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Therapeutic approaches to myeloma bone disease: An evolving story

Cancer Treatment Reviews, 6, 38, pages 787 - 797


Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1α/chemokine receptor for macrophage inflammatory protein-1α axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-β, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.

Abbreviations: ActRIIA - activin receptor type IIA, Akt - serine/threonine protein kinase, APRIL - proliferation-inducing ligand, BAFF - B-cell activating factor, BAFF-R - B-cell activating factor-receptor, BCMA - B-cell maturation antigen, BM - bone marrow, BMM - bone marrow microenvironment, BMSCs - bone marrow stromal cells, BPs - bisphosphonates, BSAP - bone specific alkaline phosphatase, CCR1 - chemokine receptor for MIP1α-1, CTX - C-telopeptide, DASH - dipeptidyl peptidase-IV activity and/or structure homologues, DKK-1 - Dickkopf-1, DLX5 - distal-less homeobox 5, DPP - dual dipeptidyl peptidase, ERK - extracellular signal-regulated kinases, FAP - fibroblast activation protein, Hsp90 - heat shock protein 90, IL-1 - interleukin-1, JNK - Jun N-terminal Kinase, LDH - lactate dehydrogenase, MAPK - mitogen-activated protein kinase, MBD - myeloma bone disease, M-CSF - macrophage colony-stimulating factor, MEK - mitogen-activated protein kinase, MIP-1α - macrophage inflammatory protein-1α, MM - multiple myeloma, MMPCs - multiple myeloma plasma cells, MRC - Medical Research Council, MSCs - mesenchymal stem cells, NFAT-1 - nuclear factor of activated T-cells-1, NF-kB - nuclear factor-kappaB, NTX - N-telopeptide, OB - osteoblast, OC - osteoclast, ONJ - osteonecrosis of the jaw, OPG - osteoprotegerin, PAM - pamidronate, PARP - poly ADP ribose polymerase, PCR - polymerase chain reaction, PDACs - placenta-derived adherent cells, PTH - parathyroid hormone, RANK - receptor activator of nuclear factor-κB, RANKL - receptor activator of nuclear factor-κB ligand, RUNX-2 - Runt-related transcription factor, s.c. - subcutaneous, SCID - severe combined immunodeficiency, SFRP - secreted frizzled related protein, siRNA - small-interfering RNA, SLRPs - small leucine-rich proteoglycans, SMAD - small mother against decapentaplegic, SOST - sclerosteosis, Src - sarcoma, SREs - skeletal-related events, STAT3 - signal transducer and activator of transcription 3, CAML - calcium-modulator and cyclophilin ligand, TACI - transmembrane activator and CAML interactor, TGF-β - transforming growth factor-β, TK - tyrosine kinase, TNFR - tumor necrosis factor receptor, TNF-α - tumor necrosis factor-α, TRAcP - tartrate-resistant acid phosphatase, VEGF - vascular endothelial growth factor, Wnt - wingless, ZA - zoledronic acid.

Keywords: Multiple myeloma, Myeloma bone disease, Osteolyses, Osteoblasts, Osteoclasts, Skeletal-related events.


Multiple myeloma (MM) is a plasma cell malignancy that, after prostate and breast cancers, more frequently induces bone involvement. 1 Its clinical progression is characterized by the appearance of multiple osteolytic lesions which, through a rapid loss of bone mass, lead to progressive skeletal devastation, with intractable pain, pathological fractures, hypercalcemia and frequent spinal cord compression, all of which define the myeloma bone disease (MBD). 2 At least 15% of MM patients show a pathological fracture at diagnosis, and 60% of them experience this complication during the course of the disease. Each patient usually develops 3–5 skeletal-related events (SREs) every three years. Moreover, MBD is not only a critical morbidity factor, but also adversely affects overall survival since the mortality is 20% higher in patients with multiple SREs. Therefore, treatments that can remarkably reduce the risk of bone complications in MM are urgently needed.3, 4, and 5

Several studies have demonstrated that bone provides a permissive niche to tumor cell growth and that interactions between multiple myeloma plasma cells (MMPCs) and the bone marrow (BM) contribute to bone destruction by deregulation of both soluble factors release and cell-to-cell cross talk. MBD is a consequence of increased osteoclast (OC) activation in parallel with osteoblast (OB) inhibition, resulting in impaired bone remodelling.6, 7, and 8

Bisphosphonates (BPs) represent the current standard of care in the treatment of MBD. However, complications arising from their use have stimulated schedule optimization studies and the search for alternative strategies, which are currently being evaluated in ongoing pre-clinical and clinical studies. 9

Here, we review new therapeutic approaches to MBD, with a special focus on cross-talking between BM and MMPCs as well as on the molecular mechanisms implicated in OC activation and concurrent OB suppression.

