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Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma

Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma
Literature review current through: May 2024.
This topic last updated: Nov 11, 2021.

INTRODUCTION — Bone metastases are a common manifestation of distant relapse from many types of solid cancers, especially those arising in the lung, breast, and prostate. Bone involvement can also be extensive in patients with multiple myeloma, and bone may be a primary or secondary site of disease involvement in patients with lymphoma. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Bone metastases represent a prominent source of morbidity [1,2]. Skeletal-related events (SREs) due to bone metastases include pain, pathologic fracture, hypercalcemia, and spinal cord compression. Across a wide variety of tumors with bone involvement, the frequency of SREs can be reduced through use of osteoclast inhibitors (bone-modifying agents) such as bisphosphonates or denosumab. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Multiple myeloma: The use of osteoclast inhibitors".)

A fracture that develops through an area of bone pathology is termed a pathologic fracture. In some cases, the extent of bone destruction is such that a fracture is imminent but has not yet occurred (termed an impending fracture). Pathologic fractures can be secondary to a benign lesion (eg, Paget disease, giant cell tumor of bone, hemangioma) or a malignant tumor, which may be a primary bone tumor (osteosarcoma, chondrosarcoma, lymphoma) or metastatic carcinoma, multiple myeloma, or lymphoma. The goals of treatment, regardless of underlying etiology, are to minimize morbidity and maximize function and skeletal integrity. For most patients with a completed or impending pathologic fracture of a long bone, this will necessitate surgical fixation. (See "Clinical manifestations and diagnosis of Paget disease of bone" and "Giant cell tumor of bone" and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis" and "Chondrosarcoma" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

This topic review will cover the etiology, clinical presentation, and diagnostic/staging evaluation for a suspected complete or impending pathologic fracture in patients with metastatic cancer, multiple myeloma, or lymphoma. An overview of therapeutic options in this setting, an overview of the epidemiology, clinical presentation and diagnosis of bone metastases in general, issues related to pathologic fractures in Paget disease, giant cell tumor of bone, and in patients with a primary bone tumor such as osteosarcoma, and the use of radiation therapy for the management of painful bone metastases without a pathologic fracture are discussed elsewhere.

(See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)

(See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

(See "Treatment of Paget disease of bone", section on 'Role of surgery'.)

(See "Giant cell tumor of bone".)

(See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Pathologic fracture'.)

(See "Radiation therapy for the management of painful bone metastases".)

ETIOLOGY — Bone is one of the most common sites of distant metastases from cancer and is particularly affected in multiple myeloma. Among visceral cancers, breast, prostate, lung, thyroid, and kidney cancer account for 80 percent of all skeletal metastases, but many other primary malignant tumors can spread to bone including lymphoma; uterine leiomyosarcoma; and hepatocellular, biliary, and uterine carcinomas. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Epidemiology'.)

Pathologic fractures are frequent in patients with bone metastases, developing in 5 to 29 percent [3-6]. Rates appear to be highest among patients with multiple myeloma, in which the pattern of bone metastases is purely lytic (table 1) [7]. Lytic bone disease (image 1) is created by osteoclast activation, but also osteoblast inhibition, which prevents fracture healing. (See "Multiple myeloma: Pathobiology", section on 'Osteolytic bone lesions'.)

Besides myeloma, primary cancers associated with an increased likelihood of pathologic fracture include liver and intrahepatic bile duct, and kidney and renal pelvis cancer [6].

Pathologic fractures develop less often in those with osteoblastic (as typified by prostate cancer, (table 1)) as compared with osteolytic metastases, but they still occur (image 2) [7]. (See "Mechanisms of bone metastases", section on 'Osteoblasts'.)

CLINICAL PRESENTATION — Pathologic fractures typically occur with minimal trauma, much less than would be required to break an unaffected bone, and this is an important clue to the presence of a pathologic fracture. In general, the force needed to cause a pathologic fracture in a benign bone lesion is greater than that needed in a primary or metastatic bone tumor [8].

Not infrequently, a pathologic fracture is the presenting sign of malignancy [9]. This occurs most commonly with lung carcinoma followed by renal cell carcinoma, as these are cancers that may not manifest initially with symptoms related to the primary site. Patients with a history of cancer who develop a pathologic fracture may have a single bone lesion, oligometastatic disease, multiple bone metastases, or a combination of visceral plus bone metastases.

Pain at the fracture site is the most common symptom, but patients may have ecchymoses, a soft tissue mass, edema, inability to bear weight or neurologic symptoms. A summary of presenting clinical features of pathologic fractures is presented in the table (table 2).

Long bones – Most patients with a pathologic fracture of the extremities present with pain and some with deformity. When the fracture involves the lower extremity, the patient is often suddenly rendered nonambulatory. A pathologic fracture should always be considered when patients with known bone metastases or a history of cancer develop sudden onset of pain even in the absence of deformity or inability to ambulate. This is particularly true in the upper extremity (and spine), where pain may be the only manifestation. In many cases, pain or discomfort precedes the actual fracture itself, and this is another clue to the presence of a true pathologic fracture [8].

Common sites of long bone pathologic fracture include the femur, tibia, and humerus. Within the long bones, the femur is the most commonly affected site, with most cases affecting the proximal femur [8]. Approximately 50 percent of proximal femoral pathologic fractures are located in the femoral neck, 30 percent are subtrochanteric, and 20 percent intertrochanteric (picture 1) [10].

