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Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors

Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors
Literature review current through: Jan 2024.
This topic last updated: Dec 20, 2022.

INTRODUCTION — Metastases to bone are a common site of cancer tumor burden for many types of solid tumors. Bone metastases cause substantial morbidity, including the need for radiation and/or surgery to bone, pathologic fractures, hypercalcemia of malignancy, and spinal cord compression [1,2]. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and "Clinical features and diagnosis of neoplastic epidural spinal cord compression" and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma" and "Radiation therapy for the management of painful bone metastases" and "Hypercalcemia of malignancy: Mechanisms".)

Osteoclast inhibitors (also referred to as antiresorptive agents, bone modifying agents, or bone targeting agents), such as bisphosphonates and denosumab, significantly reduce the frequency of and delay the time to onset of skeletal-related events (SREs) in patients with bone metastases from a wide variety of cancer types. The benefits of osteoclast inhibitors in patients with bone metastases from solid tumors will be presented here. The use of osteoclast inhibitors in patients with multiple myeloma, the use of osteoclast inhibitors for patients with bone loss related to cancer treatment (eg, aromatase inhibitors for breast cancer and androgen deprivation therapy for prostate cancer), the use of osteoclast inhibitors in the adjuvant setting for breast cancer, the use of osteoclast inhibitors in men with metastatic castration-resistant prostate cancer (CRPC) who are receiving radium-223 in conjunction with systemic therapy, and the risks of therapy with osteoclast inhibitors in patients with advanced malignancy are all discussed separately. (See "Multiple myeloma: The use of osteoclast inhibitors" and "Evaluation and management of aromatase inhibitor-induced bone loss" and "Use of osteoclast inhibitors in early breast cancer" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer" and "Bone metastases in advanced prostate cancer: Management", section on 'Prevention of bone metastasis complications'.)

BONE METASTASES IN SOLID TUMORS — Bone is the most common site of metastasis in cancer, and bone metastases are most prevalent among patients with cancer of the breast, prostate, and lung. Complications from bone metastases include pain, decreased performance status, and decreased quality of life (QOL), as well as skeletal-related events (SREs), which are defined as the need for radiation and/or surgery to bone, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. SREs are most common in patients with lytic metastases, but they can also occur in patients with blastic metastases (table 1). SREs that are accompanied by symptoms (as opposed to identified on imaging tests) are known as symptomatic skeletal events (SSEs) and represent a more clinically meaningful endpoint. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Epidemiology' and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Distribution'.)

SREs and SSEs are clinical outcomes that can be distinctly measured; therefore, they are often used as endpoints in clinical trials investigating therapies for bone metastases, although not all studies include hypercalcemia of malignancy. Bone metastases are also associated with pain, particularly with motion, which significantly impacts QOL.

Osteoclast inhibition has become an important component of managing patients with bone metastases to reduce the frequency and delay the onset of SREs and SSEs. While the frequency of SREs in patients not treated with an osteoclast inhibitor can be illustrated by the following historical data, it is important to state that improvements anticancer treatments in recent years may have also reduced the incidence of SREs [3]:

In a review of patients treated for metastatic breast cancer prior to the routine use of bisphosphonates, over 50 percent developed an SRE [4]. Other evidence suggests that in the absence of osteoclast inhibition, one SRE occurs an average of every three to four months in women with lytic bone metastases from breast cancer [5].

Data from the untreated arms of older controlled trials of osteoclast inhibitors indicate that SREs have been most common in patients with bone metastases from breast cancer (two-year cumulative incidence 68 percent), followed by prostate cancer (two-year cumulative incidence 49 percent), and non-small cell lung cancer and other solid tumors (21-month cumulative incidence 48 percent) [6-8].

In more recent phase III trials, approximately 24 percent of men with castration-resistant prostate cancer (CRPC) had an SRE within four to five months of being diagnosed with bone metastases [9]. In another trial (Cancer and Leukemia Group B [CALGB] 70604), approximately 26 percent of patients with metastatic breast cancer, prostate cancer, or multiple myeloma with at least one site of bone involvement had had an SRE prior to receiving zoledronic acid [10].

In addition to osteoclast inhibition, management of patients with metastatic bone disease requires an integrated multidisciplinary management approach. The foundation of management entails antineoplastic treatment (eg, chemotherapy, endocrine therapy, targeted therapies, external beam radiation therapy, bone-targeted radiopharmaceuticals) and may also include surgery as required for existing or impending pathologic fractures, as well as physical and/or occupational therapy to optimize function. As treatment of these patients is palliative, supportive interventions, such as analgesics and concurrent subspecialty palliative care consultation and management, are essential. (See "Radiation therapy for the management of painful bone metastases" and "Bone metastases in advanced prostate cancer: Management", section on 'Bone-targeted radioisotopes' and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma" and "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with bone pain' and "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care' and "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors", section on 'General approach to the patient'.)

Indications for osteoclast inhibitor therapy — Osteoclast inhibitors are indicated for the management of metastatic bone disease for most patients with solid tumors. However, the vast majority of the data for metastatic prostate cancer were generated in the castration-resistant state; hence, we advise that the use of osteoclast inhibitors be specifically applied to CRPC with bone metastases.

For patients in whom SREs and SSEs are unlikely (eg, those with minimal bone tumor burden) and for those with a limited expected survival (eg, those with extensive and progressive visceral metastases), treatment with osteoclast inhibitors should be considered on a case-by-case basis. Other indications for the use of osteoclast inhibition in cancer patients (eg, preventing bone loss related to androgen deprivation therapy [ADT], use in multiple myeloma) are discussed separately. (See "Use of osteoclast inhibitors in early breast cancer" and "Multiple myeloma: The use of osteoclast inhibitors" and "Bone metastases in advanced prostate cancer: Management", section on 'Prevention of bone metastasis complications'.)

