It is estimated that nearly 600,000 US citizens will die from cancer in 2013 (1). There have been autopsy reports indicating that up to 90% of patients who died from cancer have bone metastases at the time of death (2). The three most common cancers leading to death in the United States, namely lung, breast, and prostate all have an affinity to spreading to bone. The incidence of cancer will likely climb as the population ages. The sheer volume of patients with metastatic carcinoma to bone makes it imperative that the average orthopedic surgeon is familiar and comfortable with managing metastatic disease to the bone. This is particularly true around the hip where pathologic fractures can be devastating. The purpose of this chapter is to provide an overview of trends in the management of metastatic bone cancer with particular emphasis on the hip. In addition, this chapter introduces the reader to basic aspects of the pathophysiology of metastatic disease.

The concept of certain cancers spreading to bone more commonly than others is now well established. Several studies have looked at this phenomenon. In one autopsy study of 167 patients, metastatic bone disease was discovered in 73% of cases with breast carcinoma (3). The same study found that patients with renal cell carcinoma had bony metastases in one out of four patients. Patients with lung cancer had bone metastases in one out of three cases (3). It is now generally accepted that lung, breast, prostate, thyroid, and renal cell carcinoma all commonly spread to bone. Multiple myeloma of course also involves bone but this is a tumor of the marrow rather than of solid organ.

Sex is an important determinant of the type of cancer one is predisposed to develop with breast carcinoma far more common in women than in men and prostate cancer occurring only in men. A woman has a 1 in 3 probability of developing cancer in her lifetime and for a man it is 1 in 2 (1). A woman has a 1 in 8 probability of developing breast carcinoma in her lifetime and a 1 in 16 probability of developing lung cancer. Men have a 1 in 6 chance of developing prostate cancer and 1 out of 13 for lung. Lung and breast carcinoma are expected to account for 109,000 (40%) of all cancer deaths in woman in 2013. Similarly, lung and prostate will account for 117,000 cancer deaths in men in 2013 (1). All three of these tumors commonly spread to bone.

It is expected that the number of cases of cancer will continue to increase as the population ages. Similarly metastatic bone disease will become more common. The hip is commonly affected by metastases. One study found that two-thirds of cases with bone metastasis involved the bones about the hip joint (4). Another study looking at breast cancer specifically found that over half of the cases involve the femur and two-thirds of the cases involved the pelvis (5). Given the evidence, it seems clear that metastatic disease to the hip will become a more common problem as time goes on. It will be important for all orthopedic surgeons involved in the management of hip pathology to be familiar with the basic concepts and management of bone metastasis.

The propensity for carcinoma to spread to bone was noted well over 100 years ago. In the 1800s there was considerable debate as to how cancer spread. The prevailing theory at that time was that cancer spread via embolic phenomenon. Paget disagreed with this theory. He wrote a treatise published in 1889 that discussed the predilection for certain cancers to spread to bone. He credited previous authors including Langenbach as well as Fuchs who discussed this predilection in advance of Paget. However, it is Paget who discussed the seed and soil concept of metastases. He stated, “When a plant goes to seed, its seeds are carried in all directions; but they only live and grow if they fall on congenial soil” (6).

Paget was suggesting that there are characteristics within the tumor cell that allow it to spread into certain tissues but not into others. For example, as a class, breast carcinoma is able to survive and grow within bone, whereas pancreatic carcinoma less commonly invades the bone. It is unclear why one is able to adapt to the bone microenvironment where the other is not. However, when one thinks of cancer it is important to remember that there is significant heterogeneity within a tumor. That is to say, even within one tumor nodule, there is significant heterogeneity (7,8). This is an important concept when one thinks of how cancer cells progress from a small contained mass to a large tumor that spreads to other tissues. It is thought that mutations occur on a regular basis
in normal tissues. These mutations are corrected by intrinsic properties within the cell. On occasion these mutations are not corrected in the cell has the potential to become cancer (7,8). However, our body recognizes that this is occurred and clears the cells producing them to undergo an apoptosis. If the cell is able to breach this barrier and begin dividing into other cells often the immune system will recognize these cancer cells as foreign system then clears them (9).

