Chapter 47: Indications for Bone-Modifying Agents in Hematology-Oncology

Reem Abozena Shalabi; James N. Frame

INTRODUCTION

Primary Indications in Patients with Cancer

To protect bone from new metastatic lesions
To treat hypercalcemia of malignancy
To prevent treatment-related bone demineralization, osteolysis, and pathologic fractures
To treat osteolytic lesions, decrease the incidence of pathologic fractures, prevent skeletal deformities, and prevent and decrease the severity of pain

Intravenous Versus Oral Bisphosphonates

Intravenous

Much more effective than oral agents at reversing hypercalcemia and relieving bone pain, particularly in patients with breast cancer and multiple myeloma
Can overcome disadvantages associated with oral agents, including poor absorption from the GI tract (<3% oral bioavailability); have a lower incidence of adverse GI events
Require clinic/hospital administration

Oral

Convenient
Absorption can be impaired by food and beverages other than water
Associated with greater incidence of upper GI toxicity than with intravenous administration, including dysphagia; esophagitis; and esophageal, gastric, or duodenal erosion; ulceration; and perforation

Body JJ et al. J Clin Oncol 1998;16:3890–3899

Riccardi A et al. Tumori 2003;89:223–236

Hypocalcemic Effects

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Hypocalcemic Effects

Bisphosphonate

Median Time to Normocalcemia

Duration of Normocalcemia

% Achieving Normocalcemia

Zoledronic acid¹

4 days

32 days

Pamidronate^2,3

4 days

28 days

70-100

Clodronate³

3 days

14 days

Alendronate⁴

4 days

15 days

Ibandronate⁵

4 days

14 days

76.5

Etidronate⁶

4 days

29 days

References

Major P et al. J Clin Oncol 2001;19:558–567 [PubMed: 11208851]

Body JJ, Dumon JC Ann Oncol 1994;5:359–363 [PubMed: 8075034]

Purohit OP et al. Br J Cancer 1995;72:1289–1293

Nussbaum SR et al. J Clin Oncol 1993;11:1618–1623 [PubMed: 8336198]

Pecherstorfer M et al. Support Care Cancer 2003;11:539–547 [PubMed: 12783289]

Singer FR et al. Arch Int Med 1991;151:471–476

Notes

Osteonecrosis of the Jaw

The American Society of Bone and Mineral Research Task Force has defined osteonecrosis of the jaw (ONJ) as the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a healthcare professional¹
Potential risk factors for developing ONJ in patients with cancer²:
1. Poor oral hygiene and periodontal disease³
2. History of dental procedures for extractions or denture use (that may cause soft tissue injury)
3. Prolonged exposure to high doses of intravenous bisphosphonates
4. Intravenous bisphosphonate use poses greater risk than oral bisphosphonates
5. Zoledronic acid seems to cause more ONJ compared to pamidronate⁴
6. ONJ developed in 7% to 10% of patients with myeloma and 4% of patients with breast cancer
7. Among patients on oral bisphosphonates (eg, alendronate), there is a very low risk (estimated at 0.7 cases of per 100,000 person-years exposure) of developing bone osteonecrosis⁵
8. Radiation-induced damage with head and neck cancer or oral cancer³
9. Concomitant therapy with corticosteroids; chemotherapy³
Clinical presentation and diagnosis of ONJ
1. Signs and symptoms include localized pain, soft-tissue swelling and inflammation, loosening of previously stable teeth, drainage, and exposed bone. These symptoms most commonly occur at the site of previous tooth extraction or other dental surgical procedures but may also occur spontaneously. Objective signs before overt clinical presentation may include a sudden change in the health of periodontal or mucosal tissues, failure of the oral mucosa to heal, oral pain, loose teeth, or soft-tissue infection³
Supportive treatment²
1. Antiseptic oral rinses (eg, 0.12% chlorhexidine gluconate)
2. The decision to treat with an antibiotic is a clinical judgment and should be made by an oral maxillofacial surgeon or other dental specialist with the treating physician/oncologist. If an antibiotic is used, cultures should be collected to determine appropriate antimicrobial intervention. Cultures should include assessment of aerobic and anaerobic bacteria, viral, and fungal species³
3. Limited surgical debridement as needed, which usually leads to healing
The bisphosphonates class of medications have clearly enhanced care of patients with oncologic disease. ONJ is an unforeseen and unfortunate potential adverse effect associated with these medications⁶
1. All oncology patients should receive a comprehensive dental examination to include a panoramic jaw radiograph and appropriate preventive dentistry before starting bisphosphonate therapy
2. At a minimum, oncologists should perform a visual inspection of the oral cavity at baseline and at each follow-up visit to look for the presence of necrotic or exposed bone³
3. Good oral hygiene along with regular dental care is the best way to lower risk
4. Active oral infections should be treated, and sites at high risk for infection should be eliminated
5. While on therapy, patients should maintain excellent oral hygiene along with regular dental care⁵, and, if possible, avoid invasive dental procedures⁶
6. Patients should be instructed to contact their dentist if any problem develops in the oral cavity⁵
7. Patients should be instructed to inform their dentist if they are taking bisphosphonate medications⁵
8. The decision to defer or discontinue bisphosphonate therapy must be made by the treating oncologist in consultation with an oral maxillofacial surgeon or other dental specialist³

Role of Bone-modifying Agents (Bisphosphonates) in Multiple Myeloma

The American Society of Clinical Oncology (ASCO) first published evidence-based clinical practice guidelines in 2002, which were reviewed and expanded in 2007. Below is a summary of the updated guidelines⁶:

For patients with lytic bone disease on plain radiographs, a bisphosphonate is recommended. Pamidronate 90 mg administered intravenously over at least 2 hours every 3 to 4 weeks may be preferable to zoledronic acid 4 mg intravenously over at least 15 minutes due to an increased risk of ONJ with the latter⁴
Monitoring: Renal adverse events have resulted in increased caution with regard to dosing. New dosing guidelines were added to recommendations for zoledronic acid use in patients with pre-existing renal impairment
1. Practitioners should monitor patients receiving pamidronate or zoledronic acid for albuminuria every 3 to 6 months
2. In patients experiencing unexplained albuminuria (>500 mg albumin in urine per 24 hours), discontinuation of the drug is advised until renal problems are resolved. Reassessment is recommended every 3 to 4 weeks (with a 24-hour urine collection for total protein and urine protein electrophoresis). If treatment with pamidronate resumes after renal function returns to baseline, the drug should be administered over a longer infusion duration (≥4 hours) and at doses and treatment intervals not greater than 90 mg every 4 weeks
3. The ASCO practice guidelines 2007 Update Committee supported the use of screening urinalysis for proteinuria, but underscores that a 24-hour urine collection for determination of total protein and electrophoresis is required if the screening test is positive. Similar guidelines are not available for zoledronic acid; however, some Update Committee members recommended that treatment with zoledronic acid when resumed should be administered over durations greater than 15 minutes (eg, ≥30 minutes)
Duration of therapy: the ASCO 2007 Update Committee recommended monthly bisphosphonate for a maximum of 2 years after tandem transplant for multiple myeloma⁶
1. The Update Committee also recommended that physicians should seriously consider discontinuing bisphosphonate therapy in patients with responsive or stable disease, but continued use remains at the discretion of a treating physician. For patients in whom bisphosphonate therapy is discontinued after 2 years of treatment, bisphosphonate therapy may be resumed upon relapse with new-onset skeletal-related events
Bisphosphonate therapy is reasonable in a patient with multiple myeloma with osteopenia without evidence of lytic bone lesions on radiographs
Bisphosphonate therapy is not recommended in a patient with indolent myeloma or solitary plasmacytoma with no lytic bone lesions
Bisphosphonate therapy is not recommended for patients with monoclonal gammopathy of undetermined significance (MGUS)
Measuring biochemical markers to monitor bisphosphonate use is not recommended
Pamidronate or zoledronic acid is recommended for management of pain as a result of osteolytic disease and as adjunct for patients receiving radiation, analgesics, or surgical intervention to stabilize fractures
A discussion related to osteonecrosis of the jaw was added to the guidelines

The International Myeloma Working Group reviewed data published through August 2012, and developed additional recommendations for the management of multiple myeloma-related bone disease⁷:

Bisphosphonates should be considered in all patients who are receiving first-line anti-myeloma therapy
Zoledronic acid or pamidronate is recommended for preventing skeletal-related events in patients with multiple myeloma
Zoledronic acid is preferred over oral clodronate because of potential anti-myeloma effect and survival benefit

