Calcitonin (CT) is a polypeptide of 32 amino acids produced by thyroidal C cells.(1,2 When administered at high pharmacological doses, it triggers a hypocalcemic response that is partially mediated through an inhibition of bone resorption.(3,4 This effect is well explained by the binding of CT to its receptor present on osteoclasts, although comparative studies have shown that mammalian CT is less potent than salmon CT as an inhibitor of their resorptive activity.(5–7 This has led to the therapeutic use of salmon CT in conditions associated with high bone resorption such as Paget's disease or osteoporosis.(8,9 It has also led to the assumption that the physiological role of mammalian CT is to participate in calcium hemostasis through an inhibitory effect on osteoclasts. This concept has, however, been challenged by two clinical observations. In fact, it was always puzzling that thyroidectomy does not result in osteoporosis and that high circulating levels of CT in patients with medullary thyroid carcinoma do not cause the expected osteopetrosis.(10,11
Whereas this absence of evidence was not necessarily in contradiction to a physiological role of mammalian CT as an inhibitor of bone resorption, the analysis of a CT-deficient mouse model was. These mice, which are lacking exons 2–5 of the Calca gene, display an unexpected high bone mass phenotype caused by an increased bone formation at the age of 3 months.(12 Even more surprising was the fact that there was no significant change of bone resorption and basal calcium hemostasis associated with the absence of CT at this age. These results suggested that mammalian CT is a physiological inhibitor of bone formation with no apparent influence on bone resorption. However, because the deletion of exons 2–5 from the Calca gene also results in the lack of α-calcitonin gene-related peptide (αCGRP), it was not clear at that point, whether the unexpected phenotype of the Calca−/− mice was indeed caused by the absence of CT.(12
Therefore, we took advantage of another mouse model, where a translational termination codon was introduced into exon 5 of the Calca gene, thereby selectively preventing the production of αCGRP without affecting the expression of CT.(13,14 These αCGRP−/− mice did not display the high bone mass phenotype that was observed in the Calca−/− mice. In contrast, they even displayed a mild osteopenia caused by decreased bone formation.(14 These results did not only establish a physiological role of αCGRP as an activator of bone formation, but they also suggested that the additional absence of CT in the Calca-deficient mice was counteracting the absence of αCGRP and causing their high bone mass phenotype.
In this manuscript we have continued our study and analyzed the progressive development of the bone phenotypes of both mouse models with age. Whereas the sole absence of αCGRP leads to osteopenia at 6, 12, and 18 months of age, the deficiency of CT and αCGRP in the Calca−/− mice results in high bone mass. More importantly, we observed major structural changes of trabecular bone as well as an increased cortical porosity in the Calca−/− mice at the age of 12 months or older. Histomorphometric analysis revealed that 12-month-old Calca−/−-mice display a phenotype of high bone turnover with increased bone formation, but also bone resorption. This high bone turnover resulted in hyperostotic lesions in 20% of all Calca−/− mice analyzed, but it could not be explained by alterations of the serum levels of several hormones with known effects on bone remodeling. The deduced dual action of CT as an inhibitor of both bone formation and bone resorption may explain why there are no major changes of BMD in human patients with altered CT serum concentrations.