The adipose hormone leptin and its receptor are important for regulation of food intake and energy metabolism. Leptin also is involved in the growth of different tissues. In this study, we show the expression of leptin in primary cultures of normal human osteoblasts (

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/ placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was

IntroductionBone is a dynamic tissue in which the synthesis of bone matrix by osteoblasts and bone resorption by osteoclasts are coupled processes. Osteoclasts differentiate from hematopoietic precursor cells under the control of humoral factors and cell-cell contact with osteoblasts or stromal cells. Key regulators of osteoclastogenesis are members of the tumor necrosis family of receptors and ligands: receptor activator of nuclear factor (NF)-B (RANK), receptor activator of NF-B ligand (RANKL), and osteoprotegerin (OPG). RANKL is expressed by activated T cells, stromal cells, and osteoblasts. [1][2][3] When RANKL binds to RANK on osteoclast precursors, maturation and differentiation of the osteoclasts are induced, leading to bone resorption. 4,5 OPG is a soluble decoy receptor that is secreted by osteoblasts and bone marrow (BM) stromal cells and that competes with RANK for binding to RANKL. Binding of OPG to RANKL inhibits the development of osteoclasts. 6,7 The importance of OPG as a negative regulator of osteoclastogenesis is evident from experiments with transgenic mice, where overexpression of OPG leads to severe osteopetrosis and reduced numbers of mature osteoclasts. 6 In contrast, OPG knockout mice are osteoporotic. 8 Multiple myeloma (MM) is a malignancy characterized by accumulation of plasma cells in the BM. Bone destruction is a common complication of the disease and is associated with severe morbidity. A number of osteoclast-activating factors are implicated in myeloma bone disease (for a review, see Callander and Roodman 9 ). However, accumulating data suggest that a disruption of the balance between RANKL and OPG is of major importance. Histologic examination of BM biopsies from patients with MM showed enhanced expression of RANKL in the BM, as well as reduced OPG expression. 10,11 Furthermore, we have recently shown that serum OPG levels are lower in myeloma patients than in healthy individuals and that myeloma patients with osteolytic lesions have reduced levels of OPG in serum compared to myeloma patients without clinical bone disease. 12 Osteoprotegerin has a highly basic heparin-binding domain, 13 making interactions with heparin and heparan sulfates possible. A feature of both normal and malignant plasma cells is the abundant expression of syndecan-1, 14,15 which is a transmembrane proteoglycan with heparan sulfate side chains. These side chains allow interactions with several macromolecules, including extracellular matrix proteins, growth factors, cytokines, and pathogens (for a review, see Tumova et al 16 ). In addition to modifying the action of its ligands, 17,18 syndecan-1 has been shown to mediate the catabolism of several proteins. 19 Patients, materials, and methods MM and control patientsBone marrow was aspirated from the iliac crest or sternum of 33 patients with MM for diagnostic purposes before treatment (median age, 65 years; 19 men, 14 women). Twenty-seven patients who underwent BM aspiration for diagnostic purposes, but who had normal BM morphology and subsequently were not ...