Role of Bone-modifying Agents in Metastatic Breast Cancer

On February 22, 2011, the American Society of Clinical Oncology (ASCO) published an “Executive Summary of the Clinical Practice Guideline Update on Bone-modifying Agents in Metastatic Breast Cancer.”⁸ The guideline updates previously published guidance for use of bisphosphonates in patients with breast cancer (2003) and changed the term, “bisphosphonates,” to “bone-modifying agents” (BMA). A separate ASCO update will address the role of BMA for adjunctive treatment of breast cancer and for the management of treatment-associated bone loss. A summary of the 2011 guideline update follows:

For patients with breast cancer and bone metastases with evidence of bone destruction on radiographs, CT scans, or MRI, treatment with BMA, including: Denosumab 120 mg administered subcutaneously every 4 weeks, or Pamidronate 90 mg intravenously administered over not less than 2 hours every 3 to 4 weeks, or Zoledronic acid 4 mg administered intravenously over not less than 15 minutes every 3 to 4 weeks is recommended
1. Treatment with BMA for an abnormal bone scan without bone destruction is not recommended outside of a clinical trial
2. The Update Committee determined that there is insufficient evidence comparing efficacy between BMA to prefer one over another
For women with breast cancer and extra-skeletal metastases without evidence of bone metastases, treatment with BMA is not recommended
Recommendations relative to renal safety concerns with BMA (see sections in this chapter about individual BMA and consult current product labeling for guidance about dose/dosage modifications in renally impaired persons):
1. In patients with a CrCl >60 mL/min (>1 mL/s), doses/dosages, infusion times, and dosing intervals are not modified for pamidronate or zoledronic acid
  1. Product labeling for zoledronic acid includes guidance for use when CrCl is ≥30 mL/min (≥0.5 mL/s) but <60 mL/min
  2. Infusion times <2 hours for pamidronate or <15 minutes for zoledronic acid are to be avoided
2. The Update Panel recommended that serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid in accordance with FDA-approved labeling. In addition, serum electrolytes, including calcium, phosphate, and magnesium, and hemoglobin and hematocrit should be monitored regularly
  1. The risk of hypocalcemia with denosumab 120 mg every 4 weeks has not been evaluated in patients with a CrCl <30 mL/min or undergoing dialysis. Patients with impaired CrCl who receive treatment with denosumab should be closely monitored for evidence of hypocalcemia
3. For patients treated with denosumab, pamidronate, or zoledronic acid there is no evidence to guide the interval for monitoring serum electrolytes, hemoglobin, and hematocrit
Recommendations/observations relative to osteonecrosis of the jaw (ONJ) and BMA:
1. ONJ is an uncommon but potentially serious complication associated with the use of BMA
2. The Update Committee concurs with revised FDA labeling for pamidronate, zoledronic acid, and denosumab, and recommends that all patients with cancer receive a dental examination and necessary preventive dentistry prior to initiating therapy with an inhibitor of osteoclast function unless there are mitigating factors that preclude a dental assessment
  1. Patients should maintain optimal oral hygiene, and, if possible, avoid invasive dental procedures that involve manipulation of the jawbone or periosteum while receiving inhibitors of osteoclast function. Good oral hygiene includes brushing and flossing teeth after meals and use of a fluoride mouth rinse
  2. Therapy initiation with BMA should be delayed whenever possible in a setting of invasive dental procedures until the initial bone healing process of the tooth socket bone has taken place. The Update Committee consensus recommendation for initiating bone-modifying therapy after invasive manipulation of bone underlying the teeth is that it should ideally be delayed for 14 to 21 days to allow for wound healing, if the clinical situation permits
3. Most cases of ONJ have occurred in patients receiving intravenously administered bisphosphonates who have undergone invasive dental procedures. However, ONJ has been reported to occur spontaneously, and in patients treated with other BMA, including oral bisphosphonates and direct osteoclast inhibitors
Once initiated, the optimal duration of BMA is to continue therapy until, based on clinical judgment, there is evidence of substantial decline in a patient's general performance status
1. There is no evidence addressing the consequences of stopping BMA after ≥1 adverse skeletal-related events
The optimal intervals between dosing for BMA are every 4 weeks for denosumab 120 mg, subcutaneously; and every 3 to 4 weeks for pamidronate 90 mg, intravenously over 2 hours, and for zoledronic acid 4 mg intravenously, over 15 minutes
For patients with pain secondary to bone metastases, BMA are an adjunctive therapy for controlling bone pain, and are not recommended as first-line treatment for cancer-related pain
The use of biochemical markers of bone metabolism to guide or monitor BMA use is not recommended outside of a clinical trial

Vitamin D Deficiency

If a patient is receiving a bisphosphonate for osteoporosis, healthcare providers are likely to check a patient's vitamin D level. If the indication is metastatic bone disease, a vitamin D level is often overlooked
A 25-hydroxyvitamin D (25-OHD) level of approximately 30 ng/mL (~75 nmol/L) is an acceptable target
An appropriate dose of Vitamin D supplementation in oncology patients is 1000 International Units daily as endorsed by the Dietary Guidelines for Americans⁹

Musculoskeletal Pain

An FDA Alert issued in January 2008 highlighted the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates¹⁰
Severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown
The severe musculoskeletal pain associated with bisphosphonates is in contrast to the acute phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that sometimes accompanies initial intravenous administration of bisphosphonates and may occur with initial exposure to once-weekly or once-monthly doses of oral bisphosphonates
1. The symptoms related to the acute phase response tend to resolve within several days with continued drug use
Healthcare professionals should consider whether bisphosphonate use may be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug

References

Khosla S et al. J Bone Miner Res 2007;22:1479–1491 [PubMed: 17663640]

Drake MT et al. Mayo Clin Proc 2008;83:1032–1045 [PubMed: 18775204]

Ruggiero S et al. J Oncol Pract 2006;2:7–14 [PubMed: 20871729]

Zervas K et al. Br J Haematol 2006;134:620–623 [PubMed: 16889620]

American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2006;137:1144–1150 [PubMed: 16873332]

Kyle RA et al. J Clin Oncol 2007;25:2464–2472 [PubMed: 17515569]

Terpos E et al. J Clin Oncol 2013;31:2347–2357 [PubMed: 23690408]

Van Poznak CH et al. [see erratum] J Clin Oncol 2011;29:1221–1227. Erratum in: J Clin Oncol 2011;29:2293 [PubMed: 21343561]

Wang-Gillam A et al. Oncologist 2008;13:821–827

10.

Information for Healthcare Professionals: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). U.S. Department of Health & Human Services, U.S. Food and Drug Administration, 2008. (Accessed January 28, 2014, at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.htm)

REGIMENS

Regimens

Key to abbreviations and symbols: 0.9% NS, 0.9% sodium chloride injection; 0.45% NS, 0.45% sodium chloride injection; D5W, 5% dextrose injection; ASCO, American Society of Clinical Oncology; AUC, area under the plasma concentration versus time curve; CrCl, creatinine clearance; SCr, serum creatinine

ZOLEDRONIC ACID (ZOMETA^®)

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ZOLEDRONIC ACID (ZOMETA^®)

Oncology-Related Indications

Usual Dosages

Dose Adjustments for CrCl ≤60 mL/min^†

Multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard anti-neoplastic therapy^1,2

Prostate cancer should have progressed after treatment with at least one hormonal therapy^1,2

Zoledronic acid 4 mg; administer intravenously in 100 mL 0.9% NS or D5W^✫ over at least 15 minutes every 3–4 weeks (4 mg is recommended for patients with CrCl >60 mL/min [>1 mL/s])

Supplementation for myeloma and bone metastases from solid tumors: Calcium 500 mg/day orally, plus vitamin D 400 IU/day orally

Pre-Treatment CrCl

Recommended Dose

50–60 mL/min (0.83–1 mL/s)

3.5 mg

40–49 mL/min (0.66–0.81 mL/s)

3.3 mg

30–39 mL/min (0.5–0.65 mL/s)

3 mg

^†Doses are calculated to produce an AUC (0.6 mg · hour/L) similar to that achieved in patients with CrCl = 75 mL/min (1.25 mL/s)

Baseline SCr

SCr Increase

Action

Hypercalcemia of malignancy: Serum Ca²⁺ ≥12 mg/dL (≥3 mmol/L)¹

Zoledronic acid 4 mg intravenously in 100 mL 0.9% NS or D5W^✫ over at least 15 minutes every 3–4 weeks

Within normal limits

≥0.5 mg/dL (≥44.2 μmol/L)

Withhold zoledronic acid until SCr decreases to within 10% of baseline, then resume with the same dose given previously

Abnormal

≥1 mg/dL (≥88.4 μmol/L)

