Can vitamin D supplementation be dangerous? 25-Hydroxyvitamin D and 1,25-hydroxyvitamin D concentration in healthy population and primary hyperparathyroidism: a single-center experience and literature review.

Median 1,25-OH-D3 concentrations were significantly different across all groups, being highest in PHPT patients qualified for surgery, intermediate in those managed conservatively, and lowest in controls.

• Median 1,25-OH-D3 was 91.1 pg/mL in SG2 (surgical PHPT), 64.05 pg/mL in SG1 (conservative PHPT), and 46.20 pg/mL in CG (controls).
• Statistically significant differences were found between the medians of 1,25-OH-D between all pairs of groups (SG1 vs. SG2; SG1 vs. CG; SG2 vs. CG).
• Study group consisted of 85 PHPT patients and 51 controls without calcium-phosphate imbalance.

Median 25-OH-D3 concentrations did not follow the same pattern as 1,25-OH-D3 across groups.

• Median 25-OH-D3 was 30.00 ng/mL in CG, 32.75 ng/mL in SG1, and 27.6 ng/mL in SG2.
• Unlike 1,25-OH-D3, 25-OH-D3 levels were not highest in the surgically treated PHPT subgroup.
• The divergence between 25-OH-D3 and 1,25-OH-D3 patterns across groups motivated introduction of the VD-AR metric.

The vitamin D activation ratio (VD-AR), defined as the ratio of 1,25-OH-D to 25-OH-D, was highest in PHPT patients qualified for surgery.

• Median VD-AR was 3.32 in SG2 (surgical PHPT), lower in SG1 (conservative PHPT), and lowest in CG.
• Statistically significant differences in VD-AR were found between all pairs of groups.
• VD-AR was introduced as a novel ratio to capture the relative activation of vitamin D in the context of PHPT.

Higher VD-AR was independently associated with greater probability of hypercalcemia above 11 mg/dL in a logistic regression model.

• In the logit model for calcium, the structural parameter for VD-AR was statistically significant.
• The model correctly classified 74.1% of cases.
• Higher VD-AR value was associated with greater probability of serum calcium exceeding 11 mg/dL.

Both higher VD-AR and higher iPTH independently predicted indication for parathyroidectomy in a logistic regression model.

• In the logit model for indication for parathyroidectomy, the structural parameters for both VD-AR and iPTH were statistically significant at the 0.05 significance level.
• The model correctly classified 72.9% of cases.
• Higher VD-AR and independently higher serum iPTH concentration each increased the probability of surgical indication.

A VD-AR cut-off of 3.3 was identified as clinically relevant.

• The authors suggest VD-AR cut-off of 3.3 as clinically relevant based on the study findings.
• This cut-off was derived in the context of distinguishing PHPT patients requiring surgery from those managed conservatively and from healthy controls.
• The clinical relevance relates to predicting hypercalcemia severity and surgical indication in PHPT.

The study examined the potential danger of vitamin D supplementation in the context of PHPT, where PTH-driven conversion of 25-OH-D to 1,25-OH-D may be dysregulated.

• PHPT is characterized by excessive PTH secretion from parathyroid cells insensitive to suppressive effects of hypercalcemia.
• The impact of both 25-OH-D and 1,25-OH-D in PHPT pathogenesis was described as 'still poorly researched' prior to this study.
• The study design compared PHPT patients (n=85) divided into surgical (SG2) and conservative (SG1) subgroups against healthy controls (n=51).