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Multiple myeloma: The use of osteoclast inhibitors

Multiple myeloma: The use of osteoclast inhibitors
Literature review current through: Jan 2024.
This topic last updated: Oct 05, 2022.

INTRODUCTION — Osteolytic bone disease is a major feature of multiple myeloma (MM) that can lead to severe disability and morbidity, including pain, decreased performance status, and decreased quality of life, as well as skeletal-related events (SRE), a composite endpoint defined as the need for radiation or surgery to bone, pathologic fracture, spinal cord compression, and/or hypercalcemia of malignancy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Clinical presentation'.)

When used in patients with MM, osteoclast inhibitors decrease the frequency of pathologic vertebral fractures and other SREs and decrease skeletal-related pain.

The use of osteoclast inhibitors in patients with MM will be presented here. The role of these agents in the management of hypercalcemia and bone metastases from other malignancies is presented separately, as are more details regarding the side effects associated with each agent. Bone imaging in MM is also presented separately.

(See "Treatment of hypercalcemia".)

(See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

(See "Medication-related osteonecrosis of the jaw in patients with cancer".)

(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

MECHANISMS OF ACTION — Osteoclast inhibitors (ie, bisphosphonates, denosumab) inhibit bone resorption by suppressing osteoclast activity. Clinically, this translates into fewer lytic bone lesions and fewer skeletal events (eg, pathologic fracture). The mechanism of action differs by class:

Bisphosphonates – Bisphosphonates are synthetic analogues to inorganic pyrophosphates found within the bone matrix that, unlike natural pyrophosphates, are resistant to hydrolysis by phosphatases found in the blood. Bisphosphonates are incorporated into the bone matrix and have a direct apoptotic effect on osteoclasts, affect their differentiation and maturation, and thereby, act as potent inhibitors of bone resorption. (See "Pharmacology of bisphosphonates", section on 'Mechanism of action'.)

There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, with somewhat different effects in inhibiting osteoclasts. The nitrogen-containing bisphosphonates (eg, pamidronate, zoledronic acid, ibandronate) are more potent osteoclast inhibitors than the non-nitrogen-containing bisphosphonates (eg, clodronate, etidronate).

DenosumabDenosumab is a monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL). RANKL is a key component in the pathway for osteoclast formation and activation. Inhibition of RANKL inhibits bone resorption. (See "Mechanisms of bone metastases", section on 'RANK/RANKL signaling pathway and bone remodeling'.)

INDICATIONS — Osteoclast inhibitors are an essential part of the management of skeletal lesions in patients with MM. While they do not repair existing bone damage, they prevent the development of new lesions. Osteoclast inhibitors can be administered in conjunction with anti-MM therapy directed at the plasma cell clone and do not appear to increase the toxicity of anti-MM therapy.

Use in symptomatic myeloma

Whom to treat — Most experts recommend monthly treatment with an osteoclast inhibitor to patients with MM and one or both of the following:

Lytic lesion(s) on imaging (plain x-ray, computed tomography [CT], magnetic resonance imaging [MRI], or combined fluorodeoxyglucose [FDG] positron emission tomography-computed tomography [PET/CT])

Osteopenia or osteoporosis on bone densitometry

In contrast, experts differ in their use of osteoclast inhibitors in patients with MM who have no bone lesions identified on cross-sectional imaging (CT, MRI, PET/CT) and have normal bone density. We do not routinely offer osteoclast inhibitors in this setting given an uncertain benefit and potential toxicities. Other experts offer osteoclast inhibitors to all patients with MM requiring treatment regardless of identifiable bone disease. This latter approach is recommended by the American Society of Clinical Oncology (ASCO) [1], International Myeloma Working Group (IMWG) [2], European Myeloma Network (EMN) [3], National Comprehensive Cancer Network (NCCN) [4], and the Royal Australasian College of Physicians [5]. (See 'Society guideline links' below.)

Efficacy and toxicity — Support for the use of osteoclast inhibitors in patients with bone lesions is based on numerous randomized trials that have demonstrated improved outcomes with intravenous bisphosphonates when compared with placebo [6-17] and trials that suggest a similar benefit from denosumab when compared with zoledronic acid [18,19]. In patients with MM and skeletal lesions, these agents reduce the number of vertebral fractures, skeletal-related events (SRE; a composite endpoint defined as osteolytic bone lesions, pathological fractures, and/or hypercalcemia), and associated pain. While some studies have suggested an overall survival (OS) benefit in subpopulations [6,7,9-12], others have not [20,21].

