Bone pain Flashcards
Structure of bone
Cortical bone
- Outer layer of all bones (80% of skeletal mass)
- Covered by periosteum, a fibrous sheath
Trabecular bone
- Found in the epiphyseal area of the long bone, large proportion of rips, spine, and skull
- Less dense, woven appearance
Mechanisms of cancer-induced bone pain
Peripheral sensitization
- Tumour seeded into bone may result result in an inflammatory influx (macrophages, neuts, T cells) which may result in the release of pain-inducing factors (cytokines, interleukins, chemokins etc.
- Peripheral nocicepters respond to these algogenic agents, either by being directly excited or lowering their threshold for activation
Progressive increase in innervation
- As tumour grows, growth factors released by the tumour stimulate increased innervation
- State of spinal sensitization can occur
Structural damage/compression
- Tumour growth can damage the distal processes of nerves within the bone marrow, mineralized bone, and periosteum
Osteoclast and acidosis
- Increased osteoclast activation may result in a decreased extracellular pH (osteoclasts rely on an acidic environment)
- May result in nociceptive transmission due to decreased pH (can be excited or sensitized by protons)
Mechanical instability
- Uncoupled osteoblastic/osteoclastic activity can lead to mechanical instability of bones and lead to pain
Vascular occlusion
Clinical features of pain from bony mets
- Pain is the most common presenting symptom, though 30-50% of patients are asymptomatic
- Bone mets are the most common source of pain in patients with advanced cancer
- Advanced breast and prostate cancer are most commonly associated with malignant bone disease
Pain
- Onset, may be intermittent but then may progress to continuous/baseline pain with episodes of spontaneous or movement-induced breakthrough pain
- Pain may occur in response to normally benign activities (e.g. coughing, turning in bed, gentle movement)
- Often well localised, aching or sharp in quality. Also described as ‘throbbing’ or ‘tingling’
- Provoked or aggravated by applying pressure
- May have a migratory pattern, where pain may appear in one site, then move to another site with total resolution at the previous site
- May be associated with thermal hyperalgesia, paresthesias, and dynamic allodynia (pain with light brushing to skin) or static allodynia (pain with light pressure)
- May have significant impact on quality of life and function
Skeletal complications of bone mets
- Pathological fractures
- Pain (most common presenting symptom)
- Hypercalcemia
- Cord compression
30-50% of patients may be asymptomatic!
Normal bone turnover
RANKL - expressed by osteoblasts and marrow stromal cells, stimulates osteoclasts to stimulate bone resorption. Stimulated by certain interleukins, PTH, PTHrp. Some cancer cells produce RANKL directly.
RANK receptor - expressed on pre-osteoclasts and mature osteoclasts. When activated, starts bone resorption.
OPG - produced by osteoblasts, binds to RANKL and inhibiting interaction between RANK and RANKL
Bone formation - osteoblasts stimulated, osteoclasts inhibited
Bone resorption - osteoblasts inhibited, osteoclasts activated
In bony mets:
- Relatively higher levels of RANKL than to OPG (either due to direct tumour production or production of PTH-rp) which results in more osteoclastic activation (lytic lesions)
- Conversely, tumours can secrete factors that promote growth, differentiation, and activity of osteoblasts (sclerotic lesions)
Investigations for painful bony mets
Plain radiographs
- Areas of absent density or absent trabecular structure (osteolytic lesions)
- Areas of increased density and sclerotic lesions or rims (Osteoblastic lesions)
- Can confirm symptomatic lesions or suspicious lesions found on bone scan
- Useful to assess patients at risk of pathological fractures
- Limited - 30-75% of normal bone mineral content must be lost before lytic lesions in the vertebrae become apparent (may take months)
- Sensitivity 44-50%, but more specific than bone scan
Bone scans
- Tracer accumulates in areas of increased osteoblastic activity
- Sensitivity 62-100%, Spec 78-100%
- May give false negatives in myeloma or false positives with osteoarthritis, infection, trauma, or Paget’s disease
- May not show purely lytic lesions or rapidly progressive disease where there is little chance for new bone formation
CT with bone windows
- Sensitivity 71-100%
- Readily available, identifies lesions earlier than with XR
- Not as useful if there is concern about soft tissue involvement (e.g. nerve impingement, cord compression)
MRI
- Can provide information about bone and bone marrow
- Better contrast resolution than CT for soft tissue and spinal cord
- Sensitivity 85 - 100%, Spec 73-100%. Comparable to PET, but more readily available
- Useful if there is concern re: nerve impingement or cord compression (don’t order with contrast)
