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 ClinicPhoenix, 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) Infectionb) Primary neoplasmc) Metastatic diseased) Osteoporosis e) 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?

DiagnosisSecondary 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) Infectionb) Primary neoplasmc) Metastatic diseased) Osteoporosis e) 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

DiagnosisDue to the fact serum phosphate was low, a 24-hour urine

chemistry was ordered.

– Fractional excretion of phosphate was high at 38.4% (normal = 5-20%).

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) TSHb) Dexamethasone suppression testc) Fibroblast growth factor 23 (FGF-23)d) Genetic testing positive for t(X;18)(p11;q11). e) CDL 43f) Glomerular filtration rateg) 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.

Jan de Beur, S. M. JAMA 2005;294:1260-1267. With Permission.

Mechanisms of FGF-23 Excess in Renal Phosphate-Wasting Syndromes

DiagnosisClassically, 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)

DiagnosisWhich imaging study is best for detecting/localizing neoplasms

associated with tumor-induced osteomalacia?

a) Plain filmsb) CTc) MRId) F-18 FDG PET-CTe) Indium 111-pentetreotide scintigraphyf) Technetium-99m PET

DiagnosisWhich 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

In this particular case a F18 FDG PET CT was used.

Genitourinary-associated tracer

Tumor

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 90

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

Four months postoperativePreoperative

Outcome

Preoperative Three years postoperative

Outcome

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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):158-62.

• 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.

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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.