Some complications related to osteoclast inhibitor therapy are shared by bisphosphonates and denosumab (eg, osteonecrosis of the jaw, hypocalcemia and other electrolyte abnormalities, and atypical femoral fractures), while others are unique to bisphosphonates (eg, nephrotoxicity, flu-like symptoms/acute phase response, ocular toxicities, musculoskeletal pain, atrial fibrillation) or denosumab (eg, rebound vertebral fractures, infections) (table 1). Risks of therapy with osteoclast inhibitors are discussed in more detail separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

A 2017 Cochrane systematic review found that, when compared with placebo or no treatment, bisphosphonate therapy resulted in [17]:

Fewer vertebral fractures – Relative risk (RR) of 0.74, 95% CI 0.62-0.89. Estimate that for every 1000 patients treated with a bisphosphonate, approximately 94 fewer patients will experience a vertebral fracture.

Fewer SRE – RR 0.74, 95% CI 0.63-0.88. Estimate that for every 1000 patients treated with a bisphosphonate, approximately 104 fewer patients will experience an SRE.

Better control of skeletal-related pain – RR 0.75, 95% CI 0.60-0.95. Estimate that for every 1000 patients treated with a bisphosphonate, approximately 130 fewer patients will experience skeletal-related pain.

Increased osteonecrosis of the jaw – RR 4.61, 95% CI 0.99-21.35. Estimate that for every 1000 patients treated with bisphosphonates, about one patient will develop osteonecrosis of the jaw.

Similar rates of nephrotoxicity – Frequency of elevated serum creatinine estimated at 4 to 6 percent regardless of treatment.

Bisphosphonates did not appear to improve OS (hazard ratio [HR] 0.90, 95% CI 0.76-1.07) or progression-free survival (HR 0.75, 95% CI 0.57-1.00). However, there was significant heterogeneity among various bisphosphonates with respect to their effect on OS. There appeared to be a dose/potency effect with a subset analysis suggesting improved OS with zoledronic acid (HR 57, 95% CI 0.43-0.75), the most potent bisphosphonate.

Since intravenous bisphosphonates improve pain control, their use is recommended for patients with pain due to osteolytic disease, and as an adjunct to radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures. Pain control appears to take effect relatively rapidly. At least one study noted an onset of analgesia within approximately one week of beginning intravenous pamidronate in patients with symptomatic bone metastases [22]. Additional methods for managing skeletal events in patients with MM are presented separately. (See "Multiple myeloma: Overview of management", section on 'Skeletal lesions and bone health'.)

Randomized trials have not formally studied the effect of bisphosphonates in patients with bone lesions identified by CT, MRI, or PET/CT that are not visualized on skeletal x-rays. However, treatment of this subgroup with monthly intravenous bisphosphonate therapy is supported by the Medical Research Council (Myeloma IX) trial, which demonstrated that patients with MM without bone disease on skeletal x-rays who were receiving anti-MM treatment experienced fewer SRE with monthly zoledronic acid compared with daily oral clodronate [23]. It is unknown what proportion of this subgroup would have demonstrated bone loss or bone lesions with further imaging such as MRI, PET/CT, and/or bone densitometry.

Use in smoldering MM, MGUS, or solitary plasmacytoma — We do not routinely offer osteoclast inhibitors to patients with monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, or smoldering multiple myeloma (SMM). Osteoclast inhibitors are offered to these patients only if they have another indication for their use, such as osteoporosis or osteopenia on bone mineral density studies, at doses used for osteoporosis. (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Solitary extramedullary plasmacytoma" and "Solitary plasmacytoma of bone".)

In two randomized, open-label phase III trials that enrolled a total of 340 patients with SMM, administration of a bisphosphonate (zoledronic acid or pamidronate) for one year did not postpone progression to symptomatic MM, although it did reduce SRE (osteolytic bone lesions, pathological fractures, and/or hypercalcemia) at the time of progression by 25 to 50 percent [24,25]. It is not known how many of these patients would have qualified for treatment with an osteoclast inhibitor based on cross sectional imaging and bone densitometry.

