Treatment of Bortezomib Increases Osteoblast Function in Patients with Multiple Myeloma.

Myeloma bone disease is caused by an enhanced osteoclast activation and impaired osteoblast function. Until now, there is no specific treatment to restore osteoblast activity, and anti-myeloma therapies that lead to a disease remission are usually not associated with an increase of osteoblast markers. Recently, preclinical data suggested that proteasome inhibitors may enhance osteoblast function. Bortezomib (Velcade) represents the first substance from this group which is clinically used in relapsed multiple myeloma. To evaluate whether there is clinical evidence for an osteoblast stimulation under bortezomib treatment, we analyzed serum levels of two specific osteoblast markers, i.e. bone-specific alkaline phosphatase (BAP) and osteocalcin, in 25 multiple myeloma patients treated with bortezomib alone or in combination with dexamethasone. 56 percent of patients achieved a complete or partial remission. In the whole group of patients, mean serum levels of osteocalcin significantly increased from 6.3 μg/l before treatment to 10.8 μg/l after three months of therapy (P=0.024). In parallel, mean levels of BAP increased from 19.7 U/l to 30.2 U/l (P<0.0005). The increase in BAP was irrespective of the combination with dexamethasone and was noted both in responders and in non-responders. This is of special interest, since it implicates that the increase in osteoblast function may be a direct effect of bortezomib on osteoblasts and not an indirect consequence of the reduced myeloma burden. Proteasome inhibition may modulate the Wnt/b-catenin pathway, a major signalling pathway in osteoblasts. Myeloma patients with osteolytic lesions have been shown to overexpress DKK-1, an inhibitor of the Wnt/b-catenin pathway. Recent experiments on mesenchymal cells showed that proteasome inhibitors decreased the DKK-1 production. Moreover, proteasome inhibition elevates cytoplasmatic b-catenin levels by inhibition of its degradation. In addition, animal models gave evidence that proteasome inhibitors stimulate the bone morphogenetic protein (BMP)-2 mediated osteoblast differentiation. Taken together, these preclinical observations suggest that proteasome inhibition may enhance osteoblast activity. Our study gives clinical evidence for a significant improvement of osteoblast function under bortezomib. This is of special interest, since it demonstrates additional effects of proteasome inhibitors and may provide a novel treatment approach in myeloma bone disease.