Bone Health and Breast Cancer Management

Attention to bone health is an important aspect of managing breast cancer in women. Many women with breast cancer are postmenopausal and therefore at increased risk for osteoporosis. In addition, some of the agents used for the treatment of breast cancer have adverse effects on bone (chemotherapy and aromatase inhibitors). For example, aromatase inhibitors (eg, anastrozole, letrozole, exemestane), which are used to treat early-stage breast cancer in postmenopausal women, can cause osteopenia and osteoporosis.

Finally, bone is the most common site of metastasis in breast cancer. Metastasis to bone causes pain, pathological fractures, hypercalcemia, and spinal cord compression, as well as contributing to mortality.[1, 2]  

A study by Lipton et al found that in patients with bone-only metastases, serum beta C-terminal telopeptide (B-CTx) of type I collagen was a significant predictor of shortened recurrence-free survival (RFS). B-CTx is a marker of bone resorption, and increased resorption favors the growth of cancer cells.[3]

Increasing evidence indicates that in postmenopausal women with breast cancer, adjuvant bisphosphonate treatment not only improves bone density but also decreases bone metastasis and improves overall survival. In patients with metastatic breast cancer, bisphosphonates and denosumab have been shown to decrease skeletal-related events, including fractures; hypercalcemia; and increased need for radiation, surgery, or pain medication.

For more information, see Breast Cancer, Breast Cancer Staging, Adjuvant Therapy for Breast Cancer, and Breast Cancer Treatment Protocols.

Bisphosphonate Therapy

Bisphosphonates, which inhibit resorption of bone by osteoclasts, have been studied extensively in breast cancer. Bisphosphonates can delay the development of skeletal-related events in women with metastatic breast cancer and show promise in preventing bone loss induced by chemotherapy or hormonal therapy. Emerging data suggest that adjuvant therapy with bisphosphonates may prevent disease recurrence and prolong survival, specifically in postmenopausal women.[4]

The Early Breast Cancer Trialists' Collaborative Group found that in postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy produced highly significant reductions in recurrence (rate ratio [RR] 0.86, P=0.002), distant recurrence (RR 0.82, P=0.0003), bone recurrence (RR 0.72, P=0.0002), and breast cancer mortality (RR 0.82, P=0.002). In premenopausal women, however, bisphosphonate treatment had no apparent effect on any outcome.[5]

In the setting of metastatic disease, bisphosphonates have little or no effect on survival. However, intravenously administered bisphosphonates do appear to provide a continuous effect on bone for the duration of their use.

In general, adverse effects for bisphosphonates include bone, joint, or muscle pain, as well as nausea, vomiting, and diarrhea. Oral bisphosphonates pose a higher risk of heartburn and esophagitis than their intravenously administered counterparts.

Denosumab

In September 2011, denosumab (Prolia) was approved by the U.S. Food and Drug Administration (FDA) to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer. A dose of 60 mg is administered subcutaneously every 6 months.

Denosumab is a fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL), which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density.

Vitamin D

Vitamin D supplementation may be indicated in women treated for breast cancer, to aid with bone mineral density.[6] A double-blind, placebo-controlled, randomized phase II trial by Restelli et al found that high-dose vitamin D supplements improved aromatase inhibitor–induced musculoskeletal symptoms in women on adjuvant anastrozole for breast cancer.[7] Vitamin D also appeared to have a positive effect on bone loss on these patients.

Vitamin D supplementation may offer benefits beyond bone health. Some evidence suggests that low vitamin D status enhances the risk for development or progression of breast cancer.[8]  A study from Thailand reported that vitamin D deficiency (25[OH]D concentration below 16 ng/mL was independently associated with poor survival in breast cancer patients.[9] A study from Ireland determined that all-cause mortality was lower in women who began vitamin D supplementation after breast cancer diagnosis, compared with nonusers of vitamin D (hazard ratio= 0.84 [95% CI: 0.73, 0.99]).[10]

Exercise

A study by Winters-Stone et al found that a combined program of resistance and impact exercise reduced risk factors for fracture among postmenopausal breast cancer survivors and may be of particular benefit for those taking aromatase inhibitors. In this 1-year trial, women who participated in thrice-weekly progressive, moderate-intensity resistance plus impact exercise (n=52) maintained bone mineral density (BMD) at the lumbar spine, while women in the control group (n=54), who performed stretching exercises only, consistently lost BMD at the lumbar spine. In addition, women who were doing combined exercises and were on aromatase inhibitors had the greatest increase in lean mass, while those doing stretches who were not on aromatase inhibitors appeared to have a slight decrease in lean mass.[11]

A growing body of evidence suggests that bisphosphonates may have antitumor activity. In a study of a first-generation bisphosphonate, clodronate, in patients with primary operable breast cancer, Powles et al reported a significant improvement in 5-year bone relapse–free survival.[12]

A 2008 study examined the potential role of bisphosphonates in cancer treatment–induced bone loss and found that aromatase inhibitors or androgen deprivation can be risk factors for osteopenia, osteoporosis, and bone fracture and that this risk can be mitigated with appropriate bisphosphonate therapy.[13]

In a study of anastrozole therapy for breast cancer, Markopoulos et al found that patients who had pretreatment osteopenia or osteoporosis received protection against bone loss if oral risedronate was added to their regimen.[14] However, patients with a normal bone mineral density before starting treatment were at very low risk for osteoporosis.