Spine – Pathologic fractures of the thoracic or lumbar spine typically present with pain on axial load, such as sitting or standing. Counter-intuitively, other pathologic spine fractures, particularly at the thoracolumbar junction, may present with pain in recumbency. The patient will report sleeping in a recliner for several weeks as the genesis of the pain is an unstable kyphosis. Cervical spine pathologic fractures present with pain on flexion and extension of the neck. Additionally, at the atlanto-axial junction, patients will experience severe rotational pain and may have radiating pain to the occiput suggestive of occipital neuralgia.

Other sites – Patients with a fracture of the pelvis may present with pain that radiates into the buttock; tumors of the pelvis may compress or invade the sciatic nerve causing true sciatica. A fracture in the scapula may present with numbness, tingling, and loss of function in the ipsilateral arm.

Pain characteristics – Pain from a pathologic fracture must be distinguished from the much more common "biologic pain syndrome" in cancer patients with bone metastases. The term "biologic pain" refers to pain that occurs in the night or early morning and that resolves over the course of the day. This pain does not denote fracture or instability, but rather the diurnal variation in endogenous steroid secretion from the adrenal gland. With decreased steroid secretion at night, patients with bone metastases may experience pain, occasionally severe, from inflammatory mediators that are secreted by the tumor, and this may resolve with increased activity (causing release of endogenous steroids) or exogenous steroid administration. While pain of this type denotes the presence of tumor in bone, it is not reflective of a fracture.

Neurologic symptoms – Neurologic symptoms are not uncommon in patients with a pathologic vertebral compression fracture. Typically, the deficits, such as weakness, numbness, and tingling, result from soft tissue tumor compressing the spinal cord or cauda equina rather than the pathologic fracture itself. Epidural spinal cord compression is a devastating manifestation of metastatic bone disease involving the spine. It can be caused by tumor extension into the epidural space and/or a pathologic spine fracture with bone compressing the spinal cord. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)

EVALUATION

General principles — Patients with a suspected complete or impending pathologic fracture should undergo a thorough and systematic assessment prior to developing a therapeutic plan. The key components of the evaluation process are to delineate the osseous and soft tissue extent of the lesion and its relationship to adjacent structures, establish the tissue diagnosis of the index lesion, determine overall skeletal involvement by tumor, detect other metastases that may require concomitant treatment, and provide an estimate of the patient's overall prognosis. Although the majority of patients with a complete or impending pathologic fracture have an established diagnosis of cancer, a systematic and detailed workup to identify the primary site is required for patients who present with metastatic bone disease without an established diagnosis of cancer. (See 'Patients with a remote or no history of cancer' below.)

A complete and comprehensive medical history should include prior smoking history that might predispose to lung, renal, and bladder cancers as well as any personal history of cancer, the current oncologic status, and related treatments [11]. The patient should be asked about sensory and motor dysfunction, walking ability, urinary retention or overflow incontinence, and/or bowel incontinence or constipation. The physical examination should include the principal symptomatic area as well as other symptomatic sites, focusing on the extent of soft tissue tumor extension and its relationship to the neurovascular bundle of the extremity, the neurovascular status of the affected extremity, the presence of limb edema, muscle strength, and the range of motion of the affected joint(s). Assessment of anal sphincter tone and eliciting symptoms of urinary retention or overflow incontinence are important for patients with spinal metastases particularly in those presenting with perineal numbness. Bladder scans assessing postvoid residuals are commonly used to assess suspected neurogenic urinary symptoms. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)

Special attention should be paid to examining potential primary sites (breast, thyroid, prostate) if there is only a remote or no history of cancer. Moreover, the general medical condition of the patient and fitness for operative intervention must be assessed, underscoring the need for a comprehensive physical examination. (See 'Patients with a remote or no history of cancer' below.)

Diagnosis — The diagnosis of a complete or impending pathologic fracture is usually established radiographically. Tissue diagnosis may not be needed preoperatively for patients with a pathologic fracture who have a previous histologic diagnosis of metastatic bone disease or radiographic evidence of multiple bone lesions. However, in a patient with a solitary bone lesion with or without a history of cancer, every attempt should be made to secure a diagnosis prior to surgical fixation.

Among patients age 40 and older presenting with radiographically aggressive-appearing bone lesions, metastatic carcinoma is the most likely diagnosis, followed by multiple myeloma and lymphoma, with primary bone sarcomas being distinctly less likely. However, the possibility of sarcoma has to be kept foremost in consideration until a tissue diagnosis is established, because the surgical treatment for primary sarcomas is different from that for metastatic tumors.

Radiographic studies — A radiograph of the entire involved bone from the joint proximal to the joint distal is the initial diagnostic test for evaluation of bone pain to assess bone structure, integrity, extent of tumor involvement, presence of pathologic fracture or risk of impending fracture, and to identify less obvious areas of involvement that may affect decision making regarding operative intervention. Complete radiographs of the entire affected long bone should be scrutinized for other lesions that warrant prophylactic stabilization. (See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Management principles'.)

Radiographs can detect osteolytic lesions, which appear lucent and often with aggressive permeative involvement of the bone (image 3). Radiographs can also detect osteoblastic lesions, which appear sclerotic, as well as mixed osteolytic and osteoblastic lesions in which there are both sclerotic and lytic lesions (image 4).

Pathologic fracture can occur in osteoblastic, osteolytic, or mixed lytic and blastic disease.

Metastases usually occur in the diaphysis or metadiaphysis of the proximal long bones or within the axial skeleton. In either case, a fracture line may be visible, and the normal alignment may be displaced (image 2). Compression fractures of the vertebral bodies lead to a collapse of the endplates (image 5). It may be difficult to distinguish pathologic vertebral collapse related to underlying tumor from osteoporotic vertebral collapse. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Imaging abnormalities'.)

