"Grief never mended no broken bones," wrote Charles Dickens (1812-1870) in 1836.

Molecular/cellular biologist Vishwas Paralkar wrote: "The skeleton has the unique ability to repair and heal itself after injury." That rebuttal of Dickens' epigram appeared in the Proceedings of the National Academy of Sciences (PNAS) released online May 13, 2003. Its title: "An EP₂ receptor-selective prostaglandin E₂ agonist induces bone healing." Paralkar, a principal investigator at Pfizer R&D Labs in Groton, Conn., is lead author of the PNAS paper.

"The main finding," he told BioWorld Today, "is that we have dissected and identified the EP₂ mechanism of prostaglandin (PG), which is responsible for local bone healing. PGE₂, produced at the site of fracture injury_, causes significant increases in bone mass and bone strength, including treatment of osteoporosis, when administered systemically or locally to the skeleton. However," he added, "due to side effects, including diarrhea, lethargy and flushing, PGE₂ is an unacceptable therapeutic option for bone healing."

Paralkar cited "two new things in the PNAS paper. First," he noted, "the EP₂ receptor itself has not been definitely identified as playing a role in the local induction of bone healing. So it has a potential usefulness for fracture repair that is really novel. This paper was one of the first reports showing the role of these receptors in fracture healing.

"The EP₂ selective agonist, CP-533,536 [a Pfizer code number]," Paralkar went on, "has the ability to heal canine long bone segmental and fracture model defects without the objectionable side effects of PGE₂. This suggests that the EP₂ receptor subtype is a major contributor to PGE₂'s local bone anabolic activity.

"The morbidity and mortality associated with impaired/delayed fracture healing remain high," Paralkar observed. "In 10 percent of cases, fractured bones heal more slowly (malunion) or fail to heal (nonunion). These require additional costly medical intervention to repair the fracture. Malunions and nonunions cause significant patient morbidity, limiting quality of life and increasing health care costs."

Tempted By Surgery-Free Options? Can Be Tough!

"Bone healing without surgery," Paralkar explained, "could mean malunion or nonunion. One would have to go back and resurgerize in order to break and set the bone again and try to induce the fracture-healing process. The other treatment," he continued, "would be standard of care, using autografts for taking bone from a site within yourself and grafting it into the side that is not healing. Otherwise, going in with pins and clamping the fracture rigid in order to induce healing.

"Our objective," he said, "was to identify a small molecule with the ability to promote fracture healing and prevent malunions. So our main message would be that we have separated out the unacceptable side effects of prostaglandin and identified the acceptable mechanism that would lead to bone healing."

That "mechanism" took the form of an EP₂ selective agonist, an as-yet nameless compound identified as CP-533,536 and tested on the broken tibial bones of 40 anesthetized lab rats and 63 anesthetized beagles. "We had a program looking at receptor-selective agonists with the PG receptors EG₂," Paralkar recalled. "So this compound came from direct chemical synthesis specifically done in Pfizer's chemical lab. I work in the biology department.

"When injected directly into the tibial bone marrow of rats," Paralkar recounted, "CP-533,536 mimicked the effects of PGE₂. That is, it increased total bone area, mineral content and mineral density. Because it's a local injection, we tested without any difficulty.

"We conducted three separate experiments on the dogs," he recounted. "Nos. 1 and 2 were similar. A 1.5-cm critical sequential defect was cut in the beagles' mid-ulna. Then we closed the surgical incisions on the animals' forelimbs and injected them with the CP compound. This showed we could get bone healing, but we would need daily injections. This made no sense from the point of view of humans. We couldn't expect the patient to come in every day for a stated number of days. That was the limiting factor. So what we did was develop a biodegradable matrix, which allowed us to give one application or injection - and it induced healing in this model.

"Canine test three was a separate experiment, where we used a different protocol. This model healed itself - the first one with the ability to heal. And it showed a capacity, without any help, to heal faster than the normal process. Over all, when administered to dogs with fractured ulnas, the CP small molecule significantly accelerated healing, without the side effects of prostaglandin. These results suggest that CP-533,536 may be a promising alternative to surgery for the enhancement of bone healing."

28 Rats, 63 Beagles Populate Preclinical Tests

"Given the high morbidity associated with fracture malunions," the PNAS paper concluded, "and the limitations of current procedures for augmenting fracture healing, such as the use of autografts and allografts, the development of this alternative treatment for bone healing has the potential to meet a significant medical need."

"What we have here on this score," Paralkar commented, "is really the preclinical data in animal models, which shows the potential utility from the clinical point of view. So the implication in terms of human therapeutics remains to be demonstrated from controlled clinical trials.

"The present status of our work," Paralkar observed, "and where we would go from here, is in product development. That's where we are with this compound. We are now in the ongoing stage of planning Phase I, Phase II and Phase III clinical trials.

"Pfizer is in the early on process of development inside the clinic. Depending on the site, the whole time frame of finishing all the human trials could easily take a number of years. Given the number of factors, it's hard to predict at this point," Paralkar said. "Pfizer has several patents issued on CP533,536 and related processes. Commercialization efforts are under way now. That developmental process may well take a number of years, and I can't speculate on that. The main thing I would like people to realize is that this data is preclinical at this point. The developmental part in the controlled clinical trials would really decide the usefulness of this product. And that," Paralkar concluded, "is yet to be seen."