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Cancer treatment–induced bone loss and the role of zoledronic acid
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Individuals undergoing treatment for cancer are known to be at greater risk for bone loss, subsequent osteoporosis and fractures. Although this risk may be influenced by factors unrelated to cancer or cancer treatments, such as hereditary risk, hormone ablative therapies result in significant bone loss in both men and women.
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The use of aromatase inhibitors in postmenopausal women with breast cancer suppresses estrogen production beyond that of natural menopause and is associated with accelerated bone loss and fractures in a significant proportion of patients. Ovarian ablation (oophorectomy) or suppression (with luteinizing hormone–releasing hormone agonists) is often used alone or in combination with other therapies (eg, aromatase inhibitors or tamoxifen [Nolvadex, Zeneca]) for premenopausal breast cancer treatment, which accelerates bone loss and increases the risk for fractures in these women.
In men, accelerated bone loss is associated with androgen deprivation therapy used for treatment of prostate cancer. This phenomenon is often referred to as cancer treatment–induced bone loss (CTIBL) and may also be attributed to other therapies used during cancer treatment (eg, corticosteroids and chemotherapy).
There are currently no FDA-approved agents for the prevention or treatment of CTIBL. However, conventional therapies for managing osteoporosis have been used successfully. Intravenous bisphosphonates have been shown to decrease the incidence of skeletal-related events and are recommended by ASCO as adjunctive therapies for patients with bone metastases due to breast or prostate cancers.
Bisphosphonates are recommended for men receiving androgen deprivation therapy for prostate cancer as well. Similar guidelines for patients with early-stage breast cancer are currently not available, but researchers from many ongoing clinical trials are examining this issue.
Management of osteoporosis
The management of osteoporosis involves both nonpharmacologic therapy (eg, increase weight-bearing exercise) and pharmacologic therapy. Currently available medications for prevention and/or treatment of osteoporosis include bisphosphonates, calcitonin, selective-estrogen receptor modulators, recombinant parathyroid hormone, and calcium and vitamin D supplementation. Hormone therapy, consisting of estrogens with or without progestins, is generally not recommended for patients with a history of breast cancer. Human recombinant parathyroid hormone (Teriparatide, Forteo) is indicated for treatment of osteoporosis in women and men who are refractory to other therapies, but its use is limited in patients with cancer due to data from animal studies indicating an increased risk for osteosarcoma.
Of the remaining available pharmacologic therapies for osteoporosis, bisphosphonates are generally considered the most effective agents in maintaining bone mineral density and preventing fractures (ie, vertebral, nonvertebral and hip), and bone building may be seen in some patients as evidenced by increasing BMD.
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Choosing a bisphosphonate
Choosing among the available bisphosphonates is a complex decision. Clodronate is not yet available in the United States. Etidronate is generally avoided due to adverse effects on the quality of bone formation and an increase in other gastrointestinal adverse effects (eg, GI ulceration and perforation). Alendronate, ibandronate (Boniva, Roche) and risedronate are all available in oral formulations administered as daily, weekly or monthly doses (see table 1) and have similar toxicity profiles. Oral bioavailability of these agents is low (0.5% to 1%), but the potency of the drug that reaches the systemic circulation and ultimately the bones is usually adequate to maintain healthy bone metabolism for many patients.
For some patients at high risk for osteoporosis or under conditions promoting bone loss (eg, hormone-deprivation therapy for cancer) use of oral bisphosphonates may not be adequate to maintain BMD and prevent fractures. Intravenous formulations are available for ibandronate, pamidronate and zoledronic acid. Of these agents, only ibandronate and zoledronic acid are indicated by the FDA for treatment of osteoporosis and may be used for patients who continue to lose bone on or are unable to tolerate an oral bisphosphonate.
Ibandronate is administered as 3 mg IV every three months and zoledronic acid was recently approved as a 5-mg once-yearly IV preparation (Reclast, Novartis). Zoledronic acid is also available as a 4-mg IV dose for treatment of bone metastases secondary to breast cancer, other solid tumors, including prostate cancer, and myeloma and for treatment of hypercalcemia of malignancy. This is also the dose that was used in trials with zoledronic acid for CTIBL.
