The role of bone-modifying agents in myeloma bone disease.

Overview and Epidemiology

Multiple myeloma

Multiple myeloma (MM) is a neoplasm caused by malignant proliferation of plasma cells in the bone marrow. It is characterized by the production of monoclonal immunoglobulins, which can lead to end organ damage. MM presents commonly as anemia, bone pain (with skeletal lesions), hypercalcemia, and kidney failure. ( 1 , 2 ) It is diagnosed most commonly at ages of 65 to 74 years. In the United States, an estimated 34,920 new cases of MM will be diagnosed in 2021, with an estimated 12,410 deaths, accounting for 1.8% of all new cancers and 2.0% of all cancer deaths. ( 3 ) The estimated overall 5‐year survival is 55.6%. ( 4 )

Myeloma bone disease

Osteolytic lesions with or without diffuse osteopenia, pathologic fractures, and focal lytic lesions are common features seen in patients with MM. Myeloma bone disease (MBD) occurs in approximately 80% to 95% of patients. ( 5 , 6 ) MBD predominantly affects the axial skeleton and can have serious skeletal consequences such as spinal cord compression and pathologic fractures requiring radiotherapeutic and/or surgical intervention), commonly referred to as skeletal‐related events (SREs). ( 7 ) Fractures are observed in approximately 50% of MM patients. ( 6 ) Even in patients in remission or with low‐grade stable disease after stem cell transplantation, fractures were reported in up to 13% of patients. ( 8 ) MBD can have debilitating effects on the quality of life of MM patients and in their survivorship with respect to severe pain, psychological distress, and loss of autonomy. ( 9 ) Most importantly, it is also associated with increased morbidity and mortality. ( 10 , 11 , 12 )

Pathogenesis of MBD

Skeletal homeostasis is a complex and multifactorial process of interactions between the bone matrix, osteoclasts, osteoblasts, osteocytes, and the immune system. ( 13 , 14 ) Osteoclasts and osteoblasts are derived from distinct cellular lineages. Osteoclasts are derived from fusion of mononuclear cells of the monocyte–macrophage lineage. ( 15 ) They are regulated by receptor activator of NF‐κB (RANK), its ligand RANKL, and the decoy receptor osteoprotegerin (OPG). ( 16 ) Osteoblasts evolve from mesenchymal cells to osteocytes through a differentiation process called osteoblastogenesis. This process is regulated by the Wingless‐type (Wnt) signaling and β‐catenin pathways. ( 17 , 18 ) In normal bone metabolism, bone resorption and formation are regulated by a coupled function of osteoclast and osteoblast. Imbalance between bone‐resorbing osteoclasts and bone‐forming osteoblasts causes significant dysregulation of bone homeostasis and resultant MBD. The interactions among MM cells, residential cellular components of the bone, and immune cells favor the expansion of MM cells and the destruction of normal bone structures (Figure URE 1 ). It has also been shown that once the destructive bone disease occurs, it does not completely reverse even once MM is in remission. Therefore, developing new therapies targeting MBD is important not only for MM disease control, but also for the quality of life of MM survivors.

Upregulation of osteoclast activity

Increased activity of osteoclasts is observed in MM that occurs through several pathways: the RANK/RANKL pathway, the Notch signaling pathway, and other factors that favor osteoclastogenesis. RANKL is produced primarily by osteocytes and promotes osteoclast activity by binding to RANK. OPG is secreted by osteoblasts, bone marrow stromal cells (BMSCs), and osteocytes, and inhibits interaction of RANK with RANKL. OPG was shown to inhibit the development of osteolytic bone disease in MM. ( 19 ) In general, an increase in the RANKL/OPG ratio favors bone destruction. ( 20 , 21 ) This is seen in inflammatory diseases such as rheumatoid arthritis and in several types of cancers. Direct interaction of MM cells with BMSCs leads to increased expression of RANKL, and decreased expression of OPG by BMSCs and osteocytes in the bone microenvironment. The activated intracellular Notch signaling pathway results in increased production of RANKL, which binds to RANK and promotes osteoclastogenesis. ( 22 , 23 , 24 ) Interactions between BMSCs, MM cells, and immune cells induce release of proosteoclastogenic factors and several cytokines such as interleukin‐1b (IL‐1b), IL‐3, IL‐6, IL‐11, and IL‐17. ( 24 ) These cytokines increase osteoclast activity and decrease osteoblastogenesis, leading to increased bone resorption. In addition, activin A, initially isolated as a gonadal protein, a member of the transforming growth factor‐β (TGF‐β) superfamily, is found to have a broad spectrum of biological functions including regulating the extracellular matrix formation and mineralization of the bone. ( 25 , 26 ) MM cells induce the secretion of activin A by BMSCs, which stimulates osteoclast growth and possibly inhibits osteoblast function. ( 27 , 28 ) Activin A levels are found elevated in MM patients, especially in those with advanced disease and extensive MBD. ( 29 )

Downregulation of osteoblast activity

Suppressed activity of osteoblasts occurs because of aberrant Wnt signaling in MM. ( 30 ) Inhibitors of the canonical Wnt pathway, such as sclerostin, Dickkopf‐like protein 1 (DKK‐1), and soluble frizzled‐related proteins (sFRP), inhibit bone formation. ( 31 , 32 ) Sclerostin, a glycoprotein produced by osteocytes, impedes the activation of the canonical Wnt pathway, inhibiting osteoblast maturation and impairing bone mineralization. ( 33 , 34 , 35 ) Furthermore, it induces apoptosis of osteoblasts through caspase activation and increases the RANKL/OPG ratio, resulting in enhanced osteoclastogenesis. Another antagonist of the Wnt pathway is DKK‐1, which is secreted by MM cells. ( 36 ) Osteoblastogenesis and new bone formation are inhibited by the binding of DKK‐1 to lipoprotein receptor‐related protein (LRP)‐6. In addition, DKK‐1 enhances secretion of sclerostin ( 37 ) and increases the RANKL/OPG ratio, resulting in increased osteoclastogenesis. ( 38 ) Several other Wnt pathway regulatory factors including periostin, Runt‐related transcription factor 2, and Growth factor independence 1 are also deregulated in MM. ( 24 )

As this brief discussion demonstrates, MBD is complex and involves the dysregulation of several pathways and physiologic processes. Detailed pathophysiologic mechanisms of MBD have been described in detail in other reports. ( 24 , 39 ) Furthermore, recent preclinical work has implicated the Hippo pathway in the pathogenesis of MBD. ( 40 ) In general, the mechanisms involved are still being uncovered, and better understanding of the mechanisms involved in MBD will result in innovative treatment approaches.

