New treatment shows promise for kids with life-threatening bone disorder

March 7, 2012
At the beginning of the study, one patient's hand has almost no visible bone in an X-ray (left). After 24 weeks of treatment, substantial bone formation is visible in the same hand (right). Credit: The New England Journal of Medicine, copyright 2012

Doctors at Washington University School of Medicine in St. Louis, working with Shriners Hospital for Children and other institutions, have identified a promising new treatment for a rare and sometimes life-threatening bone disorder that can affect infants and young children.

Known as hypophosphatasia, the condition upsets , blocking important minerals such as calcium from depositing in the skeleton.

In the March 8, 2012, issue of the , researchers report that at one year of treatment with a new compound, young patients with the most severe forms of hypophosphatasia typically showed greatly improved symptoms, including increased , better breathing and improved motor development. Some children made enough progress to walk.

"This was a small trial, but we were thrilled to see these results," says first author Michael P. Whyte, MD, professor of medicine, of pediatrics and of genetics at Washington University School of Medicine in St. Louis, who treats patients at Shriners Hospital for Children in St. Louis. "From our experience with studies in mice, we had high hopes. But I think the outcome thus far is beyond anything we had expected."

Hypophosphatasia varies greatly in severity. Its mildest forms may not become apparent until adulthood, and sometimes it may only affect teeth. But in childhood and especially infancy, it can lead to bone weakness, known as rickets. In its most severe forms, hypophosphatasia can lead to death by and has been estimated to occur in about one in 100,000 births. But this number varies worldwide. It is most common in the Mennonite community in Manitoba, Canada, where one in every 2,500 newborns shows severe disease.

"When the condition is extremely severe, a baby may be born with almost no visible bones in an X-ray," says Whyte, also the medical and scientific director of the Center for and Molecular Research at Shriners Hospitals for Children in St. Louis. "If an infant has fractured or very thin ribs, the thorax is not going to work properly as a bellows, and respiration is compromised. Together with the profound muscle weakness also seen in severe hypophosphatasia, respiratory lethality is a frequent consequence."

Eleven infants and young children diagnosed with severe hypophosphatasia were recruited to participate in the study. At the beginning, they ranged in age from 20 days to three years. Since there is no approved medical therapy for hypophosphatasia, all 11 patients could receive the experimental treatment, a compound called ENB-0040, also known as asfotase alfa.

At the beginning of the study, nine of the 11 patients had severe or extremely severe rickets; two were classified as moderate. Most patients required respiratory support to help them breathe. Delayed in motor development, most could only turn their heads while lying on their backs. Two of the older children (between 2 and 3 years old) could sit unsupported, but could not crawl or pull to standing.

Nine of the patients completed one year of treatment. One patient withdrew from the treatment, and one patient died due to sudden fever and sepsis that was not attributable to the experimental therapy.

After six months of treatment, most patients showed substantial healing of rickets. After one year, six patients were breathing unaided. Of the nine patients who completed one year of treatment, all made progress, sometimes significant, in motor development. One progressed to moving all limbs against gravity, one to sitting unsupported, two could crawl, one pulled to standing, and two started taking steps. Of the two older children who could only sit, both progressed to walking after a year of treatment.

As with many genetic disorders, hypophosphatasia is caused by mutations that impair an important protein. In this case, the protein is an enzyme called alkaline phosphatase.

Impaired alkaline phosphatase can't break down chemicals as it should. One of the chemicals that builds up as a result is known to inhibit mineralization, blocking calcium and phosphate crystals from growing and entering the skeleton to build normal bone.

The experimental treatment used in this study, ENB-0040, is a manufactured form of normal alkaline phosphatase, but enhanced so that it is targeted to bone.

Treating these patients by giving them normal alkaline phosphatase is not a new idea, Whyte says. More than two decades ago, he and his colleagues at Washington University attempted to treat patients with hypophosphatasia by giving them blood plasma with excess alkaline phosphatase.

That unsuccessful study showed that raising alkaline phosphatase levels in the blood was not enough. More recently, Whyte's industry collaborators have provided the missing link: Adding a short protein chain that adheres to bone allowed the to be targeted to the skeleton.

Paving the way for this human study, Whyte and his colleagues then showed that the targeting chain worked well in a mouse model of severe hypophosphatasia, restoring normal life span to mice, as long as they received daily injections of ENB-0040 starting at birth.

The nine patients who completed one year of treatment continue to receive therapy and are now participating in an extension study. For more information about clinical trails recruiting patients with hypophosphatasia, visit

Explore further: Researchers look to dogs to better understand intricacies of bone cancer

More information: Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz, RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. New England Journal of Medicine. Vol 366. Pages 904 – 913. March 8, 2012.

Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. Journal of Bone and Mineral Research. November 2008.

Related Stories

Researchers look to dogs to better understand intricacies of bone cancer

July 28, 2011
A new University of Minnesota discovery may help bone cancer patients fight their disease more effectively, according to new research published in the September issue of Bone.

Recommended for you

Mind-body therapies immediately reduce unmanageable pain in hospital patients

July 25, 2017
Mindfulness training and hypnotic suggestion significantly reduced acute pain experienced by hospital patients, according to a new study published in the Journal of General Internal Medicine.

Researchers report new system to study chronic hepatitis B

July 25, 2017
Scientists from Princeton University's Department of Molecular Biology have successfully tested a cell-culture system that will allow researchers to perform laboratory-based studies of long-term hepatitis B virus (HBV) infections. ...

Research examines lung cell turnover as risk factor and target for treatment of influenza pneumonia

July 24, 2017
Influenza is a recurring global health threat that, according to the World Health Organization, is responsible for as many as 500,000 deaths every year, most due to influenza pneumonia, or viral pneumonia. Infection with ...

Scientists propose novel therapy to lessen risk of obesity-linked disease

July 24, 2017
With obesity related illnesses a global pandemic, researchers propose in the Journal of Clinical Investigation using a blood thinner to target molecular drivers of chronic metabolic inflammation in people eating high-fat ...

Raccoon roundworm—a hidden human parasite?

July 24, 2017
The raccoon that topples your trashcan and pillages your garden may leave more than just a mess. More likely than not, it also contaminates your yard with parasites—most notably, raccoon roundworms (Baylisascaris procyonis).

Google searches can be used to track dengue in underdeveloped countries

July 20, 2017
An analytical tool that combines Google search data with government-provided clinical data can quickly and accurately track dengue fever in less-developed countries, according to new research published in PLOS Computational ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.