Zoledronic acid in metastatic castrate-sensitive prostate cancer: A state-of-the-art review.

Introduction

Approximately one in eight American men will be diagnosed with prostate cancer during their lifetime, making it the most common cancer in men after skin cancer [ 1 ]. It is estimated that 15 %–17 % of men over age 50 have occult prostate cancer, with this percentage increasing as age advances [ 2 ]. Moreover, autopsy studies show that nearly 70 % of men over 80 years old have occult prostate cancer [ 3 ]. Although only about one in 41 men will die from prostate cancer, it remains the second leading cause of cancer-related death among American men [ 1 ]. Prostate cancer spreads through local extension into the capsule and seminal vesicles, via the lymphatic system to regional lymph nodes, or through the bloodstream to bones and other visceral organs given that bone metastases were found in 90 % of men who had died with metastases of prostate cancer [ 4 ].

Metastatic prostate cancer, either de novo metastatic or relapsing after local therapy, are classically divided in two successive categories: castrate sensitive disease where medical or surgical castration could assume the control, and castrate resistant disease where the disease progressed despite the castration [ 5 ].

Treatment of metastatic castrate-sensitive prostate cancer

Androgen deprivation therapy (ADT), also known as castration therapy, is the cornerstone of systemic treatment for metastatic prostate cancer either de novo or for relapsed disease [ 6 ]. The critical role of androgens in promoting prostate cancer growth was first demonstrated by Huggins and Hodges in the 1940 s, leading to the development of ADT as a standard treatment for advanced prostate cancer. ADT is primarily palliative and results in a decline in prostate-specific antigen (PSA) levels and/or objective tumor responses in over 90 % of patients with advanced prostate cancer [ 7 ]. Despite the near-universal initial response to ADT, the duration of effectiveness varies significantly, influenced by various clinical and biological factors. On average, the median time to develop castration resistance or PSA progression while on ADT monotherapy is approximately 7 to 12 months [ 8 ]. The objective of ADT, either as surgical castration or medical castration, is to reduce testosterone levels below 50 ng/dL. Surgical castration is achieved through bilateral orchiectomy, while medical castration can be accomplished using either LHRH agonists (such as leuprolide and goserelin) or LHRH antagonists (such as degarelix and relugolix).Both forms of castration are associated with a range of side effects, including impotence, loss of libido, weakness, fatigue, hot flashes, loss of muscle mass, anemia, depression, cardiovascular issues, and a gradual loss of bone density over time [ 9 ].

Several clinical trials have explored the intensification of ADT in metastatic castration-sensitive prostate cancer (mCSPC). These trials have investigated the addition of secondary therapies to enhance clinical outcomes and improve overall survival (OS), such as docetaxel chemotherapy or novel hormonal therapies known as ARPI (Androgen Receptor Pathway inhibitors), such as abiraterone acetate, apalutamide, enzalutamide, and darolutamide.

Two randomized controlled trials, the CHAARTED and STAMPEDE (cohorts C) studies, demonstrated improved overall survival (OS) with the addition of six cycles of docetaxel to the ADT backbone [ 10 , 11 ]. Based on these findings, the combination of docetaxel and ADT has become one of the standard treatment regimens for mCSPC. Subgroup analyses of the CHAARTED study, focusing on the “volume” or extent of metastatic disease (high versus low), revealed that the benefit of adding docetaxel is most pronounced in patients with high-volume metastatic disease. High-volume disease was defined as having four or more bone metastases, with at least one lesion located outside the axial skeleton (i.e., skull, ribs, or extremities), or the presence of visceral metastases. Building on the new standard of ADT/docetaxel, the PEACE-1 study, a multicenter European trial, investigated the benefits of adding abiraterone acetate known as the triplet therapy for mCSPC. The results supported the addition of abiraterone to ADT and docetaxel, in high-volume metastatic disease, as recently presented [ 12 ]. Also, the ARASENS study confirmed the efficacy of the triplet darolutamide, ADT and docetaxel in an international, placebo-controlled, randomized phase 3 trial [ 13 ]. Darolutamide was, thereafter, approved by the FDA in 2022 for use in combination with docetaxel as well as ADT for patients with mCSPC. Interestingly, apalutamide and enzalutamide have both received FDA approval for use associated to ADT for mCSPC treatment [ 14 , 15 ].

The HORRAD and STAMPEDE trials evaluated the efficacy of prostate radiation therapy (RT) in patients with more diffuse metastatic disease treated with ADT alone [ 6 ]. Neither trial showed an overall improvement in overall survival (OS) for the entire population. However, in a pre-planned subgroup analysis of the STAMPEDE trial, there was an observed improvement in OS for patients with low-volume metastatic disease. These findings suggest that definitive prostate RT may have a role in the treatment of low volume mCSPC [ 6 ].