Osteocytes

Although the formation and resorption of the bone is directly attributed to osteoblasts and osteoclasts, the majority of cells in the bone microenvironment are osteocytes, which constitute >95% of bone cells. Osteocytes are the central regulators of both osteoblast and osteoclasts. Osteocytes secrete sclerostin, an inhibitor of bone formation, and RANKL, which promotes osteoclastogenesis. Apoptotic osteocytes (seen in disuse, glucocorticoid treatment, estrogen deficiency) induces osteoclast precursor recruitment and bone resorption. ( 41 , 42 ) MM cells interact with osteocytes in the bone microenvironment and can promote MBD by increasing osteocyte apoptosis, increase sclerostin and RANKL production, and inhibit osteoblast differentiation. The interactions of MM cells and osteocytes are reciprocal. Osteocytes are shown to activate Notch signaling via Notch3, which leads to increased MM cell proliferation, and has the capacity to change the Notch receptor repertoire expressed by MM cells. ( 23 ) In vivo studies inhibiting Notch signaling, alone or in combination with other anti‐apoptotic treatment led to the inhibition of MM cell growth. ( 43 , 44 )

Treatment of MBD

In patients with MM and/or MBD, various treatment strategies are available. Management of underlying MM is crucial as MBD will ensue or progress without adequate control of underlying MM. Preventative therapies are needed to delay MBD progression. ( 45 ) Currently, the mainstay of preventative therapies are antiresorptive agents (Table 1 ). ( 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ) However, these agents are limited in not being able to promote new bone formation or repair existing bone lesions. ( 56 ) Newer anabolic agents that promote osteoblastogenesis and bone formation can potentially repair existing bone lesions and could improve MBD (Table 2 ). ( 57 , 58 , 59 , 60 , 61 , 62 , 63 ) In addition to bone‐modifying agents, antitumor therapies, radiotherapy, and surgery are other options used in the treatment of MBD. ( 11 , 45 )

Antiresorptive therapies

Bisphosphonates

Bisphosphonates (BPs) have been the most widely used antiresorptive medication in treating MM and MBD. BPs are pyrophosphate analogues that avidly bind to hydroxyapatite and get incorporated into the bone matrix. ( 64 ) All BPs have two phosphate groups with a central carbon atom; however, their affinity for binding with hydroxyapatite depends on the composition of the side chains. ( 65 ) Bisphosphonates are classified into two main types based on their affinity for binding with hydroxyapatite: (i) BPs containing nitrogen, such as pamidronate and zoledronic acid, and (ii) non–nitrogen‐containing BPs, such as etidronate and clodronate; the nitrogen‐containing BPs are 100‐fold to 10,000‐fold more potent. ( 66 ) Bisphosphonates suppress osteoclast activity and thus favorably change the balance between bone formation and destruction, resulting in increased bone mass, and there is experimental evidence suggesting that BPs may have a mitogenic effect on osteoblasts. One of proposed pathway is BP's effect on suppressing RANKL and increasing OPG in human osteoblasts, leading to bone formation. ( 67 , 68 , 69 , 70 )

In terms of SREs, none of the BPs approved by the US Food and Drug Administration (FDA) (clodronate, pamidronate, or zoledronic acid) showed superiority over the others in a recently conducted Cochrane network meta‐analysis. ( 70 ) However, in a randomized controlled study, zoledronic acid was shown to be superior to clodronate for decreasing SREs in symptomatic newly diagnosed patients with MM. ( 56 ) In addition, patients randomized to the zoledronic acid arm showed improved overall survival and progression‐free survival, in addition to that attributed to the preventative effects of SREs. This increase in survival is in keeping with findings from preclinical studies and can be attributable to direct or indirect anti‐MM effects. ( 71 )

Adverse effects of BPs include acute‐phase reactions, which present within the first few hours or days after initiation of BP and often resolve with symptomatic management. ( 72 , 73 ) Other serious adverse events may occur, including renal impairment, osteonecrosis of jaw (ONJ), and atypical femoral fractures. Renal impairment can occur with BPs because the kidneys eliminate BP exclusively. ( 64 , 65 ) Renal damage is multifactorial, ( 74 ) and higher risk of renal damage is seen in high doses of BP and with faster infusion rates. ( 75 ) The true incidence of renal damage following BP therapy is unknown. A study evaluating the use of BP in patients with breast cancer and MM found renal damage in 10.7% of patients who received zoledronic acid and 9.3% of patients who received pamidronate. ( 75 ) Renal damage from BPs is a notable adverse event because renal damage can progress to renal failure. ( 72 ) Another serious adverse event following BP therapy is ONJ, which occurs in a minority of patients. The risk of ONJ is dependent on the dose and duration of exposure to BP. ( 76 ) Other risk factors for the development of ONJ following BP therapy include dental infections, advanced age, smoking, diabetes mellitus, and therapy with cyclophosphamides. ( 77 , 78 , 79 ) In the event of BP‐induced ONJ, the BP is discontinued, and most patients can be managed with conservative measures such as optimal dental hygiene and antibiotics. ( 80 ) Some patients may require surgical excision of necrosed bone. Atypical femoral fractures following BP therapy have been recognized as a serious consequence of prolonged exposure to BPs. ( 81 , 82 , 83 ) Patients may or may not present with pain in the thigh or groin region, and potential atypical fractures should be investigated in patients on BPs who present with skeletal pain. ( 84 ) The pathogenesis of atypical fractures following BP therapy has been postulated to be related to long‐term suppression of bone remodeling; however, the exact mechanisms remain unknown. ( 72 , 85 )

Denosumab

Excessive production of a key component, RANKL, in the pathogenesis of MBD has been associated with increased bone resorption. ( 84 ) Denosumab is a fully human monoclonal antibody against RANKL that impedes the interaction of RANKL with RANK. Initial phase I/II clinical trials of denosumab demonstrated decreased bone resorption markers, resulting in a decrease in bone resorption. ( 86 , 87 )

To further determine the role of denosumab in the management of MBD in patients with MM, a phase III randomized, placebo‐controlled study of 1718 patients with newly diagnosed MM with at least one documented lytic bone lesion was conducted. ( 47 ) Patients were randomized in a 1:1 allocation ratio to receive 120 mg denosumab subcutaneously with intravenous placebo or to receive 4 mg intravenous zoledronic acid with subcutaneous placebo, every 4 weeks. Patients in the denosumab group had a similar time to first SRE (hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.85–1.14) as patients in the zoledronic acid group. Further post hoc analysis using a 15‐month landmark timepoint revealed that denosumab was superior to zoledronic acid with respect to the time to first SRE development (HR 0.66; 95% CI, 0.44–0.98). No difference in overall survival was observed between the groups. Further subgroup analysis to evaluate the effect of denosumab on progression‐free survival showed that denosumab had a statistically significant greater progression‐free survival rate when compared to zoledronic acid, suggesting an additive effect of denosumab with antimyeloma therapy. ( 88 ) Patients receiving denosumab had fewer adverse events related to renal toxicity (10% vs. 17%), likely because the clearance of denosumab, in contrast to BPs, occurs via the reticuloendothelial system and is independent of renal function. ( 90 , 91 ) Moreover, acute‐phase reactions, a classic adverse event that occur frequently in patients who receive BPs, occurred in 5% of patients receiving denosumab, compared to 9% of patients receiving zoledronic acid. ( 91 ) In contrast, the incidence of hypocalcemia was higher with denosumab (17%) compared to zoledronic acid (12%). The incidence rate of ONJ in patients receiving denosumab was similar to that of patients receiving zoledronic acid (4% vs. 3%, p = 0.15). This study confirmed that denosumab as an option as a bone‐modifying agent in MM and may be particularly useful in MM patients with renal insufficiency that precludes the use of zoledronic acid.

Denosumab should not be abruptly discontinued due to the risk of rebound osteoporosis, ( 92 ) and multiple spontaneous vertebral fractures have been observed in studies with longer follow‐up after stopping denosumumab. ( 93 ) MM patients who start denosumuab should be counseled that that they must continue denosumab at minimum every 6 months or bridge to BP therapy if they choose to discontinue every 4‐week denosumab dosing at some point to prevent rapid bone turnover. ( 94 ) If adherence to denosumab therapy is anticipated to be a challenge, then BP therapy may be preferred in such patients. Monitoring bone resorption biomarkers such as C‐telopeptide (CTX) or N‐telopeptide (NTX) to determine the optimal timing of BP bridging after denosumab discontinuation has also been explored although has not been clearly defined for routine practice.