Adverse events associated with the oral bisphosphonates include primarily GI adverse effects associated with oral administration (eg, GI reflux, ulceration and perforation); however, rare effects include renal dysfunction and osteonecrosis of the jaw. These medications require an empty stomach to ensure maximal absorption. Instructions regarding proper administration are helpful to decrease the incidence of GI effects such as remaining upright for at least 30 minutes after administration. The incidence and severity of rare adverse events (eg, renal dysfunction and ONJ) increases with increasing duration of therapy and IV administration, but are still relatively infrequent and generally manageable conditions. Nonetheless, monitoring for these adverse events (eg, routine serum creatinine or dental examinations) is imperative to ensure early intervention.
Calcitonin does not appear to be as effective as the bisphosphonates and is generally considered for patients who are not able to tolerate bisphosphonate therapy. Raloxifene is a selective-estrogen receptor modulator that is indicated by the FDA for osteoporosis and could have the added benefit of breast cancer risk reduction. However, the risk for thromboembolism is significant with raloxifene and concomitant use with other hormonal therapies (eg, aromatase inhibitors, tamoxifen or toremifene) used to treat cancer is contraindicated. Also, bisphosphonate therapy may be more effective for management of osteoporosis compared with raloxifene. Calcium and vitamin D supplementation are also important for all patients and should be encouraged in addition to the use of other bone-targeted therapies.
Management of CTIBL
To date, treatment of CTIBL is similar to managing patients with osteopenia or osteoporosis without cancer. Oral bisphosphonates are generally used first-line when a patient’s T-score begins to fall into the osteopenic range (T-score –1 to –2.5 SD) or the osteoporotic range (T-score <–2.5 SD) range. Researchers investigating the use of these agents for prevention of bone loss focus on the bisphosphonates.
Clodronate and risedronate have shown a preventive effect when administered after chemotherapy-induced premature ovarian failure. Three clinical trials have demonstrated that zoledronic acid (4 mg) may be effective in countering bone loss due to aromatase inhibitor therapy. In the Zometa/Femara Adjuvant Synergy Trial, researchers examining the use of zoledronic acid for this indication randomly assigned patients to zoledronic acid (4 mg IV every six months) at the beginning of adjuvant letrozole, or delayed administration when their T-score fell below –2.0 SD or they had a clinical fracture. An added endpoint in this trial is time to distant recurrence/relapse of their cancer. Preliminary results from this trial after one year of follow-up indicate that BMD was increased with zoledronic acid when administered with letrozole. When zoledronic acid administration was delayed, significant reductions in BMD were apparent during the first year. Long-term effects on bones, cancer relapse rates and differences between initiation time points are expected to be reported from this trial with further follow-up.
For men with prostate cancer, conflicting results have been reported with the oral bisphosphonates alendronate and risedronate. Use of IV bisphosphonates (pamidronate or zoledronic acid every three months) prevented androgen deprivation–induced bone loss in the hip and lumbar spine in men with nonmetastatic prostate cancer receiving an LH-RH agonist. In this trial, pamidronate maintained BMD, but zoledronic acid appeared to increase BMD. Unfortunately, none of the researchers of these trials have yet to report changes in fracture rates. However, more information will be forthcoming as these patients are followed for longer periods. Also, effects on overall survival will be important to note in these trials.
Reclast (zoledronic acid 5 mg)
As noted above, zoledronic acid has generally been studied as a 4-mg dose for the treatment or prevention of CTIBL. However, this dose of zoledronic acid has not been FDA-approved for this indication and use is not likely to be reimbursed unless the patient also has a diagnosis of metastatic cancer. With the approval of zoledronic acid 5 mg for osteoporosis (Reclast, Novartis), the clinician is in a quandary as to what to do. Most of the data with zoledronic acid in patients with cancer at high-risk for osteoporosis have been with a 4-mg dose administered every three to six months (as noted above).
Reclast, as it is approved (5 mg yearly), has been studied in one large trial to date. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial was a randomized, double blind, placebo-controlled study. It was composed of postmenopausal women with osteoporosis. The researchers compared zoledronic acid 5 mg with placebo. A previous cancer diagnosis was not an exclusion criterion for the trial; therefore cancer patients were likely included although data regarding this characteristic were not stated in the publication. Other osteoporosis medications were allowed during the trial and included agents such as hormone therapy, raloxifene, tamoxifen and calcitonin. The concomitant use of raloxifene was noted in 41.6% of the patients assigned zoledronic acid and 42.1% of the patients assigned placebo, confounding the results of this trial.
