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Published in final edited form as: Semin Oncol Nurs. 2022 Apr 25;38(2):151273. doi: 10.1016/j.soncn.2022.151273

Bone health considerations in breast cancer

Kristen L Fessele 1
PMCID: PMC9512392  NIHMSID: NIHMS1832478  PMID: 35477651

Abstract

Objectives:

The treatment of breast cancer requires the use of multiple modalities to achieve local control of disease and to prevent distant recurrence. Among patients whose tumors are hormone receptor positive, endocrine therapy for up to 10 years in the adjuvant setting can be an important component of such therapy, but it is not without adverse events. Ovarian suppression or estrogen restriction can have a rapid and clinically significant detrimental effect on bone mineral density, leading to potential osteoporotic fracture. This paper reviews the major causes of breast cancer treatment induced bone loss and pharmacologic and non-pharmacologic management strategies to maintain bone health in this population.

Data Sources:

PubMed and international clinical practice guidelines.

Conclusion:

A holistic, long-term approach is needed to identify and offer early intervention to patients at high-risk of significant bone density loss. A combination of routine screening, use of oral or intravenous bone-modifying agents, oral supplementation of calcium and vitamin D and physical activity including weight-bearing exercise are required to maintain adequate bone health during treatment for breast cancer.

Implications for Nursing Practice:

Oncology nurses are well-situated in the primary and survivorship care teams for patients with breast cancer to provide proactive education on the need to assess and actively manage bone health. Non-pharmacologic interventions such as dietary supplementation and physical activity are key to health promotion and are within the nursing scope of practice to emphasize with this patient population.

Keywords: Bone density, Health promotion, Breast neoplasms, Survivorship, Osteoporotic Fractures, Nurses

Therapies against cancer have advanced significantly in the past decades but may result in lasting adverse effects. Successful treatment of breast cancer generally requires the use of multiple modalities to achieve long term disease free survival, including surgery, radiation and chemotherapy, and blockade of hormonal stimulation to tumor cells identified to be responsive to estrogen or progesterone. The latter strategy can be associated with significant decreases in bone mineral density, which may be especially impactful among patients with pre-existing risk factors for osteoporosis and skeletal fractures. The purpose of this paper is to review how breast cancer treatment may increase the risk of clinically significant bone mineral density (BMD) changes, and how clinicians can assess and manage these changes across the cancer experience.

Globally, breast cancer affected approximately 2.3 million women and caused 685,000 deaths in 2020, surpassing lung cancer among women as the highest cancer incidence1. By the end of that year, there were 7.8 million female survivors of breast cancer diagnosed in the past 5 years, making it the most prevalent cancer in the world1. Incidence rates are highest in Australia/New Zealand, Belgium, northern and southern European nations with lowest rates in Central America, Eastern and Middle Africa and South Central Asia2. Mortality rates follow a different pattern, with women in countries in economic transition experiencing 17% higher mortality than those in nations with a higher economic human development index2,3.

In the United States, the median age at diagnosis is 62, though non-Hispanic Black women have the highest incidence of diagnosis before age 40 and the highest mortality at any age4. Non-Hispanic Black women experience the highest breast cancer mortality rates at 28.4 deaths per 100,000 cases, twice that of Asian/Pacific Islanders who have the lowest incidence and death rates (11.5 per 100,000)5. Over the past 2 decades, mortality from breast cancer decreased by 40% among high-income nations in part due to more effective screening, early diagnosis and improved treatment regimens5. Early diagnosis is key; approximately 64% of patients are diagnosed with localized breast cancers and have an estimated 5 year survival of 99%6. Of note, of the 1% of male breast cancers diagnosed annually, about half are diagnosed with regional disease or distant metastases7.

