**1. Introduction**

With an aging worldwide population, the importance of effectively treating muscle loss and osteoporosis is increasing. The characteristic of osteoporosis is bone mass loss and microarchitectural deterioration of bone tissue. Osteoporotic bone can easily fracture even in a minor collision [1], and osteoporotic fractures are one of the most common injuries encountered in the emergency department [2]. The most osteoporotic fracture locations were distal radius, proximal femur, and vertebral compression fractures. Calcium is the most abundant mineral in the body, 99% of which is found in the teeth and bones. Apart from bone, the two main organ systems responsible for calcium homeostasis are the intestines and kidneys [3–5]. Vitamin D improves the ability of the intestines to absorb calcium [6], and a calcium plus vitamin D supplement has been used to prevent osteoporotic fractures. A meta-analysis revealed a significant 15% reduction in the risk of total fractures

**Citation:** Chuang, C.-H.; Yang, S.-F.; Liao, P.-L.; Huang, J.-Y.; Chan, M.-Y.; Yeh, C.-B. Association of Thiazide Use in Patients with Hypertension with Overall Fracture Risk: A Population-Based Cohort Study. *J. Clin. Med.* **2022**, *11*, 3304. https:// doi.org/10.3390/jcm11123304

Academic Editor: Gianluca Testa

Received: 26 April 2022 Accepted: 7 June 2022 Published: 9 June 2022

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and a 30% reduction in the risk of hip fractures when patients use calcium plus vitamin D supplementation for fracture prevention [7]. The kidneys play a key role in both calcium reabsorption and excretion. Approximately 200 mg of calcium per day is typically excreted by adults through the kidneys via urine [8], but this value varies by diet and serum parameters. Reducing the excretion of calcium from urine is one strategy to maintain adequate calcium in the human body [9].

In older people, hypertension is a common disease, and initial control through nondrug therapies, such as lifestyle modifications, body weight management, and increased exercise, is recommended [10,11]. Antihypertensive medications are used if non-drug therapy cannot achieve adequate blood pressure control. Many types of antihypertensive drugs have been developed. The four main classes of medications used in combination therapies for the treatment of hypertension are thiazide diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). The combination use of antihypertensive medications can achieve synergistic effects in blood pressure reduction with fewer doses [12–14]. Physicians select an antihypertensive treatment for a patient according to their underlying diseases or contraindications [15,16]. Patients with a reduced ejection fraction should initially be treated with a beta-blocker and an ACEI or ARB [16]. Patients with chronic kidney disease and proteinuria should be treated with an ACEI or ARB plus a thiazide diuretic or CCB [17]. If patients with diabetes mellitus have proteinuria, combination therapy should include an ACEI or ARB [18].

Thiazide diuretics have long been widely used as antihypertensive agents. Thiazides are defined as a third-line antihypertensive because they are less effective at reducing blood pressure than are ACEIs or ARBs. Thiazides inhibit the Na+/Cl cotransporter (NCC) in the convoluted renal distal tubule. The NCC facilitates the reabsorption of sodium from the distal tubules to the interstitium. A decrease in sodium reabsorption results in an increase in urine output, leading to a decrease in plasma volume and decreased blood pressure.

In addition to reducing blood pressure, thiazides control calcium homeostasis and increase bone density. Thiazides reduce urinary calcium excretion and stimulate osteoblast differentiation and bone mineral formation [7]. The mechanism by which thiazides reduce calcium excretion remains unclear. In some studies, thiazide has been used in idiopathic hypercalciuria [19]. Li et al. reported that the long-term use of thiazide diuretics reduces the incidence of recurrent renal calculi and the 24-h urinary calcium level [20]. By reducing calcium loss, the bone density and calcium within bones increase. Aung et al. reported that thiazide could reduce the incidence of hip fractures [21].

In perimenopausal or postmenopausal women, osteoporotic fractures are one of the common complications [22]. Several therapies have been proposed to prevent them. Calcium plus vitamin D, hormone therapy, or combination therapy are the current primary treatments to protect against osteoporotic fractures [23].

Our primary outcome of the study was the fracture rate of the hypertensive participant and the adjusted hazard ratio between the thiazide user and the non-user for hypertension using data from the Taiwan National Health Research Database of Taiwan (NHIRD). Our second objective was to determine whether thiazide can prevent fractures in perimenopausal or postmenopausal women.