- Can distinguish between insufficiency and pathologic fracture (can demonstrate infiltration of tumour into bone marrow)
PET scan
- Not commonly used in PC due to cost
- Likely more specific, but perhaps less sensitive than a bone scan
Types of bony mets
Osteolytic lesions
- Destruction of normal bone
- Myeloma, breast cancer, renal cell carcinoma, melanoma, non-small cell lung cancer, non-hodgkin lymphoma, thyroid cancer or langerhans-cell histiocytosis
- Mediated by osteoclasts
- Relatively higher levels of RANKL than to OPG (either due to direct tumour production, tumour production of pro-osteoclastic factors, or production of PTH-rp) which results in more osteoclastic activation (lytic lesions)
Osteoblastic lesions (sclerotic)
- Osteoblastic predominant
- Prostate cancer, carcinoid, small cell lung cancer, Hodgkin lymphoma or medulloblastoma
- Mediated by osteoblasts
- Tumours can secrete factors that promote growth, differentiation, and activity of osteoblasts (sclerotic lesions)
Mixed
- Breast cancer (though more typically lytic), GI cancers, squamous cell
UTD approach to detecting bone mets
- For suspected extremity lesions, XRs first. If impending or complete pathologic fracture suspected or XRs are ambiguous, consider CT or MRI without contrast to evaluate for surgical stabilization
- In any case where a patient has significant back pain (even without neuro signs) or neurologic symptoms, get a spinal MRI without contrast to rule out cord compression. If symptoms persist but imaging is negative, consider a PET
- Initiate analgesia while testing/planning is underway
- Consider a PET scan if:
- Need for comprehensive whole body cancer staging
- Rapidly progressive mets with minimal reactive bone formation
- Ewing sarcoma with primary lytic tumour - If the patient has myeloma
- Primary lytic lesions - get a whole body plain radiograph skeletal survey
- Primary sclerotic lesions - get a bone scan
Initial pharmacologic approach to managing malignant bone pain
- WHO ladder (NSAIDs or acetaminophen for mild pain, opioids if mod/severe or not adequate controlled with non-opioids
- Consider treatment of incident pain with oral transmucosal fentanyl and prophylactic dosing prior to trigger activities
- Increasing around the clock medication MAY improve breakthrough pain (preventing or limiting severity)
Non-opioid pharmacological agents may be specifically used for bone pain
NSAIDs
- No evidence that they are uniquely more effective in bone pain compared to other pain syndromes
- Risk of GI toxicity - prescribe with a PPI, though no strong evidence to support doing so.
- Monitor renal function
Steroids
- Little evidence to support use in bony pain, but commonly used
- Given side effects, best used short term until other analgesics can exert effect
- May prevent pain flare following radiotherapy
Bisphosphonates
- Bind to bone matrix and cause osteoclast apoptosis and reduce bone resorption
- Regular administration shown to reduce skeletal-related events, especially in breast CA, prostate CA, and MM
- Can provide modest pain relief over time (but not immediate analgesia - typically 12 weeks or so)
- IV is preferred, better bioavailability, less GI toxicity, and probably more effective for analgesia
- In some RCTs, pamidronate appears to provide the greatest magnitude of pain relief
- Monitor for renal impairment (especially with rapid infusions) and osteonecrosis of the jaw
Denosumab
- Monoclonal antibody that inhibits RANKL (and thus osteoclast formation, function, and survival)
- Modestly more effective than bisphosphonates, but cost can be prohibitive
Calcitonin
- Used for management of pain from osteoporotic fractures
- No evidence to support use in metastatic bone pain
Non-pharm approaches to management of pain from bony mets
- Non-weight bearing techniques
- Heat and ice
- Gentle message
- OT/PT for support/assistive devices to reduce pain
Indications to refer to Rads for bone pain
- External beam rads standard approach to management of painful bony mets when there is inadequate pain control with analgesics
- 40% of patients can expect at least 50% pain relief
- Slightly less than 30% can expect complete pain relief at one month
- No difference in pain outcomes between single and multiple fractions
- Single-fraction may result in higher rate of re-treatment, more pain flares, and potentialy greater risk of fracture
- Multiple-fraction is preferred for previously irradiated areas, to treat or prevent pathologic fractures, and for spinal cord or cauda equina involvement
Radiopharmaceuticals and application to bony mets
- Radioactive agents administered IV, which localize to metastatic bone sites and deliver radiation in a highly focal manner
- Strontium-89 and Smarium-153
- Systematic review shows improved pain control and decreased analgesic consumption