^✫Notes: Avoid mixing zoledronic acid with calcium- or other divalent cation-containing solutions, such as Lactated Ringer's Injection

Do not administer zoledronic acid through a common intravenous line or the same fluid pathway through which other drugs are being administered

Dose adjustments of zoledronic acid are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to the initiation of therapy (ie, with SCr <4.5 mg/dL; <400 μmol/L)

Note: Patients with SCr ≥4.5 mg/dL (≥400 μmol/L) were excluded from trials of hypercalcemia of malignancy

Toxicity

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Toxicity

>10%

Fever (30–40%), nausea/vomiting (29%), constipation (26.7%), hypomagnesemia (10.5%), hypotension (10.5%)

1–10%

Bone/back pain (10%), flulike syndrome, injection site reaction, dyspepsia, hypocalcemia, hypophosphatemia, hypermagnesemia, increased serum creatinine

<1%

Rash, pruritus, increased liver transaminases, chest pain, ocular inflammation, uveitis, iritis, scleritis, episcleritis, conjunctivitis, osteonecrosis of jaw

References

Ibrahim A et al. Clin Cancer Res 2003;9:2394–2399 [PubMed: 12855610]

Zometa (zoledronic acid) Injection product label, October 2009 (revised). Novartis Pharmaceuticals Corporation, East Hanover, NJ

Efficacy

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Efficacy

Zometa Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors

I. Analysis of Proportion of Patients with a SRE^✫

II. Analysis of Time to the First SRE

Study

Study Arm & Patient No.

Proportion

Difference^† & 95% CI

P-Value

Days (Median)

Hazard Ratio^‡ & 95% CI

P-Value

Prostate cancer

Zometa 4 mg (n = 214

Placebo (n = 208)

33%

44%

−11%

(−20%, −1%)

0.02

Not reached

321

0.67

(0.49, 0.91)

0.011

Solid tumors

(other than breast or prostate)

Zometa 4 mg

(n = 257)

Placebo

(n = 250)

38%

44%

−7%

(−15%, 2%)

0.13

230

163

0.73

(0.55, 0.96)

0.023

^✫SRE: skeletal-related event

^†Difference for the proportion of patients with a SRE for Zometa 4 mg vs. placebo

^‡Hazard ratio for the first occurrence of a SRE for Zometa vs. placebo

Note: In these studies, Zometa infusion duration was increased from 5 to 15 minutes every 3–4 weeks due to renal toxicity; the median treatment durations for the prostate cancer group and solid tumors group were 10.5 mo and 3.8 mo, respectively

Zometa Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer

I. Analysis of Proportion of Patients with a SRE^✫

II. Analysis of Time to the First SRE

Study

Study Arm & Patient No.

Proportion

Difference^† & 95% CI

P-Value

Days (Median)

Hazard Ratio^‡ & 95% CI

P-Value

Multiple myeloma and breast cancer

Zometa 4 mg

(n = 561)

Pamidronate

(n = 555)

44%

46%

−2%

(−7.9, 3.7%)

0.46

373

363

0.92

(0.77, 1.09)

0.32

^✫SRE: skeletal-related event

^†Difference for the proportion of patients with a SRE for Zometa 4 mg vs. pamidronate 90 mg

^‡Hazard ratio for the first occurrence of a SRE for Zometa vs. pamidronate 90 mg

Note: In these studies, Zometa infusion duration was increased from 5 to 15 minutes every 3–4 weeks due to renal toxicity; pamidronate 90 mg was administered intravenously every 3–4 weeks; the median treatment duration was 12 months

Pooled Study Data^† of Zometa Compared to Pamidronate in Patients with Hypercalcemia of Malignancy^‡

Variable^§

Zometa 4 mg

Pamidronate 90 mg

Complete response

Patient numbers

Response rates

Patient numbers

Response rates

By Day 4

45.3%

33.3%

By Day 7

86.2%^✫

63.6%

Duration of response

Patient numbers

Median duration (d)

Patient numbers

Median duration (d)

Time to relapse

30^✫

Duration of CR

^✫P-value <0.05 vs. pamidronate 90 mg

^†Data were derived from two identical multicenter, randomized, double-blind, double-dummy studies of Zometa 4 mg given intravenously over 5 minutes or pamidronate 90 mg given intravenously over 2 h. The two multicenter trials of hypercalcemia of malignancy were combined in a preplanned analysis. The most common tumor types were lung, breast, head and neck, and renal; median patient age is 59 years. The Zometa infusion duration of 5 minutes, as performed in this study, is not recommended due to an increased risk of renal failure. Zometa should be administered intravenously over not less than 15 minutes

^‡Hypercalcemia of malignancy was defi ned as a corrected serum calcium (CSC) concentration of ≥12.0 mg/dL (≥3.00 μmol/L)

^§Primary effi cacy variable was the proportion of patients who had a complete response (defi ned as the lowering of the CSC to ≤10.8 mg/dL (≤2.70 μmol/L) within 10 days after Zometa administration

The proportion of patients whose CSC normalized by Day 10 were 88% and 70% for Zometa 4 mg and pamidronate 90 mg, respectively (P = 0.002)

Monitoring Therapy

Prior to therapy: See Guidance, Caveat, and Comments section for Zometa dosage adjustments relative to renal function (creatinine clearance may be calculated using the Cockcroft Gault formula)
1. Patients treated with Zometa should not be treated with Reclast (contains same active ingredient as Zometa)
2. Caution is advised when Zometa is used in conjunction with loop diuretics (may increase hypocalcemia), thalidomide (may increase risk of renal dysfunction), and other potentially nephrotoxic drugs
For patients with hypercalcemia of malignancy:
1. Initiate treatment only after: (1) adequate hydration with 0.9%NS; (2) adequate urine output of ≈2 L/d throughout therapy; and (3) avoidance of over-hydration, especially in patients with CHF
2. Encourage ambulatory patients to maintain hydration orally
3. If hypercalcemia persists or recurs, there should be ≥7 days between consecutive treatments
Supplementation for myeloma and bone metastases from solid tumors: calcium 500 mg/day, administer orally + Vitamin D 400 International Units/day, administer orally
During therapy:
1. Standard hypercalcemia-related metabolic parameters, such as levels of calcium, phosphate, magnesium, and serum creatinine, should be carefully monitored. Short-term supplemental therapy may be necessary if hypokalemia, hypophosphatemia, or hypomagnesemia occurs
2. For patients with multiple myeloma and metastatic bone lesions of solid tumors, the serum creatinine should be measured before each dose of zoledronic dose and treatment withheld for renal deterioration (see Guidance, Caveats, and Comments section for dose adjustments)
Patient counseling information:
1. Patients should be instructed to tell their healthcare provider if they have kidney problems before being given Zometa
2. Patients should be informed of the importance of getting their blood tests (eg, serum creatinine) during the course of their Zometa therapy
3. Female patients should not be given Zometa if they are pregnant or breast feeding, or plan to become pregnant
4. Patients should be advised to have a dental examination prior to treatment with Zometa and should avoid invasive dental procedures during treatment
5. Patients should be informed of the importance of good dental hygiene and routine dental care
6. Patients with multiple myeloma and bone metastases should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily
7. Patients should be aware of the most common side effects of Zometa, including anemia, nausea, vomiting, constipation, diarrhea, fatigue, pyrexia, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, worsening of their malignancy, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain

ZOLEDRONIC ACID (RECLAST^®)

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ZOLEDRONIC ACID (RECLAST^®)

Indications

Usual Doses, Administration Routes, and Schedules

Guidance, Caveats, and Comments

Treatment of osteoporosis in postmenopausal women

Prevention of osteoporosis in postmenopausal women

Treatment to increase bone mass in men with osteoporosis

Treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be using glucocorticoids for at least 12 mo (≥7.5 mg of prednisone or equivalent per day in clinical trial)

Zoledronic acid 5 mg; administer intravenously in 100 mL ready to infuse solution over at least 15 minutes through a separate vented infusion line every 12 months (up three doses in clinical trials)

Zoledronic acid 5 mg; administer intravenously in 100 mL ready to infuse solution over at least 15 minutes through a separate vented infusion line every 2 years

Zoledronic acid 5 mg; administer intravenously in 100 mL ready to infuse solution over at least 15 minutes through a separate vented infusion line once annually up to a total of 2 doses

Zoledronic acid 5 mg; administer intravenously in 100 mL ready to infuse solution over at least 15 minutes through a separate vented infusion line

Exclusions: patients with baseline creatinine clearance <30 mL/min (<0.5 mL/s); urine dipstick ≥2+ or increase in serum creatinine >0.5 mg/dL (>44.2 μmol/L) during screening visits; pregnant women; patients being treated with Zometa for oncology indications

