in a close future will be required in large scale to proportionate a better quality of life. It will contribute in a unique way to diminish the osteoporosis incidence, considered a global health problem.

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Publication Dates

• Publication in this collection
  21 Sept 2005
• Date of issue
  Mar 2002

History

• Accepted
  27 Nov 2001
• Received
  25 July 2001