Although osteoclast inhibitors are widely available, and despite their proven efficacy, the available data suggest that a large proportion of patients (between 20 and 50 percent) who are otherwise eligible are not receiving osteoclast-inhibiting treatment to prevent SREs [11-16], suggesting that adherence with present guidelines may be suboptimal.

Considerations prior to initiating an osteoclast inhibitor

Calcium and vitamin D — For patients in whom an osteoclast inhibitor is indicated, preexisting hypocalcemia and/or vitamin D deficiency should be corrected prior to treatment. Ongoing assessment is needed during therapy due to the risk of secondary hyperparathyroidism.

Patients with solid tumors may be vitamin D deficient, which places them at risk for hypocalcemia if they are treated with an osteoclast inhibitor without additional calcium (and vitamin D) supplementation [17,18]. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities'.)

As an example, in a combined analysis of three randomized trials involving over 5600 women with breast cancer who were randomly assigned to treatment with denosumab or zoledronic acid [18]:

Hypocalcemia was more common among patients who did not report use of calcium and vitamin D compared with those who did (16 versus 9 percent for denosumab and 7.2 versus 4.6 percent for zoledronic acid).

Serious (grade 3/4) hypocalcemia within six months of starting treatment is more common with denosumab (3 versus 1 percent).

While no fatal episodes of hypocalcemia were reported in these clinical trials, fatal hypocalcemic events have been reported by others [19].

If there are no contraindications (eg, history of recurrent renal stones), all patients receiving osteoclast inhibitors who do not have adequate dietary intake should receive calcium and vitamin D supplementation to decrease the risk of hypocalcemia. The use of calcium and vitamin D in patients who are at risk for hypercalcemia in the setting of bone metastases is not normally a concern as absorption of oral calcium is regulated by parathyroid hormone, which falls as serum calcium rises. In general, the principles and guidance on the use of calcium and vitamin D supplementation outlined by the Institute of Medicine (IOM) that apply to the general population are appropriate for patients with bone metastases from solid tumors [20]. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)

Periodic monitoring of electrolytes during therapy is discussed below. (See 'Monitoring during therapy' below.)

Dental health — The risk for osteonecrosis of the jaw with osteoclast inhibitor therapy appears to be approximately 2.8 percent at three years [21], but rises with duration of osteoclast inhibitor use [3]; we agree with the joint guidelines recommending that all patients, if possible, undergo a dental examination prior to initiation of treatment with an osteoclast inhibitor and at regular intervals during therapy [22]. This subject is covered in more detail elsewhere. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Prevention'.)

Overview of the approach to osteoclast inhibition — There are two general classes of agents used for osteoclast inhibition in patients with bone metastases from solid tumors: bisphosphonates and denosumab. (See "Mechanisms of bone metastases", section on 'Osteoclasts'.)

The selection of one osteoclast inhibitor over another is influenced by tumor type, patient preference, and other factors, such as route of administration, frequency of administration, tolerance, accessibility, and cost of therapy:

For patients with bone metastases from breast cancer and CRPC, denosumab and zoledronic acid, as well as some other osteoclast inhibitors, reduce SREs. In the case of metastatic breast cancer, international practice guideline groups have not expressed a preference for a particular agent [23-25]. While monthly denosumab may appear preferable to monthly zoledronic acid in terms of a modest improvement in SRE reduction and analgesic effects, and the fact that denosumab can be administered as a subcutaneous injection rather than an intravenous infusion, its use needs to be balanced by the significantly higher direct drug costs and the data demonstrating that a three-month dosing interval of zoledronic acid is noninferior to monthly dosing [10,26,27].

Several trials and meta-analyses now show that extended dosing intervals for zoledronic acid (ie, treatments given every 12 weeks) are equally effective and safe as four-week dosing, and this has become a standard approach for most patients with breast cancer or CRPC. The less frequent dosing regimen of zoledronic acid is more convenient to patients and more cost-effective [28-31]. Less frequent dosing may apply to other osteoclast inhibitors, including denosumab or other bisphosphonates, although the data are more limited [32], and this approach cannot yet be recommended as a standard approach. However, on a case-by-case basis, every-12-week dosing may be appropriate for informed and selected patients with bone metastases from breast cancer or CRPC. (See 'Dosing interval' below and 'Dosing interval' below.)

For patients with bone metastases from solid tumor types other than breast cancer and CRPC, both denosumab and zoledronic acid (given at standard doses) reduce SREs. Standard dosing for both agents is administration every four weeks, and there are insufficient data on the efficacy of less frequent administration of zoledronic acid or denosumab to direct dosing intervals outside of metastatic breast cancer or CRPC. Nevertheless, the evolving data on dosing intervals for osteoclast inhibitors in breast cancer and CRPC have clearly influenced clinical practice for patients receiving these drugs in the setting of other solid tumors; in the absence of data from large prospective trials, many clinicians are de-escalating zoledronate and denosumab to 12-week administration after a variable period of four-week dosing [32,33]. For patients who have bone metastases from other solid tumors, there may be circumstances (eg, no rapid bone resorption, limited burden of bone metastases, and high likelihood of response to systemic anticancer treatment) where an extended dosing interval might be appropriate if it is compatible with the patient's goals of care. Indeed, a combined Musculoskeletal Tumor Society/American Society of Clinical Oncology/American Society for Radiation Oncology (MSTS/ASCO/ASTRO) guideline for management of metastatic cancer to the femur discusses offering the 12-week dosing to all patients, regardless of histology [34].

The management of osteoclast inhibitors in multiple myeloma, including issues related to dosing interval, is discussed elsewhere. (See "Multiple myeloma: The use of osteoclast inhibitors".)

