In this presentation, diagnostic work up and treatment of painful bone metastases have been explained in detail.

1. Painful bone metastases
in adults
Ramin Sadeghi, MD

2. Introduction
 Bone is the third most common organ affected by metastases, after the lung
and liver.
 Can also be extensive in patients with multiple myeloma, and lymphoma.

3. Skeletal related events
 Skeletal-related events (SREs) that are due to bone metastases can include
 Pain
 Pathologic fracture
 Hypercalcemia
 Spinal cord compression.
 Across a wide variety of tumors involving bone, the frequency of SREs can be
reduced through the use of osteoclast inhibitors, such as bisphosphonates
or denosumab.

4. Epidemiology
 ●At postmortem, 70 to 90 percent of patients with breast or prostate cancer have
some form of skeletal metastases.
 ●Bone metastases develop in 50, 44, and 37 percent of patients with thyroid, lung,
and renal cancer, respectively .
 ●Among solid cancers, breast, prostate, lung, thyroid, and kidney cancer account
for 80 percent of all skeletal metastases. However, many other primary malignant
tumors can spread to bone, including, but not limited to, melanoma, lymphoma,
sarcoma, and hepatocellular, as well as uterine carcinomas.
 Skeletal lytic lesions are present at the time of diagnosis in approximately 60
percent of patients with multiple myeloma.
 Myeloma lesions are rarely sclerotic; when they are, they are often associated with the
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal spike, skin
changes)

5. Clinical presentation
 Mostly asymptomatic
 There is usually no reason to scan for bone metastases in the absence of symptoms
unless routine laboratory studies indicate an elevated alkaline phosphatase or an
elevated calcium level.
 Symptomatic patients
 Usually presents with pain

6. Pain
 The character of the pain
 somatic (ie, achy, sharp, well-localized)
 neuropathic (ie, burning, shooting, radiating).
 Worse at nights
 It may be constant or exacerbated by movement of the joint or involved bone
(so-called "incident" pain).
 Sudden severe pain may be caused by a pathologic fracture, and prompt
evaluation, especially in patients with a history of cancer, is necessary.

7. Neurologic symptoms
 Neurologic symptoms are not uncommon in patients with vertebral
metastases
 causing spinal cord compression or spinal instability.
 Symptoms of cord compression range from pain to neurologic deficits, including
motor weakness and paralysis, sensory deficits, bowel and bladder dysfunction,
and ataxia.
 Typically, the deficits result from soft tissue tumor compressing the spinal cord or
cauda equina, rather than the pathologic fracture itself.

8. Distribution
 Predominantly involves areas of red marrow, such as the skull, axial skeleton,
or the medullary portion of the appendicular skeleton.
 Less commonly, metastases can be cortically-based surface lesions, although
this almost always occurs in the appendicular, rather than the axial, skeleton.
 The most common locations
 the vertebral column, sacrum, pelvis, and proximal femurs
 Within the spine, the lumbar, followed by the thoracic and cervical.
 Metastatic disease is distinctly unusual in anatomic sites distal to the elbow in
the upper extremity and distal to the knee in the lower extremity (termed
acrometastasis).
 Lung and renal cell cancers are the most common primary sites

9. Detection and diagnosis
 The choice of imaging should be guided by
 The clinical presentation
 Underlying histologic type of tumor
 Osteoblastic versus osteolytic patterns vary

14. Extremity pains
 Plain radiographs of the affected area for initial evaluation.
 If a complete or impending pathologic fracture is suspected
 cross-sectional imaging with contrast-enhanced computed tomography (CT) or
magnetic resonance imaging (MRI) can delineate those patients who may require
urgent surgical stabilization.

15. Back pain
 Contrast-enhanced spinal MRI is indicated even in the absence of any
neurologic signs
 to evaluate bone metastasis,
 to rule out epidural extension of tumor and spinal cord compression.
 MRI also differentiates between metastasis and spondylodiscitis.

16. Biopsy
 For patients with no history of cancer, biopsy of skeletal abnormality is
necessary for diagnosis.
 For patients whose cancer is in remission, documentation of a pathologic
diagnosis may be necessary if this is the first evidence of recurrence or
disease progression.
 For patients with known history of stage IV malignancy or who were found to
have other visceral metastasis on staging or restaging evaluation, clinical
diagnosis with one or more imaging modalities may be sufficient to make a
presumptive diagnosis of bone metastasis.

17. Choice of skeletal survey
 For most patients with a known cancer capable of mixed lytic and blastic
metastasis or pure blastic metastases, skeletal scintigraphy (bone scan) is
indicated.
 For pure lytic tumors, such as multiple myeloma, a plain radiographic skeletal
survey is indicated to screen the skeleton.
 For patients with lytic primary tumors, including Ewing sarcoma family of
tumors (EFT), 18-labeled fluorodeoxyglucose PET integrated with CT
(integrated 18-FDG-PET/CT) is the recommended initial step.
 For patients with sclerotic multiple myeloma (the POEMS syndrome), as well
as EFT with a sclerotic primary tumor and for all other patients with
suspected bone metastases, bone scan is recommended.