About 80% of breast cancers are invasive at the time of diagnosis, and histologic classification has extended beyond the major labels of ductal vs. lobular to focus on the molecular subtypes that drive proliferation and predict responsiveness to targeted therapies. Major biomarkers include the hormonal estrogen and progesterone receptors (ER and PR), human epidermal receptor (HER) expression and Ki67 activity, a marker of tumor cell proliferation5. Nearly three-quarters of breast cancers are hormone receptor positive7. Approximately 1 in 5 non-Hispanic Black women are diagnosed with “triple negative,” or tumors without clinically actionable expression of estrogen, progesterone or HER receptors. This is nearly double the proportion of other groups and contributes to higher mortality rates due to fewer targeted therapeutic options.

Therapeutic approaches to breast cancer treatment

For early stage (stage I – III) disease, the therapeutic approach involves excision of the primary tumor, either through mastectomy or breast conserving surgery like lumpectomy, and axillary staging of lymph nodes to determine evidence of regional spread8. Radiation therapy is recommended to the whole breast after conservation surgery and regional nodes if positive on axillary staging, or to the chest wall after mastectomy to minimize local recurrence. Depending on hormone receptor and HER status, tumor size, nodal involvement and the recurrence score on a multigene assay, systemic therapy is frequently recommended to minimize disease recurrence. Chemotherapy may be offered before surgical resection to reduce tumor bulk or after recovery for patients with risk factors such as tumors > 0.5cm, positive lymph nodes, HR negativity, or a higher multigene assay recurrence score8. Tumors with HER overexpression receive targeted therapy with monoclonal antibodies such as trastuzumab or pertuzumab8. The subgroup of patients without these features may be candidates for adjuvant endocrine therapy alone post-surgery and radiation rather than chemotherapy8.

Endocrine therapy can be provided through several methods; 1) direct blockade of hormone receptor sites on tumor cells by the antiestrogenic compound tamoxifen, 2) suppression of estrogen production from the ovaries by surgical removal or use of gonadotrophin-releasing hormone (GnRH) agonists in premenopausal women or 3) the use of aromatase inhibitors (AI) to prevent of conversion of androstenedione into estradiol9–11. Patients with ER and/or PR positive tumors should receive endocrine therapy for up to 10 years8,12 to decrease primary disease recurrence and the incidence of second breast cancers.

Postmenopausal women with stage I to III HR positive breast cancer may attain this 10 year accumulation through receipt of either tamoxifen for 2 to 3 years followed by 7 to 8 years of an aromatase inhibitor, a sequence of 5 years of each agent or 10 years of tamoxifen when AIs are not tolerated12. Breast cancer treatment for men is similar to guidelines for women, though 5 to 10 years of tamoxifen therapy is recommended as the preferred option for HR positive disease. Evidence suggests that an AI alone is less effective in men unless a GnRH agonist is also administered13–15.

Premenopausal women with stage II or III HR positive tumors who will receive adjuvant chemotherapy followed by endocrine therapy frequently undergo ovarian suppression for up to 5 years to decrease risk of disease recurrence. Those with stage I or II disease and higher risk features who will receive chemotherapy may also consider adding ovarian suppression, but the data remains equivocal on the benefit of this for low-risk patients eligible to receive only adjuvant endocrine therapy10.

In non-life threatening metastatic breast cancer with HR positive tumors, endocrine therapy with AIs can be a first line alternative option to systemic chemotherapy, or may repeated if last successful use was more than 12 months prior suggesting lack of acquired resistance16–18. In this setting, AIs may be combined with fulvestrant, a selective down-regulator of the estrogen receptor or with a CDK4/6 inhibitor such as abemaciclib, palbociclib or ribociclib in the first line setting8.

AIs such as anastrozole, exemestane and letrozole are associated with an increase in cardiovascular disease (OR 1.3, p = .01) and bone fractures (OR 1.47, p < .001) but also a notable decrease in venous thrombotic events and endometrial carcinoma compared to tamoxifen (OR 0.55, p < .001 and OR 0.34, p < .001 respectively19). Treatment-related adverse events impacting quality of life are a leading cause of medication non-adherence among patients initiating AIs and may include arthralgias and myalgia in up to 82% of patients20, vasomotor symptoms and vaginal dryness21–23 and cognitive dysfunction21. There are similar and notable adverse events associated with ovarian suppression therapy, including hot flashes and sweats, weight gain, vaginal dryness and sexual dysfunction and importantly for the focus of this paper, decreased bone mineral density10.

