Pathophysiology

Skeletal metastases can be lytic (increased bone resorption), sclerotic (increased osteoblast activity), or mixed, based on the activity of osteoclasts and osteoblasts. Most tumor-induced skeletal destruction is mediated by osteoclasts, spurred by malignant cells secreting osteoclast activators such as PGE, TGF-α/β, EGF, TNF, IL-1, and procathepsin D. Bone resorption and buildup are usually both accelerated in the affected bone, evidenced by increased osteoclast activity and resorption cavities even within sclerotic lesions. Multiple myeloma, prostate, breast, lung, kidney, and thyroid tumors are the primary source of 80% of bone metastases. The spine, pelvis, ribs, skull, and proximal femur are most likely to host skeletal metastases. The most common symptom of acute BMD is a pain in the spine, pelvis, or extremities after the bone has been weakened by the tumor. Anemia also results from invasion of the spine, pelvis, ribs, skull, upper arm, and legs, since those regions of bone marrow produce a high level of RBCs. As the disease progresses and bone undergoes demineralization, pathologic fractures may result.

Risk factors for metastasis have been identified in breast cancer patients. Age, menopausal status, BMI, histological type, grade, and tumor size have either unknown, conflicting relationships or no relationships to metastases. While menopausal status may or may not be related, women undergoing chemotherapy for breast cancer develop low bone mineral density in response to the direct effect of chemotherapeutic drugs on bone cells, including osteoclasts, osteoblasts, and osteocytes. There is a decrease in circulating estrogen as a result of chemotherapy-induced ovarian dysfunction, resulting in a need to favor osteoblast activity during chemotherapy treatment. Lymph node involvement may be a minor contributor to risk of metastases. Genetic factors, such as intrinsic subtype, bone-specific metastasis-related genes (102-gene, 15-gene), and molecular changes, such as those related to the MAF protein, the prolactin receptor, bone sialoprotein, and BMP8, are also risk factors.

Pharmaceuticals and Other Therapies

Commonly used treatments include bisphosphonates and the drug denosumab. Bisphosphonates are analogs of pyrophosphates and cause osteoclast apoptosis. Some studies show direct apoptotic effects on malignant tumor cells themselves. Bisphosphonates also exhibit antimyeloma and antitumor activity and increase overall survival for various malignancies.

Denosumab is a human monoclonal antibody that inhibits RANK-L, preventing osteoclast development. The effect is to delay fractures in patients who already have bone metastases. Zoledronate is a popular drug with a similar effect, and denosumab is helpful when patients do not see results after taking zoledronate or have compromised renal function. Other drugs include biologics, chemotherapeutic agents to halt development of rapidly dividing cells, and bone supportive medications. Radiation therapy is widely used (see the “Pain Management” section).

Pathologic Fracture Management

As previously mentioned, the spine, pelvis, ribs, skull, and proximal femur are most likely to host skeletal metastases. Mirel’s and Harrington’s criteria are the current standard evaluation tools to determine which patients are most likely to experience a pathologic fracture based on the lesion. These criteria account for the type, site, and size of the metastatic lesion, as well as the patient’s level of pain and its persistence. Mirel’s criteria are the most commonly used and assign a score of 1–3 to the following tumor characteristics: site of lesion, nature of lesion, size of lesion, and pain ( Table 12.1 ).

Mirel’s score of 9 or greater confers a >30% risk of pathologic fracture, and prophylactic stabilization is recommended. Most lesions with a score of 7 or less are managed nonoperatively with possibility for radiotherapy, continued chemotherapeutics, or observation. A score of 8 confers only a 15% score of pathologic fracture, and multidisciplinary discussion should be undertaken and need for fixation should be decided on a case by case basis.

Patients experience a significant improvement in functional outcomes and a reduction in pain after surgically treated skeletal metastasis, according to a 2018 multicenter study examining PROMIS (Patient-Reported Outcomes Measurement Information System) scores. Even patients with high-grade osteosarcomas (a rare primary tumor originating in the bone) benefit from surgical management of pathologic fracture. There is no additional risk of local recurrence for patients with this condition who undergo surgery, compared to patients who have not suffered a pathologic fracture and have no need for surgery.