In general, radiographs are more specific but less sensitive than bone scintigraphy or positron emission tomography (PET) scanning for detecting bone metastases and pathologic fractures. It is estimated that close to 10 percent of pathologic fractures are not confidently detected by plain radiographs [12]. One exception is that radiographs are more sensitive than radionuclide scintigraphy for purely lytic metastases (eg, multiple myeloma, some renal cell metastases). Bone scans detect osteoblastic activity resulting in new bone formation. Thus, bone lesions associated with multiple myeloma are only "hot" on bone scan in approximately 20 percent of cases. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

Cross-sectional imaging

Indications – Evaluation with cross-sectional imaging (typically computed tomography [CT]) may be needed for the evaluation of metastatic bone disease involving the shoulder, spine, or pelvis because of the complex anatomy [11]. The character of underlying bone marrow patterns of destruction can also be ascertained, along with evaluation for a soft tissue mass (image 5).

For evaluation of bone lesions at other sites including the long bones, CT scans are highly accurate for determining the integrity of the bone cortex, and this can aid in evaluating for pathologic fracture and in the assessment of fracture risk using newer technology such as CT-based structural rigidity analysis (CTRA) [12,13]. (See 'Assessing the risk of fracture' below.)

Cross-sectional imaging may also be useful for surgical planning at specific sites. As an example, if radiographs or a bone scan reveal disease on the acetabular side of the joint in a patient with a proximal femoral fracture, cross-sectional imaging of the pelvis can aid in surgical planning [14]. CT of the pelvis without intravenous contrast is sufficient for this situation as intravenous contrast is not typically needed in the evaluation of bone lesions with CT. However, CT with intravenous contrast may be desirable if the imaging is serving the dual purpose of preoperative bone assessment and evaluation of the viscera. Magnetic resonance imaging (MRI) may also be useful as a complimentary tool in this complex anatomic location, particularly when there is a question as to the diagnosis, or when exact anatomic delineation of the lesion is needed (eg, if the lesion extends into the joint).

In addition, CT scans of the chest, abdomen, and pelvis are usually done as part of the initial workup of adults with aggressive bone lesions suspected to represent metastatic disease to search for primary carcinomas (if one was not previously diagnosed), and in patients with known metastatic disease to assess burden of disease and estimate prognosis. (See 'Patients with a remote or no history of cancer' below.)

Role of MRI – MRI is both more sensitive and specific than CT for detection of bone metastases and other primary bone tumors. However, MRI is not needed for every bone lesion in the adult population where metastatic carcinoma, multiple myeloma, or lymphoma is more likely than a primary bone sarcoma. CT is easier, faster, and more comfortable for the patient, and may be better than MRI in evaluating cortical destruction because of its excellent spatial resolution. For femur lesions, there is no reliable evidence to suggest that MRI is a stronger predictor than CT for risk of fracture [15]. (See 'Differential diagnosis' below.)

However, MRI is more sensitive than CT for the detection of underlying bone marrow lesions at a fracture site (ie, if the diagnosis of a pathologic versus insufficiency fracture is in doubt) [12]. The most sensitive discriminating feature is that of a well-defined low signal abnormality on T1-weighted imaging around the fracture, indicating an underlying tumor [16]. This is particularly relevant in the spine and pelvis, both common locations for both insufficiency fractures and metastatic disease. In one study of 24 patients with nontraumatic spontaneous vertebral compression fractures, who underwent MRI followed by whole body integrated PET-CT and followed by fine needle aspiration (FNA) cytology to confirm the lesion, the sensitivity and specificity of MRI for malignant lesions were 90 and 79 percent, respectively [17]. The specificity of MRI and PET combined was 100 percent for benign lesions.

Advanced MRI techniques have been developed to assist with distinguishing insufficiency fractures from pathologic fractures, including diffusion-weighted MR imaging [18-22] and dynamic contrast-enhanced imaging [23]. Dynamic contrast-enhanced MRI may also be useful to assess fracture risk in patients with vertebral fractures and multiple myeloma [24]. (See 'Assessing the risk of fracture' below.)

MRI with gadolinium contrast is the imaging procedure of choice for patients with spinal metastases to differentiate underlying osteoporosis from tumor involvement [17,25]. In this setting, MRI allows evaluation of the extent of medullary and extraspinal disease, and spinal cord and nerve root compression (image 6). This information is essential when one is deciding whether to operate or treat nonoperatively, and if an operation is planned, which levels require decompression and fixation. (See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Metastatic spine tumors'.)

Differential diagnosis — The main differential diagnosis in an adult aged 40 and over for a pathologic fracture caused by metastatic cancer or multiple myeloma includes benign insufficiency or stress fracture, and fracture associated with a primary benign tumor (enchondroma, fibrous dysplasia, giant cell tumor of bone, Langerhans cell histiocytosis, osteoblastoma), primary bone sarcoma (Pagetoid or postradiation osteosarcoma, chondrosarcoma, undifferentiated high-grade pleomorphic sarcoma of bone [previously termed malignant fibrous histiocytoma of bone]), plasmacytoma, and primary lymphoma of bone. When the underlying lesion associated with the fracture is aggressive in appearance, the differential diagnosis is limited to metastatic carcinoma, plasma cell dyscrasia (myeloma, solitary plasmacytoma), lymphoma, and bone sarcoma.