Anabolic therapies

Anti‐sclerostin antibodies

MBD is a consequence of both an increase in bone resorption and a decrease in bone formation. ( 95 ) Although BPs can reduce the rate of bone resorption, they do not affect bone formation, and thus MBD is not completely preventable with the use of BPs alone. Encoded by the SOST gene, sclerostin is produced by osteocytes, binds to Wnt co‐receptors, and antagonizes the pathway. ( 34 ) This is an important pathway in the pathogenesis of osteoporosis; however, its role in preventing or treating MBD has not yet been well established. In an in vitro study, MM cells co‐cultured with osteocytes led to increased expression of SOST/sclerostin in osteocytes, decreased Wnt signaling/β‐catenin, and decreased osteoblast differentiation. ( 23 )

A study in mice with MM showed similar findings with raised levels of sclerostin and a 50% decrease in OPG, which correlated with a decrease in osteoblast markers. ( 23 ) Other studies showed that anti‐sclerostin treatment in mice with MM increased trabecular bone volume and thickness. ( 97 , 98 ) In a study of patients with MM, elevated sclerostin levels were found in those with abnormal bone remodeling. ( 98 )

Recent trials have tested humanized anti‐sclerostin monoclonal antibodies romosozumab and blosozumab in patients with osteoporosis. A phase I randomized and controlled trial of subcutaneous or intravenous romosozumab versus placebo in healthy men and postmenopausal women revealed that patients who received romosozumab showed increased serum levels of bone formation markers and decreased serum levels of a bone resorption marker in comparison to patients who received placebo. ( 99 ) In a phase II, multicenter, parallel‐group study, postmenopausal women with low bone mass who received romosozumab had increased bone density and bone formation, with decreased bone resorption, compared with women who did not receive romosozumab. ( 100 ) An international, randomized, double‐blind, parallel‐group phase III trial (Fracture Study in Postmenopausal Women with Osteoporosis [FRAME]) of romosozumab at a dose of 210 mg once monthly showed a lower risk of vertebral fracture at 12 months in the patients receiving romosozumab compared to placebo. ( 101 )

Romosozumab is generally well tolerated. In the large phase III FRAME trial, injection site reactions were seen in 5.2% of patients in the romosozumab group, compared to 2.9% in the placebo group. ( 101 ) The frequencies of mortality and cardiac disorders were similar between the groups. ONJ was detected in two patients with recognized risk factors in the romosozumab group. An atypical femoral fracture occurred in one patient 3.5 months after the first dose of romosozumab. Romosozumab was approved in 2019 in Japan and the United States for the treatment of osteoporosis in patients at high risk of fracture. The efficacy of antisclerostin antibodies has not been evaluated in patients with MM.

McDonald et al. ( 97 ) evaluated the effect of antisclerostin antibody alone or in combination with BPs in myeloma murine models. Results showed that antisclerostin antibody therapy prevented suppression of osteoblastic bone formation which is induced by myeloma, prevented bone loss, lowered the number of osteolytic lesions, and most importantly, increased bone strength and fracture resistance. Combination treatment with an antisclerostin antibody and zoledronic acid improved bone mass, strength, and fracture resistance when compared to treatment with zoledronic acid monotherapy. Thus, antisclerostin antibodies alone, or in combination with other therapies may also be a promising therapeutic approach for future investigation in MM.

Parathyroid hormone

In the osteoporotic setting, parathyroid hormone (PTH) has been shown to have anabolic effects; however, the exact mechanisms for the anabolic effect remain unclear. ( 102 ) It has been postulated that PTH may increase osteoblastogenesis as well as inhibit sclerostin, a potent promoter of osteoclastogenesis. A recombinant form of PTH, teriparatide, and a recombinant analog of PTH‐related peptide, abaloparatide, are FDA‐approved for women with osteoporosis. ( 104 , 105 ) Several preclinical studies have evaluated the effects of PTH administration in MM. For example in mouse models, PTH treatment has been shown to increase bone mineral density (BMD) via upregulation of osteoblasts, and gene expression profiling of whole myeloma bones demonstrated increased expression of osteoblastic markers and reduced expression of osteoclastic markers with PTH exposure. ( 105 ) Importantly, myeloma cells did not express PTH receptors, and PTH did not impact myeloma cell growth in vitro. ( 105 ) Several case reports have shown teriparatide to improve BP‐associated ONJ by showing significant healing of necrotic bone. ( 106 )

Concerns about the safety of PTH use the MM patients remain, particularly regarding the mitogenic potential of anabolic agents such as PTH analogues in promoting MM growth. For example, high levels of PTH may enhance the growth of MM cells via the secretion of IL‐6. ( 107 ) In prostate cancer, a higher serum level of PTH has been associated with an increase in skeletal metastasis. ( 108 ) As such, in the label, teriparatide is contraindicated in patients with a history of osteosarcoma, or with increased risk of osteosarcoma with prior radiation to the bone, or metastatic bone disease. ( 109 ) Its use could also potentially exacerbate hypercalcemia that can occur in MM patients. Recently, a small pilot study of the use of teriparatide in MM was reported in which 12 patients were treated with subcutaneous teriparatide 20 μg daily without concurrent BP use for 12 months. ( 58 ) Overall, teriparitide was well tolerated, and no new SREs or hypercalcemia was observed while patients were on study. Importantly, teriparatide did result in an increase in BMD when measured in the lumbar spine by 43.8% from baseline ( p < 0.001). Thus, the encouraging results from this study could suggest a role of anabolic agents in treatment of MBD, and the utility of PTH in the treatment of MBD warrants further investigation.

Anti‐DKK‐1

DKK‐1 is a potent regulator of the Wnt signaling pathway and is found to be elevated in MM. It inhibits the Frizzled co‐receptor LRP6 and is produced by BMSCs as well as malignant plasma cells. In the presence of sclerostin, DKK‐1 decreases β‐catenin, which reduces differentiation of osteoblasts. ( 37 , 111 ) A humanized immunoglobulin G (IgG) anti–DKK‐1 monoclonal antibody, BHQ880, has been evaluated in vitro and in vivo. ( 111 ) BHQ880 was successful at reversing the inhibiting effect of DKK‐1 on osteoblast differentiation and promoted bone formation in a murine model of human MM. BHQ880 also inhibits MM cell growth and its negative effect on osteoblastogenesis, and reduced IL‐6 secretion. No direct effects were detected on osteoclastogenesis. Clinically, the use of BHQ880 has been evaluated in combination with zoledronic acid in a phase Ib study with 28 patients, and there was a trend toward increased BMD with treatment over time. ( 59 ) However, because concurrent zoledronic acid was administered in this study, the relative impact of BHQ880 on bone remodeling was uncertain in this study. A phase II study of BHQ880 in high‐risk smoldering MM ( NCT01302886 ) ( 61 ) and a randomized placebo‐controlled phase II study of BHQ880 in untreated MM patients who are not candidates for BP therapy ( NCT01337752 ) ( 62 ) are ongoing which will further define the role of anti‐DKK‐1 treatment in the setting of MBD.