Bisphosphonates in MBD

BPs administration has dramatically improved the quality of life in MM patients, significantly reducing SREs and palliating bone pain, with a consequent reduction in the use of analgesic drugs. Before the “BPs era”, SREs occurred in approximately 75% of MM patients. Starting from 1990 and following the introduction of first-generation BPs, namely Etidronate and Clodronate, SREs dropped to 68% and 36% respectively,10 and 11 and subsequently to 25% with the second-generation BPs which include pamidronate (PAM)and particularly zoledronic acid (ZA)( Fig. 1 ).12 and 13


Fig. 1 Skeletal-related events (SREs) and bisphosphonates (BPs) in multiple myeloma (MM). Before the “BPs era”, SREs occurred in approximately 75% of MM patients. Starting from 1990, with the introduction of first- and then of second-generation BPs, their incidence progressively dropped down to 25%.

BPs also exert anti-myeloma activity both by inducing apoptosis in MMPCs and modifying the tumor microenvironment.14, 15, and 16 In agreement with these data, a recent analysis from the MRC Myeloma IX Study, including 1960 patients, showed that ZA, in association with other anti-MM drugs, increases overall survival in newly diagnosed MM patients. 17 Therefore, BPs are currently considered the best available treatment for MBD. However, ZA may also induce, as already mentioned, adverse effects, such as kidney failure and osteonecrosis of the jaw (ONJ). The former is due to several potential mechanisms including the capability of BPs to form insoluble aggregates with metal ions in kidney microvessel and the podocyte mitochondrial injury, as well as the degeneration of tubular cells leading to loss of brush border and derangement of tubular Na+, K+ – ATPase expression.18, 19, 20, 21, and 22 The pathogenesis of the latter, on the contrary, is still uncertain, though it is suspected that ZA is capable of inducing a microenvironment modification that results in inhibition of angiogenesis, necrosis of the jaw and increasing susceptibility to infections in these sites.23 and 24

Although several studies have evaluated the prevalence of ONJ, differences in study design and lack of prolonged follow-up have prevented a reliable evaluation of its occurrence.25, 26, 27, 28, 29, and 30 In a large cohort of 1621 patients 31 treated with intravenous BPs, the rough ONJ incidence rates were 8%, 3% and 5% in patients with MM, breast or prostate cancer, respectively. Migliorati et al. 32 have recently revisited the ONJ prevalence in 22 different studies that revealed an overall recurrence of 6.1%. However, in a parallel study the same group 33 reported a weighed prevalence of 13.3% in selected clinical trials characterized by documented follow-up. The use of dentures, history of dental extraction and protracted administration of BPs have been shown to be associated with increased risk for the development of ONJ. 31 On the other hand, cancer patients, especially those with MM, are constitutively at risk for kidney failure, although its occurrence in relation to ZA combined with conventional chemotherapy is not well defined. The rates of kidney failure associated to long-term treatment with ZA have been described to be as high as 30% in all cancer patients receiving ZA.27, 31, 34, 35, 36, 37, 38, and 39

A number of organization have prepared guidelines, mainly based on good-clinical-practice, for use of BPs in MM. For instance, both the European Myeloma Network and the American Society of Clinical Oncology recommend that BPs should be discontinued in patients who develop ONJ and, independently of this complication, after 2 years in patients without active bone disease, although these drugs can be resumed in case of relapse.40 and 41 The National Comprehensive Cancer Network also defines similar recommendations, though a 2 year continuative period of BPs treatment is not considered a further risk for developing ONJ. 42 Alternative therapeutic approaches are thus needed for patients ineligible to receive BPs in the presence of novel SREs.

Therapeutic approaches targeting OC pathways

OC hyperactivation is a major pathogenetic mechanism in MBD, as shown by analyses on bone marrow biopsies from MM patients that have clearly shown a close relationship between OC number, bone resorption areas and tumor burden. 43

MMPCs interact with bone marrow microenvironment (BMM) and constitute, together with OBs and stromal cells, a functional neoplastic unit secreting a number of soluble factors, such as OC-activating cytokines( Fig. 2 ).These include receptor activator of nuclear factor-κB ligand (RANKL), which plays a major role in MM osteoclastogenesis; IL-6, a survival factor for MMPCs; tumor necrosis factor-α (TNF-α); IL-1;macrophage inflammatory protein-1α (MIP-1α) and macrophage colony-stimulating factor (M-CSF). 44 At the same time, OC activation promotes MMPCs proliferation and survival by the release of IL-6, creating a vicious circle that progressively leads to the onset of bone lesions. Therefore, these reciprocal interactions represent new promising targets for the treatment of MBD ( Table 1 ).


Fig. 2 Treatment approaches targeting osteoclast (OC) pathways. Denosumab, a RANKL neutralizing monoclonal antibody (mAb), inhibits OC maturation and activation. MLN3897, a mAb against CCR1, prevents OC formation and functions promoted by CCL3. AKT and ERK1/2 pathways, that are involved in osteoclastogenesis, can be inhibited by inactivating Src with Dasatinib. OCs are important cell sources of BAFF. LY2127399, an anti-BAFF mAb, reduces both tumor burden and osteoclastogenesis. The figure also shows OC suppression through Etaracizumab, a fully humanized mAb against integrin αVβ3. Finally, inhibition of enzymes involved in bone matrix degradation, such as Cathepsin K, is a possible novel therapeutic strategy for MBD.

