Potential Link Found Between Vitamin D Therapy, Higher Hypercalcemia Risk in CKD

Patients with chronic kidney disease (CKD) and elevated levels of parathyroid hormone who are treated with active vitamin D therapy experienced significantly higher risks of hypercalcemia, investigators concluded in a meta-analysis.

Active vitamin D therapy was found to significantly increase the risk of hypercalcemia among patients with nondialysis chronic kidney disease (ND-CKD) and secondary hyperparathyroidism (SHPT) compared with placebo, according to a recent meta-analysis.

The systematic literature review and meta-analysis, published in Clinical Kidney Journal, used published randomized, placebo-controlled clinical trials of active vitamin D to clarify the relationship between active vitamin D and SHPT in patients with ND-CKD. SHPT is a common complication in patients with CKD and is characterized by the excessive secretion of parathyroid hormone (PTH), which can lead to worsened kidney function. The condition affects 40% to 82% of patients with stage 3 and stage 4 CKD.

“These observations highlight the urgent need for new treatments for SHPT in patients with ND-CKD that effectively reduce PTH levels, while avoiding undesired elevations in serum calcium,” wrote the investigators.

SHPT is also heavily associated with CKD-mineral bone disorder and if elevations in serum PTH are not addressed, patients can experience bone disease and vascular and valvular calcification, which can lead to increased risks of bone fractures, cardiovascular disease, and mortality.

The pathogenesis of SHPT involves several factors, including presence of hypocalcemia, phosphate retention, and associated increases in serum fibroblast growth factor 23 and insufficient levels of vitamin D. Patients with CKD frequently have low levels of vitamin D, which contributes heavily to the development of SHPT.

The investigators searched 3 literature databases, and their data cutoff was May 14, 2020. For inclusion, the studies had to be randomized, double-blind, placebo-controlled trials of adults with ND-CKD and SHPT, evaluating single-agent active vitamin D. The studies also had to involve at least 30 participants per treatment arm and have a study period of at least 6 weeks.

Overall, 1704 articles were identified, of which 6 studies covering 799 patients were eligible for the analysis. The duration of the studies ranged between 16 weeks and 2 years. Five of the studies evaluated the use of paricalcitol and 1 evaluated alfacalcidol. Across the studies, hypercalcemia was reported in 1.1% to 43.3% of patients treated with active vitamin D therapy, which was considerably higher than patients treated with a placebo (range, 0.0%-3.4%).

During the primary meta-analysis on all 6 studies, the investigators observed that patients with ND-CKD and SHPT treated with active vitamin D therapy experienced a 6.6-fold increased risk of hypercalcemia compared with those treated with placebo (odds ratio [OR], 6.63; 95% CI, 2.37-18.55; P < .001).

Two sensitivity analyses were performed to assess the robustness of the results from the primary analysis. One sensitivity analysis involved the exclusion of a study that was identified to have a high risk of bias and found that active vitamin D therapy was associated with a 6.2-fold greater probability of hypercalcemia vs placebo (OR, 7.22; 95% CI, 2.21-23.60; P = .001). The other analysis excluded 2 studies that accounted for a large proportion of the observed hypercalcemia episodes, finding that active vitamin D therapy was associated with a 2.0-fold greater risk of hypercalcemia vs placebo (OR, 3.03; 95% CI, 1.06-8.71; P = .039).

The meta-analysis and review had several limitations, including the small the number of studies, heterogeneity of the study designs, and lack of control for confounding factors.

“Future analyses of real-world data may help overcome a number of these limitations because this could enable a larger and broader population to be evaluated,” noted the investigators.


Cozzolino M, Bernard L, Csomor PA. Active vitamin D increases the risk of hypercalcaemia in non-dialysis chronic kidney disease patients with secondary hyperparathyroidism: A systematic review and meta-analysis. Clin Kidney J. November 29, 2021;14(10):2437-2443. doi: 10.1093/ckj/sfab091