A 66-year-old man comes to the office due to several weeks of back and lower extremity pain. The pain feels dull and achy and is worsened by movement, causing him to have difficulty bearing weight and ambulating. He has had no bladder or bowel dysfunction, extremity weakness, or numbness. The patient takes metformin for type 2 diabetes mellitus. He drinks 2 alcoholic beverages daily. Physical examination shows no gross abnormality or deformity of the back or extremities. There is no swelling or redness of the legs, and neurological examination is normal. A radiograph of the right lower extremity is shown in the exhibit. Laboratory results are as follows: Which of the following is the most likely explanation for this patient's bone changes?

Question

A 66-year-old man comes to the office due to several weeks of back and lower extremity pain.  The pain feels dull and achy and is worsened by movement, causing him to have difficulty bearing weight and ambulating.  He has had no bladder or bowel dysfunction, extremity weakness, or numbness.  The patient takes metformin for type 2 diabetes mellitus.  He drinks 2 alcoholic beverages daily.  Physical examination shows no gross abnormality or deformity of the back or extremities.  There is no swelling or redness of the legs, and neurological examination is normal.  A radiograph of the right lower extremity is shown in the exhibit.  Laboratory results are as follows:  Which of the following is the most likely explanation for this patient's bone changes?

Quizplus · Accepted Answer

11ec160b_3af5_a0de_9249_3db451a722f1_MD0001_00 This patient with mild renal insufficiency, normocytic anemia, hypercalcemia, and bone pain has the classic manifestations of multiple myeloma (MM), a plasma cell malignancy associated with excessive production of monoclonal immunoglobulin (paraprotein). Myeloma cells replicate in the bone marrow and release cytokines that stimulate osteoclasts and inhibit osteoblasts, which leads to the generation of purely osteolytic (radiolucent) bone lesions. Bone remodeling is tightly regulated by osteocytes (stromal bone marrow cells that are embedded within the lacuna-canalicular network) in conjunction with signals from the bone marrow and the bone surface. The RANK/RANKL pathway plays a prominent role. RANK is a transmembrane receptor on the surface of osteoclast precursors, which is activated by RANK-ligand (RANKL) produced by osteocytes. Activation of RANK leads to the differentiation of osteoclast precursors into mature osteoclasts. Myeloma cells stimulate osteoclast maturation by producing RANKL and by destroying osteoprotegerin (OPG), mediated by a secreted proteoglycan. They also uniquely inhibit osteoblast activity by secreting cytokines that block osteoblast function (eg, IL-3, IL-7, Wnt pathway inhibitors). This tilts the balance of bone remodeling strongly toward osteolytic bone destruction, which results in many of the characteristic findings seen in MM, including bone pain, hypercalcemia (liberation of calcium during osteolysis), and purely radiolucent (osteolytic) bone lesions. (Choice A) Decreased urinary calcium excretion can be seen with thiazide diuretic use and can result in hypercalcemia. However, this effect is associated with an increase in bone density; radiolucent bone lesions would not be seen. (Choices B and C) 1,25 dihydroxyvitamin D and parathyroid hormone break down bone by increasing RANKL and decreasing OPG expression. Although vitamin D toxicosis and hyperparathyroidism can be associated with hypercalcemia, they are not associated with anemia or elevations in total serum protein. (Choice D) Several tumors that spread to the bones stimulate osteoclasts, but only myeloma cells also inhibit osteoblasts. Therefore, myeloma cells are one of the few tumors to cause purely osteolytic (radiolucent) lesions. Most other tumors have at least some areas of sclerosis (osteoblastic activity). Educational objective: Multiple myeloma is a plasma cell malignancy associated with purely radiolucent (osteolytic) bone lesions due to the stimulation of osteoclasts and the inhibition of osteoblasts. Myeloma cells stimulate osteoclast development by secreting RANK-ligand and destroying osteoprotegerin, which increases RANK activity and results in osteoclast differentiation. __________ References: Pathogenesis of bone disease in multiple myeloma: from bench to bedside. (http://www.ncbi.nlm.nih.gov/pubmed/29330358)

A 66-Year-Old Man Comes to the Office Due to Several