Nonetheless, in patients not on other osteoporosis medications, treatment with zoledronic acid produced a 70% reduction in the risk for vertebral fracture compared with placebo. The incidence of hip fracture and all clinical fractures during a three-year period were also reduced by 41% in women assigned zoledronic acid vs. 33% in women assigned placebo. Based on these results, the FDA approved Reclast (Novartis) for treatment of postmenopausal osteoporosis.
Having two doses of zoledronic acid currently on the market with differing FDA-approved indications makes billing and reimbursement complicated and confusing. Zoledronic acid as a 4-mg dose for treatment of bone metastases due to cancer comes in a 4 mg/5 mL single-use vial and requires further dilution in normal saline or D5W prior to administration. Zoledronic acid as a 5-mg dose for treatment of osteoporosis comes in a 5 mg/100 mL bag for IV infusion and does not require further dilution (also does not yet have a J-code for billing). Both formulations are administered in 15 minutes via IV infusion and appear to have similar adverse event profiles (from indirect comparisons).
Keeping both doses on the shelf seems redundant, but given the current approval and billing situation there appears to be little recourse to do anything else. The 4-mg dose of zoledronic acid should be used for patients with existing bone metastases for prevention of SREs or for treatment of hypercalcemia of malignancy. Use of the 5-mg dose of zoledronic acid should be reserved for treatment of patients with osteoporosis or CTIBL. Table 2 lists the appropriate J-codes and CPT codes for administration of the two different formulations.
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*Effective January 1, 2008. **For solid tumors, the ICD 9 Code for bone metastases (198.5) should accompany an ICD 9 code for the primary cancer (eg, malignant neoplasm of prostate - 185). The codes in this table are provided for informational purposes only and their use does not guarantee payment. It is the sole responsibility of each provider to confirm all coding and billing information with specific third-party payers, as policies may differ. It is also the sole responsibility of each provider to determine the most appropriate codes to use when billing to ensure that the coding and billing for all services and products are appropriate and correct. J-code for zoledronic acid (5 mg/100 mL bags) not yet available |
Summary
Although there are multiple appropriate therapies for the management of osteoporosis, few agents have been studied for CTIBL. Oral bisphosphonates are by and large the most commonly prescribed agents for this condition, but little data exists to support this indication and many patients may be refractory to this cumbersome therapy.
With the approval of once-yearly zoledronic acid for osteoporosis, the use of this agent for management of CTIBL may now be reimbursed and may be more convenient for patients. However, most of the researchers using zoledronic acid for management or prevention of CTIBL have used a dose of 4 mg, not 5 mg, administered every three to six months, not yearly. Therefore, the clinician is in a quandary as to what dose and schedule to choose. Also, only time will tell as to what third-party payers will decide to cover for these medications. Until we have more information, the most appropriate course of action would be to reserve the 5-mg dose of zoledronic acid for patients with earlier-stage cancer with CTIBL who are unable to tolerate or are refractory to oral bisphosphonates and use the 4-mg dose for management of patients with bone metastases. Calcium and vitamin D supplementation and incorporation of weight-bearing exercise into their daily routine is also paramount to successful management of CTIBL or osteoporosis and should be emphasized through patient education in addition to any prescribed medications.
Jaime Anderson, PharmD, is an Oncology Pharmacy Resident at The University of Texas M.D. Anderson Cancer Center.
Laura Boehnke Michaud, PharmD, BCOP, FASHP, is Manager of Clinical Pharmacy Services at The University of Texas M.D. Anderson Cancer Center.
For more information:
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.
- Brufsky AM. Cancer treatment–induced bone loss: pathophysiology and clinical perspectives. Oncologist. 2008;13:187-195.
- MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative efficacy of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008;148:197-213
- Reclast (zoledronic acid) product information. East Hanover, NJ: Novartis Pharmaceuticals Corp.; August 2007.
- Red Book for Windows [CD-ROM]. Vol 47. Greenwood Village, CO: Thomson Healthcare.