Thus, nowadays, the standard of care for mCSPC is attributed differently according to the disease volume: it is either the triplet combination of ADT/docetaxel with abiraterone or darolutamide, or ADT plus an ARPI for high volume disease. For low volume mCSPC, it is ADT combined with either an ARPI or radiation therapy (RT) to the prostate.

Zoledronic acid as member of the bisphosphonate family

Zoledronic acid is a high potency aminobiphosphonate with osteoclastic inhibiting activity. It is incorporated into the skeleton without being degraded and consequently decreases bone turnover and inhibits of the bone's reparative ability [ 16 ].

Zoledronic acid has been approved for prevention and treatment of osteoporosis and glucocorticoids-induced osteoporosis, treatment of Paget's disease, hypercalcemia, multiple myeloma and bone metastasis [ [17] , [18] , [19] , [20] , [21] ]. However, prolonged use of zoledronic acid suppresses bone turnover disabling repair of microdamage [ 22 ].

Off-label uses of zoledronic acid include adjuvant therapy in breast cancer, bone loss in postmenopausal patients related to aromatase inhibitor therapy, and bone loss related to androgen deprivation therapy [ 23 ].

To explore the use of this molecule in this review, we included recent guidelines, such as the APCCC 2022, ESMO 2020, and the guidelines from Brown, Handforth et al. in JBO 2020. We then incorporated findings from key clinical trials such as STAMPEDE trial. The controversies surrounding the use of zoledronic acid and other treatments in metastatic studies are discussed below.

Bone protection for treatment-related bone-loss

Treatment-related bone loss is a well-established concern for patients with prostate cancer (PC) receiving hormonal treatments. ADT can reduce bone mineral density (BMD) by an estimated 2–8 % per year, significantly increasing the risk of fractures due to cancer treatment-induced bone loss [ 24 , 25 ]. Additionally, the addition of ARPIs to ADT may further increase the risk of osteoporotic fractures compared to ADT alone [ 26 , 27 ].

The risk of fractures can be mitigated by using bone-protecting agents (BPAs) like the bisphosphonate zoledronic acid and other alternatives such as the receptor activator of nuclear factor κ B ligand (RANKL) inhibitor denosumab. When BPAs are used in this setting, the interval of administration varies between a few months to one year. Denosumab 60 mg every 6 months, or zoledronic acid 5 mg every 12 months are advised for patients with a dual-energy X-ray absorptiometry (DEXA) T score of <−2.0 and/or at least two of the following risk factors: age >65 years; T score <−1.5; current or former smoker; body mass index <24 kg/m 2 ; family history of hip fractures; personal history of fragility fractures at age >50 years; or use of oral glucocorticoids for >6 months [ 28 ]. Many patients with prostate cancer (PC) meet at least two of the risk criteria for treatment-related bone loss, and as a result, they may not necessarily require a DEXA scan to be eligible for the initiation of BPA therapy. While tools like the Fracture Risk Assessment Tool (FRAX) were not specifically designed for patients on ADT and therefore do not account for cancer treatment-induced bone loss, they can still be valuable for clinicians to assess fracture risk and evaluate individual risk factors.

The current European Association of Urology (EAU) guidelines strongly recommend that patients starting long-term ADT should undergo a baseline DEXA scan to assess BMD. If BPA therapy has not been started, repeat DEXA measurements should be performed every 2 years. For patients with a DEXA T score <−2.5 or additional risk factors that increase annual bone loss by more than 5 %, the EAU guidelines strongly recommend offering BPA therapy such as zoledronic acid 5 mg every 12 months or denosumab 60 mg every 6 months [ 28 ].

According to the Advanced Prostate Cancer Consensus Conference (APCCC) 2022 panel members, only 19 % recommended BPA treatment for most mCSPC patients starting ADT in combination with an ARPI. However, this figure increased to 40 % in the APCCC 2024 panel. This shift in opinion may be attributed to recent evidence indicating that the higher fracture risk associated with hormonal therapies often occurs independently of T scores, as ADT not only leads to a quantitative reduction in bone mineral density (BMD) but also causes qualitative changes in bone mass [ 29 , 30 ].