Supplementation: elemental calcium orally, 1000–1500 mg/d and vitamin D orally, 400–1200 IU/d

All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels

Pre-existing conditions: pre-existing hypocalcemia and disturbances of mineral metabolism (eg, hypo-parathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine) must be treated before initiating therapy with Reclast. Clinical monitoring of calcium, phosphorus, and magnesium levels is highly recommended for these patients

EFFICACY: Treatment Summary of Osteoporosis in Postmenopausal Women (Reclast vs. Placebo)

Outcome

Reclast (N = 3875) Event Rate^✫, n (%)

Placebo (N = 3861) Event Rate^✫, n (%)

Absolute Risk Reduction in Fracture Incidence, % (95% CI)

Relative Risk Reduction in Fracture Incidence % (95% CI)

Any clinical fracture^§

308 (8.4)

456 (12.8)

4.4 (3.0, 5.8)

33 (23, 42)^†

Clinical vertebral fracture

19 (0.5)

84 (2.6)

2.1 (1.5, 2.7)

77 (63, 86)^†

Non-vertebral fracture^✫^✫

292 (8.0)

388 (10.7)

2.7 (1.4, 4.0)

25 (13, 36)^‡

^✫Event rates based on Kaplan-Meier estimates at 36 mo

^†P-value<0.001

^‡P-value <0.0001

^§Excludes finger, toe, and facial fractures

^§Includes clinical thoracic and clinical lumbar vertebral fractures

^✫✫Excludes finger, toe, facial, and clinical thoracic and lumbar fractures

EFFICACY: Prevention of Osteoporosis in Postmenopausal Women with Osteopenia (Reclast vs. Placebo)^✫

Outcome

Clinical study: 581 women with osteopenia; 2-year randomized, multi-center, double-blind, placebo-controlled study. Age ≥45 years, stratified by years after menopause: Stratum I (<5 years after menopause; n = 224) and Stratum II (≥5 years after menopause; n = 357). Strata I and II patients were randomized to one of three groups: (1) Reclast given at randomization and at month 12 (Stratum I, n = 77; Stratum II, n = 121); (2) Reclast given at randomization and placebo at month 12 (Stratum I, n = 70; Stratum II, n = 111); and (3) Placebo given at randomization and month 12 (n = 202)

Change in BMD relative to baseline, %

Reclast given at randomization and placebo at month 12:

(1) Resulted in a 6.3% increase in BMD (Stratum I) and a 5.4% increase in BMD (Stratum II) over 24 months as compared to placebo (both P <0.0001)

(2) Resulted in a 4.7% increase in total hip BMD (Stratum I) and a 3.2% increase in total hip BMD (Stratum II) over 24 months as compared to placebo (both P <0.0001)

^✫All participants received 500 to 1200 mg of elemental calcium plus 400 to 800 IU of vitamin D supplementation per day

EFFICACY: Treatment to Increase Bone Mass in Men with Osteoporosis (Reclast vs. Control)^✫

Outcome

Clinical study: 302 men, ages 25–86 years (mean age, 64 years) with osteoporosis or significant osteoporosis secondary to hypogonadism assessed in a randomized, multicenter, double-blind, active controlled study for 2 years. Patients were randomly assigned to Reclast 5 mg administered intravenously over at least 15 minutes once annually for up to two doses, or to an oral weekly bisphosphonate (active control) for up to 2 years

Change in BMD relative to control, %

Annual infusion of Reclast was non-inferior to oral weekly bisphosphonate active control based on the percentage change in lumbar spine BMD at month 24 relative to baseline (Reclast: 6.1% increase; active control: 6.2% increase)

^✫All participants received 1000 mg of elemental calcium plus 800–1000 IU of vitamin D supplementation daily

EFFICACY: Treatment and Prevention of Glucocorticoid-induced Osteoporosis (GIO) in Patients Expected to be Using Glucocorticoids for at Least 12 Months (Reclast vs. Control)^✫

Outcome

Clinical Study: 833 women and men, aged 18–85 years (mean age, 54.4 years) treated with prednisone ≥7.5 mg/day, orally (or equivalent) assessed in a randomized, multicenter, double-blind, stratified, active controlled study. Patients were stratified by their duration of pre-study corticosteroid use (≤3 months [prevention subpopulation] vs. >3 months [treatment subpopulation]), and randomized to either Reclast administered intravenously over at least 15 minutes or to an oral daily bisphosphonate (active control) for 1 year

Change in BMD relative to control, %

GIO treatment subpopulation: Reclast demonstrated a significant mean increase in lumbar spine BMD compared to active control at 1 year (Reclast 4.1%, active control 2.7%) with a treatment difference of 1.4% (p <0.001)

GIO prevention subpopulation: Reclast demonstrated a significant mean increase in lumbar spine BMD compared to active control at 1 year (Reclast 2.6%, active control 0.6%) with a treatment difference of 2.0% (p <0.001)

^✫All participants received 1000 mg of elemental calcium plus 400–1000 IU of vitamin D supplementation daily

Adverse Reactions in Women with Postmenopausal Osteoporosis (Select)

>10%

Arthralgia (18%–24%), fever (18%), headache (8%–12.4%), pain in extremity (5.9%–11%), myalgia (4.9%–11%)

2%–10%

Flu-like symptoms (8%), dizziness (7.6%), headache (7%), general pain (1.5%–3%)

<2%

Transient increase in serum creatinine within 10 days after dosing (1.8%), atrialfibrillation (1.3%), injection site reaction (0%–0.7%), decline in serum calcium to <7.5 mg/dL (0.2%), iritis/uveitis/episcleritis (<0.1%–0.2%), osteonecrosis of the jaw (1/3862 in Study 1)

Adverse Reactions in Women with Postmenopausal Osteopenia (Select)

>10%

Arthralgia (18.8%–27.3%), generalized pain (14.9%–24.2%), pyrexia (21%), headache (14.6%–20.4%), back pain (16.6%–18.2%), chills (18.2%), nausea (11.6%–17.1%), fatigue (9.9%–14.6%), hypoesthesia (2.2%–5.6%)

2%–10%

Pain in extremity (3.9%), influenza-like illness (1.5%–3.3%),

<2%

Malaise (1.0%–2.2%), abdominal distension (0.6–2.0), iritis/episcleritis/conjunctivitis (1.1%)

Adverse Reactions in Men with Osteoporosis (Select)

>10%

Myalgia (19.6%), fatigue (17.6%), headache (15.0%), musculoskeletal pain (12.4%)

2%–10%

Chills (9.8%), influenza-like illness (9.2%), abdominal pain (7.9%), malaise (7.2%), increased serum creatinine (2%)

<2%

No reports on osteonecrosis of the jaw in this cohort

Reclast^® (zoledronic acid) Injection product label, Revised 01/2010. Novartis Pharmaceuticals Corporation; East Hanover, NJ

PAMIDRONATE DISODIUM (AREDIA)

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PAMIDRONATE DISODIUM (AREDIA)

Oncology-Related Indications

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

Multiple myeloma with osteolytic bone lesions on plain radiographs^1,2

Pamidronate 90 mg intravenously in 250–500 mL 0.9% NS, 0.45% NS, or D5W, over 1–4 hours, every 3–4 weeks

In patients with Bence-Jones proteinuria and dehydration, ensure adequate hydration with 0.9% NS before administering pamidronate

Metastatic breast cancer with abnormal bone radiographs ± pain^1,2

Baseline

Retreatment

Action

Normal SCr

SCr increased ≥0.5 mg/dL (≥44 μmol/L)

Hold until SCr is within 10% of baseline^†

Abnormal SCr

SCr increased ≥1.0 mg/dL (≥88 μmol/L)

Hold until SCr is within 10% of baseline^†

Steroid-induced osteoporosis^✫3,4

Pamidronate 60 mg intravenously in 250 mL 0.9% NS, 0.45% NS, or D5W over 2 hours every 12 weeks for 48 weeks, or pamidronate 150 mg orally, daily for 12–24 months^‡

Pamidronate is available outside the United States in a tablet formulation containing 150 mg of the active drug

Toxicity

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Toxicity

>10%

Nausea/vomiting (27%), injection site reaction (18%), abdominal pain/GI complaints (15%), hypertension (15%), constipation (12.6%), and fever

1–10%

Anemia (6%), tachycardia (6%), hypothyroidism (6%), hypomagnesemia (4.9%), leukopenia (4%), hypophosphatemia (1.9%), hypotension (1.9%), rash (1%), flulike syndrome, bone/back pain, anorexia, hypocalcemia, fluid overload

