Use of Bone-Modifying Agents in Oncology Patients

TON - JULY 2012 VOL 5, NO 6 — July 19, 2012

Use of Bone-Modifying Agents in Oncology Patients

With advances in the diagnosis and treatment of cancer, the estimated 5-year survival rate for cancer patients has significantly improved to approximately 67%.1 The most common malignancies in men and women in the United States—breast and prostate cancers— have 2 of the highest 5-year survival rates reported, at 90% and 99%, respectively.1 As oncology patients are living longer, bone health has become a pertinent issue in the treatment of both metastatic and nonmetastatic oncology patients.2

Pharmacologic therapies utilized in the treatment of metastatic and nonmetastatic cancer, including hormone deprivation and corticosteroids, can stimulate osteoclast activity and result in bone demineralization. Prolonged therapy may result in significant bone loss leading to osteoporosis and bone fractures in both the metastatic and nonmetastatic populations.2

Bone Health in Metastatic Cancer

In 2011, the American Society of Clinical Oncology (ASCO) published updated guidelines on the role of bone-modifying therapies in the management of metastatic breast cancer. While prior guidelines did include management of treatment-associated bone loss, ASCO limited this publication update to metastatic disease.4 Key changes in recommendations from this ASCO guideline update include4:

  • Bone-modifying agents are recommended for patients with metastatic disease and evidence of bone destruction; the following agents are recommended (none is recommended over another):
    • Denosumab 120 mg subcutaneously (SC) every 4 weeks
    • Zoledronic acid 4 mg intravenously (IV) over at least 15 minutes every 3 to 4 weeks
    • Pamidronate 90 mg IV over at least 2 hours every 3 to 4 weeks
  • Bone-modifying agents should be utilized as an adjunctive therapy, not as first-line treatment, for cancer- related bone pain, in addition to standard-of-care pain-management strategies (eg, nonsteroidal anti-inflammatory agents, opioid and nonopioid analgesics)

This published guideline limits discussion to metastatic breast cancer with bone metastases.4 Since other solid tumors, including prostate cancer, frequently metastasize to the bone, clinicians should similarly support the implementation of bone-modifying therapies to promote bone health and decrease skeletal-related events in patients with bone metastases due to solid tumors.3

Bone Health in Nonmetastatic Cancer Some anticancer treatments commonly seen in breast and prostate cancer, including hormone deprivation and corticosteroids, increase osteoclast activity and result in loss of bone mass.2 Bone-modifying therapy should be considered for cancer patients with 1 of the following2:

  • T-score below -2.0 or
  • 10-year Fracture Risk Assessment Tool (FRAX) score:
    • ≥3% for hip fractures
    • >20% for all major fractures

In 2011, the US Food and Drug Administration (FDA) completed the evaluation of the two phase 3 clinical trials of denosumab 60 mg SC every 6 months to prevent bone loss. These trials included patients with prostate cancer receiving androgen-deprivation therapy and breast cancer receiving aromatase inhibitors.5,6 As a result of these studies, the FDA expanded the approved indications for denosumab 60 mg SC every 6 months to include the following7:

  • Treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer
  • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer
  • Treatment of postmenopausal women with osteoporosis at high risk for fracture

Also in 2011, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) submitted a position paper on preventing bone loss and fractures in postmenopausal women receiving aromatase inhibitors for breast cancer.8

At a minimum, the final publication recommends measuring serum concentrations of parathyroid hormone, calcium, and 25-OH vitamin D prior to initiation of an aromatase inhibitor to establish the risk for osteoporosis. Pharmacologic interventions, including vitamin D and calcium supplementation, should be considered for all patients receiving aromatase inhibitors to promote bone health.8 Bone-modifying therapy with either zoledronic acid 4 mg IV over at least 15 minutes every 6 months or denosumab 60 mg SC every 6 months should be considered in patients with osteoporosis or osteopenia with risk factors for fractures and continue as long as aromatase inhibitor therapy is maintained.8

There is no clear recommendation for bisphosphonate therapy in nonmetastatic prostate cancer for patients receiving androgen-deprivation therapy. Recent evaluations have studied zoledronic acid 4 mg IV every 3 months for 1 year and found that therapy improved bone mineral density. The FDA has approved the use of alendronate, risedronate, and zoledronic acid in men to decrease fractures and increase bone density.9

Oral bisphosphonate therapy can be considered as an alternative to IV therapy, but these agents may be associated with additional adverse effects and variable compliance. In an evaluation on medication adherence, preference, and satisfaction in 250 postmenopausal women with low bone-mineral density, investigators determined that patients were significantly more compliant with denosumab 60 mg SC every 6 months compared with alendronate 70 mg by mouth once weekly.10 Additionally, at 12 months’ follow-up, those receiving denosumab were more likely to report being very satisfied or quite satisfied with the dosing frequency, route of administration, convenience, and overall satisfaction with treatment.10

