The bone complications that can occur in cancer patients arise either from bone destruction mediated by metastases or from unintended adverse effects of cancer treatment on bone. The result is weakened bone that can produce a number of symptoms and problems related to the condition of the patient.

Bone tumors can be classified as either primary or metastatic. Primary bone cancer involves a tumor that originates in the bone. Metastatic, or secondary, bone cancer originates in another organ, and spreads, or metastasizes, to bone. Metastatic bone cancers are much more common, especially from cancers starting in lung, breast, and prostate tissue.

Bone metastases can be classified, according to the end result of the metastases, as osteolytic, which causes a hole in the bone and weakens it, or osteoblastic, which makes the bone very dense. The metastases also can be mixed—a combination of the two.

Bone loss also can be caused by cytotoxic therapy directed toward the tumor or by surgical or hormonal therapy leading to estrogen or androgen depletion. This is referred to as treatment-related osteoporosis or cancer-treatment–induced bone loss (CTIBL); it requires preventive and corrective measures.

In the normal bone remodeling process (See Section, Overview of Healthy Bone), resorption and formation of bone are coupled and balanced (Figure 1). New bone is synthesized in appropriate amounts in the location where old bone has been resorbed. "Coupled" means that the functions of osteoblasts and osteoclasts are very tightly and intimately interconnected. "Balanced" means that the amount of bone that is broken down and the amount of new bone that is formed are equivalent.¹

When cancer affects the bone, imbalances arise in this process.

As bone remodeling becomes imbalanced, osteoclastic activity becomes excessive (Figure 2). The osteoblasts cannot make up the lost bone; therefore, there is a net loss of bone.

This imbalance occurs in noncancer patients with osteoporosis as well as in patients with cancer and osteolytic lesions.¹

In bone remodeling that is uncoupled but balanced, the activities of both osteoblasts and osteoclasts are abnormal (Figure 3). This represents a process in which there is no net change in bone; however, bone formation and resorption are disorganized. There are areas of inappropriately increased amounts of bone and areas of inappropriately decreased amounts of bone.

This situation occurs primarily with mixed metastatic lesions in cancer. Of note, even in the case of osteoblastic metastases, the inhibition of osteoclasts (bone resorption) is important to help balance out the abnormal remodeling process.¹

When bone remodeling is uncoupled and imbalanced, osteoblastic activity becomes abnormal (Figure 4). A net increase in bone formation often occurs at sites with no previous bone resorption. This is commonly seen in osteoblastic lesions in patients with prostate cancer metastases.

In remodeling that is uncoupled and imbalanced, there is actually an excessive amount of newly woven weak bone that is easily fractured.¹

As shown in Figure 5, the primary malignant neoplasm promotes new blood vessel formation, and these blood vessels carry cancer cells to capillary beds in the bone. Aggregates of tumor cells and other blood cells form embolisms that lodge in distant capillaries in bone. Cancer cells can adhere to vascular epithelial cells to escape the blood vessels. As cancer cells enter the bone, they contact factors in the microenvironment of the bone that support the growth of metastases.²

Figure 5. Development of bone metastasis. (click image for larger view)
Reproduced with permission from Nature Reviews Cancer: Mundy GR. Nat Rev Cancer.
2002;2:584-593. Copyright © 2002. Macmillan Magazine.

As shown in the accompanying diagram of osteolytic metastasis (Figure 6), interactions between tumor cells and osteoclasts cause osteoclast activation and bone destruction and can stimulate aggressive growth and behavior of tumor cells. Tumor cells produce PTHrP (parathyroid hormone-related peptide), which activates osteoblasts to make RANKL (receptor activator of nuclear factor-κB ligand) and downregulate OPG (osteoprotegerin).² Osteoclast precursors are activated, which leads to osteolysis. Bone-derived growth factors, including TGF-β (transforming growth factor-β) and IGF1 (insulinlike growth factor 1) are then released, and extracellular calcium concentrations are raised. When growth factors bind to receptors on the tumor cell surface, autophosphorylation (P) and signaling through SMAD (cytoplasmic mediators of most TGF-β signals) and MAPK (mitogen-activated protein kinase) occurs. Extracellular calcium binds and activates a calcium pump. Signaling through these pathways results in proliferation of tumor cells and production of PTHrP. Other cytokines might also be involved, such as interleukin (IL)-1, IL-6, IL-11 and IL-18.²

Figure 6. Osteolytic bone metastasis.
Reproduced with permission from Nature Reviews Cancer: Mundy GR. Nat Rev Cancer.
2002;2:584-593. Copyright © 2002. Macmillan Magazine.

Tumor cells produce factors such as FGFs (fibroblast growth factors), BMPs (bone morphogenic proteins), PDGF (platelet-derived growth factor), and TGF-β. These factors can stimulate osteoblast activity and subsequent bone formation. Proteases, such as PSA (prostate-specific antigen), are induced by activators, such as urokinase (uPA). Proteases can activate latent TGF-β, release IGFs from inhibitory binding proteins (IGFBPs) and inactivate the osteolytic factor PTHrP to promote bone formation.² This model is shown in Figure 7.

