**2. Pathogenesis of multiple myeloma bone disease**

#### **2.1. Introduction**

The reason for the excessive loss of bone mass observed in MM is multi factorial. For many years attention was primarily focused on the increase in bone degradation which is observed in the majority of MM patients.

**3. Normal bone remodelling**

resulting in decreased bone formation.

plays a role in the recruitment of osteoclasts.

Osteoclasts are the cells responsible for bone resorption. They originate from the monocytemacrophage cell line. Differentiation of hematopoietic precursor cells into mature osteoclasts requires different environmental factors of which macrophage-colony stimulating factor (M-CSF) and receptor activator for NF-κB ligand (RANKL) play an essential role. The early step in osteoclastogenesis seems to be influenced by M-CSF [7], whereas RANKL initiates differ‐ entiation, cell fusion, and activation of mature osteoclasts [8]. During osteoclast development the cell replaces the nonspecific esterase activity with tartrate-resistant acid phosphatase isotype 5b (TRACP 5b), which is believed to be specific for osteoclasts. Osteoclastogenesis results in the formation of large multinucleated cells located on the bone surface where bone degradation takes place. Bone degradation is achieved by an active secretion of protons from the osteoclasts into the resorption pits. The protons decrease the pH and cause decalcification of the bone matrix [9]. After decalcification the collagen fibres are degraded mainly by the

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 219

Osteoblasts are responsible for the formation of new bone following osteoclast-mediated bone resorption. Osteoblasts originate from differentiated mesenchymal stem cells under the influence of Runt-related transcription factor (Runx2) and the wingless type signalling (Wnt) factors. Runx2 is required for the differentiation of mesenchymal cells into osteoblasts [11]. The Wnt-pathway mediates the formation of a complex, which in turn inhibits the proteasomal degradation of β-catenin. The increasing level of β-catenin has a stimulating effect on osteoblast differentiation and maturation [12]. The Wnt-pathway can be inhibited by Dickkopf 1 (DKK1),

Mature osteoblasts are lined in groups located along the newly resorbed bone. Placed on the resorption site, the osteoblasts secrete the components needed to generate bone matrix, mainly collagen type 1 [13]. The bone formation ends with calcification of the newly synthesized bone. During bone formation some osteoblasts are incorporated into the bone matrix and become

Activation of bone remodelling is not yet clearly understood. However, it is thought that osteocytes may, at least partly, be of importance for the activation of bone remodelling. Osteocytes in the bone matrix may respond to mechanical stimulation and via communication through their networks of canaliculli initiate bone resorption. Osteocyte death probably also

Bone remodelling takes place on bone surface where the osteoclasts and osteoblasts are covered by a canopy of flattened cells of osteoblast lineage [14;15]. The space between the canopy and the bone surface undergoing remodelling is named the bone remodelling com‐ partment (BRC). Disruption of the BRC canopy may impair bone remodelling [16]. Several factors of importance for the regulation of bone remodelling have been identified during the last decades. Within this chapter, we will only review some of the most important. The RANKL, RANK, and the decoy receptor osteoprotegerin (OPG) are probably the most significant factors in the regulation of normal physiological bone remodelling. RANK is expressed on the surface

proteolytic enzymes cathepsin K and various matrix metalloproteinases [10].

osteocytes. Bone lining cells and the canopy cells are also of osteoblast lineage.

Over the last decade however, it has become increasingly evident that impaired bone formation also plays an important role in MM bone disease. In monoclonal gammopathy of unknown significance (MGUS) and early stage MM with preserved bone structure, normal or even increased bone formation may be observed. With disease progression and development of osteolytic lesions bone formation becomes impaired, and this may be an important contribu‐ ting factor for the development of osteolytic lesions (see figure 1).

The interaction between the bone marrow microenvironment and the myeloma cells is also considered to be crucial. A large number of cytokines and chemokines, that regulate the activity of bone resorbing osteoclasts and bone forming osteoblasts, have been identified and studied in MM. Recently, a structure consisting of a flat layer of osteoblast lineage cells, that separates the bone surface from the bone marrow during bone remodelling, has been described. Disruption of this cell layer, called the bone remodelling compartment (BRC) canopy, allows direct contact betweenmyeloma cells andthe activebone remodellingcells, andthismayaffectbothcelltypes. OsteocyteshavebeensparselyinvestigatedinMM.However, a recent article illustrates that also this type of cell may be important for a better understanding of MM bone disease [6].

With permission from the author; Søndergaard T. The effect of simvastatin on bone markers in multiple myeloma and a description of the bone remodeling compartment. University of Southern Denmark, 2008.

**Figure 1.** Number of studies evaluating biochemical markers of bone turnover in MM patients in a ten year period. Bone resorption markers are uniformly elevated, while the bone formation markers are more divergent, with in‐ creased levels observed in early stages of MM.
