Perspective Chapter: Management of Bone Health in Breast Cancer Patients

Abstract

Breast cancer is the most common cancer in the world. There are several implications of bone health in early and late breast cancer cases. In early breast cancer, the therapy might cause reduction of bone mineral density due to early menopause induction or as a side effect of therapy options, such as aromatase inhibitors. In late-stage breast cancer, most common site of metastasis is in the skeletal bone. Early management of bone metastasis needs special focus because of skeletal-related complications such as fractures, pain, hypercalcemia, and surgery. This chapter will focus on most common diagnostic and therapeutic measures of osseous metastasis, in early and advanced breast cancer.

1. Introduction

Breast cancer is the most common cancer in women with a worldwide annual incidence of 2.3 million cases and 685,000 death per year [1]. There is a clear correlation between bone health and breast cancer [2], as bone mineral density can be severely reduced through early menopause or endocrine therapy, including aromatase inhibitors [3]. Secondly, there is also a clear relationship between osteo-oncologic treatment including densoumab and bisphosphonates and outcome in early breast cancer [4]. Thirdly, in stage IV breast cancer, bone is the most common site of metastasis [5].

Disease-specific events related to bone metastasis include complications, such as spinal cord and nerve compression and pathological fractures, needing surgical interventions and/or radiotherapy. This is therefore a major endpoint in treatment of metastatic breast cancer, since targeted therapy has the potential to significantly improve outcome in early and metastatic breast cancer [6].

This chapter will give you an overview on bone health management and prevention in early and metastatic breast cancer patients.

2. Bone remodeling

Bone remodeling is an important process in maintaining bone health, as approximately 10% of the bone is renewed every year [7]. This is a balanced process coupling bone resorption and bone formation. However, in the absence of bone formation, bone resorption continues to occur normally. This process happens with predilection in the elderly population and with even more affinity in postmenopausal women.

Bone remodeling is characterized by a succession of osteoclastic resorption of already formed bone, followed by de novo bone synthesis by osteoblasts.

Development of bone metastasis refers to a specific interaction between osteoclasts, osteoblasts, and several inflammatory modulators such as Parathyroid PTH, Parathyroid hormone-related protein PTHrP, Cyclooxygenase 2 COX-2/PEG-2, interleukins 1 and 11 (IL-1, IL11), tumor necrosis factors TNF-alpha, TGF-beta [8]. In metastatic breast cancer, osteoblasts secrete macrophage colony stimulating factor (M-CSF), which binds to c-fms, and receptor activator of nuclear factor kappa B ligand (RANKL), which binds to RANK, thus stimulating differentiation of pre-osteoclasts into osteoclasts. RANKL inhibitors can be therefore successfully used to stop osteoclastic activity [9].

3. Management of bone health in early breast cancer

The most common breast cancer subtype is luminal cancer with positive estrogen- and progesterone-receptor (ER/PR) expression. Around 50% of all human epidermal growth factor receptor 2 (HER2)-enriched subtypes also express estrogen ER and progesterone PR [10]. These hormonal receptor (HR)-positive cancers are clearly estrogen-driven malignancies; however, estrogen also has a protective effect on bone, and reduced levels can trigger bone loss. Hormonal therapy with aromatase inhibitors (AI) (usually anastrozole, exemestane, or letrozole) represents standard of care in early postmenopausal and in high-risk pre-menopausal patients. In the latter group they are usually administered in combination with a gonadotropin-releasing-hormone receptor antagonist (GnRH-A).

In the postmenopausal patients, use of aromatase inhibitors is shown to lead to a bone mineral density loss of about 2% per year, while in combination with GnRH analogues, bone mineral density loss can reach even 7% and more [11].

Real world data looked at patterns of bone loss in women with breast cancer [12]. In this particular analysis, bone mineral density of patients was significantly decreased in the lumbar spine (6.8%), followed by femoral neck (4.6%), and hip (3.5%). Bone loss seemed to be greatest in the first year.

Chemotherapy was also associated with bone loss at all sites, and the premenopausal status at moment of diagnosis was significantly associated with bone loss in the lumbar spine. No significant relationship between health behavior status and bone mineral density change could be demonstrated.

Based on different guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and the Swiss SVGO (Swiss Association Against Osteoporosis), patients with early-stage breast cancer should receive comprehensive care measures focusing on bone metastasis prevention. This includes regular bone scans (DEXA Scans), life style modifications, calcium and vitamin D supplementation, and bisphosphonates.

