Bone Disease in Multiple Myeloma: Biologic and Clinical Implications.

1. Introduction: MM Pathogenesis

Multiple Myeloma (MM) is a malignancy of clonal plasma cells (PCs) localized in the bone marrow (BM) that mostly affects patients over 65 years old [ 1 ]. There is no clear cause of MM development; however, genetic and microenvironmental abnormalities play a role in its pathogenesis [ 2 ]. MM is the second-most-common hematological malignancy, accounting for 10% of hematological neoplastic disorders, with around 35,000 new cases and 12,000 deaths each year [ 3 , 4 , 5 ]. The proliferation of malignant monoclonal PCs in the bone marrow produces elevated levels of a serum, patient-specific immunoglobulin and its light chain (M-protein) [ 6 , 7 ].

MM arises from a premalignant asymptomatic condition known as monoclonal gammopathy of undetermined significance (MGUS). MGUS is defined as the accumulation of <10% clonal BM PCs, <30 g/L serum M-protein, and the absence of end-organ damage, which can include hypercalcemia, renal insufficiency, anemia, or bone-disease-related osteolytic lesions (CRAB) [ 8 ]. MGUS diagnosis has increased in incidence over the past 20 years, partially attributed to advancing detection methods [ 9 , 10 , 11 ]. MGUS can remain stagnant or progress into a more advanced, asymptomatic condition, recognized as smoldering or asymptomatic MM (SMM) [ 9 , 10 ]. SMM refers to the accumulation of >10% clonal BM PCs and/or >30 g/L serum M-protein without any CRAB symptoms. Until 2014, the diagnostic criteria of MM required one or more CRAB pathologies to occur in addition to the criteria for SMM to be considered a symptomatic and treatable disease [ 3 ]. In 2014, the International Myeloma Working Group (IMWG) updated their criteria for active and symptomatic MM to include patients with either >60% PC infiltration in the BM, >100 mg/L light-chain involvement, a >100 kappa/lambda light-chain ratio, or more than one focal bone lesion site, with or without the presence of CRAB symptoms [ 12 ].

In the last 20 years, treatment options for MM patients, such as immunomodulatory drugs (IMiDs), proteasome inhibitors, monoclonal antibodies, and autologous stem cell transplants, have paved the way for extending patient overall survival [ 13 ]. In 1997, the expected overall survival for MM patients was 2.5 years, whereas a 2013 study found that number to have increased to 5.2 years [ 14 , 15 ]. Although major advances continue in the field of MM research, the disease remains not only incurable in most patients, but the additional physical impact of bone disease poses daily threats to patient safety and wellbeing, even while in remission [ 16 , 17 ]. This review focuses on the cellular and molecular mechanisms of MM bone disease and provides an overview of the current treatment modalities.

SRE Definition, Cord Compression, and Fractures

Uncontrolled malignancies are the cause of most cancer-related mortalities [ 18 ]. Bone, specifically in the spine and ribs, is a common site for metastasis in breast, prostate, lung, kidney, and hematological cancers, which together account for around 350,000 deaths per year [ 18 ]. Due to increased vascularity, abundant growth factor, and prostaglandin production, the bone marrow microenvironment is an attractive space for the colonization of tumor cells [ 18 ]. In MM specifically, bone-disease-related lesions are the second-most-prevalent CRAB feature [ 19 ]. Over 80% of newly diagnosed MM patients will develop detectable bone disease [ 2 , 20 ].

The potential to improve MM disease detection and staging has been at the forefront of research for the last two decades. As recently as 2003, the IMWG recommended conventional skeletal survey as its method for staging and bone disease evaluation [ 21 , 22 ]. However, detection methods have since improved and evidence of a lack of its sensitivity has gained ground. Studies have found that to detect changes in bone mass via conventional X-rays, 30–50% of the bone needs to be destroyed [ 21 , 23 ]. Underestimation of bone destruction is a major problem that can lead to incorrect staging and delayed initiation of treatment [ 24 ]. Radiological-based skeletal survey accuracy is impaired by the surrounding soft tissue around the bone. Imprecision in detection has given way to other methods, such as MRI, fluorodeoxyglucose PET (FDG-PET), and PET-CT imaging, as more accurate modalities, although more expensive [ 21 , 25 ]. More sensitive testing, such as MRI and PET-CT imaging, shows appreciable bone disease involvement of 95% and 91%, respectively [ 26 , 27 ]. Due to the high-contrast material of the bone and bone marrow fat, low-dose CT provides better osteolytic lesion detection [ 28 ]. A multicenter study confirmed previous results that between 20 and 25% of patients with negative skeletal survey scans will show bone lesions using CT [ 21 , 28 , 29 , 30 , 31 ]. Although CT scans are the current standard-of-care procedure, it is important to acknowledge that these modalities may not be available everywhere.

The median overall survival of MM patients is 6 to 7 years [ 32 ]. One study found that survival is reduced to 2 to 3 years after the initial diagnosis of bone metastasis [ 33 , 34 ]. Not only do bone-disease-related osteolytic lesions result in a severe decrease in quality of life, higher costs of healthcare, and a decrease in functional independence, but it puts patients at risk of a life-threatening skeletal-related event (SRE), such as a pathologic fracture and disability, spinal cord compression, severe bone pain, and the need for surgical intervention [ 9 , 26 ]. Due to the proximity of the central nervous system to weakening and lytic bones, symptoms, such as paresthesia and burning sensations, are common among patients who have MM with bone involvement [ 35 ].

2. Myeloma Bone Disease

Bone tissue is made up of both organic and inorganic components [ 36 ]. The organic components include osteocytes, bone-lining cells, osteoclast cells (OCs), osteoblast cells (OBs), collagen fibers, proteoglycans, and glycoproteins [ 36 ]. The inorganic material consists of mostly calcium and phosphate and makes up 60% of bone mass [ 36 ]. Normal maintenance and remodeling of bone tissue in healthy humans is a continuous process and is finely balanced between the interplay of the OC and OB activity [ 26 ]. Maintaining a strong and light mineralized bone structure is a heavily regulated process within the body and, when disrupted, the marrow microenvironment is a common site for disease development [ 35 ].

OBs originate from mesenchymal stromal stem cells within the bone marrow and are responsible for the formation of structural bone material [ 36 ]. Located in the periosteum and endosteum, OBs produce the components of the extracellular matrix, such as structural macromolecules, including type-I collagen, proteoglycans, and cell-attachment proteins; OBs lay the foundation for bone mineralization [ 36 ]. Surrounding matrix vesicles deliver calcium, phosphate, alkaline phosphatase, adenosine triphosphatase, inorganic pyrophosphatases, among other proteinases, to catalyze hydroxyapatite crystal formation [ 36 , 37 ]. In the process, structural proteins, such as type-I collagen, act to guide and orient mineralization to maintain the shape and structure of all bones [ 36 ].

2.1. Basic Biology of Non-Diseased State (Expanding Pathogenesis)

Bone formation requires transcription factor Runx2/Cbfa1 activity and is responsible for mesenchymal stem cell differentiation into OBs [ 38 ]. Osterix, another transcription factor, also induces bone formation [ 38 , 39 ]. One study found that double-knockout (Runx2 − /Cbfa1 − ) mice were deficient in OBs and bone formation [ 38 , 40 ]. However, the overexpression of Runx2 can stunt bone formation due to heavy regulation in the BM microenvironment [ 41 ]. Markers, such as collagen−1, are expressed due to the activation of Runx2/Cbfa1 during osteoblastogenesis and, therefore, can be clinically followed to track a patient’s disease [ 38 ].

OCs are large, multinucleated, specialized bone resorbing cells vital for normal bone remodeling [ 42 ]. They originate from hematopoietic precursors in the monocyte and macrophage lineage [ 42 , 43 ]. OCs are located within the Haversian canals, attached to the endosteal surfaces and calcium hydroxyapatite matrices, where they recede bone structure through proteolytic degradation and acid decalcification [ 42 , 43 ]. OCs accomplish these functions with proteins, including carbonic anhydrase II, calcitonin receptors, tartrate-resistant acid phosphatase, and lysosomal proteases [ 44 ].

The BM microenvironment is a well-endowed source of cytokines, such as interleukins, tumor necrosis factors (TNF), colony-stimulating factors, and growth factors that play key roles in structural regulation [ 36 ]. The understanding of the relationships between receptor activator of nuclear factor κB (RANK), its ligand (RANKL), and osteoprotegerin (OPG) have especially led to major advancements in bone homeostasis. RANKL is a cytokine and TNF family protein expressed by OBs; it binds to the RANK receptor on both precursor and mature OCs [ 43 ]. This interaction is necessary to initiate differentiation, activation, and survival of OCs [ 45 ]. Of note, it was found that rats devoid of RANK and RANKL genes had no OCs [ 45 , 46 ]. Therefore, the existence of OCs is dependent on both RANK and RANKL genes. OPG is another member of the TNF family expressed by OBs [ 2 ]. It functions as a protagonist and ‘decoy’ receptor to RANK by also binding RANKL as a regulatory step to minimize bone resorption and osteopenia [ 2 ]. In OPG knockout mice, early onset osteoporosis and vascular calcification have been shown to develop, confirming OPG’s role in maintaining bone integrity [ 2 , 47 ]. By inhibiting the RANK/RANKL interaction, OPG plays an important role in preventing OC-induced bone resorption [ 45 ]. Not only does it slow the proliferation of mature OCs, but it directly inhibits the differentiation of precursor OCs too [ 43 ]. The activation of both the macrophage colony-stimulating factor (M-CSF) and immunoreceptor tyrosine-based activation motif (ITAM) signaling pathways also play major roles alongside RANK and RANKL in OC activation [ 42 , 43 , 48 , 49 ]. M-CSF and ITAM, among other cytokines, act in tandem to regulate OC precursor differentiation and proliferation [ 43 ].