- Main adverse effects are thrombocytopenia and neutropenia
- Onset of analgesia may not occur for MONTHS
Indications:
- Multiple painful bone mets where conventional analgesics are ineffective and local field rads is not possible
- Must consider performance status, marrow function, use of other marrow suppression agents (e.g chemo/rads), alternative treatments, and prognosis
Orthopedic intervention in bony mets
Consultation with ortho if:
- Bone pain that is difficult to manage due to pathologic fracture or impending pathologic fracture (>50% loss of bone at a symptomatic site)
- Fractured proximal femur is a clear indication to consider surgery (depending on prognosis) as internal fixation or endoprosthetic reconstruction provides superior relief of pain
- Consider use of scoring system for risk of pathologic fracture (Mirels’ scoring system) but may over or under estimate need for surgery
- Evidence to support benefit in terms of QOL is weak
- Surgery has best evidence in patients with a prognosis >6 months, otherwise post-op complications may limit benefit (though patients with short prognosis may still benefit)
Mirel’s scoring system for risk of pathologic fractures
- Higher score = higher risk
- Criticised due to potential for under or overestimating risk/need for surgery
Scores given (from 1-3) for:
- Osteolytic lesions (versus osteoblastic)
- Involvement of peritrochanteric area of the femur rather than for non-weight bearing bones
- Involvement of more than one third the circumference of a bone
- Association with functional pain
A score of 9 or more indicates that surgery is warranted
Incidence of spinal cord compression
- Highest in multiple myeloma (7.9%), varies widely by cancer site
- Epidural cord compression in 25% of lung cancer patients, 16% in prostate Ca, 11% in myeloma (Oxford)
Symptoms of cord compression
Upper Motor neuron symptoms (epidural spinal cord compression)
- Pain excerbated by recumbency, cough, sneeze, strain
- Crescendo pain
- Pain aggravated by laying down
- Lhermitte’s sign
- Spasticity
- Hyperreflexia below lesion
- Weakness (symmetric - typically develops to paralysis within 7 days!)
- Numbness/parasthesias (symmetric, ascending, upper level of sensory loss may correspond to location of tumour)
- Sphincter dysfunction (later)
- Spinal tenderness to percussion
Lower Motor neuron symptoms (Cauda equina)
- Hypotonia
- Areflexia or hyporeflexia
- Weakness (symmetric)
- Numbness/parasthesias (especially saddle anesthesia)
- Sphincter dysfunction (later)
- Fasciculations
Predictive risk factors for cord compression
- Inability to walk
- Increased DTRs
- Compression fractures on spine radiographs
- Presence of bony mets
- Bony mets diagnosed more than a year earlier
- Age less than 60 years
Diagnosis of cord compression
- MRI without contrast
Management of cord compression
- Weak evidence for steroids and optimal dosing. Typically steroids are prescribed for suspected or confirmed cord compression
- Best functional outcomes in patients with slowest development of motor deficits before treatment
- Patients who remain ambulatory prior to intervention most likely to maintain functional status
No clear consensus on indications for surgery vs radiation vs both
- Surgery followed by radiotherapy seem to recover ambulatory ability faster and maintain a longer period of ambulatory status, but surgery is significant mortality rates (30-day is up to 13% mortality, post-op complication rate of 54%)
Radiotherapy
- Some types of cancer may be less radiation sensitive
- Lymphoma, MM, Postate, and breast CA are likely to be rads sensitive
Surgery
- Indicated in cases of mechanical instability
E.g.:
- Subluxation/translation
- Presence of a de novo radiographic bone deformity
- Greater than 50% vertebral body collapse
- Bilateral facet destruction
- Movement related pain (as opposed to tumour related or biologic)
- Involvement of junctional segment (e.g. thoracolumbar, occipitocervical, cervicothoracic)
Signs of mechanical instability in cord compression
Surgery indicated for vertebral bone mets
- Indicated in cases of mechanical instability
E.g.:
- Subluxation/translation
- Presence of a de novo radiographic bone deformity
- Greater than 50% vertebral body collapse
- Bilateral facet destruction
- Movement related pain (as opposed to tumour related or biologic)
- Involvement of junctional segment (e.g. thoracolumbar, occipitocervical, cervicothoracic)
Reasons for difficulty controlling breakthrough bony pain
- Mismatch between temporal onset of pain to temporal onset of analgesia from opioids
- Mismatch between resolution of pain (typically resolves in less than 30 minutes if movement related) and duration of opioid analgesia (typically 4 hours for IR)
- Poor opioid responsiveness of some aspects of bone related pain
Prevention of osteonecrosis of the jaw as a bisphosphonate side effcet
