Frequency
Not all pains described by the patients as “bone pain” are actually due to disorders of, or originate in the bones. Often the pain is due to faulty weight-bearing and transfer of muscle tension to bones and joints. Bone pain must always be taken seriously, it may herald a malignancy.
Genuine bone pain can be classified according to extent:
▶ Generalised bone pain: Usually due to a metabolic disorder or extensive metas- tases. This type of pain is often dull, aching and difficult to localise accurately.
▶ Localised bone pain: frequently, but not always, shows a typical X-ray picture.
Bone pain is the most frequent symptom in patients with osseous metastases. More than 50% of these patients experience bone pain before or at the time of diagnosis of skeletal metastases. The pain is constantly present and may increase in intensity.
Multiple myeloma and osteomyelosclerosis are also often accompanied by severe bone pain.
Differential Diagnosis
This includes numerous conditions which must be excluded before therapy is in- stituted. The main causes are listed below.
Oncologic and hematologic conditions:
▶ Skeletal metastases
▶ Multiple myeloma
▶ Leukemias
▶ Osteomyelosclerosis
▶ Malignant lymphomas
▶ Storage disorders
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▶ Systemic mastocytosis
▶ Granulomatous disorders
▶ Eosinophilic granuloma
▶ Osteomyelitis
Osteologic and orthopedic conditions:
▶ Fractures
▶ Arthroses
▶ Tendonopathies
▶ Osteoporoses with fractures
▶ Transient osteoporosis (bone marrow edema syndrome)
▶ Muscle cramps
▶ Osteomalacia
▶ Paget’s disease of bone
▶ Complex regional pain syndrome (Sudeck’s disease)
▶ Heterotopic calcification
▶ Aseptic loosening of prosthesis
Pathogenesis
Bone pain has a complex etiology, incompletely understood. Mechanical factors include:
▶ Increased pressure in the bone marrow
▶ Bending or distortion of bone
▶ Stretching of the periosteum and/or endosteum
▶ Destruction of bone
Inflammatory, humoral and neural factors also play a role. Prostaglandins, hista- mine, serotonin, bradykinin and other cytokines can all act as triggers or as modula- tors. Bone pain is mediated primarily by stimulation of nociceptors (pain receptors) in the periosteal and endosteal sheaths of the bones. It can also be caused by irrita- tion and lesions of the afferent nerve fibers within the bone marrow. These fibers regulate blood flow through bone, bone marrow and sinusoids. Sensory nerve fi- bers are also present, as demonstrated for example by the pain induced when bone marrow is aspirated. Results of recent studies have implicated the RANKL/OPG system as a major factor in triggering bone pain. Moreover, tumor cells themselves secrete cytokines which stimulate T lymphocytes and osteoclasts which leads to further release of inflammatory mediators as bone is resorbed. Generalised bone pain is also caused by the increased pressure resulting from bone marrow infiltra- tion (metastatic, leukemic) or by edema of the bone marrow. Paraneoplastic bone pain is mediated indirectly by the tumor by way of the hormone-like substances it secretes.
Diagnosis
Any description of pain should include the following aspects: onset, duration, in- tensity, type, localisation, radiation, temporal pattern. For example:
▶ Type: dull, stabbing, aching or variable?
▶ Intensity: remains constant or varies?
▶ Localisation: focal, delimited or generalised?
▶ Radiation: point of origin – where to?
▶ Time pattern: onset sudden or slow, transient or recurrent “comes and goes”.
Bone pain is often dull or sharp and stabbing. Focal, penetrating pains are due to periosteal involvement. In practice, bone pain is often diffuse, referred and diffi- cult to localise precisely. Bone pain in patients with tumors includes several clinical types, which may require different treatments:
▶ Dull, deep, constant ache
▶ Movement-associated pain (inflammatory?)
▶ Radiating neurogenic pain
The treatment of bone pain in patients with malignancies should be an integral part of the overall management.