2.2. MM Diseased State

OC-driven bone destruction is not unique to cancer. Bone disease is common in many different conditions, including osteoporosis, which also results from the decoupling of OC and OB regulation [ 50 ]. In MM, malignant PCs also disrupt this careful balance that favors a net resorption of bone due to the widespread activation of OCs [ 26 , 51 ]. In fact, this disruption has been seen as early as in MGUS. It has been observed that patients with MGUS have higher rates of resorption and osteoporosis, measured by bone mineral density [ 52 ]. Conversely, evidence has shown that osteoporosis can increase the risk of MGUS [ 53 , 54 , 55 ].

In MM, tumor PCs produce both OC-activating and OB-inhibiting factors [ 56 ]. In fact, even in deep remission, OB activity is suppressed in MM [ 17 ]. MM differs from other malignancies with bone involvement because it exhibits little to no bone formation, whereas in metastatic breast and prostate cancers, both OCs and OBs are upregulated, emphasizing the need to protect and rebuild the structural integrity of bones in MM [ 50 , 57 ].

The complete mechanisms by which MM cells inhibit OB formation and differentiation remain unclear. However, many signaling factors have been identified as bone formation antagonists, such as the Wnt signaling pathway inhibitor Dickkopf1 (DKK1) and interleukin-7 (IL−7) [ 58 ]. DKK1 is secreted directly from tumor PCs to inhibit OB differentiation [ 59 ]. Increased expression of DKK1 has been shown to be correlated with bone-disease-related osteolytic lesion severity, whereas IL−7 secreted by BM stromal cells suppresses Runx2/Cfba1 promoter activity, a necessary transcription factor for OB formation [ 44 , 58 , 59 , 60 ].

Runx2/Cfba1-mediated transcription and osteoblastogenesis have been shown to be inhibited by MM cells in vitro [ 58 ]. As a result, OB precursor formation and differentiation were reduced, as seen by lower expression of alkaline phosphatase, osteocalcin, and collagen-I [ 38 , 58 ]. This finding was seen in mature OBs as well [ 61 , 62 ]. Results showed that MM cells can directly inhibit OB proliferation and even make OBs more prone to apoptosis [ 61 , 62 ]. Runx2/Cfba1 also stimulates OPG secretion by OBs [ 58 ]. Therefore, the inhibition of Runx2/Cfba1 not only reduces the development and expansion of OBs, but it allows OC expansion to be even further unregulated. Runx2/Cfba1 activity can also be inhibited via cell-to-cell contact between osteoblastic progenitor cell membrane protein VCAM-1 and MM cell’s VLA-4 protein, which have been seen to upregulate RANK following contact [ 38 , 58 ].

Tumor-PC-related OC activation pathways are also well documented. MM BM microenvironments are known for their ability to foster favorable conditions to perpetuate uncontrolled tumor growth through processes, such as increased angiogenesis and increased circulation of growth factors, such as IL−6 and vascular endothelial growth factor (VEGF) [ 2 , 63 ]. More specifically, MM PCs produce cytokines specifically to develop a microenvironment that promotes malignant proliferation and cell survival ( Figure 1 ) [ 38 , 51 , 64 , 65 ]. For example, RANK has been shown to increase vascular permeability and angiogenesis through activation of nitric oxide synthase in endothelial cells to improve the circulation of tumor-promoting factors [ 66 ]. The release of humoral factors, such as IL−6, among other cytokines stimulates the upregulation of RANKL, thus, promoting OC activation, bone resorption, and the release of bone calcium and growth factors stored in the bone matrix ( Figure 1 ) [ 67 ]. Other factors, such as IL−1, IL−3, E series prostaglandins, and TNF-α, increase remodeling and resorptive activity resulting in a vicious cycle of bone turnover, more growth factor dissemination, and hypercalcemia [ 68 ]. Found in one study, tumor PCs can also stimulate RANKL upregulation while downregulating OPG expression, which has even more severe side effects than in healthy counterparts and asymptomatic MM patients, ( Figure 1 ) [ 51 , 69 ]. Levels of serum OPG usually indirectly correlate with MM bone disease severity [ 51 , 70 ]. Similarly, one group discovered that RANKL/OPG ratios are also indirectly related to expected survival, showing unfavorable implications for MM patients [ 2 , 71 ].

Data suggest that the anabolic effect of anti-MM therapy has been shown to mitigate aggressive bone resorption. Proteosome inhibitors (PIs), such as bortezomib, have been observed to do so through stimulating Runx2/Cbfa1 activity [ 72 , 73 ]. Bortezomib’s anti-MM activity further allows a recovery of OB levels, seen through an increase in alkaline phosphatase expression [ 72 , 73 , 74 , 75 ]. Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, in addition to proteosome inhibitors, have been shown to reduce RANKL production by blocking its production [ 76 , 77 ]. IMiDs specifically inhibit OC formation and RANKL upregulation [ 78 ].

Hypercalcemia of malignancy (HCM) is a common complication of various advanced cancers, including MM, lung, breast, and kidney cancers [ 79 ]. While it can present as mild to life threatening, HCM is often related to a more advanced and aggressive disease burden, especially in MM [ 79 , 80 ]. Prognostically, HCM is associated with significantly inferior survival rates (26 months vs. 48 months, p < 0.001), although other factors, such as high-risk FISH cytogenetics (del17p, t [4; 14], t [14; 16]), can influence survival and ISS disease staging [ 80 ]. Approximately one-third of patients will experience such metabolic complications, resulting from extensive bone destruction directed by the MM cell secretion of RANKL and other pro-destruction cytokines, such as DKK1, tumor necrosis factors, and macrophage inflammatory protein (MIP-1α) [ 79 , 80 ]. All of these cytokines can also be over-expressed by other cells surrounding the tumor microenvironment, leading to an increased accumulation of calcium in the serum, resulting in life-threatening complications, such as dehydration, confusion, acute renal insufficiency, or even a comatose state [ 35 ].

2.3. Available Treatment Agents

OC-specific targeting agents have been a focus of treatments for bone-related diseases, such as osteoporosis, among numerous other malignancies, including breast cancer, prostate cancer, and MM, for many decades. Bisphosphonates (BPs) were the first drug class to both treat and prevent bone-disease-related osteolytic lesions. Randomized placebo controlled trials revealed that BPs show efficacy in treating and preventing SREs [ 26 ]. Other agents are in development to target upregulated pro-osteoclastogenic and/or anti-osteoblastogenic molecules. In MM, such targets include: IL−3, activin A, TRAF6, and BTK [ 76 ].

Molecularly, BPs are related to inorganic pyrophosphates and are recognized by their phosphorus–carbon–phosphorus structural backbone [ 81 ]. In contrast to inorganic pyrophosphates, BPs are synthetic and hydrolysis-resistant molecules that have a high affinity to calcium and, therefore, target areas of high resorption on bone hydroxyapatite surfaces [ 82 , 83 ]. Mechanistically, BPs restrict OC activity via the mevalonate pathway of protein prenylation through inhibiting farnesyl pyrophosphate synthase, thereby inducing OC apoptosis and preventing bone resorption [ 84 ]. Significant advancements in the MM and BP fields, following the development of higher-potency nitrogen-containing agents, such as intravenous pamidronate and zoledronic acid, have proved momentous in improving patient bone pain relief, SRE prevention, and hypercalcemia, among other aspects of patients’ quality of life [ 81 , 85 ].

Pamidronate was the first BP to show a clinical benefit in MM [ 81 ]. Before pamidronate, another BP, clodronate, showed efficacy in delaying osteolytic lesion development, but did not significantly improve bone pain or the incidence of bone fracture [ 86 ]. In a randomized study, patients with stage III MM and at least one osteolytic lesion were given pamidronate every four weeks for nine cycles [ 85 ]. It was found that the time to the first SRE, pathologic fracture, and radiation treatment to a lesion were all significantly less than in the placebo group ( p = 0.001, p = 0.006, p = 0.05) [ 85 ]. These findings led to its Food and Drug Administration (FDA) approval in 1995 [ 85 ]. Over the course of the study, the placebo group experienced more SREs, more frequent hypercalcemia, and a worse quality of life [ 85 ]. Even within the first month of treatment, bone pain and analgesic-drug use was reduced in the pamidronate group [ 85 ], although overall survival was no different [ 85 ]. Similar results were found in another randomized, double-blind study observing pamidronate efficacy over 21 cycles [ 87 ]. In this study, pamidronate reduced overall SRE incidence after 12, 15, 18, and 21 months versus the placebo group in MM [ 87 ]. Pamidronate considerably improved the quality of life and prognosis of MM patients, especially those with heavy bone disease involvement; however, its two- or four-hour intravenous (IV) administration limits accessibility [ 88 ].

Zoledronic acid (ZA) is a more potent BP that has also shown efficacy in clinical trials [ 81 ]. ZA became the first BP to show efficacy in solid tumors (excluding breast cancer), such as prostate and non-small-cell lung (NSCLS) cancers [ 88 , 89 , 90 ]. The median time to progression improved but was not significantly different in the ZA treatment group over the pamidronate treatment group, 136 days vs. 113 days [ 91 ]. Similar non-significant results were found in another study, including the mean number of annual SRE incidents in ZA versus pamidronate, 1.00 SREs vs. 1.39 SREs [ 92 ]. Overall, SRE prevention was similar between the two BPs; however, in patients with moderate to severe HCM, ZA showed significant benefit over pamidronate in mediating calcium levels [ 92 ]. ZA has also shown evidence of anti-MM activity. In comparison to clodronate, the MRC Myeloma IX trial showed that ZA therapy reduced mortality by 16% and improved overall survival to 50 months vs. 44.5 in the clodronate group ( p = 0.04) [ 93 ], meaning that both BP and anti-MM therapies can positively impact patient survival and SRE prevention. SRE incidence decreased with ZA, 27% vs. 35% ( p = 0.0004) [ 93 ]. The findings of this trial prompted the National Comprehensive Cancer Network (NCCN) and the International Myeloma Working Group (IMWG) to recommend BPs to treat symptomatic MM along with anti-MM therapy [ 81 , 94 , 95 ]. The other advantage of ZA is its considerably shorter safe administration time of 15–30 min [ 88 ]. Based on these findings, ZA received FDA approval in 2002 and was incorporated into American Society of Clinical Oncology guidelines for MM bone disease following two randomized studies that demonstrated noninferiority to pamidronate in number and time to development of SREs [ 85 , 88 , 96 ].

