Optimizing skeletal wellness in general, and in cancer patients in particular, involves patient individualization, adherence to lifestyle guidelines, and the use of appropriate supplements and restorative therapeutic agents. It is especially important to identify patients at greater risk for skeletal deterioration through a good physical examination; in-depth personal, lifestyle, and family history; and testing for bone loss when and where indicated, especially in aging patients.

Lifestyle modifications should be discussed and suggested, including strong directives to:

• Cease smoking¹
• Reduce alcohol consumption¹
• Increase exercise²
• Improve dietary intake of protein, calcium, vitamin D²

Supplements for calcium and vitamin D should be considered if dietary or environmental exposure is limited or if patients are at high risk for bone loss.² For postmenopausal women who have lost the beneficial bone preserving effects of estrogen and for men in later stages of life, hormone replacement approaches may be indicated as will the use of antiresorptive agents.³

Prevention of skeletal complications in cancer patients is critical to maintaining bone health and reducing morbidity and mortality. The chronic nature of medical care for cancer patients necessitates management with long-term supportive/palliative care toward:

• Minimizing skeletal bone pain
• Reducing fracture rate
• Relieving spinal cord compression
• Maintaining a patient's activity level and QOL

With the onset of later stages of cancer and metastasis to bone, more aggressive therapies and procedures are required. The chart below lists the traditional therapeutic approaches and the goals of those approaches.

Important options for preventing and treating bone loss in aging patients, and especially in those with advanced cancer and metastatic implications, are the antiresorptive agents. These agents target the bone-resorbing osteoclastic system (see sections Overview of Healthy Bone and Skeletal Complications in Cancer) and include:

• Selective estrogen replacement modulators (SERMs)¹
  – Currently raloxifene and tamoxifen
• Calcitonin (injection or intranasal)
  – Used in the management of hypercalcemia of malignancy (HCM)^4,5
• Gallium nitrate (5-day continuous infusion)
  – Used in the management of HCM⁵
• Bisphosphonates
  – Used in the management of HCM, bone metastases, and osteoporosis^5,6

The bisphosphonates are a growing class of antiresorptive agents that vary in application and potency. Patients with advanced cancer are at risk for bone destruction from bone metastases.⁷ Bisphosphonates can inhibit bone resorption, correct hypercalcemia, reduce pain, reduce fracture rate, and improve quality of life.⁸ They also can inhibit formation of new osteolytic lesions.⁷

Patients who are receiving treatment for early-stage cancer are at risk for cancer-treatment–induced bone loss (CTIBL). Although, currently, no therapy has been approved specifically for treating or preventing CTIBL, some bisphosphonates show promise in early evidence from clinical trials to aid in treating and preventing CTIBL.⁷ The bisphosphonates also inhibit osteoclast-mediated osteolysis.⁷

Bisphosphonates have been developed over the last 30 years and are divided into first-generation nonnitrogen-containing bisphosphonates (eg, clodronate) and nitrogen-containing bisphosphonates, or N-BPs, (eg, pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid). Both classes of bisphosphonates have different mechanisms of action.⁹

The primary pharmacologic action of bisphosphonates is inhibition of bone resorption. Nonnitrogen-containing bisphosphonates are metabolized by osteoclasts to nonhydrolyzable cytotoxic adenosine triphosphate (ATP) analogues, which, at high concentrations, inhibit mitochondrial ATP/adenosine diphosphate translocase, thereby resulting in loss of mitochondrial membrane potential and direct induction of apoptosis. High affinity of bisphosphonates ensures that cytotoxic concentrations accumulate within osteoclasts.⁹

At the same time, N-BPs affect osteoclast activity and survival through a different mechanism of action, as indicated in the figure below.⁹ Once inside the osteoclast, the N-BPs inhibit a key enzyme, farnesyl diphosphate synthase, thereby interfering with a variety of cellular functions essential for the bone-resorbing activity and survival of osteoclasts. Several intermediates in the pathway, including farnesyl pyrophosphate and geranyl-geranyl pyrophosphate, are required for posttranslational modification (prenylation) of guanosine triphosphate-binding proteins, which act as signaling molecules involved in the regulation of cell proliferation, cell survival, and cytoskeletal organization. Intracellular vesicle transport is affected, which in turn prevents osteoclasts from forming a tight-sealing zone or "ruffled borders," which are required for bone resorption.⁹

Figure. Schematic representation of the mevalonate pathway and the effects of nitrogen-containing bisphosphonates. Apppi=adenosine triphosphate analogue; FPP=farnesyl diphosphate; HMG CoA=3-hydroxy-3-methylglutaryl coenzymeA; N-BPs=nitrogen-containing bisphosphonates.
Reproduced with permission from Green JR. Oncologist. 2004;9(suppl 4):3-13.
© AlphaMed Press 1083-7159.

Many bisphosphonates are available and will be discussed individually throughout this website.

