Femoral hip osteoporotic fracture risk in Jordanian cohort and their relationships with hypertension and antihypertensive drugs

Background : Osteoporosis and hypertension (HTN) are frequent and often coexisting diseases among the elderly. Recent studies suggested that both diseases may share the same etiopathology. Moreover, the treatment of hypertension can either positively or negatively affect the bone mineral density (BMD) and consequently, either improving or worsening the patients’ osteoporosis statuses, respectively. Aim : The primary aim of this study is to determine the odd ratios, pearson and spearman correlations, and the distribution rates of the HTN statuses and their corresponding anti-HTN medications, in addition to other investigated comparative variables, across two categorized cohorts; the lower risk of femoral hip osteoporotic fracture (fHOPF) cohort [Cohort I] versus the higher fHOPF cohort [Cohort II], in Jordanian cohort. Methods : The investigated studied participants were either allocated to non-HTN versus HTN cohorts (Cohort I vs Cohort II, respectively). Also, the anti-HTN medications were categorized into 6 major medication’s group; Group I-VI. Both aforementioned categorized 2 patients’ cohorts and 6 medications’ groups were analyzed via chi square test to express the comparison results as distribution rates strength of associations (odd ratios), Pearson chi-square statistic (χ 2), Goodness of Fit (G-Test of independence), and Pearson (r) and Spearman (ρ) correlations. Patients who were on thiazide or thiazide like diuretics with ACEIs or ARBs had the lowest incidence rate of higher risk of fHOPF (50%), followed by patients who were on BBs with thiazide or thiazide like diuretics (66.7%), CCBs with thiazide or thiazide like diuretics (85%), CCBs with ACEIs or ARBs (85.7%), and lastly for patients who took CCBs with or without BBS (100%) [R & ρ [-0.390±0.081 &-0.362±0.068], χ 2 & G-Test [18.685 & 18.805], p-Value [0.002 &0.002]]. Results : Overall, 206 participants who were clinically diagnosed for osteoporotic fracture risk at our rehabilitation and rheumatology clinic between Sep 2021 and Nov 2021, were studied to investigate the differences of the various investigated independent variables across the 2 dichotomized HTN related cohorts; Cohort I-II. In this study, 49.03% (101 of the eligible patients) were allocated to the non-HTN affected cohort (Cohort I) and 50.97% (101 of the overall participants) were comparatively allocated to the HTN affected cohort (Cohort II). Conclusion : The thiazide or thiazide like diuretics and ACEIs or ARBs, alone or in combination, may positively improve the femoral hip bone mineral densities and consequently mitigate the risk of osteoporotic fractures.


Introduction
Hypertension affected patients, especially when accompanied with chronic kidney diseases, (CKD) are often have a higher probability of bone architectural distortion and consequently a higher likely of osteoporotic fracture. Indeed, the exaggerated rate of ageing related dual hypertension and osteoporosis cases are substantially elevated year by year in our society [1][2][3] .
Differently to CKD associated secondary hyperparathyroidism which is related to the excess phosphorus retention, hypertension associated secondary hyperthyroidism is primarily related to urinary calcium hypersecretion status. In both aforementioned mechanistic scenarios, a substantially quantity of calcium is released from bone, which may lower bone mineral density and subsequently the osteoporotic fracture risks. However, excess phosphate retention with/without excess calcium excretion, can increase FGF23 expression and consequently lower 1-α-hydroxylation of the endogenously circulated cholecalciferol or 25-OH-cholecalciferol. Both hypertension and chronic kidney diseases are known independent risk factors for osteoporosis complications [4][5][6][7][8].
Physiologically, bone resorption and deposition dynamic remodeling processes are closely regulated by various cytokines and hormones secretions which are demonstrated to be indirectly involved in the osteoporosis pathophysiology. For example, The Angiotensin II (AT II) in the renin-angiotensin system (RAS), is significantly induced the expression of RANKL (receptor activator of NF-κB ligand) in osteoblasts cells which accordingly leading to the activation of osteoclasts. It is known that the AT II receptors are substantially expressed in both osteoclast and osteoblast cultures, and AT II ultimately activates osteoclast cells which are the primary responsible for bone resorption. [9][10][11][12] Recent clinical studies suggest that several antihypertensive drugs, particularly the angiotensin-converting enzyme inhibitors (ACEIs), AT II receptor blockers (ARBs), and the thiazide diuretics, are positively correlated with the BMDs. Blockage AT II at AT II receptors via either ACEIs or ARBs may mitigate the bone resorption rate at osteoclast culture level. Additionally, the researchers also propose that thiazide and thiazide like diuretics, such as hydrochlorothiazide and chlorthalidone, respectively, may shift the calcium balance into the positive direction, owing to its significant calcium reabsorption tendency, which may indirectly lower the osteoclasts related calcium resorption rate. The use of the aforementioned anti-HTN medications, either individually or in combination with each other, could have promising results in mitigation the ageing associated dual HTN and osteoporosis statuses. [13][14][15][16][17] In this study, we primarily aimed to investigate the major differences across the 2 comparative tested cohorts; non-HTN affected cohort (Cohort I) and HTN affected cohort (Cohort II) regarding various multi-dimensional issues. Also, we aimed in this study to explore the differences of distributional rates of both the femoral hip bone mineral density (fH_BMD) and the femoral hip osteoporotic fracture (fHOPF) risk across the 6 selected anti-HTN medications' groups; calcium channel blockers (CCBs) [