Intraoperative outcomes and postoperative return to mobility are improved in patients who receive prophylactic pathologic fracture surgery for metastases in the long bones. Long bones require different surgical management than the other sites of skeletal metastases (i.e., vertebral sites). Surgical intervention can either focus on the entire bone or the affected segment of the bone. Focusing on the entire bone reduces the likelihood of later reoperation and also decreases the incidence of disease progression. Intramedullary nailing (IMN) is the preferred treatment for pathologic fracture of the long bones. The nail should be locked, and the diameter and length should be as large as possible. Ideally, the surgeon will be able to place the nail in the bone after reaming to ensure the correct size and fit before placing bone cement. The load-sharing elements of intramedullary nails provide weight-bearing earlier than other methods of surgical management. Mobility postsurgery usually returns to the patient’s presurgery status. Evidence shows that prophylactic surgery with intramedullary nail (IMN) can reduce the risk of impending pathologic fracture. It is worth noting that reaming of the bone to insert the nail in IMN surgery does not increase metastatic dissection. There are particular effects of intramedullary nailing on specific long bones. For example, the humerus may be shortened by this surgery, but this does not result in worse functional outcomes for the patient. A recent study has shown that an intramedullary nail combined with an auxiliary plate and bone cement may contribute additional stability to the limb.

The spine is a common site of bone metastasis. Metastasis often leads to extremely painful compression fractures, which usually occur on the anterior side of the vertebrae. These fractures and the resulting collapse of these bones could cause paralysis or make the spinal cord more prone to metastatic compression, necessitating swift treatment as soon as the patient is identified as being at risk for fracture. Patients with metastatic tumors to the spine experience significant pain reduction from surgical treatment via percutaneous vertebroplasty and kyphoplasty. Polymethacrylate (PMMA) cement is injected into the defect during this procedure. Vertebroplasty can be accomplished by guiding a needle into the posterior vertebral body, while kyphoplasty uses balloon inflation to create a more amenable space for cement injection. Prior to vertebroplasty, the surgeon must determine whether there is a risk for cancer to spread into the spinal cord.

Limitations and Risks

Unfortunate outcomes can occur due to surgical and nonsurgical treatments. In some cases initial surgery to manage pathologic fracture fails. Patients can undergo a new fracture, or hardware can malfunction. Revision surgery in the long bones has been comparatively more successful with an endoprosthesis than with an intramedullary nail. There is minimal follow-up time available in most patient populations to assess the long-term effects of percutaneous vertebroplasty and kyphoplasty. However, these procedures are minimally invasive, and their improved outcomes, compared to open surgery, have been demonstrated. Radiation therapy can cause destruction of healthy tissue through tissue necrosis and fibrosis. The destruction of the microvasculature can also create a hypoxic environment, allowing free radical damage to progress. The evidence from clinical trials on radiosurgery is inconclusive due to differing outcomes. Pharmaceutical treatment to delay bone degradation, while effective, can have serious side effects. Bisphosphonates, for example, are nephrotoxic. These drugs can also paradoxically increase the risk of fracture and hypercalcemia.

Patients with cancer often also have compromised cardiopulmonary systems, and their postoperative outcomes can be risky due to fat or air embolisms. Fat embolism syndrome is possible after intramedullary nailing procedures in particular. The hypervascular nature of pathologic tissue in the bone being reamed for nail entry makes this syndrome more likely than in other procedures, as this process can open up paths into the circulatory system. Evidence suggests that negative pressure reaming may reduce the chance of embolic syndromes postsurgery. Surgeons should consider using a reamer that irrigates and aspirates to lessen the risk. PM&R physicians are highly qualified among clinicians to identify signs of stroke and embolic events and should be aware that postsurgery embolic events can occur in cancer patients due to their unique risks.

Noninvasive Predictors of Pathologic Fracture

Since patients who undergo prophylactic treatment for pathologic fracture have better outcomes than those who undergo treatment after fracture, PM&R physicians should be prepared to identify impending pathologic fractures within their scope of practice to recommend orthopedic treatment. Tumors that survive targeted treatment and/or continue to cause persistent pain indicate that patients require surgical intervention. If patients are at risk for fracture and elect not to undergo surgery, it is imperative to obtain radiographic data when deweighting a limb to ensure that the redistributed weight will not compromise other areas of the skeleton.

Technological tools for predicting pathologic fractures are improving tremendously. For patients receiving hormone treatment, the World Health Organization FRAX tool can be used. This tool predicts the 10-year fracture risk of patients by using data on bone mineral density, among other parameters, and can account for the osteoporotic changes brought on by hormone therapy by defining this treatment as a secondary osteoporosis parameter. A study of men receiving prostate cancer androgen deprivation therapy treatment showed that this tool provides greater insight into fracture risk than bone mineral density alone.