We offer osteoclast inhibitors at doses used for osteoporosis to patients with MGUS and osteopenia or osteoporosis. This is supported by a phase II open-label trial that reported improved bone mineral density among 54 patients who received zoledronic acid every six months for one year [26]. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)

PRETREATMENT EVALUATION — Before starting an osteoclast inhibitor, patients must be evaluated for comorbidities that may alter drug selection, dosing, and administration.

Laboratory evaluation — We perform the following laboratory evaluation in all patients prior to starting an osteoclast inhibitor:

Renal function – We evaluate serum creatinine, estimated glomerular filtration rate, and a spot urine sample for albumin. Renal function impacts the choice and administration of osteoclast inhibitors. Bisphosphonates are nephrotoxic and require dose adjustment or discontinuation in the setting of renal impairment. In contrast, denosumab is not nephrotoxic, is not renally cleared, and is not dose-adjusted for renal function. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Proteinuria and kidney injury'.)

Calcium and vitamin D – At baseline, we measure levels of serum calcium and vitamin D (25-hydroxyvitamin D, also called calcidiol). Low levels are repleted at baseline and all patients are advised to take daily calcium and vitamin D supplements. Hypocalcemia is a potential side-effect of all osteoclast inhibitors, especially denosumab. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities'.)

Imaging — Perform cross-sectional imaging (eg, computed tomography [CT], whole body fluorodeoxyglucose [FDG] positron emission tomography with computed tomography [PET/CT], or magnetic resonance imaging [MRI]) prior to starting bisphosphonate therapy to document skeletal lytic lesions and provide a baseline for comparison after therapy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

Some patients with MM have no bone lesions on cross-sectional imaging. In such cases, we perform dual-energy x-ray absorptiometry (DXA) to assess bone density. Those with osteoporosis or osteopenia are offered an osteoclast inhibitor at doses used for MM. Experts differ in their approach to patients with MM who have no bone lesions identified on cross-sectional imaging and have a normal DXA. We do not offer an osteoclast inhibitor to such patients, while other experts do. (See 'Use in symptomatic myeloma' above.)

Preventive dentistry — Before initiating an osteoclast inhibitor, all patients should receive a comprehensive dental examination and preventive dentistry to treat active oral infections and eliminate sites at high risk for infection (table 2).

While on therapy, we instruct patients to:

Maintain excellent oral hygiene with daily home care (table 3) and periodic dental cleanings.

Avoid/minimize invasive dental procedures (eg, extraction and placement of dental implants). Less invasive procedures (eg, cavity repair, placement of crown, root canal) are allowed.

These measures are important to minimize the risk of osteonecrosis of the jaw (ONJ). Osteoclast inhibitors increase the risk of ONJ. The risk is increased substantially following invasive dental procedures.

Risk factors, prevention and management of medication-related ONJ is discussed in more detail separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer".)

CHOICE OF AGENT AND ADMINISTRATION — Our choice of osteoclast inhibitor is largely driven by renal function, toxicities, and cost.

Patients with normal renal function — For most patients with normal renal function (creatinine clearance [CrCl] >60 mL/min) who have MM requiring an osteoclast inhibitor, we suggest zoledronic acid or pamidronate rather than denosumab (algorithm 1). Of these, we prefer zoledronic acid based on its shorter infusion time, greater potency, and one trial (Myeloma IX) that suggested an overall survival (OS) benefit with zoledronic acid when compared with oral clodronate [23,27].

Denosumab is a reasonable alternative for patients with ongoing acute phase reactions (flu-like syndromes) after repeated dosing with a bisphosphonate. Its use in other patients with normal renal function is less attractive given its markedly higher cost and similar efficacy when compared with intravenous zoledronic acid [18,19].

Initial dosing and administration are as follows:

Zoledronic acid 4 mg intravenously over ≥15 minutes every four weeks.

Pamidronate 90 mg intravenously over ≥2 hours every four weeks.