These issues inform our treatment approach, which is also outlined in the algorithm (algorithm 1):

For patients with bone metastases from breast cancer or CRPC, our preferred osteoclast inhibitor regimen is zoledronic acid 4 mg (or renally dosed) every 12 weeks. However, some clinicians may prefer every-four-week administration, at least initially, for patients with extensive or highly symptomatic bone metastases from breast cancer or CRPC. (See 'Dosing interval' below.)

For other solid tumors, monthly denosumab 120 mg might be favored. The subcutaneous mode of administration may be more convenient for some patients, particularly if they are not receiving systemic intravenous anticancer therapies (ie, patients receiving endocrine therapy or oral chemotherapy). However, a bisphosphonate remains a reasonable alternative, particularly if there are financial constraints. (See 'Efficacy' below.)

If a bisphosphonate is chosen, we prefer zoledronic acid to others in this class because zoledronic acid has shown efficacy in multiple tumor types, it appears to be a more effective bisphosphonate than pamidronate, it requires a shorter infusion time than does pamidronate. For patients who are at increased risk of renal toxicity and for those who prefer an oral regimen, oral ibandronate or clodronate are reasonable. The substitution of oral for intravenous bisphosphonates can only be recommended for metastatic breast cancer. (See 'Other bisphosphonates' below.)

The recommended dose and schedule for denosumab for the prevention of SREs are 120 mg administered subcutaneously every four weeks. There are evolving data addressing less frequent dosing than every four weeks for denosumab, and this cannot yet be considered a standard approach [32,33]. However, on a case-by-case basis, every-12-week dosing may be appropriate for informed and selected patients with bone metastases from breast cancer or CRPC. (See 'Dosing interval' below and 'Dosing interval' below.)

For patients with bone metastases from solid tumors other than breast cancer and CRPC, the every-four-week dosing schedule for both zoledronic acid and denosumab remains a standard approach. However, the MSTS/ASCO/ASTRO guideline for management of metastatic cancer advocates for considering zoledronic acid 12-week dosing for patients with metastatic carcinoma without limitation by primary tumor histology [34]. In our view, there may be circumstances (eg, no rapid bone resorption, limited burden of bone metastases, and high likelihood of response to systemic anticancer treatment) where an extended dosing interval might be appropriate if it is compatible with the patient's goals of care.

EFFICACY AND DOSING CONSIDERATIONS FOR INDIVIDUAL AGENTS — Multiple randomized trials have demonstrated significant reduction in the frequency of and an increase/delay in the time to onset of skeletal-related events (SREs) in patients with bone metastases from a variety of solid tumors who are treated with an osteoclast inhibitor. We recommend the use of osteoclast-inhibiting therapy to reduce the risk of skeletal complications for most patients with bone metastases from solid tumors. For patients in whom SREs are unlikely (eg, those with minimal bone tumor burden) and for those with a limited expected survival (eg, those with progressive visceral metastases despite established anticancer therapies), treatment with osteoclast inhibitors should be considered on a case-by-case basis.

Denosumab

Mechanism of action — Denosumab is a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand (RANKL). Inhibition of bone resorption can be achieved by targeting RANKL, a key component in the pathway for osteoclast formation and activation. (See "Normal skeletal development and regulation of bone formation and resorption" and "Mechanisms of bone metastases", section on 'Osteoclasts'.)

Efficacy — Denosumab effectively reduces the risk of first and subsequent SREs in patients with bone metastases from a wide variety of tumors, including multiple myeloma. (See "Multiple myeloma: The use of osteoclast inhibitors".)

Three similarly designed trials have directly compared denosumab with zoledronic acid in patients with breast cancer [11], prostate cancer [9], and multiple myeloma or bone metastases from a solid tumor other than breast or prostate cancer (40 percent non-small cell lung cancer, 10 percent multiple myeloma, 50 percent other tumor types) [35].

A patient-level meta-analysis of these three phase III trials comparing zoledronic acid with denosumab for metastatic bone disease concluded that denosumab was superior to zoledronic acid in reducing the risk of a first on-study SRE (hazard ratio [HR] 0.83, 95% CI 0.76-0.90) and in delaying the time to a first SRE or hypercalcemia of malignancy (median 26.6 versus 19.4 months) [36]. Overall survival and disease progression rates were similar with both treatments.

Similar conclusions were reached in a Cochrane analysis of three trials conducted in women with breast cancer; compared with a bisphosphonate, the use of denosumab reduced the risk of an SRE by 22 percent (risk ratio [RR] 0.78, 95% CI 0.72-0.85) [37]. One of the studies that reported data on overall survival noted no significant differences between the two treatments.

From the standpoint of adverse effects, in contrast to zoledronic acid, denosumab is not associated with acute phase reactions. Both osteoclast-inhibiting treatments are associated with a risk of electrolyte disturbances, with hypocalcemia being more common with denosumab. Renal function needs to be considered with both agents, and zoledronic acid dosing is impacted by the calculated creatinine clearance. Osteonecrosis of the jaw occurred at a similar rate with both agents. (See 'Complications' below.)

Impact on quality of life — From the standpoint of pain and quality of life (QOL), denosumab has demonstrated modest but statistically significant benefit over zoledronic acid [30,32,38,39].

In an open-label randomized trial that compared denosumab 120 mg dosed every 4 versus every 12 weeks, the health-related QOL at 48 weeks was similar between the dosing intervals, as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) functional domain, physical subdomain [32]. (See 'Dosing interval' below.)

The analgesic efficacy of osteoclast inhibitors in patients with cancer-related bone pain is discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Osteoclast inhibitors'.)

Dosing interval — The recommended dose and schedule for denosumab for the prevention of SREs are 120 mg administered subcutaneously every four weeks. There are limited data addressing less frequent dosing than every four weeks for denosumab, and this approach cannot yet be recommended as a standard approach. However, on a case-by-case basis, every-12-week dosing may be appropriate for informed and selected patients with bone metastases from breast cancer or castration-resistant prostate cancer (CRPC). For patients who have bone metastases from other solid tumors, there may be circumstances (eg, no rapid bone resorption, limited burden of bone metastases, and high likelihood of response to systemic anticancer treatment) where an extended dosing interval might be appropriate if it is compatible with the patient's goals of care.