21. Plain radiograph
 Generally not used for metastasis screening
 However, the radiographic bone survey remains the standard for the initial staging
of multiple myeloma.
 Plain radiographs are more sensitive than bone scan for purely lytic metastases
(eg, multiple myeloma, some renal cell metastases)

25. Plain radiographs
 The extent of cortical compromise seen on plain radiographs is an important
indicator of the risk of a pathologic fracture in tubular bones

27. Cross sectional imaging
 Evaluation of suspected complete or impending pathologic fractures
 Suspected epidural spinal cord compression
 metastatic bone disease involving the shoulder, spine, or pelvis because of the
complex anatomy
 if other imaging studies are equivocal and there is a strong clinical suspicion
of bone metastases

28. CT scanning
 CT demonstrates superior bony detail and can detect osteolytic and
osteoblastic metastases within the bone marrow before there is sufficient
destruction to become evident on plain radiographs
 However, CT is not more sensitive than bone scan.
 CT scans are also highly accurate for determining the integrity of the bone
cortex, and this can aid in the diagnosis of a complete pathologic fracture and
in the assessment of fracture risk

30. MRI
 Soft tissue resolution of CT is inferior to MRI.
 If spinal cord compression or nerve impingement is suspected, contrast MRI should
be used for evaluation.
 MRI is more sensitive than CT to detect small metastases
 on a per-lesion basis, the sensitivity and specificity rates for MRI were 90 and 96
for CT were 77 and 83 percent for bone scan, were 75 and 94 percent
 Normal bone marrow has high signal intensity on T1-weighted images.
 Metastatic lesions Have decreased signal on T1-weighted sequences
 On T2-weighted images have a higher signal and they enhance with gadolinium.
 MRI with and without contrast is the gold-standard study when spinal cord
compression and/or epiduraldisease/nerve root impingement is suspected

31. MRI
 Particularly useful for demonstrating bone marrow lesions at a potential
fracture site to distinguish a pathologic versus insufficiency fracture.
 The most sensitive discriminating feature is that of a well-defined, low-signal
T1-weighted abnormality around the fracture, indicating an underlying tumor

32. Metastatic collapse

33. Compression fracture

34. Bone Scan
 The most widely used method to detect bone metastases because it provides
visualization of the entire skeleton within a reasonable timeframe and at a
reasonable cost
 Among patients with a variety of malignancies, including breast, lung, and
prostate cancer, bone scan is reasonably sensitive (79 to 86 percent) and
specific (81 to 88 percent) for the diagnosis of bone metastases
 However, it is less sensitive for detecting tumors with little to no osteoblastic
activity (such as multiple myeloma)
 SPECT can increase the accuracy

36. 18-F-FDG PET
 FDG-PET/CT is clearly superior than bone scan for detection of bone
metastases albeit much more expensive
 A major benefit of FDG-PET over bone scan is its ability to screen for distant
metastases at sites other than bone
 PET is preferred over Bone scan
 rapidly progressive metastases that are associated with minimal reactive bone
formation
 for the staging of lymphomas that are routinely avid for radiolabeled glucose (eg,
diffuse large B cell lymphoma, Hodgkin lymphoma
 for staging the bone in Ewing sarcoma with a lytic primary tumor.

37. F18-PET
 Using (18)-fluorine-labeled sodium fluoride (18F-NaF PET/CT) may offer
increased sensitivity and specificity in evaluating metastatic bone disease
compared with 99mTc-based bone scan in a wide variety of clinical settings
 Much more expensive and not yet recommended for routine use

39. Low-dose, whole-body computed
tomography
 one setting in which whole-body, low-dose CT may have utility is in patients
with multiple myeloma as an alternative to skeletal survey

40. Whole-body magnetic resonance
imaging
 Whole-body MRI has the potential to detect more destructive bone lesions in
the axial skeleton (particularly the spine) than bone scan or, among patients
with multiple myeloma, whole-body radiographs.
 However, on a per-patient basis, whole-body MRI is less sensitive and less
specific than integrated PET/CT and less sensitive than bone scan
 In patients with suspected or newly diagnosed myeloma, MRI has become the
gold-standard imaging method for early detection of bone marrow
involvement
 Where whole-body MRI is not available, MRI of the spine and pelvis can be used

41. Differential diagnosis
 The differential diagnosis of a lytic bone abnormality includes primary
malignant bone tumors, bone metastases from distant primary sites, as well
as several benign bone lesions.
 The differential diagnosis of a sclerotic or blastic bone lesion is narrower. A
bone island, calcifying enchondroma, osteoid osteoma, bone infarct, fibrous
dysplasia, and Paget disease of bone.

