Skeletal related events (SREs), also known as symptomatic skeletal events, occur due to bone instability related to the treatment of advanced prostate cancer or due to the spread of prostate cancer to the bone (metastases). This results in localised pain at the site of spread and increased risk of fractures. Metastases to the spinal column can result in a pathological fracture with collapse of the vertebrae leading to spinal cord compression. SREs are associated with increased risk of mortality, pain, and low-quality of life. Symptomatic bone lesions may require radiotherapy or surgical intervention to improve symptoms. Patients may also present with high calcium levels in the blood.
Why does this happen?
The reason for this occurrence 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 the bone.
How common are skeletal related events?
It has been estimated that up to 50% of people with metastatic castrate resistant prostate cancer could develop SREs1. The risk of fractures over the 5 years after initiating treatment increases from 12.6% in untreated patients to 19.4% in those on androgen deprivation therapy2. It has been found that 80% of people about to start treatment, already have abnormal bone mineral density (BMD), compounding the risk of fractures3.
How is one's risk assessed?
Prior to any treatment a BMD scan (bone densitometry) should be performed. A specialised x-ray device measures the top of the femur (leg bone) and determines fracture risk. 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
- previous 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 intake and losing weight.
A carefully tailored exercise plan, as recommended by an exercise physiologist, has been effective in reducing the risk of SREs. However only 30-40 % of men with prostate cancer perform the recommended amount of exercise4. This may be due to the cancer itself or related to side effects of treatment. Some studies suggest that adherence to exercise increases when appropriate and acceptable exercise modalities are proposed.
Depending on the level of risk some specialists will recommend vitamin D and calcium supplementation with ongoing regular reassessment of risk.
Bone-modifying agents (BMAs) such as bisphosphonates (e.g. zoledronic acid) and human monoclonal antibodies/ RANK ligand inhibitors (e.g. denosumab) may delay the development of SREs. Both drugs act on cells in the bone (osteoclasts), which normally are responsible for breaking down bone, to allow for new bone formation. Electrolyte and kidney function should be monitored, and specialists may request a dentist referral due to a rare side effect affecting the jaw.
While 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 either 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 BMAs combined with antiandrogens such as enzalutamide or abiretarone versus these treatments alone.
The optimum treatment schedule remains controversial. The REDUCED trial noted some benefit to a 12 weekly dosing interval versus the traditional 4 weekly interval. The optimal duration of treatment with BMAs, once initiated, has not been determined. In clinical practice, these agents are often continued indefinitely until a patient either no longer tolerates them or there is progression of disease. With the increasing effectiveness of modern anticancer agents leading to enhanced control of systemic disease, including bone metastases, it is possible that the role of BMAs will be diminished.
The future
Several trials are investigating novel therapies which prevent the spread of cancer to bone or minimise the destructive effects once in the bone.
References
- Anton A et al. Real-world incidence of symptomatic skeletal events and bone-modifying agent use in castration-resistant prostate cancer - an Australian multi-centre observational study. European Journal of Cancer, 2021; 157:485-492.
- Walsh PC. Risk of fracture 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. Physical Therapy, 2022;102:1-13.
About the Author
Kalli Spencer
MBBCh, FC Urol (SA), MMed (Urol), Dip.Couns (AIPC)
Kalli is an internationally renowned Urological Surgeon, specialising in oncology and robotic surgery. He trained and worked in South Africa, before relocating to Australia where he has 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 improved cancer care and facilitating community prostate cancer support groups.
