Breast cancer bone metastasis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Assistant Editor(s)-In-Chief:Jack Khouri, Associate Editor(s) in Chief:  Soroush Seifirad, M.D.[2]

## Overview

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* Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid , RANKL-RANK inhibitors like Denosumab, also has been recommended and studied for the treatment of bone metastases..Additionally, External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.

## Osteoclast Inhibitors

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### Bisphosphonates

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#### Indication

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Bisphosphonates constitute a mainstay therapy for patients with bone metastases, they can prevent skeletal complications and palliate bone pain. It should be noted that there is no proven survival benefit. Therapy with high dose bisphosphonates should be initiated after a documented diagnosis of osseous metastases because it has been shown that they do not decrease the incidence of skeletal events in women without metastatic disease.

#### Pharamacology

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Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast apoptosis and inhibition of osteoclast maturation and differentiation [1]. Furthermore, they may trigger the apoptosis of cancer cells, inhibit matrix metalloproteinase 1 (an enzyme that degrades extracellular matrix proteins), reduce angiogenesis and disturb the adhesion of tumour cells to bone [2]. The bisphosphonates are analogs of pyrophosphate, with carbon replacing the central oxygen. Their affinity for hydroxyapatite, the main bone mineral, is made possible by the side chains (R1 and R2) from the central carbon [3].

There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, that are different in their action on the osteoclasts. The nitrogen containing bisphosphonates (Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid) are more potent osteoclast inhibitors than the non-nitrogen containing bisphosphonates which include Etidronate, Clodronate, and Tiludronate.

#### Treatment Guidelines

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In the United States, only the intravenous pamidronate and zoledronic acid are approved by the FDA for treatment of osseous metastases. The American Society of Clinical Oncology (ASCO) recommends that:

* Osteoclast inhibitors including bisphosphonates be initiated in the management of patients with metastatic breast cancer and evidence of bone destruction on plain radiographs, CT, or MRI (but not bone scans) even if asymptomatic
* Bisphosphonates administration: Intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks
* There is no clear difference between oral or intravenous formulations of bisphosphonates and no clear superiority of either zoledronic acid or pamidronate [4].

Another important concept is that bone modifying agents including bisphosphonates should be adjunctive for bone pain control and not a replacement for analgesics, radiotherapy, or surgery [5] [6]. There is no recommended duration of treatment; the ASCO guidelines suggest that bone modifying agents be continued until evidence of substantial decline in a patient’s general performance status [4].

#### Side Effects

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* Phase III studies have shown that less than 2 percent of patients experience serious toxicity from bisphosphonates [7].

* Side effects include inflammatory reactions including the acute phase reaction, phlebitis and ocular inflammation (conjunctivitis, uveitis, scleritis). The acute phase reaction is a flu-like syndrome with fever, chills, myalgias and arthralgias occuring in approximately half of the patients; it is more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans [8]. It is classically seen within 3 days after infusion and is self limiting within 1 to 3 days. Acetaminophen or non-steroidal antiinflammatory drugs intake prior to infusion may decrease symptom severity [7]. The occurence of the acute phase reaction and its intensity tends to lessen after subsequent infusions.

* Renal insufficiency is another complication of bisphosphonate therapy and it is both dose- and infusion time-dependent. Nephrotoxicity can be reduced by slow infusion durations, providing adequate hydration prior to bisphosphonate infusion and withholding concomitant nephrotoxic medications. The ASCO recommends no change in dose, infusion time, or interval if creatinine clearance is superior to 60 mL/min. For patients receiving IV bisphosphonates, the creatinine level should be monitored before each infusion [4].

* Electrolyte disturbances can occur in patients on bisphosphonates which necessitates regular monitoring of serum calcium, magnesium, and phosphate during therapy.

##### Osteonecrosis of the Jaw

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Osteonecrosis (avascular necrosis) of the jaw (ONJ) is a more common complication with zoledronic acid compared with pamidronate. It is defined as an area of exposed bone in the maxillofacial or mandibular region that does not heal within 8 weeks of identification by a healthcare provider, in a patient who has been exposed to a bone-modifying agent administered either IV or orally, and has not had radiation therapy to the craniofacial region [9]. The pathophysiology is unclear. The most common complaints are pain and/or numbness in the affected region, tooth mobility, and soft tissue swelling. Conservative management with debridement, mouth rinses and antibiotics could result in healing [10].

US FDA labeling and ASCO guidelines for bone-modifying agents (including Bisphosphonates and Denosumab) suggest dental examination and necessary preventive dentistry for cancer patients before initiating therapy with these agents [4]. Maintaining oral hygiene and avoiding dental procedures of the mandible, maxilla or periosteum should be advised. Patients receiving therapy with bisphosphonates should get calcium and vitamin D supplementation to reduce the risk of bisphosphonate-induced hypocalcemia. Also, it should be noted that vitamin D deficiency increases the risk for bisphosphonate-induced hypocalcemia.

