Cancer Therapy-induced Bone Loss Research Articles

Cancer Treatment-Induced Bone Loss in Hormone-Sensitive Cancer: The Paradigm of Cancer Survivor Bone Health Management.

Cancer therapy-induced bone loss (CTIBL), occurring especially in hormone-treated breast and prostate cancer patients, is a noteworthy long-term consequence of cancer treatments. Because of its negative impact on the quality life of cancer survivors, it deserves much attention. We here summarize the pathophysiology of CTIBL in breast and prostate cancer, its clinical presentation, management, and treatment.

Abstract P4-10-17: Changes of bone turnover markers during perioperative anthracycline- and/or taxane-based chemotherapy in pre- and postmenopausal patients with primary breast cancer

Abstract Background: Loss of bone mineral density (BMD) is among the well known sequelae of pharmacological therapy of patients (pts) with primary breast cancer (PBC). Cancer therapy induced bone loss (CTIBL) progresses more rapidly as compared to normal age-related changes of BMD and is best known to be associated with aromatase inhibitors in postmenopausal pts. Chemotherapy (Ctx) may also lead to a deterioration of BMD but in contast to endocrine Tx, this phenomenon is by far less elucidated and, at least in younger pts, mostly interpreted as a secondary effect following Ctx induced ovarian failure. Previous investigations focused on the classical CMF scheme, whereas conclusive data regarding direct effects of more recent Ctx protocols on the bone metabolism of PBC pts are still lacking. This translational project was initiated to gain detailed insights into the influence of anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of both pre- and postmenopausal PBC pts in the clinical routine. Methods: Data of 109 pts (premenopausal: 49; postmenopausal: 60) with non-metastatic Ctx-naïve PBC exposed to neoadjuvant or adjuvant Ctx were analyzed. 84 pts (75%) had estrogen receptor-positive (ER+) disease, HER2- overexpression was found in 18 pts (17%). 16 pts (15%) received A-based Ctx, 34 pts (31%) received T-based Ctx, and 59 pts (54%) received A/T-based Ctx. Trastuzumab was given to 17 pts (16%) with HER2-positive disease. Serum bone markers including the C-telopeptide of type I collagen (ICTP) indicating osteoclast activity, the N-propeptide of type I collagen (P1NP) measuring osteoblast activity, and alkaline phosphatase (AP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and AP over time were analyzed by repeated-measure ANOVA. Results: 600 Ctx cycles were analyzed. Baseline levels of ICTP (p = 0.0027), P1NP (p = 0.0063), and AP (p = 0.0007) were significantly higher in post- versus premenopausal pts. AP levels remained largely unchanged during Ctx. Trends showing an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and thereafter increased to C6. These changes were highly significant (p = 0.0024). Conclusions: Our study represents one of the first systematic evaluations of bone turnover in pts exposed to modern A- and/or T-based Ctx for PBC in the clinical routine. Postmenopausal pts presented with higher baseline levels of all three markers which may be attributable to an enhanced bone turnover related to the loss of ovarian function prior to the initiation of Ctx. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity whereas osteoblast suppression recovered until the end of Ctx in premenopausal pts. Whether these effects will translate into an increased risk of CTIBL remains a matter of further investigations which should clearly focus on the individual menopausal status. Citation Format: Kurbacher CM, Rauschenbach N, Kurbacher AT, Sperling S, Herz S, Monreal K, Kurbacher JA. Changes of bone turnover markers during perioperative anthracycline- and/or taxane-based chemotherapy in pre- and postmenopausal patients with primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-17.

Skeletal Health Part 1: Overview of Bone Health and Management In the Cancer Setting

Cancer-induced bone disease and cancer therapy-induced bone loss are significant skeletal problems related to the treatment for urological and other cancers. Our team of specialists and nurse practitioners developed a nurse practitioner-led Bone Support Clinic for urologic cancer patients at a university hospital in London, England, United Kingdom, to address this issue. The clinic has been well-accepted, has made a positive impact on the patient journey, helps to ensure continuity of care, and highlights patients who require assessment or treatment for impending skeletal-related events in a timely fashion. This article has been divided into two parts for improved readability.

Skeletal Health Part 2: Development of a Nurse Practitioner Bone Support Clinic for Urologic Patients

Part 1 of this article highlighted the potential negative effects of cancer on the skeleton and provided an overview of available treatment options. Part 2 presents a nurse practitioner-led Bone Support Clinic, which was developed for patients with cancer-induced bone disease and cancer therapy-induced bone loss. This clinic, started in 2011 in a university medical center urology/oncology outpatient center in London, England, United Kingdom, has been a collaborative effort among a multidisciplinary team of doctors, nurse practitioners and nurses. Patients have responded positively to the improved continuity of care, and we have been able to assess and treat impending skeletal-related events in a more timely manner The needs of our patient population and problems with the existing service are reviewed, and the importance of a multidisciplinary approach to these problems is discussed. Initiation of a nurse practitioner-led Bone Support Clinic and the impact of timely response to the effects of cancer and cancer therapies on the skeletal system are outlined and offered as a model.