Measurement of bone turnover markers, such as urinary or serum n-telopeptide of type-I collagen (uNTX or sNTX, respectively) can help inform treatment decisions and predict patient disease status, risk profile, bone metabolism status, and BP activity [ 97 ]. High baseline sNTX levels are generally associated with elevated risk of SRE [ 98 , 99 ] One study found that in patients who achieved a partial or complete response from anti-MM therapy and whose baseline sNTX levels were also suppressed, sNTX levels remained suppressed [ 100 ]. Another study that tracked how uNTX levels related to overall survival and SRE risk between patients receiving either ZA, pamidronate, or placebo found that when uNTX levels normalized (defined as <64 nmol/mmol creatinine) in patients treated with ZA, patient’s risk profile decreased [ 101 ]. Those whose uNTX levels normalized were found to have a decreased risk of death by 48% in breast cancer, 59% in HRPC, and 57% in NSCLC ( p = 0.0017, p < 0.0001, p = 0.0116, respectively) [ 101 ]. This information confirms a 50% reduction in the risk of experiencing an SRE in breast cancer found in another study ( p = 0.0031) [ 33 ]. Even after the cessation of BP therapy, those who achieved a clinical response to anti-MM therapy continued to have suppressed sNTX levels 6 months following their last ZA dose [ 100 ]. To determine better ZA-dosing schedules for the spectrum of patient disease risks and bone metabolism, the Z-MARK study stratified patients who received BP therapy for between 1 and 2 years based on baseline uNTX levels [ 98 ]. In this study, ZA 4 mg was given either every 4 weeks (patients with uNTX ≥ 50 nmol/mmol creatinine) or every 12 weeks (patients with uNTX < 50 nmol/mmol creatinine). Patients initially treated every 12 weeks were switched to treatment every 4 weeks if one of three events occurred, including: disease progression, SRE incident, or uNTX level increase [ 98 ]. In those cases, a more aggressive, monthly ZA infusion may be needed to treat bone resorption [ 98 , 102 ]. Overall, 32.5% of patients (38 of 117 patients) were switched to a more frequent ZA treatment schedule, while the rest (79 patients) remained in the ZA 12-week treatment group [ 98 ]. This study found that uNTX levels were not necessarily predictive of SRE incidences, even in patients with elevated uNTX levels, but that bone metabolism can be maintained with ZA 4 mg administration every 12 weeks [ 98 ]. Similarly, another study assessing the risk profile of SREs between patients treated with ZA either every 4 or 12 weeks found no significant difference in MM patients ( p = 0.14) [ 103 ], therefore, confirming the safety and efficacy of the less frequent treatment interval.

Bisphosphonate Safety Precautions

Patients receiving long-term BP therapy are at risk of osteonecrosis of the jaw (ONJ). ONJ is a serious and painful adverse event recognized as exposed and necrotic bone in the maxillofacial region that persists for eight weeks related to BP therapy [ 104 , 105 ]. The majority of cases take around four months to heal [ 104 , 105 ]. Severe complications in light of invasive dental procedures can occur as the molecules remain on maxillofacial surfaces, although the mechanism of action is not yet fully understood [ 4 ]. Preventative strategies, such as avoiding tooth extractions (exclusive of root canals, dental cleanings), while on BP therapy and/or holding BP therapy for 90 days before and after invasive elective procedures has shown effectiveness in reducing ONJ incidence and is, thereby, recommended by the IMWG [ 106 ]. Studies suggest that between 4 and 11% of patients will develop ONJ and the risk of development increases directly with prolonged BP exposure [ 4 , 107 ]. Pamidronate 30 mg also showed reduced incidence of ONJ compared to pamidronate 90 mg [ 108 ]. Moreover, there is little difference in incidence rate between ZA and other BPs [ 109 ].

Renal toxicity is another limiting factor for patients undergoing BP therapy as it can induce acute renal damage [ 110 , 111 ]. BPs are excreted unmetabolized through the urine and can, therefore, form insoluble precipitates with calcium in the renal tubuli and, most frequently, result in acute tubular necrosis [ 81 , 91 ]. Therefore, previous hypercalcemia-related renal impairment can exacerbate dysfunction. The accumulation of BP molecules in the renal tract facilitates renal dysfunction and relates directly with the length of BP treatment [ 81 ]. For that reason, the FDA recommended BP dosage adjustment based on creatinine clearance [ 112 ]. In a key phase III study, ZA showed elevated renal impairment in the 8 mg dosage group compared to pamidronate (90 mg in 250 mL for 2 h), suggesting that a dose reduction to 4 mg in 100 mL over 15 min was safer than IV infusion of ZA in 5 min [ 91 ].

BPs serve to prevent bone loss but can adversely affect bone formation and quality, so the development of agents with the ability to improve both functions is currently an unmet need [ 113 ]. Alternative agents, such as the sclerostin (Scl) inhibitor and monoclonal antibody, romosozumab, have demonstrated both anticatabolic and anabolic-promoting effects in treating osteoporosis [ 113 ]. Sclerostin functions to antagonize the Wnt/β-catenin pathway to inhibit bone formation, as well as upregulate RANKL levels [ 113 , 114 , 115 ]. Data suggest that the activation of both the Wnt and β-catenin pathways, via a Scl inhibitor, promote osteoblast formation and survival and, thus, are a promising therapeutic target for combatting MM bone disease [ 113 ]. Pre-clinical studies in MM have shown that the deletion of the gene that encodes sclerostin, SOST, prevents MM bone disease in immune-deficient mice [ 113 ]. Activin A is another potential target to treat bone disease. Sotatercept, a recombinant activin receptor that binds activin A and GDF11 with high affinity, is currently being investigated in early trials [ 116 ]. Activin A is also involved in OC activation and OB inhibition and is upregulated in MM [ 113 , 117 ]. Sotatercept has been shown to increase bone mineral density in phase-1 studies in MM [ 116 ]. Although these agents show promising data in preclinical and early clinical studies, BPs remain the mainstay treatment of bone disease.

3. Denosumab

Denosumab is a more recently developed agent for treating metastatic bone disease. Alternatively to BPs, denosumab is a fully human monoclonal antibody administered subcutaneously that targets RANKL to inhibit osteoclastogenesis and OC-mediated bone resorption [ 26 ]. Unlike ZA, pamidronate, clodronate, and other BPs, denosumab does not persist in bone tissue nor does it rely on renal clearance, rather, reticuloendothelial clearance [ 26 , 118 ]. It also has a circulatory half-life of 26 days, similar to other monoclonal antibodies [ 26 , 118 ]. Despite efficacy shown by ZA in prolonging SREs and reducing skeletal complications, bone metastasis still occurs [ 91 ]. There are also limitations to ZA, such as renal complications and its IV administration, that pose problems for patients, suggesting the need for therapies that further minimize toxicities and provide more easily administered cocktails for treating metastatic bone diseases. Denosumab was first established as effective in the treatment of osteoporosis. A Phase III study, FREEDOM, enrolled 7886 women with osteoporosis where denosumab 60 mg was given every six months and demonstrated superiority to placebo in its efficacy, reducing vertebral, nonvertebral, and hip fracture risk [ 119 ]. In 2010, the FDA approved denosumab for the treatment of postmenopausal women with osteoporosis at high risk for fracture as a result of this trial.

3.1. Denosumab in Metastatic Bone Disease

Denosumab’s effectiveness in preventing SREs in metastatic bone disease was tested in three separate, but identically designed, Phase III randomized, double-blind trials in breast cancer, prostate cancer, and solid tumors (excluding breast and prostate) or MM ( Table 1 ). Patients were treated with either denosumab 120 mg s.c. or ZA 4 mg i.v. every four weeks along with recommended calcium and vitamin D supplements if necessary [ 120 , 121 , 122 ]. The endpoints of the studies were noninferiority and superiority tests to evaluate the time to first SRE. The third study in solid tumors plus MM and excluding prostate and breast cancers (mainly lung and MM) enrolled 1776 patients and found similar results as the others in the time to the first SRE being longer with denosumab amongst all patients (20.6 months vs. 16.3 months; 0.84 with 95% CI: 0.71–0.98; p = 0.0007 noninferiority; p = 0.06 superiority) [ 120 ]. By tumor stratification, both patients with MM and non-small-cell lung cancer showed equivalence in delaying the first SRE, not superiority [ 120 ].

In all three studies, denosumab demonstrated a reduction in renal toxicity but no difference in overall survival compared to ZA [ 120 , 121 , 122 ]. In patients with a baseline creatinine clearance ≤60 mL/min, ZA showed a noticeably higher risk of renal AEs (including acute renal failure, increased creatinine, and increased urea ect.), 21.6% of patients in the ZA arm versus 11.3% in the denosumab arm [ 120 ]. Due to the related renal toxicity in ZA, 8.9% of doses were withheld because of elevated serum creatinine [ 120 ]. One meta-analysis of all three studies of denosumab versus ZA in metastatic cancer also found a similarly appreciated risk of renal AEs in the ZA treatment arm compared to denosumab, 11.8% vs. 9.2% ( p = 0.002) [ 124 ]. Despite dose reductions in ZA, potentially renal-toxicity-related AEs and flu-like syndrome were both higher than that of denosumab [ 120 , 121 , 122 ]. Incidences of creatinine clearance reduction were also higher in the ZA arm [ 122 ]. However, incidences of hypocalcemia, a recognized AE, occurred more frequently in the patients treated with denosumab [ 120 , 121 , 122 ]. Of note, most cases were asymptomatic and only a small number of participants required a calcium supplement [ 120 , 121 , 122 ]. Denosumab’s lack of renal clearance and no evidence of renal effects present it as a safer therapeutic option for patients with renal impairment [ 120 ].

