1. Osteomalacia d/t Fanconi syndrome d/t Multiple myeloma Department of Endocrinology and Metabolism Yu Tae Kyung 1

2. Osteomalasia Disorder of mineralization of newly formed matrix in adults Singer, RF. Metabolic bone disease. In: Textbook of Rheumatology, 1985 cf) Rickets : Disorder of defective mineralization of cartilage in the epiphyseal growth plates of children 2

3. Cause Abnormal vitamin D metabolism causing secondary hyperparathyroidism and hypophosphatemia Deficient intake or absorption(m/c) Dietary, Inadequate sunlight exposure. Malabsorption, Gastrectomy, Small bowel disease, Pancreatic insufficiency Defective 25-hydroxylation Biliary cirrhosis, Alcoholic cirrhosis, Anticonvulsants Loss of vitamin D binding protein Nephrotic syndrome Defective 1-alpha 25-hydroxylation Hypoparathyroidism, Renal failure, Vitamin D-dependent rickets type 1 Defective target organ response to calcitriol Vitamin D-dependent rickets, type II (Hereditary vitamin D resistant rickets, HVDRR) 3 Mineralization defects Abnormal matrix Chronic renal failure, Osteogenesis imperfecta, Fibrogenesis imperfecta, Axial osteomalacia Enzyme deficiency Hypophosphatasia (rare) Inhibitors of mineralization Fluoride, Aluminium, Bisphosphonates Phosphate deficiency Decreased intake Antacids Impaired renal reabsorption Primary defects X-linked hypophosphatemic rickets (vitamin D resistant rickets, VDRR), Hereditary hypophosphatemic rickets with hypercalciuria, Sporadic acquired hypophosphatemic rickets, Fanconi Syndrome- Wilson disease, cystinosis, multiple myeloma Secondary defects Primary hyperparathyroidism, Secondary hyperparathyroidism (renal tubular acidosis, type 1 and disorders of vitamin D metabolism), Oncogenic osteomalacia

4. Fanconi syndrome - Disorder of the proximal tubular function - Primary phosphate wasting -> osteomalacia/rickets -Other tubular defects Bicarbonate -> type 2 RTA -> acidosis, hypokalemia, hyperchloremia Hypouricemia Aminoaciduria -> Growth failure Glucosuria - Polyuria, polydipsia, dehydration - Multiple myeloma is m/c cause in adults 4 Cause

5. Clinical Presentations Asymptomatic/osteopenia Diffuse bone pain, tenderness -At lower spine, pelvis, and lower extremities -Ass with Fractures to ribs, vertebrae, and long bones -dull and aching, aggravated by activity, weight bearing Muscle weakness -Proximal -muscle wasting, hypotonia, and discomfort with movement, waddling gait 5

6. Radiographic findings Reduced bone density with thinning of the cortex (m/c) changes in vertebral bodies Looser zones Secondary hyperparathyroidism (rare) - subperiosteal resorption of the phalanges, bone cysts, and resorption of the distal ends of long bones 6

7. Bone biopsy using double tetracycline labeling 1. ↓distance between tetracycline bands 2. Unmineralized matrix osteoid seam ≥15 microns, osteoid volume ≥ 10 % 7 Diagnosis

8. Noninvasive diagnosis - Bone films - Plasma P, Ca, ALP, BUN, Cr, electrolytes, and calcidiol -Osteoporosis Postmemopausal women, elderly pts, pts with chronic corticosteroid Normal Ca, P, ALP, VitD merabolities, PTH -Osteomalacia At least 2 ( ↓Ca, ↓P, ↑ALP, or specific radiologic findings) 8 Diagnosis

9. Laboratory findings 9 DisorderPhosphate CalciumALP Vitamin D deficiency with secondary hyperparathyroidism ↓↓ to low normal↑ Conditions associated with urinary wasting ↓Normal Metabolic acidosisNormal Proximal renal tubular acidosis↓Normal HypophosphatasiaNormal ↓ Osteogenesis imperfecta and axial osteomalacia Normal OsteoporosisNormal * Renal P wasting - Fe P(<5%), 24 hr urinary P (<100mg)

10. Reversal of the underlying disorder, if possible Correction of hypophosphatemia, hypocalcemia, and vitamin D deficiency - Vitamin D and its metabolites Vit D, Calcidiol, calcitriol, dihydrotachysterol Plasma Ca(N), urinary Ca(↑), bone density(↑) Ex. Osteomalacia of renal tubular acidosis : 5000 to 10000 UI/day Vit D -> 800 UI/day Vit D, sodium and/or potassium citrate -Calcium intake At least 1000mg/day Plasma Ca(N), urinary Ca(N) 10 Treatment

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14. Renal involvement of multiple myeloma - Common in multiple myeloma and implies much worse prognosis. -Caused by the excess production of monoclonal light chains, almost always accompanied by light chain proteinuria. -Proximal tubule injury is the most common mode -Often presents with proximal tubular functional abnormalities, such as Fanconi syndrome Contrib Nephrol. Basel, Karger, 2007, vol 153, pp 87–104 14 Q) Improve tubular function after Tx for myeloma ?

15. Nephron 1990;55:332-335 Adult Fanconi Syndrome Secondary to κ-Light Chain Myeloma: Improvement of Tubular Functions after Treatment for Myeloma Shinishi Uchida, Osamu Matsuda, Takanori Yokota, Tamiko Takemura, Ryoichi Ando, Hiroyoshi Kanemitsu, Hiroyuki Hamaguchi, Shozo Miyake, Fumiaki Marumo Musashino Red Cross Hospital, Department of Internal Medicine, Musashino-City, Tokyo; Japanese Red Cross Medical Center, Department of Pathology, Shibuya-ku, Tokyo; Tokyo Medical and Dental University, Second Department of Internal Medicine, Bunkyo-ku, Tokyo, Japan A 66-year-old man with κ-light chain multiple myeloma had adult Fanconi syndrome. Renal tubular transport abnormalities consisted of renal tubular acidosis, renal glycosuria, aminoaciduria, phosphaturia and renal hypouricemia. After therapy for multiple myeloma, urinary Bence Jones protein became undetetable, and all these renal tubular abnormalities except urate wasting were corrected. Histological examination revealed electron-dense tubular and rod-like deposits in proximal rubular epithelium. This clinical observation suggests that the renal tubular transport defects were secondary to the myeloma process, possibly due to Bence Jones proteinuria. 15

16. Q) Improve tubular function after Tx for myeloma ?