<1%

Allergic reaction (dyspnea, angioedema, anaphylaxis), hypokalemia, transient proteinuria, ocular inflammation, uveitis, iritis, scleritis, episcleritis, jaw osteonecrosis

^✫Not an FDA-approved indication

^†When resuming treatment after a hiatus for renal impairment, administer pamidronate over at least 2 hours at doses not >90 mg and not more frequently than every 4 weeks after renal function returns to baseline

^‡An oral formulation is not available for commercial use in the United States

References

Hillner BE et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000;18:1378–1391 [PubMed: 10715310]

Aredia product label, October 2003. Novartis Pharmaceutical Corporation, East Hanover, NJ

Smith MR et al. N Engl J Med 2001;345:948–955 [PubMed: 11575286]

Reid IR et al. Lancet 1988;331:143–146

CLODRONATE DISODIUM (BONEFOS, OSTAC)

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CLODRONATE DISODIUM (BONEFOS, OSTAC)^✫

Oncology-Related Indications

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

Treatment of hypercalcemia of malignancy:^†,1,14 serum Ca²⁺ ≥12 mg/dL (≥3 mmol/L)¹

Clodronate 300 mg/day; administer intravenously in 500 mL 0.9% NS or D5W over 2 hours for up to 5 days,

Clodronate 1500 mg single dose; administer intravenously in 500 mL 0.9% NS or D5W over not less than 4 hours

Treatment with intravenous clodronate may continue for >5 days but should not exceed 10 days for a single hypercalcemic episode

Intravenous Clodronate

Dose Modifications in Renal Impairment

CrCl (mL/min)

Dose Reduction

50–80 (0.83–1.33 mL/s)

25%

12–50 (0.2–0.83 mL/s)

25–50%

<12 (<0.2 mL/s)

50%

Maintenance treatment after effective IV treatment for hypercalcemia^{†,2,3,4,5,14,14}

Clodronate 1600 mg/day (range: 400–3200 mg); administer orally, indefinitely

Note: Typical treatment duration of 6 mo may be extended depending on the course of the disease; it may be necessary to restart after interruption

Clodronate disodium is available outside the United States in:

400-mg capsules

520-mg tablets (higher bioavailability)

800-mg tablets

The oral bioavailability of one 520-mg tablet approximately equals two 400-mg capsules or one 800-mg tablet

Clodronate should be taken with water at least 2 hours before or 2 hours after eating, drinking, or taking other medications

Multiple myeloma (regression of bone lesions)^†,5,6,7

Clodronate 1600–3200 mg/day; administer orally,

Clodronate 1040–2080 mg/day; administer orally

Metastatic bone disease^{†,5,7,8,9,10,11,12,13}

Clodronate 300 mg/day; administer intravenously in 250–500 mL D5W or 0.9% NS over 2–3 hours, for 8–14 consecutive days, followed by:

Clodronate 1040–2080 mg/day; administer orally, indefinitely, or

Clodronate 1600 mg 2 times daily or 1600 mg/day (as a single 1600-mg dose, 800 mg twice daily, or 400 mg 4 times daily); administer orally, indefinitely

Note: Studies have examined treatment durations of 4–11 weeks. Treatment likely will continue for longer durations with clodronate or another agent

ORAL Clodronate

Dose Modifications in Renal Impairment

CrCl (mL/min)

Dose Reduction

50–80

No dose reduction

30–50

25%

<30

50%

Oral clodronate should not be taken with milk or food containing calcium or other divalent cations It is important to establish and maintain full hydration with oral or IV fl uids prior to the infusion of clodronate disodium

Toxicity

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Toxicity

>10%

Dysgeusia (50%)

1–10%

Bone/back pain, nausea/vomiting, constipation, diarrhea, dyspepsia, abdominal pain, flatulence, abdominal distention, dysphagia, transient proteinuria (IV form)

<1%

Hyperparathyroidism (0.6%), increased serum creatinine, gastritis, gastric ulceration, increase in liver transaminases, ocular inflammation, uveitis, respiratory impairment in aspirin sensitive patients, hypersensitivity (respiratory symptoms), rash, hypocalcemia, hypomagnesemia

References

Bonefos (disodium clodronate) product label. Bayer Inc. Toronto, Ontario, Canada. Revised January 18, 2010

Percival RC et al. Br J Cancer 1985;51:665–669 [PubMed: 3158326]

Rastad J et al. Acta Med Scand 1987;221:489–494 [PubMed: 2955674]

Ziegler R, Scharla SH. Recent Results Cancer Res 1989;116:46–53 [PubMed: 2527400]

Clodronic acid. In: Sweetman SC, ed. Martindale, the Complete Drug Reference, 33rd ed. Grayslake (IL): Pharmaceutical Press;2002:751–752

Coleman RE Am J Clin Oncol2002;25(6 Suppl 1):S32–S38 [PubMed: 12562049]

Diel IJ et al. N Engl J Med 1998;339:357–363 [PubMed: 9691101]

Adami S et al. J Urol 1985;134:1152–1154 [PubMed: 2932559]

Heidenreich A et al. J Urol 2001;165:136–140 [PubMed: 11125382]

10.

Rizzoli R et al. Bone 1996;18:531–537 [PubMed: 8805993]

11.

Kanis JA et al. Bone 1996;19:663–667 [PubMed: 8968035]

12.

Body J-J et al. J Clin Oncol 1998;16:3890–3899 [PubMed: 9850035]

13.

McCloskey EV et al. Br J Haematol 1998;100:317–325 [PubMed: 9488619]

14.

Clasteon^® (clodronate disodium) product label. Sepacor Pharmaceuticals, Inc., Mississauga, Ontario, Canada. Revised April 14, 2009

ALENDRONATE SODIUM (FOSAMAX)

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ALENDRONATE SODIUM (FOSAMAX)

Oncology-Related Indication (s)

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

Treatment and prevention of osteoporosis in postmenopausal women

Treatment to increase bone mass in men with osteoporosis

For the treatment of steroid-induced osteoporosis in men and women receiving a daily dose equivalent to ≥7.5 mg prednisone and who have low bone mineral density^✫

Alendronate 5 mg; administer orally, daily

Alendronate 10 mg; administer orally, daily

Dose Adjustments

Elderly patients

No adjustments

CrCl ≥35 mL/min (≥0.58 mL/s)

No adjustments

CrCl <35 mL/min (<0.58 mL/s)

Do not administer drug

Contraindications:

Abnormalities of the esophagus that delay esophageal emptying, such as stricture or achalasia
Inability to stand or sit upright for at least 30 minutes
Patients at increased risk of aspiration
Hypocalcemia

Alendronate 5, 10, or 15 mg; administer intravenously^† over 2 hours

Not recommended if CrCl <35 mL/min (<0.58 mL/s)

Toxicity

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Toxicity

>10%

Fever (intravenous formulation)

1–10%

Constipation (3.1%), diarrhea (3.1%) headache (2.6%), gastritis/gastric ulceration (1.5%), nausea/vomiting, abdominal pain, flatulence, abdominal distention, dysphagia, hypocalcemia, hypophosphatemia

<1%

Increases in liver transaminases (intravenous formulation), iritis, scleritis, episcleritis, osteonecrosis of the jaw

References

Fosamax tablets and oral solution product label, September 2003. Merck & Co., Inc., Whitehouse Station, NJ

Nussbaum SR et al. J Clin Oncol 1993;11:1618–1623 [PubMed: 8336198]

RISEDRONATE SODIUM (ACTONEL)

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RISEDRONATE SODIUM (ACTONEL)

Oncology-Related Indications

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

For the prevention and treatment of steroid-induced osteoporosis in men and women receiving a daily dose equivalent to ≥7.5 mg prednisone

Risedronate 5 mg; administer orally daily

Dosage Adjustments

Elderly Patients

No Adjustments

CrCl ≥30 mL/min (≥0.5 mL/s)

No adjustments

CrCl <30 mL/min

Do not administer drug

Toxicity

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Toxicity

>10%

Arthralgia (32.8%), bone/back pain (26.1%), headache (18%), nausea/vomiting (10.9%), abdominal pain (11.6%), diarrhea (10.6%)

1–10%

Flulike syndrome (9.8%), rash (7.7%), chest pain (5%), asthenia (4.9%), hypercholesterolemia (4.8%), flatulence (4.6%), gastritis/gastric ulceration (4.1%), conjunctivitis (3.1%), pruritus (3%), abdominal distention, dysphagia

<1%

Iritis, scleritis, episcleritis, osteonecrosis of jaw

Actonel product label, March 2003. Proctor and Gamble Pharmaceuticals, Cincinnati, OH