Denosumab 120 mg subcutaneously every four weeks. If denosumab is discontinued, at least one dose of an intravenous bisphosphonate must be given to prevent rebound osteoclast activity that can lead to rapid bone loss and increased risk of fractures [28,29].

Studies comparing these agents have reported similar efficacy [8,9,16,18,19]. The choice among them is principally made based on administration time, cost, and side effect profiles (table 1). (See 'Efficacy and toxicity' above.)

An important caveat is that zoledronic acid is preferred among patients with hypercalcemia because it is more effective than pamidronate at reversing hypercalcemia [30]. (See "Treatment of hypercalcemia", section on 'Choice of drug and dosing'.)

Patients should be monitored periodically for a number of complications. Uncommon but important toxicities seen with all osteoclast inhibitors include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fractures. Toxicities specific to bisphosphonates include flu-like symptoms (acute-phase reaction); nephrotoxicity; and bone, joint, and muscle pain. (See 'Monitoring during therapy' below and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

Zoledronic acid, pamidronate, and denosumab are approved by the US Food and Drug Administration for this indication. Clodronate is approved in many countries other than the United States, for either oral or intravenous use in this setting, although it is likely less effective. In a large randomized trial of patients with previously untreated MM (Myeloma IX), long-term monthly administration of zoledronic acid reduced skeletal-related events (SRE) and improved OS when compared with daily oral clodronate [23,27,31].

Patients with renal insufficiency — For most patients with renal insufficiency (CrCl ≤60 mL/min) who have MM requiring an osteoclast inhibitor, we suggest denosumab rather than an intravenous bisphosphonate (algorithm 1). Unlike bisphosphonates, denosumab is not nephrotoxic, is not renally cleared, and is not dose-adjusted for renal function. As such, denosumab avoids the potential for iatrogenic kidney damage. Bisphosphonates remain a less expensive reasonable alternative to denosumab. Patients with impaired renal function from myeloma-related causes that are initially treated with denosumab may be switched to a bisphosphonate if their renal function normalizes with effective anti-myeloma therapy.

Dosing and administration are as follows:

Denosumab 120 mg subcutaneously every four weeks. If denosumab is discontinued, at least one dose of an intravenous bisphosphonate must be given to prevent rebound osteoclast activity that can lead to rapid bone loss and increased risk of fractures [28,29].

Zoledronic acid 4 mg intravenously over 30 to 60 minutes every four weeks. This longer infusion time is used to decrease the maximum serum concentration, an effect that preclinical models suggest may decrease the risk of nephrotoxicity. This differs from dose adjustments based on CrCl provided in the prescribing information [32].

In our experience, the uncommon MM patient permanently on dialysis due to either non-MM related kidney damage or from MM that is irreversible can safely receive zoledronic acid 4 mg over 60 minutes every four weeks.

Pamidronate 90 mg intravenously every four weeks. Infusion time depends on CrCl [1]:

CrCl ≥30 mL/minute: administer over ≥2 hours

CrCl <30 mL/minute: administer over 4 to 6 hours

Patients should be periodically monitored for a number of complications. Uncommon but important toxicities seen with all osteoclast inhibitors include osteonecrosis of the jaw, hypocalcemia, and atypical femoral and metatarsal stress fractures. Toxicities specific to denosumab include rebound vertebral fractures and infections. (See 'Monitoring during therapy' below and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

Denosumab has been compared to zoledronic acid in two randomized trials with mixed results:

A randomized trial comparing denosumab versus zoledronic acid in patients with bone metastases included 180 patients with MM [18]. A subgroup analysis of these patients suggested more favorable survival among those who received zoledronic acid (HR 2.26; 95% CI 1.13-4.50).

A larger placebo-controlled randomized trial compared denosumab versus zoledronic acid in 1718 patients with previously untreated MM with measurable bone lesions [19]. Both treatment arms had similar time to first SRE and OS. Denosumab resulted in lower rates of renal toxicity (eg, doubling of creatinine from baseline 3 versus 7 percent) and higher rates of hypocalcemia (17 versus 12 percent). Although more patients receiving denosumab developed osteonecrosis of the jaw (3 versus 2 percent), this difference did not reach statistical significance.