PathFX is an algorithm designed to provide insightful survival estimates for patients with pathologic fractures. The model requires inputs, including age, sex, performance status, red and white blood cell counts, site(s) of primary tumor, whether solitary or multiple metastases are present, whether organ metastases are present, and other optional inputs, including the physician’s estimate of survival and whether lymph node metastases are present. The algorithm is validated using previously validated, large international data sets. PathFX enables a multidisciplinary team of physicians to evaluate the survival estimates for patients at specific points in time and to use this information to make decisions with their families to meet the patient’s personal goals. Those with longer survival estimates may opt for riskier surgeries, while those with shorter may decide upon palliative treatments with fewer side effects and less recovery time. Treating physicians, including orthopedic surgeons, oncologists, and PM&R doctors, can consult this tool to decide how to manage care as a multidisciplinary team while empowering the patient with the most accurate knowledge about their prognosis.

In a study of metastatic cancer to the spine originating from breast tumors, CT scans served as radiological predictors of impending vertebral pathologic fracture. Load-bearing capacity, axial rigidity, and bending rigidity determined from CT scans are appropriate radiographic criteria to assess the vertebral metastases. A machine learning algorithm built with CT radiograph and clinical data has also demonstrated predictive capabilities for pathologic proximal femur fractures. PM&R physicians, orthopedic surgeons, and oncologists should remain abreast of technological developments in the field as tools such as PathFX and algorithm-based prediction tools continue to develop.

In the clinical setting, PM&R physicians can implement tests to analyze patients’ life expectancy and progression of metastasis. The results of short physical performance battery and fast gait speed tests can predict early mortality in survivors of cancer. The 6-minute walk distance test, which observes the maximum distance a patient can move over a 30 m course in 6 minutes, was shown to be independently predictive of survival in patients with active metastatic cancer. These tests may indicate decreasing function due to declining bone health, and subsequent reduction in survival estimates. Routine blood work should be implemented to check for hypercalcemia. Symptoms of hypercalcemia include dehydration, thirst, drowsiness, fatigue, anorexia, and constipation. The consequences of uninhibited hypercalcemia include cardiac arrhythmias and renal failure. While patients with mildly elevated calcium levels may not require immediate attention, levels above 3.5 mol/L constitute an oncologic emergency.

Prevention of Pathologic Fracture Through Physical Medicine and Rehabilitation

Rehabilitation that begins upon cancer diagnosis has been termed “prehabilitation” in the literature. Prehabilitation has been shown to improve hospital stay, postoperative outcomes, and tolerance of cancer treatment. However, evidence shows that targeted exercise therapy does not prophylactically prevent pathologic fracture. Patients benefit more from safety measures to reduce their fall risk. Such efforts involve restricting forces with high resistance, high compression, or high rotational force/torque on the affected limb. The use of assistive devices to offload weight-bearing is recommended. However, there is conflicting evidence on whether weight-bearing activity is more likely to result in pathologic fracture than nonweight-bearing activity. Compensatory measures to prevent weight-bearing on the affected side, including or in addition to assistive devices, can be critical in preventing further injury. Increasing the tone and strength of supportive muscles can greatly reduce the pain a patient experiences from a compromised joint or vertebrae. Isometric contractions in particular are useful to stabilize and deweight an area of pain or clinical concern. With regards to compensatory movements, clinicians should remember that overuse injuries are high in cancer survivors and educate patients about risks of repetitive compensation.

Vertebral fractures present other challenges. Patients with vertebral metastases do not have a lower chance of pathologic fracture while wearing an immobilizing orthopedic corset. Those who exhibit increasingly intense pain in the lower back are likely to have metastatic spinal cord compression (MSCC). Patients with MSCC can also exhibit motor and sensory symptoms, along with bladder and bowel incontinence. This condition presents with pathologic fracture about 30%–40% of the time, which compounds the effects of MSCC. Pathologic fracture in the spine can also present with thoracic kyphosis accompanied by radicular pain and subsequent hypoventilation, and with abdominal pain leading to increased abdominal pressure that can impact food intake. A higher number of vertebral metastases, higher growth rate of the primary tumor, more pain, larger tumors within the vertebral body, and involvement of the vertebral end plate and three columns have been associated with increased risk for pathological fracture. The presence of osteolytic lesions, more than 25% occupancy of the vertebral body, and involvement of the end plate and three columns are candidates for surgical stabilization. Vertebral pathologic fracture is associated with reduced ambulatory function after decompression surgery for MSCC. With knowledge of the risk factors and symptoms the PM&R physician can act swiftly once they suspect that a patient has spinal metastasis; quick recognition and treatment is critical to containing the problem. After surgery, 67%–100% of patients no longer have pain, with up to 70% having improved mobility.

