Bone pain

Question 1

Structure of bone

Answer 1

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

Question 2

Mechanisms of cancer-induced bone pain

Answer 2

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

Question 3

Clinical features of pain from bony mets

Answer 3

• 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

Question 4

Skeletal complications of bone mets

Answer 4

• Pathological fractures
• Pain (most common presenting symptom)
• Hypercalcemia
• Cord compression

30-50% of patients may be asymptomatic!

Question 5

Normal bone turnover

Answer 5

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)

Question 6

Investigations for painful bony mets

Answer 6

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

Question 7

Types of bony mets

Answer 7

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

Question 8

UTD approach to detecting bone mets

Answer 8

1. 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
2. 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
3. Initiate analgesia while testing/planning is underway
4. 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
5. If the patient has myeloma
   - Primary lytic lesions - get a whole body plain radiograph skeletal survey
   - Primary sclerotic lesions - get a bone scan

Question 9

Initial pharmacologic approach to managing malignant bone pain

Answer 9

• 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)

Question 10

Non-opioid pharmacological agents may be specifically used for bone pain

Answer 10

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

Question 11

Non-pharm approaches to management of pain from bony mets

Answer 11

• Non-weight bearing techniques
• Heat and ice
• Gentle message
• OT/PT for support/assistive devices to reduce pain

Question 12

Indications to refer to Rads for bone pain

Answer 12

• 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

Question 13

Radiopharmaceuticals and application to bony mets

Answer 13

• 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

Question 14

Orthopedic intervention in bony mets

Answer 14

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)

Question 15

Mirel’s scoring system for risk of pathologic fractures

Answer 15

• 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

Question 16

Incidence of spinal cord compression

Answer 16

• 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)

Question 17

Symptoms of cord compression

Answer 17

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

Question 18

Predictive risk factors for cord compression

Answer 18

• 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

Question 19

Diagnosis of cord compression

Answer 19

• MRI without contrast

Question 20

Management of cord compression

Answer 20

• 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)

Question 21

Signs of mechanical instability in cord compression

Answer 21

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)

Question 22

Reasons for difficulty controlling breakthrough bony pain

Answer 22

1. Mismatch between temporal onset of pain to temporal onset of analgesia from opioids
2. 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)
3. Poor opioid responsiveness of some aspects of bone related pain

Question 23

Prevention of osteonecrosis of the jaw as a bisphosphonate side effcet

Answer 23

• 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

Question 24

Chemotherapy for bony pain

Answer 24

• 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

Question 25

Hormone therapy for bony pain

Answer 25

- 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

Question 26

Interventional analgesia for vertebral collapse

Answer 26

- 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)

Question 27

Epidural or spinal analgesia for bone pain

Answer 27

- 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

Question 28

Pregabalin for bone pain

Answer 28

- Acts on calcium channels | - May be useful as an adjuvant, particularly given the neuropathic component of bone pain

Question 29

Management of Cord Compression: Steroids

Answer 29

- 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

Question 30

Management of Cord Compression: Surgery vs Rads

Answer 30

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)

Question 31

Symptoms of epidural cord compression

Answer 31

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

Question 32

Symptoms of Cauda equina

Answer 32

Lower Motor neuron symptoms (Cauda equina) - Hypotonia - Areflexia or hyporeflexia - Weakness (symmetric) - Numbness/parasthesias (especially saddle anesthesia) - Sphincter dysfunction (later) - Fasciculations

Question 33

Localization of spinal cord compression: Cord

Answer 33

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

Question 34

Localization of spinal cord compression: Conus and epiconus medullaris

Answer 34

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)

Question 35

Localization of spinal cord compression: Cauda

Answer 35

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