After old age sets in, the elderly body's bones don't turn to mush, but rather to sponge or Swiss cheese. That disorder, as its name implies, is osteoporosis - excessive porosity of the bones. It affects 20 million Americans, about 80 percent of them women. And some 1.3 million fractures due to osteoporosis afflict people 45 years of age or older.

Although all aging bones are affected, compression fractures of the vertebrae and traumatic breakage of the wrists and thighbones are most common. After hip fracture, a majority of elderly patients fail to recover activity, and nearly 20 percent die within the following year. Fear of further falls and fractures brings on depression. Osteoporosis occurs when bone resorption (by osteoclasts) outpaces bone formation.

"Blood-forming stem cells may not enter this world alone," observed hematologist/oncologist David Scadden at Harvard Medical School in Boston. "They may have birthing partners," he added, "cells that live in bone marrow, with which they interact. As the number of bone-forming osteoblast cells increases, so, too, does the number of blood-forming hematopoietic stem cells."

Scadden is senior author of a paper in Nature dated Oct. 16, 2003, and titled "Osteoblastic cells regulate the hematopoietic stem cell niche."

"In this journal article," he told BioWorld Today, "we show how cultured bone marrow cells from transgenic mice are better able to support HSCs [hematopoietic stem cells] than are similar cells taken from normal animals. We were using a HSC as a model for stem cell behavior. We found that we could target the microenvironment where the stem cells live as a way to get an effect in the HSCs themselves.

"In general," Scadden recalled, "the standard approach for modifying stem cells has been to look at them in isolation. We thought that - given their responsiveness to the environment in vivo - perhaps if we could look at manipulating that environment, we could have a secondary effect on stem cells. That indeed is what we found," he continued. "This points to unraveling the complexity of both the niche and the way we could try to induce a change in the stem cells."

Parathyroid Hormone Plus Osteoblasts Build Bones

"The component of the niche would be osteoblasts," Scadden continued. "We could target that with bone-building parathyroid hormone [PTH], a medicine that's already available in the clinic for human patients. Using PTH, we actually increased the number of stem cells in the mice, and got a marked effect as to their ability to survive. This setting," Scadden pointed out, "also mimics what occurs in humans who are in a bone marrow transplant setting."

Scadden made the point that "parathyroid hormone is approved by FDA as a hormone treatment used in osteoporosis to increase bone mass. We found that bone-forming cells were a key component of this niche. We used that hormone to target that cell and found that we increased the number of stem cells. We transplanted animals with a limited number of stem cells, and 73 percent of them died. But if we gave them this parathyroid hormone, none of them died. So this experiment demonstrates that one can manipulate the environment to have a therapeutic effect on stem cells. It might be useful applied to other stem cell settings, up to a point of manipulating the osteoblast as a way to get more HSCs.

"And as this may well have parallels in humans," Scadden went on, "for which there is already an approved drug. We are actually going to go pretty quickly into human clinical trials in the next few months. We have a concept sheet that's been reviewed by our transplanters and a protocol team in place.

"We assess all of the long bones in our mice, and that would be true in humans too. In adults, stem cells develop on the marrow cavity inside long bones. There will be a couple of settings in our therapeutic approach. There are a group of patients who need a bone marrow transplant plus certain treatment options for lymphoma or myeloma. In those cases, about 20 percent of them do not have enough stem cell to safely go through the procedure. If we could expand the stem cells by giving them this parathyroid hormone in advance of collecting stem cells, then one could harvest from those patients and potentially increase their HSCs.

"That's one setting," Scadden went on. "The other is that there are people who need a transplant from someone else, patients, for example, with leukemia. They require what's called an allogeneic transplant from a donor. Finding one who's immunologically matched is complicated. Some people are willing to donate to unrelated fellow beings. Only a third of them will have a relative who can donate. A second third will be able to have cells that they obtain from one of these registries. But that still leaves a third of the patients without a donor."

One Solution: Belly-Button Blood Bank

"Regarding that dilemma, the government has set up umbilical cord blood banks," Scadden noted. "This is a resource that's out there and available; it would actually match most of the need. But stem cells in umbilical cord blood are insufficient in number for adults. If one could use fewer umbilical cord stem cells by giving PTH, then potentially you could now make that much available and overcome the shortfall. Or if you could expand the stem cells outside the body before you transplant them, that might also help. I don't know if any of this is true," Scadden hedged, "but these PTH studies point out that it's a possibility.

"The Massachusetts General Hospital has recently applied for a use patent on our strategy," Scadden said. "We've also been in contact with putative commercial partners, and have had some early discussions with a pharmaceutical company.

"If these approaches are considered therapies applying cells exogenously - that is, taking them and putting them back into people - this suggests that they may not be the only method. Maybe we can find ways to manipulate them in vivo pharmacologically. This study," Scadden concluded, "would point to one such strategy, providing an entry point for pharmaceuticals into stem cell therapy."