Bone pain in cancer patients may have various causes:
▶ Due to the tumor itself (85%)
▶ Due to therapy (17%)
▶ Associated with the tumor (9%)
▶ Independent of the above (9%)
About 70–80% of the patients may suffer from more than one type of bone pain.
Pain can be evaluated clinically using one or more of the pain scores available:
▶ Verbal rating scale (VRS)
▶ Visual analogue scale (VAS)
▶ Numeric rating scale (NRS)
Though there is a close correlation between these scales, changes are better docu- mented by VAS. Careful observation of the patient also provides a good oppor- tunity to evaluate the situation. The presence or absence of sleep disturbance is another important factor. Complete biochemical and hematological investigations should be performed to detect metabolic, inflammatory and malignant conditions and/or complications. Imaging techniques should be used to demonstrate osseous and other lesions; and directed bone biopsies should be taken in equivocal cases.
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Treatment Strategies
The first aim is elimination of the cause of the bone pain by specific therapy of the condition diagnosed if possible, for example:
▶ Vitamin D for osteomalacia
▶ Antibiotics for osteomyelitis
▶ Radiotherapy for focal neoplastic lesions Treatment of tumor-induced bone pain also includes:
▶ Physical therapy (exercises, physiotherapy)
▶ Central and peripheral analgesics
▶ Additional medications (antidepressants, tranquilisers, muscle relaxants)
▶ Invasive therapy (peridural or intrathecal opioids)
▶ Antineoplastic therapy (chemo and radio therapy)
▶ Antiresorptive therapy (bisphosphonates, calcitonin)
Administration of analgesics according to the “analgesic ladder” of the WHO:
Step 1 Non-opioids with adjuvants
Step 2 “Weak” opioids in combination with acetaminophen and adjuvants Step 3 “Strong” opioids with adjuvants
More than 95% of patients can be treated satisfactorily with this stepwise approach to cancer pain management. Less than 5% require invasive pain therapy and be- fore this is carried out, bisphosphonates or calcitonin should be given. Calcitonin inhibits local prostaglandin production as well as stimulating release of endog- enous opiates in the brain, although this has not yet been confirmed by placebo- controlled studies.
Bisphosphonates
The alleviation of pain by bisphosphonates has been demonstrated in several pla- cebo-controlled clinical trials (Fig. 23.1). The effect is often felt within a day and may last for weeks or months, depending on the dose administered. However, not all physicians, even experts in the field, are aware of the alleviation of bone pain by bisphosphonates. Markers of bone resorption correlate closely with the analgesic effect.
Success of bisphosphonate therapy is indicated by:
▶ Reduction of pain intensity
▶ Reduction in use of analgesics
▶ Reduction in need for radiotherapy
▶ Reduction in surgical interventions
The following protocols are recommended for tumor-induced bone pain:
▶ Clodronate (Ostac®) 600 mg infusion every 3–4 weeks
▶ Clodronate (Ostac®) 1600 mg orally daily
▶ Pamidronate (Aredia®) 60–120 mg infusion every 3–4 weeks
▶ Zoledronate (Zometa®) 4 mg i.v. infusion every 3–4 weeks
▶ Ibandronate (Bondronat®) 2–6 mg infusion every 3 to 4 weeks
▶ Ibandronate (Bondronat®) 50 mg orally daily
Until recently, bisphosphonates were given when bone pain was presumably caused by osteolytic lesions. Pain induced by osteoblastic metastases, or osteomy- elosclerosis or systemic mastocytosis also responds rapidly and for long periods to bisphosphonate therapy. In practice, all large studies of metastatic carcinoma and multiple myeloma have confirmed the analgesic effects of bisphosphonates on pain due to osteolytic as well as osteoblastic and mixed metastases.
This indicates that relief of bone pain by bisphosphonates is not due exclusively to inhibition of osteoclasts, but that the bisphosphonates also act on other cells such as T lymphocytes and stromal cells and thereby exert an effect on the RANKL/OPG system.
Fig. 23.1 Decrease of pain under therapy with ibandronate in patients with breast cancer
