Bone targeted therapies in advanced breast cancer

DOI: https://doi.org/10.4414/smw.2017.14440

Background

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. Despite great progress in therapeutic and diagnostic breast cancer research, 30% of all female cancers are breast carcinoma. The incidence is increasing, which is mostly owing to demographic aging and a manifestation of risk factors in the modern lifestyle. However, recent years brought a decline in mortality and an improvement in survival, probably due to advances in diagnostics, screening and treatment protocols. However, 20 to 30% of patients still relapse after diagnosis. Even late relapses, two decades after diagnosis, are possible.

Breast cancer is one of the most heterogeneous diseases. Personalised management approaches are needed in order to assure the best possible outcome, as well as to avoid over- or undertreatment. Novel endocrine and targeted therapies have the potential to significantly impact both the physiological and psychological health of breast cancer patients and survivors. Only a fraction of treatment strategies are individualised. Individual treatment strategies are based not only on the TNM classification, but also on specific clinicopathological features and a careful risk assessment for each patient, such as specific endocrine and targeted approaches for Her2-positive breast cancers. Over- or undertreatment should be avoided. But whereas there are several recognised prognostic factors (e.g., axillary node status, tumour size/type/grade, lymphatic and vascular invasion, proliferative markers, patient age and status), predictive markers in breast cancer (essential for decision making since they suggest the outcome of patients irrespective of treatment) are limited.

Advanced disease is per se very complex and patients face the burden of aggressive therapy with various, sometimes severe, side effects. These include bone thinning with resulting fractures and joint pain. Approximately 70% of patients with advanced breast cancer experience bone metastases, which may produce poor quality of life and some of the highest rates of skeletal-related events (SREs). SREs are defined as pathological fractures (excluding major trauma), radiation therapy to bone, surgery to bone, or spinal cord compression. Although bone metastases do not involve vital organs, they may have deleterious effects and compromise the patient's general state.

Approximately 7% of women with breast cancer are diagnosed before the age of 40 years. Younger age is an independent predictor of adverse outcome and survival rates are worse when compared with those in older women. The proportion of aggressive subtypes, such as triple negative breast cancer, is higher in younger patients. Neo- and adjuvant chemotherapy, radiotherapy and antihormonal medication are the current standard. Hormone depleting therapies, especially in young women receiving dual blockade with gonadotrophin releasing hormone and aromatase inhibitors, are detrimental to the skeleton. Prevention of resulting bone loss by bone targeted therapies is therefore of utmost importance.

Thus, it is important to study and propose medication for effective and efficient bone targeted therapy. Oral and intravenous formulations of bisphosphonates and denosumab are now successfully used in patients with bone metastatic breast cancer for prevention of SREs such as bone pain, pathological fractures, spinal cord compression and hypercalcaemia of malignancy [1, 2]. Bisphosphonates and denosumab are also used to prevent bone loss associated with antioestrogen therapy [3, 4]. In Switzerland, denosumab is approved as endocrine therapy for patients with breast cancer and prostate cancer, to prevent bone mineral density loss. Both types of substance have been suggested to additionally have antitumour potential. Strikingly, recent research has suggested a beneficial effect for adjuvant use of zoledronate in postmenopausal patients [5–7]. Recently, denosumab also has been shown to have a beneficial effect on disease-free survival in postmenopausal patients with hormone receptor positive breast cancer [8]. The properties of denosumab and of bisphosphonates as a class are summarised in table 1.

Current guidelines

The current American Society of Clinical Oncology (ASCO) evidence-based clinical practice guidelines for the use of bisphosphonates in breast cancer recommend their use only for patients with evidence of metastatic bone destruction. For all patients, and especially for all those with an increased risk of tumour-therapy induced loss of bone mass, the possibilities of osteoprotection should be discussed. All patients should receive a dental examination and appropriate preventive dentistry before and during the therapy to prevent jaw necrosis. The risk for oral necrosis of the jaw is up to 8% in patients with regular bisphosphonate and denosumab treatment, especially in those with risk factors such as extractions or paradontosis.

Life-style factors (physical activity, cessation of smoking, alcohol abstinence), and avoidance of underweight are on the list of nonpharmacological options. Supplements of vitamin D3 and calcium are not contraindicated. However, the approved agents include denosumab (120 mg subcutaneously every 4 weeks), intravenous pamidronate (90 mg over no less than 2 hours) and zoledronic acid (4 mg over no less than 15 minutes every 3–4 weeks). To date, reports suggest that the efficacy of these agents is comparable and modifications in dose, infusion time or dosing interval do not bring further benefits. The dosage must be adjustment according to renal function, measured as serum creatinine levels. Creatinine clearance between 30 and 60 ml/min requires a dose reduction for zoledronate [9, 10]. Monitoring of biochemical markers are not suggested. Similar guidelines have been developed by the National Comprehensive Cancer Network (NCCN) [11–14].

There are a number of open questions in clinical practice, which are still not covered by the guidelines. Firstly, there are no clear recommendations on the treatment duration (to date therapy with bisphosphonates is generally continued for 2–5 years), the cessation time-point, or treatment interval / dose adjustment for patients who receive bone-modifying agents for years. Current guidelines of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynaecological Oncology Group, AGO) vaguely suggest interval prolongation from every 4 weeks to every 12 weeks for women who have already been taking zoledronate and who have stable disease [15].

Another important issue, especially in terms of health economics, is the question of administration frequency. Currently, a study of the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK, Swiss Group for Clinical Cancer Research), called REDUSE, is investigating the 1-monthly versus 3-monthly administration of denosumab.

The adjuvant administration of bisphosphonates is still controversial since the relevant available data are in part contradictory [16–19]. The recommendations in the recent version of the AGO guideline include adjuvant administration of bisphosphonates to improve the survival of postmenopausal women, based on a meta-analysis by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) [20–22]. Recent data from the adjuvant denosumab in breast cancer study ABC-SG18 suggest that denosumab can be used for all patients with hormone receptor-positive breast cancer who are receiving adjuvant aromatase inhibitor therapy, irrespective of their bone health status and not only when they have an established osteoporosis [8]. Long-term data on risk profiles, especially for elderly and multimorbid patients, are sparse. Last but not least, potential benefits and risks of the preventive use of these medicines are not yet elaborated.

Pathophysiology of bone metastasis

Metastasis is a consequence of a cascade of events and interactions between the tumour cell and the cellular elements in the bone microenvironment [23]. The complex nature of the latter involves multiple pathways that lead to bone metastasis, for example, via receptor activator of nuclear factor-kappa B (RANK) / RANK ligand (osteolysis in skeletal metastasis), Wnt (wingless int) proteins, endothelin-1, or bone morphogenetic proteins (osteoblastic metastasis) [24, 25]. The simplified description of the process is that of progressive growth at the primary site, a vascularisation phase, invasion, detachment, embolisation, survival in the circulation, arrest at the site of a metastasis, extravasation, evasion of host defence and progressive growth [26–28]. However, at the moment of installation of cancer cells, the normal process of bone turnover is disturbed, leading to lytic, sclerotic or mixed metastases. This causes considerable pain and diminishes the possibility of cure [29, 30]. Metastasising tumour cells mobilise and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion [31, 32]. Research is continuously aiming to elaborate on the pathophysiology of bone metastasis, which is critical to developing new approaches to prevent bone metastasis or inhibit its progression.