The available data on less frequent dosing intervals for denosumab are as follows:

One phase II trial randomly assigned 111 patients with bone metastases from prostate, breast, or other cancers to bisphosphonates every four weeks or subcutaneous denosumab 180 mg every 4 or every 12 weeks; the duration of the study was short: only 25 weeks [40]. There was no reported difference in the rate of SREs in the every-4-week versus every-12-week denosumab arms. There was, however, some suggestion of a rise in bone turnover markers in some patients who received the longer dosing interval (a result that had been reported by others), but as yet, it is unknown whether or not this correlates with SREs [41].

Additional information on the comparability of less frequent denosumab administration is available from the REaCT-BTA study, an open-label, randomized, pragmatic study [30,32]. Of the 263 enrolled patients with metastatic breast cancer (60 percent) or CRPC, denosumab 120 mg was the most commonly chosen osteoclast inhibitor and was used in 56 percent of study participants, while the rest received either zoledronic acid (24 percent) or pamidronate (20 percent). The primary endpoint was patient-reported health-related QOL. In the latest analysis, 12-week dosing was not inferior to four-week dosing for any of the primary or secondary endpoints, including symptomatic skeletal events, reported rates of renal impairment, symptomatic hypocalcemia, or osteonecrosis of the jaw. In subgroup analysis, there were no differences in any of the primary or secondary endpoints for the specific osteoclast inhibitor, according to tumor type, or whether de-escalation was performed in patients starting bone-targeted agents at the time of randomization or in those already established on a bone-targeted agent [30].

The efficacy and safety of less frequent dosing for osteoclast inhibitors are further supported by a meta-analysis of five randomized trials of pamidronate, zoledronic acid, or denosumab in patients with bone metastases from breast cancer [26,27,40-43]. The summary RR for on-study SREs in patients receiving standard (61 of 443 patients) versus less frequent dosing (49 of 392 patients) was 0.90 (95% CI 0.63-1.29). A second meta-analysis further supports these findings [44].

These data add to the body of evidence that de-escalation of the common osteoclast inhibitors for metastatic bone disease is a reasonable alternative to monthly dosing in an informed patient who is not at imminent risk for significant SREs. The strongest data in support of 12-week dosing intervals are in metastatic breast cancer and CRPC treated with zoledronic acid. We await the results of the Swiss REDUSE trial of denosumab 120 mg every 4 or 12 weeks before routinely recommending 12-week denosumab dosing intervals, at least initially. Of note, the REDUSE trial only enrolls patients with metastatic breast or prostate cancer, and thus, it will not inform the benefits of extended dosing intervals for denosumab in other solid tumor types. Nevertheless, the evolving data on dosing intervals in breast cancer and CRPC have already influenced clinical practice for patients with a variety of solid tumor types [33]. (See 'Overview of the approach to osteoclast inhibition' above.)

Bisphosphonates

Mechanism of action — Bisphosphonates are analogs of pyrophosphate with carbon replacing the central oxygen (figure 1). Bisphosphonates decrease bone resorption and increase mineralization by inhibiting osteoclast activity [45,46]. Bisphosphonates have a direct apoptotic effect on osteoclasts, affect their differentiation and maturation, and thereby, act as potent inhibitors of bone resorption. In preclinical models, bisphosphonates have also been shown to influence macrophages, gamma delta T cells, osteoblasts, and tumor cells [46]. (See "Mechanisms of bone metastases", section on 'Osteoclasts'.)

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

Efficacy — In a 2017 meta-analysis of randomized trials in advanced breast cancer, compared with placebo, bisphosphonates significantly reduced the absolute risk of SREs (excluding hypercalcemia) by 14 percent (RR 0.86, 95% CI 0.78-0.95) [37]. Treatment was also associated with a significant delay in median time to SRE, improvements in bone pain, and improvements in global QOL. However, there was no difference in overall survival.

There are substantial data supporting the analgesic potential of all of the parenteral bisphosphonates, including clodronate, ibandronate, pamidronate, and zoledronic acid, as well as oral ibandronate and clodronate. In a Cochrane review, a significant improvement in bone pain was reported after receiving a bisphosphonate in patients with bone metastases from breast cancer in 6 of 11 studies [37].

Quality of life — Bisphosphonates have a modest impact on bone pain and QOL [47]. However, the analgesic effects are modest, and osteoclast inhibitors should not be used as the sole therapy for bone pain [24]. This subject is discussed in detail elsewhere.

Specific bisphosphonates

Zoledronic acid

Efficacy — In placebo-controlled trials, zoledronic acid has effectively decreased the risk of SREs in women with bone metastases from breast cancer [48-51], in men with bone metastases from CRPC [52], and in patients with bone metastases from other solid tumors [7,53,54].

On the other hand, benefit for administration of zoledronic acid in men with castration-sensitive metastatic prostate cancer could not be shown in the randomized ALLIANCE 90202 trial. (See "Bone metastases in advanced prostate cancer: Management", section on 'Castration-sensitive disease'.)

It is of note that the United States Prescribing Information for zoledronic acid in patients with bone metastases states that prostate cancer should have progressed after treatment with at least one hormonal therapy, while the United States Prescribing Information for denosumab for bone metastases does not specifically restrict approval to men with CRPC. Nevertheless, use of both of these agents is typically restricted to metastatic CRPC. (See "Bone metastases in advanced prostate cancer: Management", section on 'Castration-resistant disease'.)

Impact on quality of life — Compared with placebo, zoledronic acid decreases pain severity and improves QOL for patients with metastatic bone disease:

In the metastatic breast cancer trial, patients who took zoledronic acid had significantly greater decreases in pain scores compared with placebo after four weeks of treatment [51].