The major bisphosphonates approved by the US Food and Drug Administration for oncology are pamidronate and zoledronic acid. Pamidronate, zoledronic acid, clodronate, and ibandronate are approved overseas by the European Medicines Agency and by the Ministry of Health, Labor and Welfare, Pharmaceutical and Medical Devices Evaluation Center, in Japan.

Relative potencies of the N-BPs, with respect to inhibition of FPP synthase and bone resorption activity, are shown in the table below. These potencies are related to specific side-chain composition.⁹ IC₅₀ is 50% of the inhibitory concentration; the lower the IC₅₀ value, the more potent the agent.

IC₅₀ = 50% of the inhibitory concentration.
^*Mean values calculated from dose-response plots of inhibition of FPP synthase in J774 cell homogenates based on three experiments.
^†Inhibition of 1,25-dihydroxyvitamin D₃-induced calcium release from mouse calvaria in vitro. Data represent means of several experiments.
Reproduced with permission from Green JR. Oncologist. 2004;9(suppl 4):3-13.
© AlphaMed Press 1083-7159.

Bisphosphonate therapy has become a standard of care for patients with malignant bone disease⁷ and is the most effective therapeutic option³ for cancer-related bone loss. However, the bisphosphonates have widely different characteristics and may be administered orally or intravenously. The orally administered agents have low bioavailability, are poorly absorbed, and may be associated with esophageal and gastrointestinal toxicities. The intravenous agents are more potent, moving rapidly from the blood to adhere to bone.⁸ These agents generally are not metabolized in vivo and are usually excreted unaltered⁸; therefore, monitoring of renal function is required.¹²

Although bisphosphonates usually are administered either orally or intravenously, some of these agents have both an oral and an intravenous formulation; however, these formulations differ in action and dose. The bisphosphonates described below are in current use or in clinical investigation.

Ibandronate¹³

• Approved in Europe; investigational in the United States
• Intravenous formulation
  – Hypercalcemia of malignancy
     - Moderate disease: 2 mg (500-mL solution) single dose infused over 2 h
     - Severe disease: 4 mg (500-mL solution) single dose infused over 2 h
     - Normal range usually reached within 7 d
  – Prevention of skeletal events in patients with breast cancer and bone metastases
     -6 mg (500-mL solution) infused over 1 h every 3 to 4 wk
• Oral formulation
  – Prevention of skeletal events in patients with breast cancer and bone metastases
  – 50 mg daily, 30 minutes before food

Zoledronic Acid¹⁴

• Approved in the United States and in Europe
• Intravenous formulation only
  – Hypercalcemia of malignancy
     - 4 mg (100-mL solution), maximum single dose, infused over 15 min
     - Re-treat if necessary
  – Metastatic bone lesions from multiple myeloma, all types of solid tumors
     - 4 mg (100-mL solution) infused over 15 min every 3 to 4 wk

Pamidronate¹⁵

• Approved in the United States and in Europe
• Intravenous formulation
  – Hypercalcemia of malignancy
     - Moderate disease: 60 to 90 mg, single dose, infused over 2 to 24 h
     - Severe disease: 90 mg, single dose, infused over 2 to 24 h
     - Re-treat if necessary >7 d from initial dose
  – Osteolytic bone lesions of multiple myeloma and breast cancer
     - 90 mg infused over 2 to 4 h every 3 to 4 wk

Clodronate¹⁶

• Approved in Europe
• Intravenous and oral formulations
• Intravenous formulation
  – 1500 mg (500-mL solution) single dose infused over no less than 4 h
• Oral formulation
  – Following intravenous therapy, recommended daily dose of 1600 to 2400 mg as a single dose or 2 divided doses, with copious amounts of fluids (not milk) and on an empty stomach

Skeletal Impact of Clodronate in Metastatic Bone Disease

• Significantly decreases skeletal events vs placebo (P<.001)¹⁷
• Less effective than intravenous pamidronate (90 mg monthly) at ameliorating pain or preventing bone resorption¹⁸
• Oral clodronate at 2400 mg/day is similar to intravenous pamidronate at 60 mg once every 3 weeks, but has gastrointestinal side effects¹⁹
• Oral clodronate reduces loss of bone mineral density (BMD) in patients with primary breast cancer who are receiving chemotherapy/tamoxifen therapies²⁰

New treatment options under investigation include⁵

• Monoclonal antibodies to RANKL (activator of NF-κB ligand), which block RANKL stimulation of recruitment, differentiation, and activation of osteoclasts
• Monoclonal antibodies to parathyroid hormone-related peptide (PTHrP), which block PTHrP activity in HCM and bone metastases

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13.	Bondronate® (ibandronate sodium) [Prescribing Information.] European Medicines Agency. Available at http://www.rochecanada.com/pdf/bondronatpmE.pdf Accessed November 2004.
14.	Zometa® (zoledronic acid) [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. 2003.
15.	Aredia® (pamidronate) [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. 2003.
16.	Ostac® (clodronate) [Prescribing Information]. Nutley, NJ: Hoffmann-La Roche; 2004.
17.	Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol. 1993;11:59-63.
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