How do you differentiate between multiple myeloma and osteoporosis/osteopenia in patients with suspected bone disease?

Differentiating Multiple Myeloma from Osteoporosis/Osteopenia

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), whereas osteoporosis/osteopenia shows only diffuse bone density loss without these hematologic abnormalities. 1, 2

Key Clinical Distinctions

Pattern of Bone Involvement

Multiple myeloma presents with:

• Focal lytic lesions (punched-out holes) visible on skeletal survey, particularly in skull, spine, ribs, and pelvis 3
• Pathologic fractures occurring with minimal trauma, especially vertebral compression fractures 4, 5
• Asymmetric bone destruction with lesions appearing in specific locations rather than diffuse involvement 3
• Nearly 80% of patients have bone disease at diagnosis, with spine being the most frequently affected site 4

Osteoporosis/osteopenia presents with:

• Diffuse, symmetric bone density reduction without focal lytic lesions 6
• Compression fractures that occur in osteoporotic bone but without the punched-out appearance 6
• Gradual bone loss affecting trabecular bone preferentially 6

Essential Laboratory Findings

For multiple myeloma diagnosis, you must find: 3, 1, 2

• Monoclonal protein (M-protein) on serum protein electrophoresis with immunofixation
• Abnormal serum free light chain ratio (kappa/lambda)
• Elevated total protein with decreased albumin-to-globulin ratio
• Monoclonal protein in 24-hour urine collection (Bence Jones protein)
• ≥10% clonal plasma cells on bone marrow biopsy with CD138 staining 3, 2

For osteoporosis/osteopenia, these tests are normal:

• No monoclonal protein on SPEP/immunofixation
• Normal serum free light chains
• Normal bone marrow plasma cell percentage (<10%)
• No M-protein in urine 6

CRAB Criteria (End-Organ Damage)

Multiple myeloma requires at least one of: 1, 2, 7

• Calcium elevation: serum calcium >11.5 mg/dL
• Renal insufficiency: creatinine >2 mg/dL or creatinine clearance <40 mL/min
• Anemia: hemoglobin <10 g/dL or ≥2 g/dL below normal
• Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

Osteoporosis/osteopenia lacks CRAB criteria:

• Normal calcium, renal function, and hemoglobin
• Only diffuse bone density loss without focal lytic lesions 6

Diagnostic Algorithm

Step 1: Initial Laboratory Screen

When bone disease is suspected, immediately order: 3, 1

• Complete blood count (looking for anemia)
• Comprehensive metabolic panel (calcium, creatinine)
• Serum protein electrophoresis with immunofixation
• Serum free light chain assay with kappa/lambda ratio
• Quantitative immunoglobulins (IgG, IgA, IgM)
• 24-hour urine protein electrophoresis with immunofixation

Step 2: Imaging Selection

For suspected myeloma: 3

• Whole-body low-dose CT or FDG-PET/CT is now preferred over skeletal survey (detects 25.5% more lesions than plain radiographs)
• MRI is superior for detecting bone marrow infiltration and spinal involvement
• Skeletal survey is acceptable only when advanced imaging is unavailable

For osteoporosis evaluation:

• DEXA scan showing T-score between -1.0 and -2.5 (osteopenia) or ≤-2.5 (osteoporosis) 6
• Plain radiographs show diffuse osteopenia without focal lesions

Step 3: Confirmatory Testing

If laboratory screen suggests myeloma (M-protein present or abnormal FLC ratio): 3, 1, 2

• Proceed immediately to bone marrow aspiration and biopsy
• Request cytogenetics and FISH for del(17p), t(4;14), t(14;16), del(13q)
• Ensure CD138 staining to accurately quantify plasma cells

If laboratory screen is normal:

• Diagnosis is osteoporosis/osteopenia, not myeloma
• No bone marrow biopsy needed 2

Critical Pitfalls to Avoid

Common Diagnostic Errors

Do not confuse severe osteoporosis with myeloma: 6, 8

• Severe osteoporosis can cause vertebral compression fractures similar to myeloma
• Always check for M-protein before assuming osteoporosis in patients with multiple vertebral fractures
• Lumbar spine BMD correlates with fracture risk in both conditions, but only myeloma has M-protein

Do not miss early myeloma in MGUS patients: 2, 8

• MGUS (M-protein <3 g/dL, <10% plasma cells, no CRAB) can progress to myeloma
• Bone disease may begin even in MGUS stage, though less severe 8
• Follow MGUS patients every 3-6 months with M-protein quantification and CBC 1

Do not order unnecessary bone marrow biopsies: 2

• If M-protein is absent and imaging shows only diffuse osteopenia, bone marrow biopsy is not indicated
• Bone marrow biopsy is mandatory only when M-protein is detected or CRAB criteria are present

Age and Presentation Considerations

Multiple myeloma typically presents: 3, 7, 9

• Median age 65-70 years (85% of patients >65 years)
• With bone pain that worsens at night or with movement 1
• With unexplained anemia (73% at presentation) 9
• With renal dysfunction (19% have acute kidney injury at diagnosis) 9

Osteoporosis typically presents:

• More commonly in postmenopausal women
• Often asymptomatic until fracture occurs
• Without systemic symptoms (no anemia, renal dysfunction, or hypercalcemia)

Imaging Characteristics Summary

Myeloma on imaging: 3, 4

• Focal lytic "punched-out" lesions on CT/skeletal survey
• FDG-avid lesions on PET/CT
• Focal or diffuse marrow replacement on MRI
• Spinal cord compression in 20% of cases

Osteoporosis on imaging: 6

• Diffuse decreased bone density on DEXA
• Thinned cortices and decreased trabecular bone on radiographs
• No focal lesions or marrow abnormalities
• Vertebral compression fractures show uniform density loss