Material and methods
This observational retrospective study was conducted for 206 participants who were clinically diagnosed for osteoporotic fracture risk at our rehabilitation and rheumatology clinic between Sep 2021 and Nov 2021 at Prince Rashid bin Al-Hasan Military Hospital, Royal Medical Services, Irbid, Jordan. Subjects who were previously diagnosed with chronic kidney disease [calculated glomerular filtration rate (GFR) <30 mL/ min/1.73m2), based on cockcroft equation], chronic liver disease [child-pugh score is B or C grade], inherited/metabolic bone disease [e.g., hyperparathyroidism/hypoparathyroidism, osteomalacia, pagets disease, osteogenesis imperfecta], or took antiresorptive therapy [e.g., bisphosphonate, calcitonin, strontium ranelate, and teriparatide] were excluded from this study.
Hypertension (HTN) affected participant was defined for whose blood pressure ≥130/85mmHg or the participant is actively on anti-hypertensive medication. Information that was collected at the attended clinic, by a questionnaire, included age, actual body weight (ABW), height (Ht), HTN status or anti-HTN medication(s), menopausal age, functionality status, co-morbidity burden, smoking status, diet life-style, and history of family fracture. Co-morbidity burden was assessed via Age-adjusted Charlson Comorbidity Index (ACCI). Protein density (PD) [< or ≥ 2.5 g/100 Cal] and the fruit/vegetable consumption (FVC) pattern [intermittent versus regular] were approximated from the participants' diet life-style information.
Bone mineral density was measured using a dual-energy X-ray absorptiometry (DEXA) at the total lumbar spine (L1-L4) and left hip. DEXA scans of the anteroposterior spine and the proximal femoral hip participant's data were abstracted from the DEXA recorded database. These DEXA related database included primarily femoral hip T and Z-Scores, femoral hip BMD in g per cm2 (fH_BMD), Lumbar T and Z-Scores, Lumbar BMD (LBMD), 10-year risk of femoral osteoporotic fracture related FRAX score (<3% or ≥3%), and 10-year risk of major overall osteoporotic fracture related FRAX score (< or ≥20%). T-score values were used to determine the diagnosis of osteoporosis. A T-score within 1 SD (+1 or -1) of the young adult mean indicates normal bone density. A T-score of 1 to 2.5 SD below the young adult mean (-1 to -2.5 SD) indicates low bone mass. A T-score of 2.5 SD or more below the young adult mean (more than -2.5 SD) indicates the presence of osteoporosis. In this study, the higher probability of fHOPF was determined as either T-Score is <-2.5 (regardless of FRAX is < or ≥ 3%) or T-Score is between -1 and -2.5 but the FRAX is ≥3%. In contrast, the lower probability of fHOPF was determined as T-Score is between -1 and -2.5, and the FRAX is <3% or the T-Score is >-1 (regardless of FRAX is ≥ or <3%).
The investigated studied participants were either allocated to non-HTN versus HTN cohorts (Cohort I vs Cohort II, respectively). Also, the anti-HTN medications were categorized into 6 major medication's group; Group I-VI. Both aforementioned categorized 2 patients' cohorts and 6 medications' groups were analyzed via chi square test to express the comparison results as distribution rates strength of associations (odd ratios), Pearson chi-square statistic (χ 2), Goodness of Fit (G-Test of independence), and Pearson (r) and Spearman (ρ) correlations. The comparative investigated independent variables that were tested across the 2 patients' cohorts, including of particular both gender distribution rates and ratios, age ranges, vit D levels, nutritional indexes' statuses (PD and FVC patterns), smoking and corticosteroidal (Cs) statuses, anthropometrical variable of body mass index (BMI), and both the osteoporosis risk assessment instrument and tool (ORAI and OST, respectively). Statistical analysis was performed using Statistical Package for Social Science (SPSS) software version 23.0. Statistical significance was set at 5%.