### Denosumab

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As mentioned in the pathogenesis section, the RANKL-RANK signaling pathway is a main molecular tool used by osteoclasts to resorb bone. Denosumab is a monoclonal antibody to the RANKL that inhibits it from binding to RANK leading to osteoclast inhibition. Denosumab is FDA approved to prevent SREs in patients with bone metastases from solid tumors at a dose of 120 mg subcutaneously every four weeks. In a randomized double-blind phase III trial comparing the efficacy of Denosumab to zoledronic acid in delaying time to first SRE, Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001) [11]. This trial also showed that overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. Renal toxicity and acute-phase reactions occurred more frequently with zoledronic acid but hypocalcemia occurred more frequently with denosumab [11]. The most common side effects of denosumab are fatigue, nausea and hypophosphatemia; dyspnea is the most common serious side effect. The Combination of denosumab with an IV bisphosphonate for the treatment of bone metastases is not recommended. Calcium and vitamin D supplementation is recommended during therapy with denosumab to prevent hypocalcemia.

## Palliative Radiation Therapy

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According to the American Society of therapeutic Radiation Oncology (ASTRO):[12]

* External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases

* Although various fractionation schemes can provide good rates of palliation, numerous prospective randomized trials have shown that 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction can provide excellent pain control and minimal side effects. The longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers

* Repeat irradiation with EBRT might be safe, effective, and less commonly necessary in patients with a short life expectancy

* Bisphosphonates do not obviate the need for EBRT for painful sites of metastases and might, indeed, act effectively when combined with EBRT

* Surgical decompression and stabilization plus postoperative RT should be considered for selected patients with single-level spinal cord compression or spinal instability unless the patients have an anticipated life expectancy that is too short. Kyphoplasty and vertebroplasty might be useful for the treatment of lytic osteoclastic spinal metastases or in cases of spinal instability for which surgery is not feasible or indicated. They do not obviate the need for EBRT, and no data are available to suggest that the addition of vertebroplasty or kyphoplasty further improve symptoms or has a greater effect on clinically significant endpoints than EBRT alone. Additional prospective trials are needed to better define whether a patient population exists that would benefit from treatment with kyphoplasty or vertebroplasty, and, if so, how those procedures should best be sequenced with EBRT.

### Bone Metastasis

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* Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients.

Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

* Pathologic fracture,
* A requirement for surgical intervention and palliative radiotherapy to bone lesions,
* spinal cord compression,
* hypercalcemia of malignancy [13].

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

* Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.
* A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though the predominant osteoblastic disease can occur [14].

The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including:

* PTHrP (Parathyroid Hormone–related Peptide),
* Tumor Necrosis Factor α (TNF-α),
* Cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11

* These factors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP [15].

Pathophysiology of bone metastasis in breast cancer. The diagram is the authors' (Soroush Seifirad) own work.

## References

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1. ↑ Dunstan CR, Felsenberg D, Seibel MJ (2007) Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 4 (1):42-55. DOI:10.1038/ncponc0688 PMID: 17183355
2. ↑ Coleman RE (2005) Bisphosphonates in breast cancer. Ann Oncol 16 (5):687-95. DOI:10.1093/annonc/mdi162 PMID: 15802276
3. ↑ Fleisch H (1998) Bisphosphonates: mechanisms of action. Endocr Rev 19 (1):80-100. PMID: 9494781
4. ↑ 4.0 4.1 4.2 4.3 Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al. (2011) American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29 (9):1221-7. DOI:10.1200/JCO.2010.32.5209 PMID: 21343561
5. ↑ Diel IJ (2007) Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: a review. Support Care Cancer 15 (11):1243-9. DOI:10.1007/s00520-007-0244-9 PMID: 17393190
6. ↑ Costa L, Major PP (2009) Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol 6 (3):163-74. DOI:10.1038/ncponc1323 PMID: 19190592
7. ↑ 7.0 7.1 Tanvetyanon T, Stiff PJ (2006) Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 17 (6):897-907. DOI:10.1093/annonc/mdj105 PMID: 16547070
8. ↑ Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM (2010) Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 95 (9):4380-7. DOI:10.1210/jc.2010-0597 PMID: 20554708
9. ↑ Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B et al. (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. J Oral Maxillofac Surg 67 (5 Suppl):2-12. DOI:10.1016/j.joms.2009.01.009 PMID: 19371809
10. ↑ Lazarovici TS, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N (2009) Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients. J Oral Maxillofac Surg 67 (4):850-5. DOI:10.1016/j.joms.2008.11.015 PMID: 19304045
11. ↑ 11.0 11.1 Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH et al. (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28 (35):5132-9. DOI:10.1200/JCO.2010.29.7101 PMID: 21060033
12. ↑ Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P et al. (2011) Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 79 (4):965-76. DOI:10.1016/j.ijrobp.2010.11.026 PMID: 21277118
13. ↑ Coleman RE, Rubens RD (1987). "The clinical course of bone metastases from breast cancer". Br J Cancer. 55 (1): 61–6. PMC 2001575. PMID 3814476.CS1 maint: PMC format (link)
14. ↑ Coleman RE, Seaman JJ (2001). "The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases". Semin Oncol. 28 (2 Suppl 6): 11–6. PMID 11346860.
15. ↑ Chiang AC, Massagué J (2008). "Molecular basis of metastasis". N Engl J Med. 359 (26): 2814–23. doi:10.1056/NEJMra0805239. PMID 19109576.

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