Renal Complications Need Consideration in CIBD

Theresa A. Guise, MD

Bisphosphonates and denosumab are bone-modifying agents that prevent or delay cancer-induced bone disease (CIBD) and skeletal-related events (SREs) by inhibiting bone resorption.¹Because these agents are administered as palliative care, avoiding toxicity is critically important.²Specifically, renal toxicity may pose a concern when treating with bisphosphonates, which are delivered at high doses intravenously (IV).²

Bisphosphonates

Bisphosphonates are a class of drugs that bind to bone material and induce osteoclast apoptosis, thus reducing hypercalcemia and the risk of fracture in cancer patients.³While 40% to 60% of bisphosphonate delivered IV binds to the bone, the remaining drug remains unmetabolized and is eliminated by the kidneys via glomerular filtration and active tubular excretion.⁴The mechanism of renal toxicity from bisphosphonates is not fully understood; however, it is thought to result from renal cell damage and apoptosis.⁴

Treatment with zoledronic acid, the most commonly used bisphosphonate, has been reported to be associated with acute tubular necrosis, which can lead to kidney failure.²Treatment with pamidronate, another common bisphosphonate, was found to reduce the risk of renal impairment by half compared with zoledronic acid.²However, pamidronate treatment has been associated with nephritic syndrome and a range of glomerular lesions.⁵The reason for differences in renal toxicities among bisphosphonates is not well understood.⁵

Because of these toxicity risks, it is recommended that patient renal function be evaluated before beginning treatment with bisphosphonates.²Because multiple myeloma (MM) can affect kidney function, patients with MM must be closely monitored and are at high risk for renal complications following bisphosphonate treatment.²The rate of creatinine clearance and estimated glomerular filtration rate may be useful for determining dosing and treatment frequency for patients with cancer.²

A key topic of interest is whether drug holidays would be beneficial in patients with cancer who are receiving bisphosphonate therapy, as a means to prevent adverse effects from prolonged treatment, including renal toxicity. Clinical trials have shown both beneficial and detrimental effects from bisphosphonate drug holidays in cancer patients.⁶Further investigation is needed to determine whether adverse effects from bisphosphonate treatment are reduced with drug holidays and, if so, to determine optimal schedules for drug holidays in different patient populations.⁶

Denosumab

Denosumab is a monoclonal antibody against receptor activated nuclear factor-κB ligand (RANKL) that prevents osteoclast formation, function, and survival by preventing activation by RANK.³

Denosumab was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of bone loss in patients with breast or prostate cancer who are receiving hormone ablation therapy.

In 3 identical phase III clinical trials of patients with prostate cancer, breast cancer, and advanced cancers (excluding breast and prostate) or MM, denosumab was compared with zoledronic acid for the prevention of SREs and renal toxicity.⁷

Denosumab reduced risk of a first SRE by 17% in patients with cancer compared with zoledronic acid.⁷Unlike zoledronic acid, dosing of denosumab did not require monitoring or modification based on renal status, although hypocalcemia was more common in patients treated with denosumab.⁷

Allan Lipton, MD, professor of medicine and oncology at the M.S. Hershey Medical Center of the Pennsylvania State University said, “These efficacy gains coupled with the convenience of a subcutaneous injection and no need for renal monitoring make denosumab an attractive option for these patients.”⁸

Clinical Pearls

• Renal toxicity is a concern when treating with bisphosphonates, which are delivered at high doses intravenously for cancer treatment.
• Although the mechanism of renal toxicity from bisphosphonates is not fully understood, it is thought to result from renal cell damage and apoptosis.
• It is recommended that patient renal function be evaluated before beginning treatment with bisphosphonates.
• Additional investigation is needed to determine whether adverse effects from bisphosphonate treatment are reduced with drug holidays.
• Dosing of denosumab does not require monitoring or modification based on renal status.

Denosumab was approved and granted Orphan Drug Designation by the FDA on December 8, 2014, for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.⁹

Before Bisphosphonates

Overall, treatment with bisphosphonates or denosumab is well-tolerated in patients with unimpaired renal function at the start of treatment. These agents have been instrumental in reducing SREs in patients with cancer and in improving quality of life.⁵

“Before we had bisphosphonates, if a breast cancer patient had bone metastases for 2 years, she had a 64% chance of developing a SRE: fracture or pain,” said Theresa A. Guise, MD, professor of oncology at Indiana University School of Medicine.

“With the advent of bisphosphonates, this was reduced to 43% with the less potent bisphosphonates, then 34% with the more potent zoledronic acid. Denosumab shows further improvement with a 27% incidence rate,”¹⁰Guise said.

References

1. Rizzoli R, Body J-J, Brandi M-L, et al. Cancer-associated bone disease. Osteoporos Int. 2013;24(12):2929-2953.
2. Diel IJ, Bergner R, Grötz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol. 2007;5(10):475-482.
3. American Cancer Society. Systemic treatments for bone metastases. American Cancer Society Web site. Available at: http://www.cancer.org/treatment/understandingyourdiagnosis/bonemetastasis/bone-metastasis-systemic-treatments. Updated February 17, 2014. Accessed December 7, 2014.
4. Body J-J, Pfister T, Bauss F. Preclinical perspectives on bisphosphonate renal safety. Oncologist. 2005;10(suppl 1):3-7.
5. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385-1393.
6. Tandon VR, Sharma S, Mahajan A. Bisphosphonate drug holidays: Can we recommend currently? J Midlife Health. 2014;5(3):111-114.
7. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48(16):3082-3092.
8. Killingsworth P. Amgen sites new studies, claiming experimental drug denosumab superior to Zometa. Living with Multiple Myeloma Web site. Available at: http://multiplemyelomablog.com/2010/10/amgen-sites-new-studies-claiming- experimental-drug-denosumab-superior-to-zometa.html. Published October 12, 2010. Accessed December 8, 2014.
9. FDA Approves Denosumab for Treatment of HCM. Available at: http://www.prnewswire.com/news-releases/fda-approves-amgens-xgeva-denosumab-for-the-treatment-of-hypercalcemia-of-malignancy-refractory-to-bisphosphonate-therapy-300005931.html. Accessed December 9, 2014.
10. Harris J. Denosumab reduced breast cancer skeletal-related events further than zoledronic acid. Healio: Endocrine Today Web site. Available at: http://www.healio.com/endocrinology/news/online/%7Bde7674b4-b530-4594-aa04- a47c3f83f300%7D/denosumab-reduced-breast-cancer-skeletal-related-events-further- than-zoledronic-acid. Published December 11, 2009. Accessed December 8, 2014.