Figure 1 demonstrates general practical guidelines in breast cancer and other cancer subtypes. Our own data [2] showed treatment adherence in only 75% of patients with breast cancer (small single center analysis).

Figure 1.

Treatment recommendation for bone health in cancer patients. Demonstrated bone health guidelines for patients with breast cancer and other cancers, under endocrine therapy. Adapted from Coleman R. [13, 14].

4. Current date and use of bisphosphonates

4.1 Zoledronic acid and mode of action

Zoledronic acid is one of the nitrogen-containing antiresorptive agents, which inhibits osteoclast proliferation. Owing to the chemical similarity to inorganic pyrophosphate, zoledronic acid (and other bisphosphonates) attaches to hydroxyapatite binding sites on the osseous extracellular matrix [2, 15, 16]. The exact mechanism of apoptosis induction in osteoclasts is not fully understood. However, animal experiments have suggested that zoledronic acid inhibits specific transferases, such as geranyl transferase I inhibitor (GGTI-298), leading to loss of protein prenylation in osteoclasts, disrupting their cytoskeleton and inducing programmed death [15, 17, 18]. The main effect is reduced bone resorption, which allows for more time for bone formation and remodeling [9, 19]. It has also been hypothesized that zoledronic acid might stimulate osteoblastic differentiation and bone mineralization. Zoledronic acid seems to have the highest potential among bisphosphonates, because of its high affinity to bone, especially bones undergoing active resorption and increased turnover, such as in malignant processes [20].

4.2 Current guidelines and data on bisphosphonates

Current NCCN guidelines recommend adjuvant bisphosphonate therapy for 3–5 years in the case of menopausal patients with early stages of breast cancer, as well as in patients who recently went through menopause and who are under treatment with GnRH-A and aromatase inhibitors. In daily clinical routine, many oncologists use zoledronic acid [21].

The recently published Southwest Oncology Group (SWOG) S0307 trial was a randomized three-arm trial including more than 6000 patients, aiming to assess differences in zoledronic acid, oral clodronate, and oral ibandronate therapies. No significant difference in disease-free survival and overall survival for the three drugs was found. Authors concluded that oral bisphosphonates could be a valid option with regards to osteo-oncologic treatment [22].

In a 2017 published Cochrane analysis, data collected from more than 37,000 patients were also able to demonstrate the benefits of bisphosphonate therapy. This showed a clear survival benefit with addition of bisphosphonates for postmenopausal patients (HR 0.77, 95% CI 0.66–0.90; p = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity), but not for premenopausal patients (HR 1.03, 95% CI 0.86–1.22; p = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity) [5].

In conclusion, for women with early breast cancer, bisphosphonates were able to reduce the risk of bone metastases and provide an overall survival benefit compared to the placebo or no bisphosphonates group. There is preliminary evidence suggesting that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate.

The Early Breast Cancer Clinical Trials Group (EBCCTG) designed a meta-analysis incorporating data from more than 18,000 women, derived from 26 randomized adjuvant bisphosphonate trials in breast cancer. In postmenopausal patients, there was a statistically significant reductions in the 10 years recurrence rate, (RR = 0.72, 95%, CI = 0.60–0.86, 6.6% vs. 8.8%; two-sided Pp = .0002), as well as in the breast cancer mortality rate (RR = 0.82, 95% CI = 0.73–0.93, 14.7% vs. 18.0%; two-sided p = .002) with the addition of bisphosphonates. The reduction was independent of choice of bisphosphonate therapy, estrogen receptor expression status, axillary lymph node involvement, or use of adjuvant chemotherapy [10].

5. Current data and use of Denosumab

Denosumab is a human recombinant monoclonal antibody against RANKL. Inhibition of RANKL leads to reduced maturation of preosteoclasts into osteoclasts, osteoclast survival, and activity. As a result, diminished bone resorption occurs [20].

In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-18 Study (ClinicalTrials.gov NCT00556374), 3425 postmenopausal women with early luminal breast cancer and aromatase inhibitor therapy were randomized to receive denosumab 60 mg every 6 months or placebo. The primary endpoint was occurrence of clinically relevant fractures. Secondary endpoints included disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). In the follow-up presented at American Society of Clinical Oncology (ASCO) 2022 with an 8-year follow-up, all clinical endpoints were positive: fractures were 201 in the denosumab and 255 in the placebo arm (HR 0.76, 95% CI 0.63–0.92, p = 0.004). The absolute 9-year DFS difference is 3.5% (79.4% vs. 75.9%, respectively). No new safety signals were presented at the meeting. The authors concluded that denosumab should be considered in routine practice for patients with early hormonal-receptor positive breast cancer [23].