3.2. Denosumab in MM

The third phase III study comparing the efficacy of ZA and denosumab in metastatic cancer, excluding breast and prostate cancer, found there to be no difference in overall survival in the total patient cohort; however, in MM specifically, overall survival was found to be worse in denosumab-treated patients [ 120 ]. Although equivalence was shown between ZA and denosumab in MM in delaying the first SRE, MM was not given indication for denosumab [ 26 , 120 ]. These results may be due to important limitations of the study. The MM patient population was a small cohort limited to 10% of the broader study while lung cancer patients counted for 40% [ 26 , 120 ]. Further, due to an imbalance in MM patient prognostic factors, anti-MM therapies, and withdrawals, it is challenging to make conclusions about the efficacy of SRE prevention and treatment of denosumab versus ZA in MM [ 120 , 123 ].

An international, randomized, and double-blind study only enrolling MM patients was conducted to address these limitations. This phase III study enrolled 1718 newly diagnosed patients and stratified by prognostic factors, intent to undergo autologous stem cell transplant (ASCT) and anti-MM therapy in a control and double-blind analysis of denosumab versus ZA [ 123 ]. Among other inclusion criteria, patients who presented with at least one x-ray or CT-confirmed bone lesion and a creatinine clearance ≥30 mL/min (due to ZA-dosing restrictions) were included [ 123 ]. As with the previous three trials, the primary and second endpoints were whether denosumab is noninferior and superior, respectively, to ZA in time to the first SRE (defined as a pathologic fracture) [ 123 ]. Likewise, dosing levels and treatment schedules were consistent to the previous three phase III studies (s.c. denosumab 120 mg and i.v. placebo every four weeks or s.c. placebo and intravenous ZA 4 mg) [ 123 ]. The first endpoint was met, as denosumab was found to be noninferior to ZA in delaying the time to the first SRE (22.83 months vs. 23.98 months; HR = 0.98 (0.84–1.14); p = 0.01 noninferiority) [ 123 ]. Overall survival, an exploratory secondary endpoint, was also found to be similar between treatment groups [ 123 ]. However, progression-free survival favored denosumab-treated patients 46.1 months vs. 35.4 months ( p = 0.036), presenting denosumab as an effective and safe treatment in MM [ 123 ]. Renal-toxicity-associated AEs was more common in the ZA arm (17% vs. 10%; p < 0.001) and even further pronounced in patients with baseline renal impairment (baseline creatinine clearance ≤ 60 mL/min), 26% in the ZA arm versus 13% in the denosumab arm [ 123 ]. Hypocalcemia was elevated with denosumab treatment, 17% vs. 12%, but most cases were grade 1–2 [ 123 ], whereas ONJ occurred more often with denosumab, although not significantly, 4% vs. 3% [ 123 ]. A higher risk of ONJ with denosumab was confirmed in a study in osteoporosis patients (HR: 3.49, 95% CI 1.16 to 10.47, p = 0.026) [ 125 ].

These findings are in support of denosumab as a standard-of-care therapeutic agent for MM. Although the findings were limited by a creatinine clearance of ≥30 mg/min due to the study being blinded, denosumab is a compelling option for patients with renal insufficiency, thus, establishing denosumab along with bisphosphates as integral as adjuvant therapies.

Further exploratory studies have confirmed denosumab’s efficacy, not only in SRE prevention, but in measuring progression-free survival (PFS). Extending from the MM only denosumab versus ZA phase III double-bind study, a significant improvement in PFS in denosumab versus ZA was concluded in newly diagnosed MM patients [ 126 ]. These results were especially significant in patients with intent to undergo ASCT with denosumab compared to ZA (46.1 months vs. 35.7 months; p = 0.002) [ 126 ]. Of those who had frontline triplet induction therapy or bortezomib-only therapy (without IMiD) saw the biggest PFS benefit [ 126 ]. A potential synergistic effect between denosumab and bortezomib was suggested by the fact that both interact with RANKL and bortezomib is known to reduce DKK1 levels [ 126 , 127 , 128 ]. Proteosome inhibitors (PIs), including bortezomib, have shown previous evidence for suppressing osteoclast differentiation and stimulating osteoblastogenesis to promote bone formation [ 77 , 129 , 130 , 131 ]. Of note, patients with ASCT intent are generally younger and can endure more intensive anti-MM treatment. To account for older patients, it was found that those <70 years of age still experienced a PFS benefit with denosumab; however, this information was not statistically powered [ 126 ]. Although this meaningful clinical benefit was seen in newly diagnosed patients given denosumab therapy, there remain many unanswered questions and endpoints that require further investigation.

4. Guideline Recommendations

Bisphosphonates have served as the standard of care for the prevention and treatment of mm bone disease. However, a more robust understanding of the pathophysiology of antiresorptive therapies, such as RANKL inhibitor denosumab, has led to updated treatment recommendations [ 111 ]. The 2021 IMWG guidelines recommend BP therapy, specifically ZA or pamidronate, in all patients with active MM, with regular kidney monitoring, whether or not MBD is present [ 111 ]. Pamidronate is also recommended for patients with severe renal impairment, including those on dialysis [ 132 ]. Clodronate is not approved in the United States because ZA was proven to be superior for preventing SREs and improving survival [ 12 , 93 ]. It is approved for use in Canada and the United Kingdom, however [ 12 , 93 ]. The ASCO guidelines also recommend BPs after the MRC IX Trial showed that BP therapy showed benefit in patients without lytic lesions [ 12 , 93 , 133 ]. In patients with MGUS or SMM, BP treatment is only recommended if a patient also has osteoporosis, unless they have high-risk SMM or SMM with an MRI or PET/CT-confirmed lesion [ 111 ]. Then, patients can be considered for BP therapy similar in schedule and dosing to that of active MM [ 111 ]. Patients treated with BPs are also recommended to receive calcium and vitamin D supplementation, once calcium levels have been normalized [ 111 ]. Denosumab is recommended for newly diagnosed MM, and relapsed and refractory MM with bone disease involvement [ 111 ]. In patients with renal impairment and HCM, denosumab is recommended [ 92 , 111 ]. Even for patients with creatinine clearance <30 mL/min, denosumab can be given under close monitoring [ 111 ]. Patients with MGUS or solitary plasmacytoma who also have osteoporosis are recommended to receive denosumab for bone disease treatment and prevention [ 111 ].

Regarding dosing and treatment schedules, it is recommended that ZA 4 mg is administered intravenously every 3–4 weeks for 15 min for those with symptomatic MM for SRE prevention and treatment [ 111 ]. It is also recommended that pamidronate 30 mg or 90 mg is administered every 3–4 weeks as well for the same indication [ 111 ]. In patients with HCM, ZA is recommended over pamidronate due to proven superiority [ 134 ]. However, in MM with HCM that is refractory to BPs, denosumab is recommended [ 111 ]. ZA is also favored over pamidronate due to its shorter infusion time. Treatment with ZA is recommended to continue for 12 months. If a very good partial response or better is achieved, then the frequency of dosing can be reduced to every 3, 6, 12 months, or until discontinuation or the physician’s discretion [ 111 ]. After discontinuation, BP treatment should be reinitiated at the time of biochemical relapse to lower the risk of an SRE [ 111 ]. Regarding ONJ, it is recommended that a comprehensive dental exam is conducted before BP therapy and current oral infections must be healed [ 12 ]. While on therapy, invasive dental exams should be avoided. If a procedure is unavoidable, denosumab should be discontinued 30 days before and held until the incision is fully healed [ 111 ]. Due to subjective risk factors, changes to treatment should be considered on a patient-by-patient basis. Subcutaneous administration of denosumab 120 mg once a month with calcium and vitamin D supplementation is recommended as well [ 111 ]. The duration of treatment can extend until unacceptable toxicity occurs [ 111 ]. Changes to dosing schedules are only recommended after 24 months of treatment on a patient-by-patient basis [ 111 ]. At this point, it is also recommended that discontinuation of denosumab is avoided due to data showing a rebound of elevated resorptive activity, characterized by osteoclastogenesis, rapid decline in bone mineral density, and a greater risk of vertebral fractures between 6 and 12 months after treatment extinction [ 111 , 135 , 136 ]. If denosumab is discontinued, the European Calcified Tissue Society recommends beginning BP therapy to minimize the magnitude of OC rebound [ 135 ]. This rebound effect is not yet completely understood, but it is suspected that either the dysregulation of Wnt inhibitors SOST and DKK1 are involved, or that a dormant pool of osteoclast precursors is stimulated following the suspension of denosumab, leading to a surge in RANKL levels [ 137 ]. One case-control study found higher bone turnover markers and lower SOST levels in denosumab cessation versus treatment-naïve patients [ 137 , 138 ]. Data to support the discontinuation of denosumab are limited but, based on previous and relevant clinical data from denosumab in osteoporosis, the IMWG recommends a single intravenous dose of ZA at least 6 months following discontinuation or another denosumab 120 mg injection at the same timepoint. More clinical information is needed.

