The incidence of fractures is higher in patients with cancer who have undergone a hematopoietic stem cell transplant (HSCT) compared with individuals in the general population, according to new research now available online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.57.8195).
“Our results highlight that the risk of bone loss and fractures is a significant problem during the survivorship period following HSCT,” said the study's corresponding author, Huifang Lu, MD, PhD, Associate Professor and Director of the Bone Health Clinic at the University of Texas MD Anderson Cancer Center. Published literature has shown that bone loss occurs early and rapidly after HSCT, although those earlier studies were small and of short duration, she added.
Fractures can lead to morbidity and mortality, but identifying patients at high risk and instituting treatment early on can potentially prevent this, Lu explained.
Asked for her perspective, Theresa Hahn, PhD, Professor of Oncology at Roswell Park Cancer Institute, said she considered the study to be well done, conducted with a large cohort of patients over a long period of time, and to have a strong statistical analysis. The paper may also help oncologists identify HSCT recipients who need to be monitored for fractures, she said.
To determine the rate of fractures because of bone loss, Lu and her colleagues conducted a retrospective study of 7,620 patients older than 18 who had received an HSCT at MD Anderson between January 1, 1997, to December 31, 2011; patients were observed until December 31, 2013.
The investigators compared the age- and sex-specific incidence rates per person-year of fracture with those reported for the U.S. general population, using the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey.
Overall, eight percent (602) of patients developed a fracture, including 11 percent (419) of patients who received an autologous transplant and five percent (183) of individuals who underwent an allogeneic procedure. Vertebral fractures (53%) were slightly more common than nonvertebral fractures (47%).
The estimated relative risk of having a fracture for women who had had a stem cell transplant was about eight times higher than in the general U.S. female population age 45 to 64, when compared with the two population databases. Men who underwent stem cell transplant who were 45 to 64 years old had an estimated relative risk of fracture seven to nine times higher than in the general U.S. male population.
The age of the patients who experienced fractures was surprising, Hahn said: “You wouldn't be expecting a higher number of fractures in people in their 40s, 50s, and early 60s.”
After univariate cause-specific hazard models, being older than 50 at the time of transplant, having multiple myeloma, solid organ tumors, and autologous transplant were associated with a higher hazard of developing a fracture.
Multivariable models showed that compared with patients with other hematologic cancers, the risk of fracture among individuals with myeloma was five times higher. The risk was 1.6 times higher among those with solid organ and other tumors.
Additionally, patients who underwent autologous transplantation were 45 percent more likely to develop a fracture than those who underwent an allogeneic transplant. Lu said that she and her colleagues are currently exploring why the risk of fracture was higher in patients who received autologous transplant.
Oncologists need to ask whether the cancer is predisposing patients to fractures, or whether some other disease process is occurring, said Philip McCarthy, MD, Professor of Oncology and Internal Medicine and Director of the Blood and Marrow Transplant Center at Roswell Park Cancer Institute: “Is it the transplant itself, or the therapy that predisposes patients to bone loss?”
The immunosuppressive drug cyclosporine, radiation, intestinal injury from transplantation that causes poor calcium intake, not enough sun exposure, and not exercising enough are all reasonable explanations for why fractures may be occurring in transplant patients, said Joseph Antin, MD, Chief of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute.
Hahn noted that another possibility is the use of corticosteroids, more commonly used in the allogeneic transplant setting.
Also asked his opinion, Frederick Singer, MD, Director of the Endocrinology and Bone Disease Program at the John Wayne Cancer Institute at Providence Saint John's Health Center in Santa Monica, California, said: “Steroids have a large influence on bone. You can get fractures without major apparent bone loss since the quality of bone is also affected.”
Another consideration is that most of the fractures in the study occurred in patients with multiple myeloma, who experience breaks as part of their condition, Antin noted. “Oncologists who are treating multiple myeloma expect to see skeletal complications.”
Myeloma patients are also more commonly treated with autologous transplant, Hahn pointed out. This may be one reason why there was a higher rate of fractures in the autologous transplant group in the study.
The transplant data in the study also includes women with breast cancer, who used to undergo autologous procedures for their malignancies, McCarthy said, adding that this treatment approach is no longer used. Specifically, of the 801 patients who underwent an HSCT for a primary solid tumor, 46 percent had breast cancer.
