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Overview

Practice Essentials

Metastatic bone disease occurs when cancer spreads from a primary organ site to bone. The spine is the most common location of metastatic disease. See the image below.

Lateral radiograph shows sclerotic metastasis of the L2 vertebra in a 54-year-old man with prostatic carcinoma.

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Diagnosis

Pain is an important symptom of musculoskeletal metastases, but it is nonspecific. The pain pattern can be helpful if, in addition to being activity related, it is present at rest and at night, especially in patients older than 50 years. However, this pain pattern can be present in patients with osteomyelitis and Paget disease, and in these instances, it is also nonspecific.

Testing

Laboratory tests that can be used to aid in the diagnosis of metastatic bone disease include the following:

Serum alkaline phosphatase: Indirect reflection of bone destruction
Serum protein electrophoresis
Urinalysis, urine protein electrophoresis
N-telopeptide of type II collagen: Marker of bone resorption but not widely used

Imaging studies

The following radiologic studies may be used to evaluate metastatic bone disease:

Radiography: For the basic assessment of the extent of a tumor and the degree of cortical erosion; can also be used for skeletal survey in patients with multiple myeloma
Computed tomography: Most sensitive imaging modality to detect bone destruction, providing the best assessment of the extent of cortical destruction
Magnetic resonance imaging: Most sensitive study for the assessment of the anatomic (intramedullary and extraosseous) extent of a lesion
Bone scanning: Very sensitive study for the detection of occult lesions and the assessment of the biologic activity of lesions
Angiography: Depicts devascularization of vascular metastases; may also be used to assess pain palliation in patients with nonresectable metastases

Procedures

Biopsies should be obtained from any soft-tissue mass or, if no soft-tissue mass is present, from the most accessible bone in a mechanically safe area (eg, metaphysis vs diaphysis, acetabulum vs subtrochanteric femur).

In selected patients with metastatic disease of the spine, the following diagnostic procedures may be performed:

Percutaneous core needle biopsy
Open biopsy

See Workup for more detail.

Management

The life span of patients with metastatic bone disease is limited; thus, the goal of management needs to be centered on returning as much function as possible as rapidly as possible. Patients with metastatic bone disease are generally treated with surgery or radiation therapy.

Radiation therapy

Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis, because nearly 95% of patients who are ambulatory at the start of radiation therapy remain so. Consequently, the possibility of regaining cord function once it is lost as a result of spinal metastasis is dismal. Therefore, such loss needs to be avoided by early diagnosis, treatment, and, if indicated, surgical intervention.

Surgery

The goals of surgical intervention for spinal surgery in patients with metastatic bone disease includes decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine.^{[1, 2]}Anterior or posterolateral decompression, combined with anteroposterior reconstruction, may be used in the following:

Diagnostic spinal surgery
Cervical spinal surgery
Thoracic and lumbar spinal surgery

Vertebroplasty, in which polymethylmethacrylate is percutaneously introduced, may be a minimally invasive treatment alternative for patients with one- or two-level vertebral body compression fractures.^[3]

For the management of long-bone metastatic disease accompanied by an impending or completed fracture, open internal fixation is usually the preferred method of treatment. Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred.^[4]

Devices and/or procedures used in the surgical fixation of long bones include the following:

Standard or cemented stems
Dynamic hip screws or plates
Intramedullary fixation devices
Total hip arthroplasty

Pharmacotherapy

Medications used in the treatment of metastatic bone disease include the following:

Monoclonal antibody antineoplastic agents (eg, denosumab)
Calcium metabolism modifiers/bisphosphonates (eg, pamidronate, zoledronate, and ibandronate)

See Treatment and Medication for more detail.

Background

The orthopedic surgeon has two major tasks to perform when treating patients who develop bone metastases.^[1] The first task is to biopsy a bony lesion of unknown origin, which may be found during evaluation/staging studies or as a result of a patient's symptoms. (See Workup.) The second is to manage the stabilization of impending or already completed pathologic fractures of bones in a critical area, such as an upper or lower extremity, the pelvis, or the spine.

