Transcript Basic Science - OrthopaedicsOne

Sixty-one year old male with seven-year
history of joint pain, weakness, and
multiple fractures
Chris Estes, D.O.
Chris Beauchamp, M.D.
Matthew Zarka, M.D.
Mayo Clinic
Phoenix, Arizona
September 15, 2008
•
HPI: 61 y/o male with seven year history of progressive hip, knee and shoulder pain. 3 ½
years ago he became confined to a wheelchair due to chronic pain, weakness and multiple
pathologic fractures. Prior to seven years ago he was healthy and employed as an electrician.
No history of musculoskeletal problems prior to seven years ago.
•
Medical Hx: Good health. He is a Syrian who was born in Iran and moved to the U.S. in 1973.
No prior surgeries. He smokes 1.5 ppd x 30 years and eats a healthy diet.
•
No family history of metabolic bone disease
•
Medications: Vicodin 7.5/500 2-3 tab bid, Morphine ER 30 mg 1.5 tab qd.
•
Physical Exam: A+O x3, lucid, pleasant. Cachectic body habitus. Extremities with severe
quadraparesis of proximal muscle groups. Painful, decreased passive ROM of shoulders,
knees and hips. Severe thoracic kyphosis with buckling of sternum. He had lost all dentition.
•
X-rays reveal severe osteopenia, bilateral femoral neck fractures, bilateral proximal humerus
fractures, multiple vertebral compression fractures
What is the diagnosis? (seven images to follow)
Multiple thoracic
vertebral compression
fractures with resultant
kyphosis, sternal fracture
and buckling.
Diagnosis
The differential diagnosis includes:
a)
b)
c)
d)
e)
Infection
Primary neoplasm
Metastatic disease
Osteoporosis
Metabolic bone disease
Which labs would you order first?
Diagnosis
• Initial labs reveal:
–
–
–
–
–
–
WBC 8,400
Hgb 14.7 mg/dL
Platelets 294,000
Calcium (8.9-10.1 mg/dL) = 9.9
Alkaline Phosphatase (45-115IU/L)= =284
ESR (0-22mm/hr) = 9
• Infection is highly unlikely.
• Which labs would you order next in order to rule out
metabolic bone disease?
Diagnosis
Secondary lab studies reveal:
– (Low) 25 (OH) Vit D (25-80ng/mL) = 15
– (Low) 1,25 (OH) Vit D (22-67pg/mL) = 10
– (Low) Phosphorus (2.5-4.5 mg/dL) = 1.4
– (Normal) Creatinine (0.8-1.4mg/dL) = 0.6
– (Normal) PTH (10-55 /mL) = 31
Diagnosis
What is the etiology of this patient’s disease?
a)
b)
c)
d)
e)
Infection
Primary neoplasm
Metastatic disease
Osteoporosis
Metabolic bone disease
Diagnosis
What is the etiology of this patient’s disease?
e)
Metabolic bone disease
Differential Diagnosis
• Abnormal vitamin D metabolism
• Inhibitors of mineralization
– aluminum, fluoride, bisphosphonates
• Impaired renal phosphorus reabsorption
– X-linked hypophosphatemic rickets
– Autosomal dominant hypophosphatemia
– Tumor-induced osteomalacia
• Dietary deficiency
– Vitamin D Deficiency Osteomalacia
– Calcium deficiency
– Phosphorus deficiency
• Abnormal Vitamin D metabolism
• Enzyme deficiencies
– Hypophosphatasia
• Renal Osteodystrophy
Diagnosis
Due to the fact serum phosphate was low, a 24-hour urine
chemistry was ordered.
– Fractional excretion of phosphate was high at 38.4% (normal = 520%).
Diagnosis
This patient has:
–
–
–
–
–
–
Hypophosphatemia
Hyperphosphaturia
Healthy diet
Minimal medications
Normal creatinine
Age of 61
Given this information we can likely attribute his condition to a
condition caused by impaired renal phosphorus reabsorption.
Diagnosis
Conditions secondary to impaired renal
phosphorus reabsorption:
1) X-linked hypophosphatemic rickets
(XLHR)
2) Autosomal dominant
hypophosphatemic rickets (ADHR)
3) Tumor-induced osteomalacia (TIO)
• Given patient’s age (61), this
the likely diagnosis
Typically present in
childhood, however ADHR
infrequently has delayed
age of onset
Diagnosis
An abnormal value of what additional lab would support your
suspected diagnosis?
a)
b)
c)
d)
e)
f)
g)
TSH
Dexamethasone suppression test
Fibroblast growth factor 23 (FGF-23)
Genetic testing positive for t(X;18)(p11;q11).
