Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Case

We present the case of a 67-year-old Caucasian lady with hypophosphatasia receiving compassionate access to asfotase alfa.

She was diagnosed with hypophosphatasia aged 29 years when she presented with foot pain from metatarsal fractures.  Her diagnosis was made biochemically, with persistently low serum alkaline phosphatase (ALP) (initially 14 U/L, normal range [NR] 30-110 U/L) and elevated urinary phosphoethanolamine (PEA) (43 mmol/mol creat, NR <5 mmol/mol creat).  Bone biopsy in 1981 showed osteomalacia, consistent with hypophosphatasia. In 2017, a novel heterozygous ALPL mutation was identified (c.202_204delACG, p.Thr68del) affecting the alkaline phosphatase domain, categorised as “likely pathogenic”.   Assessing family history proved very difficult as she had migrated from the Netherlands as a child.

Relevant history included ulcerative colitis initially managed with prednisolone enemas and salazopyrin, both ceased upon total colectomy with J-pouch formation at age 35 years.

In retrospect, the patient had early deciduous teeth loss; and she reported lower limb pain and weakness during childhood although no fractures.  Following her presentation, she had numerous fractures and required 29 separate orthopaedic procedures, including bilateral intramedullary femoral nails.  Her historic fracture rate appeared to increase with age, such that she required eight separate orthopaedic procedures between ages 60 and 64 years, and she even fractured her radius picking up a cup of tea.  At age 63 years, she was wheelchair-bound and required hoist transfers, rendering her house-bound. She required assistance with all activities of daily living, including writing, eating, drinking, and hair brushing, due to pain, fracture risk and limb deformity.  She required opiate analgesia, paracetamol and non-steroidal anti-inflammatory drugs.  At age 65 years, a suprapubic catheter was inserted and end ileostomy formed because of increasingly problematic toileting.

In July 2018, at age 66 years, the patient received compassionate access to enzyme replacement therapy asfotase alfa 1mg/kg subcutaneous injection three times per week. This was well tolerated with mild injection site reactions.

Her pain rapidly improved, allowing cessation of all analgesia. On the patients Brief Pain Inventory, a questionnaire grading pain severity and impact on functioning, her baseline score of 70 improved to 17 after six weeks of treatment. Her function improved markedly, assessed formally by a physiotherapist and by questionnaires (Table 1).  She can now sit unsupported.  She can walk during hydrotherapy and is making progress towards weight-bearing.  Her bone deformities limit her ability to stand unassisted; consideration is being given for osteotomies to improve limb alignment. Her quality of life is much better - she is now able to feed herself, write, and brush her hair, and to help with light housework.

Her biochemistry showed increased bone turnover markers and ALP, with normalisation of PEA (Table 2).  HDP-labelled bone scintigraphy demonstrated fracture healing, with reduced uptake at old fracture sites, and generalised increased background uptake (Fig. 1).  She has had no new fractures.

This case demonstrates that asfotase alfa can greatly benefit adults with disabling hypophosphatasia, even when started late in life.

Discussion

Hypophosphatasia is a rare metabolic condition resulting from loss-of-function mutations in ALPL, which codes for tissue non-specific alkaline phosphatase (TNSALP).  Diminished TNSALP activity reduces hydrolysis of inorganic pyrophosphate (PPi) to inorganic phosphate; as a consequence, extracellular levels of PPi (a potent bone mineralisation inhibitor) increase.

Hypophosphatasia has a very broad phenotype - from absence of bone mineralisation and in-utero fetal death to mild musculoskeletal disturbances in adulthood.  In part this arises from its complex genetics. Most severe cases are due to recessive mutations; less severe cases may be dominantly or recessively inherited. Predicting phenotype is further affected by incomplete penetrance (approx. 30% for dominant mutations) and variability expressivity (differing severity of disease in affected individuals).  To date, over 360 mutations in ALPL have been identified, causing variable residual TNSALP activity according to the region(s) of TNSALP affected.^1,2,3.

Until recently, hypophosphatasia management was limited to best supportive care, with the most severe cases dying in utero or in early life.  Asfotase alfa is a recombinant TNSALP fusion protein, consisting of a TNSALP ectodomain, a human IgG₁ Fc domain, and a terminal deca-aspartate motif for binding to hydroxyapatite.  Asfotase alfa dramatically improved skeletal mineralisation, respiratory function and survival in life-threatening perinatal and infantile hypophosphatasia^4.  A trial of older children, aged 6-12 years, demonstrated sustained radiological and functional improvements over a five year period⁵.  In 2016, asfotase alfa was approved by the Australian Therapeutics Goods Administration for use in paediatric onset hypophosphatasia. 

A 2019 publication of asfotase alfa use in an adolescent and adult population (ages 13 to 66 years) demonstrated functional improvements, sustained over five years of therapy⁶.  Two case studies of two adults aged 41 and 61 years demonstrated fracture healing after initiation of asfotase alfa⁷.

The long term safety of asfotase alfa is still being assessed.  Injection site reactions are frequent; and ectopic eye calcification and nephrocalcinosis have been reported⁸.  Optimal dose and duration of therapy are both unclear; and whether it should be offered to all individuals (particularly adults) with hypophosphatasia is a moot point.

This woman had progressive and debilitating hypophosphatasia resulting in innumerable fractures and considerable morbidity.  She was fortunate to receive compassionate access to asfotase alfa; and has had amazing functional improvements allowing her to re-engage with life.  Her case demonstrates that asfotase alfa has a role in the treatment of adults with hypophosphatasia.  However, its high cost (>$AU 2,500,000/year) means optimal dose, timing, and duration need consideration.

Key learning points:

1. Hypophosphatasia has a broad clinical spectrum. Even cases presenting later in life can have disabling disease.
2. Enzyme replacement with asfotase alfa can improve fracture burden, functional status and quality of life in adults with hypophosphatasia.
3. Optimal dose and duration of treatment is unknown.
4. The high cost of asfotase alfa means subsidised treatment is likely to be restricted to those with most severe disease; however, this may include adults as well as children.