Treating osteoporosis: a near miss in an unusual case of FGF-23 mediated bone loss

Abstract

Oncogenic osteomalacia is a potentially curable condition caused by phosphaturic mesenchymal tumours. We present the case of 54-year-old woman who presented with bony pains and muscle weakness, and was erroneously treated with bisphosphonates elsewhere on the basis of Dual Energy X-ray Absorptiometry (bone density) scan that showed ‘severe osteoporosis’. Further evaluation revealed the presence of hypophosphatemia, with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid avid lesion involving left mandible on PET scan. Surgical excision of lesion led to improvement in her symptoms with normalisation of phosphorus, and histopathology was diagnostic of mesenchymal phosphaturic tumour. A diagnosis of oncogenic osteomalacia was made. A repeat bone mineral density assessment done a year later showed dramatic improvement. A meticulous examination and evaluation is warranted for any patient presenting with bony pains and muscle weakness. The detection of hypophosphatemia in an elderly individual should prompt the consideration of oncogenic osteomalacia, as localisation and excision of tumour usually results in cure.

Background

Osteoporosis is known to have reduced bone mass with disruption of bone architecture which results in increased risk of fragility fractures. This bone loss is more pronounced in women after menopause. However, there exists rare causes of low bone mass, such as hyperparathyroidism, hyperthyroidism, Cushing’s syndrome, drug-induced osteoporosis and osteomalacia which should be excluded before initiating treatment for osteoporosis. We report a patient diagnosed with severe osteoporosis and initiated on bisphosphonates elsewhere, but was later found to have oncogenic osteomalacia.

Case presentation

A 54-year-old postmenopausal woman, presented to our outpatient department with multiple bony pains, height loss and non-inflammatory arthralgias since 2 years. She also reported that she had significant loss of appetite during this period. She denied history of fractures, hot flushes, dysuria, renal stones or use of over-the-counter medications. There was no comorbid illness or family history of similar disease. She was evaluated elsewhere for these complaints and was diagnosed to have severe osteoporosis at the femoral neck and lumbar spine. Although she was initiated on bisphosphonate therapy elsewhere, this did not have significant impact on her symptoms and was subsequently stopped after 2 months. She had progressive difficulty in walking, was unable to rise from a squat, and over the next few months, was confined to bed.

On examination, her height was 147 cm with a body mass index of 22.6 kg/m². She had kyphoscoliosis, tenderness over bones and severe proximal myopathy. There was no lymphadenopathy, blue sclera, neck swelling or breast lumps.

Investigations

Her complete haemogram and inflammatory markers were normal. Bone biochemistry revealed a phosphorus level of 1.3 (n=2.5–4.6) mg/dL, albumin-corrected calcium of 9.0 (n=8.3–10.4) mg/dL, magnesium 2.1 (n=1.8–2.4) mg/dL, 25-hydroxyvitamin-D of 38.9 (n=30–70) ng/mL, parathormone of 102 (n=8–54) pg/mL, alkaline phosphatase of 420 (n=40–125) U/L. Tubular maximum reabsorption of phosphate (TmP)/Glomerular Filtration Rate (GFR) calculated was 1.3 (n=2.5–4.5) mg/dL. X-ray of pelvis showed fractures involving the pubic ramus.

Dual Energy X-ray Absorptiometry (DXA) scan (figure 1) showed T-score of −5.3 at the neck of femur and −4.5 at the lumbar spine (L1–L4).

Figure 1.

DXA scan of femoral neck and lumbar spine showing severe osteoporosis (T-score of < −3.5).

Differential diagnosis

With the above clinical picture and investigation results, a diagnosis of hypophosphatemic osteomalacia was considered. Fibroblast growth factor-23 (FGF-23) level was 1094 RU/mL (21.3–91). As the possibility of tumour induced osteomalacia (TIO) was thought likely, functional imaging with Ga⁶⁸DOTATATE Positron Emission Tomography – Computed Tomography (PET - CT) was done, which showed diffuse osteopenia and a 10×9 mm sized lytic lesion in the left mandible (figure 2).

Figure 2.

Ga⁶⁸ DOTATATE PET CT scan displaying a 10×9 mm sized lytic lesion in the left mandible.

Treatment

After optimal medical therapy for hypophosphatemia, she was subjected to a left posterior segmental mandibulectomy with pectoralis major myocutaneous flap reconstruction. The biopsy showed features consistent with phophaturic mesenchymal tumour. Following surgery her phosphate supplements were stopped. On the fifth postoperative day, her serum phosphorus improved to 3.9 mg/dL.

Outcome and follow-up

She made gradual recovery of both bone pains and muscle weakness. Her FGF-23 was 369 RU/mL following surgery. Four months later, her phosphorus and FGF-23 were 4.8 mg/dL and 44 RU/mL, respectively. One year later, a follow-up DXA scan (figure 3) displayed dramatic improvement in the T-score values to –1.3 at the neck of femur and –1.7 at the lumbar spine (L1–L4). She was completely asymptomatic and independent in carrying out her activities of daily living at the end of 1 year.

Figure 3.

Follow-up DXA scan of femoral neck and lumbar spine showing marked improvement in bone mineral density.