Other therapies with undetermined role in MBD

TGF‐β has been implicated to play a role in MBD. ( 45 ) The use of a TGF‐β inhibitor, neutralizing antibody 1D11, in mice showed increased osteoblast differentiation and improved bone disease, yet no improvement in overall tumor burden was noted. ( 112 ) Further evaluation is needed because TGF‐β can act as both a tumor suppressor and an oncogene, and the long‐term side effects of using TGF‐β–neutralizing antibodies have not been evaluated. Another agent under investigation is sotatercept, a soluble recombinant activin receptor type 2A ligand fused to the human immunoglobulin G (IgG) Fc domain, which disrupts downstream cascades by binding to activin A/B plus members of the TGF‐β family. In a phase II trial in newly diagnosed and/or relapsed MM patients, the addition of sotatercept to melphalan, prednisolone, and thalidomide revealed increased levels of bone‐specific alkaline phosphatase, a biomarker for bone formation. ( 57 ) Other antitumor therapies with effects on bone metabolism have also been evaluated but are beyond the scope of this review.

Society Guidelines

Several societies have developed guidelines for the screening, prevention, monitoring, and treatment of MBD in patients with MM. Here we highlight some of the most clinically relevant recommendations.

Screening

The National Comprehensive Cancer Network (NCCN) recommends imaging of any patient with suspected MM. ( 113 ) For initial diagnostic workup, they recommend the use of whole‐body low‐dose computed tomography (CT) or FDG‐PET/CT. When advanced imaging is not available, a skeletal survey is acceptable; however, it is significantly less sensitive. Following treatment of MM, the NCCN panel recommends use of advanced imaging, including whole‐body fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT, low‐dose CT scan, or whole‐body magnetic resonance imaging (MRI) without contrast, as clinically indicated for follow‐up. The NCCN also recommend using the same imaging modality as used for the initial assessment.

Prevention and treatment of MBD

Several guidelines from international organizations, including the American Society of Clinical Oncology (ASCO), ( 114 ) British Committee for Standards in Haematology, ( 115 ) European Myeloma Network, ( 116 ) European Society for Medical Oncology, ( 1 ) International Myeloma Working Group (IMWG), ( 94 ) and NCCN ( 117 ) recommend initiating BP therapy in all MM patients who require systemic chemotherapy regardless of presence of underlying bone disease. Here we focus on the ASCO and IMWG recommendations. ( 95 , 115 ) They recommend initiating BP therapy in active myeloma requiring systemic chemotherapy with or without lytic bone lesions or compression fractures seen on imaging. The use of BPs is not recommended in patients with solitary plasmacytoma, smoldering (asymptomatic) MM, and in patients with monoclonal gammopathy of undetermined significance unless they have osteopenia or osteoporosis.

The ASCO guidelines recommend the use of pamidronate (90 mg administered over a minimum of 2 h) or zoledronic acid (4 mg administered over a minimum of 15 min) every 3 to 4 weeks. Alternatively, they recommend using denosumab given its non‐inferior efficacy when compared to zoledronic acid in a large phase III study, ( 47 ) in the section of the Treatment of BMD, Table 1. The IMWG preferred options include zoledronic acid (with or without MBD present on imaging) and denosumab (only when MBD present on imaging) and also should be considered for patients with renal impairment. A second option would be pamidronate when zoledronic acid or denosumab are not available or contraindicated.

In patients with mild to moderate renal impairment (defined as an estimated creatinine clearance between 30 and 60 ml/min), a reduced dosage of zoledronic acid with no changes in infusion time or interval is recommended. Zoledronic acid is not recommended in patients with severe renal impairment. In patients with existing severe renal impairment (serum creatinine level greater than 3.0 mg/dl (265 mmol/L) or an estimated creatinine clearance of <30 ml/min), pamidronate (90 mg administered over 4 to 6 h), or denosumab are recommended.

The ASCO guidelines recommend treatment with bone‐modifying agents for a period of up to 2 years. In patients in whom BPs are withdrawn, the BPs should be resumed upon new onset of SREs. Less frequent dosing (every 3 months rather than every 3 to 4 weeks) has been evaluated ( 46 , 118 ) and should be considered in patients with stable or responsive disease. The IMWG recommends zoledronic acid monthly during initial therapy and in patients with less than a very good partial response (VGPR) as per IMWG response criteria. However, if patients achieve at least a VGPR after receiving monthly administration for ≥12 months, then a decreased frequency of every 3–6 months, or yearly based on osteoporosis dosing, or stopping zoledronic acid can be considered. If discontinued, zoledronic acid should be reinitiated at the time of biochemical relapse. If denosumab is used, it should be administered monthly and should not be discontinued abruptly given its reversible mechanism of action and risk of rebound osteoporosis. Data on the optimal approach to discontinue denosumab is lacking, and current recommendations are to either administer a single dose of zoledronic acid at least 6 months after the last dose of denosumab or continue denosumab every 6 months after discontinuation of the monthly injection.

Regular monitoring of patients receiving BPs is needed. Serum creatinine should be evaluated prior to each dose of BP therapy, serum calcium should be monitored regularly, and vitamin D should be monitored intermittently. Every 3 to 6 months, patients should be evaluated for the presence of albuminuria in a spot urine sample, and if albuminuria is detected, the BP should be discontinued, and a 24‐h urine collection should be obtained. The use of biochemical bone metabolism markers to monitor the effects of bone‐modifying agents has not been well studied and there is no formal recommendation at this time. Finally, prior to initiation of BPs, all patients should have a comprehensive dental exam and be advised to maintain excellent oral hygiene and to avoid dental extractions while on BP therapy.

Conclusion

The overall survival of MM patients has improved significantly over the last two decades with the incorporation of new drugs to the MM therapeutic armamentarium. However, MBD is a common complication of MM that significantly contributes to patient morbidity and mortality. The mainstay of treatment of MBD has been with antiresorptive agents including BPs and denosumab, which have been proven to be efficacious. However, these therapies are not without adverse events, which need to be recognized and treated appropriately. Newer agents for the management of MBD are under development and could potentially change the treatment landscape in patients with MM and MBD. A higher fracture rate above the general population is observed in MM patients, even those who achieve and maintain deep remissions after systemic chemotherapy. Moreover, with longer durations of response and overall survival as well as greater exposure to corticosteroids as part of myeloma therapy, osteoporotic insufficiency fractures relative to pathologic fractures from new lytic lesions will likely becoming increasingly relevant for patients in long‐term survivorship. Future directions in managing MBD include (i) targeting specific MM patient populations for aggressive MBD therapy who are at high‐risk for progressive MBD such as genetically defined high‐risk MM patients; (ii) potentially validating the use of bone‐turnover markers in larger studies to optimize the use of MBD therapy in MM patients; and (iii) exploring the use of novel osteoporosis agents such as the anti‐sclerostin monoclonal antibody romosozumab in MBD.

Disclosures

Huifang Lu declares research funding from Genentech. Xerxes Pundole: None; now working at Amgen Inc.; all related research contributions were completed while employed at The University of Texas MD Anderson Cancer Center. Hans C. Lee declares consulting fees from Amgen, Celgene, Genentech, GlaxoKlineSmith, Janssen, Sanofi, and Takeda and research funding from Amgen, Celgene, Daiichi Sankyo, GlaxoKlineSmith, Janssen, Regeneron, and Takeda.

Author Contributions

Huifang Lu: Synthesis of information, literature search, manuscript writing and editing. The author takes full responsibility for the integrity of the data analysis. Xerxes Pundole: Synthesis of information, literature search, manuscript writing and editing. Hans C. Lee: Synthesis of information, literature search, manuscript writing and editing.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/jbm4.10518 .

Acknowledgments

We thank Sunita Patterson of Scientific Publications, Research Medical Library, MD Anderson Cancer Center for editing. We thank Jordan Pietz, MA, CMI of MD Anderson Cancer Center for the professional illustration.