Targeting bone microenvironment: Clinical implications

Bone-targeting agents such as bisphosphonates are well established for the prevention and treatment of osteoporosis and the prevention of skeletal related events associated with bone metastases from solid tumours including breast cancer [1]. In the early breast cancer seeting, treatment-induced bone loss is a major clinical problem, leading to substantial morbidity and subsequent health care cost [2]. There are multiple reasons for bone loss in breast cancer patients, including existing risk factors (smoking, family history, low body weight), but endocrine therapy (particularly ovarian function suppression in premenopausal women and aromatase inhibitors in postmenopausal women) presents the most important burden on bone health in these patients [3]. In addition to lifestyle recommendations, anti-resorptive drugs have been demonstrated to prevent and treat cancer-treatment induced bone loss [4]. With respect of cancer-therapy induced bone loss (CTIBL), several trials have demonstrated the usefulness of adjuvant bisphosphonates for the prevention and treatment of CTIBL both in premenopausal [5] and postmenopausal women [6,7]. As a result, anti-resorptive therapy is part of current guidelines for the treatment of breast cancer patients [8]. Current clinical guidelines recommend the use of bisphosphonates in breast cancer patients on endocrine therapy if their fracture risk (assessed by DXA and or tools such as the FRAX score) is presumably increased [9]. While bisphosphonates have been studied in randomized trials in the adjuvant setting of early breast cancer to investigate their ability to either prevent cancer treatment induced bone loss, there are also indications in these trials about their potential to prevent disease recurrence and metastases [10]. The exact mechanism of this anti-cancer activity in the adjuvant setting remains unknown, and several potential ways of action have been proposed. In addition to preclinically established direct anti-tumour properties of bisphosphonates, a putative impact on the bonemicroenvironment

Direct effects on bone metabolism induced by perioperative anthracycline- and/or taxane-based chemotherapy depend on the menopausal status of patients with primary breast cancer.

1035 Background: Whereas cancer therapy-induced bone loss (CTIBL) is among the well-known sequelae of adjuvant endocrine therapy in patients (pts) with primary breast cancer (PBC), the knowledge ab...

4P - Influence of anthracycline- and/or taxane-based chemotherapy on bone metabolism of patients with primary breast cancer

Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC.Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA.Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024).Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations.Disclosure: All authors have declared no conflicts of interest. Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC. Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA. Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024). Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations. Disclosure: All authors have declared no conflicts of interest.

Chemotherapy- and irradiation-induced bone loss in adults with solid tumors.

It is estimated that bone loss occurs in 70 % of all patients dying from cancer, causing a significant disease burden in cancer patients. Bone loss is caused by cancer itself and its metastases, but also by cancer therapies. Of the cancer therapy-induced bone loss, hormone therapies are best known for their bone damaging abilities. However, chemo- and radiotherapy may result in bone loss too. In this review, direct and indirect effects of various chemotherapies (such as methotrexate, imatinib, and taxanes) that cause bone loss are discussed. Furthermore, we discuss bone loss caused by radiotherapy and radionuclides, of which the latter may be reduced with the introduction of the alpha-emitter Radium-223. Finally, agents preventing chemotherapy- or radiotherapy-induced bone loss, in particular denosumab and bisphosphonates, are being reviewed for their efficacy in preventing chemotherapy- and irradiation-induced bone loss in cancer patients.

Bone mineral density and FRAX as predictors of fracture risk in women with breast cancer.

121 Background: The number of cancer survivors is rising in the USA, the 2007 CDC analysis of the SEER database estimated 11 million cancer survivors, with 90% being over the age of 65 years. Of these, 70% are women, and the most common cancer in survivors is breast cancer. Cancer therapy induced bone loss (CTIBL) contributes to an increase in fracture risk in women with breast cancer. Fractures are responsible for considerable morbidity, disability, hopitalizations and mortality in older adults. Fractures are often the cause for nursing home placement in seniors. Our objective was to analyze the prevalence of fractures after breast cancer therapy and to assess the effect of cancer therapy, clinical risk factors, bone density and the World Health Oragnization (WHO) fracture risk assessment [FRAX] as predictors of fracture occurrence. Methods: The study population consisted of breast cancer patients with invasive breast cancer who participated in a genetic databank within a NCI-Comprehensive Cancer Center. Demographic and clinical characteristics were abstracted from the EMR. Participants were followed for 6-12 years. Results: A total of 439 women with breast cancer were assessed; 79 had sustained fractures during the observation period (116 fractures), fractures occurred at multiple skeletal sites in 27 cases. The prevalence of fractures was 18%. Baseline characteristics revealed that women who sustained fractures were mostly Caucasian (91%, p=0.08), and had a family history of osteoporosis (36.9%, p=0.03). The time to fracture was 4.0 years (range 0-12 years) from diagnosis. Fracture cases had lower BMD at the femoral neck 0.86 ± 0.13 gm/cm2 (T-score= -1.0, p=0.04) than non- fracture cases, although BMD was in the low normal range. Eight cases of hip fractures were identified with a median age of 55 years (32-67 years) Median T-score -0.75. Cox proportional hazard analysis failed to identify any specific risk factors for fractures. Conclusions: Fractures occur shortly after commencing cancer therapy. BMD and FRAX risk calculation were not able to identify women who fractured. Occurrence of fractures in breast cancer raises the possibility of cancer-induced impairment in bone quality.

