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Study: Bone-protecting drugs cut the risks for fractures caused by metastatic prostate cancer treatments

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At a glance In-depth
Study findings Clinical trials
Strengths and limitations Guidelines
What does this mean for me? Questions for your doctor



What is this study about?

The PEACE-III trial is an ongoing study looking at the benefit of (a type of hormonal therapy) alone or in combination with radium-223 dichloride (a mildly radioactive form of the metal radium) to treat castration-resistant cancer (mCRPC) that has spread to the bone. Early results presented at the 2021 American Society of Clinical Oncology (ASCO) meeting showed that the addition of a bone-protecting agent, BPA, (e.g., zoledronate or denosumab) to treatment with alone or in combination with radium-223 (ra223) almost abolished the risk of bone fracture. While the PEACE-III trial is ongoing and the results for combined with radium-223 for cancer are unknown as yet, it is clear that BPAs will be a key component for managing bone fractures during these types of treatments.


Why is this study important?

While the rate of cancer is increasing, therapies to treat the disease are improving. Better treatments are resulting in improved quality of life and survival. However, some of these treatments may lead to the weakening of a patient’s bones, resulting in an increased risk of fracture. Because of this, bone health is emerging as one of the most important considerations for men receiving treatment for cancer. There is an urgent need for increased focus on managing the bone health of men receiving cancer treatments. This study includes findings about how the addition of a bone-protecting agent BPA is important for treatments that might otherwise weaken bone health.

cancer and bone metastases

Patients with prostate cancer are initially treated with medical or surgical androgen deprivation to lower the levels of androgens made in the testicles. However, most patients develop what is termed (CRPC). mCRPC generally has a poor prognosis with shortened survival.

Bones are the most common site of cancer spread (or ). Among patients with prostate cancer, more than 90 percent have bone metastases, which not only affects quality of life by causing significant pain but can also reduce overall survival. Almost half of mCRPC patients develop significant bone pain and skeletal-related complications such as fractures or both.

Traditional treatments for patients with mCRPC and bone , including androgen inhibitors and internal radiotherapy, can weaken bones and increase the risk for bone breaks.


PEACE-III is a phase III study comparing (an androgen inhibitor) alone versus plus radium-223 dichloride (a type of internal radiotherapy that is given intravenously) in cancer patients with to bone. The researchers want to determine whether adding radium-223 to improves outcomes for these patients. It is important to note that the combined treatment of and Ra-223 is not approved standard of care and is currently not used outside of clinical trials.  

Radium-223 is administered intravenously and delivers radiation directly to the bone; like calcium, it is taken up by the bone. Importantly, radium-223 has been shown to reduce pain and prolong survival in men with cancer that has metastasized to the bone. While lowers male hormone levels and helps to prevent cancer from returning, it can cause bone loss and .

An earlier study designed similarly to PEACE-III showed that combining radium-223 with another () significantly increased the rate of fractures. Because of this observation, bone protecting agents (BPAs) were mandated for all PEACE-III patients regardless of the study arm to which they were assigned.

Either zoledronate (a bisphosphonate) or denosumab (a monoclonal antibody) were given to patients participating in PEACE-III. Both drugs are bone-protective agents that prevent bone from breaking down.


Study findings

A total of 267 men with newly diagnosed mCRPC were randomly assigned to one of two groups:

  • alone (133 patients)
  • plus radium-223 (134 patients)

136 patients enrolled in PEACE-III after BPAs were mandated and were given a bone-protecting agent (e.g., zoledronate or denosumab) regardless of whether they were in the only group or the plus radium-223 group.

At 12 months:

  • Among patients in the plus radium-223 arm, bone fractures occured in 37% of those who did not receive a BPA compared to 3% of patients who received a BPA.
  • Among patients in the alone arm, bone fractures occurred in 16% of patients who did not receive a BPA compared to 3% in patients who did receive a BPA.

