Osteoporosis (OP) is asymptomatic disease until the experience of falls or impacts that cause broken bones or fractures happened. Estrogen deficiency, abnormality in bone matrix components and interleukins expression can impact on bone homeostasis which gradually paved to osteoclastogenesis over activation leading to bone loss. A current case-control study was designed to explain the alteration in certain biochemicals, bone matrix components, immunological and molecular parameters that which accompanied with OP in the postmenopausal women. The period of study's investigation was from December 2022 to July 2023. All participants provided written informed consent, and the study was approved by Department of Biology, College of Science, University of Baghdad Ethical Council (Reference code CSEC/0922/0092, on 26-9-2022). One hundred and ten postmenopausal women were randomly chosen to participate in this study based on specific criteria from Al-Wasity Hospital, Medical City and Al- Imamein Kadhimein Medical City Hospitles, Baghdad, Iraq. The age of the participants was ranged from 45 to 70 years. Firstly, Dual Energy X-ray Absorptiometry (DEXA) scan was performed to all participants in order to assess the precence or abscense of OP disease. Out of 110 samples, 70 samples were confirmed with OP. Meanwhile, 40 samples were control. Venous blood samples were collected from all participants to estimated compelet blood count (CBC), immunological parameters as C-Reactive Protein (CRP), Rheumatoid Facter (RF), Anticyclical Citrullinated Peptide Antibody (ACPA), Interleukin-8 (IL8), Interleukin (IL-17), and Interleukins-22 (IL-22) using enzyme link immunosorbent assay (ELISA) technique, Parathyroid Hormone (PTH), and Calicum (Ca+2), bone matrix component parameters osteopontin (OPN), osteocalicn (OCN), and osteonectin (ON), in addition to,Osteopontin gene SNP rs11730582 polymorphism was determined by the Hight Resolution Melting (HRM) analysis. Highly significant (P≤0.01) decrease in WBC count (6.30±0.18 k/mcL) and HGB (9.900±0.132 g/dL) were observed in OP patients as when compared with the control group, WBC was (8.26±0.27k/mcL) and HGB was (13.321±0.287 g/dL), Conversely, highly significant (P≤0.01) increase was recorded in ESR (43.73±1.76 mm/hr), PLT (437.88±7.00 1083/uL) in OP patients in compare with control, (21.10±1.25mm/hr), and (226.79±9.39 1083/uL), respectively. However, highly significant (P≤0.01) increase was noticed in immunological parameters: CRP was (18.26±1.33 pg/ml), RF (IU/ml) results were positive, and ACPA was (23.26±2.74EU/ml) in OP patients when compared with control, CRP (2.92±0.18 pg/ml), RF (IU/ml) results were negative, and ACPA was (6.26±0.56 EU/ml). Beside to, highly significant (P≤0.01) increase was recorded in IL-8 serum level (249.08 ±19.98ng/ml), IL-17 (107.862±9.25ng/ml), and IL-22 (57.73±2.47 ng/ml) in OP patients as compared with the healthy control group were IL-8 (65.29 ± 5.62 ng/ml), IL-17 (46.135 ± 8.66 ng/ml) and IL-22 (13.57 ± 3.16 ng/ml). The mean PTH serum level of OP patients group was (77.80±1.79pg/mL) and in control group was (35.81±2.06pg/mL), whereas a highly significant (P≤0.01) decrease in mean of Ca⁺² serum level was recorded in OP patients (4.89±0.21 mmol/L) in compared with control group (9.63±0.13 mmol/L). Additionally, high significant (P≤0.01) increase was detected in OPN serum level (16.88±0.77 ng/ml) and OCN (29.86±2.25ng/ml) in OP patients as compared with the healthy control group (5.95±0.41ng/ml and 10.73±0.86ng/ml), respectively. In contrast, ON serum level recorded a highly significant (P≤0.01) decrease in the patient group (1.78±0.971ng/ml) compared with the control group (3.42±0.20ng/ml). The frequency of homozygote TT genotype in patient's analysis was, (14.3%), (10/70) than control group (27.5%), (11/40). While, the frequency heterozygote TC and homozygote mutant CC genotypes were [TC= (71.42%) 50/70 and CC= 14.3% (10/70)] and these genotypes frequency were not significantly differet from those of the control group, (TC= 60%, (24/40), and (CC= 12.5% 5/40). P-value was different (0.0158) significantly in genotype distribution of rs11730582 polymorphism in OP patients whereas, the P-value of rs11730582 was (0.1500) non-significant in control group. In conclusion, this study found that OPN, OCN, and ON protein act as a sensitive monitoring indicator can be used in early detection of osteoporosis. And because of the capacity to activate osteoclastogenesis and promote bone resorption, IL-8, IL-17, IL-22 and rs11730582 of OPN gene polymorphism may be serve as a biomarkers, pro-inflammatory and immune-stimulating factors in OP development.