The positive impact of zoledronic acid on QOL was explored further in a study involving over 100 patients who were administered a total of nine infusions in either a community- or hospital-based setting [55]. At the end of the study, global QOL (assessed using the EORTC QLQ-C30) was significantly improved compared with baseline by 8 percent, particularly in the domains of physical, emotional, and social functioning.

Studies investigating extended dosing intervals for zoledronic acid (ie, 4 mg every 12 versus every 4 weeks) have shown similar patient-reported outcomes across the dosing intervals for the endpoints of pain and Eastern Cooperative Oncology Group (ECOG) performance status in Cancer and Leukemia Group B (CALGB)/Alliance 70604 [10] and for health-related QOL, pain, and global health status in REaCT-BTA [32]. (See 'Dosing interval' below.)

However, the analgesic effects are modest [47], and osteoclast inhibitors, such as zoledronic acid, should not be used as the sole therapy for bone pain [24]. This subject is discussed in detail elsewhere.

Dosing interval — The approved dose and schedule of administration for zoledronic acid are 4 mg every three to four weeks, with the dose adjusted for creatinine clearance. However, there are sufficient data in metastatic breast cancer and CRPC to support less frequent dosing (every 12 weeks rather than every 4 weeks), and we suggest this approach for most patients. A 2017 focused guideline update on the role of osteoclast inhibitors in metastatic breast cancer from the American Society of Clinical Oncology and Cancer Care Ontario, as well as the European Society for Medical Oncology guideline on bone health, supports every-12-week dosing as an alternative to monthly therapy [24,25]. A year 2020 joint guideline on treatment of metastatic carcinoma and myeloma of the femur from the Musculoskeletal Tumor Society/American Society of Clinical Oncology/American Society for Radiation Oncology also supports 12-week dosing as an alternative to monthly therapy for metastatic carcinoma of all histologies [34].

Some may prefer to mimic the approach utilized in the ZOOM [26] and Optimize 2 [27] phase III studies of metastatic breast cancer where patients had approximately one year of zoledronic acid dosed every three to four weeks prior to switching over to every-12-week dosing. Indeed, the European Society of Medical Oncology 2020 guideline on bone health expresses the preference for initial monthly therapy for at least three to six months, before de-escalating to every 12 weeks for most patients, regardless of histology [25]. In our view, the strongest data to recommend a change in dosing interval for patients with bone metastases is in breast cancer and the strongest data in support of initiating zoledronic acid at 12-week dosing is in breast, prostate, and multiple myeloma. Hence, we continue to treat patients with other tumor types, at least initially, with every-three- to four-week dosing of zoledronic acid, if a bisphosphonate is chosen. However, there may be circumstances (eg, limited burden of bone metastases, high likelihood of response to systemic anticancer treatment, patient preference) where an extended dosing interval might be appropriate for the individual.

Data in support of the 12-week dosing interval of zoledronic acid in select tumor types are available from at least five trials [10,21,26,27,32] and several meta-analyses. The following represents the range of findings:

CALGB (ALLIANCE) 70604 – The noninferiority of less frequent zoledronic acid administration from the initiation of osteoclast inhibitor therapy in a wide range of patients was shown in the CALGB (ALLIANCE) 70604 trial, which randomly assigned 1822 patients with bone metastases (855 with breast cancer, 689 with prostate cancer, 278 with myeloma; no other tumor types) to the same dose of zoledronic acid (adjusted based upon calculated creatinine clearance) every 4 or every 12 weeks for two years starting with the first dose. The noninferiority margin was set at 7 percent absolute difference in the proportion of patients developing at least one SRE within two years, the primary endpoint. There was no statistically significant difference in the proportion of patients who developed at least one SRE (29.5 versus 28.6 percent for the every-4-week and every-12-week treatment, respectively) [10]. The lower border of the 95 percent confidence interval for the risk difference between the groups was greater than the noninferiority margin regardless of whether the analysis assumed that dropouts (ie, individuals who did not complete two years of treatment) did or did not have an SRE. There was also no significant difference in the time to first SRE in either group, in pain scores, or in the risk of jaw osteonecrosis. There was also no difference in the proportion of patients with renal dysfunction (1.2 versus 0.5 percent with every-4-week versus every-12-week therapy), although notably, in this trial each dose of zoledronic acid was modified according to the creatinine clearance prior to each dose, which is different from what is recommended in the United States Prescribing Information. Patients receiving zoledronic acid every four weeks had a significantly higher rate of increased creatinine (defined as an increase of ≥0.5 mg/dL with a baseline creatinine level ≤1.4 ng/dL, or an increase of ≥1 mg/dL in patients with a baseline creatinine level above 1.4 ng/dL) compared with those treated every 12 weeks (19.9 versus 15.5 percent, p = 0.02).

The association of the dosing interval of zoledronic acid with the risk of osteonecrosis of the jaw (ONJ) was explored in the prospective, observational osteonecrosis of the jaw study, Southwest Oncology Group (SWOG) S0702 [21]. There were 3491 analyzable participants with a variety of tumor types (1120 breast cancer, 580 myeloma, 702 prostate cancer, 666 lung cancer, 423 other tumors), and 87 developed confirmed cases of osteonecrosis of the jaw (three-year cumulative incidence 2.8 percent, 95% CI 2.3-3.5%). Patients for whom the planned zoledronic acid dosing interval was every less than five weeks (comprising 87 percent of the study population) had a higher likelihood of developing osteonecrosis of the jaw than did those who had a planned dosing interval of five weeks or more (3.2 versus 0.7 percent, HR 4.65, 95% CI 1.46-14.81, p = 0.009).

