Bone Disease

Myeloma bone disease can cause the bones to become thinner and weaker (osteoporosis), and it can make holes appear in the bone (lytic lesions). The weakened bone is more likely to break under minor pressure or injury (pathologic fracture). The bones most commonly affected are the spine, pelvis, ribs, skull, and the long bones of the arms and legs.

Myeloma bone disease can result not only in fractures, but in pressure on the spinal cord (spinal cord compression), the need for surgery to prevent or repair broken bones, and/or the need for radiation treatments to the bone to control the myeloma and relieve pain. These are collectively known as "skeletal-related events."

More than 80% of multiple myeloma patients develop bone problems during the course of their disease; 70% of these patients have bone loss in the spine.

The official International Myeloma Working Group (IMWG) definition of the minimal amount of bone damage that requires therapy is:

• more than one focal lesion of at least 5 mm in size on MRI, or
• one or more lytic bone lesions detected on CT scan, including whole-body low-dose CT or PET/CT.

What Are Focal Lesions?

Focal lesions are early, abnormal areas in the bone marrow that signal the development of a lytic lesion within the next 18-24 months. An otherwise asymptomatic patient whose MRI scan shows more than 1 focal lesion of at least 5 mm in size has what is called a "myeloma-defining event," and should be treated for active disease.

What Are Lytic Lesions?

Lytic lesions are areas where bone has been destroyed, leaving a hole in the bone. These lesions in the spine are common, and when severe, can lead to one or more vertebral compression fractures, which can be painful and even disabling. Lytic lesions in the long bones of the leg or in the hip may require surgery to reinforce and stabilize the bone.

What Causes Lytic Lesions?

In the healthy skeleton, there is a dynamic balance between the breakdown of old bone tissue (performed by cells called osteoclasts) and the building of new bone tissue (performed by cells called osteoblasts). These two actions — breakdown and build-up of bones — are coupled in a delicate interplay to ensure the health of the skeleton.

Multiple myeloma upsets the osteoclast-osteoblast balance by uncoupling their functions. Myeloma cells produce osteoclast-activating factors, signaling osteoclasts to break down bone uncontrollably. At the same time, they prevent bone repair by inhibiting the formation of osteoblasts.

The result is too much bone breakdown and too little bone build-up: the bones are weakened, leading to lytic lesions, which in turn can lead to pathologic fractures. As bone is broken down, calcium is released from the bones into the bloodstream. If this release happens too quickly, a condition called hypercalcemia can occur. Hypercalcemia increases bone destruction and frequently impairs kidney function.

Evaluating Bone Disease

Various types of imaging studies are used to diagnose and monitor bone disease in multiple myeloma:

• X-ray: Despite its many limitations, conventional skeletal survey with x-ray remains the standard of care to diagnose bone disease in patients with suspected myeloma.
• CT (computed tomography): Current NCCN (National Comprehensive Cancer Network) guidelines list skeletal survey or whole-body low-dose CT scan as the preferred studies for diagnosing myeloma bone disease, giving doctors the choice to do the more sensitive (and more expensive) CT study if insurance reimbursement is available.
• MRI (magnetic resonance imaging) is a sensitive study for detecting early focal lesions in the bone marrow.
• PET (positron emission tomography) is used in diagnosis, prognosis, and assessment of response to treatment, often coupled with CT of the areas that are picked up by PET. PET is used to assess disease both in bone and in soft tissue (extramedullary disease).
• Learn more with this IMWG publication: Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group

Treatment

The best approach to treating bone disease requires

1) effective treatment of the myeloma 

2) use of a supportive "bone-modifying" treatment to prevent further bone loss.

Currently, three such bone-modifying agents (BMAs) are available for multiple myeloma. They are not chemotherapy, and they do not treat MM. They prevent further bone damage and correct and/or prevent hypercalcemia. These drugs also carry a risk of osteonecrosis of the jaw (ONJ), so patients should have a dental evaluation before starting treatment with a bone-modifying agent and should have dental exams at least once a year thereafter. Both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) include all three drugs as treatment options for MM patients with bone disease.

• Aredia® (pamidronate) and Zometa® (zoledronic acid or zoledronate) belong to a class of drugs called bisphosphonates. Bisphosphonates are small inorganic molecules that bind to the surface of damaged bones. At the site of bone damage, bisphosphonates inhibit and destroy osteoclasts. They are administered intravenously. All patients taking bisphosphonates should have their kidney function closely monitored, particularly those with known kidney impairment.
• Xgeva® (denosumab) is a monoclonal antibody targeting a protein that controls bone regeneration and remodeling (RANK-Ligand, or RANK-L). It is given as a monthly subcutaneous injection (a shot under the skin). Xgeva does not cause kidney-related side effects and is a safer choice for patients with kidney impairment than the bisphosphonates.

