The incidence of fractures is “compellingly higher” after receiving hematopoietic stem cell transplantation, according to a retrospective study of patients receiving transplants for treatment of multiple myeloma, other hematologic malignancies, and some solid tumors (mostly breast and ovarian) as well as a small number of patients being treated for other diseases. This finding led the study authors to recommend that all patients undergoing or planning to undergo stem cell transplantation have their bone health assessed early in their treatment and, if indicated, start measures to prevent bone loss and fractures.

The study involved a total of 7,620 patients who underwent a stem cell transplant at The University of Texas MD Anderson Cancer Center, Houston, from 1997 to 2011 and were observed until the end of 2013 “to ascertain occurrence of fractures,” the MD Anderson researchers reported in the Journal of Clinical Oncology.¹ Results of the study were also summarized in other publications, including The Lancet Oncology.²

Fractures developed in 602 patients (8%), which is a significantly greater incidence than among the general population in almost all subgroups. “The striking difference was an approximately eight times greater risk in females and an approximately seven to nine times greater risk in males aged 45 to 64 years old when compared with the National Health Interview Survey and National Hospital Discharge Survey fracture rates,” the investigators noted.

In an interview with The ASCO Post, the study’s corresponding author, Huifang Linda Lu, MD, PhD, commented that part of the higher fracture rate among women might be attributed to early menopause, but “the average age of men in the study was about 49 and 50, and at that age, men don’t just fracture.” The cause of these striking differences in women and younger men “has got to be something related to malignancy and the stem cell transplant,” said Dr. Lu, who is Associate Professor, Rheumatology and Clinical Immunology at MD Anderson.

Factors Linked to Higher Risk

Being older than 50 years at the time of transplantation and receiving an autologous transplant are two factors that place patients at a greater risk of fracture, the study found. All patients were older than 18, and 52.5% were older than 50. More than 50% of the patients died before experiencing a fracture.

Among the 602 patients who developed a fracture were 11% of patients (419) who had an autologous transplant vs 5% of patients (183) who had an allogeneic transplant. “We are currently investigating the risk factors associated with these two groups of patients. One plausible explanation is that patients with multiple myeloma often receive an autologous transplant,” Dr. Lu said.

“Multiple myeloma in itself can affect bone,” she continued. “The pathophysiology of multiple myeloma affecting bone involves several mechanisms. One is generalized osteoporosis that might have a continued adverse effect even after the [transplant]. This may contribute to the increased risk for fractures in this population.”

Multiple myeloma was the reason for hematopoietic stem cell transplantation in 22% of patients. The most common reason, responsible for 67% of the patients in the study, was a hematologic malignancy other than multiple myeloma. In addition, 11% of the patients had solid tumors or “hematologic conditions like aplastic anemia, myeloid dysplasia, or myelodysplastic syndrome, which are not considered cancer but are managed with protocols very similar to the leukemia transplants,” Dr. Lu explained.

“The majority of the indications for [hematopoietic stem cell transplantation] for solid tumors in our study was breast cancer. These patients suffer from common risk factors for bone loss as postmenopausal women do. This may be one possible explanation for the observed increased risk. However, this represents a very small percentage of the overall study population.” Dr. Lu pointed out that the breast cancer patients were enrolled about 15 years ago, “before we had the powerful hormonal ablation therapy.” These patients would have been “completely out of choices. There were no aromatase inhibitors, and there was not a lot to offer.” There are many other options now, she noted.

Supportive Therapies May Increase Risk

The similarity between the increased rates of fractures observed in patients undergoing solid organ transplant and stem cell transplant “suggests that transplantation and the associated supportive therapies administered may play a key role in the increased risk of fractures,” according to the study report. Supportive therapies cited in the report include myeloablative conditioning regimens, high-dose steroids, and ­cyclosporine.

“These are just a few. Glucocorticoids may be the strongest supportive therapy of all and have been demonstrated individually either in vitro or in vivo to adversely affect bone. The effect of these supportive therapies on bone after [hematopoietic stem cell transplantation] has to be further evaluated,” Dr. Lu noted.

“Steroids are probably the most effective immunosuppressive medication to treat graft-vs-host disease after [stem cell transplant],” Dr. Lu added. “Whenever possible a steroid-sparing reagent should be tried to avoid steroid use. Our stem cell transplant colleagues are constantly researching new reagents or combination therapies that are steroid sparing.”

Importance of Exercise

Patients may have “associated comorbidities, lifestyle factors, and genetic predispositions that may increase the risk of fractures following [hematopoietic stem cell transplantation],” the researchers noted. The investigation of genetic predispositions that may increase the risk of fractures following transplant “is slowly emerging,” Dr. Lu noted. “Little is known yet about the genes and genetic variants that regulate bone mass and susceptibility to fractures.”