Table 1 A list of the main drugs under investigation in myeloma bone disease.

Therapeutic agents Drug denomination Target Study phase References
RANKL-neutralizing antibody Denosumab OC Phase III clinical trials (already approved for other malignancies) 53
Anti-Baff-neutralizing antibody LY2127399 OC Phase I clinical trial in association with bortezomib 59
Decoy receptor for BAFF and APRIL Atacicept OC Phase I/II clinical trials 60
CCR1 inhibitors MLN3897 OC Preclinical studies 66
Src/Abl inhibitors Dasatinib OC Phase I/II clinical trials (already approved for other malignancies) 72 and 73
MEK inhibitors AS703026; AZD6244 OC Phase II clinical trials 84, 85, 86, and 87
p38MAPK inhibitors LY2228820 OC Phase I clinical trials 89, 90, 91, and 93
DASH inhibitors PT-100 OC Preclinical studies (Phase II/III for other malignancies) 95
Hsp90 inhibitors SNX-2112 OC Preclinical studies 96
Anti-DKK1 BHQ880 OB Phase II clinical trials 116 and 117
TGF-β inhibitors SB431542; Ki26894 OB Preclinical studies 130, 131, and 132
Decoy receptor for Activin A ACE-011; RAP-011 OC and OB Phase II clinical trials 138
Cytotherapy PDACs OC and OB Preclinical studies 155

RANK/RANKL pathway

RANKL binds its receptor, RANK, an integral membrane protein on the surface of OC precursors, and allows their maturation to OCs.45 and 46 Several studies have demonstrated that MMPCs stimulate RANKL production by bone marrow stromal cells (BMSCs) through a cell-to-cell contact, resulting in increased RANKL circulating levels in patients with MM. 47 In normal conditions, osteoprotegerin (OPG), a soluble decoy receptor of RANKL belonging to the tumor necrosis factor receptor (TNFR) superfamily, modulates its effects and prevents excessive bone resorption. 48 In patients with MM, serum OPG levels are instead greatly decreased because of the neutralizing effect of CD138, that produces an increase of the soluble RANKL/OPG ratio correlated with enhanced OC activation and the extent of MBD. 49 The RANK/RANKL/OPG axis, which plays a crucial role in the regulation of the OC function, is an important target of novel therapeutic strategies aimed at down-regulating hyperactive osteoclastogenesis. 43 Recombinant human OPG-Fc inactivates RANKL, 50 thus interfering with bone resorption in patients with MM, post-menopausal osteoporosis or bone metastases from breast cancer. 51

Another RANKL inhibitor is Denosumab (AMG 162, Amgen Pharmaceutical), a fully human anti-RANKL monoclonal antibody with a half-life longer than OPG-Fc and a remarkable anti-resorptive effect. 52 In a recent double-blind study, subcutaneous (s.c.). Denosumab was evaluated in comparison with intravenous ZA in patients with MM or advanced cancers and bone metastases (excluding breast and prostate). The Denosumab effect was judged non-inferior to ZA in preventing or delaying SREs, whereas in another study a single s.c. administration of Denosumab induced reduction in the level of bone resorption markers persistent up to 80 days, compared with the 30 days of BPs. Although ONJ occurred at similar rates in both groups, Denosumab induced renal failure and acute-phase reactions less frequently. 53 These results indicate that Denosumab is a promising treatment in patients with MBD. Additional trials are in progress to investigate its effectiveness in the treatment of cancer-induced bone disease and in other bone loss disorders. 54

BAFF-neutralizing antibodies

B-cell activating factor (BAFF) of the TNF family and proliferation-inducing ligand (APRIL) promote MMPCs survival and BMSC adhesion.55 and 56 BAFF binds the TNF-related receptors, such as B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), and ultimately its own receptor BAFF-R. APRIL binds TACI, BCMA and heparan sulfate proteoglycans, such as syndecan-1. In MM, BAFF and APRIL are expressed by cells of BMM and particularly by OCs. 57

Neri et al. 58 have demonstrated that BAFF-neutralizing antibodies reduce both tumor burden and OC differentiation in vivo, thus reducing the number of osteolytic lesions. A phase I study combining a BAFF-neutralizing antibody with Bortezomib in twenty patients showed an overall response rate of 55%, including six partial responses, four very good partial responses and one complete response, with a safety profile similar to that of Bortezomib used as a single agent, 59 whereas Atacicept (TACI-Ig), a decoy receptor for BAFF and APRIL, is currently being investigated in a Phase I/II clinical trial in patients with refractory or relapsed MM or progressive Waldenström’s macroglobulinemia. Atacicept appears to be safe and clinically active, in that in a recent phase-1 study carried out on 11 patients with MM who completed initial treatment, 5 patients were progression-free after cycle 1 and 4 patients were progression-free after extended therapy. 60

hMIP-1α/CCR1 pathway in MM

hMIP-1α is a chemokine involved in the interactive loop between OCs and MMPCs. It is secreted by both cell types and interacts with 2 receptors, namely chemokine receptor for MIP-1α (CCR1) and CCR5. hMIP-1α exerts osteoclastogenic activity mostly via CCR1, and stimulates migration, adhesion and survival of MMPCs through interactions with both CCR1 and CCR5.61 and 62 Bone marrow expression and serum levels of MIP-1α have indeed been reported to correlate with bone disease extension.63 and 64 In agreement with these evidences, it has been reported that hMIP-1α targeting by neutralizing antibodies or antisense strategies reduces the tumor burden and inhibits the development of osteolytic lesions in vivo. 65