References

1 Moreau P , San Miguel J , Sonneveld P , et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow‐up . Ann Oncol . 2017 ; 28 ( Suppl_4 ): iv52 ‐ iv61 . 28453614 10.1093/annonc/mdx096

2 Hameed A , Brady JJ , Dowling P , Clynes M , O'Gorman P . Bone disease in multiple myeloma: pathophysiology and management . Cancer Growth Metastasis . 2014 ; 7 : S16817 . 10.4137/CGM.S16817 PMC4133035 25187738

3 Siegel RL , Miller KD , Fuchs HE , Jemal A . Cancer statistics, 2021 . CA Cancer J Clin . 2021 ; 71 ( 1 ): 7 ‐ 33 . 33433946 10.3322/caac.21654

4 National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Myeloma. 2021 . https://seer.cancer.gov/statfacts/html/mulmy.html . Accessed May 29, 2021.

5 Moreau P , Attal M , Caillot D , et al. 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 ( 25 ): 2911 ‐ 2918 . 28686535 10.1200/JCO.2017.72.2975 PMC5578392

6 Kyle RA , Gertz MA , Witzig TE , et al. Review of 1027 patients with newly diagnosed multiple myeloma . Mayo Clin Proc . 2003 ; 78 ( 1 ): 21 ‐ 33 . 12528874 10.4065/78.1.21

7 Terpos E , Berenson J , Cook RJ , Lipton A , Coleman RE . Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease . Leukemia . 2010 ; 24 ( 5 ): 1043 ‐ 1049 . 20376081 10.1038/leu.2010.62

8 Pundole XN , Barbo AG , Lin H , Champlin RE , Lu H . Increased incidence of fractures in recipients of hematopoietic stem‐cell transplantation . J Clin Oncol . 2015 ; 33 ( 12 ): 1364 ‐ 1370 . 25779562 10.1200/JCO.2014.57.8195 PMC5320933

9 Silbermann R , Roodman GD . Myeloma bone disease: pathophysiology and management . J Bone Oncol . 2013 ; 2 ( 2 ): 59 ‐ 69 . 26909272 10.1016/j.jbo.2013.04.001 PMC4723362

10 Sonmez M , Akagun T , Topbas M , et al. Effect of pathologic fractures on survival in multiple myeloma patients: a case control study . J Exp Clin Cancer Res . 2008 ; 27 : 11 . 18577267 10.1186/1756-9966-27-11 PMC2438338

11 Tosi P . Diagnosis and treatment of bone disease in multiple myeloma: spotlight on spinal involvement . Scientifica . 2013 ; 2013 : 104546 . 24381787 10.1155/2013/104546 PMC3870870

12 Zagouri F , Kastritis E , Zomas A , et al. Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies . Eur J Haematol . 2017 ; 99 ( 5 ): 409 ‐ 414 . 28675766 10.1111/ejh.12923

13 Mori G , D'Amelio P , Faccio R , Brunetti G . The interplay between the bone and the immune system . Clin Dev Immunol . 2013 ; 2013 : 720504 . 23935650 10.1155/2013/720504 PMC3725924

14 Xiao W , Wang Y , Pacios S , Li S , Graves DT . Cellular and molecular aspects of bone remodeling . Front Oral Biol . 2016 ; 18 : 9 ‐ 16 . 26599113 10.1159/000351895 PMC10754210

15 Teitelbaum SL , Ross FP . Genetic regulation of osteoclast development and function . Nat Rev Genet . 2003 ; 4 ( 8 ): 638 ‐ 649 . 12897775 10.1038/nrg1122

16 Boyce BF , Xing L . Functions of RANKL/RANK/OPG in bone modeling and remodeling . Arch Biochem Biophys . 2008 ; 473 ( 2 ): 139 ‐ 146 . 18395508 10.1016/j.abb.2008.03.018 PMC2413418

17 Baron R , Kneissel M . WNT signaling in bone homeostasis and disease: from human mutations to treatments . Nat Med . 2013 ; 19 ( 2 ): 179 ‐ 192 . 23389618 10.1038/nm.3074

18 Huang W , Yang S , Shao J , Li YP . Signaling and transcriptional regulation in osteoblast commitment and differentiation . Front Biosci . 2007 ; 12 : 3068 ‐ 3092 . 17485283 10.2741/2296 PMC3571113

19 Croucher PI , Shipman CM , Lippitt J , et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma . Blood . 2001 ; 98 ( 13 ): 3534 ‐ 3540 . 11739154 10.1182/blood.v98.13.3534

20 Boyle WJ , Simonet WS , Lacey DL . Osteoclast differentiation and activation . Nature . 2003 ; 423 ( 6937 ): 337 ‐ 342 . 12748652 10.1038/nature01658

21 Mulcahy LE , Taylor D , Lee TC , Duffy GP . RANKL and OPG activity is regulated by injury size in networks of osteocyte‐like cells . Bone . 2011 ; 48 ( 2 ): 182 ‐ 188 . 20854946 10.1016/j.bone.2010.09.014

22 Colombo M , Mirandola L , Platonova N , et al. Notch‐directed microenvironment reprogramming in myeloma: a single path to multiple outcomes . Leukemia . 2013 ; 27 ( 5 ): 1009 . 23307030 10.1038/leu.2013.6

23 Delgado‐Calle J , Anderson J , Cregor MD , et al. Bidirectional Notch signaling and osteocyte‐derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma . Cancer Res . 2016 ; 76 ( 5 ): 1089 ‐ 1100 . 26833121 10.1158/0008-5472.CAN-15-1703 PMC4775415

24 Terpos E , Ntanasis‐Stathopoulos I , Dimopoulos MA . Myeloma bone disease: from biology findings to treatment approaches . Blood . 2019 ; 133 ( 14 ): 1534 ‐ 1539 . 30760454 10.1182/blood-2018-11-852459

25 Eijken M , Swagemakers S , Koedam M , et al. The activin A‐follistatin system: potent regulator of human extracellular matrix mineralization . FASEB J . 2007 ; 21 ( 11 ): 2949 ‐ 2960 . 17449718 10.1096/fj.07-8080com

26 Luisi S , Florio P , Reis FM , Petraglia F . Expression and secretion of activin A: possible physiological and clinical implications . Eur J Endocrinol . 2001 ; 145 ( 3 ): 225 ‐ 236 . 11517001 10.1530/eje.0.1450225

27 Fuller K , Bayley KE , Chambers TJ . Activin A is an essential cofactor for osteoclast induction . Biochem Biophys Res Commun . 2000 ; 268 ( 1 ): 2 ‐ 7 . 10652202 10.1006/bbrc.2000.2075

28 Kawabata N , Kamiya N , Suzuki N , Matsumoto M , Takagi M . Changes in extracellular activin A: follistatin ratio during differentiation of a mesenchymal progenitor cell line, ROB‐C26 into osteoblasts and adipocytes . Life Sci . 2007 ; 81 ( 1 ): 8 ‐ 18 . 17512555 10.1016/j.lfs.2007.04.011

29 Terpos E , Kastritis E , Christoulas D , et al. Circulating activin‐A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post‐lenalidomide and dexamethasone therapy . Ann Oncol . 2012 ; 23 ( 10 ): 2681 ‐ 2686 . 22492699 10.1093/annonc/mds068

30 Spaan I , Raymakers RA , van de Stolpe A , Peperzak V . Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential . J Hematol Oncol . 2018 ; 11 ( 1 ): 67 . 29776381 10.1186/s13045-018-0615-3 PMC5960217