Imaging may assist in the differential diagnosis. In one series, compared with pathologic fractures caused by metastatic bone tumors (including multiple myeloma), fractures caused by a primary bone sarcoma had a higher incidence of lytic destruction of the bone cortex, mineralization, and a soft tissue mass on radiographs and CT scans, and a periosteal abnormality on MRI [26]. Taken together, all of these features had a high negative predictive value (with their absence highly suggestive of a metastatic cancer rather than primary bone sarcoma). However, the absence of these features might also point towards a benign bone lesion as well.

Insufficiency versus pathologic fractures — Insufficiency fractures are a type of stress fracture that occur in metabolically weakened bone (ie, prior radiation therapy, osteoporosis, osteomalacia, Paget disease of bone). Distinguishing them from a pathologic fracture due to metastatic disease or myeloma can pose significant diagnostic dilemmas, given that they may share imaging features on radiographs. Additional cross-sectional imaging with CT or MRI as well as technetium-99 (99mTc) bone scintigraphy and/or integrated PET/CT scanning can help in narrowing the differential and identifying other lesions. A summary of the most sensitive discriminating features between stress fractures and pathologic fractures on imaging studies is provided (table 3).

The utility of PET/CT in differentiating benign versus malignant spine fractures can be illustrated by the following reports:

In one series, the maximal Standardized Uptake Value (SUVmax) was significantly lower with benign as compared with malignant cases (1.36 ± 0.49 versus 4.46 ± 2.12) [27].

In another review of patients who underwent fluorodeoxyglucose (FDG)-PET within six weeks of spine needle biopsy, the mean SUV was 7.1 for malignant tumors compared with 2.1 for benign lesions (p <0.02) [28]. PET was a significantly better predictor of malignancy in nonsclerotic bone lesions. In lytic or mixed lytic-sclerotic bone lesions, there was a 100 percent concordance between PET using an SUV cutoff of 3 and needle biopsy.

PET may be particularly useful in patients with multiple myeloma, in whom the nature of the spine fracture may be more difficult to determine due to the presence of concomitant osteoporosis [17,27,29,30]. In this setting, an SUVmax of 3 to 4 is highly specific for a pathologic fracture. Particularly in patients with myeloma, PET/CT SUVmax >3.2 is a useful discriminant between old and new pathologic fractures [31].

An important point is that in most settings, the optimal cutoff for discrimination of benign and malignant lesions is not established; values between 2 and 4.7 have been suggested [28,29]. Furthermore, while PET is a sensitive screening tool for detecting cancer, it should not replace the need for biopsy, if needed, to conclusively establish a diagnosis. (See 'Diagnostic biopsy' below.)

Diagnostic biopsy

Solitary bone lesion or no prior cancer history – An impending or complete pathologic fracture in a patient with a solitary bone lesion, with or without a history of cancer, should never be fixed without a tissue diagnosis. Should the lesion prove to be a primary mesenchymal malignancy (eg, osteosarcoma, chondrosarcoma) an attempt at surgical repair could jeopardize not only the opportunity for limb salvage, but also the possibility of cure. Although there are no published data that indicate how often a solitary lesion of the bone in a patient with a history of cancer is a non-metastatic solitary primary bone tumor, estimates are that this occurs 10 to 20 percent of the time [14].

Additional issues that pertain to evaluation of patients with a remote or no history of cancer are discussed below. (See 'Patients with a remote or no history of cancer' below.)

Multiple bone metastases or known cancer – Preoperative tissue diagnosis may not be needed for patients with a pathologic fracture and a previous histologic diagnosis of metastatic bone disease or radiographic evidence of multiple bone lesions.

Biopsy method – If a patient has a history of cancer without prior documentation of bone metastases and a confirmatory diagnosis of metastatic disease is all that is required, needle biopsy can be an excellent method to acquire enough tissue simply to document the presence of metastatic disease. CT-guided FNA is easy to perform and accurate in this setting [32]. Core biopsy has higher diagnostic accuracy for determining the type, grade, and specific diagnosis of musculoskeletal tumors [33,34]. Ultrasound-guided core biopsy of a bone lesion is also possible if the lesion has an extraosseous soft tissue mass. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Biopsy techniques'.)

An open biopsy may be needed in a minority of cases. If needed, open biopsy may be done in the operating room immediately prior to possible internal fixation if frozen section pathology support is available. If the patient is taken to the operating room without an established diagnosis of metastatic disease, multiple myeloma, or lymphoma, a separate incisional biopsy should be done of the bone lesion itself, and the surgeon should wait until the pathologist examining the frozen section provides a definitive diagnosis prior to proceeding with any intervention. No instrumentation should be introduced into the intramedullary canal (including a guide rod for an intramedullary nail) before the diagnosis is established. Obtaining reamings to establish the diagnosis of an unknown lesion is contraindicated, as this unnecessarily violates uninvolved areas of the bone and surrounding soft tissues that can severely compromise the ability to care for a sarcoma if that is the ultimate diagnosis. (See 'Differential diagnosis' above.)

If the biopsy is to be done in advance by interventional radiology, discussion with the radiologist performing the biopsy is critical as the biopsy should be performed in a location that will permit excision of the biopsy tract should a primary sarcoma be diagnosed [35]. Consultation with an orthopedic oncologist is advised if questions about the diagnostic biopsy arise. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Planning the biopsy'.)

If the biopsy is to be done in the operating room prior to planned potential intervention, discussion with the pathologist is important. The discussion should include the known clinical information regarding the history or absence of a known cancer, the findings of all preoperative staging studies, and any prior treatments that might affect the condition of the tissue.

