AACE Southern States Chapter Lecture Unusual Bone Cases Basics Osteoporosis Osteomalacia Renal Osteodystrophy Multiple Myeloma 1
Osteoporosis Definition Modeling, Bone Remodeling Bone Resorption > Bone Formation Wnt RANKL, OPG, RANK Osteomalacia Mineralization Defect Low serum phosphate levels Vitamin D Deficiencies FGF- 23 Excess PTH Elevated 2
Basic Pathways Calcium, PTH, Calcitriol FGF-23, Klotho, Phosphorus, Vitamin D LRP- 5, Wnt, Beta Catenin RANK, OPG, RANKL 3
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Case A 79-year-old female initially presented in 1976 with weakness, soreness, bone pains, and fractures (pelvic, clavicular and hip) She had persistently low serum phosphorus, high urine phosphate excretion and high alkaline phosphatase and normal PTH and calcium levels She was treated as hypophosphatemic osteomalacia with high doses of phosphate and vitamin D supplements. In 1983 after treatment with phosphorus and calcitriol the PTH and calcium levels rose. Bone biopsy at that time showed osteomalacia and osteitis fibrosa cystica 8
Case In 1984, she underwent parathyroidectomy with removal of 2 ¾ glands (1 was reimplanted in the forearm, ¼ of the left lower gland [~50 g] was left in place) with improvement in her serum phosphorus, calcium and PTH levels. A repeat bone biopsy showed no osteitis fibrosa cystica and almost no evidence of osteomalacia. Over the next 5 years, phosphorus again declined, 1,25(OH) 2 D was found to be undetectable and she was restarted on phosphate supplements and calcitriol with minimal response. In 1998 she again developed tertiary hyperparathyroidism (hypercalcemic) and underwent re-exploration of her neck. At this time the 50-g remnant had hypertrophied to 900 g and a 5 th gland was found in the left carotid sheath. Both these glands were resected. CASE After the second surgery, she developed hungry bone syndrome requiring treatment with calcium and vitamin D. Calcium and phosphorus levels normalized without need for phosphorus replacement. PTH levels were low which was consistent with hypoparathyroidism. In 2002, tumor-induced osteomalacia was suspected and a sestamibi scan and MRI were done, localizing 2 right-sided intracranial tumors to the meninges. The patient refused neurosurgery. In 2009 FGF 23 levels were checked and found to be in the range of 3300-4850 RU/mL (normal 0-180). 9
Case In the past 6 years, phosphorus has trended down, PTH rising, calcium normal, FGF 23 markedly increased to ~12500 U/L She developed R knee pain, different in character from her osteoarthritis. She received intra-articular steroids with no improvement. Further evaluation on MRI showed a proximal tibial tumor. On 6/29/2010, she had biopsy of the tumor which showed: PHOSPHATURIC MESENCHYMAL TUMOR + for FGF 23 mrna by RT-PCR On 7/20/2010, she had resection and currettage of the tumor. After surgery, we started Sensipar 30 mg bid, Calcitriol 0.25ug bid and neutraphos 500mg tid Currently, PTH is still elevated, calcium low normal, phosphorus lownormal, FGF 23 is still elevated but has decreased to ~600 10
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Lessons Learned Patient had osteomalacia associated with hypophosphatemia The patient had elevated FGF23 levels which lowered the serum phosphorus and the calcitriol levels The patient had secondary and tertiary hyperparathyroidism which also contributed to lowering the serum phosphorus Lesson Learned Parathyroidectomy either surgically or medically increased the serum phosphorus and prevented or treated the osteomalacia. There are some similarities to renal osteodystrophy: Elevated FGF23, tertiary hyperparathyroidism, recurrent parathyroid tumors. 12
Elevated FGF23 Diseases X- Linked Hypophosphatemic Rickets PHEX Autosomal Dominant Hypophosphatemic Rickets Autosomal Recessive Rickets DMP Dentin Matrix Protein ENPP1 Tumor Induced Osteomalacia McCune Albright, Fibrous Dysplasia Treatment of FGF 23 Mediated DX Current recommendations: Calcitriol Phosphorus 13
Hyperphosphatemia The most common cause is ESRD The rarest causes are genetic diseases which are unassociated with renal disease Tumoral Calcinosis Rare genetic bone disease associated with ectopic bone formation in subcutaneous tissues, around joints and intravascularly. Autosomal recessive disease caused by mutations in FGF23, Klotho or GALNT3. Pathophysiology: FGF23 is a phosphatonin and inhibits 1-25(OH) Vit D3 14
Tumoral Calcinosis FGF23 deficiency is associated with high serum phosphate and elevated 1-25 (OH) Vit D3 levels Case History HPI: 58y/o AA with a tumoral calcinosis resected from rt. buttocks. Age 4y/o couldn t walk secondary to leg pain 18y/o claudication 25y/o atrial septal defect repair Age 48y/o multiple foot and leg surgeries and eventually bilateral AKA 15
