J Clin Endocrinol Metab. 2017 Apr 1;102(4):1237-1243.

Primary aldosteronism as a risk factor for vertebral fracture

 

Abstract

Some observational studies have revealed an association between excessive aldosterone levels and reduced bone mineral density (BMD). However, whether patients with primary aldosteronism (PA) are at higher risk of fracture than healthy individuals remains unclear. This study aimed to clarify whether PA represents a risk factor for vertebral fracture. We enrolled 56 PA patients and 56 age- and sex-matched healthy individuals. Serum and urinary biological parameters, BMD, and presence of vertebral fractures (VFs) were evaluated in both groups. We compared parameters between PA and control subjects and performed multiple logistic regression analyses after adjustments for variables. Patients with PA showed higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), higher hemoglobin (Hb)A1c and triglycerides, higher urinary calcium-to-creatinine ratio (uCa/uCr), and lower high-density lipoprotein cholesterol (HDL-C) than controls (p <0.05, each). Prevalence of VFs was significantly higher in PA subjects (44.6%) than in controls (23.2%, p <0.05). PA patients showed severe fracture more frequently than controls. Multivariate logistic regression analyses adjusted for age, sex, and body mass index identified PA as being associated with the presence of VFs (odds ratio, 3.13; 95% confidence interval, 1.30-7.51; p <0.05). This association remained significant after further adjustment for SBP and DBP, HbA1c, triglycerides, and HDL-C, but not after adjustment for uCa/uCr and BMD. We identified PA as a risk factor for VF, independent of blood pressure, HbA1c, and lipid profile. Fracture severity was significantly higher in PA subjects than in age- and sex-matched controls.

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Supplement 

Osteoporotic fractures are an important worldwide problem affecting mortality, quality of life and the medical economy. In recent years, emerging studies have suggested that these fractures are associated with hypertension and cardiovascular disease (CVD). One factor that may explain the relationships among fractures, hypertension, and CVD is activation of the renin-angiotensin-aldosterone system (RAAS). Chronic stimulation of the RAAS is associated with hypertension and CVD, and negatively affects bone metabolism due to the effect of angiotensin II. However, whether aldosterone excess itself represents a risk factor for fracture remains unknown.

 

Primary aldosteronism (PA) is the most common cause of secondary hypertension and is found in 6.0-9.5% of hypertensive patients. PA is associated with high mortality and is known to cause damage to various organs. On the other hand, aldosterone increases renal calcium excretion in the renal distal tubules by decreasing tubular reabsorption of sodium and calcium. Previous reports have shown that aldosterone excess induces urinary excretion of calcium, leading to bone mineral density (BMD) loss and high levels of parathyroid hormone (PTH), and patients with PA are at higher risk of osteopenia and osteoporosis than patients with essential hypertension (1,2). However, whether patients with PA are at higher risk for fracture than healthy individuals remains unclear.

 

Table 1. Baseline characteristics of patients with primary aldosteronism and controls

Values are expressed as mean ± SD.

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PTH, parathyroid hormone; uCa/uCr, urinary calcium-to-creatinine ratio; %TRP, percentage tubular reabsorption of phosphate; U-NTx, urine type I collagen cross-linked N-telopeptide; PAC, plasma aldosterone concentration; PRA, plasma renin activity; ARR, aldosterone-to-renin ratio; L BMD, bone mineral density at the lumber spine 2-4; FN BMD, bone mineral density at the femoral neck; VF, vertebral fracture.

 

In this study, VFs were found in 25 subjects with PA and in 13 controls (Table 1). The prevalence of VF was significantly higher in PA subjects (44.6%) than in controls (23.2%, p <0.05). Furthermore, PA patients showed severe fracture more frequently than controls (23.2% vs. 3.6%, p <0.01). The VF rate did not significantly differ between PA subtype (aldosterone producing adenoma and idiopathic hyperaldosteronism). Multivariate logistic regression analyses adjusted for age, sex, and BMI identified PA as a factor associated with the presence of VF (odds ratio, 3.13; 95% confidence interval, 1.30-7.51; p <0.05). This association remained significant after further adjustment for SBP, DBP, HbA1c, TG, and HDL-C, but not after adjustment for uCa/uCr (p=0.062), L- and FN-BMD (p=0.173 and p=0.103, respectively) (Table 2).

 

Table 2. Associations between primary aldosteronism and presence of vertebral fracture

Model 1: adjusted for age, sex and body mass index

SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; uCa/uCr, urinary calcium-to-creatinine ratio; L BMD, bone mineral density at the lumber spine 2-4; FN BMD, bone mineral density at the femoral neck

 

This study revealed that fracture risk was increased in patients with PA. Furthermore, severity of fractures seemed higher in subjects with PA because the ratio of subjects with grade 2 or 3 VF was significantly higher in PA patients than in controls. This is the first report to find that the prevalence of VF and fracture severity were significantly higher in PA subjects than in age- and sex-matched controls. Moreover, our study revealed that PAC, PRA, and ARR showed no significant differences between PA subjects with and without VF. Between the PA subtypes of APA and IHA, aldosterone production is higher in APA than in IHA (data not shown). Although provided only as reference data because of the small number of patients in our study, comparison of the VF rate between the APA and IHA subgroups showed no significant differences. These results suggest that the degree of aldosterone production is not associated with fracture risk. Recently, Wu and colleagues studied the long-term effect of hyperaldosterone on fracture risk using a longitudinal population database from the Taiwan National Health Insurance. They reported that PA is tightly associated with higher risk of bone fracture, even in the case where the competing risk of death was controlled. This report presents same result as us (3).

 

Bone fragility in patients with PA may be induced by aldosterone itself. No reports have clarified the direct effects of aldosterone on bone. Several reports have shown that mineralocorticoid receptors (MRs) are observed in human osteoblasts, osteocytes, and osteoclasts. However, direct effects of aldosterone to these cells. On the other hand, continuous administration of aldosterone to rats induced persistent rises in urinary calcium and elevations in PTH with a concomitant decrease of BMD and bone strength. An aldosterone infusion study in humans showed that aldosterone affects the parathyroid glands indirectly by reducing serum calcium levels. These results indicate that aldosterone excess increases fracture risk via urinary calcium excess through the effects of aldosterone on the distal tubule. In our study, plasma aldosterone concentration correlated positively with uCa/uCr, and the prevalence of VFs was significantly higher in PA subjects than in controls. This association became non-significant after additional adjustment for uCa/uCr. These findings suggest that aldosterone excess markedly affects calcium excretion and this effect is partly associated with an increased risk of VF.

 

References

  1. Ceccoli L, Ronconi V, Giovannini L, Marcheggiani M, Turchi F, Boscaro M, Giacchetti G. Bone health and aldosterone excess. Osteoporos Int 2013; 24:2801-2807
  2. Petramala L, Zinnamosca L, Settevendemmie A, Marinelli C, Nardi M, Concistre A, Corpaci F, Tonnarini G, De Toma G, Letizia C. Bone and mineral metabolism in patients with primary aldosteronism. Int J Endocrinol 2014; 2014:836529
  3. Wu VC, Chang CH, Wang CY, Lin YH, Kao TW, Lin PC, Chu TS, Chang YS, Chen L, Wu KD, Chueh SJ. Risk of Fracture in Primary Aldosteronism: A Population-Based Cohort Study. J Bone Miner Res 2017; 32:743-752