Assessing the risk of fracture — Some patients with bone metastases do not have a completed pathologic fracture, but are at risk for fracture because of the extent of bone involvement (ie, impending fracture). It is important to identify these patients. For these patients, preventing fracture is an important goal of therapy given the association between pathologic fractures and reduced survival in patients with malignant bone disease, and also to avoid the morbidity of a pathologic fracture [36,37]. There are potential clinical and economic benefits to performing surgery prophylactically over waiting until after the fracture occurs [38,39]:

Comparing 19 patients who underwent surgery for pathologic fractures with 21 patients who underwent prophylactic stabilization, one group found that mean total and mean direct costs were significantly higher in the pathologic fracture group. In addition, length of stay was longer in the fracture group [38].

In a separate study based on the Nationwide Inpatient Sample (NIS), analysis of patients with metastatic cancers from 2002 to 2010 showed that prophylactic treatment was favored over treatment after the fractures occurred in some endpoints but not others [39]. Significantly lower rates of blood transfusion, hemorrhage/hematoma, postoperative anemia, renal failure, myocardial infarction, and mortality were seen in the prophylactically treated group from the NIS study, but there were no differences in length of stay or hospital charges.

The difficulty in interpreting data from studies such as these is in assuring that the groups treated for impending pathologic fractures did indeed have an impending fracture, since the definition is controversial, as will be discussed subsequently. Hence, future studies are needed to better define the impending pathologic fracture group and compare those patients with patients who have already fractured.

Because of anatomical considerations, the definition of an impending fracture differs among the three major anatomic sites (long bones, acetabulum, and vertebrae).

Long bones — Historically, the classic definition of an impending pathologic fracture in a long bone included greater than 2 or 3 cm of cortical involvement, lytic destruction of 50 percent of the width of bone, or avulsion of the lesser trochanter as seen on radiographs [40-44]. However, subsequent evaluation has shown that interpretation of radiographs by clinicians is poorly sensitive and poorly specific [45].

Mirels scoring system — Mirels scoring system was developed to address the void in objective criteria for predicting fracture risk in the setting of metastatic disease to bone (table 4) [46]. This system is based on four criteria (clinical evaluation and radiographic appearance), each weighted with one to three points, with the total score linked to both fracture risk and recommendations for prophylactic surgical treatment. According to the original manuscript, score of ≥9 defines an impending pathologic fracture for which prophylactic stabilization is recommended.

Mirels scoring system is quite simple, and has proven to be valid across experience levels and between specialties [47-49], although there are limitations:

While the scoring system is highly sensitive, specificity for actual fracture prediction is limited. Fracture risk for the defined "impending fracture" risk category (≥9) was only 33 percent in the original series [46]; others report a specificity of only 13 percent [50].

Although most reports support acceptable interobserver and intraobserver reproducibility, these findings have not been universal [48,51,52].

The risk of humeral fracture utilizing Mirels system may require an adjustment of the definition in order to yield comparable fracture risks to those derived from the original population, which was predominantly femoral fractures [49].

Mirels scoring system represents a good initial estimate of fracture risk, but most clinicians still rely upon clinical judgment and experience, although in at least one study, this was no better than Mirels score at predicting pathologic fracture [47]. Regardless, the following issues are pertinent (see "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Management principles'):

Most orthopedic surgeons would agree that prophylactic stabilization should be considered for all lesions with significant, functionally limiting pain that is exacerbated by weight bearing [14].

Patients who have failed radiation therapy for a painful bone metastasis in a weight-bearing bone, and who have ongoing pain are often candidates for prophylactic fixation regardless of their Mirels score.

Finally, if the surgeon is fairly certain that a specific lesion will ultimately require fixation, it is usually better to perform surgery prior to irradiation and prior to the development of a complete pathologic fracture.

CT-based structural rigidity analysis — More recently, researchers at the Beth Israel Deaconess Biomechanics Laboratory at Harvard University have had success in prediction of fracture in patients with pediatric benign bone lesions utilizing CTRA, which has led to a prospective Musculoskeletal Tumor Society (MSTS) study examining the use of the same technology in patients with long bone involvement by metastatic disease. CTRA provides a measure of reduced load capacity of bone based on changes in both material and geometric properties at the weakest cross section [53,54].

Results from the MSTS study suggest equal or better sensitivity (100 versus 67 percent) and specificity (61 versus 48 percent) compared with Mirels scheme in fracture prediction for femoral lesions due to metastatic disease [55]. Receiver operating characteristic (ROC) analysis also indicated CTRA to be statistically significantly more accurate than the classic Mirels definition of impending fracture, which was no better than chance at fracture prediction in the femur.

In a later study involving 124 patients with 149 metastatic lesions at different skeletal sites, orthopedic oncologists selected a treatment plan based on the Mirels method, and then CTRA was performed [13]. After providing the CTRA results, surgeons changed their operative plan in 36 patients. Follow-up of patients who did not undergo fixation resulted in seven fractures; CTRA predicted these fractures with 100 percent sensitivity and 90 percent specificity, whereas the Mirels method was 71 percent sensitive and 50 percent specific.

While CTRA is promising, to date, it has required processing of the CT-based data obtained with a phantom provided by the team doing the analysis. Neither the phantoms nor the analysis are available outside of the research study. However, emerging evidence suggests that phantomless air-fat-muscle calibration may provide equivalent results, which would improve access to this more advanced technique [56].