In parallel with these results, Vallet et al. 66 have shown that MLN3897, a specific CCR1 inhibitor, blocks the differentiation of OC progenitors by down-regulating cell-fusion and c-fos expression. Moreover, MLN3897 abrogates the proliferative advantage of MMPCs mediated by OC and interferes with both the adhesion between OC and MM cells, and the OC cytokine secretion. Future trials targeting the hMIP-1α /CCR1 pathway will assess whether or not these results are susceptible of clinical application.

Src inhibitors

Considerable interest has recently been focused on the possible role of sarcoma (src) oncogene in the pathogenesis of MBD. This gene is highly expressed by several cell types and codes for a non-receptor tyrosine kinase (TK) which phosphorylates a number of substrates, such as adhesion molecules (vinculin), soluble enzymes (enolase, LDH) and transmembrane TK receptors. 67 Src contributes to the regulation of many cellular events, including not only migration, proliferation and differentiation, but also bone homeostasis. The activation of serine/threonine protein kinase (Akt) by this kinase is essential for RANKL-induced OC differentiation and survival, thus emphasizing its involvement in bone remodeling. This role is also confirmed by the occurrence of the osteopetrosis phenotype in src-deficient mice. 68 Therefore, drugs inhibiting the activity of src tyrosine kinase or its downstream effectors may represent an efficient therapeutic strategy for MBD. 69

Dasatinib (BMS354825), a dual Src/Abl inhibitor, has been shown to suppress the proliferation of human MM cells, increase their apoptosis and reduce their ability to produce vascular endothelial growth factor (VEGF) as well as other angiogenic factors. 70 Moreover, administration of Dasatinib (150 mg/kg/die) delayed both tumor growth and angiogenesis in a murine xenograft model of MM, in which Dasatinib exerted a synergic effect with a number of anti-myeloma agents, such as Melphalan, Prednisone, Bortezomib and Thalidomide. 71

A group of seven patients with relapsed MM received Dasatinib, and serum levels of osteocalcin and bone-specific alkaline phosphatase (BSAP) were serially assessed as markers of bone formation, together with the urinary N-telopeptide (NTX) collagen fragment, that is usually released in OC-mediated bone destruction. Following its administration, the evaluation of these parameters showed a decreased OC function, with no change of OB activity. 72 Clinical trials evaluating the role of Dasatinib in MM are ongoing 73 and its overall safety profile seems manageable. However, myelosuppression is a recurrent adverse event, though reversible after dose reduction or treatment discontinuation, and other side effects including pleural effusion, headache, peripheral edema and gastrointestinal symptoms may also occur. 74

Targeting αVβ3

This heterodimeric membrane glycoprotein, which is a member of the cell-surface receptor superfamily that mediates cell-to-cell and cell-to-matrix interactions, is highly expressed by OCs. Through αvβ3, these cells bind a variety of extracellular matrix proteins, including vitronectin, osteopontin and bone sialoprotein. The binding of the β3 subunit to the Arg-Gly-Asp amino acid motif, expressed by matrix sialoproteins, drives OC polarization, leading to a ruffled-border rearrangement that is an important initial step of the bone resorption process. 75 Thus, interaction of αvβ3 with matrix sialoproteins ultimately drives the expression of bone-resorbing effectors such astartrate-resistant acid phosphatase (TRAcP), through the activation of extracellular signal-regulated kinases (ERK) 1/2, c-Fos and nuclear factor of activated T-cells (NFATC1) (cytoplasmic, calcineurin-dependent-1). 76 Furthermore, αvβ3 expression is involved in angiogenesis, invasiveness and metastatization of a number of tumors. In MM, αvβ3 enhances PCs adhesion to the extracellular matrix, promotes their growth by cell-to-cell contact with OC and up-regulates the release of metalloproteinase-2 and -9.77 and 78

A fully humanized monoclonal antibody against αvβ3, namely Abegrin (Etaracizumab), has been studied over the past few years. It has been shown to reduce the proliferation and the metastatic potential of several tumors, such as melanoma, ovarian, prostate and breast cancers and to reduce OC bone erosive activity in these tumors, as well as in other skeletal disorders.77, 79, and 80 Our studies have shown that, under certain conditions, MMPCs may acquire an OC-like phenotype as multinucleated cells expressing TRAcP, and produce erosive pits on experimental bone substrate in relation to the expression of αvβ3.81 and 82 Thus, overexpression of αvβ3 in MMPCs apparently correlates with an increase of their OC-like functional properties. Abegrin could be a useful drug in MBD, not only to decrease the bone resorptive activity by OCs but also to down-regulate the direct bone resorption exerted by OC-like MMPCs. 83

Other OC pathway inhibitors

Inhibition of several signaling pathways can concurrently modulate OC differentiation, MM/BMSC interactions and MM growth. Therefore, inhibition of these pathways may be an efficient approach to treat MBD.