In one study of patients with breast carcinoma, 19% of the patients developed a pathologic fracture or hypercalcemia as the first sign that the carcinoma had spread to bone. Moreover, 10% of the patients suffered spinal cord compression, and 9% of them experienced bone marrow failure. (See Prognosis and Treatment.)

In patients with bone metastases, it is important to develop strategies that emphasize maintenance of function, including ambulation, for the remainder of these patients’ lives and to intervene when possible before a fracture occurs. The morbidity and mortality associated with metastatic bone disease are greater when intervention is delayed. (See Prognosis and Treatment.)

In females, the breasts and lungs are the most common primary disease sites; approximately 80% of cancers that spread to bone arise in these locations.^{[5, 6, 7, 8, 9]}In males, cancers of the prostate and lungs make up 80% of the carcinomas that metastasize to bone.^[10]The remaining 20% of primary disease sites in patients of both sexes are the kidney, gut,^[11]and thyroid, as well as sites of unknown origin. (See Pathophysiology and Etiology)

Pathophysiology and Etiology

Previously, the two main theories of how tumor cells metastasize and grow in bones were Paget's fertile soil hypothesis and Ewing's circulation theory. Subsequently, a substantial amount of work more clearly defined the metastatic process to bone. Bone metastases occur in a predictable distribution. In order of frequency, the most common locations include the following:

Spine
Pelvis
Ribs
Proximal limb girdles

The red marrow theory, combined with knowledge about the cytokine stimulation of metastases, provides an excellent explanation of how this distribution occurs.

Metastases distal to the knee and elbow are extremely uncommon, but approximately 50% of these acral metastases are secondary to primary lung tumors. Carcinomas, such as those of the breast and prostate, rarely exhibit such a distinct pattern.

Metastasis and bone destruction

In 1995, Mundy and Yoneda described the cellular events necessary for the success of the metastatic process, including the attachment of tumor cells to the basement membrane, the production of proteolytic enzymes by tumor cells (eg, metalloproteinases, which are enzymes that disrupt basement membranes), and the migration of tumor cells through the basement membranes into surrounding tissue, especially the arteriolar network.^[12]

Cells from the primary site must, through the process of neovascularization or through migration to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce proteolytic enzymes that disrupt the basement membrane.

The cells then migrate through the basement membrane and float away in the bloodstream to a distant site. The process through which these tumor cells are attracted to a specific site in the body is not completely clear, though type I collagen, a byproduct of bone resorption, has been shown to be a chemotactic factor that attracts tumor cells to bone.

If they survive the journey to the distant site, the tumor cells attach to the basement membrane of the vessel wall using proteolytic enzymes (integrins/cadherins). After disrupting the receptor site basement membrane, they migrate into the substance of the distal host tissue. Producing chemotactic factors, as well as RANK ligand (RANKL; a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts), these cells stimulate osteoclast activity, causing bone resorption and leading to the formation of pockets or holes in the bone in which the tumor cells grow.

Another important substance that stimulates bone resorption is parathyroid hormone ̶ related peptide (PTHrP). This substance is expressed by breast carcinoma cells, as well as by oat cell tumors of the lung, and is a potent stimulant of osteoclasts. Guise et al reported elevated PTHrP levels in the bone marrow plasma (as compared with serum plasma levels) in rats with tumors.^[13]

Mundy and Yoneda also reported that myeloma cells are especially adapted to producing bone destruction through direct stimulation of osteoclasts.^[12]During the resorption process, the osteoclasts release interleukin (IL)-6, which is a major regulatory factor in the growth of myeloma cells. Additional myeloma cells further stimulate increased osteoclastic production in a continuous feedback mechanism. This enhances survival of the tumor cells and further destruction of the bone.

