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BONE HEALTH

Women with breast cancer are at an increased risk for the development of bone loss and osteoporosis because of adjuvant therapies; these changes may be extremely rapid in onset. Osteoporosis is a “silent disease” that is often not recognized until a fracture event. Osteoporosis results in the deterioration of the bony microstructure, particularly in the vertebrae, ribs, and hips, culminating in fragility fractures and an increase in overall mortality. Maintenance of bone integrity is an important issue in breast cancer care because weakening of the bony matrix represents a major factor in OS. Current therapies profoundly influence the metabolic effectiveness of the skeletal structure.

Risk factors for osteoporosis, excluding the diagnosis of breast cancer, are well recognized and include both nonmodifiable and modifiable variables, particularly in the elderly population.159

Nonmodifiable risk factors include a family history of osteoporosis (genetically based), having a small, thin frame,160,161 increasing age, a prior fracture, and the early onset of menopause. These all contribute to the increased risk of osteopenia and osteoporosis (Table 2).162-167

In addition, indications for the treatment of other medical conditions necessitate certain pharmacologic interventions not specifically related to treatment of the breast cancer itself
(Table 2). These include drugs commonly prescribed for gastrointestinal symptoms or diseases, psychotropic agents, glucocorticoids, hormonal therapies for thyroidal malfunction, anticonvulsants, and anticoagulants for treatment of cardiac disease such as atrial fibrillation.

Gastrointestinal complaints, including those related to gastroesophageal reflux and peptic ulcer disease, result in one of the most commonly prescribed medications: proton pump inhibitors, which approach 150 million prescriptions annually.168 These often-prescribed drugs decrease the intestinal absorption of calcium and therefore result in a decrease in bone mineral density (BMD), an effect that is reversible after discontinuation of therapy, usually within 12 months.169-171

Nearly 10% of Americans are prescribed antidepressants annually.172 Second-generation antidepressants, 
SSRIs, are commonly dispensed and rank third in all drug classes prescribed in the US.173 Serotonin receptors are present in all major bone cells and, as such, the neuroendocrine system of bony structures may be subjected to interference by the administration of SSRIs.174-177

Many survivors of breast cancer are prescribed medications for depression diagnosed either before or after their initial diagnosis of breast cancer. Patients with comorbidities such as depression are therefore at additional risk of BMD depletion. Add to this the compounding issues affecting depressed individuals, such as decrease in exercise, poor eating habits, lack of sun exposure, tobacco use, and an increase in alcohol intake, and the increased risk of fracture events rises even higher.178,179 Those caring for survivors of breast cancer must be aware of patients who are receiving antidepressants, particularly those receiving SSRIs, who may be at an increased risk of osteoporosis and subsequent fractures.178

Long-term corticosteroid therapy, often employed in the treatment of multiple inflammatory and autoimmune diseases, is also a well-recognized risk factor for osteoporosis.164,179 Steroidal therapy leads to osteoporosis by decreasing bone formation through multiple and complex mechanisms, which are beyond the scope of this review.180-183 As with the proton pump inhibitors, the osteoclastic effect of corticosteroid therapy appears to decrease fracture risk after discontinuation of therapy.184 Multiple other drugs prescribed for patients with breast cancer for concurrent diseases, including anticonvulsant and anticoagulation medications, may affect BMD, further contributing to osteoporotic fractures, particularly in the aging population. The literature is conflicting, but one should be aware that these classes of medications might increase the risk of fracture events (Table 2).185-187

