Elevated autonomous aldosterone production is more common than previously believed. Primary aldosteronism is estimated to cause “essential” and resistant hypertension in up to 10% and 20% of adults. These numbers are significant given wide prevalence of high blood pressure in the general population.
This original study suggests that primary aldosteronism is also a unique contributor to vertebral fracture, raising its risk by 3 fold. Authors hypothesize that excessive aldosterone causes fracture by reducing bone quality rather than bone density. A partial effect could also be its ability to increase urinary calcium excretion in the distal tubule.
Important to note the association of hyperaldosteronism with metabolic syndrome, higher A1c and Triglycerides and lower HDL.
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Context: 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.
Objective: This study aimed to clarify whether primary aldosteronism represents a risk factor for vertebral fracture (VF).
Design and Patients: We enrolled 56 patients with PA and 56 age- and sex-matched healthy individuals. Serum and urinary biological parameters, BMD, and presence of VFs were evaluated in both groups. We compared parameters between PA and control participants and performed multiple logistic regression analyses after adjustments for variables.
Results: Patients with primary aldosteronism showed higher sBP, dBP, higher A1c and TGs, higher urinary calcium/creatinine ratio, and lower HDL than controls (P < 0.05, each). Prevalence of VFs was significantly higher in patients with PA (44.6%) than in controls (23.2%, P < 0.05).
Patients with PA 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 to 7.51; P < 0.05). This association remained statistically significant after further adjustment for systolic and diastolic blood pressure, HbA1c, triglycerides, and high-density lipoprotein cholesterol but not after adjustment for calcium-to-creatinine ratio and BMD.
Conclusions: We identified PA as a risk factor for VF, independent of blood pressure, HbA1c, and lipid profile. Fracture severity was significantly higher in patients with PA than in age- and sex-matched controls.
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Osteoporotic fractures are an important 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). A population-based case-control study identified hypertension as a risk factor for hip fracture. A twin cohort study of around 32,000 patients reported that CVD was a risk factor for hip fracture and that this relationship involved genetic factors. Furthermore, the presence of at least one vertebral fracture (VF) compared with no VF at baseline was associated with a threefold increase in the risk of cardiovascular events in postmenopausal women.
One factor that may explain the relationships among fractures, hypertension, and CVD is activation of the renin-angiotensin-aldosterone system. Chronic stimulation of the renin-angiotensin-aldosterone system 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% to 9.5% of hypertensive patients. PA is associated with high mortality and is known to cause damage to various organs. Milliez et al. reported that patients with PA have higher a prevalence of cardiovascular and cerebrovascular diseases. Such reports have shown that PA is an important factor associated with atherosclerotic disease, beyond its effects on intravascular volume and blood pressure (BP).
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. A recent study reported that VF tended to become more prevalent in PA than in non-PA. However, whether patients with PA are at higher risk for fracture than healthy individuals remains unclear.
This study revealed that fracture risk was increased in patients with PA. Furthermore, severity of fractures seemed higher in patients with PA because the ratio of patients with grade 2 or 3 VF was significantly higher in patients with PA than in controls. The VF rate in the control group in our study was high. Ethnic differences in the incidence of VF exist—namely, compared with Western populations, Japanese people have a higher incidence of VF. The VF rate in our control group, however, was slightly higher than fracture rates previously reported in Japanese people. One possible reason for this higher VF rate is that our control group included participants being screened for osteoporosis. However, the VF rate in the PA group was still significantly higher than in the control group. Our results are consistent with previous studies reporting that VFs tended to be more prevalent, and the prevalence of osteoporosis was higher in patients with PA than in those without PA. To our knowledge, this is the first report to find that the prevalence of VF and fracture severity was significantly higher in patients with PA than in age- and sex-matched controls.