Another barrier that cells have to overcome includes hypoxia. As a mass-containing tumor cells grows, the cells at the center of the mass do not have the same oxygen supply as those on the outside of the tumor mass. This relative hypoxia drives different gene expression including MMP-9, MMP-1, and VEGF (8). Many cells will die and the tumor can become necrotic. However, some cells can adapt to the relative hypoxia and thrive to form another colony of tumor cells that are resistant to hypoxia (8).

A key component that allows tumor cells to overcome obstacles is tumor heterogeneity (8). If the tumor cells were genetically the same, then they would not be able to overcome these barriers. For instance, if all the cells were susceptible to hypoxia then they would all die under hypoxic conditions. If all the cells were recognizable by the immune system then it would all be cleared by the immune system. In fact this is likely what happens to many potentially cancerous masses. It is however the selective pressure placed on a heterogeneous population of tumor cells that selects resistant properties (8). The same phenomenon occurs with chemotherapy. When chemotherapy is administered, it is deemed a success when the tumor mass shrinks. However, the tumor will often become resistant to chemotherapy and the tumor mass will grow back. In fact the chemotherapy has selected out those cells that are resistant to the agent used. They then grow and a new chemotherapy drug must be given. This is one of the reasons why chemotherapeutic agents are often given in tandem or in groups. The idea is that if you target multiple areas within a cancer mass the hope is that you will eradicate all subgroups of cancer cells.

In order for a cancer cell to become a metastatic cancer cell it must go through certain processes. First it must be able to live and survive locally where it formed (7,8,10). This could be in the form of a precancerous lesion in the breast. Over time through selective pressure, a mass begins to form. Most of the cells are not able to leave environment from which they formed. However, due to cellular heterogeneity and ongoing mutations, some cells acquire the ability to grow and break through the basement membrane and spread into local lymphatics or blood vessels. Once cancer cells get in to the vascular or lymphatic system they have to be able to penetrate the endothelia lining and then survive inside the lumen of these vessels (7,8,10). This is not a trivial matter as flow within blood vessels can be quite turbulent. In addition the immune system is obviously quite active within these systems as well. So simply making it into the lymphatic system or vascular system does not guarantee a tumor cell will become a metastatic tumor. In fact, fewer than 0.01% of cancer cells which are injected into the vascular system of animals survive (11). However, again, selective pressures select for those cells that can survive in this environment. The cells then must be able to reattach to the lumen of the blood vessel or lymphatic and then spread through the endothelial lining into a new environment such as bone. The cancer cell must be able to co-opt the local environment to grow. In bone it must stimulate osteoclasts to breakdown bone (12). When the osteoclasts break down bone growth factors are released (12). If the tumor cell has receptors for these growth factors they are selected to grow versus those that do not have said receptors. These are examples of how tumor cells must adapt or are selected to grow in different environments.

A key component of the interaction of cancer cells and normal bone appears to be mediated by the osteoprotegerin (OPG)/receptor activator of NF-κB (RANK) and its ligand (RANKL). Normally OPG and RANKL are produced by osteoblasts and osteocytes to balance the breakdown of bone by osteoclast which expresses RANK. Cancer cells that tend to spread to bone are able to subvert this system to favor tumor growth (13). Breast and prostate carcinoma have both been shown to express key components of the OPG/RANK system. RANK/RANKL has been shown to correlate with disease stage and progression prostate cancer (14). Further RANK/RANKL appears to be an important regulatory pathway in breast cancer initiation, progression, and metastasis (15,16). Its expression by breast cancer cells portends a worse prognosis in the presence of bone metastasis but not in visceral metastasis (17).

The orthopedic surgeon is called most commonly to assess patients with painful metastases. It is pain that is the most common symptom and it is the most feared symptom with many patients stating that they would consider suicide in the face of severe pain (18,19,20). Still pain remains poorly treated in many patients (19).

The cause of pain is not always obvious and requires a careful history and physical examination. For instance, hemipelvic pain that is as severe while lying down as it is when standing is very different than pain that is relieved while supine and only occurs with standing. The latter presentation is more consistent with “mechanical” pain and it may be associated with a structural problem. The former presentation is more consistent with “biologic” pain which may or may not have structural component. The origin of “biologic” pain is thought to be related to the release of prostaglandins and osteoclast-activating factors that sensitize nociceptors and produce pain (21).

