Systemic Therapy for Bone Metastases

August 24, 2012 Adverse Drug Reactions, Drug Informatics, Hematology, Pharmacology, Therapeutics No comments , , ,

zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.


Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities. (more…)

No bisphosphonate superior to another in multiple myeloma

July 7, 2012 Adverse Drug Reactions, Hematology, Therapeutics No comments , , , ,

May 17, 2012 — None of the bisphosphonates used as supportive therapy in multiple myeloma is superior to any of the others, according to a meta-analysis published online May 16 in the Cochrane Database of Systematic Reviews.

The last Cochrane review on this topic was published in 2010. In this update, 2 studies were added; the cohort is now 6692 patients from 20 trials.

This updated review concludes that zoledronate (Zometa) appears to be superior to both etidronate (Didronel) and placebo. However, it was not superior to pamidronate (Aredia) or clodronate (Bonefos) for improving overall survival or any other outcome, such as vertebral and nonvertebral fractures.

“Whether zoledronate is superior to any other bisphosphonate drug remains an open question,” lead researcher Ambuj Kumar, MD, MPH, from the Center for Evidence-Based Medicine and Health Outcomes Research at the University of South Florida in Tampa, said in a statement.

“In light of the inconsistencies we see in the data, it is difficult to recommend any drug as a preferential treatment for clinical practice,” he explained.

The choice of bisphosphonate for multiple myeloma patients “should ideally be based on evidence from comparative trials,” the authors write, but they point out that to date, there are only 4 head-to-head comparative studies of these agents.

Questions About Superiority

The question of whether zoledronate is superior to other bisphosphonates was raised after a randomized trial showed an improvement in overall survival, independent of the prevention of skeletal-related events.

The data from that study, originally presented at the 2010 annual meeting of the American Society of Clinical Oncology and published later that year (Lancet. 2010;376:1989-1999), showed that zoledronate was significantly better than clodronate in preventing skeletal-related events (27.0% vs 35.3%; P = .0004).

Compared with clodronate, zoledronate also significantly reduced the risk for death by 16%, significantly improved median overall survival (50.0 vs 44.5 months; P = .0118), and significantly improved progression-free survival (19.5 vs 17.5 months; P = .0179).

Despite these promising results, Jeffrey Davies, PhD, BM, a medical oncologist from the Dana-Farber Cancer Institute in Boston, Massachusetts, cautioned that it is still too early to consider changing clinical practice. In a Lancet podcast that accompanied the publication of those data, he pointed out that the study authors postulate that zoledronate might have direct antimyeloma activity, in addition to its effect on preventing bone disease. They suggest that all myeloma patients should receive zoledronate from the time of their initial diagnosis, whether or not they have bone disease.

Dr. Davies explained that administering bisphosphonates is already part of standard clinical practice for myeloma patients who present with bone disease; however, it is not known if zoledronate “is superior to other bisphosphonates such as pamidronate (which is commonly used), has a similar mechanism of action, is less expensive, or is associated with less toxicity,” he said.

According to Dr. Davies, the study findings did not demonstrate a clear survival benefit with zoledronate in the one third of myeloma patients who did not have bone disease at the time of diagnosis. “It remains unclear to me whether this subset of patients will benefit from prophylactic treatment with zoledronate or any other bisphosphonate,” he said.

No Significant Differences

The updated Cochrane meta-analysis comprised 16 randomized controlled trials comparing a bisphosphonate with placebo or no treatment, plus 4 trials that had a different bisphosphonate as the comparator.

Although the pooled results showed no direct effect of bisphosphonates on overall survival, compared with placebo or no treatment (HR, 0.96, P =.64), there was a statistically significant heterogeneity among the trials for overall survival (I², 55%; P = .01).

A network meta-analysis was conducted of the bisphosphonates that were not compared in head-to-head trials. These results showed that overall survival was better with zoledronate than with etidronate (HR, 0.43) or placebo (HR, 0.61), but there were no differences between zoledronate and other bisphosphonates.

The pooled analysis showed that bisphosphonate use was not associated with a statistically significant improvement in progression-free survival, compared with placebo or no treatment. The pooled HR for progression-free survival was 0.70 (P = .18); there was no heterogeneity among these trials (I², 35%; P = .20).

There was, however, a beneficial effect of bisphosphonates, compared with placebo or no treatment, for preventing pathologic vertebral fractures (relative risk [RR], 0.74; I² = 7%) and skeletal-related events (RR, 0.80; I², 2%), and decreasing pain (RR, 0.75; I², 63%). Rates of osteonecrosis of the jaw seen in the 9 observational studies (1400 patients) ranged from 0% to 51%.

No Preferential Treatment

In the “context of multiple treatment comparison uncertainty analysis, zoledronate ranked as the best treatment, followed by clodronate and pamidronate,” the authors note. But no difference was observed when pamidronate was compared with clodronate or zoledronate for all outcomes.

“It would, however, be difficult to recommend zoledronate as a preferential treatment for clinical practice in the light of inconsistencies seen across the types of analysis,” they conclude. “These findings underscore the need for comparative evaluation of the newer potent aminobisphosphonates, especially zoledronate vs pamidronate, in an RCT to enable appropriate healthcare decision making.”

The study was supported by Center for Evidence-Based Medicine at the University of South Florida, the Department of Internal Medicine at the University of Bonn in Germany, Leukämie-Initiative Bonn e.v. in Germany, and the Cochrane Haematological Malignancies Group in Germany. The authors have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. 2012;5:CD003188. Abstract