The efficacy and safety of less frequent dosing are further supported by at least three meta-analyses, all of which are limited to trials conducted in patients with breast cancer [43,44,56]. In one representative meta-analysis of five randomized trials [26,27,40-42] of pamidronate, zoledronic acid, or denosumab in patients with bone metastases from breast cancer [43], the summary RR for on-study SREs in patients receiving standard (61 of 443 patients) versus less frequent dosing (49 of 392 patients) was 0.90 (95% CI 0.63-1.29). De-escalation of zoledronic acid in patients with bone metastases specifically from breast cancer is also supported by a second, more recent meta-analysis of five randomized trials [56].

These data add to the body of evidence that de-escalation of all common osteoclast inhibitors for metastatic bone disease is a reasonable alternative to monthly dosing in an informed patient who is not at imminent risk for significant SREs. Importantly, not all trials have consistently supported less frequent dosing [26,42,53,57]. An unanswered question is whether there are subpopulations of patients with metastatic breast cancer or CRPC for whom initial therapy every four weeks is preferred with a later transition to less frequent dosing after a period of bone stability (preloading). An additional unanswered question is whether there could be benefit in escalating dosing from every three months to monthly in the setting of increasing risk of SREs. In our practice, we limit the use of initial extended dosing to those patients without extensive bone metastases or significant bone pain and a high likelihood of response to underlying systemic treatment.

Other bisphosphonates — When a bisphosphonate is chosen, we suggest zoledronic acid over other bisphosphonates for patients with bone metastases from solid tumors. Of the available bisphosphonates, zoledronic acid has the greatest efficacy shown to date [50,58], and it is approved for patients with bone metastases from a wide variety of solid tumors.

Although zoledronic acid is a preferred agent, other bisphosphonates that have demonstrated efficacy in reducing SREs in patients with bone metastases from solid tumors are clodronate, ibandronate, and pamidronate. A major advantage of zoledronic acid over pamidronate is the shorter infusion time. However, if zoledronic acid is not available, pamidronate is a reasonable alternative, at least for women with metastatic breast cancer. For patients who are at increased risk of renal toxicity and for those who prefer an oral regimen, oral ibandronate or clodronate are reasonable. This substitution of oral for intravenous bisphosphonates can only be recommended for metastatic breast cancer.

Efficacy

Clodronate and ibandronate Clodronate and ibandronate are approved for use in metastatic bone disease outside the United States. Oral ibandronate has similar efficacy to intravenous ibandronate [59]. Patients prescribed oral bisphosphonates should be counseled on the potential for gastrointestinal side effects, which may compromise patient adherence [60,61]. Further discussion of this topic is covered separately. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Gastrointestinal'.)

Both clodronate and ibandronate are effective at reducing SREs due to bone metastases, although the bulk of data are in metastatic breast cancer:

Oral clodronate has been shown to reduce the combined rate of all morbid SREs by approximately 30 percent compared with placebo in trials conducted in metastatic breast cancer [62-64]; the benefits of intravenous and oral clodronate in advanced prostate cancer have been more difficult to define, although long-term data from the MRC PR04 and PR05 trials suggest improved survival among men with metastatic disease [65-67]. (See "Bone metastases in advanced prostate cancer: Management", section on 'Bisphosphonates'.)

In two randomized trials, both conducted in breast cancer, oral ibandronate significantly reduced the overall risk of an SRE (HR 0.62) compared with placebo [68]. Intravenous ibandronate has been shown to be as efficacious as a single fraction of radiation therapy for treatment of localized bone pain from metastatic disease in men with prostate cancer [69], although there are no data addressing benefit for other SREs. (See "Bone metastases in advanced prostate cancer: Management", section on 'Bisphosphonates'.)

Although some data suggest that oral ibandronate is equivalent to intravenous zoledronic acid [70], a large open-label randomized trial directly comparing these two agents in 1400 patients with metastatic breast cancer suggested that zoledronic acid was preferred [71]:

The annual rates of SREs were 0.499 and 0.435 with ibandronate and zoledronic acid, respectively (rate ratio 1.15, 95% CI 0.97-1.36). The upper confidence interval exceeded the predefined margin for noninferiority, and hence, the oral ibandronate arm could not be deemed as noninferior in reducing the frequency of SREs.

The rates of osteonecrosis of the jaw were similarly rare in both groups (<1 and 1 percent, respectively); however, patients treated with ibandronate had a lower incidence of nephrotoxicity (25 versus 32 percent).

A greater comparative efficacy of intravenous zoledronic acid over oral bisphosphonates in breast and prostate cancer was noted in a mixed treatment meta-analysis [58].

Oral clodronate and ibandronate are administered daily. Ibandronate (oral, intravenous) is available in the United States, but is only approved for treatment of osteoporosis. Clodronate is not available in the United States; outside of the United States (eg, Canada), oral clodronate is approved for treatment of osteolytic bone metastases.

Pamidronate – Pamidronate consistently reduces the risk of SREs in patients with breast cancer and lytic bone metastases compared with placebo [6,72-76]. On the other hand, at least one trial has failed to demonstrate any advantage of pamidronate over placebo for preventing SREs in men with advanced CRPC [77].

The evidence to support a preference for zoledronic acid over pamidronate comes largely from a phase III trial involving 412 women with metastatic breast cancer and osteolytic bone metastases who were randomly assigned to treatment with zoledronic acid or pamidronate [50]. Although both agents resulted in an equivalent incidence of SREs (46 versus 50 percent), after two years of therapy, an Andersen-Gill multiple event analysis showed that zoledronic acid was associated with a lower overall risk for an SRE (RR 0.80, 95% CI 0.66-0.97) [78].

Pamidronate is administered as a 90 mg infusion over one to two hours repeated every three to four weeks. Until more information is available, less frequent dosing cannot be recommended [32,79].