Changes in body composition are important in the context of pathologic fracture. Cancer patients can exhibit cachexia (overall weight loss, including the loss of muscle mass) and sarcopenia (loss of muscle mass and muscular atrophy). The inclusion of nutritional experts to the multidisciplinary team of clinicians early on can help to delay or decrease cachexia and sarcopenia. Patients suffering from metastatic bone disease in particular exhibit decreased muscle strength. Monitoring the patient’s degree of sarcopenia and concurrent decline in strength can be an important indicator for improper chemotherapeutic dosing and metastatic tumor progression. Patients may become osteoporotic as a result of hormone treatments for cancers of the prostate, breast, and ovaries. To preserve bone mass, patients with bone metastases who are undergoing osteoporotic changes should perform functional loading activities for as long as they are able. This includes walking that results in a positive change for bone mass.

Pain Management

Patients with bone metastases have a spectrum of goals during cancer treatment, and their wishes generally depend on their prognosis. Survival rates vary depending on the location of the primary tumor. In a recent study, 1-year survival after bone metastasis diagnosis was lowest in patients with lung cancer and highest in patients with breast cancer. At 5 years of follow-up, only patients with breast cancer had over 10% survival. The poor prognosis for patients with bone metastases emphasizes the need for palliative care with the primary goal of pain reduction. Palliative treatments for advanced bone metastasis include radiation, chemotherapy and electrochemotherapy, embolization, radio-frequency ablation, and high-intensity focus ultrasound.

Pain management is critical for patients with bone metastases. About 75% of patients with skeletal metastasis present with pain. Surgical treatment for pathologic fracture generally relieves much of the severe pain associated with bone metastases and is the primary treatment for impending fracture or fractures that have already occurred. For persistent or additional pending pathologic fractures after surgery, osteoprotegerin causes apoptosis of osteoclasts to reduce the risk of fractures and associated pain. Other options for residual pain, though not without their own side effects, include corticosteroids, opioids (though the analgesic effect decreases over time), NSAIDS, and ET-1, which antagonize the effect of nociceptive stimuli at receptors. Tricyclic antidepressants can also be used to change the perception of pain and any depressive symptoms that arise but carry their own side effects as well. Less effective options include bisphosphonates, such as zoledronate, that are effective in delaying disease progression but not as helpful for pain management. Denosumab, like bisphosphonates, is less effective in pain management and more effective in preventing the physiological changes that lead to pain.

Other courses for pain management include radiation therapy. Within 2 weeks of administration for metastases, patients report that pain declines dramatically. Both fractionated and nonfractionated courses of radiation are equally effective for pain reduction. Radiation after surgery improves patient function and reduces the need for other surgeries to provide pain relief. The most common method of administration is local field radiation that relieves pain with minimal side effects in 50%–60% of cases and provides partial relief in 80%. In more severe cases hemibody irradiation is used for widespread metastatic disease. This can target larger fields of the upper body, midsection, or lower body, and supplements local field radiation. Injection of radiopharmaceuticals is also helpful for pain relief and easier to administer and to tolerate compared to hemibody radiation. A short treatment schedule generally provides quick relief.

Chemotherapeutic drugs have a wide variety of side effects, some of which are highly relevant in the PM&R scope of practice. Post chemotherapy, cancer patients are at a higher risk of balance impairment and falling. Cancer patients also experience chronic fatigue due to treatment side effects and resulting general weakness that compounds their risk of falling. This can discourage the patient from undergoing rehabilitation and therapy that is essential for a few reasons. The side effects of chemotherapy can be managed through a supervised therapeutic exercise program. Aside from its benefits for chemotherapy, the importance of aerobic and resistance training in managing cancer recovery and relief from difficult treatments indicates that the patient’s ability to move is integral to their fight against the disease. For patients with comorbidities, aerobic exercise in particular has been noted to help with cardiac, vascular, and pulmonary diseases. Patients with decreased bone density still benefit from rehabilitative weight-bearing activities, though engaging them in the exercises can be difficult due to pain. Physical rehabilitation after pathologic fracture is a form of personal empowerment; patients with the freedom of movement have a new weapon in their arsenal to fight cancer.

Functional pain has proven to be the most accurate predictor of pathologic fracture; pain associated with functional activity is considered a risk for pathologic fracture. However, physical function and pain intensity are only moderately correlated. In cases where function and pain are not aligned, further examination may be necessary to assess disease progression. Cancer patients may experience chemotherapy-induced neuropathies and nerve injury unrelated to function. As a result, they may experience musculoskeletal compromise with exaggerated pain or without any pain or sensation. The Brief Pain Inventory tool is a reliable way to assess pain in patients with metastasis to the bone and is more useful than simple numerical pain measurements. Breakthrough pain occurring during functional exercises, especially that associated with function, should be assessed by an orthopedist. Neurological symptoms, as well as autonomic dysfunction, maybe the first indicators of new metastases. Clinical judgment and patient monitoring are necessary to determine whether the patient needs to be reassessed by an oncologist and/or orthopedic surgeon.