zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.

Bisphosphonates

Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities.

Renal toxicity with an increase in creatinine levels from baseline may occur in approximately 10% of patients receiving zoledronic acid or pamidronate. The renal toxicity is related to the specific bisphosphonate, the dose schedule, the duration of administration, and concomitant medications. Creatinine clearance should be assessed prior to administration of intravenous bisphosphonates. Lowing the dose according to treatment guidelines and prolonging the infusion time may reduce this problem.

Osteonecrosis of the jaw (ONJ) is an uncommon adverse event that occurs in 1.4% of patients receiving bisphosphonates. It usually develops after a dental procedure. Other risk factors for development of ONJ include glucocorticosteroids, preexisting dental or periodontal disease, and use of thalidomide. The appearance of an area of necrotic bone in the oral cavity in a patient who has not received radiation therapy to this area is a typical presentation of ONJ.

The use of bisphosphonates in patients without cancer has not been conclusively associated with an increased rsik for developing cancer. There is no evidence that the use of bisphosphonates increases the risk for a new primary tumor or disease progression in patients with cancer.

Denosumab

Receptor activator of RANKL is expressed on the surface of marrow stromal cells, activated T cells, and osteoblasts. Denosumab is a fully human monoclonal lgG2 antibody that binds to RANKL, thus inhibiting the interaction between RANK and RANKL. This process results in diminished osteoclast activity, decreased bone resorption, and increased bone mass. Denosumab has been approved by FDA for treatment of osteoporosis in postmenopausal women, prevention of SREs in patients with bone metastases from solid tumors, but it is not indicated for the prevention of SREs in patients with multiple myeloma.

An increased incidence of pancreatitis has been found with this drug. Transient hypocalcemia may occur more frequently with denosumab (5.5%) than with zoledronic acid (3.4%). Although renal toxicity may develop with denosumab, it is less common than with zoledronic acid.

An increased risk of serious infections, including endocarditis, erysipelas, cellulitis, and infectious arthritis, has been reported with denosumab.

Although ONJ is uncommon with denosumab, the phase III trials in the setting of bone metastases revealed similar or even higher rates of ONJ with denosumab than with zoledronic acid.

Markers of Bone Turnover

Monitoring markers of bone turnover such as NTX and bone-specific alkaline phosphatase (BALP) maybe useful in assessing the extent of bone disease in patients with solid tumors metastatic to bone and multiple myeloma. NTX is released into the bloodstream and excreted in the urine during osteoclast-mediated bone resorption.

One study showed that in patients with solid tumors the majority of patients with bone metastases had elevated urinary NTX, compared with healthy yong adults. Also elevated NTX levels were correlated with an increased risk for SREs and disease progression, compared with low NTX levels. In addition, increased levels of BALP were related to an adverse outcome.

Bone turnover markers may also reflect response to treatment. An analysis of patients with bone metastases from non-small cell lung cancer found that a decrease in urinary NTX levels was associated with a response to therapy as well as improvement in time to disease progression.

Guidelines for Bone-Targeted Therapy

The guidelines stipulate that therapy with bone-modifying agents is recommended only for patients with evidence of bone destruction due to bone metastases from breast cancer.

The approved agents include denosumab (120 mg subcutaneously every 4 weeks), intravenous pamidronate (90 mg over no less than 2 hours), and zoledronic acid (4 mg over no less than 15 minutes every 3 to 4 weeks). There is insufficient evidence to demonstrate greater efficacy of one agent over another. No change in dosage, infusion time, or interval of administration is required for patients with a calculated creatinine clearance of more than 60 mL/min. Serum creatinine levels should be monitored before each dose. In patients with a creatinine clearance between 30 and 60 mL/min, a dose reduction detailed in the package insert for zoledronic acid should be used.

The ASCO guidelines also recommend that all patients should receive a dental examination and appropriate preventive dentistry before therapy with bone-modifying agents is initiated and should maintain optimal oral health thereafter. Standards of care for management of bone pain from cancer should be employed in conjunction with therapy with bone-modifying agents. Furthermore, the use of biochemical markers to monitor these pharmacologic agents is not recommended. There are no contraindications to the use of calcium and vitamin D supplements.