In order to make an informed decision, it is essential to assess fracture risk from baseline, particularly in patients on ADT, including those who have been on ADT for several years or are also undergoing corticosteroid therapy. In the light of this, the guidelines recommend using the FRAX® tool. FRAX® is user-friendly and does not require specialist knowledge, making it suitable for general practice or outpatient settings. It incorporates a limited number of clinical risk factors and it is easy to use [ 31 ]. Given that current evidence suggests fracture risk in ADT users is BMD-dependent, it is reasonable to include bone mineral density (BMD) in the FRAX® risk calculation for all prostate cancer patients, wherever feasible. Since newer studies have also shown that ADT not only affects bone mineral density (BMD) but also influences volumetric BMD (vBMD), areal BMD (aBMD), bone microstructure, strength, and body composition. While DXA remains a valuable tool for assessing BMD, the Antelope study suggests that HR-pQCT (high-resolution peripheral quantitative computed tomography) should also be considered as an additional tool for evaluating bone health [ 32 ].

Zoledronic acid to treat bone metastases in mCSPC

Complications from bone metastases are well known and classified as skeletal-related events (SREs). SREs include bone pain, pathological fractures, the need for radiation therapy (RT) to bone, tumor-related orthopedic surgical interventions, and spinal cord compression. While bone metastases in prostate cancer are primarily osteoblastic, there is also a significant osteolytic component, driven by osteoclast activity. Although pathologic fractures can occur, they are generally less frequent compared to cancers that predominantly feature osteolytic bone disease.

The addition of zoledronic acid, one injection every three to four weeks, is proved effective in term of SREs reduction in metastatic castrate resistant prostate cancer (mCRPC) [ 33 ]. Zoledronic acid, approved by the US FDA in 2002 for preventing SREs in men with mCRPC, was tested in a phase 3 trial with 643 patients. The study compared two doses of zoledronic acid (4mgand8mg) to placebo, but switched to a 4 mg dose for all participants due to renal impairment concerns in the higher-dose group. Zoledronic acid significantly reduced SREs (33.2 % vs. 44.2 % for placebo, P = 0.021), delayed the time to first SRE by 167 days, and decreased bone pain during an extended 24-month phase.

However, the efficacy of adding monthly Zoledronic acid, as part of metastatic bone therapy, to the standard doublet or triplet therapy in mCSPC is still not clear. Moreover, specific side effects of monthly Zoledronic acid could exceed its potential benefit in castrate sensitive setting.

Controversial results about the use of zoledronic acid in mCSPC

Reports in the literature assessing the added value of monthly zoledronic acid associated to ADT and ARPIs in the castrate sensitive setting are controversial. These findings are summarized in the table below ( Table 1 ). Table 1 Studies and their key finding about the use of zoledronic acid in mCSPC. Study Population N Study groups Key findings T.H. Diamond et al study(2001) Metastatic PC 21 MAB + pamidronate vs MAB Significant increase in LS (+7.8 % vs −5.7 % p = 0.0001) and femoral neck (+2.0 % vs −2.3 % p = 0.0007) BMD in pamidronate group compared to MAB group C.W. Ryan et al study (2007) Localised and metastatic PC receiving ADT < 12 months 42 Zoledronic acid + ADT vs placebo + ADT Increase in LS (+4.9 % vs − 2.2 % p < 0.0001) and femoral neck (0.9 % vs − 3.2 % p < 0.0001) BMD in zoledronic acid group compared with placebo STAMPEDE 2023 high-risk, locally advanced, metastatic or recurrent PC 2962 ADT alone vs ADT plus zoledronic acid ADT plus docetaxel vs ADT plus zoledronic acid and docetaxel. 64 % reduction in fracture risk (HR, 0.36; 95 % CI, 0.22–0.57, P < 0.0005) in the metastatic setting. No OS improvement CALGB 90,202 trial (2014) bone mCSPC on ADT 645 zoledronic acid y vs placebo No difference in the time to first (SRE) (median 31.9 vs. 29.8 months, HR 0.97) between the two groups. OS not significantly different (median 38 vs. 36 months, HR 0.88, 95 % CI 0.70–1.12).

A post hoc analysis of STAMPEDE data revealed that zoledronic acid, when used as 4 mg every 3 weeks for 6 cycles, then every 4 weeks for 2 years in the hormone-sensitive setting, significantly reduced the risk of fracture-related hospitalizations. Despite the absence of survival benefit from the addition of zoledronic acid, the authors of this analysis concluded that these results support the use of zoledronic acid to decrease fracture risk in patients with mCSPC [ 34 ]. The incidence of fractures was high among all patients randomized in the original STAMPEDE trial. Currently, no studies specifically focus on the risk of fracture or potential improvement based on factors in the metastatic setting. For instance, it is debatable whether certain groups of men with metastatic castrate-sensitive prostate cancer (mCSPC) starting ADT could benefit more from bone protective therapy. These groups may include men with osteoporosis or low bone mineral density (BMD) before treatment, older men, particularly those over the age of 70, who are more susceptible to bone density loss, and patients with additional fracture risk factors such as a history of smoking, alcohol use, or low body weight. Furthermore, patients on medications that contribute to bone loss (anticonvulsivants, corticosteroids) could also be candidates for bone-protective agents.

