Impaired calcium sensing distinguishes primary hyperparathyroidism (PHPT) patients with low bone mineral density

Abstract

Context A subset of PHPT patients exhibit a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other dysfunctions, but the underlying reasons for this disparity in clinical presentation remain unknown. Objective We sought to identify new mechanistic indices that could inform more personalized management of PHPT. Design Pre-, peri-, and postoperative data and demographic, clinical, and pathological information from patients undergoing parathyroidectomy for PHPT were collected. Univariate and partial Spearman correlation was used to estimate the association of parathyroid tumor calcium sensing capacity with select variables. Patients or Other Participants An unselected series of 237 patients aged >18 years and undergoing parathyroidectomy for PHPT were enrolled. Main outcome measures Calcium sensing capacity, expressed as the concentration required for half-maximal biochemical response (EC50), was evaluated in parathyroid tumors from an unselected series of 74 patients and assessed for association with clinical parameters. The hypothesis was that greater disease severity would be associated with attenuated calcium sensitivity and biochemically autonomous parathyroid tumor behavior. Results Parathyroid tumors segregated into two distinct groups of calcium responsiveness (EC50 <3.0 and ≥3.0 mM). The low EC50 group (n=27) demonstrated a mean calcium EC50 value of 2.49 mM [95% confidence interval (CI): 2.43–2.54 mM], consistent with reference normal activity. In contrast, the high EC50 group (n=47) displayed attenuated calcium sensitivity with a mean EC50 value of 3.48 mM [95% CI: 3.41–3.55 mM]. Retrospective analysis of the clinical registry data suggested that high calcium EC50 patients presented with a more significant preoperative bone mineral density (BMD) deficit with a T-score of −2.7, (95% CI: −3.4 to −1.9) versus 0.9, (95% CI: −2.1 to −0.4) in low EC50 patients (p < 0.001). After adjusting for gender, age, BMI, 25 OH vitamin D level and preoperative iPTH, lowest T-score and calcium EC50 were inversely correlated, with a partial Spearman correlation coefficient of −0.35 (p=0.02). Conclusions Impaired calcium sensing in parathyroid tumors is selectively observed in a subset of patients with more severe bone mineral density deficit. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity as measured by bone mineral density in patients with PHPT.

Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT

“…Tumors derived from PHPT patients with osteoporosis fell almost exclusively within Clusters 2 and 3, with only a single instance found in Cluster 1. The association between calcium-resistant tumor gene expression profiles and bone mineral density loss observed in this sample set provides molecular evidence supporting our earlier report of a link between tumor biochemical behavior and PHPT clinical presentation (Weber et al 2017).…”

“…Using this approach, we showed that parathyroid tumors exhibiting calcium resistance were strongly associated with reduced bone density in patients with sporadic, non-familial PHPT (Weber, et al 2017). The finding that attenuated calcium responsiveness in a subset of parathyroid tumors is selectively linked to clinically significant bone mineral density (BMD) loss suggests the existence of phenotypically distinct sub-classes of PHPT patients with differential disease courses and alternative underlying etiologies.…”

Influence of Serum Biochemistry on Bone and Kidney Phenotypes in Subjects With Symptomatic Primary Hyperparathyroidism

“…This abnormal calcium or 1, 25-(OH) 2 D sensing in tumours along with autonomous PTH secretion can explain the lack of correlation between PTH and 25-OHD in our cohort. Impaired calcium sensing in parathyroid tumours was indeed observed in one subset of patients with severe bone mineral density de cit [20].…”

Parathyroid adenoma combined with a rib tumor as the primary disease: A case report

“…The primary target organ of PHPT is the kidney, which can develop into kidney stones[ 5 ]. It can also manifest as urinary calculi and osteolytic bone changes, as well as other systemic lesions[ 6 , 7 ].…”