The mitogen-activated or extracellular signal-regulated protein kinase MEK/ERK signaling pathways mediate MMPC proliferation and hyperactive osteoclastogenesis. MEK inhibition, indeed, not only induces G0–G1 cell cycle arrest and apoptosis via caspase 3 and poly-ADP ribose polymerase (PARP) cleavage in MMPCs, but also interferes with the late phase of OC differentiation through down-regulation of NFATC1 and c-FOS. A clinical trial is ongoing.84, 85, 86, and 87

In addition, activation of p38α mitogen-activated protein kinase (MAPK) may increase BMM production of IL-6, MIP-1α, RANKL and other cytokines implicated in MBD by blocking the degradation of their mRNA. Furthermore, p38α MAPK is directly involved in OC maturation, 88 while its inhibitors have been demonstrated to reduce MM growth as well as to inhibit OC activity.89, 90, and 91 Interestingly, down-regulation of p38α MAPK activity significantly enhances Bortezomib-induced MM cytotoxicity, by inhibiting the phosphorylation of heat shock protein (Hsp)-27. 92 On the other hand, Bortezomib exerts its anti-osteoclastogenic effect in part through the inhibition of p38α MAPK pathway, 145 suggesting that the combination of agents targeting this signaling is an attractive treatment option in MBD. Currently, a phase I study is ongoing. 93

Fibroblast activation protein (FAP) is a member of the serine protease family, known as DASH, which exhibits dual dipeptidyl peptidase (DPP) and collagenase proteolytic activity. Ge et al. 94 have demonstrated that FAP expression is consistently up-regulated in OCs after co-culture with MMPCs and in myelomatous SCID-hu mice. Moreover, inhibition of FAP expression by small-interfering RNA (siRNA) reduced MMPC survival in co-cultures. Recently, the same research group 95 has shown that PT-100, a specific DASH inhibitor, abrogates the capacity of OCs to support the survival of primary MMPCs, may affect the expression of adhesion molecules in OCs co-cultured with MMPCs, and finally inhibits the differentiation of OCs. As a result of these effects, PT100 restrains MM tumor growth, resulting in reduction of MM-induced bone disease.

Hsp90 is a chaperone protein that promotes both the maturation and conformational stabilization of a subset of cellular proteins, involved in proliferation and survival signals. SNX-2112, a selective Hsp90 inhibitor, exerts several anti-MM effects, including the induction of MMPC apoptosis via caspase-3, -8, and -9 activation and PARP cleavage. In addition, SNX-2112 suppresses angiogenesis by abrogation of the eNOS/Akt pathway and prevents OC formation by down-regulating both ERK/c-fos and PU.1. 96

Cathepsin-K inhibition

OC-mediated bone matrix degradation is primarily induced by acid secretion via chloride channels and protonic ATP pumps, and through the release of collagenolytic enzymes. 97 Among these, Cathepsin-K, a lysosomial proteinase largely produced by OCs, plays a central role in bone remodelling process since knock-down mice develop an osteopetrosis phenotype. 98

The Cathepsin-K inhibitor Odanacatib is presently being investigated for osteoporosis. 99 In patients with bone metastatic breast cancer it has been shown to induce a reduction of NTX excretion similar to that of BPs. 100 Furthermore, Leung et al. 101 have recently described the activity of Odanacatib on lysosomial vesicular trafficking pathways as having a major inhibiting effect on OCs. The blockade of bone matrix degradation enzymes might be a novel therapeutic option in MBD.

VEGF-dependent angiogenesis is enhanced in MM BMM, in parallel with osteoclastogenesis and tumor progression. OCs secrete proangiogenic factors which cooperate with VEGF from MMPCs and MMSCs to increase angiogenesis. VEGF also improves OC survival, their bone resorption activity and recruitment through the activation of the Akt, ERK and MAPK pathways.102, 103, and 104 Therefore, a close link between MMPCs, OCs and vascular endothelial cells can become established in MBD, with a consequent vicious cycle of myeloma cell growth, angiogenesis and bone destruction. 105 Bevacizumab, an anti-VEGF monoclonal antibody, blocks VEGF binding to its receptor. It has been approved for the treatment of several solid cancers and is currently being studied in hematological malignancies, including MM albeit with no end-point for MBD. 106 However, the evaluation of bio-markers functionally implicated in both angiogenesis and bone disease including MIP-1α, is under investigation in these studies. 107

Blocking negative regulators of OB differentiation

Together with enhanced OC activity, OB function in MM is severely impaired, as revealed by the deficiency of osteocalcin and bone morphogenetic proteins in erosive lesions. Therefore, the formation of the osteolytic lesions is not accompanied by concurrent bone remodeling. 108 MMPCs inhibit the differentiation of OB precursors and promote apoptosis in mature OBs through several factors such as DKK-1, IL-7 and IL-3. 109 Another antagonist of terminal OB maturation is transforming growth factor (TGF)-β, whose inhibition releases stromal cells from their differentiation arrest. Interestingly, although immature mesenchymal stromal cells enable MMPC growth and survival, mature OBs seem to prime their apoptosis and cell-cycle arrest in G1 stage, through small leucine-rich proteoglycans (SLRPs), as decorin and lumican. Moreover, mature OBs produce much less IL-6 than mesenchymal stromal cells.110, 111, and 112 Hence, therapeutic strategies improving OB differentiation can be considered a rational approach to MBD ( Fig. 3 ). In this context, the main agents and their study phase are reported in Table 1 .


