High-Normal Parathyroid Hormone Levels and Mortality: Insights from the ELSA-Brasil Study on Age and Sex Differences

Study Background

Elevated parathyroid hormone (PTH) levels are traditionally associated with hyperparathyroidism and secondary complications such as osteoporosis and cardiovascular (CV) disease. In high-risk groups, including older adults (75–85 years) and patients undergoing coronary angiography, elevated PTH correlates with adverse CV outcomes and increased all-cause mortality. However, it remains unclear whether high-normal PTH levels—those at the upper limit of the reference range—in healthy, normocalcemic, middle-aged adults also confer increased mortality risk, and how sex and age might modulate this risk. Understanding these relationships in a general population cohort could advance biomarker-driven early risk stratification for cardiometabolic disease.

Study Design

The ELSA-Brasil study is a large community-based longitudinal cohort consisting of Brazilian adults, designed to investigate chronic diseases and their risk factors. In this analysis, 4,736 participants with a mean age of 51.7 years (55% females) and normocalcemic status were followed over a median period of 11.2 years. Baseline serum PTH concentrations were quantified using electrochemiluminescence immunoassay. The primary outcomes were cardiovascular and all-cause mortality. Statistical analyses employed Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause mortality and Fine-Gray competing-risk models to calculate subdistribution hazard ratios (sHRs) for cardiovascular mortality, adjusting for total calcium and other pertinent covariates. Subgroup analyses based on sex and age (≤64 vs >64 years) were performed to elucidate effect modification.

Key Findings

Participants with baseline PTH levels exceeding 56 pg/mL—considered high-normal—demonstrated a notable increase in mortality risk. Specifically, elevated PTH was independently associated with:

– Cardiovascular mortality: nearly doubled risk (sHR 1.92; 95% CI 1.22–3.01).
– All-cause mortality: 61% increased risk (HR 1.61; 95% CI 1.25–2.07).

Sex-stratified analyses revealed that high PTH significantly increased CV mortality among females (sHR 2.79; 95% CI 1.37–5.70), but not males, suggesting a sex-specific vulnerability. Conversely, the elevated all-cause mortality risk associated with high PTH was consistent across both sexes.

Age-stratified analysis indicated heightened CV mortality risk with elevated PTH among individuals aged 64 years or younger (sHR 1.80; 95% CI 1.05–3.09), while older adults did not show a statistically significant association. For all-cause mortality, increased risks were observed irrespective of age group.

These results underscore that PTH at the higher end of normal may be an early indicator of cardiometabolic risk, particularly in younger adults and women.

Expert Commentary

The findings highlight the nuanced role of PTH beyond overt hyperparathyroidism, proposing that even high-normal PTH levels may contribute to cardiovascular pathophysiology through mechanisms such as vascular calcification, endothelial dysfunction, and inflammation. The sex-specific vulnerability in females might reflect interactions between PTH and sex hormones or differential calcium metabolism, although mechanistic studies are needed to elucidate these pathways. The attenuation of risk in older adults could be due to competing health risks or survivor bias.

This study strengthens the rationale for incorporating PTH measurement into cardiovascular risk assessments in community-dwelling adults. However, caution is warranted in extrapolating findings beyond the Brazilian cohort due to genetic, environmental, and lifestyle differences. Furthermore, while the study adjusts for calcium levels, potential confounders such as vitamin D status or kidney function should be thoroughly considered in future analyses.

Conclusion

In a large prospective Brazilian cohort of middle-aged normocalcemic adults, elevated serum parathyroid hormone levels within the high-normal range were independently associated with increased cardiovascular and all-cause mortality. The excess cardiovascular mortality risk was particularly evident in females and younger adults, suggesting PTH may serve as an early, sex- and age-sensitive biomarker of cardiometabolic risk. These findings encourage further research to demystify underlying biological mechanisms and validate PTH’s utility in clinical risk stratification for preventive cardiology.

Funding and Registration

The ELSA-Brasil study is supported by the Brazilian Ministry of Health and the Brazilian Ministry of Science, Technology and Innovation. The clinical trial registration details and ethical approvals are documented in prior ELSA-Brasil publications.

References

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