Patients with breast and prostate cancer may develop osteoporosis as a consequence of therapeutic hypogonadism, an important strategy in controlling hormone-dependent growth in these cancers. Unfortunately, estrogen and testosterone deficiencies lead to increased bone resorption and diminished bone density owing to abnormally increased bone production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha, as well as reduced bone synthesis of transforming growth factor-beta 1 (Janssens et al. 2005). Additionally, an abnormal increase in the ratio of RANKL (receptor activator of nuclear factor kappa-B ligand) to osteoprotegerin leads to increased osteoclastogenesis. Because estrogen- and androgen-deprivation therapies severely decrease hormone levels, similar or even worse microarchitectural abnormalities, manifesting clinically as osteoporosis or fractures, are expected in survivors of breast or prostate cancer compared with non–cancer survivors who have hormonal deficiencies.

Bone loss in the spine is more rapid and severe within the first year of various treatments for breast cancer (2.6–7.7%) than with natural menopause (averaging 2% per year for 5–10 years). More importantly, the annual incidence of vertebral insufficiency fractures is higher in patients with early-stage breast cancer than in the general population. Results from the Women’s Health Initiative found that breast cancer survivors had a 15% higher rate of all fractures, regardless of the treatment they received, than women without any cancer history (Chen et al. 2005).

In patients with prostate cancer, androgen deprivation therapy (bilateral orchiectomy, leuprolide, or other gonadotropin-releasing hormone analogues), either alone or in combination with an antiandrogen therapy (e.g., flutamide, bicalutamide), causes profound hypogonadism characterized by loss of libido, muscle mass, and bone. Significant bone loss can occur in men within a year of castration or 6 months after initiating treatment with a gonadotropin-releasing hormone (GnRH) analogue. The annual incidence of osteoporotic fractures is higher in patients with prostate cancer treated with surgical or medical castration than in those who receive nonhormonal treatment or in healthy men (Melton et al. 2003). Fractures occur within 2 years of beginning androgen deprivation therapy and increase in frequency with the duration of the therapy. Importantly, skeletal fractures in patients with prostate cancer may be associated with decreased survival, independent of the pathologic stage of the cancer.

Hematopoietic stem cell transplantation can lead to significant bone loss, most notably in the femoral neck, within the first 3–6 months after transplantation. In addition to increasing the risk of developing a hip fracture, reduced femoral neck BMD in patients undergoing transplantation is associated with avascular osteonecrosis.

Radiotherapy after surgical resection of breast, prostate, or gynecologic cancer can increase the risk of developing rib or pelvic insufficiency fractures. Exposure to high-dose corticosteroids used with systemic chemotherapy or to treat graft-versus-host disease exacerbates bone loss acutely. Other conditions, such as vitamin D deficiency or decreased physical activity during and after cancer therapy, may potentiate bone loss in this patient population.

The National Comprehensive Cancer Center Network published guidelines on bone health surveillance in cancer patients. These guidelines incorporated fracture risk analysis by BMD, FRAX (an online calculation tool developed by the World Health Organization), and risk factors for bone loss, with guidance of pharmacologic therapy for low bone mass or osteoporosis (Gralow et al. 2009).

Prevention and treatment of bone loss in cancer patients has been best studied in breast cancer survivors receiving bisphosphonates for the prevention of bone loss related to chemotherapy, tamoxifen, and AIs (Gnant et al. 2008; Greenspan et al. 2008). Early initiation of bisphosphonate therapy may be beneficial in preventing or delaying bone loss. The clinical value of this practice will need to be validated, however, by demonstration of diminished fracture rates in longer follow-up studies of these patients. Very few trials have evaluated the effect of antiresorptive agents in patients with prostate cancer who undergo androgen deprivation therapy. For now, bisphosphonates remain the standard of care for men with osteoporosis.

Anabolic therapy with teriparatide, or parathyroid hormone 1-84, induces bone formation and prevents fractures in both men and women with severe osteoporosis. However, anabolic therapy induces production of growth factors that may theoretically induce tumor growth or tumor activation. Prior skeletal radiotherapy often precludes the use of teriparatide because of the perceived increased risk of developing osteosarcoma in these patients. These agents have not yet been investigated in patients with cancer; therefore, the risks and benefits of the use of anabolic agents should be considered carefully for cancer survivors (Hu et al. 2007).

Finally, denosumab, a fully human monoclonal antibody against RANKL to inhibit osteoclast activation, has been investigated in postmenopausal women with osteoporosis, cancer-related bone loss, and metastatic bone disease (Ellis et al. 2009; Smith et al. 2009; Stopeck et al. 2010; Boonen et al. 2011; Fizazi et al. 2011; Henry et al. 2011). Advantages of denosumab include the lack of nephrotoxicity and the reversibility of the suppressive effect on osteoclast activity.

Currently, no reports on the bone-protective effects of calcium and vitamin D in patients with cancer have been published. However, supplementation with vitamin D has been shown to reduce the risk for hip fractures in healthy ambulatory women. Evaluations of low bone mass are recommended to include an assessment of vitamin D status.

