Impaired Calcium Sensing in Parathyroid Tumors Is Selectively Associated with Lower Bone Mineral Density in Patients with Primary Hyperparathyroidism

Presentation Number: SAT 340
Date of Presentation: April 1st, 2017

James Koh*1, Thomas J Weber1, Samantha Thomas2, Joyce Hogue1 and Julie Ann Sosa3
1Duke University Medical Center, Durham, NC, 2Duke University, 3Duke University, Durham, NC

Abstract

Bone loss and fractures are a major source of morbidity in patients with primary hyperparathyroidism (PHPT). A clinically distinct subset of PHPT patients with a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other physical dysfunctions has been recognized for some time, yet the underlying reasons for this disparity in clinical presentation remain unknown. To identify new mechanistic indices that could inform personalized post-operative management of PHPT, we developed a comprehensive clinical registry of PHPT patient information and related these data to live-cell functional assessment of parathyroid tumor biochemical signaling capacity. We assembled data from 228 patients undergoing parathyroidectomy for PHPT at our institution, aligning pre-, peri-, and post-operative records of patient disease course with demographic, clinical, and pathological information. Calcium sensing capacity in parathyroid tumors was evaluated in an unselected series of 71 patients from the registry. Intracellular calcium flux was recorded ex vivo at single cell resolution in intact tumor specimens from these patients as a readout of calcium sensitivity, expressed as the concentration required for half-maximal response (EC50). Parathyroid tumors segregated into two distinct groups of calcium responsiveness. One group (n=25) demonstrated a mean calcium EC50 value of 2.48 mM [95% CI: 2.43 – 2.54], consistent with reference normal activity. In contrast, a second group (n= 46) displayed attenuated sensitivity with a mean calcium EC50 value of 3.48 mM [3.41 – 3.55]. The bimodal distribution of EC50 values in the overall patient cohort was consistent with mechanistically separable sub-populations of parathyroid tumor behaviors. Retrospective analysis of the clinical registry data using Wilcoxon Rank Sum and Fisher’s Exact tests suggested that patients whose tumors displayed reduced calcium sensitivity (high EC50) presented with significantly more pronounced radiographic evidence of pre-operative BMD deficit. BMD as measured by lowest T-score was -0.9 [-2.1 - -0.4] for patients in the low EC50 group compared to -2.7 [-3.4 - -1.9] in the high EC50 group (p < 0.001). After adjusting for gender, 25 OH vitamin D level, age, BMI, and pre-operative iPTH, lowest T-score and calcium EC50 were found to be inversely correlated, with a partial Spearman correlation coefficient of -0.351 (p=0.02). This observation challenges the predominant paradigm of PHPT as an etiologically monolithic disorder and implies that a distinction between tumor-intrinsic and tumor-extrinsic drivers of PHPT could underlie differences in PHPT disease course, provenance, and outcome. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity, bone density loss, and the potential for post-parathyroidectomy BMD re-accrual.

 

Disclosure: JAS: Member, Data Monitoring Committee, Medullary Thyroid Cancer Consortium Registry, Novo Nordisk, Astra Zeneca, GlaxoSmithKline, Eli Lilly. Nothing to Disclose: JK, TJW, ST, JH