MONITORING DURING THERAPY — All patients receiving an osteoclast inhibitor should be monitored periodically for the following:

Calcium and vitamin D – Advise patients to take daily supplemental calcium (1000 mg daily) and vitamin D (at least 400 international units [IU] daily). Measure serum calcium periodically (eg, at least monthly among those on active anti-myeloma therapy) and measure vitamin D levels less frequently (eg, yearly). (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities'.)

Dental health – Periodic assessment of oral health focused on preventive dentistry. (See 'Preventive dentistry' above.)

Patients receiving a bisphosphonate (zoledronic acid or pamidronate) require additional monitoring:

Serum creatinine – Measure serum creatinine before each dose. Hold the bisphosphonate in patients who develop renal deterioration with no other apparent cause. Treatment can be resumed cautiously once renal function returns to within 10 percent of baseline [1]. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Management and prevention'.)

Urine albumin – Perform a spot urine assessment of albumin every three to six months. If the spot urine testing reveals albumin (otherwise unexplained), perform a 24-hour urine collection to quantitate the total protein, urine protein electrophoresis (UPEP), and albumin. Hold the bisphosphonate in patients with >500 mg/24 hours of urinary albumin. Reassess every three to four weeks with a 24-hour urine collection. When renal function returns to baseline, pamidronate can be restarted with an infusion duration (≥4 hours), at doses no greater than 90 mg every four weeks [1].

The routine evaluation of biochemical markers of bone metabolism to monitor bisphosphonate use is not recommended. These markers are under evaluation in clinical trials for their ability to predict improvement in symptoms of pain and quality of life [33]. (See "Use of biochemical markers of bone turnover in osteoporosis".)

COMPLICATIONS — Some complications related to osteoclast inhibitor therapy are shared by bisphosphonates and denosumab (eg, osteonecrosis of the jaw, hypocalcemia and other electrolyte abnormalities, and atypical fractures), while others are unique to bisphosphonates (eg, renal insufficiency, acute phase responses, ocular toxicities, musculoskeletal pain, atrial fibrillation) or denosumab (eg, rebound vertebral fractures, infections) (table 1). Risks of therapy with osteoclast inhibitors are discussed in more detail separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

Evaluation and management of medication-related osteonecrosis of the jaw is discussed in more detail separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Treatment of established MRONJ'.)

Interventions for the management of skeletal lesions are also discussed separately. (See "Multiple myeloma: Overview of management", section on 'Skeletal lesions and bone health'.)

LONG-TERM MANAGEMENT

Duration of therapy — There are limited data regarding the optimum duration of osteoclast inhibitor therapy, and experts differ in their approach. We offer monthly treatment for a period of at least two years. After two years, we reassess tolerability and suggest continued monthly administration in all patients, as long as it is well tolerated.

If the MM progresses during therapy, the osteoclast inhibitor is continued and adjustments are made to the anti-MM therapy directed at the plasma cell clone. Similarly, if the patient has a skeletal event (eg, a compression fracture or pathologic fracture), the osteoclast inhibitor is continued since this treatment reduces the relative number but does not prevent these complications altogether [34].

Other experts may reasonably discontinue the osteoclast inhibitor after two years in patients with responsive or stable MM with plans to restart the osteoclast inhibitor at MM progression [1]. Importantly, if denosumab is discontinued, at least one dose of an intravenous bisphosphonate must be given to prevent rebound osteoclast activity that can lead to rapid bone loss and increased risk of fractures [28,29]. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Rebound vertebral fractures'.)

Additional experts may decrease the frequency of treatments in patients without active MM (eg, those on maintenance therapy) [1,2,5]. (See 'Should the dose interval/frequency be adjusted?' below.)

The different expert perspectives regarding duration of therapy reflect different values and preferences for the potential toxicities and benefits with continued treatment. Data on prolonged use in the setting of MM are limited as randomized trials largely stopped osteoclast inhibitor therapy at or before two years [6-9,11-14,19,21,35]. It is unclear if therapy beyond two years results in further skeletal benefits and/or increased toxicity.

