Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer

Correspondence to: Ricardo Fernandes, Division of Medical Oncology, London Regional Cancer Program, University of Western Ontario, 790 Commissioners Road East, London, Ontario N6A 4L6. E-mail: ricardo.fernandes@lhsc.on.ca n DOI: https://doi.org/10.3747/co.27.6631 ES SE N TI A LS F O R P R A C TI TI O N ER S IN O N C O LO G Y Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer


INTRODUCTION
Bone is the most common site of metastasis in many malignancies, including breast (70%), prostate (70%-90%), thyroid (60%), lung (35%), and renal cell carcinomas (35%), and bone metastases can be associated with morbidity and mortality 1,2 .Since the start of the 2000s, there has been sustained growth in the understanding of the underlying biology of bone metastases and widespread incorporation of inhibitors of osteoclast function-namely, bisphosphonates and receptor activator of nuclear factor κB ligand inhibitors (denosumab)-into clinical practice [3][4][5] .
Bone metastases can be either osteolytic, osteoblastic, or mixed, and they most commonly occur in the long bones (femur and humerus) and axial skeleton 6,7 .These lesions lead to bone destruction, resulting in significant morbidity and impaired quality of life (qol).In clinical trials, the efficacy of bone-targeted agents (btas) is commonly assessed using the rate of skeletal-related events (sres), which occur in approximately 27%-40% of patients with metastatic castration-resistant prostate cancer (crpc) and metastatic breast cancer (mbca) 2,8 .Given that sres and impaired patient qol are both so important for patient care, it is essential that the full range of multimodal and multidisciplinary therapies are readily available for patients [9][10][11][12] .

Types of BTAs
For the purposes of this review, we focus on the two types of btas that are approved for use in clinical practice: bisphosphonates and denosumab.Bisphosphonates act primarily as inhibitors of osteoclast activity and have been studied in the management of a variety of malignancies.In oncology, the most commonly used agents are zoledronate and pamidronate.In patients with mbca and bone metastases, bisphosphonates have been shown to significantly reduce the incidence of sres, but have not been shown to improve progression-free survival or overall survival [13][14][15] .A 2017 meta-analysis showed that bisphosphonates reduce the risk of sres in advanced breast cancer by 14% 16 .Additionally, a Cochrane review concluded that there is some evidence to support modest pain relief associated with the use of bisphosphonates, although current guidelines do not recommend such use exclusively for analgesic purposes 17,18 .In patients with crpc metastatic to bone, zoledronate has been shown to reduce sres by 36% 19 .
Denosumab is a fully human monoclonal antibody that acts by inhibiting the receptor activator of nuclear factor κB ligand, which stimulates the activity and development of osteoclasts, thereby reducing their activity and growth.Denosumab was shown to be superior to zoledronate in patients with bone metastasis from mbca and crpc by delaying the onset of first and subsequent sres 14,20 .In a meta-analysis of three randomized clinical trials, denosumab reduced the risk of a first sre by 17% and delayed the time to first sre by a median of 8.2 months 21 .In one report in patients with mbca, denosumab, compared with zoledronate, also showed a benefit in health-related qol measures 22 .

Treatment Considerations and Toxicities
The toxicities of btas are well studied, and bisphosphonates and denosumab all share a number of adverse events, including hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures.Patients who are starting a bta should receive appropriate calcium and vitamin D supplementation to reduce the risk of hypocalcemia, which occurs more frequently with denosumab (12.4%) than with bisphosphonates (5.3%) 23,24 .Risk of osteonecrosis of the jaw is rare with either therapy, occurring at rates less than 2% in the first year of treatment 25 .The risk is higher with denosumab than with bisphosphonates and increases with longer duration of therapy.Dental examination before bta initiation is recommended by most practice guidelines, and ongoing symptom inquiry is important throughout treatment for prompt identification of this serious adverse event 18 .
Bisphosphonates are specifically associated with nephrotoxicity, and renal function must be monitored 26 .The risk can be reduced by adhering to recommended doses, dosing intervals, and infusion rates as described later in this article 27 .

