ABSTRACT

Primary hyperparathyroidism (PHPT) is characterised by increased secretion of PTH from the parathyroid glands in absence of adequate hypocalcemic stimulation. The continued hypersecretion leads to enhanced bone resorption - and to a lesser extent formation - resulting in low bone mass and increased risk of fractures.

When patients with PHPT are cured by surgery, bone metabolism returns to normal. The reversibility of the condition itself and of its consequences on the skeleton makes PHPT a suitable model for studying skeletal PTH effects in vivo.

In the dept. of endocrinology, Odense University Hospital, we recruited 27 patients with PHPT, who were candidates for surgical cure (PTX) using the patients as their own controls. We studied the changes in bone under the influence of high levels of PTH, and during normal levels after PTX. BMD increased significantly after surgery and bone turnover markers decreased. This indicates that the patients exhibited hyperparathyroid biochemistry accompanied by the typical pattern of increased bone turnover and decreased BMD during PHPT, and reversal of these changes upon successful parathyroidectomy.

First, the secretion of the bone resorptive cytokines IL-6 and TNF α in peripheral blood in vitro was assessed by whole blood culture. The production of the soluble receptor sIL-6R was also measured. The production of IL-6 and the IL-6 x sIL-6R product was increased in patients with PHPT compared with after PTX. In the hyperparathyroid state, IL-6 level - to our surprise - was negatively correlated with bone turnover markers. Furthermore, a significantly positive correlation between IL-6 and BMD at the spine and distal forearm was found. This suggests that the effect of PTH on the skeleton is not directly relayed through the TNF-IL-6 cytokine pathway.

Secondly, we measured the serum levels of osteoprotegerin (OPG), a decoy receptor that blocks bone resorption. Serum OPG was not affected by PTX. Patients with the highest levels of serum OPG before surgery had the smallest subsequent BMD changes and a borderline higher spine BMD at presentation. This indicates that serum OPG may affect bone metabolism and ultimately BMD, but is not directly related to PTH action.

Finally, quantitative RT-PCR on bone biopsies revealed that the RANKL/OPG mRNA ratio decreased significantly after surgery. Before surgery, the RANKL/GAPDH gene expression ratio showed positive correlations with bone turnover markers. This indicates that OPG and RANKL gene expression within the human bone microenvironment is influenced by PTH and points towards a role for local skeletal RANKL production in causing increased bone resorption in primary hyperparathyroidism.