Zometa or Xgeva: Tailoring Bone Therapy in Multiple Myeloma

The advent of bone-targeting therapies has transformed the management of complications in multiple myeloma. Two key agents, zoledronic acid (Zometa) and denosumab (Xgeva), are recognized as primary options in clinical settings. 

Progressive bone disease is a common risk among multiple myeloma patients, arising from the dysregulation of bone turnover processes.

In a healthy body, bone cells called osteoclasts break down and remove old or damaged bone, while another type of bone cell, osteoblasts, is responsible for building and forming new bone tissue. These two types of cells work together to keep bones strong and healthy.

Breaking Down Bone Disease in Myeloma 

To illustrate this at the cellular level, consider bones as brick walls. The osteoclasts, or the “workers,” normally remove old bricks to make room for new ones. However, in multiple myeloma, the osteoclasts remove too many bricks or bone tissue, weakening the wall and leaving it full of holes. 

If left untreated, a patient will experience an imbalance characterized by heightened osteoclast activity and suppressed function of osteoblasts' “repair team.” This leads to osteolytic lesions, pathological fractures, and skeletal-related events (SREs) that significantly impair patients' quality of life.

Zometa and Xgeva’s Mechanisms of Action 

Zometa is administered intravenously (via IV) and functions as a bisphosphonate, much like a strong adhesive on the bone's surface. It binds to areas where bone breakdown is occurring. 

When osteoclasts begin resorbing bone, they take up Zometa, which interferes with the cells’ internal processes. This disruption hampers the osteoclasts’ ability to break down bone effectively, ultimately slowing down bone loss and helping to maintain overall bone strength.

Xgeva is a monoclonal antibody administered as a subcutaneous injection that targets a protein called RANKL. RANKL functions as a signal or "boss" that tells osteoclasts when to break down bone. By binding to RANKL, Xgeva prevents it from interacting with its receptor, RANK, on immature osteoclasts. This action stops these cells from maturing into active bone-resorbing osteoclasts.

Essentially, Xgeva working upstream silences the signals that lead to bone degradation, thereby keeping the bone structure more intact over time.  

Clinical Efficacy of Zometa and Xgeva 

The differing mechanisms of action may have an impact on your clinical outcome. 

Zometa has been shown to reduce skeletal-related events by about 12% compared to other bisphosphonates. Notably, this treatment provides survival benefits, increasing progression-free survival (PFS) by roughly 2 months and overall survival (OS) by about 5.5 months. 

In contrast, a phase-3 study comparing these treatments revealed that both Zometa and Xgeva delay the first skeletal-related event similarly roughly between 23 and 24 months. Data suggests Xgeva may extend PFS by an additional 10.7 months compared to Zometa. 

Despite this promising difference in delaying disease progression, overall survival outcomes remain similar between the two treatments.

Which Is Right for You?

Choosing between these agents depends on patient-specific factors. 

Zometa is cleared through the kidneys, so patients with renal issues require close monitoring and possible dose adjustments. Listed side effects include temporary flu-like symptoms and, rarely, osteonecrosis of the jaw (ONJ). Because Zometa’s uptake depends on bone resorption, its effects may be slightly delayed. 

Xgeva offers a convenient option, especially for patients with mobility challenges, and is safer for those with renal impairment, though calcium levels must be monitored to prevent hypocalcemia. 

Both treatments carry a similarly low risk of ONJ, and if you are scheduled for any dental work, it is very important to notify your care team and your dentist before receiving treatment.

It's also worth noting that cost can be a factor; Zometa tends to be more affordable, while Xgeva offers advantages in convenience and safety for some patients.

Overall, both Zometa and Xgeva are key tools in managing bone disease in multiple myeloma, allowing clinicians to tailor therapy to each patient's unique clinical situation while balancing efficacy, safety, and quality of life.

Discuss with your doctor which is right for you. 

For more learning on this subject, check out the following educational videos on HealthTree University: 

Zometa: All About Bisphosphonate Therapy: Zometa (Zoledronic Acid) or Aredia (Pamidronate)

Xgeva: All About XGEVA (Denosumab)

Sources: 

• Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study
• Osteoclast differentiation and activation | Nature
• Management of bone disease in multiple myeloma - PubMed
• All About Bisphosphonate Therapy: Zometa (Zoledronic Acid) or Aredia (Pamidronate)