Previous reports about the renin-angiotensin-aldosterone system and bone metabolism have shown that angiotensin II excess accelerates osteoporosis by activating osteoclasts via the receptor activator of nuclear factor–κB ligand pathway. However, under conditions where PAC levels are chronically elevated with concomitant suppression of angiotensin II and renin, bone fragility in patients with PA could not be explained by the effect of angiotensin II. Bone fragility in patients with PA may be induced by aldosterone itself. To our knowledge, no reports have clarified the direct effects of aldosterone on bone. Several reports have shown that mineralocorticoid receptors are observed in human osteoblasts, osteocytes, and osteoclasts. Treatment with eplerenone, a specific blocker of mineralocorticoid receptors, ameliorated the decreased bone volume and cortical bone thinning caused by prednisolone in vivo. However, the direct effects of aldosterone on bone are poorly understood.
An aldosterone infusion study in humans showed that aldosterone affects the parathyroid glands indirectly by reducing serum calcium levels. Actually, patients with PA showed higher levels of urinary calcium as well as lower serum calcium and BMD than patients with essential hypertension. 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, PAC correlated positively with uCa/uCr, and the prevalence of VFs was significantly higher in patients with PA than in controls. This association became nonsignificant 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.
Whether aldosterone affects PTH secretion directly via the parathyroid gland remains unclear. A recent study of 3105 individuals from the general population revealed higher PTH concentrations in individuals with a higher ARR than in those with a lower ARR. These findings suggest that aldosterone excess is associated with PTH elevation. Previous reports have presumed that higher urinary calcium excretion and secondary increases in PTH induce bone loss. However, in this study, there were no significant differences in PTH levels between patients with PA and controls. Moreover, PTH was not identified as a factor associated with VF (data not shown). Our results suggest that secondary elevations of PTH are unrelated to vertebral fragility in patients with PA. PTH excess mainly causes fragility of cortical bone. The absence of a difference in PTH is probably because our study focused on the vertebra, which are predominantly cancellous bone.
This study showed that comparison of patients with PA and controls revealed no significant differences in BMD values. Moreover, there were no differences in BMD at any site between PA patients with and without VFs. Our results suggest that PA may cause bone fragility attributed to the deterioration of bone quality. The rate of non-VFs in predominantly cortical bone sites did not differ between the PA group and control group in our study. The deterioration of bone quality in PA may involve deterioration in the microstructure of cancellous bone.
Hypertension is reportedly associated with bone loss. In this study, logistic regression analyses showed an association between PA and VF, and this association was still significant after additional adjustment for systolic BP and DBP. This suggests that patients with PA have a higher risk of VF, independent of BP.
One of the complications of PA is impaired glucose tolerance. A meta-analysis has shown diabetes mellitus as a risk factor for fracture, and we also reported that patients with type 2 diabetes have a higher risk of VF than those without diabetes. In the current study, HbA1c was higher in patients with PA than in controls, but PA was still a risk factor for VF after adjustment for HbA1c. Actually, the mean HbA1c in patients with PA was 6.4% in this study, which is somewhat lower than that of patients with diabetes, who had a higher risk of fracture. Therefore, it seems unlikely that bone fragility is caused by dysregulated glucose metabolism.
Some patients with PA have renal dysfunction. Chronic kidney disease is also a risk factor for VF. In the current study, renal function did not differ between those with and without PA, and PA represented a risk factor for VF after adjustment for renal function.
Several limitations of this study must be clarified. First, we diagnosed PA by suppression or stimulation tests without histopathological diagnoses after surgery. The diagnosis of PA in this study was based on biochemical studies. Currently available histopathological methods are insufficient to conclusively establish a diagnosis of PA. Second, the sample size in this study was small, and all participants were Japanese. Third, we did not evaluate concentrations of serum 25-hydroxyvitamin D. Patients with PA have been reported to have a higher prevalence of vitamin D deficiency. Finally, the conclusions of this study are weakened by the cross-sectional design. A longitudinal study is necessary to clarify the causal direction of these.
In conclusion, we identified PA as a risk factor for prevalent VF independent of BP. In addition, fracture severity was significantly higher in patients with PA than in age- and sex-matched controls.