CDL 43
Glomerular filtration rate
Serum aldosterone
Diagnosis
An abnormal value of what additional lab would support your
suspected diagnosis?
c)
Fibroblast growth factor 23 (FGF-23)
Tumor-induced osteomalacia
• Acquired neoplasm of mesenchymal origin
• Causes a paraneoplastic syndrome of renal phosphorus loss through the
secretion of “phophatonins”. The best characterized of these molecules is
fibroblast growth factor 23 (FGF 23).
– FGF23 leads to decreased expression of a sodium-phosphate cotransporter in
proximal tubule of nephron resulting in hyperphosphaturia and
hypophosphatemia
• Very similar to pathophysiology of:
– X-linked hypophosphatemic rickets
– Autosomal dominant hypophosphatemic rickets (see next slide)
– FGF23 also decreases activity of renal 1-alpha-hydroxylase, causing:
• normal 25 (OH) Vit D
• Low 1,24 (OH) Vit D
• Hypophosphatemia affects many physiologic pathways. In this patient the
most prominent manifestations were muscle weakness and osteomalacia.
– As exemplified by this case, symptoms can be severe.
Mechanisms of FGF-23 Excess in Renal Phosphate-Wasting
Syndromes
Jan de Beur, S. M. JAMA 2005;294:1260-1267. With Permission.
Diagnosis
Classically, the diagnosis if tumor-induced osteomalacia is confirmed with the
following:
–
Elevated Fibroblast growth factor 23 (FGF23) Our patient had an FGF23 of 1680 RU/mL
(normal <180 RU/mL)
–
Normal serum calcium
–
Normal intact PTH
–
Normal 25 (OH) Vit D
–
Low 1,25 (OH) Vit D
–
Hyperphosphaturia
–
Hypophosphatemia
–
Localization of causative tumor!!!
(Secondary to the effects of FGF23)
Diagnosis
Which imaging study is best for detecting/localizing neoplasms
associated with tumor-induced osteomalacia?
a)
b)
c)
d)
e)
f)
Plain films
CT
MRI
F-18 FDG PET-CT
Indium 111-pentetreotide scintigraphy
Technetium-99m PET
Diagnosis
Which imaging study is best for detecting/localizing neoplasms
associated with tumor-induced osteomalacia?
e)
Indium 111-pentetreotide scintigraphy
Diagnosis
Indium 111-pentetreotide scintigraphy
– Many mesenchymal tumors associated with TIO express
somatostatin receptors (SSTRs)
– Pentetreotide is a somatostatin analog
– However, some TIO-associated tumors do not express SSTRs
– F-18 FDG PET-CT may also be useful. However, this marker is not
ideal for detecting neoplasms with low metabolic rates such as
those found in tumor-induced osteomalacia.
Diagnosis
Genitourinary-associated
tracer
Tumor
In this particular case a F18 FDG PET CT was used.
MRI was used to further localize
the lesion:
Tumor
Testes
Treatment
• Give the history, characteristic labs and localization
of a causative tumor, we are now confident in our
diagnosis of tumor-induced osteomalacia.
• What is the best option for treatment of this
condition?
•
•
•
•
•
•
Observation
Medical treatment with calcitrol and phosphate supplementation
Oral bisphosphonates
Renal transplant
Surgical resection
Neoadjuvant chemotherapy and resection
Treatment
• Surgical excision of the entire lesion is curative
– Serum phosphorus returns to normal within days
– Bone density is typically restored within one year
– Inability to localize tumor often delays definitive treatment
• If the tumor is undetectable, medical therapy with calcitrol and phosphate
is effective in some cases
• There has been one case report of successful medical therapy with
Octreotide while a patient was awaiting surgery. It was hypothesized that
somatostatin receptors regulate secretory activity, as in many other
endocrine tumors. (Seufert et al)
– However, there are also reports of this therapy being ineffective. At least one group does not
recommend the widespread use of somatostatin analogues for the treatment of this disease.
(Paglia et al)
• There has been one case report of a femoral head lesion successfully
treated with radiofrequency ablation.