Advanced breast cancer often attacks the bone and could help to explain why the risk of fracture was higher in the autologous group. “In someone five years out from an autologous transplant for breast cancer with bone metastases, there is no surprise at the risk for fracture,” he said.
Research conducted at Roswell Park by McCarthy, Hahn, and their colleagues (Biol Blood Marrow Transplant 2010;16:1130-1137) demonstrated that risk factors for bone mineral density loss were different between autologous and allogeneic stem cell transplant patients. Specifically, lymphoma was associated with more bone loss after autologous transplant than myeloma, while increased steroid dose was a significant risk factor after allogeneic transplant, McCarthy explained.
Hahn said that because transplant patients are at risk of fractures more than a decade after the procedure, oncologists need to make sure to do a good job of screening for osteoporosis and fracture risk.
Bone density loss and fracture risk are independent of one another—“you can have normal bone density and still have a high risk of bone fractures,” she explained. This study helps with identifying and quantifying who needs to be screened and watched for fractures after HSCT. Older patients with myeloma are particularly at risk, and both autologous and allogeneic transplant recipients need to be monitored.
Identifying patients at high risk for fractures following HSCT can have a tremendous clinical impact with early intervention and prevention of bone loss, Lu said. “We would like to focus on the fact that prevention of bone loss is better than reversal of bone loss, since bone loss is a multifactorial, dynamic, and complicated process.”
She said that she and her colleagues recommend:
- Screening all patients shortly before or after HSCT and possibly six months later;
- Instituting general supportive measures such as calcium and vitamin D supplementation;
- Counseling on healthy living habits; and
- Use of pharmacological interventions when indicated, instituted sooner rather than later.
“We believe that instituting preventive measures early on will be instrumental in reducing the morbidity and mortality related to bone loss during the survivorship period,” Lu said.
Singer pointed out that while Lu et al emphasize preventive measures for bone loss and fractures, there was very little discussion about medical treatment. “Fractures may occur in cancer patients years after treatment, and the incomplete attention to preventing them astonishes me,” he said.
He noted that in 1991, the FDA approved the bisphosphonate Fosamax (alendronate) for treating osteoporosis, and data for the present study goes back to 1997, six years after the drug's availability. In the time since then, many other drugs to prevent osteoporosis have been approved.
McCarthy said that physicians at Roswell Park aggressively use bisphosphonates to prevent bone less, especially after it was noticed that patients would lose as much density in three months on a DEXA scan as the general population would over the span of five to 15 years. Roswell Park physicians perform a DEXA scan before transplant to see if patients are already osteoporotic or osteopenic and could benefit from the agents, he explained.
Bisphosphonates are not without their drawbacks, however, McCarthy cautioned, pointing to the well-known possible side effect of osteonecrosis of the jaw (ONJ), for example.
Other options from other classes of drugs are the rank ligand inhibitor denosumab, which also may cause ONJ in patients with poor dentition, and teriparatide, which can increase the risk of bone cancer. He said that patients need to be monitored closely for side effects, but the risk is often worth the benefit of preventing fracture.
One recent paper found that intravenous zoledronic is effective for preventing bone loss in adult allogeneic stem cell transplant patients at risk for developing osteoporosis, McCarthy noted, citing Biol Blood Marrow Transplant. 2013;19:1361-1367.
Singer said that studies are available that demonstrate that bisphosphonates prevent fractures in patients with osteoporosis but not in stem cell transplant patients. And while conducting a large, randomized, double-blind trial would be ideal for demonstrating that osteoporosis drugs can help prevent fractures in patients who undergo stem cell transplantation, such a trial probably will not be able to be done because of the recruitment challenges.
Moreover, he said, clinicians don't necessarily need this type of data to support the benefits of prescribing bisphosphonates—“If you prevent bone loss, you should reduce the number of fractures.”
Regarding avenues of research, Antin said that research needs to answer some overarching questions about the best way to prevent bone loss or regenerate bone in high-risk groups.
McCarthy agreed, noting that investigators need to come up with strategies to prevent bone loss and look at risk factors, both clinical and genetic.