Finite element modeling — Current clinical methods for fracture prediction rely on two-dimensional imaging techniques; a new technique called finite element modeling (FEM) integrates three-dimensional imaging to improve the accuracy of fracture predictions. This technique shows a strong correlation of predicted and actual bone strength with clinical or experimentally created defects of the femur [57]. The superior ability of FEM for fracture prediction compared with the Mirels score was shown in an analysis of 33 patients with metastatic femoral lesions, of whom 28 completed four months of follow-up without fracture and five went on to fracture [58]. There were three modeled experimental loading cases that simulated activities of daily living: axial compression (AC), level walking (LW), and aggressive stair ascent (ASA). Although sensitivity (ability to predict fracture) was similar for FEM and the Mirels criteria specificity (the ability to correctly predict the non-fracture cases) was better for FEM under the AC and LW loading conditions (71 and 86 percent, respectively, for FEM compared with 43 percent for Mirels), it was poorer for the ASA (21 percent) conditions. Newer modeling procedures such as these need to be refined and standardized before widespread use in the clinic [59]. In a more recent FEM femoral study, sensitivity, but not specificity, was improved over clinical evaluation [60]. In the spine, the correlation between FEM models and created defects has been lower than with femoral defects [61].

FDG-PET/CT — The latest in the evolution of techniques for fracture prediction is integrated positron emission tomography/computed tomography using fluorodeoxyglucose (FDG-PET/CT) [62]. In retrospective work from Memorial Sloan Kettering Cancer Center, one specific PET parameter (total lesion glycolysis value >81) differentiated at-risk from not-at-risk lesions with an accuracy of 83 percent, sensitivity of 85 percent, and specificity of 80 percent. This work was based on a comparison of 27 proximal femoral pathologic fracture cases with available FDG-PET/CT scans that had been done within three months prior to the fracture versus a control series of 55 patients with proximal femoral lesions who also had FDG-PET/CT scans. More prospective work is needed in this promising area before FDG-PET can be used for fracture prediction.

Acetabulum — Because of the complex anatomy of the acetabulum, a simple definition of impending pathologic fracture is neither possible nor useful for planning surgical reconstruction at this site. Further, unlike in the long bones of the extremities, there is no simple prophylactic surgical procedure for acetabular lesions of proven benefit that will reliably prevent fracture and alleviate symptoms. In most instances, the procedure of choice is a complex total hip arthroplasty, which is indicated with or without a fracture. Although some surgeons have begun to advocate for cementoplasty, a percutaneous procedure analogous to kyphoplasty or vertebroplasty procedures in the spine where cement is injected into peri-acetabular defects, the results of cementoplasty in the acetabulum are still being evaluated.

Classically, the location and extent of cortical destruction in the acetabulum [63] are used to evaluate the biomechanical impact on function:

Class I – The lateral cortices and superior and medial walls are structurally intact

Class II – The medial wall is deficient

Class III – The lateral cortices and superior wall are deficient

Class IV – There is extensive acetabular involvement (of the lateral cortices and superior and medial walls)

Destruction of the superior and medial walls has been suggested to constitute mechanical compromise, necessitating operative intervention [11]. However, ultimately, it is the impact on the patient's function that must be given the most weight in determining the need for operative intervention for acetabular lesions.

Assessing spinal stability — The debate about prophylactic fixation of an impending fracture of a long bone is also applicable to spinal metastases. There is no widely accepted definition of what constitutes an unstable spine [64,65]. Older approaches to defining spinal instability relied mainly on clinical features (ie, a diagnosis of spinal instability can be made clinically if the patient has pain on motion that is not present at rest) with support from diagnostic imaging [66-68].

A classification system for spinal instability in neoplastic disease was developed based on the available evidence and expert consensus opinion consultation [69]. Systematic reviews of the literature to identify the best evidence for clinical, radiographic, and pathologic factors that relate to neoplastic spinal instability in the cervical and thoracolumbar spine served as the framework to guide an expert consensus from the Spine Oncology Study Group, an international group of 30 spine oncology experts from around the world. Six individual components of spinal instability were scored, with a final Spine Instability Neoplastic Score (SINS) representing a composite score of the individual components (table 5). According to this classification, patients with a score of 7 or higher are considered to be at risk for spinal instability and warrant surgical consultation.

While the published evidence was considered in deriving the SINS, this classification system is not evidence-based and it reflects broad expert opinion of spinal neurosurgeons. Nevertheless, it represents a contemporary consensus approach to defining spinal instability. Regardless of the radiographic findings, the clinician should consider every patient with pain caused by movement to be unstable until proven otherwise. This subject is discussed in more detail elsewhere. (See "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Mechanical (spinal stability)'.)

Developing technologies for vertebral body fracture risk prediction include CTRA, which has been shown to be highly accurate [54]. However, neither the phantoms nor the software are widely available for use in the spine at this time [70]. (See 'CT-based structural rigidity analysis' above.)

PET/CT plus MRI — In patients with myeloma, a positron emission tomography/computed tomography (PET/CT) with a SUVmax >3.5 combined with magnetic resonance imaging (MRI) showing diffuse or multifocal signal abnormality appears to be predictive of an impending vertebral compression fracture [31]. (See 'PET scan' below.)

Completing the diagnostic and staging workup

Whole body skeletal evaluation — 99mTc bone scintigraphy is highly sensitive for identifying and evaluating the extent of bone metastases (image 7). However, standard bone scans lack anatomic detail and radionuclide uptake is not specific for metastases. Bone scans may spuriously display a large variety of inflammatory, infectious, post-traumatic, and benign neoplastic conditions. Therefore, confirmatory radiographs (or cross-sectional imaging) are typically carried out for any site that is found to be positive on the bone scan. One of the most common benign unrelated neoplasms identified in adults in this situation is an enchondroma, which is usually diagnosed by its characteristic chondroid matrix mineralization pattern seen on radiographs. (See "Nonmalignant bone lesions in children and adolescents", section on 'Enchondroma'.)