Denosumab 120 mg costs nearly USD 2000 per dose in the United States, whereas ZA 4 mg and pamidronate 90 mg cost approximately USD 50 and USD 30, respectively [ 12 ]. Significant differences in price warrant consideration in choosing a treatment regimen. Factors, such as efficacy profile, treatment toxicity, economic viability, intravenous infusion chair accessibility, and infusion time, all need to be considered. Regarding cost effectiveness of ZA versus denosumab, one study set out to compare value propositions from the perspectives of patients, payers, and society [ 138 ]. Given real-world data and from similar studies analyzing the cost effectiveness of denosumab versus ZA in solid tumors, incremental quality-adjusted life-year and net monetary benefits from each treatment were quantified [ 138 ]. The study concluded that denosumab is a cost-effective treatment option given its benefits in SRE prevention and progression-free survival based on direct and indirect medical costs [ 123 , 138 ]. Given this information, there is support for denosumab’s value as a therapeutic option over ZA; however, projection-based analysis has its own limitations and, therefore, more observation is needed to provide a conclusive comparison. It is also important to acknowledge cost feasibility disparities in clinical settings that may restrict access to denosumab, making ZA a more attractive regimen in that case.

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Author Contributions

Conceptualization, writing—original draft preparation, revision, visualization, writing—review and editing Z.S.B.; Conceptualization, supervision, writing—review and editing E.B.K.; Conceptualization, supervision, writing—review and editing N.R. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

N.R.: consulting for Amgen, Bluebird Bio, BMS, Celgene, and Janssen.

References

1. Bergstrom D.J. Kotb R. Louzada M.L. Sutherland H.J. Tavoularis S. Venner C.P. Côté J. LeBlanc R. Reiman A. Sebag M. Consensus guidelines on the diagnosis of multiple myeloma and related disorders: Recommendations of the myeloma canada research network consensus guideline consortium Clin. Lymphoma Myeloma Leuk. 2020 20 e352 e367 10.1016/j.clml.2020.01.017 32249195

2. Raje N.S. Bhatta S. Terpos E. Role of the RANK/RANKL pathway in multiple myeloma Clin. Cancer Res. 2019 25 12 20 10.1158/1078-0432.CCR-18-1537 30093448

3. Rajkumar S.V. Kumar S. Multiple Myeloma: Diagnosis and Treatment Mayo Clin. Proc. 2016 91 101 119 10.1016/j.mayocp.2015.11.007 26763514 PMC5223450

4. The International Myeloma Working Group Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group Br. J. Haematol. 2003 121 749 757 10.1046/j.1365-2141.2003.04355.x 12780789

5. Global Burden of Disease Cancer Collaboration Fitzmaurice C. Abate D. Abbasi N. Abbastabar H. Abd-Allah F. Abdel-Rahman O. Abdelalim A. Abdoli A. Abdollahpour I. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: A systematic analysis for the global burden of disease study JAMA Oncol. 2019 5 1749 1768 10.1001/jamaoncol.2019.2996 31560378 PMC6777271

6. Ho M. Patel A. Goh C.Y. Moscvin M. Zhang L. Bianchi G. Changing paradigms in diagnosis and treatment of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) Leukemia 2020 34 3111 3125 10.1038/s41375-020-01051-x 33046818

7. Maes A. Menu E. Veirman K.D. Maes K. Vand Erkerken K. De Bruyne E. The therapeutic potential of cell cycle targeting in multiple myeloma Oncotarget 2017 8 90501 90520 10.18632/oncotarget.18765 29163849 PMC5685770

8. Kyle R.A. Durie B.G.M. Rajkumar S.V. Landgren O. Blade J. Merlini G. Kröger N. Einsele H. Vesole D.H. Dimopoulos M. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management Leukemia 2010 24 1121 1127 10.1038/leu.2010.60 20410922 PMC7020664

9. Kim C. Bhatta S. Cyprien L. Fonseca R. Hernandez R.K. Incidence of skeletal-related events among multiple myeloma patients in the United States at oncology clinics: Observations from real-world data J. Bone Oncol. 2018 14 100215 10.1016/j.jbo.2018.100215 30666288 PMC6329702

10. Costa L.J. Brill I.K. Omel J. Godby K. Kumar S.K. Brown E.E. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States Blood Adv. 2017 1 282 287 10.1182/bloodadvances.2016002493 29296944 PMC5727774

11. Landgren O. Kyle R.A. Pfeiffer R.M. Katzmann J.A. Caporaso N.E. Hayes R.B. Dispenzieri A. Kumar S. Clark R.J. Baris D. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study Blood 2009 113 5412 5417 10.1182/blood-2008-12-194241 19179464 PMC2689042

12. Mikhael J. Ismaila N. Cheung M.C. Costello C. Dhodapkar M.V. Kumar S. Lacy M. Lipe B. Little R.F. Nikonova A. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline J. Clin. Oncol. 2019 37 1228 1263 10.1200/JCO.18.02096 30932732

13. Branagan A. Lei M. Lou U. Raje N. Current treatment strategies for multiple myeloma JCO Oncol. Pract. 2020 16 5 14 10.1200/JOP.19.00244 32039665

14. Kumar S.K. Dispenzieri A. Lacy M.Q. Gertz M.A. Buadi F.K. Pandey S. Kapoor P. Dingli D. Hayman S.R. Leung N. Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients Leukemia 2014 28 1122 1128 10.1038/leu.2013.313 24157580 PMC4000285

15. Kumar S.K. Rajkumar S.V. Dispenzieri A. Lacy M.Q. Hayman S.R. Buadi F.K. Zeldenrust S.R. Dingli D. Russell S.J. Lust J.A. Improved survival in multiple myeloma and the impact of novel therapies Blood 2008 111 2516 2520 10.1182/blood-2007-10-116129 17975015 PMC2254544

16. Bird S.A. Boyd K. Multiple myeloma: An overview of management Palliat. Care Soc. Pract. 2019 13 1178224219868235 10.1177/1178224219868235 32215370 PMC7065505

17. Roodman G.D. Osteoblast function in myeloma Bone 2011 48 135 140 10.1016/j.bone.2010.06.016 20601285

18. Ban J. Fock V. Aryee D.N.T. Kovar H. Mechanisms, diagnosis and treatment of bone metastases Cells 2021 10 2944 10.3390/cells10112944 34831167 PMC8616226

19. Padala S.A. Barsouk A. Barsouk A. Rawla P. Vakiti A. Kolhe R. Kota V. Ajebo G.H. Epidemiology, staging, and management of multiple myeloma Med. Sci. 2021 9 3 10.3390/medsci9010003 PMC7838784 33498356

20. Coluzzi F. Rolke R. Mercadante S. Pain management in patients with multiple myeloma: An update Cancers 2019 11 2037 10.3390/cancers11122037 PMC6966684 31861097

21. Yee A.J. Raje N.S. Denosumab for the treatment of bone disease in solid tumors and multiple myeloma Future Oncol. 2018 14 195 203 10.2217/fon-2017-0403 29052442

22. Moreau P. Attal M. Caillot D. Macro M. Karlin L. Garderet L. Facon T. Benboubker L. Escoffre-Barbe M. Stoppa A.M. Prospective evaluation of magnetic resonance imaging and [( 18 )F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: Results of the IMAJEM study J. Clin. Oncol. 2017 35 2911 2918 10.1200/jco.2017.72.2975 28686535 PMC5578392

23. Hillengass J. Moulopoulos L.A. Delorme S. Koutoulidis V. Mosebach J. Hielscher T. Drake M. Rajkumar S.V. Oestergaard B. Abildgaard N. Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: A study of the International Myeloma Working Group Blood Cancer J. 2017 7 e599 10.1038/bcj.2017.78 28841211 PMC5596388

24. Edelstyn G.A. Gillespie P.J. Grebbell F.S. The radiological demonstration of osseous metastases. Experimental observations Clin. Radiol. 1967 18 158 162 10.1016/S0009-9260(67)80010-2 6023348

25. Simeone F.J. Harvey J.P. Yee A.J. O’Donnell E.K. Raje N.S. Torriani M. Bredella M.A. Value of low-dose whole-body CT in the management of patients with multiple myeloma and precursor states Skeletal. Radiol. 2019 48 773 779 10.1007/s00256-018-3066-6 30218303 PMC6447458

26. Durie B.G. The role of anatomic and functional staging in myeloma: Description of Durie/Salmon plus staging system Eur. J. Cancer 2006 42 1539 1543 10.1016/j.ejca.2005.11.037 16777405

27. Princewill K. Kyere S. Awan O. Mulligan M. Multiple myeloma lesion detection with whole body CT versus radiographic skeletal survey Cancer Investig. 2013 31 206 211 10.3109/07357907.2013.764565 23406213

28. Hinge M. Andersen K.T. Lund T. Jørgensen H.B. Holdgaard P.C. Ormstrup T.E. Østergaard L.L. Plesner T. Baseline bone involvement in multiple myeloma—A prospective comparison of conventional X-ray, low-dose computed tomography, and 18flourodeoxyglucose positron emission tomography in previously untreated patients Haematologica 2016 101 e415 e418 10.3324/haematol.2016.146092 27390357 PMC5046664

29. Mahnken A.H. Wildberger J.E. Gehbauer G. Schmitz-Rode T. Blaum M. Fabry U. Günther R.W. Multidetector CT of the spine in multiple myeloma: Comparison with MR imaging and radiography AJR Am. J. Roentgenol. 2002 178 1429 1436 10.2214/ajr.178.6.1781429 12034612

30. Schreiman J.S. McLeod R.A. Kyle R.A. Beabout J.W. Multiple myeloma: Evaluation by CT Radiology 1985 154 483 486 10.1148/radiology.154.2.3966137 3966137

31. Du J.-S. Yen C.-H. Hsu C.-M. Hsiao H.-H. Management of myeloma bone lesions Int. J. Mol. Sci. 2021 22 3389 10.3390/ijms22073389 33806209 PMC8036461

32. Saad F. Lipton A. Cook R. Chen Y.-M. Smith M. Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease Cancer 2007 110 1860 1867 10.1002/cncr.22991 17763372

