The Bone-parathyroid Crosstalk in Primary Hyperparathyroidism

Interactions Between Bone and Parathyroid Tumors in Patiens With Primary Hyperparathyroidism (The PARABONE Study)

The PARABONE study aims to investigate the interaction between bone and parathyroid glands in patients with primary hyperparathyroidism (HPT). The study consists of a clinical part aimed at evaluating a series of circulating molecules of bone derivation (osteocalcin, molecules of the WNT pathway, RANKL, osteoprotegerin, Scelrostin, FGF23) in patients with HPT. In particular, the study has as its primary objective to identify the correlation between circulating levels of PTH and levels of GlaOC and GluOC in patients with HPT.

The parathyroid glands are responsible for controlling mineral homeostasis in order to keep circulating calcium levels constant by acting on the target organs, where they induce mobilization of calcium from the bone matrix, and they promote the reabsorption of calcium from the ultra-filtrate at renal level. In turn, kidney and bone can affect the functioning of the parathyroid glands, for example through the action of FGF23 secreted by osteocytes. Primary hyperparathyroidism (HPT) is an endocrine disorder that causes bone demineralization, osteoporosis and fragility fractures, representing a frequent cause of secondary osteoporosis. It is prevalent in postmenopausal women, where it is the third most frequent endocrine pathology after diabetes and thyroid disease. In postmenopausal women, the pattern of demineralization induced by estrogen deficiency may overlap with that secondary to HPT. HPT is sustained by tumors of the parathyroid glands, mainly of a benign nature, associated with inappropriate secretion of parathyroid hormone (PTH), which causes hypercalcemia and bone, kidney and cardiovascular complications. It is known that persistent secondary hyperparathyroidism, such as that induced by idiopathic hypercalciuria or malabsorption related to vitamin D deficiency, can stimulate the proliferation of parathyroid cells and the autonomous hypersecretion of PTH. Therefore, it is conceivable that also alterations in bone metabolism, such as a persistently increased release of osteocalcin (OC), can promote the proliferation of parathyroid cells and/or hypersecretion of PTH. Interestingly, the circulating levels of carboxylated and decarboxylated osteocalcin (GlaOC and GluOC) were found to be increased in patients with HPT. Furthermore, elevated circulating OC levels appear to be predictive of multiglandular disease in HPT patients. Osteoblasts are one of the main targets of PTH action and release biologically active molecules with paracrine and endocrine action, including osteocalcin (GlaOC and GluOC), the molecules of the intracellular signaling pathway WNT and the RANK ligand (Receptor Activator for Nuclear Factor-κB, RANKL). Therefore, it is conceivable that these biologically active molecules released by osteoblasts can induce biological effects of modulating the functioning of parathyroid cells, in a sort of bone-parathyroid regulatory loop, and thus modulate the presentation phenotype and clinical severity of HPT. RANKL and sclerostin are the specific targets of monoclonal anti-osteoporotic treatments currently available; therefore understanding their potential effect on parathyroid function in HPT can provide the rationale for new therapeutic approaches for patients with HPT. The expected results will allow to improve the diagnosis of HPT, in particular to better define the extent of bone compromise related to it, evaluating circulating bone markers so far not explored. The investigators therefore intend to clarify the effect of hormones released by osteoblasts on parathyroid function, taking into account that these hormones are the target of currently available anti-osteoporotic therapies. The translational study will therefore allow to identify new pathogenetic mechanisms in parathyroid tumorigenesis promoted by endocrine factors released by osteoblasts, which will be able to provide potential targets for targeted medical treatments.

Inclusion Criteria:

Inclusion criteria for the HPT patient group:

• diagnosis of primary hyperparathyroidism according to the most recent guidelines [Marcocci et al. 2015];
• adult patients (age ≥ 18 years);
• signature of the informed consent.

Inclusion criteria for the HPT-PTX patient group:

• diagnosis of primary hyperparathyroidism with indication of surgical removal of the parathyroid tumor according to the most recent guidelines [Marcocci et al. 2015];
• adult patients (age ≥18 years);
• signature of the informed consent.

Exclusion Criteria:

• Criteria for exclusion from the study are:
• age <18 years
• diagnosis of hyperparathyroidism secondary to chronic renal failure or to vitamin D or calcium deficiency;
• pregnancy or breastfeeding (self-declaration)
• lack of informed consent