Risk of osteoporotic fracture in older patients under antihypertensive treatment

Contemporary guidelines recommend intensive blood pressure (BP) control in older patients with hypertension compared to their previous versions, which allowed a lenient approach. The 2018 European Society of Cardiology/European Society of Hypertension guideline recommends a range of 130‒139 as the target systolic BP in patients aged ≥65 years.1 The 2017 American College of Cardiology/American Heart Association guideline is even more stringent, with a systolic BP target of <130 mmHg for ambulatory adults aged ≥65 years.2 However, potential concerns exist such as hypotension, syncope, arrhythmia, injurious falls, and fractures. Osteoporotic fractures have significant clinical implications and have been shown to be associated with permanent loss of function and independence, an impaired quality of life, and a major increase in medical care costs.3 Hip and vertebral fractures have shown to be associated with an increased risk of morbidity and mortality.4 The present study aimed to evaluate the relationship between achieved BP and the risk of osteoporotic fracture among older patients who are under antihypertensive treatment. This study used the National Health Insurance Service-Senior cohort.5 The inclusion criteria were (a) age ≥65 years, (b) diagnosis of hypertension and/or antihypertensive treatment, (c) ≥1 available BP value measured during routine checkups, and (d) a medication possession ratio during the previous year ≥2/3. The exclusion criteria included (a) previous self-report history of cardiovascular disease and (b) any diagnosis of myocardial infarction, stroke, or heart failure during the previous year. The average of systolic and diastolic BP during the study duration was used as the exposure variable. The main outcome variable was major osteoporotic fractures. The association of on-treatment BP with the risk of fracture was analyzed with a time-to-first-event analysis. All statistical analyses were performed using R version 3.3.1. A total of 117,567 older adults (mean age 72.7 years; 44.2% male) with antihypertensive medical treatment (48.6% with calcium channel blockers, 32.4% with angiotensin receptor blockers, 31.8% with diuretics, 22.4% with β-blockers, and 7.4% with angiotensin-converting enzyme inhibitors) were analyzed. After a median follow-up of 5.9 years, 20,917 osteoporotic fractures occurred in 18,634 subjects (incidence rate, 3.01 per 100 person-years). Figure 1 shows fitted non-linear relationships between achieved BP and the risk of osteoporotic fractures. Fracture risk was lowest at 129/75 mmHg when unadjusted. BPs above and below the trough were associated with an increased risk of fractures. However, the risk observed for the higher values of systolic and diastolic BP mostly diminished after multivariable adjustment. Every 10-mmHg decrease of systolic BP below 129 mmHg was associated with a 5.4% (95% confidence interval, 3.0% to 7.8%) increased risk of osteoporotic fractures. Risk of osteoporotic fractures in relation to blood pressure. Multivariable adjusted hazard ratios for osteoporotic fracture associated with systolic and diastolic blood pressure: (a) unadjusted model for systolic blood pressure; (b) multivariable-adjusted model for systolic blood pressure; (c) unadjusted model for diastolic blood pressure; (d) multivariable-adjusted model for diastolic blood pressure. HR: hazard ratio; CI: confidence interval. The risk of osteoporotic fractures was also estimated after BP was treated as a categorical variable with an interval of 10 mmHg (Table 1). The risk was lowest at a systolic BP of 120‒129 mmHg and a diastolic BP of 70‒79 mmHg. Systolic BP ≥160 mmHg was associated with a significantly increased risk before adjustment, but this statistical significance was lost after multivariable adjustment. Lower systolic BP below 120 mmHg remained a significant predictor of fractures. Regarding diastolic BP, a value of 90‒99 mmHg was associated with a significantly higher risk than a value of 70‒79 mmHg. Risk of osteoporotic fractures according to systolic and diastolic blood pressure. PY: person-years; HR: hazard ratio; CI: confidence interval; BP: blood pressure. *Multivariable-adjusted model was adjusted for age, sex, low body weight, smoking, diabetes mellitus, heavy alcohol consumption, osteoporosis, dementia, Parkinson’s disease, and drug (steroid, anticoagulant, angiotensin II receptor blocker, thiazide, β-blockers). Risk of osteoporotic fractures according to systolic and diastolic blood pressure. PY: person-years; HR: hazard ratio; CI: confidence interval; BP: blood pressure. *Multivariable-adjusted model was adjusted for age, sex, low body weight, smoking, diabetes mellitus, heavy alcohol consumption, osteoporosis, dementia, Parkinson’s disease, and drug (steroid, anticoagulant, angiotensin II receptor blocker, thiazide, β-blockers). Evidence supports that old and very old patients also benefit from antihypertensive treatment.6 The Systolic Blood Pressure Intervention Trial (SPRINT) trial showed that intense BP lowering reduces the risk of major cardiovascular events and mortality also in patients older than 75 years.7 However, BP-lowering treatment is usually accompanied by unwanted adverse effects. With lower BP goals, the possibility and potential impact of adverse events related to antihypertensive treatment should be appreciated. The present study showed that the risk of osteoporotic fracture was lowest at an on-treatment systolic BP of 120‒129 mmHg and lowering systolic BP below 120 mmHg was shown to increase the risk of osteoporotic fractures. This study has several limitations. First, because of the nature of the cohort, measurement of BP was not controlled. Second, potential bias may arise as operational definitions were used for outcome variables. However, the definitions used in this study have been validated in previous studies.8 Third, despite rigorous multivariable adjustment, the influence of unmeasured confounding covariates cannot be excluded. In conclusion, this study highlights the potential risk of intensive BP treatment in older hypertensive patients. The incidence of osteoporotic fractures was remarkably high in this patient group. We found a close relationship with on-treatment BP and the risk of fracture. Systolic BP below 120 mmHg significantly increased the risk, which supports the concerns that extremely low on-treatment BP may not be safe. This study suggests physicians should weigh the risk and benefit of intensive BP control when treating older hypertensive patients. We thank Ms Moon Ju Kim for performing the data collection and statistical analyses. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Basic Science Research Program through the National Research Foundation of Korea (grant number 2019R1C1C1006611).