Patients with primary hyperparathyroidism have lower circulating sclerostin levels than euparathyroid controls

Abstract

Objective: In vitro and in vivo studies in animal models have shown that parathyroid hormone (PTH) inhibits the expression of the SOST gene, which encodes sclerostin, an osteocyte-derived negative regulator of bone formation. We tested the hypothesis that chronic PTH excess decreases circulating sclerostin in humans. Design: We studied 25 patients with elevated serum PTH concentrations due to primary hyperparathyroidism (PHPT) and 49 patients cured from PHPT after successful parathyroidectomy (PTx; euparathyroid controls (EuPTH)). Methods: We measured plasma PTH and serum sclerostin levels and the serum markers of bone turnover alkaline phosphatase, P1NP, and b-CTX. Results: As expected by the design of the study, mean plasma PTH was significantly higher (P!0.001) in PHPT patients (15.3 pmol/l; 95% confidence interval (CI): 11.1-19.5) compared with that of EuPTH controls (4.1 pmol/l; 95% CI: 3.6-4.5). PHPT patients had significantly lower serum sclerostin values compared with those in EuPTH subjects (30.5 pg/ml; 95% CI: 26.0-35.1 vs 45.4 pg/ml; 95% CI: 40.5-50.2; P!0.001) and healthy controls (40.0 pg/ml; 95% CI: 37.1-42.9; PZ0.01). Plasma PTH concentrations were negatively correlated with serum sclerostin values (rZK0.44; P!0.001). Bone turnover markers were significantly correlated with PTH, but not with sclerostin. Conclusion: Patients with PHPT have significantly lower serum sclerostin values compared with PTx controls with normal PTH concentrations. The negative correlation between PTH and sclerostin suggests that SOST is downregulated by PTH in humans.

Sclerostin

“…Interestingly, serum levels of Dkk-1 did not correlate with iPTH or any of the histomorphometry parameters. Of note, a similar inverse relationship between serum sclerostin and iPTH was recently reported in patients with primary hyperparathyroidism (24). As to circulating bone turnover markers, no correlation with serum sclerostin was found in patients with primary hyperparathyroidism (24) or in healthy postmenopausal women (25,26).…”

“…Of note, a similar inverse relationship between serum sclerostin and iPTH was recently reported in patients with primary hyperparathyroidism (24). As to circulating bone turnover markers, no correlation with serum sclerostin was found in patients with primary hyperparathyroidism (24) or in healthy postmenopausal women (25,26). However, the percentage changes in bone formation or resorption markers in early response to estrogen treatment in postmenopausal women Bone formation by osteoblasts is inhibited by SOST/sclerostin, which is expressed in osteocytes.…”

“…Of note, serum values of sclerostin were considerably higher in patients with stage 5D CKD (18) than in healthy control subjects, patients with primary hyperparathyroidism, or postmenopausal women without known CKD (23)(24)(25)(26). As suggested by Cejka et al (18), the difference between the population with CKD and people free of CKD may come from increased sclerostin retention secondary to renal function impairment and/or increased sclerostin production.…”

PTH and PTHR1 in osteocytes. New insights into old partners

“…71 SOST is a target gene for PTH in bone, 47,[72][73][74] and sclerostin levels are reduced in the presence of PTH. [75][76][77] Continuous infusion of PTH in mice suppresses SOST gene expression and reduces sclerostin protein expression in vertebral bone. The same effect has been documented in primary osteocyte cultures and in osteocytic MLO-A5 cells.…”

The sclerostin story: From human genetics to the development of novel anabolic treatment for osteoporosis

“…36 In line with the in vivo studies, patients with primary hyperparathyroidism due to chronic elevation of PTH have significantly lower serum sclerostin levels compared with patients who have undergone parathyroidectomy and have normal PTH concentrations, thus confirming the down-regulation of the SOST gene by PTH in humans. 37 Calcitonin, on the other hand, which inhibits osteoclast resorption, up-regulates sclerostin expression by osteocytes, while it decreases other osteocyte products such as MEPE and DMP. 35,38,39 Mechanical stimulation of the skeleton either through exercise or experimental loading induces bone formation, while immobilization increases the number of sclerostin positive osteocytes.…”