33. McCloskey E.V. Guest J.F. Kanis J.A. The clinical and cost considerations of bisphosphonates in preventing bone complications in patients with metastatic breast cancer or multiple myeloma Drugs 2001 61 1253 1274 10.2165/00003495-200161090-00003 11511021

34. Clézardin P. Coleman R. Puppo M. Ottewell P. Bonnelye E. Paycha F. Confavreux C.B. Holen I. Bone metastasis: Mechanisms, therapies, and biomarkers Physiol. Rev. 2021 101 797 855 10.1152/physrev.00012.2019 33356915

35. Mohamed A.M. An overview of bone cells and their regulating factors of differentiation Malays. J. Med. Sci. 2008 15 4 12 22589609 PMC3341892

36. Anderson H.C. Reynolds J.J. Pyrophosphate stimulation of calcium uptake into cultured embryonic bones. Fine structure of matrix vesicles and their role in calcification Dev. Biol. 1973 34 211 227 10.1016/0012-1606(73)90351-5 4363671

37. Giuliani N. Rizzoli V. Roodman G.D. Multiple myeloma bone disease: Pathophysiology of osteoblast inhibition Blood 2006 108 3992 3996 10.1182/blood-2006-05-026112 16917004

38. Vejlgaard T. Abildgaard N. Jans H. Nielsen J.L. Heickendorff L. Abnormal bone turnover in monoclonal gammopathy of undetermined significance: Analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens Eur. J. Haematol. 1997 58 104 108 10.1111/j.1600-0609.1997.tb00932.x 9111591

39. Komori T. Yagi H. Nomura S. Yamaguchi A. Sasaki K. Deguchi K. Shimizu Y. Bronson R.T. Gao Y.H. Inada M. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts Cell 1997 89 755 764 10.1016/S0092-8674(00)80258-5 9182763

40. Geoffroy V. Kneissel M. Fournier B. Boyde A. Matthias P. High bone resorption in adult aging transgenic mice overexpressing Cbfa1/Runx2 in cells of the osteoblastic lineage Mol. Cell. Biol. 2002 22 6222 6233 10.1128/MCB.22.17.6222-6233.2002 12167715 PMC134019

41. Li Z. Kong K. Qi W. Osteoclast and its roles in calcium metabolism and bone development and remodeling Biochem. Biophys. Res. Commun. 2006 343 345 350 10.1016/j.bbrc.2006.02.147 16554033

42. Inoue K. Ng C. Xia Y. Zhao B. Regulation of osteoclastogenesis and bone resorption by miRNAs Front. Cell Dev. Biol. 2021 9 651161 10.3389/fcell.2021.651161 34222229 PMC8249944

43. Silbermann R. Roodman G.D. Myeloma bone disease: Pathophysiology and management J. Bone Oncol. 2013 2 59 69 10.1016/j.jbo.2013.04.001 26909272 PMC4723362

44. Morony S. Warmington K. Adamu S. Asuncion F. Geng Z. Grisanti M. Tan H.L. Capparelli C. Starnes C. Weimann B. The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy Endocrinology 2005 146 3235 3243 10.1210/en.2004-1583 15845617

45. Kong Y.Y. Yoshida H. Sarosi I. Tan H.L. Timms E. Capparelli C. Morony S. Oliveira-dos-Santos A.J. Van G. Itie A. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis Nature 1999 397 315 323 10.1038/16852 9950424

46. Bucay N. Sarosi I. Dunstan C.R. Morony S. Tarpley J. Capparelli C. Scully S. Tan H.L. Xu W. Lacey D.L. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification Genes Dev. 1998 12 1260 1268 10.1101/gad.12.9.1260 9573043 PMC316769

47. Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL Proc. Natl. Acad. Sci. USA 1998 95 3597 3602 10.1073/pnas.95.7.3597 9520411 PMC19881

48. Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation Cell 1998 93 165 176 10.1016/S0092-8674(00)81569-X 9568710

49. Hameed A. Brady J.J. Dowling P. Clynes M. O’Gorman P. Bone disease in multiple myeloma: Pathophysiology and management Cancer Growth Metastasis 2014 7 33 42 10.4137/CGM.S16817 25187738 PMC4133035

50. Raje N. Roodman G.D. Advances in the biology and treatment of bone disease in multiple myeloma Clin. Cancer Res. 2011 17 1278 1286 10.1158/1078-0432.CCR-10-1804 21411443

51. Berenson J.R. Yellin O. Boccia R.V. Flam M. Wong S.-F. Batuman O. Moezi M.M. Woytowitz D. Duvivier H. Nassir Y. Zoledronic acid markedly improves bone mineral density for patients with monoclonal gammopathy of undetermined significance and bone loss Clin. Cancer Res. 2008 14 6289 6295 10.1158/1078-0432.CCR-08-0666 18829511

52. Drake M.T. Unveiling skeletal fragility in patients diagnosed with MGUS: No longer a condition of undetermined significance? J. Bone Miner. Res. 2014 29 2529 2533 10.1002/jbmr.2387 25319751 PMC4268401

53. Golombick T. Diamond T. Prevalence of monoclonal gammopathy of undetermined significance/myeloma in patients with acute osteoporotic vertebral fractures Acta Haematol. 2008 120 87 90 10.1159/000162282 18852483

54. Abrahamsen B. Andersen I. Christensen S.S. Skov Madsen J. Brixen K. Utility of testing for monoclonal bands in serum of patients with suspected osteoporosis: Retrospective, cross sectional study BMJ 2005 330 818 10.1136/bmj.38376.401701.8F 15767267 PMC556071

55. Parrondo R.D. Sher T. Prevention of skeletal related events in multiple myeloma: Focus on the RANK-L pathway in the treatment of multiple myeloma OncoTargets Ther. 2019 12 8467 8478 10.2147/OTT.S192490 31686861 PMC6798817

56. Roodman G.D. Pathogenesis of myeloma bone disease Blood Cells Mol. Dis. 2004 32 290 292 10.1016/j.bcmd.2004.01.001 15003820

57. Giuliani N. Colla S. Morandi F. Lazzaretti M. Sala R. Bonomini S. Grano M. Colucci S. Svaldi M. Rizzoli V. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation Blood 2005 106 2472 2483 10.1182/blood-2004-12-4986 15933061

58. Nierste B.A. Glackin C.A. Kirshner J. Dkk-1 and IL-7 in plasma of patients with multiple myeloma prevent differentiation of mesenchymal stem cells into osteoblasts Am. J. Blood Res. 2014 4 73 85 25755907 PMC4348795

59. Weitzmann M.N. Roggia C. Toraldo G. Weitzmann L. Pacifici R. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency J. Clin. Investig. 2002 110 1643 1650 10.1172/JCI0215687 12464669 PMC151629

60. Evans C.E. Ward C. Rathour L. Galasko C.B. Myeloma affects both the growth and function of human osteoblast-like cells Clin. Exp. Metastasis 1992 10 33 38 10.1007/BF00163574 1733645

61. Silvestris F. Cafforio P. Tucci M. Grinello D. Dammacco F. Upregulation of osteoblast apoptosis by malignant plasma cells: A role in myeloma bone disease Br. J. Haematol. 2003 122 39 52 10.1046/j.1365-2141.2003.04374.x 12823344

62. Kyle R.A. Rajkumar S.V. Multiple Myeloma N. Engl. J. Med. 2004 351 1860 1873 10.1056/NEJMra041875 15509819

63. Chauhan D. Uchiyama H. Akbarali Y. Urashima M. Yamamoto K. Libermann T. Anderson K. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B Blood 1996 87 1104 1112 10.1182/blood.V87.3.1104.bloodjournal8731104 8562936

64. Roodman G.D. Mechanisms of bone metastasis N. Engl. J. Med. 2004 350 1655 1664 10.1056/NEJMra030831 15084698

65. Min J.-K. Cho Y.-L. Choi J.-H. Kim Y. Kim J.H. Yu Y.S. Rho J. Mochizuki N. Kim Y.-M. Oh G.T. Receptor activator of nuclear factor (NF)–κB ligand (RANKL) increases vascular permeability: Impaired permeability and angiogenesis in eNOS-deficient mice Blood 2006 109 1495 1502 10.1182/blood-2006-06-029298 17038532

66. Body J.-J. Niepel D. Tonini G. Hypercalcaemia and hypocalcaemia: Finding the balance Support Care Cancer 2017 25 1639 1649 10.1007/s00520-016-3543-1 28078478 PMC5378747

67. Goldner W. Cancer-related hypercalcemia J. Oncol. Pract. 2016 12 426 432 10.1200/JOP.2016.011155 27170690

68. Giuliani N. Bataille R. Mancini C. Lazzaretti M. Barillé S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment Blood 2001 98 3527 3533 10.1182/blood.V98.13.3527 11739153

69. Seidel C. Hjertner Ø. Abildgaard N. Heickendorff L. Hjorth M. Westin J. Nielsen J.L. Hjorth-Hansen H. Waage A. Sundan A. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease Blood 2001 98 2269 2271 10.1182/blood.V98.7.2269 11568016

70. Terpos E. Szydlo R. Apperley J.F. Hatjiharissi E. Politou M. Meletis J. Viniou N. Yataganas X. Goldman J.M. Rahemtulla A. Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: Proposal for a novel prognostic index Blood 2003 102 1064 1069 10.1182/blood-2003-02-0380 12689925

71. Giuliani N. Morandi F. Tagliaferri S. Lazzaretti M. Bonomini S. Crugnola M. Mancini C. Martella E. Ferrari L. Tabilio A. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients Blood 2007 110 334 338 10.1182/blood-2006-11-059188 17371942

72. Shimazaki C. Uchida R. Nakano S. Namura K. Fuchida S.I. Okano A. Okamoto M. Inaba T. High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: Possible role of bortezomib on osteoblast differentiation Leukemia 2005 19 1102 1103 10.1038/sj.leu.2403758 15830008