Osteomalacia is a disorder of decreased bone mineralization of osteoid at sites of bone turnover, which can lead to bone pain, fracture, and difficulty walking or muscle weakness. In children, the abnormal mineralization and maturation of the growth plate at the epiphysis is called rickets. Vitamin D deficiency (related to poor nutritional intake, lack of sun exposure, or malabsorption) and renal wasting of phosphorus are common causes of osteomalacia, especially in cancer survivors. Other contributing factors include chronic kidney disease, exposure to aluminum in total parenteral nutrition, and systemic acidosis. Antineoplastic agents (e.g., ifosfamide, estramustine) can also cause or worsen osteomalacia. Treatment should include vitamin D replacement and correction of hypophosphatemia and hypocalcemia.

Glucocorticoids are used with many chemotherapy protocols and can have profound effects on glucose levels by increasing insulin resistance. Glucocorticoids can unmask preexisting prediabetic states by precipitating overt diabetes or make diabetes more difficult to control. The severity may range from asymptomatic hyperglycemia to nonketotic hyperosmolar coma. Most patients who are receiving glucocorticoids and have elevated glucose require insulin therapy to achieve blood glucose control, especially when given high-dose steroids.

Currently, there are no evidence-based, specific guidelines for the management of steroid-induced diabetes mellitus in patients with cancer. Long-acting and intermediate-acting insulin formulations are more effective at controlling glucose levels when they are combined with mealtime rapid-acting or short-acting insulin than with sliding-scale regimens that use short-acting insulin alone. Conflicting clinical study results concerning glargine and cancer have led to concerns that the mitogenic effect of insulin and insulin analogues, which cross-activate IGF-1 receptors, may promote malignancy. These concerns have drawn attention to the gap in knowledge about proper diabetic management strategies for cancer patients and survivors to maximize their survival (Eckardt et al. 2007; Hemkens et al. 2009; Home and Lagarenne 2009; Weinstein et al. 2009).

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), may cause secondary diabetes in 10–30% of patients with renal cell carcinoma. The mechanism by which temsirolimus leads to diabetes may be similar to that of tacrolimus, which decreases glucose-stimulated insulin release in the pancreatic islets.

L-asparaginase and pegylated asparaginase, used to treat hematologic malignancies, may cause hyperglycemia and occasionally diabetic ketoacidosis through unclear mechanisms (Gillette et al. 1972; Land et al. 1972). It has been postulated that inhibition of insulin, insulin receptor synthesis, or both may lead to a combined insulin deficiency and resistance syndrome. Pancreatitis, another known side effect, may contribute to hyperglycemia through islet cell destruction. Insulin therapy is frequently required to treat the hyperglycemia, which reverses upon discontinuation of treatment with L-asparaginase. Close monitoring for hypoglycemia is recommended after discontinuation of treatment with L-asparaginase. Long-term insulin therapy may not be needed in all cases of L-asparaginase-induced diabetes mellitus.

Streptozocin, used to treat malignant islet cell tumors and other neuroendocrine tumors, can lead to long-lasting impairment of pancreatic β-cells in the production and release of insulin; however, most of the effects of streptozocin are reversible upon discontinuation of treatment with the drug. Although the reported incidence of glucose intolerance varies from 6 to 60%, cases are often mild to moderate in severity.

Use of recombinant interferon-alpha (IFN-alpha-2a, -2b) to treat malignancies has been associated with the development of new-onset hyperglycemia, deterioration of glycemic control in diabetics, and diabetic ketoacidosis. Although the incidence of IFN-alpha–induced diabetes mellitus in patients with cancer is unclear, it arises in about 0.7% of patients treated for chronic active hepatitis C (Okanoue et al. 1996). The exact mechanism of IFN-alpha–induced diabetes is not well understood.

Lipid disorders are seldom evaluated in the process of active anticancer therapy because patients are often encouraged to maintain a positive metabolic balance via liberal oral intake. Some lipid disorders may be short-lived without clear clinical consequences, but some may be of clinical importance and need to be detected and treated. In general, triglyceride levels higher than 1,000 mg/dL need to be treated urgently owing to serious potential complications, such as pancreatitis and visual impairment.

Ionizing radiation is the only well-established etiology of thyroid cancer, most commonly the papillary subtype, through induction of DNA damage and formation of chromosomal rearrangements. A dose-response relationship between radiation exposure and relative risk of thyroid cancer occurs with radiation doses of ≤5 Gy (Ron et al. 1995). Female sex, age younger than 15 years when exposed to radiation, and a 20- to 30-year period since radiation exposure (even to areas outside of the head and neck) are associated with increased risk for thyroid cancer. Incidence of local invasion, multicentric disease, and distant metastasis at presentation is higher among patients with radiation-induced thyroid cancer than among patients with sporadic thyroid cancer. Thyroid carcinoma is most evident in long-term survivors of Hodgkin disease and non-Hodgkin lymphoma.

Chemotherapy is not a proven risk factor for thyroid carcinoma despite rare case reports to the contrary. The administration of radioactive iodine for diagnostic purposes does not seem to increase the risk of developing thyroid carcinoma.