Discussion

Osteomalacia, which results in poor mineralisation of the osteoid can result from various causes. The common causes of rickets and osteomalacia are shown in table 1. Oncogenic osteomalacia, also known as TIO, is a rare condition that results from the overproduction of phosphatonins from mesenchymal tumours. The tight regulation of phosphorous is essential for normal functioning of organisms. Phosphatonins are molecules that form part of the adaptive machinery to protect organisms from conditions of hypophosphatemia and hyperphosphatemia. FGF-23 is one of the chief phosphatonins, which functions to inhibit phosphorus reabsorption by reducing the expression of the sodium-phosphate cotransporter types IIa and IIc.¹

Table 1.

Causes of rickets and osteomalacia

Vitamin D deficiency	Inadequate dietary intake, poor sunlight exposure, malabsorption, increased vitamin-D catabolism by medications like phenytoin and carbamazepine, deficient hydroxylation in cirrhosis and renal failure
Deficient vitamin D action	Vitamin D resistant rickets types 1 and 2
Hypophosphatemia	Inadequate absorption of phosphate due to antacids, impaired renal reabsorption of phosphate due to various hereditary causes of hypophosphatemia (X-linked, Autosomal Dominanant (AD) and Autosomal Recessive (AR)), tumour-induced osteomalacia, renal tubular acidosis
Defective mineralisation	Fibrogenesis imperfecta, osteogenesis imperfecta, axial osteomalacia, hypophosphatasia

The paraneoplasitc syndrome of oncogenic osteomalacia presents itself as a diagnostic challenge, mainly because its identification consists of exclusion of other causes, and the localisation of these small tumours is often difficult.² They secrete phosphotonin like FGF-23 which are phosphaturic substances that lead to decreased renal reabsorption of phosphate, hypophosphatemia, muscle weakness and osteomalacia.³ Although the majority of mesenchymal tumours secrete FGF-23, other putative phosphatonins that may cause hypophosphatemic osteomalacia include secreted frizzled related protein 4, FGF-7 and matrix extracellular phosphoglycoprotein.⁴ Although phosphaturic mesenchymal tumours are described as rare tumours that occur in unusual sites,⁵ common locations include the extremities and head and neck region.⁶ When a diagnosis of oncogenic osteomalacia is considered, accurate localisation of the tumour is of utmost importance. This can often be challenging, as these tumours are usually very small. Thus, a functional imaging of the whole body, with scans extending from the head to the foot is required. Therefore, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-PET CT is utilised in identifying these tumours where the somatostatin analogues are labelled with gallium (Ga)−68 using the DOTA conjugate. The rationale for using DOTA PET is that, tumours implicated in oncogenic osteomalacia variably express five somatostatin receptors (SSTR1–5), thus allowing SSTR-based functional imaging by somatostatin analogue scintigraphy or positron emission tomography for localisation of the tumour.⁷ In the presence of more than one lesion, selective venous sampling with measurement of FGF-23 may be indicated for precise localisation.³

The treatment of choice for TIO is resection of the tumour with a wide margin to ensure that the complete tumour is removed. Although there have been occasional reports of recurrence of these tumours, complete excision usually results in improvement of symptoms, with gradual recovery of bone mass. Medical management with phosphate supplements and calcitriol is initiated as a bridge to surgery, to facilitate improvement in patient’s symptoms. Occasionally, these tumours are not localised and rarely, surgery may not result in clinical cure. In such circumstances, medical therapy with phosphate supplements and calcitriol may be continued for alleviation of symptoms. Hoffman et al report a case of linear sebaceous naevus syndrome, in which the use of octreotide helped in improving musculoskeletal symptoms, reduction of FGF-23 and normalisation of serum phosphorus.⁸ Recently, Burosumab, a monoclonal antibody directed against FGF-23 was shown to be beneficial in treating children with FGF-23 mediated X-linked hypophosphatemic rickets.⁹ The efficacy of the same, in cases of TIO where the lesion is not localised or surgery has failed, is yet to be proven.

Low bone density as measured by a DXA scan is usually considered to be diagnostic of osteoporosis. However, DXA scan does not differentiate between low bone mass caused by osteomalacia and that due to osteoporosis. The presence of symptoms such as muscle weakness and bony pains, with difficulty in walking, which are not in keeping with a diagnosis of osteoporosis, and the occurrence of pseudofractures on plain radiographs, should alert the clinician to an alternate diagnosis. The scrupulous analysis of patient’s symptoms and bone biochemical parameters would help in making a diagnosis of osteomalacia. The hypophosphatemia induced by renal phosphate wasting leads to poor mineralisation of the bone. In response to this, there is a compensatory osteoblast hyperactivity, which leads to an elevation in the levels of alkaline phosphatase. Thus, high levels of alkaline phosphatase, in the presence of typical symptomatology and supporting radiographs, form one of the telltale indicators of osteomalacia.

Thus, a careful attention to the patient’s symptomatology, complemented by stepwise assessment of laboratory parameters and radiographs, is essential in correctly diagnosing a case of osteomalacia and initiating appropriate therapeutic measures.¹⁰

Learning points.

• The occurrence of bony pains, fractures and muscle weakness, warrants further evaluation to exclude the presence of an underlying osteomalacia.

• In an elderly individual, tumour induced osteomalacia should be sought for, when patient presents with bony pains, muscle weakness and hypophosphatemia.

• Appropriate investigations and imaging will assist in forming the right diagnosis and planning suitable treatment options.

• Surgical excision of the lesion usually results in cure, with gradual improvement of symptoms.