Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

FGF23-mediated hypophosphataemic osteomalacia with low bone turnover (#22)

Yeung-Ae Park 1 , Cherie Chiang 1 , Christopher Yates 1 2
  1. Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia
  2. Department of Diabetes and Endocrinology, Western Health, Sunshine, Victoria, Australia

Case Summary

A 29-year-old female presented with chronic bilateral proximal thigh pain on a background of fibroblast growth factor 23 (FGF23) mediated hypophosphataemic osteomalacia with atypically suppressed bone turnover markers (BTM). The patient was initially diagnosed with hypophosphataemia at the age of 19 and has experienced brittle dentition, multiple fragility and insufficiency fractures with bilateral femur Looser zones, right wrist fracture, rib fractures, bilateral cuboid stress fractures and metacarpal fractures requiring multiple operations. These fractures have been complicated by non-union/markedly delayed healing and chronic pain. The patient is a highly functioning medical practitioner, with no smoking or alcohol history and no dysmorphic features. There is no history of nephrolithiasis, hearing impairment or family history of osteoporosis. Her height is 163 cm and weight is 65 kg. Other medical history includes juvenile arthritis on leflunomide and methotrexate, and narcolepsy.

 

Serum phosphate level was low (0.35 mmol/L [refence range 0.75-1.50 mmol/L]) with evidence of urinary phosphate wasting (22 mmol/24h [15-60 mmol/24h]) and low renal tubular maximum reabsorption rate of phosphate relative to glomerular filtration rate (TmP/GFR) (0.53 mmol/L [0.84-1.23 mmol/L]). FGF23 was inappropriately normal (78 ng/L [23-95 ng/L]). Serum calcium levels, 25-hydroxy vitamin D, 1,25-dihydroxyvitamin D3 and estimated GFR were normal. There was no metabolic acidosis to suggest Fanconi’s syndrome. Interestingly, parathyroid hormone (PTH) was normal (5.3 pmol/L, [1.7-10.0 pmol/L]) and bone turnover was atypically low with alkaline phosphatase (ALP) of 39 U/L (30-110 U/L), bone-specific ALP of 8.8 microg/L (5.5-24.6 microg/L), C-terminal telopeptide of type 1 collagen (CTX) of 172 ng/L (150-800 ng/L), and procollagen type I N-propeptide (PINP) of 21 mcg/L (15-70 mcg/L) in the setting of multiple fractures and poor healing. A bone biopsy demonstrated increased osteoid thickness consistent with osteomalacia and decreased number of double labels relative to bone surface. No pathogenic variants were found on targeted whole exome sequencing of genes related to hypophosphataemic rickets or osteogenesis imperfecta (Table 1). Bone mineral density on dual x-ray absorptiometry scan was normal. MRI brain revealed no evidence of Chiari malformation. A Ga-68 DOTATATE positron emission tomography scan demonstrated no mesenchymal tumours.

 

After confirming FGF23-mediated hypophosphataemic osteomalacia and satisfying Pharmaceutical Benefits Scheme (PBS) criteria, burosumab was commenced one week after cessation of calcitriol and phosphate supplementation. Recommended weight-based dosing of burosumab was complicated by hyperphosphataemia (1.91 mmol/L [0.75-1.50 mmol/L]) two weeks post-dose and after resolution a halved dose of burosumab was recommenced without further adverse events.

 

Within a month of recommencement of burosumab, a bone scan to investigate new proximal bilateral thigh pain demonstrated focally increased osteoblastic activity in the medial cortices of the proximal femoral shafts bilaterally, suggestive of new insufficiency fractures. Other areas osteoblastic activity were identified throughout the skeleton, corresponding with previous fracture sites and delayed healing (Figure 1). Surgical management was sought by the patient with bilateral intramedullary nails inserted after her orthopaedic surgeon determined the risk of fulminant fracture was high without intervention. After 3 doses of burosumab, TmP/GFR has now normalised, although symptomatic benefits are yet to occur. Clinical and radiological benefits with a repeat bone scan after 6 months of burosumab will be presented at the ANZBMS meeting.

 

Discussions

Hypophosphataemic osteomalacia has a wide range of clinical effects, including varus deformity of the lower limbs, gait disturbance, muscle weakness, enthesopathy, nephrocalcinosis and dental necrosis affecting morbidity and quality of life.1 FGF23 is a key regulator of phosphate homeostasis and increases renal phosphate excretion and decreases the production of 1,25 dihydroxyvitamin D in renal proximal tubules.2, 3 The ratio of maximal total reabsorption of phosphate compared to glomerular filtration rate (TmP/GFR) utilising fasting paired plasma and second-morning void urine phosphate levels,4 is reduced in FGF23-mediated hypophosphataemic osteomalacia.5

 

The most common cause of FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH) secondary to a loss of function pathogenic variant in PHEX gene affecting 1/20,000.6 Other inherited causes of FGF23-mediated hypophosphataemia include autosomal dominant and autosomal recessive hypophosphataemic rickets, alpha-klotho translocation, fibrous dysplasia-McCune-Albright syndrome, cutaneous skeletal hypophosphataemia syndrome, osteoglophonic dysplasia, and SGK3 mutations.1 Acquired forms of FGF23-mediated hypophosphataemia include tumour-induced osteomalacia (TIO) and intravenous ferric carboxymaltose use.1 Our patient’s extensive genomic screen did not find pathogenic gene defects, and mesenchymal tumours were excluded on a PET scan, suggestive of yet-to-be-identified pathogenic genes.

 

Historically, phosphate and 1,25 dihydroxyvitamin D supplementation have been the cornerstone of therapy. However, burosumab, a recombinant human IgG1 monoclonal antibody against FGF23, has demonstrated superior efficacy in achieving serum phosphate control,7, 8 improvements of physical ability, pain control and mineralisation defects compared to the conventional treatment.1 Fasting phosphate level should be checked at two weeks post-injection to assess for hyperphosphataemia and titration of the medication.9 Other adverse events include minor injection site reactions, pain in the extremities, fever, myalgia and rash.7 Currently, burosumab is subsidised by the PBS for XLH and those with FGF23-mediated hypophosphataemic osteomalacia without PHEX gene mutation.

 

ALP and BTM are typically elevated in patients with hypophosphataemia and rickets,10 which reflects accelerated bone remodelling.11 Our case is an atypical case of FGF23-mediated hypophosphataemic osteomalacia with inappropriately normal BTM despite evidence of osteomalacia on bone biopsy, atraumatic poor healing fractures and chronic bony pain. ALP and BTM may be normal in TIO,1 however, mesenchymal tumours have been excluded on a PET scan in our case. Whole genome sequencing of the patient and her parents may be warranted to determine the cause of hypophosphataemic osteomalacia with low BTMs in this case.

 

Take home messages:

  • FGF23-mediated hypophosphataemic osteomalacia has various clinical implications, including varus deformity of the lower limbs, gait disturbance, muscle weakness, enthesopathy, nephrocalcinosis and dental necrosis, and is typically associated with elevated bone turnover markers.
  • The most common FGF23-mediated hypophosphatemia is XLH secondary to a loss of function pathogenic variant in the PHEX gene. However, other genetic causes are possible, and more are yet to be identified.
  • Burosumab, an FGF23 antibody, leads to significant improvement in serum phosphate and fracture healing in XLH and may be an effective treatment for other causes of FGF23-mediated hypophosphatemia
  • A novel gene abnormality may explain this unusual case of hypophosphataemic osteomalacia with low bone turnover markers.

 

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