Bones of Contention: The Unintended Effects of Cancer Therapy

Therapies that can extend the life of cancer patients often have a negative impact on the skeleton, especially in those being treated for hormone-sensitive cancers. Evidence shows improvements in bone health when bisphosphonates and denosumab are administered.

Patients diagnosed with cancer are living longer, with some unanticipated ramifications. According to Facts & Figures 2018, published by the American Cancer Society (ACS), the death rate from cancer in the U.S. has declined steadily since 1991, by about 2% annually, in fact. ACS reports that, in terms of lives, this means 2.4 million people survived cancer in a roughly 20-year period. Much of this increased survivorship, of course, can be attributed to advances in cancer treatment.

Unfortunately, increased survival does not always translate to quality of life maintenance. In addition to the health problems the cancer itself causes a patient, the treatment to manage that cancer can have damaging consequences or exacerbate underlying problems — affecting the skeleton, in particular, and increasing the risk for bone loss as well as fracture. The problem is threefold: Patients with cancer have decreased bone mineral density (BMD) on dual x-ray absorptiometry (DXA) scan; the drug therapies used to treat cancer (e.g., chemotherapy drugs, glucocorticoids, aromatase inhibitors [AIs], and anti-androgen drugs) induce bone loss, according to the Endocrine Society’s Hormone Health Network; and cancer commonly metastasizes to bone, further accelerating bone loss in addition to precipitating other harmful effects. The compounded insult to BMD greatly increases the risk of fracture, which can seriously impair quality of life by causing debilitating pain; incurring great expense; and, depending on severity, possibly leading to social isolation brought about by increasing immobility, the need for assisted living or long-term nursing home care, or comorbidities or even death.

Closer Look at the Problem

Although awareness is growing among the medical community that patients with endocrine-sensitive cancers like breast and prostate (which, by the way, are the cancers with the highest incidence in women and men, respectively, according to the ACS) need to be screened for bone changes, other types of malignancies have not been studied to the same extent, and even with the greater knowledge around breast and prostate cancer, vulnerable patients are not getting identified. So, a two-person team from the Mayo Clinic in Rochester, Minn., recently investigated these gaps in “The skeletal impact of cancer therapies,” published in British Journal of Clinical Pharmacology in February. Matthew T. Drake, MD, PhD, associate professor of medicine and co-author Lucia Bedatsova (a research trainee and medical student visiting from Prague, Czech Republic) took a closer look at cancer therapies currently in use and their effects on bone. They also explored what information currently exists for preventing these effects, primarily for hormone-sensitive cancers (as well as for blood cancers, which are beyond the scope of this article). “While providers of cancer therapies have been rightfully focused on optimizing cancer treatments for their patients, it is important that these same providers also proactively recognize that many of these same cancers treatments have unintended deleterious side effects on other organ systems. Indeed, the skeleton is one of the most important organs negatively affected by a wide array of cancer therapies,” Drake says.

“We have good drugs that can be pretty simple to take that have clearly been proven to lower that risk. Cancer patients tend to be pretty motivated, so it’s usually not a very difficult conversation.” – Ann E. Kearns, MD, PhD, associate professor of medicine; chair, Quality and Safety, Division of Endocrinology, Mayo Clinic, Rochester, Minn.

Ann E. Kearns, MD, PhD, associate professor of medicine and chair of Quality and Safety in the Division of Endocrinology also at the Mayo Clinic, as well as an Endocrine Society expert on bone health, agrees: “As cancer survivorship improves, we begin to worry not about the imminently life-threatening but life-altering things.”

Breast Cancer and Bone Health

In their review, the team found that, despite clinical guidelines urging routine BMD measurements in women being treated for breast cancer, in many cases, these patients are not being adequately managed. The anti-androgenic drugs used to treat breast cancer accelerate bone loss, and this is in a population usually of advanced age, in which age-related bone loss due to age-related declines in estradiol is already occurring. “The highest risk for fracture is in the older people getting these types of treatments because they already have an increased risk, which we’re augmenting with the treatment,” said Kearns. “But,” she continues, “our oncology team here is quite astute at measuring the bone density in patients about to initiate either anti-estrogen therapy or anti-androgen therapy. They are very savvy about having that discussion with referred patients.”

In premenopausal women, the bone loss picture is not much better — they are sometimes treated with glucocorticoids for nausea in addition to hormonal and chemotherapies, combinations that co-act to reduce BMD.

