Reducing the risk of bone fractures

This review examined the safety and efficacy of zoledronic acid (Zometa) and denosumab (Xgeva), two treatments for bone loss related to advanced prostate cancer.

Advanced prostate cancer (PC) can be associated with bone damage caused by bone metastases (cancer that has spread to the bones) or by androgen deprivation therapy (ADT). ADT is a type of hormonal therapy which lowers the amount of male sex hormones (androgens) in the body, which are responsible for PC growth, thus stopping the progression of PC. However, a common side effect of ADT is loss of bone mass, or bone mineral density (BMD). BMD is a measurement of bone density and strength, and refers to the amount of minerals (such as calcium) in the bones. Low BMD is associated with a high risk of fractures (braking of the bone). Bone metastases can also lead to skeletal-related events (SREs), such as multiple fractures or spinal cord compression, which can cause back pain, loss of sensations in the limbs, and paralysis. 

Osteoclasts are bone cells that remove bone tissue, a process that can be blocked by osteoclast inhibitors. Osteoclast inhibitors are a type of therapy used to prevent SREs in metastatic PC and fragility fractures in patients treated with ADT. The current study reviewed several clinical trials on osteoclast inhibitors such as zoledronic acid or ZA and denosumab in patients with advanced PC, to assess their risks and benefits.

Zoledronic acid is a drug from the bisphosphonates class that works by slowing the breakdown of bones and by reducing the amount of calcium the bones release. In castration-resistant PC (PC that no longer responds to ADT), ZA has been shown to lead to a significant decrease in SREs (33.2%) compared to patients who received a placebo (a substance with no effect on the body used as a control 44.2%). ZA therapy also led to a decrease in bone pain. 

Denosumab works by binding to the osteoclasts, thus inhibiting their activation. In a study involving 1468 patients treated with ADT, denosumab led to a 5.6% increase in lumbar spine BMD, compared to a 1.0% loss seen in the placebo group. Denosumab also led to lower fracture rates. Trials have found that denosumab can significantly delay metastasis in high-risk patients. However, the U.S. Food and Drug Administration  (FDA) has not yet approved the drug for the prevention of bone metastases. In a comparison between denosumab and ZA, denosumab increased the time to the first SRE by 3.6 months.

Both therapies are associated with negative side effects. Kidney toxicity has been seen with higher doses of ZA, leading to the need for dose adjustments in patients with decreased kidney function. Hypocalcaemia (very low amounts of calcium in the blood) has been associated with both treatments, and it is recommended that patients also use calcium supplements during treatment with any of the drugs. Osteonecrosis of the jaw (an infection of the jaw bone) has been associated with both therapies, but rates of this complication have varied across studies. The major risk factor for this infection is dental surgery or tooth extraction. Treatment begins with antibiotics, but surgery to remove the affected bone may be necessary.

In summary, both ZA and denosumab are effective treatments for bone complications in patients with advanced PC. However, while these drugs have significant benefits, they also have multiple adverse effects, which must be taken into consideration when considering this treatment. 

Discuss with your physician the risks and benefits of osteoclast inhibitors.