- Prophylactic dental assessment
- Ongoing dental management
- Good oral hygiene
- Antibiotic therapy if indicated for local infections
Specific risk factors:
- Tooth extraction
- Local trauma
- Local infection
- Systemic chemotherapy
- Months of treatment with bisphosphonates
Chemotherapy for bony pain
- May be useful for metastatic bone pain when a tumour is very chemosensitive (e.g. small cell and non small cell lung ca, breast cancer) where bone is a common site of metastases
Hormone therapy for bony pain
- Useful for hormone sensitive tumours (breast and prostate CA)
- Can result in a dramatic effect, especially within a few days of start anti-androgen therapy for prostate CA
- Response in metastatic breast ca is slower, can take a few weeks
Interventional analgesia for vertebral collapse
- Collapse of a vertebrae itself can cause pain, but can also result in nerve root compression
Percutaneous vertebroplasty can reduce pain and treat vertebral body collapse
Complications:
- Cement leak (can encroach on the epidural space and risk root or cord compression)
- Chemothermal damage to the cord
- Cement embolism (if there is a venous leak)
Epidural or spinal analgesia for bone pain
- Can be used where patients continue to experience uncontrolled bone pain despite adequate pharmacologic and non-pharmacological management
- Infusion of opioid, sometimes in combination with clonidine. Local anesthetic may be useful for incident pain
- May be considered in patients who are too unwell or close to death to consider internal fixation of a pathologic fracture
Pregabalin for bone pain
- Acts on calcium channels
- May be useful as an adjuvant, particularly given the neuropathic component of bone pain
Management of Cord Compression: Steroids
- Weak evidence for steroids and optimal dosing. Typically steroids are prescribed for suspected or confirmed cord compression
- Best functional outcomes in patients with slowest development of motor deficits before treatment
- Patients who remain ambulatory prior to intervention most likely to maintain functional status
Management of Cord Compression: Surgery vs Rads
No clear consensus on indications for surgery vs radiation vs both
- Surgery followed by radiotherapy seem to recover ambulatory ability faster and maintain a longer period of ambulatory status, but surgery is significant mortality rates (30-day is up to 13% mortality, post-op complication rate of 54%)
Radiotherapy
- Some types of cancer may be less radiation sensitive
- Lymphoma, MM, Postate, and breast CA are likely to be rads sensitive
Surgery
- Indicated in cases of mechanical instability
E.g.:
- Subluxation/translation
- Presence of a de novo radiographic bone deformity
- Greater than 50% vertebral body collapse
- Bilateral facet destruction
- Movement related pain (as opposed to tumour related or biologic)
- Involvement of junctional segment (e.g. thoracolumbar, occipitocervical, cervicothoracic)
Symptoms of epidural cord compression
Upper Motor neuron symptoms (epidural spinal cord compression)
- Pain exacerbated by recumbency, cough, sneeze, strain
- Crescendo pain
- Pain aggravated by laying down
- Lhermitte’s sign
- Spasticity
- Hyperreflexia below lesion
- Weakness (symmetric - typically develops to paralysis within 7 days!)
- Numbness/parasthesias (symmetric, ascending, upper level of sensory loss may correspond to location of tumour)
- Sphincter dysfunction (later)
- Spinal tenderness to percussion
Lower Motor neuron symptoms (Cauda equina)
- Hypotonia
- Areflexia or hyporeflexia
- Weakness (symmetric)
- Numbness/parasthesias (especially saddle anesthesia)
- Sphincter dysfunction (later)
- Fasciculations
Symptoms of Cauda equina
Lower Motor neuron symptoms (Cauda equina)
- Hypotonia
- Areflexia or hyporeflexia
- Weakness (symmetric)
- Numbness/parasthesias (especially saddle anesthesia)
- Sphincter dysfunction (later)
- Fasciculations
Localization of spinal cord compression: Cord
Cord
- Flaccid paraparesis (symmetric)
- Pyramidal signs (Spasticity, weakness, hyperreflexia, Babinski)
- Absent reflexes or hyperreflexia (hyperreflexia below lesion)
- Symmetric level of dermatomal sensory loss
- Sphincter control initially preserved, then lost later
Localization of spinal cord compression: Conus and epiconus medullaris
Conus and epiconus medullaris (distal, bulbous part of cord
- L5-S3 weakness and Babinski if epiconus involved
- S2-S3 weakness, saddle anesthesia if conus involved
- Hyperreflexia at patella, hyporeflexia at Ankle
- Loss of sphincter control early (may be only bowel or bladder)
Localization of spinal cord compression: Cauda
Cauda equina
- No pyramidal signs (spasticity, hyperreflexia, etc.)
- Asymmetric weakness, asymmetric sensory loss in perineum and lower extremities
- Sphincter control may be preserved
- Hypoactive patellar reflexus, asymmetric ankle reflexes