Dr. Lu and colleagues are currently looking into lifestyle factors that might be altered to reduce bone loss and the risk of fractures. “These patients often suffer prolonged illness and become sedentary, not carrying out any routine weight-bearing exercise such as walking. Exercise helps in maintaining bone mass and preventing fractures. Exercise alone or in combination with occupational therapy has been shown to reduce fractures by about 25% to 50% in some studies of elderly patients in the general population,” Dr. Lu stated.

Exercise is important before and after diagnosis and transplantation. “Patients should not stop exercising and at least continue to walk,” Dr. Lu said. “Walking could be the simplest form of weight-bearing exercise. If it is continued throughout cancer treatment, before the stem cell transplant and after, that would do a whole lot of good for the patient’s bone health,” she said.

“Certainly a bedridden situation causes a lot of bone loss rapidly,” Dr. Lu continued. She noted that at MD Anderson, a program of physical therapy instituted several years ago gets patients on their feet soon after transplant surgery. “It is as simple as having a patient walk around the nurses’ station several times a day very early after the stem cell transplant. We noticed a reduction in bone and joint complications.”

Assess Bone Health Early

Patients undergoing or planning to undergo hematopoietic stem cell transplantation should have their bone health assessed early in their treatment and, if indicated, should start preventive therapy to avoid bone loss and fractures, the researchers advised in the study report, recommending a dual energy x-ray absorptiometry (DXA) scan at baseline.

“The DXA scan is the current standard method to screen for bone health in the general population and is also utilized following [stem cell transplantation]. However, fractures have been seen in patients with nonosteoporotic bone mineral density, and hence, an overall comprehensive assessment of fracture risk along with the DXA scan is important,” Dr. Lu explained.

“We also recommend a DXA scan at 6 months,” she continued. “One practical reason is that if patients missed the opportunity to have their bone health evaluated at the time of transplant, most patients’ health status stabilizes in time and they do have an opportunity to have their bone health screened at 6 months posttransplant.”

She added, “Even when patients do get a DXA scan at baseline, they may still have acquired significant bone mineral density loss in the first 6 months, as they may have experienced additional insults to the bone such as steroids to prevent and treat graft-vs-host disease, being bedridden for a prolonged period, and immobilization due to [stem cell transplant] and its complications. Consequently, the risk profile of patients to develop a fracture could change in the early posttransplant period.”

Dr. Lu acknowledged that while the 6-month assessment is recommended, “realistically, this may not happen. But if physicians across the board all keep this in mind, that gives patients a better chance at being educated on bone health.”

While loss of bone mineral density can persist for years, “there are no guidelines” for follow-up DXA scans, Dr. Lu noted.

Ongoing and Future Studies

To better understand the process of bone loss, Dr. Lu and her colleagues are evaluating a comprehensive set of risk factors for fracture development. The retrospective study will include more than 5,000 patients treated with stem cell transplant at MD Anderson Cancer Center.

“The more we work on this area—we started with just simple bone health—the more questions we have,” Dr. Lu noted. Since 90% of patients receiving stem cell transplant do not fracture, perhaps data from those patients can provide more clues about who is and is not at higher risk and help physicians give advice to their patients.

Dr. Lu said that she and colleagues are hoping to have information on that study ready to present at ASCO’s Annual Meeting in 2016. At this year’s Annual Meeting, a poster presentation by Xerxes N. Pundole, MD, MPH, Graduate Research Assistant, General Internal Medicine–Section of Rheumatology, MD Anderson Cancer Center, and the lead author of the current study, summarized data from a phase III open-label randomized trial at MD Anderson showing that intravenous ibandronate prevented bone loss in the lumbar spine among adult recipients of allogeneic stem cell transplant.³ However, the treatment did not completely prevent bone loss at the femoral neck and total hip.

As a result of that study, “we know more,” Dr. Lu said, although there are still questions about what would be the optimal drug for prevention of bone loss in transplant recipients. ■

Disclosure: Drs. Lu and Pundole reported no potential conflicts of interest.

References

1. Pundole XN, Barbo AG, Lin H, et al: Increased incidence of fractures in recipients of hematopoietic stem-cell transplantation. J Clin Oncol 33:1364-1370, 2015.

2. Bagcchi S: Stem-cell transplantation increases fracture risk. Lancet Oncol 16:e201, 2015.

3. Pundole X, Champlin RE, Popat UR, et al: A randomized controlled trial of ibandronate for the prevention of bone loss following allogeneic stem cell transplantation. 2015 ASCO Annual Meeting. Abstract 7029. Presented May 31, 2015.