Bone pain

Metastatic bone disease is among the most common causes of cancer pain [33–35]. However, a significant number of bone metastases causes no pain and the intensity or occurrence of pain is often disproportionate to the size or degree of bone involvement.

With expanded understanding of the neurophysiology and related pharmacology of cancer bone pain, clinical approaches to alleviating pain have improved. Newer suitable animal models have provided advanced insight into the mechanisms of cancer pain. It is mostly a neuropathic pain, transmitted by primary peripheral nociceptor afferents. They express a great variety of receptors that detect noxious stimuli, including heat, acidity, lipid metabolites and inflammation molecules. In a metastatic lesion with a persistent acidic, inflammatory environment, sustained stimulation occurs, causing hyperalgesia and allodynia. Thus, any medication that antagonises inflammatory mediating immune cells has a place in the treatment of cancer pain. Tumour growth activates mechanically sensitive ion channels by distension of nerve fibres, frequently entrapping them and possibly causing aberrant regeneration. Primary afferent neurones transmit to the spinal cord segment, which explains the effects of neuromodulating drugs [28, 36–38]. Radiotherapy in low doses given in a single session is a safe and effective cornerstone of pain treatment. Radioisotopes are less precise in delivering specific doses of radiation, but have little toxicity and are easily administrated and effective at subclinical sites of metastases. The use of analgesics according to the World Health Organization ladder is recommended.

Standards of care for management of bone pain from cancer should be employed in conjunction with therapy with bone-modifying agents. These potentiate the effects of analgesics in improving metastatic bone pain.

Mode of action

Zoledronic acid

Zoledronic acid is one of the nitrogen-containing antiresorptive agents, which inhibit osteoclast proliferation. Owing to the chemical similarity to inorganic pyrophosphate, zoledronic acid (and other bisphosphonates) is taken up into the hydroxyapatite elements of the osseous extracellular matrix [39–41]. 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 GGTI-298, leading to loss of protein prenylation in osteoclasts, disrupting their cytoskeleton and inducing programmed death [42–44]. The principal effect is reduced bone resorption, which allows more time for bone rebuilding and remodelling [45, 46]. It has also been hypothesised that zoledronic acid might also stimulate osteoblasts’ differentiation and bone mineralisation [47, 48]. Zoledronic acid seems to have the highest potential among the bisphosphonates because of its high affinity to bone, especially bones with an increased turnover, such as in tumour patients [49–51].

Denosumab

Denosumab is a human recombinant monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL). Inhibition of RANKL leads to reduced maturation of preosteoclasts into osteoclasts, osteoclast survival and action. As a result, bone resorption is diminished [52, 53].

Adverse effects of bone targeted therapies and their management

Adverse events associated with bone-targeted agents include osteonecrosis of the jaw, hypocalcaemia and renal insufficiency.

Acute-phase reactions

The commonest side effect is the so-called acute-phase reaction (APR), observed in 10 to 30% of breast cancer patients receiving zoledronic acid and denosumab during the first 3 days after treatment [54–57]. APR is an orchestrated global systemic physiological response to tissue injury, infection or inflammation, mediated by an increase in acute phase proteins, which are involved in the restoration of homeostasis. Clinical features are influenza-like, fever, chills, lethargy, increased catabolism of protein, increase in slow wave sleep, decreased appetite, hypotension, flushing, bone pain, arthralgia and myalgia. Laboratory results mostly show neutrophilia and leucocytosis, an increase in tumour necrosis factor-alpha and a mild increase in interleukin-6. APRs are not life-threatening, but frequently very distressing for the patients and might lead to poor treatment adherence. Although the exact mechanism is not fully understood, it is suggestive that features such as the presence of nitrogen in the bisphosphonate (zoledronate, ibandronate, pamidronate) and intravenous administration induce APR. Most reactions occur after 72 hours, regress spontaneously or with the aid of nonsteroidal anti-inflammatory drugs and antipyretics, and reappear at subsequent application [58–61].

Nephrotoxicity

Since bisphosphonates are renally excreted, a significant part of the administered dose (40–70%) passes by the renal structures [62–64]. Unmetabolised bisphosphonates diffuse passively into tubular cells and accumulate there, which might lead to apoptosis. The clinical presentation is acute kidney injury due to tubular necrosis. Histologically, focal segmental glomerulosclerosis, acute tubular injury, or minimal change disease without glomerular pathology are observed [65–68]. This type of renal insufficiency is eventually reversible after drug discontinuation (zoledronic acid) but can be irreversible (pamidronate). Denosumab seems to be the bone targeted agent least likely to be linked to renal toxicity, making it a medication of choice for patients with pre-existing renal impairment or dialysis-dependent kidney failure [60, 69, 70].

Simple prevention mechanisms apply: close monitoring of serum creatinine, calcium and phosphate levels; sufficient hydration; avoidance of concomitant nephrotoxic agents; and a temporary interruption of medication if the creatinine level increases by ≥0.5 mg/dl in patients with normal baseline renal function and if the creatinine level increases by ≥1.0 mg/dl in patients with abnormal baseline renal function. Zoledronic acid dose should be reduced in patients with impaired renal function (estimated creatinine clearance 30–60 ml/min) [10].

Hypocalcaemia

Hypocalcaemia is very common during bisphosphonate (3.4–6%) and denosumab (5.5–13%) therapy. Lethargy, fatigue, general weakness or tetany may manifest clinically [71–73]. Fatal cases have been reported [74]. Supplementation of vitamin D and calcium is crucial to prevent hypocalcaemia, especially for patients at risk, such as geriatric patients or those with impaired thyroid or parathyroid function, hypomagnesaemia, pre-existing vitamin D or renal insufficiency, with extensive osteoblastic bone metastases, or after gastric surgery. Serum vitamin D3 and albumin-corrected or ionised calcium levels should be checked before treatment and monitored continually during treatment. Low levels should be adequately corrected. As conversion of vitamin D to its active form is progressively impaired with a creatinine clearance <70 ml/min, calcitriol has been suggested as a better option than vitamin D in denosumab-treated patients with impaired kidney function [75].

Osteonecrosis of the jaw

Defects in vascularisation of the maxilla or the mandibular bone may lead to osteonecrosis of the jaw. Well-established risk factors include head and neck radiotherapy, oral surgical interventions, smoking, diabetes, anaemia, renal insufficiency, and use of glucocorticoids, chemotherapeutic and antiangiogenic agents and bisphosphonates [76–79]. Over the last 10 years, cases of jaw-bone necrosis have been associated with the use of bone targeted therapies: denosumab (2.0% of cases) and zoledronate (1.4%).

The American Association of Oral and Maxillofacial Surgeons defined osteonecrosis of the jaw as: (1) the presence of clinically evident necrotic bone exposed through the oral mucosa or facial skin which has persisted despite appropriate management for more than 8 weeks in osteoclast inhibitor-treated patients, with (2) no history of irradiation therapy to the jaw. Careful evaluation of the patients' oral health before and during bisphosphonate and denosumab treatment is mandatory. Invasive dental procedures should be avoided [80, 81].