Fig. 3 Treatment approaches targeting OB pathways. BHQ880 is a human IgG1 monoclonal antibody against DKK1, a soluble inhibitor of wingless (Wnt) signaling, secreted by MM plasma cells and restraining OB differentiation. SB431542 and Ki26894 inhibit TGF-β type I receptor kinase, interfering with the arrest of OB differentiation promoted by TGF-β. ACE-011 is a fully human fusion protein, acting as a decoy receptor for Activin A, a recently identified cytokine inhibiting OB differentiation. PTH enhances bone mass in MM by increasing the number of differentiating OBs.

DKK1 antagonist

Dickkopf-1 (DKK1) is among the factors restraining the differentiation of OBs, a soluble inhibitor of wingless (Wnt) signaling, which is secreted by MM cells, particularly in patients with osteolytic lesions.7 and 8

Extracellular antagonists of the Wnt pathway can be divided into two classes: the first includes molecules such as the DKK family which prevent the binding of Wnt ligands to LRP 5/LRP 6 co-receptors, while the second class includes soluble factors such as secreted frizzled related protein (SFRP) family, WIF-1 and Cerberus, that directly bind Wnt proteins. Factors of both classes variably down-regulate OB differentiation.113 and 114

The effects of an anti-DKK1 monoclonal antibody on bone metabolism and tumor growth have been evaluated in a severe combined immunodeficiency (SCID)-rab system. DKK1-neutralizing antibodies increased the number of osteocalcin-expressing OBs and reduced the number of multinucleated TRAcP-expressing OCs, thus restoring the bone mineral density in treated mice, which also showed a reduction of the tumor size. 115

BHQ880, a human IgG1 anti-DKK1, showed a reduction in the bone devastating effects of MMPCs as well as inhibition of their growth in a murine model of human MM. In addition, BHQ880 reduced IL-6 secretion by bone marrow stromal cells, suggesting that DKK1 promotes MMPC growth and survival by enhancing IL-6 production. 116 A phase I-II clinical trial, on patients with refractory/relapsed MM, is presently evaluating the in vivo effect of BHQ880 in combination with conventional chemotherapy and ZA. 117

Bone anabolic effects of PTH

The parathyroid hormone (PTH) is approved for the treatment of postmenopausal osteoporosis.118, 119, and 120 Although the molecular mechanisms underlying this bone anabolic effect are not fully understood, PTH has been demonstrated to increase the expression of genes encoding several components of both canonical and non-canonical Wnt pathways in OBs, and to down-regulate several Wnt signaling inhibitors, such as DKK1, sclerostin and SFRP-2. 121 Furthermore, treatment with PTH affected the expression of bone remodeling regulatory genes independent of the Wnt pathway.122, 123, and 124 In agreement with these data, Pennisi et al. 125 demonstrated that PTH improves the bone mineral density of MBD in vivo by increasing the number of differentiating OBs. For the potential contribution of PTH in tumor growth, the authors also demonstrated that, while PTH has no stimulatory effects on MMPCs in vitro, it can indirectly restrain tumor progression in vivo by both stimulating osteoblastogenesis and improving the production by OBs of anti-myeloma factors, such as decorin, lumican and CYR61. Interestingly, intermittent PTH administration also counteracts the adverse effects of glucocorticoids on bone health by reducing the susceptibility of OBs and osteocytes to apoptosis. 126 In fact, several studies127, 128, and 129 have shown that teriparatide, a recombinant human parathyroid hormone (1–34), restrains dexamethasone-induced osteoporosis more efficiently than BPs. Taken together, these data support the hypothesis that PTH, in combination with anti-MM drugs, may potentially reduce SREs in MBD.

Targeting (TGF)-β

TGF-β is abundantly sequestered in a latent form in bone matrix and released after bone resorption. As a key molecular player of MM progression, it represents a suitable target for novel therapeutics.130 and 131 In fact, Takeuchi et al. have evaluated two inhibitors of TGF-β type I receptor kinase, SB431542 and Ki26894, and found that blockade of TGF-β activity exerts a favorable effect on stromal cells in their differentiation arrest, and that terminally differentiated OBs improve bone quality and inhibit the tumor burden. Moreover, an anti-TGF-β monoclonal antibody was shown to reduce serum M protein levels and improve the bone mass in a murine model of MM. 132