Brooks JK et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:780–786

IBANDRONATE SODIUM (BONIVA)

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IBANDRONATE SODIUM (BONIVA)

Indications

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

Treatment of postmenopausal osteoporosis¹

Prevention of postmenopausal osteoporosis¹

Ibandronate 2.5 mg; administer orally daily, or

Ibandronate 150 mg; administer orally once a month, or

Ibandronate 3 mg; administer intravenously every 3 months

Ibandronate 2.5 mg; administer orally daily, or

Ibandronate 150 mg; administer orally once a month

Dose Adjustments

Elderly Patients

No Adjustments

CrCl ≥30 mL/min (≥0.5 mL/s)

No adjustments

CrCl <30 mL/min

Use is not recommended

CrCl <30 mL/min in oncologic indications

Ibandronate 50 mg; administer orally once weekly, or

Ibandronate 2 mg; administer intravenously over 1 hour every 3 weeks

Hypercalcemia of malignancy^✫^,2,3,4 serum Ca²⁺ ≥12 mg/dL (≥3 mmol/L)

Ibandronate 4–6 mg; administer intravenously over 2 hours

Ibandronate should be taken orally 60 minutes before the first food or drink of the day, and any oral medications (including antacids, vitamins or supplements). Ibandronate should be taken in an upright position with a full glass (6–8 oz) of plain water and the patient should avoid lying down for 60 minutes to minimize the possibility of GI side effects

Contraindications:

Abnormalities of the esophagus that delay esophageal emptying such as stricture or achalasia;
Inability to stand or sit upright for at least 60 min.;
Hypocalcemia;

Hypersensitivity to ibandronate sodium

Metastatic bone disease^✫^,5,6,7

Ibandronate 50 mg; administer orally daily, or

Ibandronate 6 mg; administer intravenously over 1 hour every 3–4 weeks

Effect of Ibandronate on the Incidence of Vertebral Fracture in the 3-Year Osteoporosis Study^✫

Outcome

Proportion of Patients with Fracture (%)

Placebo (n = 975)

Ibandronate 2.5 mg Daily (n = 977)

Absolute Risk Reduction % (95% CI)

Relative Risk Reduction % (95% CI)

New vertebral fracture 0–3 years

9.6

4.7

4.9 (2.3, 7.4)

52^† (29, 68)

New and worsening vertebral fracture 0–3 years

10.4

5.1

5.3 (2.6, 7.9)

52 (30, 67)

Clinical (symptomatic) vertebral fracture 0–3 years

5.3

2.8

2.5 (0.6, 4.5)

49 (14, 69)

^✫The endpoint value is the value at the study's last endpoint, 3 years, for all patients who had a fracture identified at that time; otherwise, the last post-baseline value prior to the study's last time point is used

^†p = 0.0003 vs. placebo

EFFICACY: Mean Percent Change in BMD from Baseline to Endpoint in Patients Treated Daily with Ibandronate 2.5 mg or Placebo in the 3-year Osteoporosis Treatment Study^‡

Placebo

Ibandronate 2.5 mg Daily

Lumbar spine

1.4 (n = 693)

6.4 (n = 712)

Total hip

−0.7 (n = 638)

3.1 (n = 654)

Femoral neck

−0.7 (n = 683)

2.6 (n = 699)

Trochanter

0.2 (n = 683)

5.3 (n = 699)

^‡The endpoint value is the value at the study's last time point, 3 years, for all patients who had BMD measured at that time; otherwise, the last post-baseline value prior to the study's last time point is used

EFFICACY: Mean Percent Change in Lumbar Spine BMD from Baseline in Osteoporosis Patients Treated Monthly with Ibandronate 150 mg or Daily with Ibandronate 2.5 mg

Clinical study: Randomized, double-blind, multinational, non-inferiority trial of 1602 women aged 54–81 years, who were on average postmenopausal for 18 years and had L2–L4 lumbar spine BMD T-score less than −2.5 SD at baseline. The main outcome measure was the comparison of the percentage change from baseline in lumbar BMD after 1 year of treatment with once-monthly ibandronate (100 mg, 150 mg) or daily ibandronate. All patients received 400 IU Vitamin D and 500 mg calcium supplementation daily

Exclusions: Patients with dyspepsia or concomitant use of NSAIDS, proton pump inhibitors, and H₂-receptor antagonists

Ibandronate 150 mg Monthly n = 327

Ibandronate 2.5 mg Daily n = 318

Mean Difference

Lumbar spine BMD 1 year

4.85% (95% CI: 4.41%, 5.29%)

3.86% (95% CI: 3.40%, 4.32%)

0.99%^§ (95% CI: 0.38%, 1.60%)

^§p = 0.002

EFFICACY: Prevention of Postmenopausal Osteoporosis (Ibandronate 2.5 mg Daily or 150 mg Monthly)

Clinical study: Randomized, double-blind, placebo-controlled 2-year study (Prevention Study) of 653 postmenopausal women without osteoporosis at baseline. Patient ages were 41–82 years, were on average postmenopausal for 8.5 years, and had lumbar BMD T-scores greater than −2.5 SD. Women were stratified to time since menopause (1–3 years, >3 years) and baseline BMD (T-score, greater than −1, −1 to −2.5). The study compared ibandronate at three dose levels (0.5 mg, 1 mg · 2.5 mg) with placebo. All women received 500 mg of supplemental calcium daily

Primary efficacy measure: change in BMD of lumbar spine (LS) after 2 years of treatment (Ibandronate 2.5 mg daily)

Results: (1) Ibandronate treatment resulted in a mean increase in LS BMD of 3.1% compared with placebo at 6 months and all later time points. (2) Ibandronate treatment resulted in a higher BMD response at the LS compared with placebo, irrespective of time since menopause or degree of pre-existing bone loss across all four baseline strata (time since menopause; baseline LS BMD). (3) Compared to placebo, ibandronate increased BMD of the total hip by 1.8%, the femoral neck by 2.0%, and the trochanter by 2.1%

Clinical study: Randomized, double-blind, placebo-controlled 1-year study (Monthly Prevention Study) of 160 post-menopausal women with low bone mass (T-score of −1 to −2.5 SD). Women, aged 46–60 years, were on average postmenopausal for 5.4 years. All women received 400 IU of vitamin D and 500 mg calcium supplementation daily

Primary efficacy measure: Relative change in BMD at the lumbar spine (LS) after 1 year of treatment (Ibandronate 150 mg monthly)

Results: (1) Ibandronate treatment resulted in a mean increase in LS BMD of 4.12% (95% CI: 2.96, 5.28) compared to placebo following 1 year of treatment (p < 0.0001), based on a 3.73% and −0.39 mean change in BMD from baseline in the ibandronate and placebo groups, respectively; (2) BMD at other skeletal sites was also increased relative to baseline values

Toxicity

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Toxicity

>10%

Fever (11%), with oral administration: nausea and vomiting (20%), epigastric pain and dyspepsia (25%)

1–10%

Abdominal pain, diarrhea, and constipation. Joint pain, backache, muscle aches, arthritis, arthropathy, hypertension, and hypercholesterolemia

<1%

Ocular inflammation, uveitis, scleritis

Post-marketing experience

Voluntarily reported adverse reactions post-approval (difficult to reliably determine incidence due to population of uncertain size): Hypersensitivity (anaphylaxis, angioedema, bronchospasm, and rash), hypocalcemia, musculoskeletal pain (severe or incapacitating), osteonecrosis of the jaw

References

Boniva tablets product label, Revised January, 2010. Genentech USA, Inc. South San Francisco, CA

Pecherstorfer M et al. J Clin Oncol 1996;14:268–276 [PubMed: 8558208]

Ralston SH et al. Br J Cancer 1997;75:295–300 [PubMed: 9010041]

Pecherstorfer M et al. Support Care Cancer 2003;11:539–547 [PubMed: 12783289]

Diel IJ et al. Eur J Cancer 2004;40:1704–1712 [PubMed: 15251160]

Body J-J et al. Ann Oncol 2003;14:1399–1405 [PubMed: 12954579]

Heidenreich A et al. Prostate Cancer Prostatic Dis 2002;5:231–235 [PubMed: 12496987]

ETIDRONATE SODIUM (DIDRONEL)

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ETIDRONATE SODIUM (DIDRONEL)

Indications

Usual Doses, Administration Routes and Schedules

Guidance, Caveats, and Comments

Treatment of postmenopausal osteoporosis^✫

Etidronate 200 mg; administer orally daily for 2 weeks, followed by a 13-week period with no etidronate