Additionally a key risk factor for bone loss is the duration of ADT, as it is directly linked to decreased bone mineral density, with the most significant effects often observed after 12 months. This makes prolonged ADT a strong justification for the use of bone-protecting agents [ 35 ].

In exploring other scenarios that could motivate us for the use of BPA,the CHAARTED trial, which evaluated the addition of docetaxel to ADT in high-volume mCSPC, demonstrated improved survival outcomes. Bone-targeted therapies may help manage SREs in these patients, though specific studies examining the interaction between zoledronic acid and high-volume disease are limited. Since high-volume disease typically involves more extensive bone involvement, bone-targeted therapies are likely more beneficial for managing bone complications in these patients.

Regarding genetic profiles, while germline mutations in genes like BRCA2 and ATM are linked to poorer outcomes in mCSPC and may influence responses to treatments like PARP inhibitors, there is no conclusive evidence connecting these genetic profiles to the effectiveness of zoledronic acid specifically [ 36 ]. However, these mutations may increase the risk of bone metastasis, potentially making patients with these profiles more prone SREs, which could further support the use of zoledronic acid or denosumab in these patients.

These scenarios are summarized in the diagram below ( Fig. 1 ). Fig. 1 Diagram illustrating scenarios to take into account when using Bone targeting Agents.

The guidelines from Brown, Handforth et al. in the 2020 Journal of Bone Oncology (JBO) discuss 15 randomized studies that examined the effects of bisphosphonates and denosumab in men undergoing androgen deprivation therapy (ADT) for prostate cancer. Only two studies reviewed, were in the metastatic setting: C.W. Ryan et al. study and T.H. Diamond et al. with the pamidronate group compared to placebo showed an increase in LS and femoral neck BMD in the zoledronic acid group [ 37 , 38 ].

However, in a multicenter phase II study, patients with de novo or relapsed mCSPC and bone metastases were randomly assigned in a 1:1 ratio to receive either ADT plus enzalutamide (E arm) or the same combination with the addition of monthly zoledronic acid. The primary objective of the study was to evaluate whether the addition of zoledronic acid could significantly increase the bone response rate in the experimental arm after 12 months of treatment, as assessed by whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI). WB-DW-MRI scans were conducted centrally at baseline, 6 months, and 12 months, with images being evaluated by the same radiologist for consistency. The conclusion of the study showed that the addition of zoledronic acid to enzalutamide and androgen deprivation therapy (ADT) did not improve bone disease response in patients with mCSPC [ 39 ].

In the CALGB 90202 trial, 645 men with bone mCSPC on ADT were randomly assigned to receive either zoledronic acid (4mgintravenouslyevery4weeks) or a placebo. The trial was prematurely discontinued when the corporate sponsor withdrew support [ 40 ]. With a median follow-up of 24 months, no statistically significant difference was found in the time to the first skeletal-related event (SRE) (median 31.9 vs. 29.8 months, HR 0.97). Overall survival was also not significantly different between the two groups (median 38 vs. 36 months, HR 0.88, 95 % CI 0.70–1.12).

Published guidelines from the Canadian Cancer Society (CCO) and the American Society of Clinical Oncology (ASCO) indicate that there is insufficient evidence to recommend the use of any BPA in men with bone metastases and castration-sensitive prostate cancer [ 41 , 42 ]. Moreover, the 2020 guidelines on bone health from the European Society for Medical Oncology (ESMO) specifically recommend against the routine use of bone-targeted agents, such as Zoledronic acid, in men with metastatic castration-sensitive prostate cancer [ 26 ].

In the guidelines from Brown, Handforth et al. in the 2020 Journal of Bone Oncology (JBO), no study was successful to detect differences in fracture incidence.

Zoledronic acid toxicities

Zoledronic acid is not an innocent non-toxic drug. It is often associated with an acute-phase reaction within 24 to 72 h following infusion. This reaction typically includes symptoms such as low-grade fever, myalgias, and arthralgias [ 43 ]. One potential side effect is hypocalcemia, a transient drop in calcium levels, which is more likely to occur in patients with hypoparathyroidism, vitamin D deficiency, or inadequate calcium intake [ 44 , 45 ]. Calcium levels should be closely monitored, particularly before beginning treatment and during the first few weeks afterward. Supplementation may be necessary. Bone health guidelines recommend daily supplements (800–2000 IU per day) of vitamin D3 and a daily intake of 1000–1200 mg of calcium per day. (bone health in cancer esmo) The calcium and vitamin D supplements should not be taken within one hour of bisphosphonate administration, as they can interfere with absorption.