AIs, be they steroidal (exemestane) or nonsteroidal (anastrazole and letrozole), are associated with a substantial and often rapid decrease in BMD and an increased fracture risk.188-190 These medications appear to be significantly more effective than tamoxifen adjuvant therapy in ER+ tumors in postmenopausal patients, with longer overall DFS and without the additional risk of endometrial carcinoma.185 Tamoxifen, classified as a SERM, acts like an antiestrogen in some tissues (breast) and an estrogen agonist in others (bone) and therefore is considered as a bone strengthener in women who are postmenopausal, an effect not seen in the premenopausal population.191-195 As opposed to tamoxifen, AIs block the aromatization of androgens and thereby block their conversion to estrogens, resulting in bone loss. Recovery of BMD after completion of aromatase inhibiting therapy may be only partial, especially if exemestane (steroidal-based therapy) has been used as the initial choice of antiestrogen therapy (AET).164,185,194 Such reversible effects on bone density deterioration are similar to those reported with the discontinuation of other medications previously addressed.184

Recent attention has been directed to patients who have been placed on a regimen of hormonal blockade therapy with tamoxifen, which is then discontinued after the appropriate duration. Postmenopausal women upon discontinuation of tamoxifen may suddenly experience an estrogen deprivation syndrome with respect to bone health; this results in the loss of the protective effects against the development of osteoporosis, with a subsequent increase in the risk of fracture.187-193,195 Thus, those providing long-term care for survivors of breast cancer must be aware that the abrupt discontinuation of tamoxifen requires particular attention to bone fragility and its assessment.195-199 A further issue, yet to be adequately addressed, involves those patients in whom discontinuation of tamoxifen is followed by the administration of AIs, putting bone health and density at greater risk.

To further complicate the issue, recent studies suggest a beneficial effect in the extension of hormonal blockade, specifically tamoxifen, to ten years, exceeding the previously recommended years of therapy.198,199 Although these recommendations should be cautiously interpreted, the long-term suppression of bone density must be addressed. It is hoped that by the time patients who are just beginning hormonal blockade therapies reach their five-year mark, they will have a definitive answer and/or evidence-based medicine to strongly recommend continuing those therapies for an additional five years. Additional confounding variables, especially for long-term therapies, are adherence and compliance, which are discussed in the section, Adherence and Compliance.

Finally, an extensive variety of other medical conditions, diagnoses, and pharmacologic interventions have been implicated in contributing to the development or progression of decreasing BMD from osteopenia to osteoporosis.164,168,185,188 Many of these issues are addressed only by observational studies. Therefore, although these risk factors are important, their relevance to absolute risk increase awaits further results from ongoing trials.

Myriad medical conditions have been associated with the development of osteoporosis, but two particularly common diseases must be mentioned: thyroidal conditions and DM.

Hyperthyroidism is a common disorder affecting approximately 1 in 100 individuals, and it is often accompanied by the progression of osteoporosis, especially in postmenopausal women.200 Thyroidal disorders are often a comorbidity of patients with breast cancer, and thyroxine replacement therapy must be recognized because hyperthyroidism and the treatment of hypothyroidism may both result in bone resorption, resulting in an increased risk of osteoporosis.185,201,202 Conflicting results have been reported regarding thyrotoxic conditions and the effect of thyroxine replacement therapy, suggesting that many patients are overmedicated for hypothyroidism and thus may be exposed to increasing their risk of osteoporosis.203,204 The relationship between thyroidal disease and osteoporosis remains controversial, and therefore, a diagnosis of thyroidal disease should be noted in addressing issues of survivorship in patients with breast cancer.185,205-208 Thyroidal dysfunction may be a risk factor for osteoporosis.209,210

DM has emerged as a pandemic disease affecting more than 10% of the world population.211-213 Many patients diagnosed with breast cancer enter the cancer “arena” with a preexisting diagnosis of DM. Both type 1 and type 2 DM have been associated with the exacerbation of osteoporosis214; however, the mechanism of bone weakening appears to differ between the 2 diseases. Type 1 DM (insulin-dependent) is caused by insulin deficiency resulting in hyperglycemia in young patients, and it may lead to a decrease in BMD, particularly in the spine and hips, resulting in an increased risk of fracture.215-222 Conversely, the evidence for type 2 DM (non-insulin-dependent) for the increased risk of fracture appears somewhat conflicting for reasons unknown.215,223-225 It has been suggested that the comorbidities of type 2 DM (visual impairment, gait-related neuropathy, advanced age, and obesity) may offer clues to the increase in fracture risk.215,224 Multiple studies have reported contrary results when analyzing data regarding the association of type 2 DM and osteoporosis. Some studies suggest no differences in BMD and type 2 DM; some, a lower risk of osteoporosis with type 2 diabetes; and still others, a higher risk.214,226-228

