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RANK Ligand and Skeletal-Related Events in Patients with Cancer

Bone is a common site of metastases for many patients with cancer; 65% to 75% of patients who die from breast or prostate cancer have bone metastases, and 30% to 40% of patients with non–small cell lung cancer develop bone metastasis.

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Bone is a common site of metastases for many patients with cancer; 65% to 75% of patients who die from breast or prostate cancer have bone metastases, and 30% to 40% of patients with non—small cell lung cancer (NSCLC) develop bone metastasis. Furthermore, almost all patients with multiple myeloma have been shown to develop bone disease. Skeletal-related events (SREs), including pathologic fractures, palliative radiation therapy, skeletal surgery, and spinal cord compression, often occur in these patients (Table).

Clinical Burdens of SREs


Saad et al (2007) examined the effect of pathologic fractures on the mortality rates of patients with malignant bone disease. They found the incidence of pathologic fractures was 43% in patients with multiple myeloma (220/513), 35% in patients with breast cancer (393/1130), and 19% in patients with prostate cancer (126/640). The data analysis also showed that patients with all three types of cancer had a greater risk of death when pathologic fractures developed compared with patients who did not have fractures. For breast cancer, the results showed the risk of death was 52% greater before adjustment for baseline characteristics (P < .01) and 32% higher after adjusting for previous SREs and ECOG (Eastern Cooperative Oncology Group) performance status (P < .01). Fractures were also associated with an increased risk of death in patients with multiple myeloma and prostate cancer.




Patients who experience SREs frequently have severe pain and a subsequent need for opioids. Approximately two-thirds of patients with bone metastases experience debilitating bone pain. A study by Yau et al (2004) in 534 patients observed that 76% of patients with solid tumors and bone metastases had moderate to severe bone pain. Many patients with bone metastases are treated with opioid therapy, even though it often treats the pain insufficiently.

Current Approaches to Preventing SREs







Intravenous (IV) bisphosphonates reduce cancer-related bone complications in patients with certain malignancies by delaying the onset of SREs and reducing their risk of developing SREs. IV bisphosphonates work by embedding in the bone matrix (with a skeletal half-life of up to 11 years) and inducing apoptosis of activated osteoclasts. IV bisphosphonates improve bone health by incorporating into bone and causing toxicity to osteoclasts. Like most therapies, bisphosphonates have been associated with specific adverse reactions, and, as a result, many patients go untreated. For example, IV bisphosphonates can result in nephrotoxicity in some patients, and regular monitoring of renal function is indicated. Other side effects may include nausea, fatigue, and anemia. Osteonecrosis of the jaw has also been reported in some patients, and bisphosphonates may cause a flu-like reaction. For these safety reasons, bisphosphonates may not always be prescribed.


Additionally, a retrospective analysis by Mortimer et al (2007) indicated that up to 53% of 1431 patients whose breast cancer had metastasized to the bone remained untreated with IV bisphosphonates for bone metastases.

Relationship Between RANK Ligand Pathways and SREs in Cancer



In healthy bone, remodeling is a lifelong, balanced process of bone resorption (by osteoclasts) and bone formation (by osteoblasts). RANK Ligand is a key mediator in this dynamic process. RANK Ligand is a protein expressed by osteoblasts and other cells that allows osteoclast precursors to form and differentiate into active (mature) osteoclasts by binding to its receptor RANK.



Studies have shown that RANK Ligand signaling is essential to the differentiation and activation of osteoclasts and is a key mediator in the dynamic balance of bone formation and resorption.



20,21, 24—28


RANK Ligand in Multiple Myeloma. RANK Ligand is an essential mediator of the cycle of bone destruction. In patients with multiple myeloma, it is believed that when cancer metastasizes to the bone, it triggers a cycle (Figure 1) of bone destruction which may further stimulate tumor growth by inducing osteoblasts. The increased RANK Ligand signaling disrupts the natural balance of bone remodeling by driving excessive osteoclast activity, resulting in bone destruction. Furthermore, bone resorption by osteoclasts releases growth factors and calcium from the bone matrix, which may further stimulate tumor growth and contribute to a vicious cycle of bone destruction that can result in devastating SREs.




RANK Ligand in Patients Receiving Hormone-Ablative Therapy. In patients with prostate or breast cancer, the commonly used hormone-ablative therapies are also associated with decreased bone mineral density (BMD). In these patients, reduction of sex hormone levels may lead to an increase in RANK Ligand expression. This drives excessive osteoclast activity, causing systemic bone loss, which can lead to debilitating fractures.




A recent review of claims data in women with breast cancer (N=12,368) showed that patients receiving aromatase inhibitors (AIs) were 21% (P = .02) more likely to have fractures compared with those who did not receive AIs (after adjustment for risk factors). Similarly, men treated for prostate cancer with androgen deprivation therapy (ADT) have significantly lower BMD levels (Figure 2). In a recent review of the medical records of more than 50,000 men with prostate cancer, the group of men who received ADT experienced a 54% increase in the incidence of fractures compared with the group who did not receive ADT (Figure 3).



In patients with advanced cancer, bone metastases can lead to debilitating SREs, which are associated with increased pain, morbidity, and mortality—all of which present serious challenges to our health care system. Unfortunately, current options to prevent and/or treat SREs have limitations. On the plus side, an increased understanding of the role of the RANK Ligand pathway in regulating bone metabolism has led to an exciting new era of scientific research and discovery in bone biology.


RANK Ligand has been shown to be a potentially valuable signal of bone loss and destruction in patients with various cancer-related bone diseases. Investigations of the role of RANK Ligand are ongoing.



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