United States statistics

Approximately 1.8 million patients present with cancer each year in the United States.^[14]Of these, substantial percentages (varying by primary tumor) have metastases to bone.^[15] In contrast, approximately 3900 patients per year develop primary bone or joint cancer.^[16]

Age-related demographics

The age range of patients with sarcoma is different from that of individuals with carcinoma of bone; most metastatic bone lesions occur in adults older than 50 years, while most sarcomas occur in adolescents or young adults (< 30 years). Therefore, a bone-occupying mass in an adult is much more likely to be a focus of metastatic carcinoma than to be a primary sarcoma of bone. However, in a patient with a bone lesion with no documentation of metastatic disease, caution is warranted to ensure the correct diagnosis.

Race-related demographics

In an analysis focusing on the five most common primary sources of metastatic bone disease (ie, lung, prostate, breast, kidney, and colon), Jawad et al found that non-Hispanic Blacks had a higher incidence of metastatic bone disease for primary prostate and breast cancers, whereas non-Hispanic American Indians and Alaskan Natives had a higher incidence for primary renal and colon cancers.^[17] In addition, the incidence of metastatic bone disease was higher in groups with lower socioeconomic status, possibly as a consequence of delayed diagnosis and limited access to screening modalities.

Prognosis

In general, once skeletal metastases are present, patient survival is dramatically shortened. For example, the 5-year overall survival rate for people with prostate cancer is 93%, but once skeletal metastases are present, the average survival time is only 29 months. However, patients are surviving and remaining active for longer periods as treatment protocols improve. These factors make the orthopedic surgeon's task in prophylactic or reconstructive surgery more challenging.^[18]

In addition, perioperative complications occur more frequently among patients with skeletal metastases; the perioperative mortality in this population is approximately 8%, and the perioperative infection rate is approximately 4% (though it is higher at previously irradiated sites).

Most patients with metastatic bone disease survive for 6-48 months. In general, patients with breast and prostate carcinoma live longer than those with lung carcinoma.^{[19, 20]}Patients with renal cell or thyroid carcinoma have a variable life expectancy.

Kirkinis et al studied 462 patients presenting with metastatic bone disease to the extremities or pelvis who underwent orthopedic treatment.^[21]Overall surival rates were 45% at 1 year, 29% at 2 years, and 13% at 5 years. Preoperative hemoglobin was found to be an independent predictor of better survival; lung histotype, age, pathologic fracture, and previous combined therapy were negative predictors of survival.

In a retrospective study that included 164 patients who underwent surgical treatment of metastatic bone disease (median survival, 1.6 years), Baumber et al found that a higher American Society of Anesthesiologists (ASA) grade, a high white blood cell (WBC) count, hyponatremia, a preoperative resting heart rate higher than 100 beats/min, and the type of primary cancer were significant predictors of reduced survival time at 6 and 12 months.^[22]

Clinical Presentation

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Byttner M, Wedin R, Bauer H, Tsagozis P. Outcome of surgical treatment for bone metastases caused by colorectal cancer. J Gastrointest Oncol. 2021 Oct. 12 (5):2150-2156. [QxMD MEDLINE Link]. [Full Text].
Mundy GR, Yoneda T. Facilitation and suppression of bone metastasis. Clin Orthop Relat Res. 1995 Mar. (312):34-44. [QxMD MEDLINE Link].
Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest. 1996 Oct 1. 98 (7):1544-9. [QxMD MEDLINE Link]. [Full Text].
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Turpin A, Duterque-Coquillaud M, Vieillard MH. Bone Metastasis: Current State of Play. Transl Oncol. 2019 Dec 23. 13 (2):308-320. [QxMD MEDLINE Link]. [Full Text].
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Jawad MU, Pollock BH, Wise BL, Zeitlinger LN, O' Donnell EF, Carr-Ascher JR, et al. Sex, racial/ethnic and socioeconomic disparities in patients with metastatic bone disease. J Surg Oncol. 2022 Mar. 125 (4):766-774. [QxMD MEDLINE Link].
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Kirkinis MN, Spelman T, May D, Choong PFM. Metastatic bone disease of the pelvis and extremities: rationalizing orthopaedic treatment. ANZ J Surg. 2017 Nov. 87 (11):940-944. [QxMD MEDLINE Link].
Baumber R, Gerrand C, Cooper M, Aston W. Development of a scoring system for survival following surgery for metastatic bone disease. Bone Joint J. 2021 Nov. 103-B (11):1725-1730. [QxMD MEDLINE Link].
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Hipp JA, Springfield DS, Hayes WC. Predicting pathologic fracture risk in the management of metastatic bone defects. Clin Orthop Relat Res. 1995 Mar. (312):120-35. [QxMD MEDLINE Link].
Kawaguchi M, Tateishi U, Shizukuishi K, Suzuki A, Inoue T. 18F-fluoride uptake in bone metastasis: morphologic and metabolic analysis on integrated PET/CT. Ann Nucl Med. 2010 May. 24 (4):241-7. [QxMD MEDLINE Link].
Freedland SJ, Richhariya A, Wang H, Chung K, Shore ND. Treatment patterns in patients with prostate cancer and bone metastasis among US community-based urology group practices. Urology. 2012 Aug. 80 (2):293-8. [QxMD MEDLINE Link].
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Haider MT, Smit DJ, Taipaleenmäki H. MicroRNAs: Emerging Regulators of Metastatic Bone Disease in Breast Cancer. Cancers (Basel). 2022 Jan 30. 14 (3):[QxMD MEDLINE Link]. [Full Text].
Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar. 19 (3):370-381. [QxMD MEDLINE Link].
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Media Gallery