31 Delgado‐Calle J , Anderson J , Cregor MD , et al. Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma‐induced bone disease without affecting tumor growth . Leukemia . 2017 ; 31 ( 12 ): 2686 . 28529307 10.1038/leu.2017.152 PMC5699973

32 Qiang Y‐W , Chen Y , Stephens O , et al. Myeloma‐derived Dickkopf‐1 disrupts Wnt‐regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma . Blood . 2008 ; 112 ( 1 ): 196 ‐ 207 . 18305214 10.1182/blood-2008-01-132134 PMC2435688

33 Colucci S , Brunetti G , Oranger A , et al. Myeloma cells suppress osteoblasts through sclerostin secretion . Blood Cancer J . 2011 ; 1 ( 6 ): e27 . 22829171 10.1038/bcj.2011.22 PMC3255263

34 Delgado‐Calle J , Sato AY , Bellido T . Role and mechanism of action of sclerostin in bone . Bone . 2017 ; 96 : 29 ‐ 37 . 27742498 10.1016/j.bone.2016.10.007 PMC5328835

35 Kamiya N , Ye L , Kobayashi T , et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway . Development . 2008 ; 135 ( 22 ): 3801 ‐ 3811 . 18927151 10.1242/dev.025825 PMC2694443

36 Tian E , Zhan F , Walker R , et al. The role of the Wnt‐signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma . N Engl J Med . 2003 ; 349 ( 26 ): 2483 ‐ 2494 . 14695408 10.1056/NEJMoa030847

37 Eda H , Santo L , Wein MN , et al. Regulation of sclerostin expression in multiple myeloma by Dkk‐1: a potential therapeutic strategy for myeloma bone disease . J Bone Miner Res . 2016 ; 31 ( 6 ): 1225 ‐ 1234 . 26763740 10.1002/jbmr.2789 PMC5002355

38 Gunn WG , Conley A , Deininger L , Olson SD , Prockop DJ , Gregory CA . A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin‐6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma . Stem Cells . 2006 ; 24 ( 4 ): 986 ‐ 991 . 16293576 10.1634/stemcells.2005-0220

39 Vallet S , Filzmoser JM , Pecherstorfer M , Podar K . Myeloma bone disease: update on pathogenesis and novel treatment strategies . Pharmaceutics . 2018 ; 10 ( 4 ): 202 . 10.3390/pharmaceutics10040202 PMC6321035 30355994

40 Kyriazoglou A , Ntanasis‐Stathopoulos I , Terpos E , et al. Emerging insights into the role of the Hippo pathway in multiple myeloma and associated bone disease . Clin Lymphoma Myeloma Leuk . 2019 ; 20 : 57 . 31734019 10.1016/j.clml.2019.09.620

41 Bellido T . Osteocyte apoptosis induces bone resorption and impairs the skeletal response to weightlessness . IBMS BoneKey . 2007 ; 4 : 252 .

42 Bellido T . Osteocyte‐driven bone remodeling . Calcif Tissue Int . 2014 ; 94 ( 1 ): 25 ‐ 34 . 24002178 10.1007/s00223-013-9774-y PMC3947228

43 Li M , Chen F , Clifton N , et al. Combined inhibition of Notch signaling and Bcl‐2/Bcl‐xL results in synergistic antimyeloma effect . Mol Cancer Ther . 2010 ; 9 ( 12 ): 3200 ‐ 3209 . 21159606 10.1158/1535-7163.MCT-10-0372 PMC3058809

44 Schwarzer R , Nickel N , Godau J , et al. Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model . Blood Cancer J . 2014 ; 4 : e217 . 24927406 10.1038/bcj.2014.37 PMC4080208

45 Ring ES , Lawson MA , Snowden JA , Jolley I , Chantry AD . New agents in the treatment of myeloma bone disease . Calcif Tissue Int . 2018 ; 102 ( 2 ): 196 ‐ 209 . 29098361 10.1007/s00223-017-0351-7 PMC5805798

46 Himelstein AL , Foster JC , Khatcheressian JL , et al. 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 ( 1 ): 48 ‐ 58 . 28030702 10.1001/jama.2016.19425 PMC5321662

47 Raje N , Terpos E , Willenbacher W , et al. 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 ( 3 ): 370 ‐ 381 . 29429912 10.1016/S1470-2045(18)30072-X

48 Lahtinen R , Laakso M , Palva I , Virkkunen P , Elomaa I . Randomised, placebo‐controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group . Lancet . 1992 ; 340 ( 8827 ): 1049 ‐ 1052 . 1357451 10.1016/0140-6736(92)93075-x

49 Berenson JR , Lichtenstein A , Porter L , et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group . N Engl J Med . 1996 ; 334 ( 8 ): 488 ‐ 493 . 8559201 10.1056/NEJM199602223340802

50 Berenson JR , Lichtenstein A , Porter L , et al. Long‐term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group . J Clin Oncol . 1998 ; 16 ( 2 ): 593 ‐ 602 . 9469347 10.1200/JCO.1998.16.2.593

51 McCloskey EV , MacLennan IC , Drayson MT , Chapman C , Dunn J , Kanis JA . A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults . Br J Haematol . 1998 ; 100 ( 2 ): 317 ‐ 325 . 9488619 10.1046/j.1365-2141.1998.00567.x

52 McCloskey EV , Dunn JA , Kanis JA , MacLennan IC , Drayson MT . Long‐term follow‐up of a prospective, double‐blind, placebo‐controlled randomized trial of clodronate in multiple myeloma . Br J Haematol . 2001 ; 113 ( 4 ): 1035 ‐ 1043 . 11442499 10.1046/j.1365-2141.2001.02851.x

53 Gimsing P , Carlson K , Turesson I , et al. 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 ( 10 ): 973 ‐ 982 . 20863761 10.1016/S1470-2045(10)70198-4

54 Morgan GJ , Davies FE , Gregory WM , et al. First‐line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial . Lancet . 2010 ; 376 ( 9757 ): 1989 ‐ 1999 . 21131037 10.1016/S0140-6736(10)62051-X PMC3639680

55 Morgan GJ , Child JA , Gregory WM , et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial . Lancet Oncol . 2011 ; 12 ( 8 ): 743 ‐ 752 . 21771568 10.1016/S1470-2045(11)70157-7 PMC3148431

56 Morgan GJ , Davies FE , Gregory WM , et al. Long‐term follow‐up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment . Clin Cancer Res . 2013 ; 19 ( 21 ): 6030 ‐ 6038 . 23995858 10.1158/1078-0432.CCR-12-3211

57 Abdulkadyrov KM , Salogub GN , Khuazheva NK , et al. Sotatercept in patients with osteolytic lesions of multiple myeloma . Br J Haematol . 2014 ; 165 ( 6 ): 814 ‐ 823 . 24650009 10.1111/bjh.12835 PMC4312883

58 Diamond TH , Golombick T , Manoharan A , Ramakrishna R , Bryant C . Teriparatide (recombinant human parathyroid hormone 1‐34) therapy in myeloma patients with severe osteoporosis and fractures despite effective anti‐myeloma therapy and bisphosphonates: a pilot study . Am J Hematol . 2020 ; 95 ( 10 ): E272 ‐ E276 . 10.1002/ajh.25919 32602126

59 Iyer SP , Beck JT , Stewart AK , et al. A phase IB multicentre dose‐determination study of BHQ880 in combination with anti‐myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal‐related events . Br J Haematol . 2014 ; 167 ( 3 ): 366 ‐ 375 . 25139740 10.1111/bjh.13056