Results
Overall, 206 participants who were clinically diagnosed for osteoporotic fracture risk at our rehabilitation and rheumatology clinic between Sep 2021 and Nov 2021, were studied to investigate the differences of the various investigated independent variables across the 2 dichotomized HTN related cohorts; Cohort I-II. In this study, 49.03% (101 of the eligible patients) were allocated to the non-HTN affected cohort (Cohort I) and 50.97% (101 of the overall participants) were comparatively allocated to the HTN affected cohort (Cohort II). Approximately, 33 (31.4%) of the HTN affected patients were on only CCBs (Group I) while approximately 27 (25.7%), 14 (13.3%), 20 (19.0%), 9 (8.6%), and 2 (1.9%) of the HTN affected participants were on CCBs+BBs (Group II), CCBs+ACEIs or ARBs (Group III), CCBs+Thiazide (Group IV), BBs+ACEIs or ARBs (Group V), and ACEIs or ARBs+Thiazide (Group VI), respectively.
OST: The Osteoporosis self-Assessment Tool. LBMD: Lumbar bone mineral density.  Data results of the comparative variables between the 2 tested cohorts were statistically analyzed by Chi-Square Test (at p-value< 0.05) and expressed as Numbers (Percentage). The strength of associations was also described as odd ratios (OR). The Pearson chi-square statistic (χ 2) involves the squared difference between the observed and the expected frequencies. The Goodness of Fit (G-Test of independence) uses the log of the ratio of two likelihoods and tests the goodness of fit of observed frequencies to their expected. Both the interval by interval (Pearson, r) and the ordinal by ordinal (Spearman, ρ) correlations were expressed as value± standard error of value. The studied patients were dichotomously categorized into 2 comparative cohorts Non-HTN affected cohort (Cohort I) versus HTN affected cohort (Cohort II). In this study, the higher probability of fHOPF was determined as either T-Score is <-2.5 (regardless of FRAX is < or ≥ 3%) or T-Score is between -1 and -2.5 but the FRAX is ≥3%. In contrast, the lower probability of fHOPF was determined as T-Score is between -1 and -2.5, and the FRAX is <3% or the T-Score is >-1 (regardless of FRAX is ≥ or <3%). The higher probability of fHOPF is considered as a Positive state and the lower probability of fHOPF is considered as a Negative State. For the tested categorical Tx related independent variable, 0 was assigned for the Cohort I and was considered the reference. While 1 was assigned for the Cohort II.
fHOPF: Femoral hip osteoporotic fracture.  Data results of the comparative variables between the 2 tested cohorts were statistically analyzed by Chi-Square Test (at p-value< 0.05) and expressed as Numbers (Percentage). The strength of associations was also described as odd ratios (OR). The Pearson chi-square statistic (χ 2) involves the squared difference between the observed and the expected frequencies. The Goodness of Fit (G-Test of independence) uses the log of the ratio of two likelihoods and tests the goodness of fit of observed frequencies to their expected. Both the interval by interval (Pearson, r) and the ordinal by ordinal (Spearman, ρ) correlations were expressed as value± standard error of value. The studied patients were dichotomously categorized into 2 comparative cohorts; Lower risk fHOPF cohort (Cohort I) versus Higher risk of fHOPF cohort (Cohort II),

Discussion
There are several main findings of our study, with important implications. Firstly, our study showing that the overall incidence of higher femoral osteoporotic fracture risk in HTN patients who were on at least one anti-HTN medication was 91.4%. Patients who were on thiazide or thiazide like diuretics with ACEIs or ARBs had the lowest incidence rate of higher risk of fHOPF (50%), followed by patients who were on BBs with thiazide or thiazide like diuretics ( Generally, HTN affected patients often have higher osteoporotic fractures' risk than those without. A recent study by a team found that chlorthalidone may improve bone strength and reduce the risk of osteoporotic fractures. Previous studies had suggested that both ACEIs or ARBs and thiazide-type diuretics improve vertebral and non-vertebral bone mineral densities, little studies had compared various anti-HTN medications with each other, especially in the Mediterranean population, and this gave our study its uniqueness.

Conclusion
This single-center small non-sponsored and non-funded retrospective study which primarily aimed to explore the differences of distributional rates of both the femoral hip bone mineral density (fH_BMD) and the femoral hip osteoporotic fracture (fHOPF) risk across the 6 selected anti-HTN medications' groups revealed that the thiazide or thiazide like diuretics and ACEIs or ARBs, alone or in combination, may positively improve the femoral hip bone mineral densities and consequently mitigate the risk of osteoporotic fractures. However, this study was prone to recall and selection bias but it may adjunctively assist other multi-site prospective studies, especially in Jordanian or Mediterranean cohorts,

Acknowledgments
Our appreciation goes to staff of the department of King Hussein Medical Center for their enormous assistance and advice.

Disclosure of conflict of interest
There is no conflict of interest in this manuscript

Statement of ethical approval
There is no animal/human subject involvement in this manuscript

Statement of informed consent
Owing to the retrospective design of this study, the informed consent form was waived.