Radionuclide bone scans may also fail to detect small lesions, and because 99mTc accumulates in reactive bones, it may be falsely negative in cases of purely lytic disease (classically, multiple myeloma, but also rapidly destructive lesions such as renal cell carcinoma). In such cases, a skeletal survey or whole body cross-sectional imaging is generally preferred to assess for other areas of bone involvement. In patients with multiple myeloma, both low-dose whole body CT and whole body MRI have emerged as preferred techniques to assess burden of disease, evaluate response to treatment, and evaluate for complications such as pathologic fracture or spinal cord compression. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

Single-photon emission computed tomography may also be used for whole body bone imaging to detect tumors. It may be more specific than a bone scan since it combines the radionuclide uptake of the tracer with the more anatomically specific localizing capability of the CT scan [71]. Hence, increased uptake in the spine and pelvis may be more confidently differentiated between degenerative disease and neoplastic processes.

PET scan — Integrated positron emission tomography/CT with fluorodeoxyglucose (FDG-PET/CT) offers a whole body screen for metastases in the setting of a suspected malignant pathologic fracture. PET/CT scanning may be particularly useful for assessing the whole skeleton in those patients with rapidly progressive lytic metastases that are associated with minimal reactive bone formation [72], and for staging of lymphomas that are routinely avid for labeled glucose (eg, diffuse large B cell lymphoma, Hodgkin lymphoma). However, PET/CT scanning is less sensitive than 99mTc bone scintigraphy for detection of osteoblastic metastases [73,74]. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Positron emission tomography (PET)'.)

There is limited but growing evidence that integrated PET/CT scanning using (18)-Fluorine-labeled sodium fluoride (18F-NaF) PET/CT may offer better sensitivity and specificity in evaluating metastatic bone disease compared with 99mTc-based bone scintigraphy [75]. While the use of 18F-NaF PET/CT has been increasing in clinical practice, it is not widely available and its utility in assessing for fracture risk in patients with metastatic bone disease is not established [76].

In the future, FDG-PET may play a role in the prediction of bones at risk for fracture [62]. However, this indication remains a research tool to date. The support for its use in this setting is discussed above. (See 'FDG-PET/CT' above.)

Finally, in patients with multiple myeloma, the combination of PET/CT plus MRI may provide important information about the risk of an impending fracture. (See 'PET/CT plus MRI' above.)

Laboratory evaluation — Laboratory evaluation for a patient with a completed or impending pathologic fracture should include a complete blood count; many patients with metastatic bone disease have been treated with chemotherapy and may have anemia, leukopenia, or thrombocytopenia that must be addressed prior to surgery. All patients should also be evaluated for hypercalcemia, which is most common in squamous cell lung cancer, breast cancer, kidney cancer, and multiple myeloma. (See "Hypercalcemia of malignancy: Mechanisms".)

The utility of assays for serum tumor markers in patients without a history of active cancer is discussed below. (See 'Patients with a remote or no history of cancer' below.)

Patients with a remote or no history of cancer — The evaluation of a patient with a pathologic fracture and only a remote or no history of cancer must include a search for the primary site. When there is no prior history of cancer in a patient presenting with skeletal metastases, the most common primary carcinomas are lung and renal cell cancer.

The diagnostic evaluation should precede biopsy of the painful lesion for the following reasons:

The absence of any findings beyond the pathologic fracture may indicate a primary sarcoma of bone, for which an ill-planned biopsy may compromise limb salvage or outcomes.

An unnecessary biopsy of bone in a patient with multiple myeloma can be avoided by obtaining appropriate laboratory tests. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)

A diagnostic workup will be needed even if the pathologic fracture lesion is proven to be metastatic cancer histologically [77]. This is because histologic analysis alone may not identify the primary site. As an example, in a series of 110 consecutive patients with an apparently metastatic bone lesion, FNA biopsy correctly diagnosed 15 of 16 patients with myeloma, 12 of 14 with lymphoma, and 75 of 80 with metastatic carcinoma, but the site and type of malignancy was correctly suggested in only two-thirds of those with metastatic carcinoma [32].

Another lesion may be identified in bone that is easier or safer to sample.

Staging provides the pathologist with more information on which to guide their evaluation of the tissue.

Particularly important from the surgeon's perspective, renal cell carcinomas are the second most common primary source of occult metastatic disease to bone, and the bone metastases are dangerously vascular. Recognition of a renal mass suspicious for renal cell carcinoma warrants consideration of preoperative embolization of the bone lesion prior to open biopsy or other operative intervention in order to minimize what can sometimes be catastrophic blood loss.

Diagnostic strategy — We suggest the following diagnostic strategy for skeletal metastases of unknown origin that will identify the primary lesion in approximately 85 to 88 percent of patients [77,78]. This testing should generally be carried out prior to the diagnostic biopsy:

Medical history and complete physical examination, to include the thyroid gland, breasts, and prostate gland.

Radiographs of the affected area.

99mTc bone scintigraphy (or FDG-PET) to identify other lesions, if present. A patient with multiple bone lesions is unlikely to have a primary bone malignancy.

If multiple myeloma is suspected, the search for other lesions should be performed with whole body CT or whole body MRI, or FDG-PET scan, as the bone scan may be falsely negative. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

CT scan of the chest with or without contrast. The lung is the most likely source of metastatic carcinoma when there has been no history of cancer. Chest CT may also identify evidence of metastatic disease [79].

