Hypophosphatasia is a rare, inherited metabolic disorder that affects the mineralization of teeth and bones. Mineralization involves the deposition of calcium and phosphorus into bones and teeth to ensure they are hard, strong and stable. Defective mineralization can lead to skeletal defects and contribute to other pathologies that affect the central nervous system, the gastrointestinal tract and organs such as the kidneys.

This bone disease arises from mutation in a gene called ALPL, which codes for the enzyme alkaline phosphatase (ALP). ALP is an important contributor to mineralization and mutations in ALPL lead to the production of ALP that is no longer able to participate properly in this process. When this happens, the bones soften and become susceptible to fracture and the risk of premature tooth loss is increased.

There are six different forms of this condition and in general, patients are classified as having “perinatal,” “infantile,” “childhood” or “adult” hypophosphatasia, depending on how severe the condition is and the age at which skeletal effects were first observed. In the most severe form – perinatal lethal hypophosphatasia – the mineralization process is severely impaired and infants may be stillborn due to their skeleton failing to develop properly in the womb. Infants who are liveborn have hypercalcemia and respiratory insufficiency, which can lead to respiratory failure. Another form of the condition that affects newborns is prenatal benign hypophosphatasia. Here, there are prenatal skeletal deformities, but these improve over time until the patient can be classified as having a milder childhood or adult form of the condition.

Infantile hypophosphatasia is characterized by the development of rickets at some stage between birth and six months of age. In cases of childhood hypophosphatasia, skeletal deformity due to underlying rickets may be present or absent, but the most common manifestation is premature loss of primary (baby) teeth. Adult hypophosphatasia usually develops during middle age, with the main features of disease being premature loss of secondary teeth, recurrent fractures in the feet and painful fractures in the thigh bones.

Odontohypohosphatasia is a milder form of the condition that may develop in childhood or adulthood, but only affects the teeth. The condition causes dental caries and/or premature loss of teeth, without any symptoms of osteomalacia (soft bones) being detected.

The severe forms of hypophosphatasia are estimated to affect 1 in every 100, 000 live births, while the milder forms that develop during childhood or adulthood are thought to be somewhat more prevalent. Estimates show that in the U.S, around 1 in 300 people are carriers of the condition.

Treatment

Currently, there are no approved treatments for hypophosphatasia and treatment is focused on managing symptoms and complications in order to help patients stay active and maintain their quality of life.

The management of hypophosphatasia may require the expertise of a multi-specialist team including pediatricians, dental experts and orthopedic surgeons in order to devise a treatment plan that meets all of a patient’s individual needs. Affected individuals and their family members may also benefit from genetic counselling.

Physicians may prescribe non-steroidal anti-inflammatory drugs (NSAIDs) to treat pain in the bones and joints, although these must be prescribed with caution due to the number of side effects associated with excess doses or long-term use. Vitamin B6 may be administered to control seizures in severely affected babies and infants who develop hypercalcemia may have their dietary calcium intake restricted and receive treatment with calcitonin, hydration and diuretics.

In cases where craniosynostosis (an abnormally shaped skull) is causing increased intracranial pressure, surgery may be performed to relieve the pressure. Regular dental care is recommended from as early on as possible after diagnosis and in some cases, physiotherapy and occupational therapy may be of benefit.

Among adults who experience recurrent fractures in the long bones, an orthopedic procedure called “rodding” may be performed. Here, a surgeon inserts a metal rod through a bone’s central opening in order to stabilize and strengthen it. Foot fractures might also be managed using special orthotic devices.

Potential therapies

Although no therapies have yet been found to successfully treat hypophosphatasia, there are several that are currently under investigation. In one study, hematopoietic stem cell transplantation was found to improve symptoms in two female infants with a life-threatening form of hypophosphatasia.

A drug that has been administered “off-label” called teriparatide has been found to improve fractures in adults with hypophosphatasia who have femoral pseudofractures or metatarsal stress fractures. However, further studies are needed to establish the safety and effectiveness of this drug with long-term use.

Researchers have been investigating an enzyme replacement therapy that uses a drug called asfotase alfa as a form of bone-targeted ALP replacement. Clinical trials have so far shown improved skeletal mineralization and increases in mobility, endurance, strength, respiratory function and survival. This potential therapy also requires ongoing investigation in order to establish long-term effectiveness and safety.

An anti-sclerostin antibody has also been studied and preliminary results have shown the agent acts against sclerostin to increase bone mass. Sclerostin is a protein found in bone cells that reduces the number of bone-forming cells (osteocytes).