In two studies of breast cancer patients with tumor cells detected in bone marrow, zoledronic acid proved to be more effective than placebo in eliminating these cells.[15, 16]

A study by Coleman et al found that zoledronic acid is well tolerated in the adjuvant setting and can be safely administered along with adjuvant therapy, including chemotherapy, in women with stage II/III breast cancer.[17] A separate study by Hatoum et al found that zoledronic acid is associated with a lower risk and frequency of skeletal complications and a longer follow-up time.[18]

A randomized phase III trial (SWOG 0307) that compared zolendronic acid with two oral bisphosphonates (clodronate and ibandronate) in 6097 patients with stage I-III breast cancer receiving adjuvant systemic therapy found no evidence of difference in 3-year disease-free survival by type of bisphosphonate, either in the intent to treat analysis or based on age and menopausal status. Almost three quarters of patients indicated that they would prefer an oral versus an intravenous agent, if efficacy were equivalent.[19]

The Early Breast Cancer Trialists' Collaborative Group meta-analysis included 26 randomized trials involving 18,766 women with early breast cancer and compared 2 to 5 years of bisphosphonate therapy with no bisphosphonate therapy.[5] Overall, the reductions in recurrence, distant recurrence, and breast cancer mortality with bisphosphonate therapy were of borderline significance, although the reduction in bone recurrence was significant (RR, 0.83; P = 0.004). However, subsequent analysis revealed that although bisphosphonates had no benefit in premenopausal women, in postmenopausal women, bisphosphonates produced significant reductions in the following[5] :

• Breast cancer recurrence (RR, 0.86; P = 0.002)
• Distant recurrence (RR, 0.82; P = 0.0003)
• Bone recurrence (RR, 0.72; P = 0.0002)
• Breast cancer mortality (RR, 0.82; P = 0.002)

The findings were unaffected by bisphosphonate class, treatment schedule, estrogen-receptor status, nodes, tumor grade, or concomitant chemotherapy.

In March 2017, Cancer Care Ontario and the American Society of Clinical Oncology (ASCO) issued a joint clinical practice guideline that recommends considering a bisphosphonate as adjuvant therapy for all postmenopausal women with early breast cancer who are deemed to be candidates for adjuvant therapy. The recommendation applies to women who have undergone natural menopause or menopause induced by ovarian suppression or ablation.[20]

The guidelines recommend the use of either zoledronic acid or clodronate; data on adjuvant denosumab, although promising, were found to be insufficient to support a recommendation. The recommended regimen for zoledronic acid is 4 mg intravenously (infused over 15 minutes or longer) every 6 months for 3 to 5 years. Clodronate is given in a dosage of 1,600 mg/d orally for 2 to 3 years.[20]

In the setting of metastatic disease, bisphosphonates have little or no survival effect. However, IV bisphosphonates do appear to provide a continuous effect on bone for the duration of their use.

Controlled trials have shown that administration of a bisphosphonate is associated with a delay in the development of new skeletal-related events (SREs), thus reducing or delaying the need for palliative radiation, orthopedic surgery to address pathologic fractures, and use of narcotic analgesics.[2] For this reason, monthly administration continues for an indefinite period in breast cancer patients with bone metastasi

Results of the randomized phase 3 ZOOM trial by Amadori et al, which studied the effect of decreasing the administration of zoledronic acid from every 4 weeks to every 12 weeks during the second year of treatment, suggest that the drug maintains its therapeutic effects. The ZOOM trial included 425 patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid.[21]

After follow-up of at least 1 year, the rate of skeletal-related events per patient per year in ZOOM was 0.26 (95% confidence index [CI] 0.15-0.37) in the patients who received zoledronic acid every 12 weeks, versus 0.22 (0.14-0.29) in the patients maintained on an every-4-week schedule. The upper limit of one-tailed 97.5% CI on the 0.04 difference between the groups.was 0.17, which is lower than the non-inferiority margin.[21]

Rates of the most common grade 3-4 adverse events in the 12-week group versus the 4-week group were as follows:

• Bone pain: 27% vs 30%
• Nausea: 11% vs 15%
• Asthenia: 9% vs 15%

 However, median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12.2% vs 0.0%; P=0.011).The authors recommend further investigation of this change before changing current practice.[21]