60 Phase 1, multicenter, open‐label, dose‐escalation study of sotatercept (ACE‐011) in combination with lenalidomide or pomalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT01562405 . Updated August 14, 2019. Accessed May 29, 2021. https://clinicaltrials.gov/ct2/show/NCT01562405

61 A single‐arm, open‐label, phase 2 clinical trial evaluating disease response following treatment with intravenous BHQ880, a fully human, anti‐Dickkopf1 (DKK1) neutralizing antibody in previously untreated patients with high‐risk, smoldering multiple myeloma. ClinicalTrials.gov identifier: NCT01302886 . Updated December 17, 2021. Accessed May 29, 2021. https://clinicaltrials.gov/ct2/show/NCT01302886

62 A double‐blind, placebo‐controlled, randomized phase 2 study of BHQ880, an anti‐Dickkopf1 (DKK1) monoclonal antibody (mAb), in patients with untreated multiple myeloma and renal insufficiency. ClinicalTrials.gov identifier: NCT01337752 . Updated December 17, 2021. Accessed May 29, 2021. https://clinicaltrials.gov/ct2/show/NCT01337752

63 A two part phase 1 multicenter open‐label study of DKN‐01 given intravenously. Part A: Dose‐escalation in patients with multiple myeloma or advanced solid tumors. Part B: Expansion cohort in patients with relapsed/refractory non‐small cell lung cancer (NSCLC). ClinicalTrials.gov identifier: NCT01457417 . Updated September 28, 2016. Accessed May 29, 2021. https://clinicaltrials.gov/ct2/show/NCT01457417

64 Drake MT , Clarke BL , Khosla S . Bisphosphonates: mechanism of action and role in clinical practice . Mayo Clinic Proc . 2008 ; 83 ( 9 ): 1032 ‐ 1045 . 10.4065/83.9.1032 PMC2667901 18775204

65 Russell RGG . Bisphosphonates: from bench to bedside . Ann N Y Acad Sci . 2006 ; 1068 ( 1 ): 367 ‐ 401 . 16831938 10.1196/annals.1346.041

66 Dunford JE , Thompson K , Coxon FP , et al. Structure‐activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen‐containing bisphosphonates . J Pharmacol Exp Ther . 2001 ; 296 ( 2 ): 235 ‐ 242 . 11160603

67 Im GI , Qureshi SA , Kenney J , Rubash HE , Shanbhag AS . Osteoblast proliferation and maturation by bisphosphonates . Biomaterials . 2004 ; 25 ( 18 ): 4105 ‐ 4115 . 15046901 10.1016/j.biomaterials.2003.11.024

68 Mackie EJ . Osteoblasts: novel roles in orchestration of skeletal architecture . Int J Biochem Cell Biol . 2003 ; 35 ( 9 ): 1301 ‐ 1305 . 12798343 10.1016/s1357-2725(03)00107-9

69 Maruotti N , Corrado A , Neve A , Cantatore FP . Bisphosphonates: effects on osteoblast . Eur J Clin Pharmacol . 2012 ; 68 ( 7 ): 1013 ‐ 1018 . 22318756 10.1007/s00228-012-1216-7

70 Mhaskar R , Kumar A , Miladinovic B , Djulbegovic B . Bisphosphonates in multiple myeloma: an updated network meta‐analysis . Cochrane Database Syst Rev . 2017 ; 12 : CD003188 . 29253322 10.1002/14651858.CD003188.pub4 PMC6486151

71 Croucher PI , De Raeve H , Perry MJ , et al. Zoledronic acid treatment of 5T2MM‐bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival . J Bone Miner Res . 2003 ; 18 ( 3 ): 482 ‐ 492 . 12619933 10.1359/jbmr.2003.18.3.482

72 Lee OL , Horvath N , Lee C , et al. Bisphosphonate guidelines for treatment and prevention of myeloma bone disease . Intern Med J . 2017 ; 47 ( 8 ): 938 ‐ 951 . 28782211 10.1111/imj.13502

73 Tanvetyanon T , Stiff PJ . Management of the adverse effects associated with intravenous bisphosphonates . Ann Oncol . 2006 ; 17 ( 6 ): 897 ‐ 907 . 16547070 10.1093/annonc/mdj105

74 Chang JT , Green L , Beitz J . Renal failure with the use of zoledronic acid . N Engl J Med . 2003 ; 349 ( 17 ): 1676 ‐ 1679 . 14573746 10.1056/NEJM200310233491721

75 Rosen LS , Gordon D , Kaminski M , et al. 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: a randomized, double‐blind, multicenter, comparative trial . Cancer . 2003 ; 98 ( 8 ): 1735 ‐ 1744 . 14534891 10.1002/cncr.11701

76 Hoff AO , Toth BB , Altundag K , et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates . J Bone Miner Res . 2008 ; 23 ( 6 ): 826 ‐ 836 . 18558816 10.1359/JBMR.080205 PMC2677083

77 Badros A , Weikel D , Salama A , et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors . J Clin Oncol . 2006 ; 24 ( 6 ): 945 ‐ 952 . 16484704 10.1200/JCO.2005.04.2465

78 Bamias A , Kastritis E , Bamia C , et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors . J Clin Oncol . 2005 ; 23 ( 34 ): 8580 ‐ 8587 . 16314620 10.1200/JCO.2005.02.8670

79 Jadu F , Lee L , Pharoah M , Reece D , Wang L . A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate‐related necrosis of the jaws in multiple myeloma patients . Ann Oncol . 2007 ; 18 ( 12 ): 2015 ‐ 2019 . 17804475 10.1093/annonc/mdm370

80 Khan AA , Morrison A , Hanley DA , et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus . J Bone Miner Res . 2015 ; 30 ( 1 ): 3 ‐ 23 . 25414052 10.1002/jbmr.2405

81 Gedmintas L , Solomon DH , Kim SC . Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta‐analysis . J Bone Miner Res . 2013 ; 28 ( 8 ): 1729 ‐ 1737 . 23408697 10.1002/jbmr.1893 PMC3713078

82 Nieves JW , Bilezikian JP , Lane JM , et al. Fragility fractures of the hip and femur: incidence and patient characteristics . Osteoporos Int . 2010 ; 21 ( 3 ): 399 ‐ 408 . 19484169 10.1007/s00198-009-0962-6

83 Shane E , Burr D , Ebeling PR , et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research . J Bone Miner Res . 2010 ; 25 ( 11 ): 2267 ‐ 2294 . 20842676 10.1002/jbmr.253

84 Terpos E , Szydlo R , Apperley JF , et al. Soluble receptor activator of nuclear factor kappaB ligand‐osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index . Blood . 2003 ; 102 ( 3 ): 1064 ‐ 1069 . 12689925 10.1182/blood-2003-02-0380

85 Donnelly E , Meredith DS , Nguyen JT , et al. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures . J Bone Miner Res . 2012 ; 27 ( 3 ): 672 ‐ 678 . 22072397 10.1002/jbmr.560 PMC4404705

86 Body JJ , Facon T , Coleman RE , et al. A study of the biological receptor activator of nuclear factor‐kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer . Clin Cancer Res . 2006 ; 12 ( 4 ): 1221 ‐ 1228 . 16489077 10.1158/1078-0432.CCR-05-1933

87 Vij R , Horvath N , Spencer A , et al. An open‐label, phase 2 trial of denosumab in the treatment of relapsed or plateau‐phase multiple myeloma . Am J Hematol . 2009 ; 84 ( 10 ): 650 ‐ 656 . 19714603 10.1002/ajh.21509