Very rare side effects

Very rarely, bisphosphonates and denosumab can cause scleritis, uveitis and conjunctivitis [82–87], dermatological conditions such as dermatitis, eczema and rashes [54, 88] or atypical femur fractures [89, 90].

Bone targeted therapies in early breast cancer

Zoledronic acid has been reported as a convenient agent to prevent SREs in postmenopausal women in general. The largest group of patients with breast cancer are postmenopausal women with early stage breast cancer, under oestrogen-depleting treatment. Aromatase inhibitors cause bone loss at a rate of about 1 to 3% per year. Therefore, it is crucial to know whether bone targeted therapies in this specific population are reasonable and beneficial. Hadji et al. developed a score to assess the risks of aromatase inhibitor-associated bone loss and direct treatment [91, 92].

Until now, evidence suggests that twice-yearly zoledronic acid is can be recommended for women at risk of aromatase inhibitor-associated bone loss. Bone targeted therapies for these patients are very strongly recommendable to prevent bone loss and accelerated bone turnover associated with aromatase inhibitor therapy if the T-score is <˗2.0 or if at least two fracture risk factors are present. In addition to physical activity and calcium / vitamin D supplements, baseline bone mineral density (BMD) measurement is recommended. Yearly BMD monitoring is advised thereafter. For women over the age of 75 years with one or more major risk factors, bone protection therapy with a bisphosphonate is recommended irrespective of baseline BMD. In the case of noncompliance or worsening BDM, intravenous administration is advocated. The SAMBR trial suggested that risedronate is effective in postmenopausal women at risk of fracture while receiving anastrozole [93]. The ARIBON trial evaluated the impact of ibandronate on the same population of breast cancer patients and showed that monthly oral ibandronate is a comparably efficient alternative to other bisphosphonates [94]. The Zometa-Femara adjuvant synergy trial (Z-FAST) suggested that zoledronic acid, when used concomitantly with letrozole, is able to manage bone loss and reduce osteopathic pain in this specific group of postmenopausal early breast cancer patients [95–97].

In the ABCSG-18 study, the use of denosumab 60 mg twice per year was examined. Denosumab or placebo were given to postmenopausal women receiving aromatase inhibitor therapy. The risk of osteoporosis was decreased by 50%. Furthermore, there were fewer fractures (92 vs 176 fractures, hazard ratio 0.50). The BMD increased by 6 to 10%. Finally, there was a significant survival benefit for patients receiving denosumab, in particular for patients with tumours large then 2 cm [8].

Antitumour effects of bone targeted agents

Recent preclinical and clinical studies have provided solid evidence that bisphosphonates, especially nitrogen-containing bisphosphonates (N-BPs), have antitumour activity.

In the Breast Cancer in Northern Israel study, the use of bisphosphonates for longer than 1 year was associated with a 28% relative reduction in the risk of postmenopausal breast cancer. The Women's Health Initiative (WHI) confirmed these observations for oral bisphosphonates [98, 99]. In addition to primary preventive functions, bisphosphonates are also potent secondary prevention agents. Recent studies suggest that bisphosphonates reduce the risk of bone metastasis in high-risk breast cancer patients.

For zoledronic acid, the antimetastatic effect might result from a decrease of disseminated tumour cells in the bone marrow of women undergoing neoadjuvant chemotherapy for breast cancer [100]. The antiproliferative and proapoptotic, antiadhesive effects of N-BPs are not well understood. In vitro and in vivo animal models suggest, that the modulating effects on the immune system via activation of macrophages, endothelial cells and tumour cells, as well as by stimulation of T cells and alteration of the bone microenvironment, are of the utmost importance for anticancer activity [51, 101–103]. N-BPs reduce the levels of hypoxia-inducible factor (HIF)-1α, one of the main proteins of the tumour environment, leading to disturbed anaerobic metabolism in tumour cells and a decrease in vascular endothelial growth factor secretion [104–106]. Since overexpression of HIF-1α is a negative prognostic factor, bone targeted therapies might improve disease-free survival and overall survival in some breast cancer settings. Moreover, N-BPs have been shown to inhibit invasion and angiogenesis, and thus tumour progression and metastatic spread [107]. N-BPs alter the bone marrow microenvironment, making it more hostile toward tumour cells. Thus, dormant micrometastases are less likely to be formed while systemic chemotherapy is being applied, preventing cancer recurrence [108]. Similar anticancer functions have been suggested for denosumab, since RANKL is crucial for proliferation of mammary epithelium and potentially directly contributes to mammary tumourigenesis [109–112].

Evidence-based efficacy of bone targeted therapies in breast cancer

Bone is the most common metastatic site in breast carcinoma [113–115]. Despite a decreasing incidence, bone metastases are extremely relevant for clinical progress and outcome, since the high rate of resultant SREs, such as fractures or hypercalcaemia, reduce quality of life and survival. Bone metastases are associated with more aggressive tumours, occurring primarily in younger women with larger tumour size, higher tumour grade or several positive nodes. Therefore, the life expectancy of patients with bone metastases is approximately 2.3 years, and less than a year if visceral metastases are also present [116–119].

Bisphosphonates are the treatment of choice for the prevention of SREs, for tumour-associated hypercalcaemia and for bone pain.

Meta-analyses of randomised controlled trials in advanced breast cancer with clinically evident bone metastases including patients with bone metastases showed the efficacy of intravenous bisphosphonates in preventing skeletal events (43%) compared with oral bisphosphonates. Zoledronate achieved the best results, followed by pamidronate, ibandronate and clodronate. Significant improvements were also seen in quality of life and in bone pain. Overall, a number of phase III trials demonstrated that bisphosphonates lead to a significant improvement of the quality of life, not only by reducing SREs, bone pain and hypercalcaemia, but also by diminishing the need for radiation therapy [120–124]. As expected, intravenous zoledronic acid was superior to other bone targeted agents [125–128].

Overall survival is not influenced by bisphosphonate use in women with advanced breast cancer. Intriguingly, patients without clinically evident bone metastases did not profit from bisphosphonate therapy in terms of the incidence of skeletal events, but their overall survival was significantly better, even though there was a high variability within the group.

So far, the consensus recommends denosumab as preferred agent owing to its superior efficacy compared with zoledronic acid, and simple subcutaneous route of administration. Since the price difference between denosumab and (now also generic) bisphosphonates is significant, various trials have investigated whether the application intervals can be extended, allowing for a reduced socioeconomic burden and number of adverse events. The Cancer and Leukemia Group B (CALGB) 70604, OPTIMIZE-2, ZOOM, and BISMARK trials showed noninferiority of zoledronic acid administration every 3 months (instead of monthly) for 2 years. Thus, seen from both a clinical and financial perspective, zoledronic acid given every 3 months is a reasonable alternative.

Clinical trials involving bone targeting therapies are summarised in table 2 (metastatic disease) and table 3 (nonmetastatic disease).