Radiation-induced hyperthyroidism has been described but is far less common than radiation-induced hypothyroidism, which has long-term consequences. Thyroiditis-induced thyrotoxicosis occurs within 2 years of radiotherapy in most cases; several months later, hypothyroidism occurs. Risk of developing Graves disease also increases following radiotherapy. Patients with lymphoma treated with radiotherapy constitute the largest population to develop Graves disease after radiotherapy. Patients treated with radiation for nasopharyngeal, breast, or laryngeal carcinoma may also develop Graves disease.

Cytokine therapy (e.g., IFN-alpha, interleukin-2) has also been reported to lead to thyroid disease. IFN-alpha, via autoantibody production, can lead to autoimmune thyroid disease, specifically primary hypothyroidism, transient thyrotoxicosis, or, more rarely, Graves disease. Thyroid scans showing increased homogeneous uptake in the presence of hyperthyroidism are highly suggestive of Graves disease and warrant antithyroid medications. Treatment with interleukin-2 alone causes transient hyperthyroidism followed by hypothyroidism in about 50% of patients through an unclear mechanism (Vialettes et al. 1993).

Head and neck radiotherapy, an important etiology of thyroid dysfunction, can induce primary hypothyroidism when administered in doses higher than 25 Gy to the region near the thyroid gland. Most cases of primary hypothyroidism occur about 5 years after radiotherapy. Subclinical hypothyroidism (elevated thyroid-stimulating hormone levels with normal thyroxine levels) without overt hypothyroidism occurs more often when doses of less than 40 Gy are administered. The probability of developing hypothyroidism increases with increasing radiation doses, increasing duration of follow-up after treatment, combined radiation and surgical treatments, and failure to shield midline structures. Other more immediate risk factors for hypothyroidism include thyroid resection during laryngectomy and disruption of the vascular supply of the thyroid gland during head and neck surgery.

Various agents used in cancer management have been associated with primary hypothyroidism: IFN-alpha, interleukin-2, cisplatin, bleomycin, dactinomycin, vinblastine, and etoposide. Newer antineoplastic agents such as targeted therapies or immunotherapies are associated with a variety of thyroid abnormalities. Autoimmune thyroid disease has been observed with the use of monoclonal antibodies against CD52 for chronic lymphocytic leukemia (alemtuzumab) and CTLA-4 for melanoma (ipilimumab; Hamnvik et al. 2011).

Tyrosine kinase inhibitors (imatinib, sorafenib, sunitinib, and pazopanib) can lead to increased levothyroxine requirements in patients who have undergone thyroidectomy, suggesting that tyrosine kinase inhibitors may accelerate the clearance of levothyroxine (Dora et al. 2008). Additionally, it has been hypothesized that the inhibition of vascular endothelial growth factor by tyrosine kinase inhibitors may decrease vascular supply to the thyroid gland. Prospective studies of sorafenib estimated that the risk of thyroid dysfunction with sorafenib reached 68%; however, only 6% had clinical symptoms requiring thyroid hormone replacement (Miyake et al. 2009). Similarly, 36% of patients treated with sunitinib had persistently elevated levels of thyroid-stimulating hormone, suggestive of primary hypothyroidism; this was especially evident in those who had received long-term treatment with sunitinib (Desai et al. 2006). Some patients were reported to present with thyrotoxicosis preceding hypothyroidism, which supports the theory that sunitinib leads to destructive thyroiditis (Faris et al. 2007; Grossmann et al. 2008). Impaired iodine uptake and inhibition of peroxidase activity were also suggested as potential mechanisms to explain hypothyroidism (Mannavola et al. 2007; Wong et al. 2007).

Hypopituitarism is not as common for survivors of adult nonpituitary brain tumors as it is for survivors of childhood nonpituitary brain tumors (Agha et al. 2005). IFN has been associated with hypopituitarism (Concha et al. 2003; Chan and Cockram 2004). Besides surgery, radiotherapy is often used to treat malignancies in the craniospinal region. Hypopituitarism, one of the most common complications after radiotherapy to the hypothalamus-pituitary axis, has been reported to occur in 41% of survivors of nonpituitary brain tumors (Agha et al. 2005). After adjuvant radiotherapy for pituitary macroadenoma, 36% of patients developed partial pituitary hormone deficiency and 61% had panhypopituitarism; 87% needed hormone replacement therapy to alleviate symptoms (Langsenlehner et al. 2007). The prevalence of hypopituitarism increases with the duration of follow-up.

Hypophysitis is a rare immune-related side effect that has been reported in 1–6% of patients with melanoma treated with ipilimumab. Hypophysitis leads to headaches, visual disturbances, and panhypopituitarism, and it is usually visible on magnetic resonance imaging as a pituitary enlargement with thickening of the stalk. Patients should initially receive high doses of glucocorticoids along with thyroid hormone replacement therapy. The necessary duration of replacement therapy with physiologic doses of hydrocortisone and levothyroxine could be very long, and permanent substitution therapy may be required (Dillard et al. 2010).