Case History 51y/o MI Abdominal pain, cholecystitis and superior mesenteric calcification. Past history: SH: Stopped smoking 48y/o FH: Mother and father distant cousins Physical Right buttocks 6cm firm indurated mass with thin membrane draining chalky material Bilateral AKA Case History Laboratory Calcium= 10mg/dl Phos= 6 mg/dl (high) Calcitriol= 104 (high) PTH=41 FGF23 C-terminal= 1461 (high) Lumbar spine markedly elevated. T- score=4.6 and Z-score= 6.0 16
Collaboration with M. Econs and S. Ichikawa Gene Abnormalities Identified Homozygous mutation 1st Intron of GALNT3 and FGF23 mutation High C-terminal FGF23 levels Low intact FGF23 GALNT3 GALNT3 =Uridine diphosphate-n-acetyl--dgalactosamine:polypeptide N- acetylgalactosaminyltransferase 3 GALNT3 is a Golgi associated enzyme that initiates mucin-type O-glycosylation of polypeptides. GALNT3 O-glycosylates FGF23 in a furin-like convertase recognition sequence and prevents proteolytic processing of FGF23, thereby allowing secretion of intact FGF23 17
GALNT3 Clinical presentation includes ectopic calcification and Hyperostosis-hyperphosphatemia syndrome, which is characterized by cortical hyperostosis and presents as diaphysitis usually around age 5y/o 18
Hypothesis Lower serum phosphate and decrease ectopic calcification. Intervention: Low phosphate diet, sevelamer, DATE CA Phos 1-25 D PTH Vit D FGF23. AP Sev. Niacin 4/26/2010 10 104 41 28 52 8/19/2010 9.9 6 52 1461 54 2 tab tid 8/31/2010 1000mg 1/10/2011 9.9 5.9 78 60 1405 55 1500 mg 3/17/2011 10.3 5.7 36 32 19 6/7/2011 10 4.9 36 47 20 1425 45 10/03/11 19
GALNT 3 KO Mouse Mouse Hyperphosphatemia Calcitriol high C-FGF23 elevated Intact FGF23 low No calcifications Low alk phos Males: increased BMD, infertility Patient Hyperphosphatemia Calcitriol high C-FGF23 elevated Intact FGF23 low + calcifications Low normal alk. Phos Female: fertile increased BMD Lessons Learned Elevated serum phosphorus and calcitriol are not good The combination leads to ectopic bone formation Calcification of the bone is associated with medial arterial disease and the smooth muscle cells become osteoid- like. This can be prevented or potentially reversed 20
Vascular Disease and Bone Tumoral Calcinosis OPG KO Diabetes? Chronic Kidney Disease ENPP1 KO and NTE 5 regulators of extracellular phosphate. Matrix Vesicle 21
Imel E A, Econs M J JASN 2005;16:2565-2575 22
Ms. LRP 46 y/o AA with mild degenerative arthritis and referred because of a DXA, BMD, t-score =5.0. Blind in the right eye because of bony overgrowth destroying the optic nerve Age 2.0, skull opened to alleviate pressure on brain. 23
LRP Prominent Jaw Blindness rt. eye X-rays, cortical thickness BMD- 5 s.d. above normal No sinuses Osteopetrosis? Lipoprotein receptor protein 5 abnormality LRP-5 Rare disease, Chromosome 11q11-12 Associated with osteosclerosis, mouse model, gain of function Osteoporosis-pseudoglioma Syndrome, loss of function, same gene Wnt pathway/beta-catenin BMP-2 stimulates alkaline phosphatase via the wnt pathway 24
Why the High BMD? Wnt pathway causes increased bone formation But also increases OPG, which inhibits bone resorption Positive uncoupling 25
on RANK Ligand, an Essential Mediator of Osteoclast Activity RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival RANKL RANK CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Activated Osteoclast Osteoblast Lineage Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. Bone CFU-M = colony forming unit macrophage 26
Produces a Protein Called Osteoprotegerin (OPG) Osteoclast Formation, Function and Survival Inhibited by OPG RANKL RANK OPG CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Inactive Osteoclast Osteoblast Lineage Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. Bone CFU-M = colony forming unit macrophage RANK Ligand is an Essential Mediator of Osteoclast Activity Vitamin D IL-11 TNF-α IL-1 PTH Many different factors can affect osteoclast activity, but RANK Ligand is required to mediate or permit their effects on bone resorption IL-6 PGE 2 Osteoblast or Stromal Cell RANK Ligand PTHrP Glucocorticoids Osteoclast Kostenuik PJ, Shalhoub V. Curr Pharm Des. 2001:7:613-635. Boyle WJ, et al. Nature. 2003;423:337-342. 27
SOST Gene Inactivating mutations associated with High BMD phenotype Sclerostin is made in the osteocyte and inhibits Wnt PTH may have some of its anabolic effect by inhibiting sclerostin Pharmaceutical companies are developing antibodies to sclerostin to treat osteoporosis Wnt AND Multiple Myeloma Multiple Myeloma patients have severe osteoporosis and increased osteoclast activity Bisphosphonates inhibit bone resorption, but lytic lesions not repaired Osteoblast defect Excess Dickoff, which inhibits Wnt pathway 28
Lessons Learned Wnt pathway seems to be the major pathway to bone formation. It may also reduce bone formation through OPG. Bone resorption is dependent upon RANKL, RANK and OPG Atypical Femoral Fractures with Bisphosphonates 29