Potential Treatment Found for Debilitating Bone Disease

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Heterotopic ossification (HO) is a painful and often debilitating abnormal buildup of bone tissue which consists of ectopic bone formation within soft tissues after surgery or trauma.

HO comes in two main forms—a congenital form which appears in children and another that strikes wounded military personnel and surgery patients which is triggered by severe injuries and wounds.

Promising new research in an animal study reveals a potential treatment for HO. An animal study by developmental biologists shows that a drug that interrupts a signaling-nuclear protein pathway can prevent HO. The study appeared online yesterday in Nature Medicine.

Masahiro Iwamoto, D.D.S., Ph.D., and Maurizio Pacifici, Ph.D., developmental biologists in the Division of Orthopaedic Surgery at The Children's Hospital of Philadelphia, and colleagues used retinoid agonists, a class of agents related to vitamin A, in mice that were genetically engineered to model HO in the current study.

Specifically, they used nuclear retinoic acid receptor-γ (RAR-γ) agonists, which selectively target a regulatory pathway during cartilage formation—an essential step in the development of HO.

The exact mechanism by which HO occurs is not fully understood. It occurs after trauma, surgery or deep burns causes local inflammation. This is then followed by the arrival of skeletal cells that develop into chondrocytes (cartilage cells), and are then replaced by intrusive bone.

The RAR-γ agonists prevented HO from occurring in the mice, with minimal side effects. In contrast, control mice developed HO-like bone masses. Even more encouragingly, the protective effect appeared to be permanent, persisting even after drug treatment ended.

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Furthermore, the same agent blocked HO from occurring in mice that had been genetically engineered to express a mutant protein analogous to the one found in children with FOP.

As many as 10 to 13 percent of orthopedic patients may develop HO after knee replacement or other invasive surgeries. Most of these do not have major symptoms.

The incidence of HO is far higher in wounded soldiers—nearly 65 percent—because modern weapons cause extreme, wide and deep tissue damage.

Although HO is not life-threatening, the bone growths can press against nerves and blood vessels, resulting in chronic pain, limited motion, problems fitting prosthetic limbs and other complications.

The congenital form of the disorder is called fibrodysplasia ossificans progressiva (FOP) and becomes manifest in children by the age of 5 or 6. While very rare, affecting an estimated 700 U.S. children, it is progressive and often fatal in young adults. Any surgery in children with FOP can trigger explosive HO.

"These agents have the biological properties needed to interfere with the specific events that occur in HO," said Pacifici. "If these animal results are borne out in humans, we may have very potent and effective treatments for both forms of this disease—injury-induced HO and the congenital form."

The authors cautioned that more in-depth preclinical studies must be performed before retinoid agonists are tested in humans with HO. They pointed out, however, that one retinoid agonist is already being used in a current clinical trial for another disease, and it might be possible to gain access to this agent from the manufacturer for clinical trials.

Sources
Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists; Kengo Shimono, Maurizio Pacifici, Masahiro Iwamoto, et al; Nature Medicine, published online April 3, 2011. doi:10.1038/nm.2334

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