Medical advances in the field of oncology have increased life expectancy and decreased mortality rate for many patients diagnosed with cancer. These improvements are associated with the administration of chemotherapeutic or antineoplastic agents. Unfortunately, these agents can result in side effects that impact the musculoskeletal system.

Such effects are notable in the female population and include arthralgia, peripheral neuropathy, myositis, stiffness, osteopenia, osteoporosis, and fragility fractures. In this article, we review the common antineoplastic agents used in women and their associated musculoskeletal side effects.

Antineoplastic agents
Aromatase inhibitors
Aromatase inhibitors are used to treat postmenopausal women with breast cancer. The three aromatase inhibitors currently approved by the U.S. Food and Drug Administration are anastrozole, exemestane, and letrozole. This class of drugs work by interfering with the enzyme aromatase, which produces estrogen from androgens in the body through a process called aromatization. Lower estrogen levels result in slowed growth of cancers that require estrogen.

Selective estrogen receptor modulators
Selective estrogen receptor modulator (SERM) drugs, such as tamoxifen, are used to treat breast cancer in both pre- and postmenopausal women. Tamoxifen blocks the gonadotropin-releasing hormone gonadoliberin. SERMs have been shown to be effective in the control of tumor cell development.

Vinca alkaloids
Vinca alkaloids work by halting cell division and mitosis, causing cell death, and angiogenesis. Vinca alkaloids are used for the treatment of many malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, breast cancer, and colorectal cancer. The four major vinca alkaloids in clinical use are vinblastine, vinorelbine, vincristine, and vindesine. General side effects of their use include toxicity to white blood cells, nausea, vomiting, and fatigue.

Taxanes
Taxanes promote cell death by interfering with normal cell division. Taxanes such as paclitaxel and docetaxel are commonly used to treat breast cancer and non–small cell lung cancer.

Musculoskeletal effects
Arthralgia
Arthralgia can be a common side effect of antineoplastic agents such as taxanes and aromatase inhibitors. Most of the studies on cancer treatment-induced arthralgias have focused on aromatase inhibitors. The use of aromatase inhibitors as adjuvant endocrine therapy has led to the discovery of a significant profile of musculoskeletal symptoms, especially arthralgia. It is estimated that up to 50 percent of patients treated with aromatase inhibitors experienced arthralgia. Aromatase inhibitors are also associated with bone pain, tendinitis, tendinopathy, carpal tunnel syndrome, trigger finger, and joint stiffness in the hands, wrist, knees, and ankle. At this time, the mechanism or cause of symptoms associated with the aromatase inhibitors is not understood; current theories involve inflammatory cytokines such as IL-1, TNF alpha, and IFN gamma.

Patients with chemotherapy-induced arthralgias will generally report symmetric joint pain, including pain in the hands and/or wrists, decreased grip strength, morning stiffness, and improvement in joint discomfort with use or exercise. Symptoms may improve or resolve for most, but not all, women within 2 weeks of stopping aromatase inhibitor therapy. Promising symptom management approaches include exercise and acupuncture, but more trials are needed to confirm the benefits.

Osteoporosis and osteopenia
Decreased bone mineral density is a side effect of chemotherapeutic regimens, including SERMs and aromatase inhibitors, that are used to treat common neoplasms such as breast cancer. Studies have shown that the decrease in bone mineral depletion is faster and more severe in patients with cancer treatment-induced bone loss compared to menopausal bone loss. The prevention, detection, and early management of cancer treatment-induced bone loss are essential to reduce the risk of fracture in these patients.

Standard recommendations for bone health in a postmenopausal woman include calcium, vitamin D supplementation, smoking cessation, decreased alcohol consumption, and normalization of body mass index. In addition, a combination of resistance and aerobic exercise has been associated with improvements in lean mass and muscle strength and slow decline of bone mineral density. Other treatments include the use of bisphosphonates, estrogen, parathyroid hormone agonists, and RANKL inhibitors.

Chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, enduring, and often irreversible condition that causes pain, tingling, numbness, and sensitivity to cold. Peripheral neuropathy is a common musculoskeletal side effect associated with Vinca alkaloids. Taxanes have also been associated with neurotoxicity/neuropathy.

It is estimated that between 30 percent and 40 percent of patients undergoing chemotherapy experience CIPN. CIPN often increases in severity as treatment progresses; it usually does not progress after treatment is completed.

CIPN may significantly diminish the quality of life of patients. Motor symptoms often present as distal or general weakness, muscle cramps, or gait dysfunction. Other signs include mononeuropathies, sometimes involving the cranial nerves and positive Lhermitte's sign. The diagnosis of CIPN is generally made on clinical grounds but electrophysiologic testing and skin biopsy showing small fiber neuropathy can help confirm the diagnosis of CIPN and exclude other etiologies of neuropathic signs and symptoms.

A number of agents including anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectants have been tested in the prevention of CIPN. Although some positive results have been noted with the use of vitamin B12 and the antidepressant venlafaxine, there are no agents recommended for the prevention of CIPN.

Conclusion
Women undergoing chemotherapy for common neoplasms such as breast, cervical, and lung cancer may be at risk for musculoskeletal side effects. These effects include arthralgias, osteopenia, osteoporosis, fragility fractures, tendinitis, and tendinopathy.

It is important that the orthopaedist caring for the patient is mindful of all the potential causes of a patient's symptoms. Good history taking and physical examination are paramount to ruling out other potential causes and making the proper diagnosis.

The literature surrounding the consequences of various cancer therapies, including their musculoskeletal side effects and how to treat them, continues to grow. However, there are still many unanswered questions and avenues to be explored. Further studies aimed at evaluating the mechanism of causation of the cancer treatment-induced musculoskeletal symptoms and effective treatment options are necessary and ongoing at this time. An understanding of the major effects and how to manage them, therefore, are essential to helping patients navigate this difficult time in their lives.

Izuchukwu K. Ibe, MD, is an orthopaedic resident at the Yale University School of Medicine.

Tara B. Sanft, MD, is an oncologist and assistant professor of medicine and medical director of adult survivorship for the Yale Cancer Center Survivorship Clinic at the Yale University School of Medicine.

Tish M. Knobf, PhD, RN, FAAN, AOCN, is a professor of nursing at the Yale University School of Nursing.

Theodore Blaine, MD, MS, MBA, is a professor in the department of orthopaedic surgery at the Yale University School of Medicine and a member of the AAOS Now editorial board.

Karen Sutton, MD, is a Women's Health Advisory Board member, a Council on Research and Quality member, and associate professor in the department of orthopaedic surgery at the Yale University School of Medicine.

Table 1 (PDF)

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women's Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.

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