Then repeat the cycle

Maintain adequate calcium and vitamin D intake during the 15-week cycle

Dose Adjustments

Elderly patients

No specific dosage adjustments. Evaluate renal function carefully and consider reduction

SrCr >2.5 mg/dL (>221 μmol/L)

Use cautiously

SrCr >5 mg/dL (>442 μmol/L)

Use is not recommended

Hypercalcemia of malignancy^2,3

serum Ca²⁺ ≥12 mg/dL (≥3 mmol/L)

Etidronate 7.5 mg/kg per day; administer intravenously over 2 hours for 3 consecutive days^†

Normocalcemia can be maintained after IV therapy with

Etidronate 20 mg/kg; administer orally daily for 30–90 days

Toxicity

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Toxicity

>10%

Headache, gastritis, arthralgia (low-grade fever, myalgias, arthralgias, headache)

1–10%

Diarrhea, nausea, hyperphosphatemia

<1%

Arthritis, glossitis, esophagitis, pruritus, agranulocytosis, pancytopenia

^✫Not an FDA-approved indication

^†An IV formulation is not available for commercial use in the United States

References

Didronel product label, October 2007. Proctor and Gamble Pharmaceutical, Inc., Cincinnati, OH

Ralston SH et al. Lancet 1989;334:1180–1182

Saunders Y et al. Palliat Med 2004;18:418–431 [PubMed: 15332420]

Monitoring Bisphosphonate Therapy

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Monitoring Bisphosphonate Therapy^✫,†

Tests

Zoledronic Acid^1,2,9

Pamidronate^1,3,9

Clodronate^1,4,5

Alendronate^1,6

Risedronate^1,7

Ibandronate^8,9

Etidronate¹⁰

SCr prior to single-dose

Renal impairment^‡

SCr prior to repeated treatments

Serum albumin and BUN

Unexplained albuminuria or azotemia^§,

−

CBC with differential

−

Calcium

Phosphorus

−

Magnesium

−

Hemoglobin and hematocrit

−

Oral exam; preventive dentistry

+, Complete the test or evaluation before drug administration; −, No need to test

^✫Evaluation is recommended before initial treatment with parenterally administered bisphosphonates, each repeated administration, and at the time of routine repeated visits for patients receiving oral agents (eg, monthly to quarter annually)

^†Product labeling for some products warns about a potential for fetal harm if pregnant females receive bisphosphonate treatment during gestation

^‡When resuming treatment after a hiatus for renal impairment, administer pamidronate over at least 2 hours, at doses not greater than 90 mg, and at administration frequencies not greater than every 4 weeks after renal function returns to baseline

^§In patients with multiple myeloma, discontinue bisphosphonate treatment until renal problems resolve in patients with:

Unexplained albuminuria >500 mg/24 h, or
Azotemia (an increase in SCr ≥0.5 mg/dL (>44 μmol/L), or an absolute SCr value >1.4 mg/dL (>124 μmol/L), among patients with normal baseline creatinine¹
Reassess every 3 to 4 weeks with a 24-hour urine collection for total protein and urine protein electrophoresis

In patients with multiple myeloma for whom pamidronate treatment was withheld for renal dysfunction, reinstitute pamidronate only after renal function returns to baseline, with infusion durations >2 h and at doses/schedules >90 mg every 4 weeks¹

References

Berenson JR J Clin Oncol 2002;20:3719–3736; Kyle RA et al. J Clin Oncol 2007;25:2464–2472 [PubMed: 12202673]

Zometa (zoledronic acid) Injection product label, October 2009. Novartis Pharmaceuticals Corporation, East Hanover, NJ

Aredia product label, October 2003. Novartis Pharmaceutical Corporation, East Hanover, NJ

Bonefos^® (disodium clodronate); product label, January 18, 2010. Bayer Inc., Toronto, Ontario, Canada

Clasteon^® (clodronate disodium); product label, April 14, 2009. Sepracor Pharmaceuticals, Inc., Mississauga, Ontario; Licensed by ABIOGEN PHARMA S.p.A Italy

Fosamax^® (alendronate sodium) capsules & oral solution; product label, March 2010. Merck & Co., Inc., Whitehouse Station, NJ

Actonel^® (risedronate sodium); product label, March 2010. Warner Chilcott Puerto Rico LLC, Manati, PR; Norwich Pharmaceuticals, Inc., North Norwich, NY; Chinoin Pharmaceutical and Chemical Works Private Co Ltd, Veresegyhaz, Hungary

Boniva^® (ibandronate sodium); product label, January 2010. Genentech USA, Inc. South San Francisco, CA

Van Poznak CH et al. J Clin Oncol 2011;29:1221–1227 [PubMed: 21343561]

10.

Didronel^® (etidronate disodium); product label, 2005. Procter & Gamble Pharmaceuticals; Cincinnati, OH

REGIMEN: RANK LIGAND INHIBITOR DENOSUMAB (XGEVA^®)

Regimen: Rank Ligand Inhibitor Denosumab (XGEVA^®)

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Oncology-Related Indications

Usual Doses, Administration Routes, and Schedules

Guidance, Caveats, and Comments

Prevention of skeletal-related events in patients with bone metastases from solid tumors
Denosumab is not indicated for the prevention of skeletal-related events in patients with multiple myeloma

Mechanism of action:

Denosumab is a genetically engineered human IgG₂ monoclonal antibody that binds to human release receptor activator of nuclear factor kappa B ligand (RANKL) preventing activation of the RANK receptor on osteoclasts
Osteoclast inhibition results in reduced bone resorption, tumor-induced bone destruction, and skeletal-related events (SRE)

Denosumab 120 mg; administer by subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen

Denosumab (as XGEVA^®) is available in single-use vials containing 120 mg/1.7 mL (70 mg/mL):

Prior to administration, denosumab is removed from refrigeration (2°C–8°C; 35.6°F–46.4°F) and left standing in its original packaging at room temperature (≤25°C; ≤77°F) for 15–30 minutes
- XGEVA^® should not be warmed in any other way
Using a 27-gauge needle, the entire contents of the vial are withdrawn into a syringe and injecte

Do not vigorously shake the vial

Do not expose vials to direct light or heat

Do not re-enter vials after withdrawing the drug product

Dose adjustments

No dose adjustments for renal impairment (denosumab is not eliminated by the kidney)

No clinical trials have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab

Exclusion criteria in clinical trials:

A history of ONJ or osteomyelitis of the jaw
An active dental or jaw condition requiring oral surgery
Any planned invasive dental procedure
Non-healed dental/oral surgical wounds or lesions
Previous intravenous bisphosphonate therapy
Current or previous oral bisphosphonates for treatment of bone metastases

Efficacy

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Efficacy

Denosumab^✫ Compared to Zoledronic Acid^†

Trial 1 Metastatic Breast Cancer

Trial 2 Metastatic Solid Tumors or Multiple Myeloma

Trial 3 Metastatic Castration-Resistant Prostate Cancer

Regimen

Denosumab

Zoledronic acid

Denosumab

Zoledronic acid

Denosumab

Zoledronic acid

Patient number

1026

1020

886

890

950

951

1st on study SRE

Number of patients with SRE (%)

315 (30.7)

372 (36.5)

278 (31.4)

323 (36.3)

341 (35.9)

386 (40.6)

Components of 1st SRE

Radiation to bone

82 (8.0)

119 (11.7)

119 (13.4)

144 (16.2)

177 (18.6)

203 (21.3)

Pathologic fracture

212 (20.7)

238 (23.3)

122 (13.8)

139 (15.6)

137 (14.4)

143 (15.0)

Surgery to bone

12 (1.2)

8 (0.8)

13 (1.5)

19 (2.1)

1 (0.1)

4 (0.4)

SC^§ compression

9 (0.9)

7 (0.7)

24 (2.7)

21 (2.4)

26 (2.7)

36 (3.8)

Median time to SRE

NR^‡

26.4 mo

20.5 mo

16.3 mo

20.7 mo

17.1 mo

Hazard ratio (95% CI)

0.82 (0.71, 0.95)

0.84 (0.71, 0.98)

0.82 (0.71, 0.95)

Non-inferiority P-value

<0.001

Superiority P-value

0.010

0.060

0.008

^✫Denosumab 120 mg by subcutaneous injection every 4 weeks (median duration of exposure, 12 mo [range 0.1–41 mo]; 75% received chemotherapy concomitantly)

^†Zoledronic acid 4 mg by intravenous infusion every 4 weeks with CrCl ≥30 mL/min and dose-adjusted based on CrCl

^‡Not reached

^§Spinal cord

Superiority testing performed only after denosumab was demonstrated non-inferior to zoledronic acid within trial. Survival: OS and PFS were similar in all three trials; mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (hazard ratio 2.26; n = 180)