Markers of bone turnover as tools for monitoring treated patients

Enzymes and protein products released during bone metabolism can be used to noninvasively assess bone turnover [135, 136]. They are still controversial for monitoring therapy in osteoporosis [137–140]. However, they have gained the attention of oncologists, who can track pathological processes that reflect bone destruction through bone metastasis [141–144]. Since bone targeted therapies act on skeletal cells, laboratory values that reflect osteoblastic and osteoblastic activity can suggest the individual effects of therapeutic agents. This is an elegant method to direct the antiresorptive approach, reduce the number of bone density tests, and detect potential new metastatic events and bone disease progression, since bone turnover markers respond quickly and significantly to bone-targeted (and antineoplastic) therapies, which are associated with a better prognosis [140, 145–147]. So far, there is not enough evidence to determine whether bone turnover markers are valid also for the early diagnosis of bone metastases [148, 149].

In breast cancer patients, bone metastases lead to an increase in bone turnover, which might be a paraneoplastic or/and a neoplastic effect. At the same time, the increased bone resorption leads to skeletal deficits, which are localised diffusely at different bone sites [150, 151].

Markers of bone formation include serum osteocalcin, total alkaline phosphatase, type 1 procollagen and bone-specific alkaline phosphatase. Less well characterised are bone resorption markers: urinary hydroxyproline, total pyridinoline, free deoxypyridinoline, collagen type 1 cross-linked N-telopeptides (NTx), urinary or serum collagen type 1 cross-linked C-telopeptides (CTx), bone sialoprotein and tartrate-resistant acid phosphatase-5b.

The cross-linked NTx are best for predicting skeletal morbidity and death, and monitoring response during zoledronic acid treatment, in patients with bone metastases, but their sensitivity is low (<30%) [148, 152]. To date, bone markers do not have enough power to have diagnostic or prognostic value, but in combination with other diagnostic modalities, they have great potential to improve and to personalise the therapeutic approach.

The important role of general practitioners in antiresorptive therapy of breast cancer patients

The benefits of antiresorptive therapy for breast cancer patients, in both adjuvant and palliative settings, are undeniable, but there is a great number of patients who will not profit from the therapy due to noncompliance (self-induced or due to an inability to understand schedules, dosages, etc.). Elderly patients are especially at risk of limited quality of life due to preventable SREs, simply because they lack support in therapy planning. As oncologists mostly focus on cancer-specific therapies, patients ignore or are less educated about necessary adjacent therapies, such as bisphosphonates or denosumab, including potential supplementations with calcium or vitamin D. In addition, the frequent, mild side effects of the antiresorptive therapies might lead to their discontinuation if the patients are not adequately educated on their importance [153].

The role of the general physician in this specific population is thus crucial, and collaborative efforts lead to an improvement of the quality of life of the patient. Especially in the course of treatment when a stabilisation phase has been reached, frequent contact with the family doctor can assure the continuation of preventive treatment. Proper education and encouragement of the patient to continue antiresorptive therapy, with a recommended lifestyle (proper nutrition with sufficient vitamin D and calcium, physical activity, moderate weight), have a huge impact on final success – the longest possible period without SREs and pain. Jacob et al. were able to demonstrate that women with metastatic breast cancer aged >70 years were at a lower risk of discontinuing treatment with bisphosphonates than younger patients [154]. Partridge et al. found that women aged <45 and >85 were at a higher risk of therapy discontinuation [155]. Although there are several potential reasons explaining this non-linear relation between age and therapy adherence, one is surely the closer and more regular contact with family physicians. Similar conclusions were also reached in other studies [156–159]. Also, the recommended regular dual energy X-ray absorptiometry and dental check-ups, which also influence outcome, are better organised and explained by a trusted general practitioner [160, 161].

References

1 Van Poznak CH . The use of bisphosphonates in patients with breast cancer. Cancer Contr. 2002;9(6):480–9.  

2 Coleman R . The use of bisphosphonates in cancer treatment. Ann N Y Acad Sci. 2011;1218(1):3–14. https://doi.org/10.1111/j.1749-6632.2010.05766.x  

3 Fizazi K , Bosserman L , Gao G , Skacel T , Markus R . Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182(2):509–15, discussion 515–6. https://doi.org/10.1016/j.juro.2009.04.023  

4 Milat F , Goh S , Gani LU , Suriadi C , Gillespie MT , Fuller PJ , et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013;55(2):305–8. https://doi.org/10.1016/j.bone.2013.04.012  

5 Siderova MV , Hristozov KH . Tolerability of once yearly intravenous infusion of Zolendronic acid in the treatment of postmenopausal osteporosis. Osteoporos Int. 2010;21:S365. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L70226391%5Cnhttp://dx.doi.org/10.1007/s00198-010-1247-9%5Cnhttp://findit.library.jhu.edu/resolve?sid=EMBASE&issn=0937941X&id=doi:10.1007/s00198-010-1247-9&atitle=Tolerability+of+once+ye . [Internet]. 

6 Povoroznyuk V , Grygorieva N , Vayda V , Dzerovych N , Balatska N . Effect of zolendronic acid in treatment of postmenopausal women with osteoporosis. Osteoporos Int. 2010;21:S759–60. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L70338275%5Cnhttp://dx.doi.org/10.1007/s00198-010-1433-9 . [Internet]. 

7 Palombaro KM , Black JD , Buchbinder R , Jette DU . Effectiveness of exercise for managing osteoporosis in women postmenopause. Phys Ther. 2013;93(8):1021–5. https://doi.org/10.2522/ptj.20110476  

8 Gnant M , Pfeiler G , Dubsky P , Hubalek M , Greil R , Jakesz R , et al. Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Cancer Res. 2016;76(4 Supplement):S2-02. https://doi.org/10.1158/1538-7445.SABCS15-S2-02  

9 Hillner BE , Ingle JN , Berenson JR , Janjan NA , Albain KS , Lipton A , et al.; American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol. 2000;18(6):1378–91. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10715310. https://doi.org/10.1200/JCO.2000.18.6.1378  

10 Van Poznak CH , Temin S , Yee GC , Janjan NA , Barlow WE , Biermann JS , et al.; American Society of Clinical Oncology. 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. 2011;29(9):1221–7. https://doi.org/10.1200/JCO.2010.32.5209  

11NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer. Version 2.2013. 2013. p. 1–174. 

12NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer. Version 1.2014. 2014. p. 1–74. 

13 Wood DE . National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Lung Cancer Screening. Thorac Surg Clin. 2015;25(2):185–97. https://doi.org/10.1016/j.thorsurg.2014.12.003  

14NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer [Internet]. Version 1.2016. 2016. p. 1–191. Available from www.nccn.org/patients  

15Breast G. Osteoonkologie und Knochengesundheit Osteoonkologie und. Osteoonkologie und Knochengesundheit Osteoonkologie u. 2015. 

16 Winter MC , Coleman RE . Bisphosphonates in the adjuvant treatment of breast cancer. Clin Oncol (R Coll Radiol). 2013;25(2):135–45. https://doi.org/10.1016/j.clon.2012.10.010  

17 Mathew A , Brufsky AM . The use of adjuvant bisphophonates in the treatment of early-stage breast cancer. Clin Adv Hematol Oncol. 2014;12(11):749–56.  