Results were similar at 24 months:

  •  Among patients in the plus radium-223 arm, bone fractures occurred in 52% of patients who did not receive a BPA compared to 4% in patients who received a BPA.
  • At 12 months, among patients in the alone arm, bone fractures occurred in 22% of patients who did not receive a BPA compared to 3% in patients who did receive a BPA.

This updated analysis of PEACE-III confirms that in absence of BPAs, the risk of fracture is significantly increased when radium-223 is added to . However, this risk is almost abolished by the use of BPAs, thus stressing the importance of giving BPAs to mCRPC patients.

At this time, no outcome data have been reported for PEACE-III for how with or without radium-223 impacts cancer progression.


Strengths and limitations


  • This updated analysis confirms that the addition of radium-223 to an androgen inhibitor increases the risk of fracture.
  • This study shows that adding a BPA (e.g., zoledronate  or denosumab) to treatment with radium-223 can effectively reduce the risk of fracture. 


  • This study is ongoing. Whether the combination of with radium-223 improves cancer outcomes will not be known for some time.
  • The racial or ethnic diversity of participants was not reported. Treatment response may differ by race and ethnicity.   
  • More research is needed to determine the optimal time patients should consider treatment combined with a BPA.


What does this mean for me?

Bone loss and fracture are well-known side effects of treatment for prostate cancer. If you are receiving with or without Radium-223 for treatment of mCRPC, you might want to ask your doctor about your risk of bone fracture while taking these medications and whether adding a BPA may be beneficial.


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posted 11/5/21



Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACE-III trial combining Ra223 with versus alone: An updated safety analysis. American Society of Clinical Oncology Annual Meeting. Abstract 5002.


FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

People with metastatic castration resistant prostate cancer

This article is also relevant for:

people with metastatic or advanced cancer

people with prostate cancer

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Study background

NCT02043678 was a prior clinical trial that looked at whether the addition of radium-223 to (an androgen inhibitor) could improve outcomes for men with castration-resistant cancer (mCRPC). During this trial, men who received radium-223 combined with were approximately four times more likely to experience bone fractures compared to men who received alone. This resulted in an early of trial results and led to the mandatory incorporation of bone-protecting agents (BPAs) in the PEACE-III trial, which is similar in design.


Researchers of this study wanted to know

The researchers wanted to know if the (an androgen inhibitor) combined with radium-223 could improve outcomes for patients with mCRPC with bone metastases. Because the use of BPAs was mandated in this study, the researchers were also able to determine if BPAs reduce the risk of fracture associated with these treatments.


Populations looked at in this study

This study included 267 men with newly diagnosed mCRPC that had spread to at least two different areas of the bone.


Study design

The men were into the following treatment groups:

  • alone: received 160mg of once daily
  • + radium-223: received 160mg of daily plus radium-223 intravenously (approximately once a month for six months).

Some participants began the trial before BPAs were mandated for both arms; others joined the trial after the mandate. BPAs used by the participants were either denosumab or zoledronic acid.


Study findings

The recent safety analysis of the PEACE-III trial looked at the rate of fracture in each arm before and following the BPA mandate.

Among the 237 participants included in this interim analysis:  

  •  Most participants—70% of patients in the plus radium-223 arm and 73% percent of patients in the alone arm—received a BPA.
    • 14% of men in the plus radium-223 and 22% of men in the alone arm did not use BPA at registration but started during protocol treatment.
  • At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA:
    • A total of 39 patients reported a fracture.
      • among them, 30 patients (20 in plus radium-223 arm) did not receive BPA and 9 (4 in the plus radium-223 arm) received BPA.

At year one year:

  • Among patients who did not receive BPA, the risk for bone fracture was 37% for the plus radium-223 arm, compared with approximately 16% in the alone arm. 
  • Among patients who received BPA, the risk for bone fracture was about 3% for the plus radium-223 arm, compared with 4% in the alone arm. 

This trend continued up to one and a half years.

At one and a half years:

  • Among patients who did not receive BPA, the risk for bone fracture was approximately 46% for the plus radium-233 arm, compared with approximately 22% in the alone arm. 
  • Among patients who received BPA, the risk for bone fracture was 4% for the plus radium-223 arm, compared with 3% in the alone arm. 