88 Terpos E , Willenbacher W , Shimizu K , et al. Progression‐free survival subset analysis‐denosumab vs zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double‐blind, double‐dummy, randomized controlled phase 3 study . Blood . 2018 ; 132 ( Suppl 1 ): 1969 . 10.1016/S1470-2045(18)30072-X 29429912

89 Block GA , Bone HG , Fang L , Lee E , Padhi D . A single‐dose study of denosumab in patients with various degrees of renal impairment . J Bone Miner Res . 2012 ; 27 ( 7 ): 1471 ‐ 1479 . 22461041 10.1002/jbmr.1613 PMC3505375

90 Baron R , Ferrari S , Russell RGG . Denosumab and bisphosphonates: different mechanisms of action and effects . Bone . 2011 ; 48 ( 4 ): 677 ‐ 692 . 21145999 10.1016/j.bone.2010.11.020

91 Black DM , Delmas PD , Eastell R , et al. Once‐yearly zoledronic acid for treatment of postmenopausal osteoporosis . N Engl J Med . 2007 ; 356 ( 18 ): 1809 ‐ 1822 . 17476007 10.1056/NEJMoa067312

92 Bone HG , Bolognese MA , Yuen CK , et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass . J Clin Endocrinol Metab . 2011 ; 96 ( 4 ): 972 ‐ 980 . 21289258 10.1210/jc.2010-1502

93 Cummings SR , Ferrari S , Eastell R , et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo‐controlled FREEDOM trial and its extension . J Bone Miner Res . 2018 ; 33 ( 2 ): 190 ‐ 198 . 29105841 10.1002/jbmr.3337

94 Terpos E , Zamagni E , Lentzsch S , et al. Treatment of multiple myeloma‐related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group . Lancet Oncol . 2021 ; 22 ( 3 ): e119 ‐ e130 . 33545067 10.1016/S1470-2045(20)30559-3

95 Roodman GD . Pathogenesis of myeloma bone disease . J Cell Biochem . 2010 ; 109 ( 2 ): 283 ‐ 291 . 20014067 10.1002/jcb.22403

96 Reagan MR . Anti‐sclerostin treatment prevents multiple myeloma induced bone loss and reduces tumor burden . Blood . 2015 ; 126 ( 23 ): 119 .

97 McDonald MM , Reagan MR , Youlten SE , et al. Inhibiting the osteocyte‐specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma . Blood . 2017 ; 129 ( 26 ): 3452 ‐ 3464 . 28515094 10.1182/blood-2017-03-773341 PMC5492093

98 Terpos E , Christoulas D , Katodritou E , et al. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post‐bortezomib monotherapy . Int J Cancer . 2012 ; 131 ( 6 ): 1466 ‐ 1471 . 22052418 10.1002/ijc.27342

99 Padhi D , Jang G , Stouch B , Fang L , Posvar E . Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody . J Bone Miner Res . 2011 ; 26 ( 1 ): 19 ‐ 26 . 20593411 10.1002/jbmr.173

100 McClung MR , Grauer A , Boonen S , et al. Romosozumab in postmenopausal women with low bone mineral density . N Engl J Med . 2014 ; 370 ( 5 ): 412 ‐ 420 . 24382002 10.1056/NEJMoa1305224

101 Cosman F , Crittenden DB , Adachi JD , et al. Romosozumab treatment in postmenopausal women with osteoporosis . N Engl J Med . 2016 ; 375 ( 16 ): 1532 ‐ 1543 . 27641143 10.1056/NEJMoa1607948

102 Lombardi G , Di Somma C , Rubino M , et al. The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics . J Endocrinol Invest . 2011 ; 34 ( 7 Suppl ): 18 ‐ 22 . 21985975

103 Leder BZ , Tsai JN , Uihlein AV , et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial . J Clin Endocrinol Metab . 2014 ; 99 ( 5 ): 1694 ‐ 1700 . 24517156 10.1210/jc.2013-4440 PMC4010689

104 Shirley M . Abaloparatide: first global approval . Drugs . 2017 ; 77 ( 12 ): 1363 ‐ 1368 . 28624872 10.1007/s40265-017-0780-7

105 Pennisi A , Ling W , Li X , et al. Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone . PLoS One . 2010 ; 5 ( 12 ): e15233 . 21188144 10.1371/journal.pone.0015233 PMC3004797

106 Narongroeknawin P , Danila MI , Humphreys LG Jr , Barasch A , Curtis JR . Bisphosphonate‐associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report . Spec Care Dentist . 2010 ; 30 ( 2 ): 77 ‐ 82 . 20415805 10.1111/j.1754-4505.2009.00128.x PMC4097110

107 Pirih FQ , Michalski MN , Cho SW , et al. Parathyroid hormone mediates hematopoietic cell expansion through interleukin‐6 . PLoS One . 2010 ; 5 ( 10 ): e13657 . 21048959 10.1371/journal.pone.0013657 PMC2965090

108 Schwartz GG . Prostate cancer, serum parathyroid hormone, and the progression of skeletal metastases . Cancer Epidemiol Biomarkers Prev . 2008 ; 17 ( 3 ): 478 ‐ 483 . 18349265 10.1158/1055-9965.EPI-07-2747

109 US Food and Drug Administration . FORTEO (teriparatide) label. 2020 . https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf . Accessed May 29, 2021.

110 Wang JH , Zhang Y , Li HY , Liu YY , Sun T . Dickkopf‐1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions . Medicine . 2016 ; 95 ( 24 ): e3767 . 27310953 10.1097/MD.0000000000003767 PMC4998439

111 Fulciniti M , Tassone P , Hideshima T , et al. Anti‐DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma . Blood . 2009 ; 114 ( 2 ): 371 ‐ 379 . 19417213 10.1182/blood-2008-11-191577 PMC2714212

112 Nyman JS , Merkel AR , Uppuganti S , et al. Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma‐induced bone disease . Bone . 2016 ; 91 : 81 ‐ 91 . 27423464 10.1016/j.bone.2016.07.007 PMC4996753

113 Kumar SK , Callander NS , Hillengass J , et al. NCCN guidelines insights: multiple myeloma, version 1.2020 . J Natl Compr Canc Netw . 2019 ; 17 ( 10 ): 1154 ‐ 1165 . 31590151 10.6004/jnccn.2019.0049

114 Anderson K , Ismaila N , Flynn PJ , et al. Role of bone‐modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update . J Clin Oncol . 2018 ; 36 ( 8 ): 812 ‐ 818 . 29341831 10.1200/JCO.2017.76.6402

115 Bird JM , Owen RG , D'Sa S , et al. Guidelines for the diagnosis and management of multiple myeloma 2011 . Br J Haematol . 2011 ; 154 ( 1 ): 32 ‐ 75 . 21569004 10.1111/j.1365-2141.2011.08573.x

116 Terpos E , Kleber M , Engelhardt M , et al. European Myeloma Network guidelines for the management of multiple myeloma‐related complications . Haematologica . 2015 ; 100 ( 10 ): 1254 ‐ 1266 . 26432383 10.3324/haematol.2014.117176 PMC4591757

117 National Comprehensive Cancer Network . Clinical practice guidelines in oncology ‐ multiple myeloma, version 7. 2021 . Updated April 26, 2021. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

118 Raje N , Vescio R , Montgomery CW , et al. 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 ( 6 ): 1378 ‐ 1384 . 26644410 10.1158/1078-0432.CCR-15-1864