Lateral view of the femur of a 70-year-old man with metastatic prostate carcinoma, the most common cause of osteoblastic metastases in men.
Radiograph of a patient with severe rest- and activity-related pain at the time of presentation.
Pathologic fracture. Radiograph shows a displaced fracture through an osteolytic lesion in the distal femur of a 53-year-old woman with lung carcinoma.
Radiograph shows osteolytic metastasis in the distal femur of a 51-year-old woman with breast carcinoma.
Lateral radiograph shows sclerotic metastasis of the L2 vertebra in a 54-year-old man with prostatic carcinoma.
Axial computed tomography scan shows 2 rounded, mixed osteolytic-sclerotic lesions in the thoracic vertebral body of a 44-year-old woman with lung carcinoma.
Axial computed tomography scan shows a destructive osteolytic lesion in the left acetabulum of a woman with vulval carcinoma. Soft-tissue extension into the pelvic cavity is present.
Sagittal spin-echo T2-weighted magnetic resonance image shows hypointense lesions in the T10 and L3 vertebrae in a 66-year-old man with lung carcinoma. The tumor involves the T10 pedicle. See also the next image.
Sagittal short-tau inversion recovery magnetic resonance (MRI) from a 66-year-old man with lung carcinoma. This MRI shows hyperintense lesions in the T10 and L3 vertebrae, with T10 pedicular involvement.
Sagittal short-tau inversion recovery (STIR) magnetic resonance image (MRI) in a 68-year-old man with thyroid carcinoma. This MRI shows severe compression of the L1 vertebra with retropulsion. Affected T11-L2 vertebrae show signal hyperintensity, posterior vertebral body marginal bulging, and spinal canal narrowing. See also the next image.
Sagittal gadolinium-enhanced spin-echo T1-weighted magnetic resonance image from a 68-year-old man with thyroid carcinoma. This image shows heterogeneous enhancement of the T11-L2 vertebrae, with prominent epidural component enhancement and spinal canal compromise. See also the next image.
Axial spin-echo T1-weighted magnetic resonance image (MRI) in a 68-year-old man with thyroid carcinoma. This MRI shows tumor extension from the L1 vertebral body and left pedicle into the left psoas muscle and epidural space, with resultant spinal cord compression. See also the next image.
Axial gadolinium-enhanced spin-echo T1-weighted magnetic resonance image from a 68-year-old man with thyroid carcinoma. This image shows heterogeneous enhancement of the soft tissue component of the L1 vertebral metastatic tumor.
Typical scintigraphic pattern of bone metastases in a 60-year-old man with nasopharyngeal carcinoma. This posterior technetium-99m bone scintiscan shows multiple randomly distributed focal lesions scattered throughout the skeleton, particularly the spine, ribs, and pelvis.