Myeloma bone disease and proteasome inhibition therapies

Abstract

Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-B ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin.The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points. IntroductionMyeloma bone disease is the result of increased destruction of bone that cannot be compensated for by new bone formation. Approximately 80% of patients with multiple myeloma (MM) develop skeletal complications including bone pain, osteolytic lesions, pathologic fractures, and hypercalcemia. 1 Osteolytic bone destruction is the most debilitating manifestation of MM and has a severe impact on patients' quality of life. Moreover, myeloma-associated lytic bone lesions do not repair, even in patients who are disease free for years. 2,3 Mechanisms of myeloma bone diseaseThe pathophysiology of myeloma bone disease has been studied extensively over recent years. This has led to new insights into the complex interactions between myeloma cells and osteoclasts and osteoblasts. Histomorphometric studies have revealed that myeloma cells promote osteoclastic bone resorption and suppress osteoblast activity, 4,5 thereby causing an imbalance between the processes of bone resorption and formation, which is so characteristic of myeloma bone disease [6][7][8][9] (Figure 1).The molecular mechanisms responsible for the increased osteoclastic bone resorption are also becoming clear. Under normal circumstances, receptor activator of nuclear factor-kappa B ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) regulate osteoclast formation, activity, and bone resorption. Myeloma cells disrupt the balance between RANKL and OPG by increasing the expression of RANKL and decreasing the expression of OPG. [10][11][12] The resulting increase in RANKL favors the formation a...

Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma

“…20 Recent studies demonstrated that bone markers, which reflect osteoclast and osteoblast activity, can be modulated by novel agents such as proteasome inhibitors or immunmodulatory drugs. [21][22][23][24] Because of the clinical relevance of myeloma bone disease, we hypothesized that the bone resorption marker ICTP may add to the prognostic value of ISS. Thus, we evaluated the adverse prognostic impact of ICTP in combination with established prognostic factors in a patient cohort of 100 consecutive newly diagnosed patients with symptomatic MM.…”

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

“…Pre-clinical and clinical data have shown that bortezomib has a positive effect on bone remodeling by inhibiting osteoclast formation and stimulating osteoblast differentiation. [58][59][60][61] As bortezomib influence osteoclasts as well as osteoblasts and targets different mechanisms as HDACi, combining bortezomib with JNJ-26481585 would be a promising therapeutic strategy to improve the reducing effects of bortezomib on the development of MM-related bone disease.…”

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

“…[8][9][10][11][12] In addition to its direct inhibitory effects on the proteasome, 9 bortezomib has been noted to increase the level of intracellular reactive oxygen species (ROS) as an important component of its ability to induce apoptosis, [13][14][15][16][17][18] autophagy [19][20][21] and differentiation. 22 A sustained increase in ROS generation appears, in turn, to enhance the inhibitory effects of bortezomib on proteasomal activity. 9 It has also been postulated that the bortezomib-induced increases in ROS levels in tumor cells may be the basis for its synergy with other chemotherapeutic agents.…”