Differentiating Multiple Myeloma from Osteoporosis/Osteopenia

Key Clinical Distinctions

The American College of Cardiology is not relevant here, however, the National Comprehensive Cancer Network recommends that multiple myeloma is distinguished from osteoporosis/osteopenia by the presence of clonal plasma cells (≥10% on bone marrow biopsy), monoclonal protein in serum or urine, and end-organ damage (CRAB criteria) 1, 2
Multiple myeloma presents with focal lytic lesions (punched-out holes) visible on skeletal survey, particularly in skull, spine, ribs, and pelvis 3, 4
Asymmetric bone destruction with lesions appearing in specific locations rather than diffuse involvement is characteristic of multiple myeloma 3
The National Comprehensive Cancer Network suggests that whole-body low-dose CT or FDG-PET/CT is now preferred over skeletal survey for suspected myeloma, detecting 25.5% more lesions than plain radiographs 3, 4

For multiple myeloma diagnosis, the presence of monoclonal protein (M-protein) on serum protein electrophoresis with immunofixation is required 2
Abnormal serum free light chain ratio (kappa/lambda) is also a diagnostic criterion for multiple myeloma 2
Elevated total protein with decreased albumin-to-globulin ratio is a laboratory finding in multiple myeloma 2
Monoclonal protein in 24-hour urine collection (Bence Jones protein) is a diagnostic criterion for multiple myeloma 2
≥10% clonal plasma cells on bone marrow biopsy with CD138 staining is a diagnostic criterion for multiple myeloma 6, 2

When bone disease is suspected, immediately order complete blood count, comprehensive metabolic panel, serum protein electrophoresis with immunofixation, serum free light chain assay with kappa/lambda ratio, and quantitative immunoglobulins 5, 1, 2
If laboratory screen suggests myeloma (M-protein present or abnormal FLC ratio), proceed immediately to bone marrow aspiration and biopsy 6, 1, 2

Do not confuse severe osteoporosis with myeloma, as severe osteoporosis can cause vertebral compression fractures similar to myeloma, and always check for M-protein before assuming osteoporosis in patients with multiple vertebral fractures 2
Do not miss early myeloma in MGUS patients, as MGUS can progress to myeloma, and follow MGUS patients every 3-6 months with M-protein quantification and CBC 2, 1
Do not order unnecessary bone marrow biopsies, as bone marrow biopsy is mandatory only when M-protein is detected or CRAB criteria are present 2

Multiple myeloma typically presents with bone pain that worsens at night or with movement, and with unexplained anemia (73% at presentation) and renal dysfunction (19% have acute kidney injury at diagnosis) 6, 7, 1
Osteoporosis typically presents more commonly in postmenopausal women, often asymptomatic until fracture occurs, and without systemic symptoms (no anemia, renal dysfunction, or hypercalcemia) 1, 2

Myeloma on imaging is characterized by focal lytic "punched-out" lesions on CT/skeletal survey, FDG-avid lesions on PET/CT, and focal or diffuse marrow replacement on MRI 3, 4, 2
Osteoporosis on imaging is characterized by diffuse decreased bone density on DEXA, thinned cortices and decreased trabecular bone on radiographs, and no focal lesions or marrow abnormalities 3, 2