Our preference to continue therapy places greater value on avoidance of skeletal-related events (SRE) and a potential survival benefit with prolonged treatment, while recognizing an increase in toxicity. In the randomized Medical Research Council (MRC) Myeloma IX trial, 1960 patients with newly diagnosed MM were randomly assigned to intravenous zoledronic acid or oral clodronate [23,27,31]. The assigned bisphosphonate therapy was continued at least until disease progression. In the population as a whole, those assigned to zoledronic acid experienced:

Fewer SRE (hazard ratio [HR] 0.74)

Improved progression-free survival (median 19 versus 18 months, HR 0.89; 95% CI 0.80-0.98)

Superior overall survival (OS; median 52 versus 46 months, HR 0.86; 95% CI 0.77-0.97)

A subset analysis of the 582 patients who received at least two years of bisphosphonate therapy suggested continued improvement in this OS benefit (HR 0.60) with good overall long-term tolerability. Within this subgroup, those receiving at least two years of zoledronic acid experienced low rates of osteonecrosis of the jaw (2 percent) and acute renal failure (1 percent). In other studies, the incidence of osteonecrosis of the jaw and atypical fractures increases with duration of therapy. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw'.)

Should the dose interval/frequency be adjusted? — Our contributors differ in the dosing frequency used for long-term maintenance. For most patients, some contributors administer an osteoclast inhibitor monthly, as long as it is well tolerated. Others increase the dosing interval of zoledronic acid to every three months in patients without active MM (eg, those on maintenance therapy) [1,2,5,36]. Dosing interval adjustments are not appropriate for other agents.

Studies have evaluated less frequent dosing of zoledronic acid in an effort to decrease toxicity while maintaining efficacy [37,38]. However, the only randomized study that included patients with MM had significant limitations that make it difficult to know whether less frequent administration is as effective as monthly administration.

In the open-label, multicenter CALGB 70604 trial, 1544 patients with MM or bone metastases from a solid malignancy were randomly assigned to the same dose of zoledronic acid (adjusted based upon calculated creatinine clearance) monthly or every three months for two years [37]. The two treatment arms reported a similar estimated percentage of patients who experienced at least one SRE within two years of randomization. Patients assigned to monthly administration had numerically higher rates of osteonecrosis of the jaw (2 versus 1 percent) and kidney dysfunction (1.2 versus 0.5 percent) that did not reach statistical significance.

Among the 278 patients with MM, reported rates of SRE were 26 versus 21 percent in those receiving monthly and every three month treatment, respectively. However, interpretation of these data is severely limited by the short follow-up (median 1.2 years), small number of patients with MM, and a high early drop-out rate (46 percent among those with MM). This limitation can be illustrated in a worst-case-scenario analysis that assumes no SREs among those who dropped out on the monthly administration arm and assumes SREs among all patients who dropped out on the every three month arm. In this hypothetical analysis, rates of SREs would be at least double in the every three month arm (55 versus 26 percent). This study also fails to take into account the potential survival benefit from monthly zoledronic acid that was observed in the MRC Myeloma IX trial in which monthly zoledronic acid was administered [23,27,31]. It is not known whether a similar survival benefit would be seen with every three month dosing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Bone metastases (The Basics)")

Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Whom to treat – For most patients with symptomatic multiple myeloma (MM), we recommend the use of an osteoclast inhibitor, to be given in addition to other therapies directed at the malignant plasma cell clone (Grade 1B). (See 'Whom to treat' above.)

An important exception is that we do not routinely offer an osteoclast inhibitor to the uncommon patient who has no bone lesions on cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography-computed tomography [PET/CT]) and has normal bone density given an uncertain benefit in this population and potential toxicities. Other experts offer osteoclast inhibitors to all patients with MM requiring treatment regardless of identifiable bone disease.

In patients with MM and skeletal lesions, osteoclast inhibitors reduce vertebral fractures, skeletal-related events (ie, osteolytic bone lesions, pathological fractures, and/or hypercalcemia), and associated pain. They are usually well tolerated but are associated with low rates of serious toxicities, including osteonecrosis of the jaw. (See 'Efficacy and toxicity' above.)

Limited role in smoldering MM, MGUS, or solitary plasmacytoma – We do not routinely offer osteoclast inhibitors to patients with monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, or smoldering multiple myeloma (SMM). Osteoclast inhibitors are offered to these patients only if they have another indication for their use, such as osteoporosis or osteopenia on bone mineral density studies, at doses used for osteoporosis. (See 'Use in smoldering MM, MGUS, or solitary plasmacytoma' above.)

