Metastatic bone cancer pain integrates both neuropathic and inflammatory mechanisms. A series
of events including bone mechanical compression, vessel ischemia and the release of inflammatory
factors caused exposed nerve endings to become irrevocably damaged. As the cancer progresses,
the severity of the pain increases making it one of the most painful conditions an
individual can experience. The complexity of metastatic bone cancer pain is due in
part to the unique properties of the affected tissue. Bone is a hardened mineralized matrix
that supports a rich vascular supply and dense neuronal network beneath its surface. Within its
walls bone houses many cells including those that regulate its formation and degradation.
Neoplastic cells most often successfully invade bone at the metaphyseal plate
where circulatory turbulence is minimal. Upon settling these cancer cells release
factors that target local cells chiefly osteoblasts encouraging them to activate.
Hyperactivated osteoblasts have increased surface expression of the rank ligand.
These surface proteins induce cellular changes in
nearby monocytes which begin to fuse and mature into osteoclasts.
When the metastasis originates in breast tissue there is a great increase in osteoclast
oogenesis. In this case despite increased osteoblast hypertrophy and activation,
osteoclast hyperplasia results in net resorption. The thinning of bone results in two key mechanical
events that set the stage for neuropathic pain. First the release of factors from the
matrix and second the exposure of neural vascular beds from the endosteal surface.
In the first event, factors embedded within the mineral matrix of bone
are released during osteolysis. Some of these factors nurture and stimulate the tumor which
subsequently activates more osteoblasts which then induce further osteoclast
proliferation. This vicious cycle ensures the expansion of the growing tumor which
compresses and compromises the weakened bone architecture leading to fractures and pain.
At the same time severe bone destruction leads to the persistent exposure neurovascular beds.
Without the structural protection of bone, blood flow is restricted or interrupted
by the expanding tumor. Sympathetic nerve fibers surrounding these vessels are damaged.
Alongside these mechanical events the inflammatory aspect of cancer pain is
unfolding. Hyperactivated osteoclasts release large amounts of acid as they
frantically resorbed bone. Protons further stimulate osteoclast activity thus ph is
progressively driven lower and sensitizing factors are increasingly released from the bone.
In the low PH, acid sensing ion channels on nociceptor nerve
endings cause membrane depolarization. In this perpetually acidic micro environment,
nerves begin to fire at higher amplitudes and greater frequencies.
In the micro environment created by the tumor, nerves are continually
exposed to cytokines interleukins, prostaglandins and many other factors.
Under such adverse conditions, nociceptors become increasingly sensitive firing to the
smallest mechanical and chemical stimulation and even spontaneously. These damaged nerve
endings then release their own factors which further aggravate surrounding nerve endings.
In metastatic bone cancer pain results from mixed pathological mechanisms.
From mechanical and chemical stresses local nerves become irreversibly damaged
leaving them in a neuropathic state. As the peripheral tissues continue to deteriorate,
increased firing paves the way for adverse changes to dorsal root ganglia and eventually
spinal structures that also become afflicted resulting in an enhanced level of continuous pain.