Also reference the following:

Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update

IMWG recommendations for the treatment of multiple myeloma-related bone disease

Bone Health, Pain, and Mobility: Evidence-based recommendations for patients with multiple myeloma, IMF Nurse Leadership Board

What Is a Vertebral Compression Fracture?

Sudden severe back pain can signal a vertebral compression fracture--the collapse of a vertebral body because it is too weak to withstand the pressure or stress placed upon it. Stress on a vertebra can be as little as the force of gravity on the upright skeleton, or can be the result of a fall, twist, bump, cough, or sneeze.

When a vertebral compression fracture occurs, the body's center of gravity moves forward, putting more pressure on the vertebrae adjacent to the compression fracture. A domino effect can result, causing those vertebrae to collapse as well. The spine then shortens and curves forward. This forward curvature of the spine is called "kyphosis."

Learn more with the IMF publication: Understanding Treatment of Myeloma-Induced Vertebral Compression Fractures.

Treating Vertebral Compression Fractures (VCFs)

Analgesics

Analgesics are drugs that relieve pain. They include non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and ibuprofen, and controlled substances available only by prescription. Treatment with analgesics will neither prevent further VCFs nor repair the fractures.

Radiation therapy

Radiation therapy provides pain relief in patients with impending or actual vertebral compression fractures. Radiation may be used alone or as part of a treatment program. Pain relief usually begins several days after radiation therapy. Pain-relievers may be used with radiation therapy until radiation therapy has an effect. Radiation does not repair fractures and can damage the bone marrow, which will lower the blood counts and can severely impair stem cell collection for autologous stem cell transplant. Radiation is used in instances when pain is severe and uncontrolled or when there is concern about spinal cord compression.

Bracing

For some patients with VCFs, bracing the back may be all that's needed to provide relief from the pain of the compression fracture. The brace can provide stability while systemic therapy for the myeloma is initiated and the disease is controlled.

Vertebroplasty

Vertebroplasty and kyphoplasty are minimally-invasive surgical procedures to relieve the pain of a VCF and stabilize the back. These procedures may be performed by an orthopedic surgeon who specializes in spine surgery, by a neurosurgeon, or by an interventional radiologist. The most important considerations in selecting a doctor to perform the procedure are the doctor's expertise and experience with multiple myeloma bone disease.

Indications for vertebroplasty and kyphoplasty are:

• Persistent significant pain from a fractured vertebral body confirmed on MRI.
• Persistent significant symptoms affecting daily activities that have not resolved with more conservative measures after 4 weeks of treatment.

Patients who should not have vertebroplasty and kyphoplasty are:

• Those with spinal cord compression.
• Those who have back pain unrelated to a vertebral collapse.
• Those with an infection at the VCF site.
• Pregnant women.
• Those with severe heart and lung insufficiency.

In vertebroplasty, a bone cement is injected directly into the collapsed vertebra (or vertebrae) with a syringe. Patients may receive either general or local anesthesia and must remain in bed for a minimum of one hour after the procedure to allow the cement to harden. Cement leakage outside the vertebra has been reported in 19.7% of vertebroplasty patients, most of the time without noticeable effect. However, there have been reported cases of cement pressing on adjacent nerves, or chunks of cement traveling to the lungs-- a potentially lethal complication.

While vertebroplasty has never been studied in clinical trials for multiple myeloma patients, it has been performed widely in this setting for decades.

Balloon kyphoplasty

Balloon kyphoplasty is similar to vertebroplasty in several ways: it is a minimally invasive surgical procedure that uses bone cement to stabilize a spinal fracture and reduce the pain of a VCF. Unlike vertebroplasty, kyphoplasty involves the use of an orthopedic balloon that is inserted into the space between vertebrae and inflated to create an open space. Damaged pieces of bone are pushed to the periphery of the open space to create a dam for the cement. The balloon is deflated and carefully removed, and cement is inserted to fill the void. The controlled filling of the vertebral body reduces the risk of cement leakage.

Physical activity

To maximize your daily functioning and bone health, talk to your healthcare provider about a plan for daily physical activities, including activities that help with balance, strength, and fitness. Exercise should, of course, be tailored to your bone health and overall fitness.