When to Initiate Treatment
It is widely accepted practice to initiate treatment with a bta at first radiographic evidence of bony metastases, because risk of sres is highest on diagnosis of metastatic disease and within the first year 18,28,29 .Whether all patients have to commence treatment as soon as there is a radiologic diagnosis has not been investigated.Clinical context should dictate management; in certain situations (for instance, in a patient with a low burden of disease or with visceral metastases and limited life expectancy), delaying the start of a bta might be more sensible 4 .
Aspects of the pathophysiology of bone lesions have led to some observations in the treatment of osteolytic compared with osteoblastic metastases.Bone metastases in patients with breast cancer are primarily osteolytic, and therefore treatment with inhibitors of osteoclast activity, such as bisphosphonates, is indicated 13,30 .On the other hand, bone metastases in patients with prostate cancer are primarily osteoblastic, leading to the deposition of calcium in new bone.The rationale for the use of bisphosphonates in the treatment of patients with prostate cancer comes from studies showing that abnormal osteoblastic bone formation is associated with osteoclastic bone resorption and an elevation in osteoclastic markers 31,32 .Multiple randomized trials have shown significant reductions in the frequency of sres in patients with bone metastases from a variety of solid tumours that are treated with an osteoclast inhibitor; the use of such agents is therefore recommended for most patients with bone metastases from solid tumours, regardless of whether those metastases are osteolytic or osteoblastic 15,[33][34][35] .

Choice of Agent and Dosing Schedule
The choice of bta depends on a number of factors, including tumour site, patient comorbidities, and cost-effectiveness.In mbca, a joint guideline from the American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) does not recommend one bta over another 18 .Although denosumab might be preferred based on its associated sre reduction and its subcutaneous route of administration, those benefits have to be balanced against its significantly higher drug acquisition cost.In a cost-effectiveness analysis, zoledronate given every 3 months was shown to be substantially more cost-effective than monthly denosumab in reducing sres 36 .
If a bisphosphonate is selected, zoledronate has the greatest demonstrated efficacy 37 .The joint 2017 guideline from the American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) for mbca recommends the use of zoledronate at a dose of 4 mg given intravenously over no less than 15 minutes 18 .Pamidronate 90 mg given intravenously also has demonstrated efficacy in reducing the risk of sres in mbca and would be a reasonable option, but it does have a longer infusion time (2 hours) 38 .In contrast, pamidronate did not demonstrate any benefit over placebo in the treatment of bony metastases from crpc 39 .A 2017 Genitourinary Disease Site Group guideline from Ontario Health (Cancer Care Ontario) recommended denosumab or zoledronic acid for preventing or delaying sres in men with metastatic crpc 40,41 .
In terms of dosing schedule, despite the fact that the half-life of bisphosphonates and bone turnover biomarkers exceed 1 year, the dosing interval has historically been more frequent, to coincide with every-3-weeks chemotherapy schedules 42 .Less-frequent dosing of btas in breast and prostate cancer is supported by data from three randomized controlled studies.In a meta-analysis, sre rates in patients with mbca were similar for zoledronate given every 12 weeks or every 3-4 weeks, regardless of whether patients started on standard dosing (every 3-4 weeks) or de-escalated dosing (every 12 weeks) 43 .A more recent trial evaluating the noninferiority of 12-weekly compared with 4-weekly dosing for btas in patients with breast cancer and crpc showed that a dose-de-escalated schedule can also be applied to pamidronate 44 .
Currently, the recommended dose and schedule for denosumab is 120 mg administered subcutaneously every 4 weeks 4,18 .Denosumab has also been tested in a dose-de-escalated schedule.A recent trial that evaluated the noninferiority of 12-weekly compared with 4-weekly dosing for btas suggested that the same dose-de-escalated schedule could be to 44 .To direct future treatment recommendations, one ongoing clinical trial is currently comparing 12-weekly with 4-weekly denosumab in patients with mbca and crpc 33,45 .Data so far would suggest that de-escalation of all commonly used bone agents, including denosumab, to 12-weekly therapy is a reasonable clinical strategy.