18 Theriault RL . Bisphosphonates: ready for use as adjuvant therapy of breast cancer? Curr Opin Obstet Gynecol. 2010;22(1):61–6. https://doi.org/10.1097/GCO.0b013e328334e43b  

19 Theriault RL . The role of bisphosphonates in breast cancer. J Natl Compr Canc Netw. 2003;1(2):232–41. doi:.https://doi.org/10.1677/erc.0.0110207  

20Kreienberg R, Albert U-S, Follmann M, Kopp I, Kühn T, Wöckel A, et al. Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms. Ger Cancer Soc [Internet]. 2012; 32–45. doi: https://doi.org/10.1055/s-0033-1355476  

21 Salmen J , Banys-Paluchowski M , Fehm T . Bone-Targeted Therapy. Geburtshilfe Frauenheilkd. 2015;75(6):584–7. https://doi.org/10.1055/s-0035-1546151  

22 Wilson C , Coleman RE . Adjuvant therapy with bone-targeted agents. Curr Opin Support Palliat Care. 2011;5(3):241–50. https://doi.org/10.1097/SPC.0b013e3283499c93  

23 Rosol TJ , Tannehill-Gregg SH , LeRoy BE , Mandl S , Contag CH . Animal models of bone metastasis. Cancer. 2003;97(3, Suppl):748–57. https://doi.org/10.1002/cncr.11150  

24 Virk MS , Lieberman JR . Tumor metastasis to bone. Arthritis Res Ther. 2007;9(Suppl 1):S5. https://doi.org/10.1186/ar2169  

25 Roodman GD . Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655–64. https://doi.org/10.1056/NEJMra030831  

26 Kingsley LA , Fournier PG , Chirgwin JM , Guise TA . Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609–17. https://doi.org/10.1158/1535-7163.MCT-07-0234  

27 Jacob K , Webber M , Benayahu D , Kleinman HK . Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res. 1999;59(17):4453–7.  

28 Mercadante S . Malignant bone pain: pathophysiology and treatment. Pain. 1997;69(1):1–18. https://doi.org/10.1016/S0304-3959(96)03267-8  

29 Sabino MAC , Mantyh PW . Pathophysiology of bone cancer pain. J Support Oncol. 2005;3(1):15–24. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20637323. [Internet].  

30 Kang Y , Siegel PM , Shu W , Drobnjak M , Kakonen SM , Cordón-Cardo C , et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49. https://doi.org/10.1016/S1535-6108(03)00132-6  

31 Blair JM , Zhou H , Seibel MJ , Dunstan CR . Mechanisms of disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Clin Pract Oncol. 2006;3(1):41–9. https://doi.org/10.1038/ncponc0381  

32 Weilbaecher KN , Guise TA , McCauley LK . Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–25. https://doi.org/10.1038/nrc3055  

33 Twycross R , Harcourt J , Bergl S . A survey of pain in patients with advanced cancer. J Pain Symptom Manage. 1996;12(5):273–82. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8942122. https://doi.org/10.1016/S0885-3924(96)00149-2  

34Twycross RG, Lack SA. Symptom control in far advanced cancer: pain relief. Symptom Control Far Adv Cancer Pain Reli Twycross Rg, Lack Sa, London, Pitman Publ. 1983. 

35 Grond S , Zech D , Diefenbach C , Radbruch L , Lehmann KA . Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain. 1996;64(1):107–14. https://doi.org/10.1016/0304-3959(95)00076-3  

36 Falk S , Bannister K , Dickenson AH . Cancer pain physiology. Br J Pain. 2014;8(4):154–62. https://doi.org/10.1177/2049463714545136  

37 Schwei MJ , Honore P , Rogers SD , Salak-Johnson JL , Finke MP , Ramnaraine ML , et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci. 1999;19(24):10886–97.  

38 Honore P , Mantyh PW . Bone cancer pain: from mechanism to model to therapy. Pain Med. 2000;1(4):303–9. https://doi.org/10.1046/j.1526-4637.2000.00047.x  

39 Russell RGG . Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007;119(Suppl 2):S150–62. https://doi.org/10.1542/peds.2006-2023H  

40 Rogers MJ , Frith JC , Luckman SP , Coxon FP , Benford HL , Mönkkönen J , et al. Molecular mechanisms of action of bisphosphonates. Bone. 1999;24(5, Suppl):73S–9S. https://doi.org/10.1016/S8756-3282(99)00070-8  

41Roelofs AJ, Ebetino FH, Reszka AA, Russell RGG, Rogers MJ. Chapter 81 - Bisphosphonates: Mechanisms of Action. Principles of Bone Biology (Third Edition) [Internet]. 2008. p. 1737–67. doi: http://dx.doi.org/https://doi.org/10.1016/B978-0-12-373884-4.00095-1  

42 Coxon FP , Helfrich MH , Van’t Hof R , Sebti S , Ralston SH , Hamilton A , et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000;15(8):1467–76. https://doi.org/10.1359/jbmr.2000.15.8.1467  

43 Roodman GD . Cell biology of the osteoclast. Exp Hematol. 1999;27(8):1229–41. https://doi.org/10.1016/S0301-472X(99)00061-2  

44 Diel IJ . Bisphosphonates in breast cancer patients with bone metastases. Breast Care (Basel). 2010;5(5):306–11. https://doi.org/10.1159/000322043  

45 Green JR . Chemical and biological prerequisites for novel bisphosphonate molecules: results of comparative preclinical studies. Semin Oncol. 2001;28(2, Suppl 6):4–10. https://doi.org/10.1016/S0093-7754(01)90259-3  

46 Boissier S , Ferreras M , Peyruchaud O , Magnetto S , Ebetino FH , Colombel M , et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000;60(11):2949–54.  

47 Reinholz GG , Getz B , Pederson L , Sanders ES , Subramaniam M , Ingle JN , et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res. 2000;60(21):6001–7.  

48 Hofmann A , Ritz U , Hessmann MH , Schmid C , Tresch A , Rompe JD , et al. Cell viability, osteoblast differentiation, and gene expression are altered in human osteoblasts from hypertrophic fracture non-unions. Bone. 2008;42(5):894–906. https://doi.org/10.1016/j.bone.2008.01.013  

49 Russell RGG . Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19. https://doi.org/10.1016/j.bone.2011.04.022  

50 Bellido T , Plotkin LI . Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone. 2011;49(1):50–5. https://doi.org/10.1016/j.bone.2010.08.008  

51 Clézardin P , Benzaïd I , Croucher PI . Bisphosphonates in preclinical bone oncology. Bone. 2011;49(1):66–70. https://doi.org/10.1016/j.bone.2010.11.017  

52 Boyce BF , Xing L . Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139–46. https://doi.org/10.1016/j.abb.2008.03.018  

53 Anandarajah AP , Schwarz EM . Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications. J Cell Biochem. 2006;97(2):226–32. https://doi.org/10.1002/jcb.20674  

54 Stopeck AT , Lipton A , Body J-J , Steger GG , Tonkin K , de Boer RH , et al. 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. 2010;28(35):5132–9. https://doi.org/10.1200/JCO.2010.29.7101  

55 Thiébaud D , Sauty A , Burckhardt P , Leuenberger P , Sitzler L , Green JR , et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int. 1997;61(5):386–92. https://doi.org/10.1007/s002239900353  

56 Lin JH . Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996;18(2):75–85. https://doi.org/10.1016/8756-3282(95)00445-9  

57 Moshage H . Cytokines and the hepatic acute phase response. J Pathol. 1997;181(3):257–66. https://doi.org/10.1002/(SICI)1096-9896(199703)181:3<257::AID-PATH756>3.0.CO;2-U  

58 Wark JD , Bensen W , Recknor C , Ryabitseva O , Chiodo J, 3rd , Mesenbrink P , et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int. 2012;23(2):503–12. https://doi.org/10.1007/s00198-011-1563-8  

59 Abrahamsen B . Adverse effects of bisphosphonates. Calcif Tissue Int. 2010;86(6):421–35. https://doi.org/10.1007/s00223-010-9364-1  

60 Diel IJ , Bergner R , Grötz KA . Adverse effects of bisphosphonates: current issues. J Support Oncol. 2007;5(10):475–82. Available at: https://www.researchgate.net/publication/5610810_Adverse_effects_of_bisphosphonates_current_issues_J_Support_Oncol_5475-482. [Internet].  