Nonpharmacologic interventions should also be considered to further promote bone health. Additional supportive care measures include smoking cessation, minimizing alcohol consumption, and dietary supplementation with calcium (1000-1200 mg by mouth daily) and vitamin D (approximately 10,000 IU by mouth daily).8,9

Drug Safety Monitoring Safety concerns with bone-modifying therapies include, but are not limited to, renal toxicity, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures.4,11,12 Appropriate monitoring should occur at initiation of treatment and with each dose to minimize severe toxicities.4 The ASCO guidelines recommend the following for patients receiving bone-modifying therapies4:

  1. Serum creatinine should be monitored prior to each dose of bisphosphonates
  2. Serum calcium, electrolytes, phosphate, magnesium, and hemoglobin/ hematocrit should be monitored regularly [no specific recommendation provided on the interval]
  3. Calcium should be followed closely during denosumab therapy if the calculated creatinine clearance is less than 30 mL/min [no specific recommendation provided on the interval]
  4. Prior to initiation of bone-modifying therapies, all patients should undergo a dental examination and preventive dentistry to minimize osteonecrosis of the jaw

Although bisphosphonates are known to strengthen bone and prevent fractures, there have been reports that long-term therapy can lead to fragile bones and atypical fractures of the subtrochanteric or diaphyseal femur after minimal or no trauma; these atypical fractures account for less than 1% of hip and femur fractures overall.11-13 A safety announcement published by the FDA as an update to the bisphosphonate drug safety review in 2010 indicated that it is yet unclear whether these atypical fractures are related to bisphosphonate therapy; this safety evaluation is ongoing.13

Since this FDA update, 2 studies evaluating the rates of atypical fractures in nononcology patients with osteoporosis have been published. As described below, the studies do not rule out a correlation between bisphosphonate therapy and atypical fractures, but they do confirm that the rates of atypical femur fractures are very low with concurrent bisphosphonate therapy.11,12

In the first study, an evaluation of 12,777 Swedish women with femur fractures identified atypical fractures in 59 patients.11 The investigators concluded that, because 46 of the 59 patients with atypical fractures were on bisphosphonate therapy, there was a 47-fold increased risk compared to nonusers. Based on these results, they estimated that it would take 2000 bisphosphonate users per year to have 1 case of atypical fracture to occur.11

In the second study, investigators compared the incidence of atypical fractures between patients receiving either bisphosphonate therapy or nonbisphosphonate therapy (raloxifene or calcitonin) in 33,815 patients.12 Over the median follow-up of 2.13 years, 104 subtrochanteric or diaphyseal femur fractures occurred. There was no significant difference in the incidence of atypical femur fractures between bisphosphonate users and nonusers, however.12 Nevertheless, the authors could not eliminate the possibility that bisphosphonate therapy could increase the risk of atypical fractures with prolonged use.12

Ongoing Clinical Evaluations

Many studies investigating novel therapies in the management of bone health are currently ongoing. New promising approaches to the management of bone health include tyrosine kinase inhibitors (dasatinib, cabozantinib, and saracatinib), endothelin-A receptor antagonists (atrasentan and zibotentan), and bisphosphonates tagged with radiopharmaceuticals.4,14,15 It is to be hoped that these novel therapies will provide more options for clinicians to manage the bone health of oncology patients.


  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.
  2. Gralow JR, Biermann JS, Farooki A, et al. NCCN task force report: bone health in cancer care. J Natl Compr Netw. 2009;7(suppl 3):S1-S32.
  3. Coleman RE, Guise TA, Lipton A, et al. Advancing treatment for metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res. 2008;14:6387-6395.
  4. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29:1221-1227.
  5. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745-755.
  6. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26:4875-4882.
  7. Prolia [package insert]. Thousand Oaks, CA: Amgen Inc; September 2011.
  8. Rizzoli R, Body JJ, De Censi A, et al; on behalf of the European Society for Clinical and Economical Aspects of Osteoporosis and Osteoarthritis (ESCEO). Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper [published online ahead of print January 24, 2012]. Osteoporos Int. doi:10.1007/s00198-011-1870-0, Accessed April 16, 2012.
  9. Adler RA. Management of osteoporosis in men on androgen deprivation therapy. Maturitas. 2011;68:143- 147.
  10. Kendler DL, McClung MR, Freemantle N, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporosis Int. 2011;22:1725-1735.
  11. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364:1728-1737.
  12. Kim SY, Schneeweiss S, Katz JN, et al. Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res. 2011;26:993-1001.
  13. US Food and Drug Administration. FDA drug safety communication: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. Published October 13, 2010. Accessed April 18, 2012.
  14. Hannon RA, Finkelman RD, Clack G, et al. Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a phase I study. Bone. 2012;50:885-892.
  15. Saylor PJ, Lee RJ, Smith MR. Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol. 2011;29:3705-3714.

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