Introduction Multiple myeloma MM is the most frequent cancer
Multiple myeloma (MM) is the most frequent cancer to involve the skeleton with 80–90% of patients developing bone lesions during their disease course . Myeloma bone lesions are purely osteolytic and are associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and estriol compression, as well as increased mortality . It is estimated that 20% of MM patients present with pathologic fractures, 40% develop a fracture in the first year after diagnosis, and up to 60% develop pathologic fractures over the course of their disease . Additionally, patients with pathologic fractures have a 20% increase in mortality when compared to patients without pathologic fractures . The bone destructive lesions can be extensive and severe  and bone pain, frequently centered on the chest or back and exacerbated by movement, is present in more than two-thirds of patients at diagnosis .
Multiple myeloma bone disease (MMBD) is distinct from the bone disease caused by other types of tumors that metastasize to bone and is marked by dysfunction of both bone formation and bone resorption . While osteolytic metastases from MM and other malignancies induce osteoclastic (OCL) bone resorption, myeloma bone lesions are unique in that osteoblast (OBL) activity is severely decreased or absent [7,8]. Thus, bone scans in patients with MM frequently underestimate the extent of bone disease . Furthermore, bone lesions in patients with myeloma rarely heal, even when a patient is in prolonged complete remission. MMBD can affect any bone, with predominant areas of involvement occurring in sites of red marrow, such as the vertebral bodies and ribs.
Prevalence and presentation of myeloma bone disease The clinical presentation of myeloma is variable and approximately 11% of patients are initially asymptomatic . (Disease in these patients is generally identified through routine laboratory studies.) Of symptoms reported at presentation, the most common is bone pain, which is present in more than two-thirds of patients . The American Cancer Society estimates that there will be 21,700 new cases of myeloma diagnosed in 2012, including 12,190 in men and 9510 in women, with an estimated 4690 deaths . The majority of myeloma patients are elderly, with a median age at diagnosis of 69 years and a median age at death of 74 years . Treatment of MM has improved markedly over the past 30 years, with an increase in 5-year survival from 25% in 1975 to 41% in 2007, however the disease remains incurable and MMBD remains a major contributor to the morbidity and mortality of myeloma patients. Up to 90% of MM patients have evidence of osteolysis in the form of generalized osteopenia or discrete lytic lesions over the course of their disease , and approximately 80% have radiologic evidence of bone involvement on skeletal survey . Approximately 40% of patients with MM will develop a fracture in the first year after diagnosis, and up to 60% will develop pathologic fractures . The bone destructive lesions in myeloma can be extensive and can affect any bone . The predominant areas of involvement occur in sites of red marrow, such as the vertebral bodies (49%), skull (35%), pelvis (34%) and ribs (33% of patients) . While there is an association between a patient\'s tumor burden and the number of lytic lesions present , and tumor burden, OCL number, and OCL resorptive surface area are correlated in bone marrow biopsies from MM patients [17,18], an individual\'s degree of bone disease does not have significant utility in predicting clinical outcomes. Additionally, bone lesions in patients with myeloma rarely heal, even when a patient is in prolonged complete remission. Approximately 15% of newly diagnosed MM patients are hypercalcemic due to increased bone resorption, decreased bone formation, and impaired renal function, all of which are often exacerbated by immobility. Unlike other malignancies with metastatic bone involvement, parathyroid hormone related protein (PTHrP) is rarely over-produced by myeloma cells. Thus, the severity of hypercalcemia in patients with myeloma is not correlated with serum PTHrP levels and instead reflects tumor burden . Symptomatic hypercalcemia can result in anorexia, nausea, vomiting, confusion, fatigue, constipation, renal stones, depression and polyuria, and is suggestive of a high tumor burden.