Radium Ra 223 dichloride (Xofigo – Bayer), a radiotherapeutic drug, has been approved by the FDA for intravenous treatment of castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.

The FDA, which recently approved subcutaneous (SC) administration of denosumab (Prolia – Amgen) for treatment of postmenopausal osteoporosis,1 has now approved the same drug with a different brand name (Xgeva – Amgen) and dosage for prevention of skeletal-related events (such as pathologic fracture, spinal cord compression or radiation to bone) in patients with bone metastases from solid tumors. Denosumab is a fully human anti-RANK ligand antibody that inhibits the formation, activation and survival of osteoclasts.2

A prospective, randomized, double-blind trial in 1901 patients with bone metastases from castration-resistant prostate cancer found that denosumab 120 mg injected SC every 4 weeks, compared to the bisphosphonate zoledronic acid (Zometa) 4 mg IV, delayed the time to a first skeletal event by 3.6 months (20.7 vs. 17.1 months).3 In 1776 patients with bone metastases from solid tumors or multiple myeloma, the mean time to a first skeletal event was 20.6 months with SC denosumab and 16.3 months with IV zoledronic acid.4

Denosumab can lower serum calcium concentrations, especially in patients with impaired renal function. Fatigue is the most commonly reported adverse effect. Other adverse effects of both denosumab and zoledronic acid in clinical trials have included nausea, dyspnea and diarrhea. Acute-phase reactions and renal toxicity have been less frequent with denosumab than with zoledronic acid. Osteonecrosis of the jaw, which can occur with bisphosphonates, has also been reported with denosumab.

1. Denosumab (Prolia) for postmenopausal osteoporosis. Med Lett Drugs Ther 2010; 52: 81.

2. A Lipton and C Goessl. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. Bone 2011; 48:96.

3. K Fizazi et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol 2010; 28:18s (abstr LBA4507).

4. D Henry et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Cancer Suppl 2009; 7:11 (abstr 20LBA).

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Osteoporosis is characterized by low bone mass with microarchitectural disruption and skeletal fragility that results in an increased risk of fracture. The diagnosis has traditionally been established by bone densitometry, which is generally reported in terms of standard deviations (SD) from mean values in young adults (T score). The World Health Organization (WHO) has defined normal bone mineral density (BMD) for women as a value within one SD of the young adult mean. Values 2.5 SD (T score -2.5) or more below the mean are defined as osteoporosis. The WHO has developed a computerized model (FRAX) that predicts the 10-year probability of hip fracture based on clinical risk factors and BMD at the femoral neck.

Zoledronic acid (Reclast - Novartis) is the first bisphosphonate approved by the FDA for once-yearly intravenous (IV) treatment of osteoporosis in postmenopausal women. Reclast is also approved for treatment of Paget's disease. Another IV formulation of zoledronic acid (Zometa) is approved for treatment of hypercalcemia of malignancy, multiple myeloma and bone metastases from solid tumors.

Many drugs are now marketed for treatment of postmenopausal osteoporosis, but questions remain about their use.

A 10-year study of daily oral alendronate (Fosamax) and a 7-year study of daily oral risedronate (Actonel) indicate that both drugs maintained increases in bone mineral density (BMD) and decreases in markers of bone remodeling throughout the study period. Both drugs are now more commonly taken once weekly. Available data are insufficient to compare fracture rates with alendronate and risedronate, and fracture rates are considered the most important endpoint in osteoporosis studies. Recent reports of severe pain and jaw osteonecrosis with these drugs are disturbing.

Many drugs are now marketed for treatment of post-menopausal osteoporosis (PD Delmas, Lancet 2002; 359:2018). Prevention of this disorder has been complicated by the news that hormone replacement therapy (HRT), which many women have been taking to prevent osteoporosis, increases the incidence of coronary heart disease and that of breast cancer, stroke and pulmonary embolism as well (Medical Letter 2002; 44:78).

A once-weekly 35-mg oral formulation of the bisphosphonate risedronate (Actonel) has been approved by the FDA for prevention and treatment of postmenopausal osteoporosis. A once-weekly formulation of alendronate (Fosamax) was approved last year (Medical Letter 2001; 43:26). Bisphosphonates bind to the mineral surface of bone and decrease osteoclast activity, inhibiting the resorption phase of the bone turnover cycle. These drugs are not metabolized and remain bound to bone for several weeks.

Zoledronic acid (Zometa), a new bisphosphonate, has been approved by the FDA for intravenous (IV) treatment of hypercalcemia of malignancy.