Bone Abstracts

Hypophosphatasia (HPP) occurs when there is lack of the activity of the alkaline phosphatase protein (ALP). The principal clinical manifestations are seen in the skeleton, although some infants can develop convulsions due to the failure of pyridoxine, cleaved from pyridoxal-5-phosphate by ALP, to enter brain cells.

HPP has traditionally been classified by age at presentation, with severe forms being diagnosed in utero or at birth because of fractures, short limbs and respiratory distress, or in the early months of life because of failure to thrive and increasing respiratory difficulty. Biochemical abnormalities include hypercalcaemia with hypercaliuria leading to diuresis and nephrocalcinosis. Craniosynostosis is seen in both treated and untreated individuals and may lead to raised intracranial pressure, necessitating craniectomy. A benign form with suggestive features in utero but post-natal resolution has been described. Homozygous or compound heterozygous mutations are responsible for the severe forms; heterozygous mutations affecting a single gene copy result in presentation in older individuals with early loss of primary dentition with intact tooth roots, bone pain, rachitic-like lesions, low bone mass, and recurrent, poorly healing fractures. Some cases are misdiagnosed as chronic recurrent multifocal osteomyelitis in older children, or as osteoporosis or ankylosing spondylitis in adults.

The fundamental defect is the loss of alkaline phosphatase activity; the clinical manifestations clearly speak to the function of ALP at a tissue level, which is its removal of factors that can inhibit mineralisation. These include pyrophosphate (PPi), generated from ADP and ATP by the action of ENPP-1, pyridoxal-5-phosphate (PLP), otherwise known as vitamin B6, and phosphoethanolamine PEA). Of these, PEA is commonly measured in the urine and PLP in serum. PPi is only available in the context of research studies.

The human phenotype is accurately recapitulated in the murine model of HPP, the Alpl−mouse. The mice die young with multiple fractures and intractable seizures. Mice treated with a recombinant human ALP protein linked to an Fc-fragment and deca-aspartate tail (initially ENB-0040, now asfotase alfa) showed clear resolution of the skeletal and neurological phenotypes. Further work demonstrated the value of the bone-targeting deca-aspartate motif with significantly increased residence time of the recombinant protein in bone allowing s.c. dosing on an intermittent basis.

There is a single published peer-reviewed paper describing the effects of asfotase alfa on the skeleton in young human subjects, showing significant improvement in the X-ray appearances of bone tissue and concomitant clinical improvement in respiratory function, motor development and calcium homeostasis. Children entered into the original study have now received more than 3 years of treatment. Some children have developed craniosynostosis requiring neurosurgical intervention, but it is unclear whether this is a treatment related effect, since some untreated individuals have similar problems.

The broader application of this form of intervention requires further study. It is unclear at present whether PTH or other forms of osteoblast-stimulating treatments have lasting benefit in this context. The use of bisphosphonates is certainly contraindicated and likely to worsen clinical outcomes, so it is important to consider HPP when starting such therapy in older patients with a low ALP at presentation.

Learning points: Variability in presentation with age.

Insights into the function of alkaline phosphatase at a tissue level.

Options for therapeutic intervention.