Many medical diagnoses have been identified as potential risk factors for osteoporosis. These include gastrointestinal diseases (celiac disease, malabsorption syndromes, and irritable bowel disease), autoimmune disorders (rheumatoid arthritis and lupus), and other diseases or syndromes.200,229 Because an abundance of information exists regarding the development of osteoporosis caused by coexistent morbidities, patients with breast cancer must be thoroughly evaluated for potential comorbidities, particularly in the setting of hormonal blockade with AIs when used as long-term adjuvant therapy. Chronic conditions require the long-term use of medications that may further increase the risk of osteoporotic development. Extensive confusion surrounds the issue of osteoporotic comorbidities (both disease and drug related). Until further evidence is available, it would be prudent to consider these issues as potential risk factors for osteoporosis much the same as hypertension, dyslipidemias, and DM are regarded as risk factors for CVD and cerebral vascular diseases.

There are multiple modifiable risk factors for osteoporosis in the setting of breast cancer therapy. Most of these modifiable risk factors are related to lifestyle and include alcohol and/or tobacco use, nutritional concerns (including eating disorders), maintenance of a near normal BMI, and adequate physical activity.

The excessive consumption of alcohol, defined as greater than 2 U/day to 3 U/day (1 U equals a half-pint of beer [300 mL], a glass of wine [100 mL], 1 shot of distilled spirits [25 mL]), increases the risk of an osteoporotic fracture by up to 40% compared with those with moderate to no alcohol intake.230-232 Excessive alcohol intake results in suppression of bone-forming cells and calcium metabolism. Alcoholism is also associated with multiple nutritional deficiencies, including vitamin D3 deficiency, which results in the increased production of parathyroid hormone, thereby increasing bone resorption, thus further weakening BMD.232,233 Falls, resulting from chronic heavy drinking, further increase a patient’s risk of fracture events.

Tobacco use, both historic and current consumption, affects bone density and increases fracture risk, although the mechanism of action is not well understood.230,234,235 Inhibition of osteoblastic activity, excessive estrogen breakdown, and earlier onset of menopause have been suggested as possible causes of increased bone fragility in smokers.230,236

Adequate nutrition plays a critical and complex role in bone health. Appropriate intake of calcium, phosphorus, and multiple other nutrients are essential in the maintenance of therapeutic levels of vitamin D3.237,238 It was once thought that obesity was protective against osteoporosis,239 but recent evidence fails to support this belief.240,241 Assessment and monitoring of BMD has been established as an effective and appropriate predictor of fracture risk. Osteoporosis is currently defined on the basis of BMD as established by the World Health Organization in 1994 using T-scores.199,242

Multiple technologies are available for assessing BMD; however, dual-energy x-ray absorptiometry is the most commonly employed. For each BMD value calculated, a T-score representing the average peak BMD in a young, normal reference population and a Z-score representing the standard deviation of the patient’s calculated BMD from the patient’s expected age-matched cohort are calculated. Osteopenia (decreased levels of calcium in the bones) is defined as a T-score between -1.0 and -2.5. Osteoporosis (decreased level of the bony matrix itself) is defined as a T-score equal to or less than -2.5.243,244

To further delineate the risk of fracture incidence, the World Health Organization has developed the Fracture Risk Assessment tool (FRAX), which is a risk-assessment software program that attempts to further delineate the absolute risk by combining BMD measurements and clinical and historical factors.199,242 Table 2 summarizes risk factors for osteoporosis.

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