On the other hand, there is a very huge body of evidence that intravenous bisphosphonates improve outcome in postmenopausal women with early breast cancer. In a vast systematic meta-analysis by the Early Breast Cancer Trialists Collaborative Group EBCTCG including more than 18,000 patients, clear benefit was proven in regard to the overall reduction of recurrence (RR 0·94, 95% CI 0·87–1·01; 2p = 0·08), distant recurrence (0·82, 0·74–0·92; 2p = 0·0003), bone recurrence (0·72, 0·60–0·86; 2p = 0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p = 0·002) [10]. The authors were able to thus clearly demonstrate the advantages of bisphosphonate administration in postmenopausal women. Therefore, it quickly became a worldwide current standard to use bisphosphonates in management of early breast cancer, stages I–III. Current indications, dosage, and toxicity are displayed in Table 1.

	Bisphosphonates	Denosumab
Indications	Osteoporosis, hypercalcemia of malignancy, Paget’s disease of bone, multiple myeloma, skeletal-related events (SRE) associated with metastatic bone disease in breast (and other) cancers, adjuvant therapy for postmenopausal breast cancer patients and potentially also in premenopausal patients	Unresectable giant cell tumor of bone in adults and skeletally mature adolescents; to increase bone mass in patients at high risk for fracture including ADT for non- metastatic prostate cancer or adjuvant AI therapy for breast cancer, prevention of SREs in patients with bone metastases from solid tumors, treatment of postmenopausal women with osteoporosis at high risk for fracture [24]
Dosing	Clodronate 1600 mg p.o. daily for 3–9 mo.,; Pamidronate 300–360 mg p.o. for 18–2 mo. or 45 mg i.v. until progression, 90 mg iv every 28 d for 12–24 mo.; Zoledronic acid 4 mg i.v. every 28 d for 12 mo.; Ibandronate 6 mg i.v. every 28 d or 50 mg p.o. daily	60 mg administered as a single subcutaneous injection once every 6 months, for osteoporosis [25]
Side effects	Acute-phase-like reaction, renal toxicity, osteonecrosis of the jaw	Acute-phase-like reaction, renal toxicity, osteonecrosis of the jaw
Supplementation of calcium and vit- amin D	Vitamin D and calcium supplements must not be routinely given during bisphosphonate administration (supplementation may increase the bone resorption and decrease the efficacy of bisphosphonates). Consider vitamin D supplementation in people with, or at risk of, vitamin D deficiency. Consider calcium supplements if patient’s dietary intake is low.	At least 500 mg calcium and 400 IU vitamin D daily
Monitoring	Serum creatinine prior to each dose, regular dental examinations, electrolytes/hematocrit/ hemoglobin	Electrolytes (incl. Phosphate and magnesium), signs of infections or skin rash, regular dental examinations

Table 1.

Indication, dosing, and toxicity of bone-targeted agents (adapted from Biskup [1, 20]).

SRE = skeletal-related events, ADT = androgen deprivation therapy; AI = aromatase inhibitor; i.v. = intravenous;p.o. = oral; mo = months.

6. Management of metastatic disease in breast cancer

Breast cancer can be in many cases, cured today, but around 20% of patients will experience recurrence in the first 10 years of follow-up. Late recurrence is possible and is depends on many factors such as biology and anatomic stage. Bone metastasis is the most common site of metastasis followed by lung, liver, and lymph nodes, in all breast cancer subtypes.

In advanced breast cancer, 60–80% of patients will develop bone metastasis [5]. Complications are mostly related to skeletal bone and refer mostly to pathological fractures, major surgery, radiotherapy, and spinal cord and nerve compression symptoms. This leads to loss of quality of life, pain, and increased health costs.

Hypercalcemia is, among others, a severe manifestation of metastatic disease or para-neoplastic events in breast cancer patients, related to high mortality risk. It is considered oncologic emergency requiring rapid evaluation and treatment.

Bone metastases are diagnosed through imaging, such as CT scan, MRI, PET-CT, and nuclear bone scans [26, 27]. A biopsy is usually required to confirm diagnosis and can help determine the immunohistochemical assay. Analysis of sampled bone biopsy needs more time because of preparation, which includes decalcification of the bone. Therefore, many oncologists will collect biopsies from different organs, e.g., liver, soft tissue, or lung. The receptor conversion rate (estrogen, progesterone and HER2 status) in bone metastases is much lower than in liver metastases. And this should be taken into consideration when deciding treatment options. For patients with breast cancer bone metastasis, this includes HER2-directed, endocrine-directed, and chemotherapy options.