73. Zangari M. Esseltine D. Lee C.-K. Barlogie B. Elice F. Burns M.J. Kang S.-H. Yaccoby S. Najarian K. Richardson P. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma Br. J. Haematol. 2005 131 71 73 10.1111/j.1365-2141.2005.05733.x 16173965

74. Zangari M. Yaccoby S. Cavallo F. Esseltine D. Tricot G. Response to bortezomib and activation of osteoblasts in multiple myeloma Clin. Lymphoma Myeloma 2006 7 109 114 10.3816/CLM.2006.n.047 17026821

75. Bolzoni M. Toscani D. Storti P. Marchica V. Costa F. Giuliani N. Possible targets to treat myeloma-related osteoclastogenesis Expert Rev. Hematol. 2018 11 325 336 10.1080/17474086.2018.1447921 29495905

76. Zavrski I. Krebbel H. Wildemann B. Heider U. Kaiser M. Possinger K. Sezer O. Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function Biochem. Biophys. Res. Commun. 2005 333 200 205 10.1016/j.bbrc.2005.05.098 15936724

77. Bolzoni M. Storti P. Bonomini S. Todoerti K. Guasco D. Toscani D. Agnelli L. Neri A. Rizzoli V. Giuliani N. Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules Exp. Hematol. 2013 41 387.e381 397.e381 10.1016/j.exphem.2012.11.005 23178378

78. Oyajobi B.O. Multiple myeloma/hypercalcemia Arthritis Res. Ther. 2007 9 (Suppl. S1) S4 10.1186/ar2168 17634143 PMC1924519

79. Zagouri F. Kastritis E. Zomas A. Terpos E. Katodritou E. Symeonidis A. Delimpasi S. Pouli A. Vassilakopoulos T.P. Michalis E. Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies Eur. J. Haematol. 2017 99 409 414 10.1111/ejh.12923 28675766

80. Panaroni C. Yee A.J. Raje N.S. Myeloma and bone disease Curr. Osteoporos. Rep. 2017 15 483 498 10.1007/s11914-017-0397-5 28861842

81. Russell R.G.G. Bisaz S. Fleisch H. Currey H.L.F. Rubinstein H.M. Dietz A.A. Boussina I. Micheli A. Fallet G. Inorganic pyrophosphate in plasma, urine, and synovial fluid of patients with pyrophosphate arthropathy (chondrocalcinosis or pseudogout) Lancet 1970 296 899 902 10.1016/S0140-6736(70)92070-2 4097282

82. Nancollas G.H. Tang R. Phipps R.J. Henneman Z. Gulde S. Wu W. Mangood A. Russell R.G. Ebetino F.H. Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite Bone 2006 38 617 627 10.1016/j.bone.2005.05.003 16046206

83. Hasan W.N.W. Chin K.Y. Jolly J.J. Ghafar N.A. Soelaiman I.N. Identifying potential therapeutics for osteoporosis by exploiting the relationship between mevalonate pathway and bone metabolism Endocr. Metab. Immune Disord. Drug Targets 2018 18 450 457 10.2174/1871530318666180423122409 29683099

84. Raje N. Woo S.-B. Hande K. Yap J.T. Richardson P.G. Vallet S. Treister N. Hideshima T. Sheehy N. Chhetri S. Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw Clin. Cancer Res. 2008 14 2387 2395 10.1158/1078-0432.CCR-07-1430 18413829

85. Berenson J.R. Lichtenstein A. Porter L. Dimopoulos M.A. Bordoni R. George S. Lipton A. Keller A. Ballester O. Kovacs M. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group J. Clin. Oncol. 1998 16 593 602 10.1200/JCO.1998.16.2.593 9469347

86. Berenson J.R. Lichtenstein A. Porter L. Dimopoulos M.A. Bordoni R. George S. Lipton A. Keller A. Ballester O. Kovacs M.J. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma N. Eng. J. Med. 1996 334 488 493 10.1056/NEJM199602223340802 8559201

87. Rosen L.S. Gordon D. Kaminski M. Howell A. Belch A. Mackey J. Apffelstaedt J. Hussein M.A. Coleman R.E. Reitsma D.J. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma Cancer 2003 98 1735 1744 10.1002/cncr.11701 14534891

88. Rosen L.S. Gordon D. Tchekmedyian S. Yanagihara R. Hirsh V. Krzakowski M. Pawlicki M. de Souza P. Zheng M. Urbanowitz G. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—The zoledronic acid lung cancer and other solid tumors study group J. Clin. Oncol. 2003 21 3150 3157 10.1200/JCO.2003.04.105 12915606

89. Saad F. Gleason D.M. Murray R. Tchekmedyian S. Venner P. Lacombe L. Chin J.L. Vinholes J.J. Goas J.A. Chen B. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma J. Natl. Cancer Inst. 2002 94 1458 1468 10.1093/jnci/94.19.1458 12359855

90. Rosen L.S. Gordon D. Kaminski M. Howell A. Belch A. Mackey J. Apffelstaedt J. Hussein M. Coleman R.E. Reitsma D.J. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial Cancer J. 2001 7 377 387 11693896

91. Major P. Lortholary A. Hon J. Abdi E. Mills G. Menssen H.D. Yunus F. Bell R. Body J. Quebe-Fehling E. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials J. Clin. Oncol. 2001 19 558 567 10.1200/JCO.2001.19.2.558 11208851

92. Morgan G.J. Davies F.E. Gregory W.M. Cocks K. Bell S.E. Szubert A.J. Navarro-Coy N. Drayson M.T. Owen R.G. Feyler S. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial Lancet 2010 376 1989 1999 10.1016/S0140-6736(10)62051-X 21131037 PMC3639680

93. Anderson K.C. Alsina M. Bensinger W. Biermann J.S. Cohen A.D. Devine S. Djulbegovic B. Faber E.A. Gasparetto C. Hernandez-Illizaliturri F. Multiple myeloma, version 1.2013 J. Natl. Compr. Cancer Netw. 2013 11 11 17 10.6004/jnccn.2013.0004 23307977

94. Terpos E. Morgan G. Dimopoulos M.A. Drake M.T. Lentzsch S. Raje N. Sezer O. García-Sanz R. Shimizu K. Turesson I. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease J. Clin. Oncol. 2013 31 2347 2357 10.1200/JCO.2012.47.7901 23690408 PMC4878084

95. Berenson J.R. Rosen L.S. Howell A. Porter L. Coleman R.E. Morley W. Dreicer R. Kuross S.A. Lipton A. Seaman J.J. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases Cancer 2001 91 1191 1200 10.1002/1097-0142(20010401)91:7<1191::AID-CNCR1119>3.0.CO;2-0 11283917

96. Costa L. Harper P. Coleman R.E. Lipton A. Anticancer evidence for zoledronic acid across the cancer continuum Crit. Rev. Oncol. Hematol. 2011 77 (Suppl. S1) S31 S37 10.1016/S1040-8428(11)70006-3 21353179

97. Raje N. Vescio R. Montgomery C.W. Badros A. Munshi N. Orlowski R. Hadala J.T. Warsi G. Argonza-Aviles E. Ericson S.G. Bone marker–directed dosing of zoledronic acid for the prevention of skeletal complications in patients with multiple myeloma: Results of the Z-MARK Study Clin. Cancer Res. 2016 22 1378 1384 10.1158/1078-0432.CCR-15-1864 26644410

98. Terpos E. Berenson J. Cook R.J. Lipton A. Coleman R.E. Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease Leukemia 2010 24 1043 1049 10.1038/leu.2010.62 20376081

99. Patel C.G. Yee A.J. Scullen T.A. Nemani N. Santo L. Richardson P.G. Laubach J.P. Ghobrial I.M. Schlossman R.L. Munshi N.C. Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy Clin. Cancer Res. 2014 20 3955 3961 10.1158/1078-0432.CCR-14-0434 24958808

100. Lipton A. Cook R. Saad F. Major P. Garnero P. Terpos E. Brown J.E. Coleman R.E. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid Cancer 2008 113 193 201 10.1002/cncr.23529 18459173

101. Lipton A. Cook R. Brown J. Body J.J. Smith M. Coleman R. Skeletal-related events and clinical outcomes in patients with bone metastases and normal levels of osteolysis: Exploratory analyses Clin. Oncol. 2013 25 217 226 10.1016/j.clon.2012.11.004 23219232

102. Himelstein A.L. Foster J.C. Khatcheressian J.L. Roberts J.D. Seisler D.K. Novotny P.J. Qin R. Go R.S. Grubbs S.S. O’Connor T. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial JAMA 2017 317 48 58 10.1001/jama.2016.19425 28030702 PMC5321662

103. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons American Association of Oral and Maxillofacial Surgeons position paper on Bisphosphonate-related osteonecrosis of the jaws J. Oral Maxillofac. Surg. 2007 65 369 376 10.1016/j.joms.2006.11.003 17307580

104. Badros A. Terpos E. Katodritou E. Goloubeva O. Kastritis E. Verrou E. Zervas K. Baer M.R. Meiller T. Dimopoulos M.A. Natural history of osteonecrosis of the jaw in patients with multiple myeloma J. Clin. Oncol. 2008 26 5904 5909 10.1200/JCO.2008.16.9300 19018084

105. Dimopoulos M.A. Kastritis E. Anagnostopoulos A. Melakopoulos I. Gika D. Moulopoulos L.A. Bamia C. Terpos E. Tsionos K. Bamias A. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid Haematologica 2006 91 968 971 16757414

106. Zervas K. Verrou E. Teleioudis Z. Vahtsevanos K. Banti A. Mihou D. Krikelis D. Terpos E. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: A single-centre experience in 303 patients Br. J. Haematol. 2006 134 620 623 10.1111/j.1365-2141.2006.06230.x 16889620