Toxicity

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Toxicity

Selected Per-patient Incidence of Any Severity From Trials 1, 2, and 3

Variable

Denosumab (n = 2841) %

Zoledronic Acid (n = 2836) %

Fatigue/Asthenia

Nausea/Diarrhea

31/20

32/19

Hypocalcemia^✫

Hypophosphatemia^†

Dyspnea/Cough

21/15

18/15

Headache

Bone: Osteonecrosis of the jaw^‡

1.8 (2.2 with 4-mo trial extension phase)

1.3

^✫Hypocalcemia (corrected, <7 mg/dL [<1.75 mmol/L]): 3.1% of denosumab cohort (33% experienced ≥2 episodes) vs. 1.3% of zoledronic acid cohort

^†Hypophosphatemia (<2 mg/dL [<0.65 mmol/L]): 15.4% of denosumab cohort vs. 7.4% of zoledronic acid cohort

^‡Median time to ONJ was 14 months (range, 4–25 mo)

Adverse Events

Denosumab cohort:

The most common (≥25%), included fatigue/asthenia, hypophosphatemia, and nausea
The most common serious event was dyspnea
The most common events that resulted in discontinuing treatment were osteonecrosis of the jaw and hypocalcemia

Monitoring Therapy

Prior to treatment:

Measure serum calcium, vitamin D, magnesium, and phosphorus
Correct pre-existing hypocalcemia and other levels as necessary prior to treatment
Perform an oral examination and appropriate preventive dentistry prior to the initiation of denosumab

Supplementation:

Daily oral administration of calcium (≥500 mg) and vitamin D (≥400 IU) is strongly recommended

During treatment:

Monitor serum levels of calcium, magnesium, and phosphorus, and replace as necessary
Avoid invasive dental procedures during treatment
Perform periodic oral examination and preventive dentistry
Patients who are suspected of having or who develop osteonecrosis of the jaw (ONJ) while receiving treatment with denosumab should receive care by a dentist or an oral surgeon (extensive dental surgery to treat ONJ may exacerbate the condition)

Advise patients to contact a healthcare professional for any of the following:

Symptoms of hypocalcemia, including paresthesias, muscle stiffness, twitching, spasms, or cramps
Symptoms of ONJ including pain, numbness, swelling of or drainage of the jaw, mouth, or teeth
Persistent pain or slow healing of the mouth or jaw after dental surgery
Pregnancy or nursing (women who become pregnant during Xgeva^® are encouraged to enroll in Amgen's Pregnancy Surveillance Program; 1-800-772-6436)

Advise patients of the need for:

Proper oral hygiene and routine dental care
Informing their dentist they are receiving denosumab
Avoiding invasive dental procedures during treatment with denosumab
Informing their healthcare provider if they are taking Xgeva^® (denosumab is also marketed under the proprietary name, Prolia^®)

Lipton A et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials [abstract]. Ann Oncol 2010;21(Suppl 8):viii380

Stopeck AT et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double blind study. J Clin Oncol 2010;28(35):5132–5139

Xgeva^® (denosumab) injection, for subcutaneous use; product label, August 2013. Amgen Manufacturing Limited, a subsidiary of Amgen Inc., Thousand Oaks, CA

DENOSUMAB (PROLIA^®)

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DENOSUMAB (PROLIA^®)

Indication

Usual Doses, Administration Routes, and Schedules

Guidance, Caveats, and Comments

Treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy)

Denosumab 60 mg; administer as a single subcutaneous injection in the upper arm, upper thigh; or the abdomen once every 6 months. If a dose is missed, administer the injection as soon as the patient is available and thereafter, every 6 months from the last injection

Denosumab (as Prolia^®) is available in single-use prefilled syringes and single-use vials containing 1 mL of a 60-mg/mL solution

Prior to administration, denosumab is removed from refrigeration (2°C–8°C; 35.6°F–46.4°F) and left standing in its original packaging at room temperature (≤25°C; ≤77°F) for 15–30 minutes
- Prolia^® should not be warmed in any other way
From a single-use vial, using a syringe with a 27-gauge needle, withdraw the entire contents of the vial and administer the drug by subcutaneous injection

Do not vigorously shake vials or syringes

Do not expose vials or syringes to direct light or heat

Do not re-enter vials after withdrawing the drug product

Dose adjustments

No dose adjustments are necessary in patients with renal impairment

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia^®

People sensitive to latex should not handle the gray needle cap on the single-use prefilled syringe, which contains dry natural rubber (a latex derivative)

The Effect of Prolia on the Incidence of New Vertebral Fractures

Proportion of Women with Fracture (%)^✫

Absolute Risk Reduction, % (95% CI)

Relative Risk Reduction, % (95% CI)

Placebo (N = 3691)

Prolia (N = 3702)

0–1 year

2.2

0.9

1.4 (0.8, 1.9)

61 (42, 74)

0–2 years

5.0

1.4

3.5 (2.7, 4.3)

71 (61, 79)

0–3 years

7.2

2.3

4.8 (3.9, 5.8)

68 (59, 74)

^✫Absolute risk reduction and relative risk reduction base on Mantel-Haenszel method adjusting for age group variable

The Effect of Prolia on the Incidence of Non-vertebral Fractures at Year 3

Outcome

Proportion of Women with Fracture, %^†

Absolute Risk Reduction, % (95% CI)

Relative Risk Reduction, % (95% CI)

Placebo (N = 3906)

Prolia (N = 3902)

Non-vertebral fracture^‡

8.0

6.5

1.5 (0.3, 2.7)

20 (5, 33)^✫

^✫P-value = 0.01

^†Event rates based on Kaplan-Meier estimates at 3 years

^‡Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, finger/toe phalanges

Toxicity

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Toxicity

>10%

Back pain (34.7%; same rate as control), dermatitis/eczema/rashes (10.8%)

1–10%

Musculoskeletal pain (7.6%), sciatica (4.6%), non-fatal serious infections (4%), hypocalcemia <8.5 mg/dL (1.7%; occurred at approximately day 10 after Prolia^® in patients with normal renal function), patients who withdrew from study due to ADR (2.4%; control 2.1%; most common reasons: breast cancer [causality has not been established], back pain, and constipation)

<1%

Skin infections (0.4%), pancreatitis (0.2%), infections resulting in death (0.2%; same rate as control)

Monitoring Therapy

Prior to treatment:

Measure serum calcium, vitamin D, magnesium, and phosphorus
Correct pre-existing hypocalcemia and other levels as necessary prior to treatment
Perform an oral examination and appropriate preventive dentistry prior to the initiation of denosumab

Supplementation:

Daily oral administration of calcium (at least 1000 mg) and vitamin D (≥400 International Units) is advised

During treatment:

Monitor serum levels of calcium, magnesium, and phosphorus, and replace as necessary
Avoid invasive dental procedures during treatment
Perform periodic oral examination and preventive dentistry
Patients who are suspected of having or who develop ONJ while on denosumab should receive care by a dentist or an oral surgeon (in these patients, extensive dental surgery to treat ONJ may exacerbate the condition)

Advise patients to contact a healthcare professional for any of the following:

Symptoms of hypocalcemia, including paresthesias, muscle stiffness, twitching, spasms, or cramps
Symptoms of ONJ including pain, numbness, swelling of or drainage of the jaw, mouth, or teeth
Persistent pain or slow healing of the mouth or jaw after dental surgery
Pregnancy or nursing (women who become pregnant during Xgeva are encouraged to enroll in Amgen's Pregnancy Surveillance Program; 1-800-772-6436)

Advise patients of the need for:

Proper oral hygiene and routine dental care
Informing their dentist that they are receiving denosumab
Avoiding invasive dental procedures during treatment with denosumab
Informing their healthcare provider if they are taking Prolia^® (denosumab is also marketed as Xgeva^®)

Prolia^® (denosumab) Injection, for subcutaneous use; product label, July 2013. Amgen Manufacturing Limited, a subsidiary of Amgen Inc., Thousand Oaks, CA

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Chapter 47: Indications for Bone-Modifying Agents in Hematology-Oncology

Citation

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Updated chapter to come.

INTRODUCTION

References

Notes

References

REGIMENS

References

References

References

References

References

References

References

REGIMEN: RANK LIGAND INHIBITOR DENOSUMAB (XGEVA^®)

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INTRODUCTION

References

Notes

References

REGIMENS

References

References

References

References

References

References

References

REGIMEN: RANK LIGAND INHIBITOR DENOSUMAB (XGEVA®)

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REGIMEN: RANK LIGAND INHIBITOR DENOSUMAB (XGEVA^®)