61 Kennel KA , Drake MT . Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc. 2009;84(7):632–7, quiz 638. https://doi.org/10.1016/S0025-6196(11)60752-0  

62 Nieto JE , Maher O , Stanley SD , Knych HK , Snyder JR . Pharmacokinetics, pharmacodynamics, and safety of zoledronic acid in horses. Am J Vet Res. 2013;74(4):550–6. https://doi.org/10.2460/ajvr.74.4.550  

63 Weiss HM , Pfaar U , Schweitzer A , Wiegand H , Skerjanec A , Schran H . Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos. 2008;36(10):2043–9. https://doi.org/10.1124/dmd.108.021071  

64 Perazella MA , Markowitz GS . Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385–93. https://doi.org/10.1038/ki.2008.356  

65 Edwards BJ , Usmani S , Raisch DW , McKoy JM , Samaras AT , Belknap SM , et al. Acute kidney injury and bisphosphonate use in cancer: a report from the research on adverse drug events and reports (RADAR) project. J Oncol Pract. 2013;9(2):101–6. https://doi.org/10.1200/JOP.2011.000486  

66 Markowitz GS , Fine PL , Stack JI , Kunis CL , Radhakrishnan J , Palecki W , et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003;64(1):281–9. https://doi.org/10.1046/j.1523-1755.2003.00071.x  

67 Markowitz GS , Nasr SH , Stokes MB , D’Agati VD . Treatment with IFN-alpha, -beta, or -gamma is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5(4):607–15. https://doi.org/10.2215/CJN.07311009  

68 Markowitz GS , Appel GB , Fine PL , Fenves AZ , Loon NR , Jagannath S , et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12(6):1164–72.  

69 Jackson GH . Renal safety of ibandronate. Oncologist. 2005;10(Suppl 1):14–8. https://doi.org/10.1634/theoncologist.10-90001-14  

70 Berenson JR , Vescio RA , Rosen LS , VonTeichert JM , Woo M , Swift R , et al. A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res. 2001;7(3):478–85.  

71 Scott LJ , Muir VJ . Denosumab: in the prevention of skeletal-related events in patients with bone metastases from solid tumours. Drugs. 2011;71(8):1059–69. https://doi.org/10.2165/11207370-000000000-00000  

72 Body J-J , Bone HG , de Boer RH , Stopeck A , Van Poznak C , Damião R , et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015;51(13):1812–21. https://doi.org/10.1016/j.ejca.2015.05.016  

73 Kreutle V , Blum C , Meier C , Past M , Müller B , Schütz P , et al. Bisphosphonate induced hypocalcaemia - report of six cases and review of the literature. Swiss Med Wkly. 2014;144:w13979. doi:.https://doi.org/10.4414/smw.2014.13979  

74 Do W-S , Park J-K , Park M-I , Kim H-S , Kim S-H , Lee D-H . Bisphosphonate-induced Severe Hypocalcemia - A Case Report -. J Bone Metab. 2012;19(2):139–45. https://doi.org/10.11005/jbm.2012.19.2.139  

75 Buonerba C , Caraglia M , Malgieri S , Perri F , Bosso D , Federico P , et al. Calcitriol: a better option than vitamin D in denosumab-treated patients with kidney failure? Expert Opin Biol Ther. 2013;13(2):149–51. https://doi.org/10.1517/14712598.2012.756470  

76 Marx RE . Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [1]. J Oral Maxillofac Surg. 2003;61(9):1115–7. https://doi.org/10.1016/S0278-2391(03)00720-1  

77 Junquera L , Gallego L . Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant? J Oral Maxillofac Surg. 2008;66(7):1516–7. https://doi.org/10.1016/j.joms.2008.02.012  

78 Campisi G , Fedele S , Fusco V , Pizzo G , Di Fede O , Bedogni A . Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncol. 2014;10(2):257–75. https://doi.org/10.2217/fon.13.211  

79 Sun L , Yu S . Efficacy and safety of denosumab versus zoledronic acid in patients with bone metastases: a systematic review and meta-analysis. Am J Clin Oncol. 2013;36(4):399–403. https://doi.org/10.1097/COC.0b013e31824be20e  

80 Hoff AO , Toth BB , Altundag K , Johnson MM , Warneke CL , Hu M , et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 2008;23(6):826–36. https://doi.org/10.1359/jbmr.080205  

81 Ibrahim T , Barbanti F , Giorgio-Marrano G , Mercatali L , Ronconi S , Vicini C , et al. Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study. Oncologist. 2008;13(3):330–6. https://doi.org/10.1634/theoncologist.2007-0159  

82 Coleman RE . Bisphosphonates in breast cancer. Ann Oncol. 2005;16(5):687–95. https://doi.org/10.1093/annonc/mdi162  

83 Wong MH , Stockler MR , Pavlakis N . Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2(2):CD003474. doi:. [Internet].https://doi.org/10.1002/14651858.CD003474.pub3  

84 Prommer EE . Toxicity of bisphosphonates. J Palliat Med. 2009;12(11):1061–5. https://doi.org/10.1089/jpm.2009.9936  

85 Colucci A , Modorati G , Miserocchi E , Di Matteo F , Rama P . Anterior uveitis complicating zoledronic acid infusion. Ocul Immunol Inflamm. 2009;17(4):267–8. https://doi.org/10.1080/09273940902916111  

86 Fraunfelder FW , Fraunfelder FT . Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology. 2004;111(7):1275–9. https://doi.org/10.1016/j.ophtha.2003.12.052  

87 Tanvetyanon T , Stiff PJ . Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17(6):897–907. https://doi.org/10.1093/annonc/mdj105  

88 Steger GG , Bartsch R . Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol. 2011;3(5):233–43. https://doi.org/10.1177/1758834011412656  

89 Lenart BA , Lorich DG , Lane JM . Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358(12):1304–6. https://doi.org/10.1056/NEJMc0707493  

90 Gartrell BA , Coleman RE , Fizazi K , Miller K , Saad F , Sternberg CN , et al. Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced prostate cancer. Eur Urol. 2014;65(2):278–86. https://doi.org/10.1016/j.eururo.2013.05.015  

91 Hadji P , Body JJ , Aapro MS , Brufsky A , Coleman RE , Guise T , et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol. 2008;19(8):1407–16. https://doi.org/10.1093/annonc/mdn164  

92 Hadji P , Aapro MS , Body JJ , Bundred NJ , Brufsky A , Coleman RE , et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol. 2011;22(12):2546–55. https://doi.org/10.1093/annonc/mdr017  