Inhibition of sclerostin as anabolic therapy in MBD

Sclerostin is a protein expressed by osteocytes that down-regulates bone formation by OBs. In humans, homozygous mutation of the sclerosteosis (SOST) gene, which encodes sclerostin, leads to sclerosteosis, a disease with generalized osteosclerosis and increased intracranial pressure due to the bone overgrowth in the skull, whereas heterozygous carriers of the mutation show a normal phenotype, with dense bones and low risk of fracture. Several studies are in progress to evaluate the possibility that the down-regulation of SOST mimics the heterozygous carrier state, with consequent benefits in osteoporosis and other skeletal disorders characterized by bone loss. 133 Interestingly, a recent study by Terpos et al. 134 has detected higher circulating levels of sclerostin in bone fracture-bearing MM patients than in those with no skeletal complications at diagnosis. Its concentration was inversely correlated with BSAP serum levels and directly related to collagen type-I C-telopeptide (CTX) levels. Taken together, these data support the concept that inhibition of sclerostin might be a potential therapeutic approach to enhance OB function in MM.

Novel agents with both bone anabolic and anti-catabolic activity

Since, as we have already mentioned, MBD is characterized by increased OC activity and marked suppression of OB activity, it seems reasonable to hypothesize that new treatment approaches should target the OB-OC axis by combining bone-anabolic with anti-catabolic agents.


Activin A, a recently identified cytokine belonging to TGF-β family, is essentially secreted by OBs, OCs and BMSCs and seems to act in a synergistic way with RANKL, enabling OC formation. 135 It also inhibits OB differentiation by the down-regulation of distal-less homeobox 5 (DLX5) gene expression, through small mother against decapentaplegic (SMAD)-2 activation. Its contribution to the pathogenesis of MBD is supported by the findings of high levels of this cytokine in the marrow of patients with osteolytic lesions, due to the ability of MMPCs to increase Activin A expression by BMSCs through the Jun N-terminal Kinase (JNK) pathway activation. 136 Thus, it can be considered a potential therapeutic target in bone devastating tumors as well as in other skeletal diseases.

ACE-011, a fully human glycosylated fusion protein acting as a decoy receptor for Activin A, includes the extracellular domain of activin receptor type IIA (Act RIIA) and the Fc portion of IgG1. In a Phase I study, ACE-011 was administered to healthy postmenopausal women, resulting in a sustained, dose-dependent increase of serum levels of bone formation markers, such as BSAP, and a concurrent decrease of bone resorption markers, such as CTX, without serious adverse effects. 137

A murine analog of ACE-011, namely RAP-011, has also been tested on a SCID-hu model of MM, including INA-6 MM cells injected in subcutaneously implanted fetal human bone. In this study, RAP-011 successfully reduced the number of osteolytic lesions and increased bone density, as assessed by quantitative polymerase chain reaction and alkaline phosphatase and osteocalcin RNA expression. 136 The evaluation of ACE-011 efficacy in MM is presently under investigation in a randomized, double-blind, placebo controlled study in patients receiving the MPT (Melphalan, Prednisone, Thalidomide) combination therapy. Preliminary results show that ACE-011 is able to induce a significant increase in bone formation biomarkers and antitumor activity with a concurrent decrease of bone pain, in absence of severe toxicity. ACE-011 also increases hemoglobin levels, thus supporting its potential application for chemotherapy-induced anemia. 138

Anti-MM drugs and their effects on MBD

Beyond their direct and indirect anti-tumor effects,139 and 140immunomodulatory drugs, such as Thalidomide and its derivatives Lenalidomide and Pomalidomide, also restrain MBD progression by acting on tumor microenvironment. Anderson et al. 141 demonstrated that CC-4047, a derivative of Thalidomide, is able to down-regulate the expression of an early transcription factor implicated in marrow monocyte commitment along the OC lineage, namely PU.1, and thus inhibits OC formation, with concomitant accumulation of immature granulocytes. In line with these preliminary observations, Breitkreutz et al. 142 demonstrated a similar down-regulation of PU.1 by Lenalidomide and reported that it also inhibits RANKL secretion by BMSCs and down-regulates Cathepsin-K.

Bortezomib is a boron-containing molecule that specifically inhibits the 26S proteasome, with down-regulation of the NF-kB pathway components, reduction of MM/BMM interplays and angiogenesis process.143 and 144 Bortezomib not only reduces tumor burden, but restrains the progression of MBD by interfering with osteoclastogenesis and promoting the differentiation of mesenchymal stem cells to OBs. Bortezomib is apparently effective in disrupting both early OC differentiation by inhibition of p38 protein kinase pathways and the final stage of OC differentiation by inhibiting NF-kB and AP-1 signaling. 145 Terpos et al. 146 have reported that Bortezomib in monotherapy decreases serum and urinary levels of bone resorption markers, including RANKL in patients with MM. Moreover, inhibition of the ubiquitin–proteasome pathway primes OB differentiation by increasing bone morphogenetic protein 2 level in the BMM, by inhibiting DKK1 expression and by blocking the proteolytic degradation of Runt-related transcription factor (RUNX)-2, a differentiating factor in early OBs. 147 Bortezomib also stabilizes Beta-catenin in osteogenic cells in a Wnt independent manner. 148 These effects have been clinically confirmed by the increase of BSAP and osteocalcin serum levels in MM patients responsive to Bortezomib.149 and 150 In fact, BM samples from responder patients show a higher number of functional OBs over-expressing RUNX2. 151

