What are skeleton-related events?

What are skeleton-related events?

Skeletal-related events (SREs), also known as symptomatic skeletal events, occur due to bone instability related to treatment of advanced prostate cancer or due to spread of prostate cancer to the bone (metastasis). This results in localized pain at the site of spread and an increased risk of fractures. Metastases in the spinal column can cause a pathological fracture with collapse of the vertebrae leading to compression of the spinal cord. RES are associated with an increased risk of mortality, pain, and poor quality of life. Symptomatic bone lesions may require radiation therapy or surgical intervention to improve symptoms. Patients may also have high levels of calcium in the blood.

Why did this happened?

The reason for this fact is twofold. Androgen deprivation therapy, commonly used to treat this stage of prostate cancer, has an effect on bone metabolism, reducing the production of new bone. This weakens the integrity of the bone (bone mineral density). Prostate cancer metastases can also secrete substances that can weaken bone.

How common are skeleton-related events?

It has been estimated that up to 50% of people with metastatic castration-resistant prostate cancer could develop SRE1. The risk of fractures during the 5 years after starting treatment increases from 12.6% in untreated patients to 19.4% in those with androgen deprivation therapytwo. It has been found that 80% of people who are about to start treatment already have abnormal bone mineral density (BMD), which increases the risk of fractures.3.

How is one’s risk assessed?

Before any treatment, a BMD scan (bone densitometry) should be performed. A specialized x-ray device measures the upper part of the femur (leg bone) and determines the risk of fracture. This is combined with a clinical risk assessment.

The following factors increase the risk of a fracture:

  • age >65
  • body mass index (BMI) 24
  • tobacco
  • alcohol
  • corticosteroid treatment
  • history of falls and fractures
  • family history of hip fractures

What can be done to prevent it?

A good starting point is to modify certain lifestyle factors, such as quitting smoking, reducing alcohol consumption, and losing weight.

A carefully designed exercise plan, as recommended by an exercise physiologist, has been effective in reducing the risk of SRE. However, only 30-40% of men with prostate cancer get the recommended amount of exercise.4. This may be due to the cancer itself or related to side effects of treatment. Some studies suggest that adherence to exercise increases when adequate and acceptable exercise modalities are proposed.

Depending on the level of risk, some specialists will recommend vitamin D and calcium supplementation with ongoing periodic reassessment of risk.

Bone modifying agents (BMAs), such as bisphosphonates (eg, zoledronic acid) and human monoclonal antibodies/RANK ligand inhibitors (eg, denosumab), may delay the development of SRE. Both drugs act on cells in the bone (osteoclasts), which are normally responsible for breaking down bone, to allow new bone to form. Electrolytes and kidney function should be monitored, and specialists may request a referral to the dentist due to a rare side effect involving the jaw.

Although BMAs can reduce the incidence of SREs, delay the time to onset of SREs, and improve patient quality of life, they have not been shown to improve disease-free or overall survival.

The international ERA-223 and PEACE III trials support the role of BMA, demonstrating a reduced fracture rate in men receiving BMA combined with antiandrogens such as enzalutamide or abiretone compared to these treatments alone.

The optimal treatment schedule remains controversial. The REDUCED trial found some benefit with a 12-week dosing interval versus the traditional 4-week interval. The optimal duration of treatment with BMA, once started, has not been determined. In clinical practice, these agents are often continued indefinitely until the patient no longer tolerates them or there is disease progression. With the increasing efficacy of modern anticancer agents leading to better control of systemic disease, including bone metastases, the role of BMAs may diminish.

The future

Several trials are investigating new therapies that prevent the spread of cancer to the bone or minimize the destructive effects once in the bone.


  • Anton A et al. Real-world incidence of symptomatic skeletal events and use of bone-modifying agents in castration-resistant prostate cancer: an Australian multicentre observational study. European Journal of Cancer, 2021; 157:485-492.
  • Walsh P.C. Fracture risk after androgen deprivation for prostate cancer. The Journal of Urology, 2005, 174: 929-
  • Gómez-Aparicio MA et al. Bone health and therapeutic agents in advanced prostate cancer. Frontiers in Bioscience, 2022; 27(1): 34.
  • Cagliari M et al. Feasibility and safety of physical exercise to preserve bone health in men with prostate cancer receiving androgen deprivation therapy: a systematic review. Physiotherapy, 2022;102:1-13.

About the Author


kalli spencer

MBBCh, FC Urol (SA), MMed (Urol), Dip.Couns (AIPC)

Kalli is an internationally renowned urologic surgeon, specializing in oncology and robotic surgery. He trained and worked in South Africa, before moving to Australia, where he worked at Macquarie University Hospital and Westmead Hospital. His passion for what he does extends beyond the operating room, through public health advocacy, education and community awareness of men’s health, cancer and sexuality.

Kalli has been involved with the Prostate Cancer Foundation of Australia for many years, advocating for better cancer care and facilitating community prostate cancer support groups.

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