AIs act to inhibit the effects of estrogen as well as to damage bone microarchitecture, resulting in BMD reductions at the lumbar spine which can reach more than 3% per year. Losses can be further increased when AIs are combined with other agents such as gonadotropin-releasing hormone (GnRH) agonists. Research has demonstrated that oral or intravenous bisphosphonates given concomitantly with the AI negates this loss of BMD from baseline in both premenopausal and postmenopausal women. “Some of the breast cancer patients do receive bisphosphonates — mostly zoledronic acid — here as part of adjuvant treatment for breast cancer,” Kearns says. “Such therapy has been associated with improved survival, thought to be from decreased bone metastases. Thus, the oncologist has two complementary reasons to give this drug: to improve survival and to decrease bone problems.”

“The early recognition of heightened risks for both bone loss and fractures, and the judicious implementation of practices to limit these off-target effects on bone is absolutely critical if we are to optimize the long-term health of our patients.” – Matthew T. Drake, MD, PhD, associate professor of medicine, May Clinic, Rochester, Minn.

In postmenopausal women taking AI therapy, the anti-osteoporosis drug denosumab has been shown to provide benefit. And, interestingly, on stopping AIs, some women see improvement in BMD, but such “AI holidays” have not been adequately studied.

Notably, the selective estrogen receptor modulator (SERM) tamoxifen reduces bone loss in postmenopausal women, but increases it in premenopausal women.

Prostate Cancer and Bone Health

The treatment of prostate cancer induces many of the same bone-related problems in men as does treatment of breast cancer in women and does so by similar mechanisms. Androgen-deprivation therapy (ADT) can be achieved with GnRH agonists and antagonists, but these lead to increased fracture risk. Two new drugs, abiraterone acetate, which inhibits androgen biosynthesis, and enzalutamide, an androgen receptor antagonist, have demonstrated efficacy for the treatment of prostate cancer without the fracture risk, but researchers do not yet know their effects on BMD and bone remodeling.

As with breast cancer, bisphosphonates and denosumab are effective in preventing further bone loss in men with prostate cancer. Because reducing testosterone levels also reduces estradiol levels in men and therefore provides another physiologic basis for bone loss, the SERM toremifene was studied for its potential to reverse the skeletal impact of ADT but was shown to increase the risk of venous thrombosis. Although no SERMs have yet been approved to treat bone loss in men, treatment with low-dose estradiol has been shown to reduce circulating bone turnover markers in ADT-treated men but has not been evaluated for fracture risk reduction.

Bone Gaps

In both women with breast cancer and men with prostate cancer, starting bisphosphonates at the time cancer therapy is initiated achieves a better skeletal outcome than delaying treatment. Moreover, due to the demonstrated effectiveness of antiresorptive therapies when used in conjunction with cancer therapy, guidelines recommend a skeletal health evaluation at the start of cancer therapy and potentially earlier intervention with an antiresorptive adjuvant. Again, though, this critical evaluation is not happening as routinely as it should. Why? “It’s probably just not knowing who is responsible for measuring that BMD,” explains Kearns. “For example, orthopedic surgeons fix fractures, but they don’t treat osteoporosis. Maybe primary care providers are not as aware of the effects on skeletal health that some of the treatments are having or potentially will have, so they are not picking up on that. Unfortunately, bone health kind of falls in the gap there. I would like to think that at least oncology should be advising that the bone density be measured if they’re not taking it on themselves and actively treating skeletal health. If not, they should be alerting and working with a primary care team or a specialty practice to not let these patients fall through the gap. We see a similar gap with steroid-induced osteoporosis. The rheumatologist or primary care provider is prescribing the steroids over and over, and nobody thinks twice until a fracture occurs. So, it’s not unique to cancer treatment; it’s a common concern that the skeleton gets overlooked.”

 Optimizing Skeletal Care

After identifying a patient at risk for fracture, the next step is having a discussion with the patient about how fractures can contribute to morbidity, suffering, and lifestyle changes but that most fractures are preventable. “We have good drugs that can be pretty simple to take that have clearly been proven to lower that risk. Cancer patients tend to be pretty motivated, so it’s usually not a very difficult conversation,” said Kearns.

Drake and coauthor conclude that both initial and ongoing skeletal evaluations are critical to developing the right regimen for an at-risk patient, calling this “a cornerstone of care.” “The early recognition of heightened risks for both bone loss and fractures, and the judicious implementation of practices to limit these off-target effects on bone is absolutely critical if we are to optimize the long-term health of our patients,” Drake says.

-Horvath is a freelance writer based in Baltimore, Md. She wrote about the various side effects that could result from obesity treatments in the April issue.

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