Osteoporosis is a multifactorial disease that develops through various interactions between genetic, metabolic and environmental factors, with a large influence on the biomechanics of the musculoskeletal system. Environmental factors include decreased physical activity, smoking, alcohol consumption, diminished exposure to sun (decreased vitamin D synthesis), and the use of some medications, such as glucocorticoids and anticonvulsants (Al Anouti et al, 2019). PMOP is usually characterized by a high risk of fracture, thus resulting in substantial morbidity and mortality. Ethnicity and race can also affect the incidence of PMOP.
Vascular control is vital for bone development and repair, deficiency of this control has an impact on the skeletal system. VEGF is identified as an angiogenetic factor generated by many cell types, such as endothelial cells and osteoblasts (Hiltunen et al, 2003). VEGF induces angiogenesis by facilitating endothelial cells proliferation and migration to build new blood vessels (Yoo et al, 2008). Bone formation is related with angiogenesis, and vascular invasion is essential for endochondral bone formation and fracture healing. VEGF has been reported to induce primary human osteoblast chemotaxis and differentiation. It was demonstrated that these cells express VEGFR-1 and VEGFR-2. In addition, osteoblast apoptosis can be hindered by VEGF (Hiltunen et al, 2003). Hiltunen et al. proposes that VEGF-A gene transfer mediated by adenovirus stimulates formation of bone through elevated osteoblast activity and may be beneficial for the management of osteoporosis and other diseases that necessitate effective osteogenic therapy in animal model (Hiltunen et al, 2003). Nasser et al. studied expression of VEGF between the perimenopausal, premenopausal, and postmenopausal women and between nonosteoporotic and osteoporotic women (Nasser et al, 2013). They found reduction of expression of VEGF in postmenopausal osteoporotic patients' bone and is associated with bone mineral density (BMD).
There are some research suggesting reduced VEGF values in osteoporosis [Pufe et al, 2007, Pufe et al, 2003). The decrease in VEGF values related with the measurement of BMD. Martinez et al. found an reduction of the VEGF released levels in osteoblasts due to age (Martínez et al, 2002). They concluded that VEGF may be a crucial modulating factor for remodelling of bone in PMOP patients. Also, a study conducted in Turkey showed statistically significantly lower serum VEGF concentrations in PMO patients compared to healthy controls (Senel et al, 2013).
Polymorphisms in the exons, introns, promoter, and untranslated regions (3′-and 5′-UTRs) of a gene might influence the production or function of the relevant protein (Watson et al, 2000). There is highly polymorphic VEGF gene and VEGF protein expression may be altered by functional polymorphisms of the VEGF gene. There are some reports that VEGF gene polymorphisms have a correlation with development and prognosis of several diseases (Wang et al, 2015; Han et al, 2004; Bao et al, 2019). Costa et al. studied VEGF C936T variant on 252 postmenopausal Caucasian women (136 osteoporotic and 116 non-osteoporotic). They found no significant difference in allele frequencies between osteoporotic and non-osteoporotic women (Costa et al, 2009). In the previous study conducted in our country with PMOP and VEGF 935C/T-, 2578C/A variants, no significant difference was found between osteoporotic and non-osteoporotic women in terms of frequencies of genotypes and alleles of two variants (Deveci et al, 2016). Chung et al. investigated whether or not there was an association between VEGF − 2578C/A, -1154G/A, -634G/C, and 936C/T variants and haplotypes and osteoporotic vertebral compression fractures (OVCF) in postmenopausal women in Korea (Chung et al, 2010). They found that the A-G-G-C haplotype tended to be related to OVCF in postmenopausal women in Korea.
A functional 18-bp I/D polymorphism, found gene expression was affected at position − 2549 in the promoter region of VEGF, whereby the deletion (D) allele results in a 1.95-fold elevation of transcriptional activity in comparison with the insertion (I) allele (Yang et al, 2003). This study found the possible relationship between the 18-bp I/D variant in the promoter region of VEGF and the PMOP risk for the first time in a sample of the Turkish population. The findings showed no association between VEGF I/D variant in Turkish women.
The studies on case-control association can significantly help understand the role of genes in the osteoporosis. This study has some limitations. First, our focus was on only one variant in the VEGF pathway, and the pathogenesis of PMOP may be also affected by other regulatory genes in the VEGF family signaling pathway. Second, since the sample size was rather small, the frequencies of some homozygous variants were low in groups, decreasing the statistical power. In the end, another limitation is that expression levels and blood levels of VEGF have not been evaluated.
The incidences of osteoporosis and its potentially devastating sequalae due to increasing fractures associated with disability, morbidity, and decreased quality of life. Consequently, prevention and management of osteoporosis is very important. Findings in terms of the effect of VEGF gene variants on osteoporosis pathogenesis are conflicting; however there may be clarification of data difference in terms of the genetic variability of populations. In this study, no significant association was found between VEGF I/D variant and PMOP, but the first result about this variant and PMOP in a Turkish cohort was shown. Studies with a larger population should be performed with other ethnic groups or different subjects to illuminate the effects of these variants on PMOP susceptibility.