Figure 7. Osteoblastic bone metastasis.
Reproduced with permission from Nature Reviews Cancer: Mundy GR. Nat Rev Cancer.
2002;2:584-593. Copyright © 2002. Macmillan Magazine.

The incidence of bone metastasis is higher with some tumors then others. The incidence of metastasis in various metastatic tumors are observed at autopsy, as presented in the table below.³

Adapted with permission from Coleman RE. Cancer Treat Rev. 2001;27:165-176.

Bone health risks in cancer patients can stem from treatment that directly affects bone. Also, some cancers humorally affect bone. In all cases, metastasis in later stages weakens bones.

The changes that occur with aging also affect bone health. Appropriate levels of estrogen are necessary for maintaining bone health. However, as menopause approaches, women are particularly at risk for declining estrogen levels and negative bone health. Surgically induced menopause by oophorectomy will have the same effect.¹ For men, the aging process leads to decreased levels of testosterone, resulting in increased risk for bone loss. The occurrence of osteoporosis in people older than 60 is common.⁴

How much and what type of exercise a patient does also can affect bone loss. For elderly persons, poor dietary intake of calcium, vitamin D, and other nutrients will further increase their risk for negative bone health.⁴

Finally, cancer therapy, as well as the cancer itself, will have both direct and indirect effects on bone health.⁴

Bone metastases cause considerable morbidity, including severe pain, impaired mobility, symptoms of hypercalcemia, pathologic fractures, and spinal cord compression. Cord compression can lead to paralysis or death. Hypercalcemia is potentially lethal.^5,6

Bone pain is the most common symptom associated with metastases.⁷ About 80% of patients will experience pain. Pain is often the first indication that the tumor has metastasized to the bone.⁸

Pain, in turn, has a detrimental affect on a patient's quality of life, interfering with daily activities and limiting a patient's capabilities. These effects often lead to feelings of anger, fear, and depression.

Metastatic destruction of bone reduces its load-bearing capabilities and leads to pathologic fractures. The probability of developing a pathologic fracture increases with the duration of metastatic involvement. In addition, bone metastases in the vertebral body increase the risk of developing spinal cord compression, causing significant pain and discomfort.

Moderate-to-severe hypercalcemia may cause significant health problems if left untreated, including dysfunction of the gastrointestinal tract, kidneys, and central nervous system.⁸

The necessity for pain or fracture management is clear but can significantly increase treatment costs. Bone pain is managed with radiation therapy. Studies have shown that up to 50% of the total treatment costs are attributable to the costs of managing skeletal-related events such as pain, fractures, symptoms of hypercalcemia, and spinal cord compression.⁹

In addition to metastasis, bone loss can occur as a result of cancer treatment.¹⁰ This type of bone loss is called treatment-related osteoporosis. The term CTIBL (cancer-treatment–induced bone loss) has been used to describe this condition in cancer patients and may have special implications related to severity.

Cytotoxic chemotherapy has an independently negative effect on bone cells (primarily osteoblasts) and can induce premature ovarian failure in patients with breast cancer. Premature ovarian failure leads to estrogen deprivation, which in turn leads to loss of bone mineral density (BMD).¹⁰

Hormonal therapies, such as selective estrogen replacement modulators (SERMs) and aromatase inhibitors have been shown to cause bone loss in premenopausal women with breast cancer. However, in postmenopausal women, SERMS are used to increase BMD and protect against osteoporosis. Raloxifine and tamoxifen are SERMs, and anastrozole is an aromatase inhibitor.

Androgen deprivation therapy may cause hypogonadism, which increases risk for fracture.

Other therapies that can result in treatment-related osteoporosis include glucocorticoids, gonadal ablation or suppression (ovarian and testicular), and radiation therapy to bone (causing osteonecrosis and reduced function and number of osteoblasts). Poor nutrition (ie, deficiencies in vitamin D and calcium) and immobilization also may have an effect.¹¹

1.	Coleman RE, Theriault RL, Smith MR, Rosen LS. The evolving role of bisphosphonates for cancer treatment-induced bone loss [monograph]. Release date June 2003. Available at http://www.medscape.com/viewprogram/2511pnt. Accessed November 29, 2004
2.	Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584-593.
3.	Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-176.
4.	Office of the Surgeon General. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services. October 14, 2004. Available at http://www.hhs.gov/surgeongeneral/library/bonehealth/. Accessed November 19, 2004.
5.	Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol. 1999;17:846-854.
6.	Hortobagyi GN. Novel approaches to the management of bone metastases. Semin Oncol. 2003;16:161-166.
7.	Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80:1588-1594.
8.	Coleman RE. Management of bone metastases. Oncologist. 2000;5:463-470.
9.	Groot MT. Eur Urol. 2003;43:226-232.
10.	Mincey BA. Osteoporosis in women with breast cancer. Curr Oncol Rep. 2003;5:53-57.
11.	Mundy GR. The evolving role of bisphosphonates: cancer treatment-induced bone loss. Oncology. 2004;18(suppl 3):9-10.