Patients undergoing cancer treatment are at an increased risk of fractures because many cancer therapies tend to weaken the bones. Researchers at The University of Texas MD Anderson Cancer Center are investigating treatments to prevent cancer-related bone loss and fractures as well as fracture-related sequelae such as immobility and blood clots.
Leading the effort to prevent bone loss and fractures are Huifang Lu, M.D., Ph.D., an associate professor in the Department of General Internal Medicine’s Section of Rheumatology and Clinical Immunology, and Mimi Hu, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders. Drs. Hu and Lu rotate as the director of the Bone Health Clinic, a collaborative, interdisciplinary effort by MD Anderson clinicians who treat patients at risk for bone loss. The Bone Health Clinic fills an unmet need, according to Dr. Lu. “Fracture risk in patients with cancer is an area that isn’t usually looked at,” Dr. Lu said. “Sometimes patients are referred to me for hip pain or back pain, and they actually have undiagnosed fractures. It’s really incapacitating.”
Bone loss in cancer patients
Many treatments for cancer decrease bone mineral density and increase the risk of fractures. Since bone maintenance is driven in part by hormones, hormonal therapies carry a significant risk of bone loss. Breast cancer patients and survivors, many of whom have received agents that reduce levels of estrogen, experience more severe bone loss after therapy than women in the general population do after natural menopause. Similarly, patients treated with testosterone blockers for prostate cancer often experience bone loss. Ablation of the ovaries or testicles to treat cancers affecting or affected by those organs also increases bone loss and the risk of fracture.
Other systemic therapies can also adversely affect bone. Cytotoxic chemotherapy drugs can cause bone loss most commonly by impairing gonadal function but also through direct toxic effects on bone cells. Drugs with these toxic effects include methotrexate, cyclophosphamide, ifosfamide, platinum compounds, and doxorubicin. Other cancer treatments that can increase bone loss and the risk of fracture are hematopoietic stem cell transplant, radiation therapy, and glucocorticoids.
Bone loss can also result from the cancer itself—especially cancers that affect the bone marrow, such as myeloma and leukemia—and from some conditions caused by the cancer. Decreased mobility, for example, can weaken the bones. Gastrointestinal malignancies may lead to malabsorption, and illness in general can cause patients to not get adequate nutrition; these conditions may deprive patients of vitamins and minerals needed for healthy bones, such as vitamin D and calcium. And these risk factors compound other risk factors for bone loss that patients with cancer may have, such as older age, postmenopausal status, and smoking history.
Bone loss and the resulting fractures in cancer patients are especially serious because fractures carry serious risks that could complicate cancer treatment. Hip fractures in any patient—with or without cancer—are associated with a mortality rate of 20% within 1 year, partly because of immobility and subsequent complications.
“The morbidity and mortality rates of fractures are very high,” Dr. Lu said. “And fractures seriously affect quality of life, so it is important that we prevent them in our patients. And fractures are largely preventable. We want to use the knowledge about and pharmaceutical developments for treating bone loss in the general population to benefit patients with cancer as well.”
Preventing bone loss in cancer patients
Several medications that are used to improve bone health in the general population, especially in postmenopausal women, can be used to prevent bone loss in patients undergoing cancer treatment. Bisphosphonates such as alendronate, risedronate, zoledronate, and ibandronate, which are used to treat or prevent osteoporosis, have been shown to improve or stabilize bone mineral density in patients receiving cancer treatments that can cause bone loss. This use of bisphosphonates has been well studied in clinical trials for patients with breast cancer and prostate cancer but remains to be established for patients with other cancers.
Drs. Hu and Lu sought to fill this gap through both retrospective and prospective analyses. Dr. Hu and colleagues performed a retrospective study that found that patients with medullary thyroid cancer with bone metastases who were treated with zoledronate or denosumab (a human monoclonal antibody used to treat bone loss and bone metastases) experienced fewer skeletal related events, such as fractures or any need for radiation therapy to the bone, and fewer subsequent bone metastases at additional sites. These results were presented at the annual meeting of the Endocrine Society in April. Dr. Lu and colleagues conducted a systematic review and meta-analysis (soon to be published) of patients with hematological cancers who were treated with bisphosphonates and found that the treatment prevented bone loss in the spine but not always in the hip bones.
Similarly, in a recently completed MD Anderson trial led by Dr. Lu, patients with hematological cancers who underwent hematopoietic stem cell transplant and received the bisphosphonate ibandronate for 1 year after the transplant had less bone loss in the spine than those who did not receive ibandronate. However, ibandronate was less effective in preventing bone loss in the hips. “This agent is not doing 100% of the job,” Dr. Lu said.
“We will need to try new approaches, perhaps with new medications and different timing.”
Bisphosphonates remain a promising treatment not only because of their ability to prevent bone loss in some cancer patients but also because of their favorable side effect profile.
“Bisphosphonates are reasonably safe and easy to take,” Dr. Lu said. “In rare cases, however, these drugs can lead to serious effects such as jaw osteonecrosis or atypical femur fractures, which is why we don’t want to give these drugs to every patient but only to those at risk for fractures.” Dr. Hu said, “Some of these side effects of bisphosphonates—such as abdominal discomfort, acid reflux, and musculoskeletal pain—are easy to manage, and some can be very serious but rare. We hope that talking to patients about these side effects using standard, uniform language will improve patient compliance and the effectiveness of their treatment.” At MD Anderson, standard phrasing of recommendations is used to help patients adhere to their bone loss prevention regimens as well as precautionary practices to maintain bone health, such as resistance-based exercises and consuming adequate amounts of calcium and vitamin D.
MD Anderson researchers and clinicians continue to seek ideal approaches for preventing bone loss not only through their efforts in the Bone Health Clinic but also by participating in a number of bone health initiatives. One such initiative is the Bone Health Program of Texas, a collaborative research program between academic institutions.
This cooperation will be critical for establishing approaches to maintain bone density and, more importantly, to reduce the incidence of fractures in patients with cancer. “Our understanding of what factors, besides bone mineral density changes, lead to increased fracture risk in our cancer population is deficient,” Dr. Hu said. “Further research is much needed in this area. I don’t believe that one approach fits all who happen to have low bone mass.”
Dr. Lu emphasized that identifying risk factors for fractures will enable fracture prevention in patients with those risk factors. “We’re still looking for the population of patients with cancer at the highest risk of experiencing fractures. Our goal now is to identify that group. Then our next step will be to apply the right treatment.”
Some treatments to prevent bone loss remain to be fully investigated in cancer patients. Antiresorptive drugs such as denosumab have shown promise in treating both bone loss and bone metastases in cancer patients. Teriparatide induces bone formation and prevents fractures in patients with osteoporosis, but its mechanism of action could theoretically induce bone tumor growth; therefore, its use is limited in cancer patients. Romosozumab, a new bone-enhancing drug, holds promise for cancer patients but is not currently being investigated in this population. Raloxifene, a selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women, also might be extended to patients with cancer.
In light of the findings so far, Dr. Hu said that physicians should be aware of the potential for bone loss in cancer patients. “The first step is to think about it. Now that more patients with cancer are surviving longer and experiencing long-term consequences of their disease and treatment, we need to think about bone loss as one of those potential consequences so we can screen for and manage it appropriately.”
For more information, call Dr. Mimi Hu 713-792-2841 or Dr. Huifang Lu 713-563-8866.
OncoLog, July 2016, Volume 61, Issue 7