In summary:

  • Men who received plus radium-223 without BPAs had the highest risk for bone fracture, followed by those who took alone without a BPA. 
  • The risk for a bone fracture was similar between men who received plus radium-223 with a BPA and alone with a BPA.
    • Among the plus radium-223 group, men who took a BPA were almost 14 times less likely to develop bone fractures than those who did not take a BPA.
    • Among the alone group, men who took a BPA were roughly 5 times less likely to develop bone fractures than those who did not take a BPA.


Strengths and Limitations


  • This ongoing study is looking at whether combining radium-223 with the androgen inhibitor improves outcomes for patients with mCRPC who have metastases to the bone. Because BPAs were mandated shortly after the study started, the researchers were able to look at whether or not the addition of BPAs to these treatment protocols decreased the risk for fracture.
  • Men with mCRPC have multiple treatment options, and side effects associated with medicines can reduce their quality of life and increase their risk of death. This study shows that a supplemental treatment with BPA can maintain or improve quality of life.  
  • This study also shows that the addition of radium-223 with was associated with an increased risk for bone fracture compared to alone.  


  • The study did not report on the dosage and/or duration of BPA use.
  • The age of participants was not mentioned in the study.
  • This study did not report on the racial or ethnic diversity of participants. Treatment response may differ by race or ethnicity.   



Patients with cancer often live with their disease for many years, and understanding the long-term consequences of treatment is increasingly important. Men with cancer are not routinely referred to bone specialists to monitor their bone health, even though cancer treatment can lead to bone loss and increased risk of fractures that often require hospitalization.

Although combining hormone therapies with radiation therapy is a well-validated therapeutic for the treatment of mCRPC, both treatments impact bone health. While this study was designed to look at whether the combination of and radium-223 improves outcomes in patients with mCRPC who have bone metastases compared to alone, the mandate to add BPAs to both treatment arms created an opportunity to determine whether the addition of BPAs reduced risk of fracture. Whether the mandated use of BPAs would reduce the risk of fractures in patients enrolled in PEACE-III was unclear. However, these results confirm that adding a BPA to the treatment regimen significantly reduces the risk of fracture. This will likely improve quality of life for patients and, importantly, it will also reduce mortality.



Currently, radium-223 is not recommended outside of clinical trials for use in combination with (or other androgen deprivation therapies such as ). If you are enrolled in a clinical trial that uses or another or you are prescribed radium-223, consider asking your doctor about the benefits of using bone-protecting agents to reduce your risk for bone fractures.


Share your thoughts on this XRAY review by taking our brief survey.
posted 11/5/21

Expert Guidelines
Expert Guidelines

National Comprehensive Cancer Network (NCCN) guidelines on the use of bone-protective agents for people diagnosed with  cancer recommend the following:

  • People with prostate cancer receiving radium-223: denosumab or zoledronic acid.  
  • People with cancer who will receive androgen deprivation therapy: baseline bone density scan before starting treatment. For patients whose risk for fractures is high enough to warrant therapy: denosumab, zoledronic acid or alendronate. 
  • People with with to the bone: a bone protective agents (denosumab has been shown to work better than zoledronic acid) to reduce the risk for bone fractures.

Bone-protective agents are associated with a risk of low calcium levels, and osteonecrosis of the jaw (a rare but serious deterioration of the jaw bone). Patients receiving bone-protective agents should have a baseline dental exam, practice good oral hygiene, avoid dental surgery and have their calcium levels and creatinine clearance levels monitored during treatment. 

Updated: 11/12/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • What medications are available to treat my type of cancer?
  • Has my cancer spread to my bones?
  • Is radium-223 therapy necessary for my type of cancer?
  • Does my current treatment put me at risk for bone fractures?
  • Would I benefit from taking supplemental medicines to help protect my bones?
  • Should I consult with a healthcare provider who has expertise in managing bone health for cancer patients?

Peer Support
Peer Support

The following organizations offer peer support services for people with or at high risk for cancer:

Updated: 03/08/2023

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