The hungry bone: expected and unexpected.

ate about 3 million new BMU annually, and more than 1 million function at any moment in the whole skeleton. A new BMU is a separate functional unit with regulatory mechanisms for the recruitment, differentiation and activity of precursor cells, osteoclasts, osteoblasts, supporting cells and microvascular bed. It functions in the same sense as nephrons in the kidney7. Osteoclasts and osteoblasts, the most important cell types of BMU, are continuously receiving endocrine, paracrine and autocrine signals in order to perform their programmed and coupled activity. Among osteotropic hormones, the parathyroid hormone (PTH) is essential for both cell types. Osteoblasts are a primary target of PTH. It is now clear that PTH is a fundamental anabolic signal that promotes differentiation and prevents apoptosis of osteoblasts8. It has also the capability of increasing gene expression and synthesis of receptor activator of nuclear factor κB ligand (RANKL), which is a major stimulus for the differentiation of active mature osteoclasts. When PTH production is excessive and sustained over time as it occurs in primary and long-standing secondary hyperparathyroidism, RANKL synthesis from cells of the osteoblastic lineage may rise up to levels higher than physiological of two orders of magnitude9. Under these circumstances, the osteoclast-mediated bone resorption overrides the osteoblast-mediated bone formation and bone loss becomes clinically apparent. Turning to HBS, osteoblast number and activity may be increased as a logical consequence of osteoclast-mediated excess resorption, e.g. in hyperparathyroidism or thyrotoxicosis. Uncoupling of osteoblast to osteoclast function, with overwhelming bone apposition even in the presence of supranormal resorption, may be a function of paracrine signals (cytokines, growth factors) that specifically activate differentiation of the osteoblastic lineage in the bone microenvironment, e.g. in Paget’s lesions or prostate cancer metastases. Since decades, clinicians are well acquainted with increased serum levels of a marker of osteoblastic activity, the alkaline phosphatase (AP) (more recently, bone-specific alkaline phosphatase, BAP), in all the above-mentioned conditions. Clinica Medica Generale (Direttore: Prof. Alberto Angeli), Università degli Studi di Torino (Ann Ital Med Int 2004; 19: IV-VI)