Is there a Cure?

Montreal-based Enobia Pharma developed ENB-0040, a drug that may help patients overcome the effects of Hypophosphatasia (HPP). The drug has undergone testing in Canada and the United States. The Winnipeg Health Region’s Children’s Hospital was the first centre in the world to enrol both adults and infants into clinical trials of the drug.

The alkaline phosphatase is given by injection under the skin. The drug was engineered to be attracted preferentially to bone tissue. There it acts by allowing phosphate and calcium to deposit and harden bones and helps to prevent bone demineralization.

Health Canada issued a notice of compliance for asfotase alfa marketed by Alexion Pharmaceuticals, Inc. as StrensiqTM, in 2015, as the first therapy for pediatric-onset (before age 18) HPP. The drug may be used in addition to supportive care to decrease the morbidity associated with the disease. Infants and children need to be checked regularly for evidence of increased intracranial pressure.

Approval of asfotase alfa was based on four prospective, open-label studies involving 99 patients who developed HPP in utero, as an infant, or as a juvenile. They received the drug for up to 6.5 years. Patients with either perinatal or infant onset of the disease who were treated with asfotase alfa showed improvement in overall survival, as well as ventilator-free survival. Ninety-seven percent of patients receiving the drug were alive at age 1 year compared with 42% of control patients selected from a natural history study group. The ventilator-free survival rates for both groups followed much the same pattern. Patients with juvenile-onset HPP also experienced improved growth and bone health compared with patients in a natural history database.

Medical/Supportive Care

Observe fractures closely.

Adult pseudofractures may require orthopedic care to heal properly.

A dentist should closely monitor all individuals with HPP.

Various treatments have been attempted, including zinc, magnesium, cortisone bisphosphonates, and plasma. The results have not been encouraging with these older therapies.

Response to teriparatide treatment was seen in terms of decreased pain in 6 postmenopausal women, and no response was seen in 1 premenopausal woman.

Evidence also suggests that donor bone fragments and marrow may provide precursor cells for distribution and engraftment in the skeletal microenvironment to form TNSALP-replete osteoblasts, which may improve mineralization. The effects of bone marrow transplant in HPP appear to be transient, as bone lesions may recur approximately 6 months after the transplantation.

Nonsteroidal anti-inflammatory (NSAID) drugs have been used in patients with childhood HPP with some clinical improvement, although more experience is warranted. Childhood HPP patients, who often complain about pain in the lower limbs without evident fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate, but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HPP and normal fibroblasts in vitro. Clinical features of childhood HP related to pain in the lower legs may be, at least in part, sequelae related to elevated PG levels, secondary to the primary metabolic defect. Consequently, NSAID treatment does improve the clinical features of childhood HPP.

Enzyme replacement therapy with partially purified plasma enzyme was attempted, but with little clinical improvement.

Some success has been achieved in delivering functional TNSALP enzyme to bone.

Surgical Care

Orthopedic surgical involvement may be necessary in patients with HPP. Rachitic deformities and gait abnormalities require orthopedic evaluation. For them to heal completely, fractures, pseudofractures, and bone deformities may require rod placement. Patients may need neurosurgery for craniosynostosis.

Diet

No special diet for HPP is followed. Monitoring calcium intake is advised. Avoid vitamin and mineral supplements for rickets. The traditional defects of vitamin D metabolism are not present in HPP, and excessive vitamin D can cause hypercalcemia and other side effects.

Activity

Although no distinct guidelines have been established, avoidance of contact sports and adequate protection of the teeth are advisable. In some cases, children sitting at desks for long periods of time may lead to exhaustion, as well as difficulty printing and writing for long periods of time. Use of a computer and a slanted desk (architect style) can relieve stress and occupational therapy may be necessary to strengthen hands and wrists. Physical therapy has proven to be greatly beneficial in restoring and maintaining mobility. Backpacks on wheels can relieve pressure of carrying heavy books. Therapeutic horseback riding and swimming can be beneficial as the muscles are exercised with little pressure to joints and bones. These forms of exercise are great equalizers for children experiencing confidence issues related to not being able to participate well in traditional sports involving lots of running. As with anything, please contact your healthcare team to draw up a protocol that is beneficial for your family as each patient differs greatly.

Consultations

The skeletal involvement of HPP requires consultation with an orthopedist. Patients with the infantile and childhood form should have regular follow-up appointments with their orthopedist. Evaluate adults for pseudofractures of the femur or stress fractures of the metatarsals.

Refer all patients with any form of HPP to a dental specialist. Construction of dentures may be necessary if the permanent teeth cannot be preserved. Patients should see a metabolic bone diseases specialist.

Patient Education

Genetic counseling is important for all families who have affected children. A pedigree is essential, especially for the childhood, adult, or odontohypophosphatasic forms, which can have either autosomal dominant or recessive forms. Options for future pregnancies, such as prenatal testing for the perinatal form, should be discussed with parents.

Stanford University’s Chronic Disease Self-Management Program (Better Choices, Better Health® Workshop):

http://patienteducation.stanford.edu/programs/cdsmp.html

and Chronic Pain:

http://patienteducation.stanford.edu/programs/cpsmp.html

are offered in many provinces under different names such as LiveWell with Chronic Conditions in Saskatchwan:

https://www.saskatoonhealthregion.ca/locations_services/Services/cdm/Documents/Home/Chronic%20Disease%20Management%20Program%20Catalogue.pdf

or Living Well Self Management Program of South Eastern Ontario:

http://www.livingwellseontario.ca/index.cfm/workshops/chronic-disease/

are excellent options for education, encouragement and support for families facing chronic disease and pain. They learn many techniques and foster relationships to build support in self-managing their disease.