Mechanisms of Cancer Treatment Induced Bone Loss

Osteoporosis is a highly prevalent problem worldwide, with an estimate of over 20 million people affected, and is associated with non-traumatic bone fracture in about 40% of postmenopausal women24. The estimated pool of long term cancer survivors is expected to expand to 22 million in the United States over the coming decade25, and many of these survivors will experience the additive risk of pre-existing osteopenia or osteoporosis exacerbated by the effects of cancer treatment.

Premenopausal women receiving antineoplastic agents commonly administered to treat breast cancer, such as cyclophosphamide, anthracyclines, taxanes and platinum agents are at high risk of chemotherapy -induced ovarian failure (CIOF), a temporary or permanent cessation of gonadal function26,27. This form of ovarian suppression is defined as amenorrhea for three months or more and a follicular stimulating hormone level of ≥ 30 mIU/mL, and is associated with rapid onset decreases in bone mass, seen in as few as 6 months after the start of therapy27. Negative effects on BMD can be seen for up to 10 years after treatment ends despite bisphosphonate therapy28.

Therapeutic reduction of circulating estrogen from ovarian suppression or inhibition of the secondary production of estradiol through aromatase enzyme disrupts the balance between bone renewal and resorption, resulting in steadily diminished bone density over the 5 to 10 year therapeutic window. Coupled with additive treatment-related risk factors such as exposure to prolonged glucocorticoids, patients receiving cancer treatment that includes endocrine therapy are at elevated risk of bone loss.

An emerging area of study related to bone loss is focused on inflammation. Cancer and other conditions that promote an inflammatory milieu, such as obesity, periodontitis, chronic kidney disease, rheumatoid arthritis and others are associated with prolonged, elevated circulation of pro-inflammatory cytokines such as numerous interleukins and tumor necrosis factor (TNF)-a that heavily influence and upregulate osteoclast activity29.

Assessment and Monitoring of Bone Density

The most common tools to assess risk for osteoporotic fracture include the FRAX and DEXA. The Fracture Risk Assessment Tool (FRAX) is an online resource (https://www.sheffield.ac.uk/FRAX/30) that provides estimates of a patient’s likelihood of experiencing an osteoporotic fracture within the next 10 years by calculating the number of clinical risk factors (age, sex, BMI, personal history of a previous fracture, parental history of hip fracture, current smoking, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis form other comorbidities, three or more units of alcohol per day) and femoral neck BMD30. The World Health Organization criteria defining osteoporosis categories is seen in Table 1.

Table 1.

The World Health Organization Criteria for Osteoporosis33

Category Bone Mineral Density Result falls within: T Score
Normal 1 SD of mean for reference population At −1.0 or greater
Osteopenia 1 to 2.5 SD below mean Between −1.0 and −2.5
Osteoporosis 2.5 SD or more below mean At or below −2.5
Severe Osteoporosis 2.5 SD or more below mean At or below −2.5 with one or more fractures
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Note: SD = Standard Deviation

Dual energy x-ray absorptiometry (DEXA or DXA) is a brief, low radiation dose imaging technique that uses two different energy level scans to differentiate the density between bone and soft tissue31 and reports bone mineral density in comparison to a young adult reference group32. DXA scans are optimally focused on the density of the femoral head or lumbar spine, but where that test is not available, a quantitative ultrasound at the heel can estimate BMD33. Per American Society of Clinical Oncology (ASCO) guidelines, patients with non-metastatic disease receiving a cancer therapy that increases risk of bone loss should undergo BMD screening every 2 years, and more frequently depending on the severity and pace of decline34.