Histology
The following four slides are histology photos
from this patient.
Histology
Phosphaturic mesenchymal tumor, low magnification. Prominent fragments of eosinophilic
calcification/dystrophic bone formation surrounded by microcystic spaces, variably sized thin
walled vessels, and moderately cellular mesenchymal component (H and E, x40)
Phosphaturic mesenchymal tumor. Syncytial mesenchymal component composed of bland oval and
spindle shaped stromal cells situated around variably sized microcystic spaces, thin walled blood
vessels, and eosinophilic dystrophic calcified debris (H and E, x100)
Phosphaturic mesenchymal tumor, higher magnification. (H and E, x200)
Phosphaturic mesenchymal tumor, high magnification. Syncytium of primitive bland, round, oval,
spindle shaped, and rare multinucleated stromal cells, admixed with thin walled blood vessels and
smudgy bluish extracellular matrix. (H and E, x400)
Outcome
• This patient successfully underwent radical resection of the
tumor on May 11, 2005.
• Most labs returned to near-normal two days post-op
• Bone mineral density returned to normal one year post-op
• Four months after surgery he could stand on his own without
assistance
• One year post op he could walk on his own without assistance
Outcome
Test (Reference Range)
Pre-operative
2 days post-op
4 months post op
12 months post op
Creatinine (0.8-1.4mg/dL
0.6
0.7
0.5
0.8
Calcium (8.9-10.1mg/dL)
9.9
9.9
10.1
9.9
Parathyroid hormone (10-55pg/mL)
31
47
58
86
Phosphorus (2.5-4.5 mg/dL)
1.4
2.4
4.4
3.4
25 (OH) Vit D (25-80ng/mL)
15
31
22
13
1,25 (OH) Vit D (22-67pg/mL)
10
120
122
87
Fibroblast growth factor-23 (<180 RU/mL)
1680
156
Lumbar spine bone density (T score)
-5.9
-1.4
0.7
Left femoral neck bone density (T score)
-3.0
-0.8
1.9
90
Outcome
Preoperative
Four months postoperative
Outcome
Preoperative
Three years postoperative
References
•
Garcia CA, Spencer RP. Bone and In-111 octreotide imaging in oncogenic osteomalacia: a case report. Clin Nucl Med. 2002
Aug;27(8):582-3.
•
Hannan FM, Athanasou NA, Teh J, Gibbons CL, Shine B, Thakker RV. Oncogenic hypophosphataemic osteomalacia: biomarker
roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1. Eur J
Endocrinol. 2008 Feb;158(2):265-71.
•
Hesse E, Moessinger E, Rosenthal H, Laenger F, Brabant G, Petrich T, Gratz KF, Bastian L. Oncogenic osteomalacia: exact
tumor localization by co-registration of positron emission and computed tomography. J Bone Miner Res. 2007 Jan;22(1):15862.
•
Jan de Beur SM. Tumor-induced osteomalacia. JAMA. 2005 Sep 14;294(10):1260-7.
•
Nguyen BD, Wang EA. Indium-111 pentetreotide scintigraphy of mesenchymal tumor with oncogenic osteomalacia. Clin Nucl
Med. 1999 Feb;24(2):130-1.
•
Seufert J, Ebert K, Müller J, Eulert J, Hendrich C, Werner E, Schuüze N, Schulz G, Kenn W, Richtmann H, Palitzsch KD, Jakob F.
Octreotide therapy for tumor-induced osteomalacia. N Engl J Med. 2001 Dec 27;345(26):1883-8.
•
Wilkins GE, Granleese S, Hegele RG, Holden J, Anderson DW, Bondy GP. Oncogenic osteomalacia: evidence for a humoral
phosphaturic factor. J Clin Endocrinol Metab. 1995 May;80(5):1628-34.
References
•
Paglia F, Dionisi S, Minisola S. Octreotide for tumor-induced osteomalacia. N Engl J Med. 2002 May 30;346(22):1748-9;
author reply 1748-9. Comment on: N Engl J Med. 2001 Dec 27;345(26):1883-8.
•
Shane E, Parisien M, Henderson JE, Dempster DW, Feldman F, Hardy MA, Tohme JF, Karaplis AC, Clemens TL. Tumor-induced
osteomalacia: clinical and basic studies. J Bone Miner Res. 1997 Sep;12(9):1502-11.