Pretreatment evaluation – Prior to starting an osteoclast inhibitor, all patients should undergo:

Laboratory testing to assess renal function and levels of calcium and vitamin D. Low levels of calcium and vitamin D are repleted at baseline and all patients are advised to take daily supplemental calcium (1000 mg daily) and vitamin D (at least 400 international units [IU] daily). (See 'Laboratory evaluation' above.)

Cross-sectional imaging (CT, PET/CT, or MRI) to document the extent of disease. We also perform dual-energy x-ray absorptiometry (DXA) in those without bone lesions on cross-sectional imaging to detect osteoporosis and osteopenia. (See 'Imaging' above.)

Comprehensive dental examination with interventions needed to treat active oral infections and eliminate sites at high risk for infection. (See 'Preventive dentistry' above.)

Choice of agent and administration – Our choice of osteoclast inhibitor is largely driven by renal function, toxicity, and cost (algorithm 1):

Normal renal function – For most patients with normal renal function (creatinine clearance >60 mL/min) who have MM requiring an osteoclast inhibitor, we suggest zoledronic acid or pamidronate rather than denosumab (Grade 2C). Of these, we prefer zoledronic acid (4 mg intravenously over ≥15 minutes every four weeks), based on its shorter infusion time, greater potency, and one trial (Myeloma IX) that suggested an overall survival benefit with zoledronic acid when compared with oral clodronate. (See 'Patients with normal renal function' above.)

Denosumab is a reasonable alternative for patients with ongoing acute phase reactions (flu-like syndromes) after repeated dosing with a bisphosphonate. Its use in other patients with normal renal function is less attractive given its markedly higher cost and similar efficacy when compared with intravenous zoledronic acid.

Renal insufficiency – For most patients with renal insufficiency (creatinine clearance ≤60 mL/min) who have MM requiring an osteoclast inhibitor, we suggest denosumab rather than an intravenous bisphosphonate (Grade 2B). Denosumab 120 mg is given subcutaneously every four weeks. Unlike bisphosphonates, denosumab is not nephrotoxic, is not renally cleared, and is not dose-adjusted for renal function. (See 'Patients with renal insufficiency' above.)

Patients with impaired renal function from myeloma-related causes that are initially treated with denosumab may be switched to a bisphosphonate if their renal function normalizes with effective anti-myeloma therapy.

Duration of therapy – There are limited data regarding the optimum duration of osteoclast inhibitor therapy, and experts differ in their approach. We offer monthly treatment for a period of at least two years. After two years, we reassess tolerability and suggest continued monthly administration in all patients, as long as it is well tolerated. The osteoclast inhibitor is continued in patients who experience a skeletal event and/or who progress on therapy. (See 'Duration of therapy' above.)

Other experts may reasonably discontinue the osteoclast inhibitor after two years in patients with responsive or stable MM with plans to restart the osteoclast inhibitor at MM progression. Importantly, if denosumab is discontinued, at least one dose of an intravenous bisphosphonate must be given to prevent rebound osteoclast activity which can lead to rapid bone loss and increased risk of fractures.

Dosing frequency for maintenance – Our contributors differ in the dosing frequency they use for long-term maintenance. For most patients, some administer an osteoclast inhibitor monthly, as long as it is well tolerated. Others increase the dosing interval of zoledronic acid in patients without active MM (eg, those on maintenance therapy). Dosing interval adjustments are not appropriate for other agents. (See 'Should the dose interval/frequency be adjusted?' above.)

Monitoring during therapy – All patients receiving an osteoclast inhibitor should have periodic monitoring of serum calcium and vitamin D, and periodic dental examinations. Patients receiving a bisphosphonate (zoledronic acid or pamidronate) also require monitoring of the serum creatinine and urine albumin. (See 'Monitoring during therapy' above.)

Evaluation and management of medication-related osteonecrosis of the jaw is discussed in more detail separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Treatment of established MRONJ'.)

Management of skeletal events – Additional methods for managing skeletal events in patients with MM are presented separately. (See "Multiple myeloma: Overview of management", section on 'Skeletal lesions and bone health'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.

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Topic 6663 Version 50.0

References

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