One must remember that hemipelvic pain and/or proximal femoral pain may be referred from the upper lumbar spine in a patient with spinal metastasis. The patient with associated numbness in a T12, L1, or L2 distribution along with pain should prompt an investigation into the upper lumbar spine. Furthermore, if imaging of the hip is normal then one should explore the possibility of referred pain from the spine.

Pain in the groin may be coming from a lesion if the pubic ramus or ilium which may be palpable in a thin patient. Tenderness to bone may help isolate the source of pain. Gentle rotation of the hip joint may help distinguish intracapsular hip pain from adjacent bony pathology. Pain with provocative maneuvers such as hip flexion and internal rotation may
help localize the pain away from the spine but they do not reliably distinguish pain from the pubic ramus and proximal femur.

One of the most important considerations during one’s initial assessment is whether a patient can ambulate or not. The ability to ambulate is not only crucial to maintaining independence and therefore quality of life, it is also the gateway to qualifying for clinical trials. If patients are unable to ambulate they are considered poor candidates for systemic therapy. It is part of the orthopedic surgeon’s job to figure out whether the patient’s inability to ambulate is related to hip pathology alone or are they simply too weak from systemic causes.

Hypercalcemia is common in patients with metastatic carcinoma and it can cause lethargy and confusion (22). In fact patients can develop arrhythmias and become comatose secondary to hypercalcemia (23). Patients may not be able to walk secondary to the effects of hypercalcemia which is treatable. It should be considered and treated aggressively when present. The baseline treatment is intravenous hydration with normal saline. Calcium retention can be caused by thiazide diuretics and they should be discontinued whereas loop diuretics can cause calcium wasting which should be considered (24). An infusion of bisphosphonates can halt the progression of calcium release into the circulation by inhibiting osteoclast function. These treatments must be started early and the orthopedic surgeon may be the first physician seeing some of these patients and may be uniquely positioned to save their life.

Plain radiographs should be the initial diagnostic test obtained in patients suspected of having bony metastases. However, the images may initially be normal as 30% to 50% of the bone must be affected before metastases show on plain radiographs. Aside from a/p and lateral views, Judet views should be considered as they allow close inspection of the anterior and posterior columns of the pelvis. Full length femur radiographs should be obtained so that one does not miss a distal femoral lesion whose symptoms are drowned out by the more proximal lesion. Placing a short proximal stem in patients with distal femoral disease is ill advised as this may lead to fracture and subsequent complex revision.

If the patient has not been diagnosed with cancer and a suspicious lesion is found on plain radiographs, then a bone scan should be obtained. The bone scan provides information about the lesion seen on plain radiographs. For instance a dense lesion seen on plain radiographs that does not uptake radiolabled diphosphate is unlikely to be cancerous. The same cannot be assumed for a lytic lesion since myeloma is known for being negative on bone scan and it is a lytic disease. Bone scans rely on osteoblasts taking up the radiolabled diphosphate and in myeloma the osteoblasts do not seem to be active. This may be because the myeloma cells can stimulate osteoclast activity directly without the need for intervening osteoblasts (25,26). Bone scans can also detect other sites of disease which can be helpful in cancer staging. In addition, the bone scan may detect a lesion that is more easily biopsied than the one detected in the hip. CT of the chest, abdomen, and pelvis complete the initial radiographic workup of a lesion without known origin.

Further imaging of the hip may include CT or MRI. CT provides useful information about the bony architecture. It may help reveal cortical disruption not seen on plain films. It will also give a more accurate view of cortical thinning and trabecular disruption. It is particularly helpful around the hip as it will give detailed information about the bone remaining around the acetabulum as well as in the anterior and posterior columns. MRI may be helpful if plain radiographs are normal but metastases are suspected. Furthermore, MRI can be helpful in detected occult fractures.

If the tumor of origin is still unknown, then a biopsy is important. Biopsy will not only direct systemic therapy, but it will also help one prepare for surgery should surgery be necessary. This is particularly important when the tumor is vascular such as renal cell, hepatocellular, and/or thyroid carcinoma. These tumors may benefit from preoperative embolization to mitigate the risk of blood loss.