Question of the Week # 2

A 75 y/o man with history of Hypertension, Pagets disease and peripheral vascular disease presents to you with complaints of chronic hearing impairment on right side. He is otherwise physically very active. Physical examination benign except for right sided sensorineural hearing deficit A skull x-ray was obtained to evaluate his paget’s disease.Lab studies reveal hemoglobin of 9.7, platelets 310, wbc 10k with normal differential, BUN 38, creatinine 1.4, calcium of 11.2. The patient is currently on alendronate for Pagets disease.

Which of the lab measure or imaging would usually be expected to be abnormal in the condition that is responsible for his skull x-ray findings and hypercalcemia?
A. Alkaline phosphatase
B. Serum Immunoelectrophoresis
C. Bone Scan
D. Carcino Embryonic Antigen
E. CA-15-3

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21 Responses

  1. b

    • Ans. B
      ( For extensive discussion on several similar highyield Step 3 topics, visit
      Archer USMLE Step 3 Review)

      Pagets disease history is a distractor in this case. Paget’s disease does not cause hypercalcemia unless the patient is immobilized because of poor control. The hypercalcemia in paget’s is secondary to prolonged immobilization not because of Paget’s per se. This patient is physically very active. The question is asking what is the usual abnormality seen in patients with MM. Because only MM explains his renal insufficiency, punched out lesions in the skull and hypercalcemia.The question also presents a skull radiograph that shows “Osteolytic” lesions with out any concomitant “Osteoblastic” process. Such pure osteolytic lesions are hallmark of MM which is why Alkaline phosphatase and Bone scans are often normal in MM. ( Recognize that Osteoblasts are the ones that are responsible for positive bone scan and increased alkaline phosphatase and hence, these are normal in MM which has no osteoblastic activity in skeletal lesions) .

      Serum and Urine electrophoresis with immunofixation may reveal a monoclonal spike and useful for confirmation of the diagnosis. Patient also has hypercalcemia, anemia and renal insufficiency which are associated features in multiple myeloma.

      Paget’s disease, on the other hand, is charecterized by mixed osteolytic and osteoblastic phases. Alkaline phosphatase is typically elevated in patients with Pagets. The skull radiograph will show a “cotton wool” appearance caused by irregular areas of sclerosis
      ( mixed lytic areas with blastic areas).

    • A phosp alkalina it is a turover of the bone, high resorption of bone

    • B

  2. nice

  3. informative

  4. Does this mean that the pt may have been previously incorrectly dx with Paget’s dz when he was really suffering from MM?

    • No, he does have a history of Paget’s disease which is chronic and as a result, he also has hearing deficit. The problem is currently having and his skull x-ray findings are unrelated to Paget’s . Paget’s history is just a dis tractor. The question aims to test your understanding of clinical presentation of paraproteinemias and MM.

  5. This is a really good question. Thanks!


  7. Thanks for posting such a nice question with so elaboratie and informative explanation. But the fact is pt is still suffering from pagets (not cured yet) and so his alkaline phosphatase level should be elevated also at this point.

    • My thoughts exactly!

    • The Question is the abnormality in which of the values correlates with condition responsible for Skull X-ray findings and Hypercalcemia.Hence the answer will be SerumImmunoElectrophoresis[Multiple Myeloma is the cause of those findings and NOT Paget’s].

  8. very informative

  9. Good, informative

  10. Thank you Dr Archer. This is a great question.
    I think that we need to understand the connection between Paget’s disease of the bone and Multiple Myeloma.
    Scenario: A patient with Paget’s disease of the bone develops Multiple myeloma (CRAB – HyperCalcemia, Renal failure, Anemia, Bone lesions – culled from Wikipedia)
    Paget’s disease is a slow process and hypercalcemia is not a diagnostic feature because calcium homeostatic mechanism override bone calcium irregularity. However, when several bones are involved and bone pains results in prolonged immobility, hypercalcemia of immobilization results.
    Also renal failure, anemia are not features of Paget’s disease of the bone.
    So, Coexisting Paget’s disease (PD) and Multiple myeloma(MM),
    Is this possible? Yes, in rare instances, (like this patient)
    Very similar to Acute transformation of Chronic Lymphocytic Leukemia (Reiter’s transformation)
    We must understand the connection between PD & MM.
    It’s like,for if Paget’s disease of the bone is osteolysis to the exponential power of x, multiple myeloma is osteolysis to the exponential power of multiples of x.
    What is the connection between multiple myeloma and paget’s disease of the bone?

    At molecular level, both PD & MM have a common denominator, (interleukins), acting through the receptor activator of nuclear factor kappa B ligand (RANKL)/ Osteoprotegerin signalling pathway.
    Interleukins stimulate bone resorption.
    Normally RANKL cause osteolysis while Osteoprotegerin cause osteoblastic activity. A balance between these two ensures normal bone calcium deposition.

    Yes PD is believed to be activated by a slow virus. Now you can see the connection? Both diseases result from immune disorder that cause lysis of bone through interleukins. PD destroys the bone slowly, giving time for osteoblastic activity. MM destroys bone rapidly, we see punched out lesions with no time for osteoblastic recovery. Therefore, activity of alkaline phosphatase, an enzyme required for bone deposition, continues to rise in PD because osteoblastic activity rises as the disease gradually progresses. In MM, bone lysis is rapid and there is no time for osteoblastic compensation and so alkaline phosphatase is not elevated.

    On the X-ray, I see punched out lesion but I also see cotton wool appearance of bone from sclerosis. Both PD & MM are responsible for Xray findings but,
    But the question becomes more specific; ‘What lab abnormality is found… in condition responsible for x-ray findings AND the HYPERCALCEMIA in this case?
    PD is not responsible for hypercalcemia here because our patient is ambulant! If he was bedridden for a prolonged time, identifying the cause of hypercalcemia would be a dilemma. So what lab abnormality is expected if MM is responsible?

    My ANSWER is abnormal serum immune electrophoresis, B

    MM is malignant proliferation of B-lymphocytes that secrete large quantity of abnormal monoclonal immunoglobulins into the blood. This can be picked up on serum protein electrophoresis. There will be a much wider gamma globulin zone and this zone will be predominated by a a monoclonal ‘M’ spike/ band.

    We also have to check urine electrophoresis. Why? Some patients (one fifth) secrete ONLY light chain proteins. These proteins (Bence-Jones proteins) are excreted in urine and cause kidney damage but the problem is that if you only check serum electrophoresis, you will miss the diagnosis of these patients.

    What is responsible for anemia?
    1. Malignant MM cells replace normal bone marrow so even though cells are normochromic and normocytic, patients develop lower red cell counts.
    2. Cytokines (interleukins) inhibit hematopoeisis resulting in anemia and infections and platelet dysfunction in this sequential order as MM gets more and more severe.

    Dr Archer, thank you so much for teaching us for free in this blog.

  11. B. Multiple myeloma. Punched out lyric lesions. Hypercal

  12. A

  13. A

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