53. Diagnostic biopsy
 If a primary tumor is known, a skeletal lesion with a typical appearance on
imaging studies (either lytic or osteoblastic) may be presumed to be
metastatic
 especially if there are multiple lesions
 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

54. Diagnostic biopsy
 For patients with an unknown primary cancer who present with a bone
metastasis, and initial staging evaluation fails to delineate the primary
malignancy, a biopsy is generally indicated
 Core needle biopsy is recommended
 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), the surgical repair could jeopardize not only the
opportunity for limb salvage, but also the possibility of cure.

55. Therapeutic options
 The goals of management for bone metastases include maximizing pain
control, preserving and restoring function, stabilizing the skeleton, and
enhancing local tumor control.
 Observation may be recommended for an asymptomatic bone metastasis with no
significant risk of pathological fracture or spinal instability, especially if life
expectancy is limited

56. Analgesia
 The World Health Organization (WHO) analgesic ladder is a widely accepted
approach for managing cancer pain

58. Systemic therapy
 Include
 osteoclast inhibitors,
 chemotherapy, and/or
 hormone therapy

59. Osteoclast inhibitors
 Including bisphosphonates and denosumab
 These agents have been shown to reduce the risk of skeletal-related events (SREs,
including pathologic fracture, spinal cord compression, the need for radiotherapy
[RT] or surgery to bone, or malignant hypercalcemia) in patients with a variety of
advanced malignancies, including multiple myeloma, breast, prostate, and lung
cancer.
 There are substantial data supporting the analgesic efficacy of all of the
parenteral bisphosphonates, includingpamidronate, zoledronic
acid, ibandronate, and clodronate as well as oral ibandronate and clodronate.
 Fewer data are available on the analgesic benefit of denosumab, and its
analgesic superiority over bisphosphonates has not been established.

60. Systemic anti-tumor therapy
 Chemotherapy and hormone therapy may contribute to pain relief by reducing
tumor bulk and/or by modulating pain signaling pathways

61. Radiation therapy
 External beam radiation therapy — EBRT is a standard approach for
symptomatic skeletal metastases, achieving pain reduction in 50 to 80
percent, which is complete in up to one-third of patients.
 Extensive, painful bone metastases may be treated with single-fraction
hemibody irradiation to the upper, lower, or mid-body. Although hemibody
irradiation can provide rapid pain relief when multiple sites of symptomatic
bone metastases are present,
 its use has largely been replaced by the administration of bone-seeking
radiopharmaceuticals, which offer a similar degree of pain relief and may be
associated with less toxicity.

62. Bone seeking radiopharmaceuticals
 Samarium-153 lexidronam (153Sm) and strontium-89 (89Sr) emit beta
particles and have been shown to be effective for palliation of pain, with
response rates between 40 and 95 percent.
 However, the onset of pain relief is slower than with EBRT, taking up to two to four
weeks
 patients can have prolonged hematologic toxicity (more prominent with 89Sr than
153Sm)
 they do not improve survival.
 approved for the relief of pain in patients with confirmed osteoblastic bone
lesions that enhance on radionuclide bone scan,
 Both agents are generally reserved for individuals with persistent or
recurrent multifocal bone pain after EBRT and/or other forms of therapy.

63. Bone seeking radiopharmaceuticals
 Contra-indications
 pregnancy and breast feeding, any evidence of Disseminated Intravascular
Coagulation (DIC), super scan pattern in the latest bone scintigraphy, any
emergency problems such as acute compression on the spinal cord and pathologic
fractures, neurologic origin as the source of bone pain, hemi body radiotherapy
during the last three months and long acting chemotherapy during the last four
weeks.

64. Bone seeking radiopharmaceuticals
 Radium 223
 223Ra dichloride is an alpha particle emitting radiopharmaceutical that is indicated
for the treatment of patients with castration resistant prostate cancer,
symptomatic bone metastases, and no known visceral metastases.

65. Ra 223
Phase III ALSYMPCA trial
(ALpharadin in SYMPtomatic Prostate CAncer)
 ●Overall survival, the primary endpoint of the trial, was significantly
prolonged including both those who had and had not received priordocetaxel.
 ●The time to first symptomatic skeletal event was significantly increased
(median 15.6 versus 9.8 months, HR 0.66, 95% CI 0.52-0.83).
 ●Was associated with a favorable safety profile, with a lower frequency of all
adverse events compared with placebo;
 ●In a prespecified subset analysis, radium-223 had similar efficacy in those
who had received prior docetaxel and those who were docetaxel naïve.
 ● Treatment was well tolerated irrespective of prior docetaxel use
 ●Treatment with radium-223 was accompanied by a better quality of life

66. Surgery
 typically reserved for lesions with a completed or impending pathologic
fracture.
 In a systematic review of 45 studies addressing the role of surgical
management of bone metastases involving the humerus, femur,
and pelvis/acetabulum (47 percent of cases with a pathologic fracture),
 surgery was associated with significant pain relief in 91 to 93 percent of cases, and
function was maintained or improved in 89 to 94 percent
 Prophylactic fixation of an impending pathologic fracture may be considered if an
osteolytic lesion involves more than 50 percent of the cortex circumferentially or if
the metastasis involves the proximal femur with an associated fracture of the
lesser trochanter