A randomized, open-label clinical trial that included 855 patients with metastatic breast cancer found no increased risk of skeletal events over 2 years in patients who received zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks. Similar results were reported in study patients with metastatic prostate cancer and multiple myeloma. The authors concluded that adminstering zoledronic acid every 12 weeks may be an acceptable option.[22]

SREs occurred in 113 patients in the 4-week group versus 119 in the 12-week group, among the 820 breast cancer patients who completed the study (hazard ratio [HR], 0.90; P = 0.43). Overall, fewer patients in 4-week group underwent bone surgery (22 vs 42; HR = 0.51; P =0.01). However, the two groups showed no significant difference in pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction. Although rates of skeletal morbidity were numerically identical in both groups, patients in the 12-week group had greater bone turnover, as indicated by higher C-terminal telopeptide levels.[22]

In general, adverse effects for bisphosphonates include bone, joint, or muscle pain, as well as nausea, vomiting, and diarrhea. Oral bisphosphonates pose a higher risk of heartburn and esophagitis than their intravenously administered counterparts.

Osteonecrosis of the jaw (ONJ), a particularly difficult and unpleasant adverse effect, has an incidence of 3% in bisphosphonate-treated breast cancer patients. Patients with underlying oral pathology (eg, previous radiation to the area, need for invasive oral procedures, poor dental hygiene) are at a higher risk of developing ONJ.

International guidelines on ONJ include the following recommendations on reducing risk of ONJ and managing cases of ONJ[23] :

• Before being started on bone-modifying agents (BMAs), patients with cancer should undergo an oral care assessment (including a comprehensive dental, periodontal, and oral radiographic exam when feasible). Based on the assessment, the dentist and oncologist should develop and implement a dental care plan to ensure that the patient undergoes any medically necessary dental procedures before starting the BMA. Once BMA therapy has been initiated, the dentist should perform follow-up on a routine schedule (eg, every 6 months).

• Members of the multidisciplinary team should address modifiable risk factors for ONJ with the patient as early as possible. These risk factors include poor oral health, invasive dental procedures, ill-fitting dentures, uncontrolled diabetes mellitus, and tobacco use.

• Elective dentoalveolar surgical procedures (eg, nonmedically necessary extractions, alveoloplasties, and implants) should not be performed during active therapy with a BMA at an oncologic dose. Exceptions may be considered when a dental specialist with expertise in the prevention and treatment of ONJ has reviewed the benefits and risks of the proposed invasive procedure with the patient and the oncology team.

• If dentoalveolar surgery is performed, patients should be evaluated by the dental specialist on a systematic and frequently scheduled basis (eg, every 6 to 8 weeks) until full mucosal coverage of the surgical site has occurred. Communication with the oncologist regarding the status of healing is encouraged, particularly when considering future use of BMAs.

• For patients with cancer who are receiving a BMA at an oncologic dose, there is insufficient evidence to support or refute the need for discontinuation of the BMA before dentoalveolar surgery. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.

• Initial treatment of ONJ consists of conservative measures such as antimicrobial mouth rinses, antibiotics if clinically indicated, effective oral hygiene, and conservative surgical interventions (eg, removal of a superficial bone spicule).

• If ONJ results in persistent symptoms or affects function despite initial conservative treatment, aggressive surgical interventions (eg, mucosal flap elevation, block resection of necrotic bone, or soft tissue closure) may be used. Aggressive surgical intervention is not recommended for asymptomatic bone exposure. Before aggressive surgical intervention, the multidisciplinary care team and patient should thoroughly discuss the risks and benefits of the proposed intervention.

• For patients who are diagnosed with ONJ while being treated with BMAs, there is insufficient evidence to support or refute the discontinuation of the BMAs. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.

In September 2011, denosumab (Prolia) gained US Food and Drug Administration (FDA) approval to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab is a fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density. A dose of 60 mg SC is administered once every 6 months.

FDA approval was based on a 2-year, double-blind, placebo-controlled study of 252 postmenopausal women with breast cancer receiving aromatase inhibitor therapy. Bone mineral density (BMD) was higher at 1 year in the lumbar spine in those treated with denosumab (+4.8%) compared with placebo (-0.7%). The treatment difference was 5.5% (95% confidence interval [CI], 4.8-6.3%; P< 0.0001). After 2 years, differences in BMD favoring denosumab were 7.6% in the lumbar spine, 4.7% in the (total) hip, and 3.6% in the femoral neck.[24]

Current American Society of Clinical Oncology (ASCO) guidelines recommend denosumab (Xgeva) at 120 mg SC every 4 weeks as an option for patients with breast cancer and evidence of bone metastases.[25]

Ovarian ablation has been found to improve survival in women with high-risk breast cancer. Similarly, luteinizing hormone–releasing hormone agonists such as goserelin have also been found to improve survival in this population. Goserelin is a known risk factor for osteoporosis, however, so it is imperative for patients on this medication to have their bone mineral density monitored.[26]