In rare cases, patients may experience severe musculoskeletal pain in the bones, joints, or muscles, which can persist for days, months, or even years after starting bisphosphonate therapy [ 46 ]. Additionally, impaired kidney function is a concern. During bone therapy, the risk of nephropathy can be minimized by avoiding nephrotoxic drugs and products, monitoring baseline creatinine levels, and progressively reducing the dose when baseline creatinine clearance is between 30–60 ml/min. Zoledronate is contraindicated for patients with a creatinine clearance of less than 30 ml/min.

Another rare but serious complication is osteonecrosis of the jaw (ONJ). The frequency of ONJ according to the literature is around 1.2–3.8 % [ 47 ], but when it occurs, it is always severe disturbing the quality of life and rarely reversible according to our daily practice. Moreover, ONJ can occur with any bisphosphonate use, especially in patients receiving long-term treatment for osteoporosis [ 48 ]. A good oral hygiene is highly recommended. To prevent the risk of ONJ, patients are advised a scheduled regular or oral check-ups, invasive dental procedures such as implants or extractions should be avoided during the period of treatment if possible. Lastly, long-term bisphosphonate use has been linked to atypical femur fractures, particularly with prolonged use beyond three to five years, in older adults (ages 65–84), those on glucocorticoids, shorter individuals, those with higher weight, and Asian Americans compared to White Americans [ 49 ]. A referral for a supervised exercise program for a minimum of 12 weeks is suggested.

Other alternatives BPA

In castration-resistant prostate cancer (CRPC), denosumab has been shown to delay the time to the first skeletal-related event (SRE) and result in an 18 % reduction in cumulative SREs compared to zoledronate. Additionally, denosumab has been observed to delay the need for analgesics [ 26 , 50 ].

When comparing toxicities of other BPA (denosumab and pamidronate) with zoledronic acid, these agents generally present similar adverse effects, although electrolyte levels should be more closely monitored. In a recent meta -analysis by Chen et al., an increased occurrence of hypocalcemia and osteonecrosis of the jaw (ONJ) was observed with denosumab compared to zoledronic acid [ 51 ]. However, denosumab demonstrated a significantly lower incidence of renal adverse events and acute phase reactions, making it the preferred treatment in patients with low creatinine levels. Additionally, denosumab appears to delay the need for analgesics more effectively than zoledronic acid. Cost-wise, however, zoledronic acid remains a more affordable option [ 52 ].

Conclusion

Bone involvement is common in metastatic hormone-sensitive prostate cancer (mHSPC). ADT remains the cornerstone of systemic treatment for metastatic prostate cancer. For all patients undergoing long-term ADT, it is recommended to take calcium and vitamin D supplements, engage in regular exercise, quit smoking, and limit alcohol intake to reduce the risk of treatment induced bone-loss. In fact, all patients receiving continuous hormonal therapy should be evaluated for potential bone-protecting agent therapy. A baseline dual-energy X-ray absorptiometry (DEXA) scan should be performed to assess BMD, with repeat scans every 2 years if antiresorptive therapy has not been initiated. Denosumab 60 mg every 6 months, or zoledronic acid 5 mg every 12 months could be used as BPA in this setting.

For men with bone metastases and castration-sensitive prostate cancer, although some studies have shown benefits in maintaining bone mineral density with the use of these agents, no solid evidence suggested an improvement in incidence of fractures among patients taking BPA. Oncologists should be aware that the use of monthly zoledronic acid for preventing or delaying complications from bone metastases. is not encouraged in the absence of other arguments supporting its use such as low bone mineral density, other risk factors of fractures or a long duration on ADT. Moreover, any potential advantage in this setting from adding zoledronic acid could be uncompensated by its toxicities. While some of these toxicities can be mitigated by using other molecules, such as anti-RANK agents, other toxicities remain common across all bone protecting agents.

CRediT authorship contribution statement

Nahed Damaj: Writing – review & editing, Writing – original draft, Visualization, Software, Resources, Project administration, Data curation. Tala Najdi: Data curation. Samah Seif: Conceptualization. Nicolas Nakouzi: Data curation. Joseph kattan: Visualization, Validation, Supervision.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nahed Damaj reports a relationship with Saint Joseph University of Beirut that includes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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