93 Van Poznak C , Hannon RA , Mackey JR , Campone M , Apffelstaedt JP , Clack G , et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol. 2010;28(6):967–75. https://doi.org/10.1200/JCO.2009.24.5902  

94 Lester JE , Dodwell D , Brown JE , Purohit OP , Gutcher SA , Ellis SP , et al. Prevention of anastrozole induced bone loss with monthly oral ibandronate: Final 5 year results from the ARIBON trial. J Bone Oncol. 2012;1(2):57–62. https://doi.org/10.1016/j.jbo.2012.06.002  

95 Brufsky A , Bundred N , Coleman R , Lambert-Falls R , Mena R , Hadji P , et al.; Z-FAST and ZO-FAST Study Groups. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist. 2008;13(5):503–14. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L351872868%5Cnhttp://theoncologist.alphamedpress.org/cgi/reprint/13/5/503%5Cnhttp://dx.doi.org/10.1634/theoncologist.2007-0206%5Cnhttp://resolver.ebscohost.com/openurl?custid=s3733374&auth. https://doi.org/10.1634/theoncologist.2007-0206  

96 Brufsky A , Harker WG , Beck JT , Carroll R , Tan-Chiu E , Seidler C , et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007;25(7):829–36. https://doi.org/10.1200/JCO.2005.05.3744  

97 Pritchard KI , Goss PE , Shepherd L . The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies. Breast. 2006;15(Suppl 1):S14–20. https://doi.org/10.1016/j.breast.2006.01.002  

98 Chlebowski RT , Chen Z , Cauley JA , Anderson G , Rodabough RJ , McTiernan A , et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol. 2010;28(22):3582–90. https://doi.org/10.1200/JCO.2010.28.2095  

99 Prentice RL , Anderson GL . The women’s health initiative: lessons learned. Annu Rev Public Health. 2008;29(1):131–50. https://doi.org/10.1146/annurev.publhealth.29.020907.090947  

100 Aft R , Naughton M , Trinkaus K , Watson M , Ylagan L , Chavez-MacGregor M , et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010;11(5):421–8. https://doi.org/10.1016/S1470-2045(10)70054-1  

101 Clézardin P . Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone. 2011;48(1):71–9. https://doi.org/10.1016/j.bone.2010.07.016  

102 Stresing V , Fournier PG , Bellahcène A , Benzaïd I , Mönkkönen H , Colombel M , et al. Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone. 2011;48(2):259–66. https://doi.org/10.1016/j.bone.2010.09.035  

103 Stresing V , Daubiné F , Benzaid I , Mönkkönen H , Clézardin P . Bisphosphonates in cancer therapy. Cancer Lett. 2007;257(1):16–35. https://doi.org/10.1016/j.canlet.2007.07.007  

104 Tang X , Zhang Q , Shi S , Yen Y , Li X , Zhang Y , et al. Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. Int J Cancer. 2010;126(1):90–103. https://doi.org/10.1002/ijc.24710  

105 Semenza GL . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32. https://doi.org/10.1038/nrc1187  

106 Lee J-W , Bae S-H , Jeong J-W , Kim S-H , Kim K-W . Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004;36(1):1–12. https://doi.org/10.1038/emm.2004.1  

107 Neville-Webbe HL , Gnant M , Coleman RE . Potential anticancer properties of bisphosphonates. Semin Oncol. 2010;37(Suppl 1):S53–65. https://doi.org/10.1053/j.seminoncol.2010.06.008  

108 Gnant M , Clézardin P . Direct and indirect anticancer activity of bisphosphonates: a brief review of published literature. Cancer Treat Rev. 2012;38(5):407–15. https://doi.org/10.1016/j.ctrv.2011.09.003  

109 Santini D , Schiavon G , Vincenzi B , Gaeta L , Pantano F , Russo A , et al. Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One. 2011;6(4):e19234. https://doi.org/10.1371/journal.pone.0019234  

110 Fata JE , Kong Y-Y , Li J , Sasaki T , Irie-Sasaki J , Moorehead RA , et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103(1):41–50. https://doi.org/10.1016/S0092-8674(00)00103-3  

111 Gonzalez-Suarez E , Jacob AP , Jones J , Miller R , Roudier-Meyer MP , Erwert R , et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7. https://doi.org/10.1038/nature09495  

112 Tan W , Zhang W , Strasner A , Grivennikov S , Cheng JQ , Hoffman RM , et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011;470(7335):548–53. https://doi.org/10.1038/nature09707  

113 Weigelt B , Peterse JL , van ’t Veer LJ . Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5(8):591–602. https://doi.org/10.1038/nrc1670  

114 Guise TA . Breast cancer bone metastases: it’s all about the neighborhood. Cell. 2013;154(5):957–9. https://doi.org/10.1016/j.cell.2013.08.020  

115 Coleman RE . Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s–9s. https://doi.org/10.1158/1078-0432.CCR-06-0931  

116 Clézardin P . Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 2011;13(2):207. https://doi.org/10.1186/bcr2835  

117 Costelloe CM , Rohren EM , Madewell JE , Hamaoka T , Theriault RL , Yu TK , et al. Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis. Lancet Oncol. 2009;10(6):606–14. https://doi.org/10.1016/S1470-2045(09)70088-9  

118 Clemons M , Gelmon KA , Pritchard KI , Paterson AHG . Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art. Curr Oncol. 2012;19(5):259–68. https://doi.org/10.3747/co.19.1011  

119 Yong M , Jensen AÖ , Jacobsen JB , Nørgaard M , Fryzek JP , Sørensen HT . Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007). Breast Cancer Res Treat. 2011;129(2):495–503. https://doi.org/10.1007/s10549-011-1475-5  

120 Body JJ , Diel IJ , Lichinitzer M , Lazarev A , Pecherstorfer M , Bell R , et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. 2004;90(6):1133–7. https://doi.org/10.1038/sj.bjc.6601663  

121 Kohno N , Aogi K , Minami H , Nakamura S , Asaga T , Iino Y , et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2005;23(15):3314–21. https://doi.org/10.1200/JCO.2005.05.116  

122 Lipton A , Theriault RL , Hortobagyi GN , Simeone J , Knight RD , Mellars K , et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88(5):1082–90. https://doi.org/10.1002/(SICI)1097-0142(20000301)88:5<1082::AID-CNCR20>3.0.CO;2-Z  

123 Theriault RL , Lipton A , Hortobagyi GN , Leff R , Glück S , Stewart JF , et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol. 1999;17(3):846–54. https://doi.org/10.1200/JCO.1999.17.3.846  

124 Tripathy D , Lichinitzer M , Lazarev A , MacLachlan SA , Apffelstaedt J , Budde M , et al.; MF 4434 Study Group. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol. 2004;15(5):743–50. https://doi.org/10.1093/annonc/mdh173  

125 Barrett-Lee P , Casbard A , Abraham J , Hood K , Coleman R , Simmonds P , et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014;15(1):114–22. https://doi.org/10.1016/S1470-2045(13)70539-4  

126 Rosen LS , Gordon D , Kaminski M , Howell A , Belch A , Mackey J , et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7(5):377–87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11693896. [Internet].  