Cytotherapy in MBD

MSCs have been investigated in the treatment of several bone diseases.152 and 153 In 1999, Horwitz et al. 154 used these cells from BM to treat children with Osteogenesis Imperfecta with encouraging results. In particular, this study demonstrated that cytotherapy increases bone mineral density and reduces the frequency of bone fractures. Because this model of cytotherapy has been successfully utilized in some metabolic and traumatic bone diseases, it has also been proposed for repairing osteogenic failure in MBD. In this context, Li et al. 155 tested the ability of human placenta-derived adherent cells (PDACs) to prevent bone loss in a SCID-rab model and showed that intra-lesional injections of PDACs significantly increased bone mineral density of bone grafts with concomitant reduction of tumor burden. This effect was associated with improvement of osteoblastogenesis and concurrent inhibition of osteoclastogenesis, while tumor suppression was correlated to restoration of OB function. Interestingly, PDACs did not remain detectable in vivo for a long time as the majority of them disappeared 3–5 weeks after injection, thus indicating specific temporal boundaries of this kind of therapeutic strategy. The same Authors155 and 156also compared the in vivo effects of PDACs with those of fetal bone-derived MSCs, and demonstrated that, although both cell types similarly inhibited MM growth, treatment of SCID-rab mice with PDACs was associated to a higher bone mass density. However, further studies are required to improve our understanding of MSCs/tumor interactions. 157


The potential use of natural agents is considered an appealing alternative to chemotherapy in cancer treatment. Resveratrol, a polyphenol (trans-3,4′,5-trihydroxystilbene), abundant in red grapes, berries and peanuts, has been reported to exert an antitumor effect. In MBD, Bhardwaj et al. 158 have found that resveratrol inhibits the proliferation and overcomes the chemoresistence of MM cells by suppressing nuclear factor-kappaB (NF-kB) and signal transducer and activator of transcription 3 (STAT3). Furthermore, it has been shown that resveratrol inhibits, at least partly, OC differentiation by impairing RANKL signaling and concurrently promoting OB differentiation by upregulating the nuclear receptor of 1,25(OH)2D3. 159 Other studies have shown that oral administration of resveratrol to ovariectomized rats increases the bone mass density in a manner similar to the BP alendronate.160 and 161 Taken together, these results indicate that resveratrol might be a potential drug in MBD. However, its safe plasma concentration is apparently lower than that required for antitumor effects in vitro, due to its rapid biotransformation into conjugate forms. Pharmacokinetic studies to evaluate more stable resveratrol derivatives are needed before it can be used in the treatment of MBD.


As already stated at the beginning of this review, MBD is not only an important morbidity factor, but also severely affects overall survival in patients with MM. The introduction of BPs has significantly reduced the incidence of SREs, improving the patients’ quality of life. Although the overall safety profile seems to be manageable, their use is still associated with the potential risk of ONJ and kidney failure, leading to treatment discontinuation. Because new pharmacological alternatives are needed, a better characterization of the pathophysiological mechanisms implicated in MBD is mandatory.

The role of OCs is crucial for bone destruction and several drugs targeting the major OC pathways, such as RANK/RANKL/OPG axis, BAFF, MEK and CCL3/CCR1 axes, have already been tested with encouraging preliminary data from preclinical and clinical studies. However, severe impairment of OB activity and alterations of the bone microenvironment contribute to the development of osteolytic disease of the skeleton. New therapeutic strategies should not only reduce OC activation, but also restore OB function and regulate MMPCs-BMM interactions, with a “targeted” approach. To this aim, novel agents disabling negative regulators of OB differentiation, namely anti-DKK1 monoclonal antibody, PTH and TGF-β inhibitors, as well as agents with dual activity in bone remodelling, such as ACE-011, are currently being studied in MBD.

However, although the molecular pathogenesis of MBD is under intensive investigation and gene expression profiling studies have remarked the genetic heterogeneity of MM cells, its treatment is still empirical. Further studies are needed to identify molecular differences between patients with indolent bone disease and those with extensive skeletal involvement, in order to predict different sensitivity to specific target treatments. Thus, new clinical trials should be aimed at evaluating both efficacy and safety of novel combinatory approaches involving conventional BPs, new OC-inhibitors and OB activators. On the other hand, the approaches of regenerative medicine using MSCs from human placenta have demonstrated the capability of these cells to repair the bone loss in a mouse model of MBD. Translation of this pioneering cytotherapy to human clinical setting may thus represent a fascinating perspective for MBD treatment in future.

Conflict of interests

All authors declare no conflict of interest.


This work was supported by the Italian Association for Cancer Research (AIRC 2011, IG 11647), and by the Italian Ministry of Education, University and Research (MIUR), PRIN 2009 (WZHMWJ). The authors are also grateful to Sabino Ciavarella for helpful contribution.


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DIMO, Department of Internal Medicine and Clinical Oncology, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare, 11 – 70124 Bari, Italy

lowast Corresponding author. Tel.: +39 805478771.