Therapeutic approaches to maintain bone density

A holistic, health promotion approach to preserve bone mass is key, as a long-term balance of pharmacologic and non-drug approaches are necessary to maintain and where possible, strengthen skeletal structure over the decade-long course of endocrine therapy and for the rest of the patient’s life.

Though the most obvious growth of the skeletal structure occurs during childhood and adolescent maturation, homeostasis of human bone remains a dynamic system throughout life. Bone remodeling is the ongoing renewal process resulting from mineral and collagen deposition by osteoblasts balanced by resorption by osteoclast cell activity35. Major stimuli driving bone remodeling include mechanical stressors and hormonal influences. Bone mineral density increases may be stimulated through osteoblastic activity when weight-bearing and the resistance forces associated with tendons pulling on their bony attachments during physical activity occur36.

Hormones that interactively influence bone remodeling include calcitonin, growth, parathyroid and thyroid hormones, glucocorticoids and estrogen35. For example, low circulating levels of calcium in the bloodstream provides feedback to the parathyroid glands to produce parathyroid hormone (PTH). PTH stimulates RANKL production, which increases osteoclast resorption and freeing calcium back into the bloodstream. This activity is normally regulated by calcitonin, which binds to receptors on osteoclasts in the presence of elevated serum calcium levels, returning to homeostasis. A prolonged state of estrogen deficiency such as postmenopause or when therapeutically suppressed results in increased RANKL production resulting in increased osteoclast activity and resorption37.

Dietary considerations

Adequate intake of calcium and vitamin D are critical to bone health. Calcium is the major component of bones and teeth, with 98% stored in the skeleton as hydroxyapatite and the remainder found in circulation to support blood vessel tone, nerve and muscle function and blood clotting38. Serum calcium level is not a valid measure of nutritional status or bone mineral density due to strict homeostatic control of the amount allowed to circulate in the bloodstream39. The recommended daily allowance (RDA) for calcium varies by age and sex (see Table 2). Adolescents aged 9 to 18 are recommended to consume 1300 mg of calcium per day during their peak bone building years. For both males and females aged 19 to 50 and males up to age 70, the RDA is 1000 mg per day. Women aged 51 to 70 should consume 1200 mg per day as should all older adults aged 70 and above39.

Table 2.

US RDA and Maximum Tolerable Doses for Calcium in Teens and Adults42

Recommended Daily Allowance
Age (years) Male Female Tolerable Upper Intake Levels
9 to 18 1300mg 1300mg 3000mg
19 to 50 1000mg 1000mg 2500mg
51 to 70 1000mg 1200mg 2000mg
> 70 1200 mg 1200mg 2000mg
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Wherever possible, consumption of whole and fortified foods containing calcium is optimal, such as dairy products, fish with edible bones such as sardines and salmon, dark green leafy vegetables40. Absorption of oral calcium intake varies by food type and co-ingestion of other substances that may bind and decrease uptake, such as iron supplements. For example, the oxalic acid in spinach limits absorption of that food’s calcium to about 5% compared to approximate 30% absorption from milk. The most common supplement formulations are calcium carbonate (taken as a tablet or in antacid form) or calcium citrate, and they are best absorbed when taken with a meal. Interestingly, the amount of elemental calcium ingested in a single dose impacts absorption, with the highest absorption occurring with doses of 500mg or less at one time. One study demonstrated about 36% absorption of a 300mg dose compared to only 28% of a 1000mg dose41.

Though hypercalcemia and hypercalciuria (urine calcium levels > 275mg/day in men and > 250mg/day in women) are rare in the healthy population, patients with cancer may be at higher risk and should avoid exceeding the RDA for calcium supplementation. The maximum tolerable doses for adolescents is 3000 mg per day, 2500 mg for ages 19 to 50 and 2000mg daily from age 51 and older42. Calcium supplements may also interact with medications including lithium, levothyroxine and quinolone antibiotics39.