Contrast-enhanced CT scan of the abdomen and pelvis. The kidney is the second most common source of metastatic carcinoma when there is no history of cancer. CT scan of the abdomen will also potentially identify visceral metastatic disease, which impacts overall prognosis. CT of the pelvis is a useful test to evaluate for pelvic adenopathy, which may suggest a diagnosis of lymphoma. Iodine-based intravenous contrast might be contraindicated in patients with multiple myeloma who have impaired renal function, so the results of the myeloma screening blood work and renal function should be obtained prior to the administration of iodine-based intravenous contrast [80].

Screening laboratory studies to include a complete blood count with differential and examination of a peripheral blood smear, liver function tests, lactate dehydrogenase, calcium, phosphorus, alkaline phosphatase, beta-2 microglobulin, and for adult males, assay for prostate specific antigen. The role of other tumor markers including alpha-fetoprotein, carcinoembryonic antigen, and CA 125 is unclear [78]. Renal function tests should be obtained prior to administration of iodine-based contrast.

In the appropriate setting, serum protein electrophoresis with immunofixation and quantification of immunoglobulins, 24-hour urine collection for protein electrophoresis, immunofixation, and analysis of serum free monoclonal light chains should be performed to screen for multiple myeloma. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'.)

Mammography for women. Although metastatic breast carcinoma to bone usually is diagnosed after the primary breast cancer diagnosis is established and treated, there is always the possibility of an occult or neglected breast mass [79,81].

Examination of the gastrointestinal tract seldom reveals the primary site and is generally not indicated in the absence of abdominal symptoms [78].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer pain" and "Society guideline links: Management of bone metastases in solid tumors".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Bone metastases (The Basics)")

SUMMARY AND RECOMMENDATIONS — Bone metastases are a common manifestation of distant relapse from many types of solid cancers, especially those arising in the lung, breast, and prostate. Bone involvement can also be extensive in patients with multiple myeloma, and bone may be a primary or secondary site of disease involvement in patients with lymphoma. Neoplastic involvement of bone represents a prominent source of morbidity, including pain, loss of function, and fracture. (See 'Introduction' above.)

Definitions

A fracture that develops through an area of bone pathology is termed a pathologic fracture. Pathologic fractures develop in 9 to 29 percent of oncology patients with bone metastases, and rates are highest among patients with multiple myeloma. (See 'Etiology' above.)

In some cases, the extent of bone destruction is such that a fracture is imminent but not complete (termed an impending fracture).

Clinical presentation

Most patients with a pathologic fracture present with pain. A pathologic fracture may develop spontaneously or may be secondary to functional activity or minor trauma. Common sites of pathologic long bone fracture include the femur, vertebral body, and humerus. (See 'Clinical presentation' above.)

Diagnosis

The diagnosis of a complete or impending pathologic fracture is usually established radiographically. A radiograph of the entire bone is needed to assess for other lesions that may warrant prophylactic stabilization. (See 'Radiographic studies' above.)

Cross-sectional imaging may be needed to establish the integrity of the bone cortex. Computed tomography (CT) is probably the imaging method of choice for most patients. However, magnetic resonance imaging (MRI) will better delineate the extent of tumors within bone, the associated soft tissue extension, and the presence of skip metastases. MRI is particularly useful for patients with spine metastases to allow evaluation of the extent of medullary and extraspinal disease, and spinal cord and nerve root compression. (See 'Cross-sectional imaging' above.)

The main differential diagnosis for a pathologic fracture caused by metastatic cancer or myeloma includes benign insufficiency fracture and primary bone tumor (osteosarcoma, chondrosarcoma, undifferentiated high-grade pleomorphic sarcoma of bone [previously termed malignant fibrous histiocytoma of bone], plasmacytoma, primary lymphoma of bone). (See 'Differential diagnosis' above.)

An impending or complete pathologic fracture in a patient with a solitary bone lesion, with or without a history of cancer, should never be fixed without a tissue diagnosis. Preoperative tissue diagnosis may not be needed for patients with a previous histologic diagnosis of metastatic bone disease or radiographic evidence of multiple bone lesions. (See 'Diagnostic biopsy' above.)

Assessing fracture risk For patients with metastases involving the long bones or spine but without an overt pathologic fracture, there is no consensus on how best to assess the risk of fracture. (See 'Assessing the risk of fracture' above.)

Mirels scoring system represents a good initial estimate of fracture risk for metastases involving long bones, but it should be tempered by clinical judgment and experience. (See 'Mirels scoring system' above.)

Assessment of spine stability is needed for patients with spine metastases to determine whether intervention is needed. The Spinal Instability Neoplastic Score, represents a contemporary consensus approach to defining spinal instability (table 5) [69]. However, every patient with movement-related or axial-load pain should be considered to have an unstable spine until proven otherwise. (See 'Assessing spinal stability' above.)

Completing the diagnostic and staging workup

The extent of skeletal involvement should be assessed using technetium-99 bone scintigraphy, radiographic skeletal survey, whole body CT, whole body MRI, or positron emission tomography scan. (See 'Whole body skeletal evaluation' above.)

Laboratory evaluation for a patient with a completed or impending pathologic fracture should include at least a complete blood count and calcium level. (See 'Laboratory evaluation' above.)

The evaluation of a patient with a pathologic fracture and only a remote or no history of cancer must include a search for the primary site. A suggested diagnostic strategy is outlined above. (See 'Diagnostic strategy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jerome Posner, MD, and Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.

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References

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