127 Rosen LS , Gordon DH , Dugan W, Jr , Major P , Eisenberg PD , Provencher L , et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100(1):36–43. https://doi.org/10.1002/cncr.11892  

128 Coleman RE . Efficacy of zoledronic acid and pamidronate in breast cancer patients: a comparative analysis of randomized phase III trials. Am J Clin Oncol. 2002;25(6, Suppl 1):S25–31. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12562048. https://doi.org/10.1097/00000421-200212001-00005  

129 Vadhan-Raj S , von Moos R , Fallowfield LJ , Patrick DL , Goldwasser F , Cleeland CS , et al. Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol. 2012;23(12):3045–51. https://doi.org/10.1093/annonc/mds175  

130 Henry DH , Costa L , Goldwasser F , Hirsh V , Hungria V , Prausova J , et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125–32. https://doi.org/10.1200/JCO.2010.31.3304  

131 Rosen LS , Gordon D , Tchekmedyian NS , Yanagihara R , Hirsh V , Krzakowski M , et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100(12):2613–21. https://doi.org/10.1002/cncr.20308  

132 Scagliotti GV , Hirsh V , Siena S , Henry DH , Woll PJ , Manegold C , et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012;7(12):1823–9. https://doi.org/10.1097/JTO.0b013e31826aec2b  

133 Saad F , Brown JE , Van Poznak C , Ibrahim T , Stemmer SM , Stopeck AT , et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23(5):1341–7. https://doi.org/10.1093/annonc/mdr435  

134 Ellis GK , Bone HG , Chlebowski R , Paul D , Spadafora S , Smith J , et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875–82. https://doi.org/10.1200/JCO.2008.16.3832  

135 Fontana A , Delmas PD . Markers of bone turnover in bone metastases. Cancer. 2000;88(12, Suppl):2952–60. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10898339. https://doi.org/10.1002/1097-0142(20000615)88:12+<2952::AID-CNCR11>3.0.CO;2-M  

136 Delmas PD . Biochemical markers of bone turnover. J Bone Miner Res. 1993;8(S2, Suppl 2):S549–55. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8122526. https://doi.org/10.1002/jbmr.5650081323  

137 Naylor K , Eastell R . Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012;8(7):379–89. https://doi.org/10.1038/nrrheum.2012.86  

138Szulc P, Bauer DC, Eastell R. Biochemical Markers of Bone Turnover in Osteoporosis. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism [Internet]. 2013. p. 297–306. doi: https://doi.org/10.1002/9781118453926.ch35  

139 Szulc P . The role of bone turnover markers in monitoring treatment in postmenopausal osteoporosis. Clin Biochem. 2012;45(12):907–19. https://doi.org/10.1016/j.clinbiochem.2012.01.022  

140 Vasikaran S , Eastell R , Bruyère O , Foldes AJ , Garnero P , Griesmacher A , et al.; IOF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420. https://doi.org/10.1007/s00198-010-1501-1  

141 Garnero P . Markers of bone turnover in prostate cancer. Cancer Treat Rev. 2001;27(3):187–92, discussion 193–6. https://doi.org/10.1053/ctrv.2000.0213  

142 Eastell R , Christiansen C , Grauer A , Kutilek S , Libanati C , McClung MR , et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):530–7. https://doi.org/10.1002/jbmr.251  

143 Seibel MJ . Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev. 2005;26(4):97–122.  

144 Seibel MJ . Biochemical markers of bone turnover part II: clinical applications in the management of osteoporosis. Clin Biochem Rev. 2006;27(3):123–38. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1579289&tool=pmcentrez&rendertype=abstract. [Internet].  

145 Coleman R , Costa L , Saad F , Cook R , Hadji P , Terpos E , et al. Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol. 2011;80(3):411–32. https://doi.org/10.1016/j.critrevonc.2011.02.005  

146 Kanis JA , McCloskey EV . Bone turnover and biochemical markers in malignancy. Cancer. 1997;80(8, Suppl):1538–45. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9362420. https://doi.org/10.1002/(SICI)1097-0142(19971015)80:8+<1538::AID-CNCR3>3.0.CO;2-G  

147 Hlaing TT , Compston JE . Biochemical markers of bone turnover - uses and limitations. Ann Clin Biochem. 2014;51(2):189–202. https://doi.org/10.1177/0004563213515190  

148 Lipton A , Cook R , Saad F , Major P , Garnero P , Terpos E , et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer. 2008;113(1):193–201. https://doi.org/10.1002/cncr.23529  

149 Berenson JR , Vescio R , Henick K , Nishikubo C , Rettig M , Swift RA , et al. A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer. 2001;91(1):144–54. https://doi.org/10.1002/1097-0142(20010101)91:1<144::AID-CNCR19>3.0.CO;2-Q  

150 Lipton A . Implications of bone metastases and the benefits of bone-targeted therapy. Semin Oncol. 2010;37(Suppl 2):S15–29. https://doi.org/10.1053/j.seminoncol.2010.10.002  

151 Singer FR , Eyre DR . Using biochemical markers of bone turnover in clinical practice. Cleve Clin J Med. 2008;75(10):739–50. https://doi.org/10.3949/ccjm.75.10.739  

152 Fizazi K , Lipton A , Mariette X , Body JJ , Rahim Y , Gralow JR , et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27(10):1564–71. https://doi.org/10.1200/JCO.2008.19.2146  

153 Talreja DB . Importance of antiresorptive therapies for patients with bone metastases from solid tumors. Cancer Manag Res. 2012;4:287–97. https://doi.org/10.2147/CMAR.S33983  

154 Jacob L , Hadji P , Kostev K . Age-related differences in persistence with bisphosphonates in women with metastatic breast cancer. J Bone Oncol. 2016;5(2):63–6. https://doi.org/10.1016/j.jbo.2016.02.006  

155 Partridge AH , Wang PS , Winer EP , Avorn J . Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21(4):602–6. https://doi.org/10.1200/JCO.2003.07.071  

156 Gallagher AM , Rietbrock S , Olson M , van Staa TP . Fracture outcomes related to persistence and compliance with oral bisphosphonates. J Bone Miner Res. 2008;23(10):1569–75. https://doi.org/10.1359/jbmr.080510  

157 Penning-van Beest FJA , Goettsch WG , Erkens JA , Herings RMC . Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis. Clin Ther. 2006;28(2):236–42. https://doi.org/10.1016/j.clinthera.2006.01.002  

158 Balkrishnan R . Predictors of medication adherence in the elderly. Clin Ther. 1998;20(4):764–71. https://doi.org/10.1016/S0149-2918(98)80139-2  

159 He W , Fang F , Varnum C , Eriksson M , Hall P , Czene K . Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. J Clin Oncol. 2015;33(20):2262–9. https://doi.org/10.1200/JCO.2014.59.3673  

160 Sidwell AI , Wilkinson TJ , Hanger HC . Secondary prevention of fractures in older people: evaluation of a protocol for the investigation and treatment of osteoporosis. Intern Med J. 2004;34(3):129–32. https://doi.org/10.1111/j.1444-0903.2004.00554.x  

161 Bell JS , Blacker N , Edwards S , Frank O , Alderman CP , Karan L , et al. Osteoporosis - pharmacological prevention and management in older people. Aust Fam Physician. 2012;41(3):110–8.