Dosing interval — The REaCT-BTA trial examined dosing intervals of pamidronate 90 mg every 4 versus every 12 weeks in 52 patients with bone metastases from breast or prostate cancer. There were no statistically significant differences in efficacy between the dosing schedules [30,32].

Less frequent dosing of pamidronate was also explored in a randomized feasibility study in which 38 women with breast cancer and "low-risk" bone metastases (essentially low-risk baseline C-telopeptide [CTx] levels and receiving intravenous bisphosphonates for three or more months) were randomly assigned to every-12-week versus every-3-to-4-week pamidronate [42]. Compared with the control group, there was a time-dependent increase in serum CTx levels in the group that received every-12-week dosing, which in a later analysis, did not appear to correlate with on-study SREs [79].

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 (possible increased risk of infection). Risks of therapy with osteoclast inhibitors are discussed in more detail elsewhere. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

DURATION OF THERAPY — For patients in whom an osteoclast inhibitor is indicated, there are no data on the optimal duration of therapy. One approach, is to continue treatment indefinitely in the absence of excessive toxicity and as long as treatment is consistent with both the patient and the clinician's joint treatment goals. However, another acceptable option for patients who have well-controlled oligometastatic disease is to interrupt bisphosphonate therapy after a period of two years.

This approach is consistent with European Society for Medical Oncology 2020 guidelines [25], and American Society of Clinical Oncology guidelines [80].

The following studies inform the debate as to duration of therapy:

A systematic review exploring longer durations of osteoclast inhibitor therapy showed that with longer follow-up, the risk of symptomatic skeletal events decreases while the risks of cumulative toxicities increases [3].

Similarly, data from the REaCT-BTA study, which evaluated an every 4 versus every 12 week dosing interval for denosumab, concluded that the number of patients experiencing one or more symptomatic skeletal events was higher in the first year after diagnosis of bone metastases compared with that in the second and third years (38.9 versus 17.5 and 24.4 percent, respectively) [31]. However, it is notable that one in four patients suffered a symptomatic skeletal event in year 3. The median duration of osteoclast inhibitor therapy was 2.3 years for breast cancer (range 0.1-9.9 years) and 3.8 years for patients with castration-resistant prostate cancer (range 1.5-9.4). (See 'Dosing interval' above.)

Additional data suggest that treatment should be administered for a minimum of six months because it usually takes this amount of time on treatment before there is a demonstrable reduction in the rate of SREs [81]. The time to improvement of bone pain may be shorter [82].

There is also interest in de-escalation of osteoclast inhibitor therapy as an alternative to treatment interruption after two years; clinical trials are needed in this area [83,84].

Patients who develop an SRE while on therapy — For patients who experience a skeletal-related event (SRE) while receiving treatment with an osteoclast inhibitor, continued therapy with denosumab or a bisphosphonate effectively improves the time to subsequent SREs [11,78]. Therefore, we continue osteoclast inhibition even after an SRE. Two acceptable options are to continue on the same osteoclast inhibitor or to change to a more potent osteoclast inhibitor.

There are only limited data to inform the choice of treatment in patients who experience an SRE while on active therapy [40,85]:

For patients who were previously treated with a bisphosphonate (oral or intravenous), a switch to denosumab may be beneficial. This was shown in a randomized, open-label phase II clinical trial of 111 patients with metastatic bone disease from a variety of solid tumors who had urinary N-telopeptide (uNTx) values above 50 nmol/L (suggesting high levels of bone turnover) while receiving intravenous bisphosphonate therapy [40]. Patients were randomly assigned to either continuation of the bisphosphonate or switching to denosumab. A significantly higher proportion of patients on denosumab had a reduction in their uNTx values to below 50 nmol/L by week 13 (71 versus 29 percent of those on an intravenous bisphosphonate). Furthermore, there were fewer on-study SREs with denosumab, although this was not statistically significant (8 versus 17 percent).

For patients initially treated with pamidronate or an oral bisphosphonate, options include transitioning to intravenous zoledronic acid (4 mg every 4 or 12 weeks) or denosumab. Data supporting benefit of zoledronic acid are inconsistent, and there are no data on denosumab in this setting:

In one trial, 31 women who developed one SRE or radiographic disease progression while receiving clodronate or pamidronate were transitioned to zoledronic acid [85]. Pain scores, quality of life (QOL), and biochemical markers of bone turnover (uNTx) were assessed at baseline, weekly during the first month, and then at week 8. Systemic treatment for their cancer was allowed only after week 4 from initiation of zoledronic acid. The proportion of patients experiencing a palliative response to zoledronic acid by week 8 was 42 percent (13 of 31). This coincided with a significant reduction in their average pain score.

However, a subsequent double-blind study in the same patient population, while confirming a greater fall in bone turnover markers with zoledronic acid, showed no benefit of zoledronic acid over continued pamidronate in terms of symptomatic skeletal events, pain, or QOL [86].

MONITORING DURING THERAPY — In our practice, we monitor patients serially with clinical exams and imaging to ensure that there is no worsening of bone disease during therapy with an osteoclast inhibitor. Monitoring tumor burden in bone requires serial assessment with a history and physical examination, laboratory studies (eg, serum alkaline phosphatase and consideration for using tumor markers, if available), and scans. The frequency of monitoring should be based upon tumor type, whether or not disease control is likely to be achieved with systemic anticancer therapy, and other clinically relevant issues, such as symptoms.

Tumor-induced osteolysis is associated with increased turnover of bone resorption markers such as urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (BAP). Bone biomarkers can provide additional information on prognosis and the likelihood of a skeletal-related event (SRE) [87,88]. However, the utility of bone biomarkers in monitoring therapy for patients receiving an osteoclast inhibitor is controversial.

We assess renal function, calcium, and electrolytes (or a biochemical profile) periodically throughout therapy. Vitamin D intake and/or levels can be assessed in the evaluation of calcium status. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities' and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Management and prevention'.)