Established as standard of care more than 20 years ago, bisphosphonates still remain a go-to drug for many oncologists in the daily clinical setting. Initial trials demonstrated reduction of skeletal-bone-related events, including, but not limited to, pain, as well as quality of life improvement for oncologic patients (See Table 2) [34, 35, 36, 37].

Regime	N	Outcome	Toxicity	Literature
i.v. pamidronate vs. Placebo q3–4 wks., 2y	382	SRE at 2 years 50 vs. 70% p < 0.001; Median time to SRE 13.9 vs. 7 mo.	Arthralgia, flu-like syndrome	[19, 28, 29]
Clodronate 1/d vs. placebo for 18 mo.	173	SRE 218.6 vs. 304.8 per 100 pts. y, p < 0.001 Vertebral fractures 84 vs. 124 per 100 pts. y, p < 0.025, No OS difference	No difference	[12, 30]
Oral ibandronate vs. placebo up to 96 wks.	564; Pooled; Analysis	Number of events per pts. 1.15 vs. 1.85, p = 0.008; Risk reduction for SRE = HR 0.62 (95% CI 0.48–0.79, p < 0.001), Death 20% vs. 15%; NS for pain, time to progression	Any AE 94 vs. 95%; Drug related AE 26 vs. 17%; Hypocalcemia 9.4% vs. 5.1%	[3, 31]
Zoledronic acid vs. i.v. pamidronate for 12 mts (in BC, MM)	1130 (BC)	SRE at 13 mo. 44% vs. 46%; Skeletal morbidity rate 1.13 vs. 1.08 events/y/NS	Bone pain 49% vs. 59%	[29, 32]
Ibandronate p.o. vs. zoledronic acid i.v. q 3–4 weeks for 96 weeks	1401	SRE 42% vs. 41% (HR 1.15, 95% CI 0.97–1.62); Median time for SRE 97 vs. 99 wks.; Median OS 111 vs. 113 wks.	Dyspepsia 35 vs. 25%; Hypocalcemia 11 vs. 11%; Renal impairment 24 vs. 32%; ONJ 5 vs. 9 events	[25, 33]
SC denosumab and i.v. placebo vs. i.v. zoledronic acid 4 mg and SC placebo q 4 wks.	2046 (BC)	Delay time to SRE HR 0.82 (95% CI 0.71–0.95, p < 0.001); Risk of multiple SRE HR 0.77 (95% CI 0.66–0.89, p < 0.001); OS: HR = 0.95 (95% CI 0.81–1.11, NS); Disease progression: HR = 1.00, (95% CI 0.89–1.11, NS); Quality of life effect: in the denosumab group, 10% more patients had a clinically meaningful improvement	AE leading to discontinuation 9.6 vs. 12.3%; Serious AE 44.4 vs. 46.5%; Pyrexia 16.7 vs. 24.4%; ONJ 2 vs. 1.4%	[1, 24]

Table 2.

Clinical trials of bisphosphonates in the metastatic setting.

BC = breast cancer, i.v. = intravenous, MM = multiple myeloma, mo. = months, NS = Not significant, ONJ = Osteonecrosis of the jaw, AE = adverse effects, OS = Overall survival, pts. = patients, SRE = Skeletal-related events, wks. = weeks, y = years.

Traditionally, standard application of zoledronic acid referred to dosing every 4 weeks, but newer trials showed that a deescalation to a 12 weekly based regime is as feasible and did not worsen outcome.

7. Summary and conclusion

Bone health is an important topic in early and advanced breast cancer. Bisphosphonates have been established in management of metastatic disease since more than 20 years ago and have shown to clearly improve the outcome in patients with bone metastasis. Since 2010, denosumab, an RANKL antibody, was also accepted and adopted as standard of care in patients with metastatic breast cancer and bone metastasis. Both options significantly reduce skeletal-bone-related complications and are important therapeutic agents considered in metastatic breast cancer cases.

In early stages of breast cancer, bisphosphonates should be used in postmenopausal women for improved outcome (recurrence risk and bone health including prevention of osteoporosis) [14].

However, patients should be informed, before treatment initiation with these agents, about possible side effects including osteonecrosis of the jaw (ONJ), pain, and flu-like symptoms.

Nowadays, bisphosphonates and denosumab are internationally recognized as part of standard practice in breast cancer treatment, and every physician should be aware of their indications, therapy regimens, and possible complications.