Primary hyperparathyroidism and the skeleton.

Today, primary hyperparathyroidism (PHPT) in the developed countries is typically a disease with few or no obvious clinical symptoms. However, even in the asymptomatic cases the endogenous excess of PTH increases bone turnover leading to an insidious reversible loss of cortical and trabecular bone because of an expansion of the remodelling space and an irreversible loss of cortical bone due to increased endocortical resorption. In contrast trabecular bone structure and integrity to a large extent is maintained and there may be a slight periosteal expansion. Most studies have reported decreased bone mineral density (BMD) in PHPT mainly located at cortical sites, whereas sites rich in trabecular bone only show a modest reduction or even a slight increase in BMD. The frequent occurrence of vitamin D insufficiency and deficiency in PHPT and increased plasma FGF23 levels may also contribute to the decrease in BMD. The effect of smoking is unsolved. Epidemiological studies have shown that the relative risk of spine and nonspine fractures is increased in untreated PHPT starting up to 10 years before the diagnosis is made. Successful surgery for PHPT normalizes bone turnover, increases BMD and decreases fracture risk based on larger epidemiological studies. However, 10 years after surgery fracture risk appears to increase again due to an increase in forearm fractures. There are no randomized controlled studies (RCTs) demonstrating a protective effect of medical treatment on fracture risk in PHPT. Less conclusive studies suggest that vitamin D supplementation may have a beneficial effect on plasma PTH and BMD in vitamin D deficient PHPT patients. Hormone replacement therapy (HRT) and maybe SERM appear to reduce bone turnover and increase BMD. However, their nonskeletal side-effects preclude their use for this purpose. Bisphosphonates reduce bone turnover and increase BMD in PHPT as in osteoporosis and may be a therapeutical option in selected patients with low BMD. Obviously, there is a need for larger RCTs with fractures as end-points that appraise this possibility. Calcimimetics reduce plasma calcium and PTH in PHPT but has no beneficial effect on bone turnover or BMD. In symptomatic hypercalcaemic PHPT with low BMD where curative surgery is impossible or contraindicated a combination of a calcimimetic and a bisphosphonate may be an undocumented therapeutical option that needs further evaluation.