Although effective inhibition of osteoclast activity can result in hypocalcemia and hypophosphatemia, most patients do not become symptomatically hypocalcemic during therapy because of compensatory mechanisms. Patients are at higher risk of electrolyte imbalance if they have renal insufficiency, decreased compensatory mechanisms, or vitamin D deficiency. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities'.)

Given the small but real risk of osteonecrosis of the jaw with both bisphosphonates and denosumab, assessments of oral health should continue throughout the course of therapy and invasive dental procedures should be avoided if at all possible. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Asymptomatic patients during therapy'.)

Atypical fractures are uncommon events. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Atypical fractures'.)

The Musculoskeletal Tumor Society guidelines provide advice on imaging and management of atypical femur fracture.

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: Management of bone metastases in solid tumors".)

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 info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

Morbidity of bone metastases – Metastases to bone are a common site of recurrence for many types of solid cancers. Bone metastases cause pain, impair quality of life, and cause skeletal-related events (SREs), including pathologic fracture, the need for radiation or surgery to bone, hypercalcemia, and spinal cord compression. Bisphosphonates and denosumab reduce the morbidity of metastatic bone disease, mainly by decreasing SREs. (See 'Introduction' above.)

Indications for osteoclast inhibitors and pretreatment considerations

For most patients with bone metastases from solid tumors, we recommend the use of a bisphosphonate or denosumab to reduce the risk of skeletal complications (Grade 1A). The vast majority of the data for metastatic prostate cancer were generated in individuals with castration-resistant prostate cancer (CRPC); hence, we advise that the use of a bisphosphonate or denosumab be specifically applied to CRPC with bone metastases, not castration-sensitive disease.

For patients in whom SREs are unlikely (eg, those with minimal bone tumor burden) and for those with a limited expected survival (eg, those with progressive visceral metastases despite anticancer therapies), treatment with osteoclast inhibitors should be considered on a case-by-case basis. (See 'Indications for osteoclast inhibitor therapy' above.)

For patients in whom an osteoclast inhibitor is indicated, dental care should be optimized prior to treatment, preexisting hypocalcemia and/or vitamin D deficiency should be corrected, and patients should be counseled on daily oral care and adequate intake of calcium and vitamin D during therapy (unless contraindicated). Renal function should be evaluated prior to dosing both denosumab and zoledronic acid. (See 'Considerations prior to initiating an osteoclast inhibitor' above.)

Choice of agent and dosing

The selection of one osteoclast inhibitor over another is influenced by tumor type, patient preference, and other factors, such as route and frequency of administration, tolerance, accessibility, and cost. For most patients with bone metastases from breast cancer or CRPC, zoledronic acid is our preferred agent. For patients with bone metastases from other solid tumors, denosumab may be favored, although zoledronic acid is a reasonable alternative. (See 'Overview of the approach to osteoclast inhibition' above.)

When a bisphosphonate is chosen, we suggest zoledronic acid over other bisphosphonates for patients with bone metastases from solid tumors (Grade 2B). Zoledronic acid has the greatest efficacy of the bisphosphonates shown to date, and it is approved for patients with bone metastases from a wide variety of solid tumors. Furthermore, a major advantage of zoledronic acid over pamidronate is the shorter infusion time. (See 'Zoledronic acid' above.)

However, if zoledronic acid is not available, pamidronate is a reasonable alternative, at least for metastatic breast cancer. For patients at increased risk of renal toxicity and for those who prefer an oral regimen, oral ibandronate or clodronate are reasonable options in metastatic breast cancer. (See 'Other bisphosphonates' above.)

If zoledronic acid is chosen, the approved schedule of administration is 4 mg IV every three to four weeks, with the dose adjusted for creatinine clearance. However, for patients with breast cancer or CRPC who have neither highly symptomatic nor extensive bone metastases, we suggest every 12 weeks rather than every 4 week dosing interval (Grade 2A). We still prefer every-four-week dosing, at least initially, for patients with breast cancer or CRPC who have extensive or highly symptomatic bone metastases. Switching to every-12-week dosing after a variable period of every-four-week dosing (eg, after three to six months) is an appropriate option for patients with stable bone disease. (See 'Dosing interval' above.)

If denosumab is chosen, the recommended dose for prevention of SREs is 120 mg administered subcutaneously every four weeks. There are limited data addressing less frequent dosing than every four weeks for denosumab, and this approach cannot yet be recommended as a standard approach. However, on a case-by-case basis, every-12-week dosing may be appropriate for informed and selected patients with bone metastases from breast cancer or CRPC. (See 'Dosing interval' above.)

There are insufficient data to recommend a longer zoledronic acid or denosumab dosing interval in patients with bone metastases from solid tumors other than breast cancer or CRPC. We continue to treat these patients with every-four-week zoledronic acid or denosumab. However, there may be circumstances (eg, no rapid bone resorption, limited burden of bone metastases, and high likelihood of response to systemic anticancer treatment) where an extended dosing interval might be appropriate for any solid tumor if it is compatible with the patient's goals of care.

Duration of therapy

For patients in whom an osteoclast inhibitor is indicated, there are no data on the optimal duration of therapy. One approach, is to continue treatment indefinitely in the absence of excessive toxicity and as long as treatment is consistent with both the patient and the clinician's joint treatment goals. However, another acceptable option for patients who have well-controlled oligometastatic disease is to interrupt bisphosphonate therapy after a period of two years. (See 'Duration of therapy' above.)

For patients who have experienced an SRE while on a bisphosphonate or denosumab therapy and receiving anticancer therapy, we suggest continuing a bisphosphonate or denosumab rather than discontinuing it (Grade 2C). (See 'Patients who develop an SRE while on therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert E Coleman, MD, FRCP, FRCPE, who contributed to an earlier version of this topic review.

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Topic 2801 Version 69.0

References

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