Duration of Treatment
American Society of Clinical Oncology guidelines recommend continuing treatment with btas indefinitely 18 .That recommendation must be balanced against long-term toxicity risks and patient-centred goals of care.Some data suggest that treatment should continue for 6 months at minimum to achieve a demonstrable reduction in the risk of sres 19 .
For patients who experience a sre while on treatment with a bta, therapy continuation is recommended to increase the time to a subsequent sre 46 .One study investigating the benefit of switching from pamidronate to zoledronic acid in patients with high-risk disease did not show any reduction in sres or qol and pain scores, and thus switching between bisphosphonates is not recommended 47 .
Treatment with newer anticancer therapies has extended life expectancy in patients with mbca and crpc by a number of years.As a result, the question of the duration of bta use should take into consideration life expectancy, overall burden of disease, and risk of sres in each individual patient.Most clinical trials have evaluated the use of btas  for only a maximum of 2 years, and hence no high-quality evidence to support their use beyond 2 years has been developed [33][34][35] .Duration of use is currently being further evaluated in a series of Canadian studies.

SUMMARY
Bone-targeted agents are an integral component of the palliative management of bony metastatic disease in mbca and crpc.Knowledge of the available agents and their role in the treatment of patients with bony metastases is essential for general practitioners in oncology.The btas have demonstrated efficacy in reducing the risk of sres and in modestly improving pain and other qol outcomes.However, it is important to remember that btas have no effect on either progression-free or overall survival, and they have significant associated toxicities and costs.Further areas of study include clarifying the optimal dose, schedule, and duration of treatment for these agents.
We recommend the use of btas to reduce the risk of sres for most patients bone metastases from solid tumours.For patients with a minimal bone tumour burden or limited expected survival, treatment with a bta should be discussed and individualized.We advise that the use of btas be specifically applied to crpc with bone metastases.In the absence of excessive toxicity, and if within the patient's and the clinician's joint treatment goals, btas should be continued indefinitely.

Key Points
n Bisphosphonates and denosumab are osteoclast inhibitors that are recommended for the treatment of bony metastases in patients with breast cancer and crpc.n Treatment with a bta can be considered at the first evidence of bony metastasis.n Before therapy begins, guidelines recommend that patients undergo dental examination because of a risk-albeit low-of osteonecrosis of the jaw.Supplementation with vitamin D and calcium should also be initiated.n If initiating a bisphosphonate, a dose-de-escalated schedule of administration every 12 weeks can be used.If initiating denosumab, the current recommendation is for administration every 4 weeks.However, the results of ongoing clinical trials suggest that a 12-weekly schedule of denosumab is reasonable.n Bone-targeted agents may be continued beyond the 2 years evaluated in clinical trials.However, given the possibility that their toxicities might outweigh their benefits with longer duration of use, ongoing clinical trials are evaluating this approach.
Table i summarizes the administration schedules and doses for those commonly used agents.Table ii shows estimated prices for btas in Canada.

TABLE I
Recommended doses and administration schedules for bone-targeted agents

TABLE II
Estimated price for bone-targeted agents in Canada prices represent a single infusion or injection per the Ontario Drug Benefit Exceptional Access Formulary, October 2015.Drug cost might be reimbursed through the Ontario Drug Benefit Plan.Drug prices are dynamic; thus, the prices listed here might not reflect current prices.Vial, 3 mg/mL injection (Pfizer Canada ULC, Kirkland, Québec) NA = not applicable.BONE-TARGETED AGENTS IN mBCa OR CASTRATION-RESISTANT PCa, Southcott et al.