January 11, 2007. A growth-factor drug commonly used to help cancer patients maintain levels of infection-fighting white blood cells during and after chemotherapy may stimulate growth of tumors in bones, a new study says.
The growth factor G-CSF, often used during cancer treatments, caused bone tumors to increase in size and intensity in laboratory mice. The mouse on the left did not receive G-CSF. The mouse on the right did, and its bone tumor shows increased intensity in this special scan. Click photo for enlarged version.
The growth factor, called granulocyte colony-stimulating factor (G-CSF) is known by the trade names Neupogen, Neulasta and Granocyte.
G-CSF's detrimental effect on bone tumors may be cancelled out by adding a bisphosphonate. These findings come from a new study by researchers in St. Louis and bear out research years ago in Australia that showed that G-CSF weakens bone.
Chemotherapy can destroy white blood cells (neutrophils). When white blood cell levels fall, a condition called neutropenia, patients are prone to fever, infection and sepsis. The level of white blood cells measured in the CBC panel before each treatment session helps the oncologist decide whether the patient can safely take a full dose of the scheduled drugs. If white blood cells levels fall too low, treatment may be delayed or halted.
By stimulating bone marrow to produce white blood cells, G-CSF is especially helpful for patients who need to take high dose, frequent, and/or combination chemotherapies. For at least a decade, though, oncologists have known that:
- G-CSF weakens bones.
- This effect is cancelled when G-CSF is given together with a bisphosphonate.
- Bisphosphonates do not interfere with G-CSF's mobilization of new white blood cells and may even enhance the process.
In 1998, researchers in Australia, where G-CSF was discovered, were aware that in patients who take it all the time to treat congenital neutropenia, G-CSF may cause osteoporosis. Might short-term G-CSF, they wondered, also weaken bones? They found that after just after 3 days of G-CSF, a specific marker of bone formation (serum osteocalcin concentration) is strongly reduced. Further, a specific marker of bone resorption (deoxypyridinoline or DPyr) "gradually elevated during the time course of G-CSF administration until day 7 after cessation of G-CSF, showing a simultaneous stimulation of bone degradation." Bone was breaking down faster than it could be rebuilt.
By adding a drug that prevents osteoporosis, the bisphosphonate Aredia (pamidronate), the Australian researchers halted this loss of bone density without interfering with the desired effects of G-CSF on white blood cell production. In fact, they said, bisphosphonate added to G-CSF enhanced "the number of circulating CFC [colony forming cells] induced by G-CSF."
Now a team at Washington University School of Medicine in St. Louis has looked at and imaged the effect of G-CSF not just on bone density but also on tumor in bone. In laboratory tests on mice, the St. Louis researchers observed that G-CSF induces bone loss and helps tumors grow in bone. They gave mice an eight-day course of G-CSF. The mice lost bone mass and when injected with cancer cells, they experienced increased bone tumor growth (the effects are captured in the images at the top of this page).
"This growth factor encourages bone breakdown, and any therapy that decreases bone density could potentially enhance tumor growth in bone," says senior author Katherine Weilbaecher, M.D., assistant professor of medicine and of cell biology and physiology.
"But there are things that can be done to counteract this," Weilbaecher says. She recommends increased awareness of bone health during cancer treatments. The St. Louis team found that mice treated with Aredia were resistant to the effects of G-CSF on bone tumor growth.
"Physicians should carefully monitor their cancer patient's bone health with regular bone density scans (DEXA) and prescribe medications to prevent bone loss when needed," Weilbaecher says. "And patients should consume enough calcium and vitamin D and get sufficient exercise to maintain strong bones."
Weilbaecher is currently investigating bisphosphonates as a means to prevent tumor metastasis to bone in breast cancer patients. Many prostate cancer patients take a bisphosphonate to protect their bone integrity.
Clinical use of G-CSF has recently increased because by speeding blood cell regrowth it allows patients to undergo more intensive chemotherapy regimens in which anticancer agents are given at more frequent intervals. Studies have suggested these dose-dense therapies could prolong survival in women with breast cancer.
"We are not at all advocating ending G-CSF use," says Weilbaecher, an oncologist with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. "G-CSF seems to have significant benefits for some cancer patients."
Although G-CSF had a strong effect on bone metastasis in the experimental mice, early clinical trials in humans using G-CSF with chemotherapy have so far shown no adverse effects on survival and no increase in bone metastasis. In fact, breast-cancer patients undergoing dose-dense chemotherapy with G-CSF support tend to have a longer disease-free period than those getting standard dosing without G-CSF.
"It's possible that women on G-CSF-supported chemotherapy could do even better if we paid more attention to skeletal health," says lead author Angela Hirbe, an M.D./Ph.D. student in Weilbaecher's lab. "Strengthening the skeleton would not only help prevent osteoporosis and fractures but also might give patients a survival advantage."
In the laboratory mice studied, G-CSF increased the number and activity of bone cells called osteoclasts, which resorb bone material as part of the normal process of bone turnover. The resulting loss of bone density created a favorable environment for bone tumor growth.
When the researchers injected melanoma or breast cancer cells into mice, those getting G-CSF developed a two-fold increase in tumor burden, a measure of the size and severity of tumors, compared to those that did not receive G-CSF.
"We used G-CSF as a tool to understand the implications for tumor growth when osteoclast activity is revved up," Weilbaecher says. "But G-CSF isn't unique in its effect. For example, antihormone therapies used to treat breast and prostate cancer also can decrease bone mineral density. We would like to see clinical trials instigated to study the effects of such cancer therapies on bone health and tumor metastasis."
This study will appear in an upcoming issue of the journal Blood and is now available online.