107. Gimsing P. Carlson K. Turesson I. Fayers P. Waage A. Vangsted A. Mylin A. Gluud C. Juliusson G. Gregersen H. Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): A double-blind, randomised controlled trial Lancet Oncol. 2010 11 973 982 10.1016/S1470-2045(10)70198-4 20863761

108. Mhaskar R. Kumar A. Miladinovic B. Djulbegovic B. Bisphosphonates in multiple myeloma: An updated network meta-analysis Cochrane Database Syst. Rev. 2017 12 CD003188 10.1002/14651858.CD003188.pub4 29253322 PMC6486151

109. Perazella M.A. Markowitz G.S. Bisphosphonate nephrotoxicity Kidney Int. 2008 74 1385 1393 10.1038/ki.2008.356 18685574

110. Terpos E. Zamagni E. Lentzsch S. Drake M.T. García-Sanz R. Abildgaard N. Ntanasis-Stathopoulos I. Schjesvold F. de la Rubia J. Kyriakou C. Treatment of multiple myeloma-related bone disease: Recommendations from the Bone Working Group of the International Myeloma Working Group Lancet Oncol. 2021 22 e119 e130 10.1016/S1470-2045(20)30559-3 33545067

111. Edwards B.J. Usmani S. Raisch D.W. McKoy J.M. Samaras A.T. Belknap S.M. Trifilio S.M. Hahr A. Bunta A.D. Abu-Alfa A. Acute kidney injury and bisphosphonate use in cancer: A report from the research on adverse drug events and reports (RADAR) project J. Oncol. Pract. 2013 9 101 106 10.1200/JOP.2011.000486 23814519 PMC3595436

112. Delgado-Calle J. Anderson J. Cregor M.D. Condon K.W. Kuhstoss S.A. Plotkin L.I. Bellido T. Roodman G.D. Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth Leukemia 2017 31 2686 2694 10.1038/leu.2017.152 28529307 PMC5699973

113. Delgado-Calle J. Sato A.Y. Bellido T. Role and mechanism of action of sclerostin in bone Bone 2017 96 29 37 10.1016/j.bone.2016.10.007 27742498 PMC5328835

114. Wijenayaka A.R. Kogawa M. Lim H.P. Bonewald L.F. Findlay D.M. Atkins G.J. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway PLoS ONE 2011 6 e25900 10.1371/journal.pone.0025900 21991382 PMC3186800

115. Yee A.J. Laubach J.P. Nooka A.K. O’Donnell E.K. Weller E.A. Couture N.R. Wallace E.E. Burke J.N. Harrington C.C. Puccio-Pick M. Phase 1 dose-escalation study of sotatercept (ACE-011) in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma Blood 2015 126 4241 10.1182/blood.V126.23.4241.4241

116. Abdulkadyrov K.M. Salogub G.N. Khuazheva N.K. Sherman M.L. Laadem A. Barger R. Knight R. Srinivasan S. Terpos E. Sotatercept in patients with osteolytic lesions of multiple myeloma Br. J. Haematol. 2014 165 814 823 10.1111/bjh.12835 24650009 PMC4312883

117. Hanley D.A. Adachi J.D. Bell A. Brown V. Denosumab: Mechanism of action and clinical outcomes Int. J. Clin. Pract. 2012 66 1139 1146 10.1111/ijcp.12022 22967310 PMC3549483

118. Cummings S.R. Martin J.S. McClung M.R. Siris E.S. Eastell R. Reid I.R. Delmas P. Zoog H.B. Austin M. Wang A. Denosumab for prevention of fractures in postmenopausal women with osteoporosis N. Eng. J. Med. 2009 361 756 765 10.1056/NEJMoa0809493 19671655

119. Stopeck A.T. Lipton A. Body J.-J. Steger G.G. Tonkin K. Boer R.H.d. Lichinitser M. Fujiwara Y. Yardley D.A. Viniegra M. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study J. Clin. Oncol. 2010 28 5132 5139 10.1200/JCO.2010.29.7101 21060033

120. Fizazi K. Carducci M. Smith M. Damião R. Brown J. Karsh L. Milecki P. Shore N. Rader M. Wang H. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study Lancet 2011 377 813 822 10.1016/S0140-6736(10)62344-6 21353695 PMC3090685

121. Henry D.H. Costa L. Goldwasser F. Hirsh V. Hungria V. Prausova J. Scagliotti G.V. Sleeboom H. Spencer A. Vadhan-Raj S. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma J. Clin. Oncol. 2011 29 1125 1132 10.1200/JCO.2010.31.3304 21343556

122. Raje N. Terpos E. Willenbacher W. Shimizu K. García-Sanz R. Durie B. Legieć W. Krejčí M. Laribi K. Zhu L. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: An international, double-blind, double-dummy, randomised, controlled, phase 3 study Lancet Oncol. 2018 19 370 381 10.1016/S1470-2045(18)30072-X 29429912

123. Lipton A. Fizazi K. Stopeck A.T. Henry D.H. Brown J.E. Yardley D.A. Richardson G.E. Siena S. Maroto P. Clemens M. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials Eur. J. Cancer 2012 48 3082 3092 10.1016/j.ejca.2012.08.002 22975218

124. Everts-Graber J. Lehmann D. Burkard J.P. Schaller B. Gahl B. Häuselmann H. Studer U. Ziswiler H.R. Reichenbach S. Lehmann T. Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis J. Bone Miner. Res. 2022 37 340 348 10.1002/jbmr.4472 34787342

125. Terpos E. Raje N. Croucher P. Garcia-Sanz R. Leleu X. Pasteiner W. Wang Y. Glennane A. Canon J. Pawlyn C. Denosumab compared with zoledronic acid on PFS in multiple myeloma: Exploratory results of an international phase 3 study Blood Adv. 2021 5 725 736 10.1182/bloodadvances.2020002378 33560384 PMC7876889

126. Heider U. Kaiser M. Müller C. Jakob C. Zavrski I. Schulz C.-O. Fleissner C. Hecht M. Sezer O. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment Eur. J. Haematol. 2006 77 233 238 10.1111/j.1600-0609.2006.00692.x 16923110

127. Terpos E. Heath D.J. Rahemtulla A. Zervas K. Chantry A. Anagnostopoulos A. Pouli A. Katodritou E. Verrou E. Vervessou E.-C. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-κB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma Br. J. Haematol. 2006 135 688 692 10.1111/j.1365-2141.2006.06356.x 17107351

128. Mukherjee S. Raje N. Schoonmaker J.A. Liu J.C. Hideshima T. Wein M.N. Jones D.C. Vallet S. Bouxsein M.L. Pozzi S. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice J. Clin. Investig. 2008 118 491 504 10.1172/JCI33102 18219387 PMC2213372

129. von Metzler I. Krebbel H. Hecht M. Manz R.A. Fleissner C. Mieth M. Kaiser M. Jakob C. Sterz J. Kleeberg L. Bortezomib inhibits human osteoclastogenesis Leukemia 2007 21 2025 2034 10.1038/sj.leu.2404806 17581612

130. Garrett I.R. Chen D. Gutierrez G. Zhao M. Escobedo A. Rossini G. Harris S.E. Gallwitz W. Kim K.B. Hu S. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro J. Clin. Investig. 2003 111 1771 1782 10.1172/JCI16198 12782679 PMC156102

131. Anderson K. Ismaila N. Flynn P.J. Halabi S. Jagannath S. Ogaily M.S. Omel J. Raje N. Roodman G.D. Yee G.C. Role of bone-modifying agents in multiple myeloma: American society of clinical oncology clinical practice guideline update J. Clin. Oncol. 2018 36 812 818 10.1200/JCO.2017.76.6402 29341831

132. Morgan G.J. Davies F.E. Gregory W.M. Szubert A.J. Bell S.E. Drayson M.T. Owen R.G. Ashcroft A.J. Jackson G.H. Child J.A. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: The Medical Research Council Myeloma IX Trial Blood 2012 119 5374 5383 10.1182/blood-2011-11-392522 22498739

133. Kumar S.K. Callander N.S. Hillengass J. Liedtke M. Baljevic M. Campagnaro E. Castillo J.J. Chandler J.C. Cornell R.F. Costello C. NCCN guidelines insights: Multiple myeloma, version 1.2020: Featured updates to the NCCN guidelines J. Natl. Compr. Cancer Netw. 2019 17 1154 1165 10.6004/jnccn.2019.0049 31590151

134. Tsourdi E. Langdahl B. Cohen-Solal M. Aubry-Rozier B. Eriksen E.F. Guañabens N. Obermayer-Pietsch B. Ralston S.H. Eastell R. Zillikens M.C. Discontinuation of denosumab therapy for osteoporosis: A systematic review and position statement by ECTS Bone 2017 105 11 17 10.1016/j.bone.2017.08.003 28789921

135. Popp A.W. Varathan N. Buffat H. Senn C. Perrelet R. Lippuner K. Bone mineral density changes after 1 year of denosumab discontinuation in postmenopausal women with long-term denosumab treatment for osteoporosis Calcif. Tissue Int. 2018 103 50 54 10.1007/s00223-018-0394-4 29380013

136. Anastasilakis A.D. Makras P. Yavropoulou M.P. Tabacco G. Naciu A.M. Palermo A. Denosumab discontinuation and the rebound phenomenon: A narrative review J. Clin. Med. 2021 10 152 10.3390/jcm10010152 PMC7796169 33406802

137. Anastasilakis A.D. Yavropoulou M.P. Makras P. Sakellariou G.T. Papadopoulou F. Gerou S. Papapoulos S.E. Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment Eur. J. Endocrinol. 2017 176 677 683 10.1530/EJE-16-1027 28283537

138. Raje N. Roodman G.D. Willenbacher W. Shimizu K. García-Sanz R. Terpos E. Kennedy L. Sabatelli L. Intorcia M. Hechmati G. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America J. Med. Econ. 2018 21 525 536 10.1080/13696998.2018.1445634 29480139