Vitamin D must be converted from its inert form of calciferol first in the liver into 25-hydroxyvitamin D [25(OH)D] also known as calcidiol. A second hydroxylation conversion occurs in the kidneys to create the physiologically active form calcitriol, or 1,25-dihydroxyvitamin D [1,25(OH)2d]42. The presence of vitamin D is necessary to facilitate calcium absorption in the intestines, and has effects on immune function, glucose metabolism and regulation of cell proliferation and apoptosis43.

The recommended daily allowance for vitamin D in males and females aged 1 to 70 years is 600 international units (IU) per day (see Table 3); after age 70 the recommendation is 800 IU42. There are few naturally occurring food sources of vitamin D, so it is commonly fortified in many foods, including animal and plant-based milks, cereals, infant formulas. The best whole food sources include fatty fish and fish liver oils, egg yolks, beef liver and some mushrooms43. Oral supplementation is advised when adequate intake or sun synthesis cannot occur. Vitamin D is a fat-soluble vitamin and can be stored in the body over time; extremely excessive dosing can lead to toxicity including renal failure, cardiac arrhythmia and death44. The maximum tolerable levels of supplementation vary by age and should not exceed 4000 IU per day for those over age 9, including during pregnancy and lactation42. It is important to note that vitamin D supplements may interact with certain medications, including orlistat, which can impair absorption from food. Vitamin D, atorvastatin, simvastatin and lovastatin are metabolized via CYP3A4, producing a potential supplement-drug interaction45. Through their effect on lowering cholesterol, all statins can reduce endogenous vitamin D synthesis43.

Table 3.

US RDA and Maximum Tolerable Doses for Vitamin D42

Recommended Daily Allowance
Age Males and Females Tolerable Upper Intake Levels
0 to 6 months 10 mcg (400 IU) 25 mcg (1000 IU)
7 to 12 months 10 mcg (400 IU) 38 mcg (1500 IU)
1 to 3 years 15 mcg (600 IU) 63 mcg (2500 IU)
4 to 8 years 15 mcg (600 IU) 75 mcg (3000 IU)
9 to 18 years 15 mcg (600 IU) 100 mcg (4000 IU)
19 to 70 years 15 mcg (600 IU) 100 mcg (4000 IU)
> 70 years 20 mcg (800 IU) 100 mcg (4000 IU)
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Sunlight, specifically UV-B radiation contact with skin converts 7-dehydrocholesterol in skin into previtamin D3. This method can be a major source of vitamin D production, but intentional exposure must be balanced with measures to protect against skin cancer and photoaging concerns. Though many factors including seasonal intensity of sunshine, use of sunscreen and individual skin melanin levels influence the amount of vitamin D produced, it is generally thought that a “dose” of 5 to 30 minutes of outdoor sun contact with exposed skin twice a week can produce adequate synthesis46.

Physical Activity

There is a robust body of evidence that physical activity is safe and effective for people with cancer47. PA improves overall health-related quality of life48 and specific symptoms such as fatigue49, depression and anxiety50. PA may improve body composition (lower body mass index and fat percentage51) which is associated with lower disease recurrence among breast cancer survivors52. Multiple clinical practice guidelines recommend that adults, including cancer survivors, participate in a minimum of 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity plus two sessions of resistance exercise per week50,53,54. Specific to bone health, resistance exercise and activities at least twice per week that generate impact forces on the skeleton at 3 to 4 times body weight (e.g. use of weights, higher-impact jumping movements) appear to be the most effective strategies to slow bone loss at the hip and spine50,55.

Pharmacologic Management – Bone modifying agents (BMA)

Bone modifying agents, including bisphosphonates and RANKL inhibitors are used in several ways in the oncology population. Patients with cancer and high risk factors for osteoporosis may receive prophylactic or treatment administration of these BMA to decelerate bone loss and prevent fractures. These agents may also be used as an adjuvant to breast cancer therapy to prevent disease recurrence in the bone and improve overall survival and are also used to treat skeletal metastatic disease56.

Bisphosphonates

Bisphosphonates bind with and prevent hydroxyapatite from being dissolved from the bone57. The specific agents commonly used in oncology differ from those used in the general population to favor those with the most evidence of effectiveness during and after administration of chemotherapy and aromatase inhibitor use.

Osteoporosis prevention and treatment.

Because the bone loss associated with aromatase inhibitors and ovarian suppression/oophorectomy can be rapid, causing clinically significant changes in BMD as early as 6 months from treatment initiation, guidelines recommend consideration of initiation of bisphosphonates in patients receiving these therapies or who have CIOF at a higher T score or FRAX estimate than in the general population34. Oral bisphosphonates commonly used to manage BMD in patients with cancer include alendronate, risedronate and ibandronate58. Zoledronic acid is administered as a 5mg dose intravenously once every 2 years as a preventative measure. For treatment of established osteoporosis, zoledronic acid may administered as a 5mg dose annually or 4mg every 6 months34.

Adjuvant use to prevent skeletal disease recurrence and improve overall survival.

A joint working group report by Cancer Care Ontario and ASCO reviewed the literature and recommends administration of zolendronic acid 4 mg IV every 6 months or clodronate 1600mg per day orally as an adjuvant to breast cancer therapy to decrease the incidence of disease recurrence in the bone and to improve overall survival56. Data supporting these recommendations come largely from the Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis of 18,766 women enrolled in 26 trials59 who received bisphosphonates for 2 to 5 years. There were significant reductions in disease recurrence in the bone (RR 0.83, p = .004 among all patients, and most pronounced in post-menopausal patients, RR 0.72, p = .0002), bone fractures (RR 0.85, p = .02) and breast cancer mortality (RR. 91, p = .04). There was no significant reduction in non-skeletal recurrence in any group (RR 0.98, p = .69)56. The optimal start time and length of therapy has not been established.

Use in bony metastatic disease.

Treatment of bony metastatic disease with BMA focuses on strengthening existing lesions, managing pain and preventing further skeletal-related events (SRE). Recommended treatments include denosumab 120 mg subcutaneously monthly, pamidronate 90 mg IV every 3 to 4 weeks or zoledronic acid 4mg every 12 weeks or every 3 to 4 weeks60. Though there may be some improvement in bony pain with administration of these agents, BMA alone were not found sufficient to completely manage pain from bony metastases. It is important to consider the wide variation in price among these agents during shared treatment decision making, as the 2019 Medicare Average Sale Price for a 4mg dose of zoledronic acid was $46.40 and $1,146 for 60 mg of denosumab (all in USD)61.

One of the most concerning adverse events of bisphosphonates is osteonecrosis of the jaw (ONJ), seen in up to 2.8% of patients with breast cancer receiving monthly infusions of zolendronic acid or pamidronate monthly for metastatic disease62. ONJ is thought to be dose and schedule dependent, with highest incidence occurring in patients with recent dental surgery or implants. Other adverse events, especially with intravenous dosing include renal impairment and flu-like symptoms. Oral administration of bisphosphonates can be associated with esophagitis, and patients are instructed to take medication with a full glass of water and to remain upright for 30 minutes to promote movement of the tablet fully into the stomach.

Implications for Nursing

Oncology nurses who work with patients treated for HR positive breast cancer will often form long term caring relationships. In addition to the highly technical, biomarker driven treatment planning and administration approach becoming more common in the acute phase of illness, HR positive patients will receive endocrine therapy approaches for up to a decade. Nurses supporting this patient population must educate proactively and repeatedly on multiple important topics, including medication adherence, identification and management of adverse events and key health promotion activities, including reduction of risk factors such as smoking and excessive alcohol intake. Regular engagement in physical activity to maintain optimal body composition, incorporation of weight-bearing exercise to stimulate osteoblast activity and concurrent intake of adequate levels of calcium and vitamin D are critical to maintain bone health.

Funding acknowledgement:

This work was funded, in part, through a grant (P30CA008748) from the National Institutes of Health, National Cancer Institute.

Footnotes

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