Impact of denosumab on bone mass in cancer patients

Cancer therapy-induced bone loss (CTIBL) is a form of secondary osteoporosis associated with systemic chemotherapy and hormonal ablation therapy. The monitoring and treatment of CTIBL is an important component of comprehensive cancer care, especially for patients with curable disease and long life expectancies. Whereas oral bisphosphonates remain the most commonly used therapeutic option for CTIBL, additional treatment options may be required for patients who do not respond adequately or are intolerant to bisphosphonates, have renal insufficiency, or are receiving treatment with nephrotoxic medications. For these patients, denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand (RANKL), offers an effective and well-tolerated alternative. Several recent randomized trials have examined the use of denosumab as treatment for CTIBL associated with hormone ablation therapy for breast and prostate cancer. Recent data suggest a possible role for RANKL inhibitors in both chemoprevention and the prevention of cancer recurrence through direct effects on breast tissue and breast cancer stem cells. The outcomes of several international Phase III clinical trials currently underway will help clarify the role of denosumab in patients undergoing cancer therapy.

Zoledronic Acid to Prevent and Treat Cancer Metastasis: New Prospects for An Old Drug

Zoledronic acid (zoledronate, Zometa™; Novartis Pharmaceuticals, Basel, Switzerland) is a nitrogen-containing bisphosphonate. Zoledronate rapidly binds to bone mineral where it is then ingested by osteoclasts. Once internalized, zoledronate inhibits the mevalonate pathway, which stops osteoclast function, and thus slows bone resorption. Zoledronate is approved for the prevention of skeletal morbidity in metastatic bone disease from solid tumors and multiple myeloma. Zoledronate is also recommended as an option for the treatment of cancer therapy-induced bone loss. In recent large Phase III studies in early breast cancer, zoledronate reduced both local and distant recurrences in women with induced or established natural menopause. Postulated mechanisms underlying the anticancer properties of zoledronate include antiangiogenic and immunomodulatory effects. A clearer understanding of these mechanisms will enable the full potential of zoledronate to be realized.

Aromatase Inhibitor Adjuvant Chemotherapy of Breast Cancer Results in Cancer Therapy Induced Bone Loss

Aromatase Inhibitors are anti-estrogen agents that have proven efficacy for adjuvant therapy of estrogen receptor positive breast cancer primarily in post menopausal women with estrogen receptor positive breast cancer but increase the risk of cancer therapy induced bone loss (CTIBL). Recent studies have shown the potential benefit of bisphosphonate therapy to play a dual role in the management of breast cancer. These studies provide evidence that bisphosphonate therapy in conjunction with aromatase inhibitors (AI), not only decreases the risk of osteoporosis but, in addition, may improve survival from breast cancer.

Bone Homeostasis and Breast Cancer: Implications for Complex Therapy and the Maintenance of Bone Integrity

The standard of care in bone metastases is antiresorptive therapy. If present in the bone, tumor cells induce a vicious cycle by stimulating the osteoclasts, which further accelerates tumor progression. The widely-used bisphosphonates or the new therapeutic option, denosumab an inhibitor of the receptor activator of NF-κB ligand (RANKL), interrupt this vicious cycle, inhibit tumor growth, and in clinical practice prevent skeleton-related events. Adjuvant oncological therapy, including chemotherapy and endocrine manipulations (ovarian ablation and tamoxifen in premenopausal, and aromatase inhibitors in postmenopausal women), increases the bone turnover and the risk of fracture. Awareness is essential for the diagnosis and treatment of cancer therapy-induced bone loss, or its prevention with appropriate calcium and vitamin D supplementation. A new possibility has been suggested for the prevention of relapse: the use of bisphosphonates in the adjuvant setting. Three large studies and their meta-analyses indicate that the inhibition of bone remodeling prevents the growth of dormant tumor cells and cancer relapse in the population of postmenopausal patients with a low-estrogen environment in the skeleton. The similar potential of a RANKL inhibitor is currently under evaluation. Since the maintenance of bone integrity is necessary for the prevention of both therapy-related side-effects and progression of the disease, the management of breast cancer at any stage requires a careful consideration of the bone homeostasis.

Histomorphometric and microarchitectural analyses using the 2 mm bone marrow trephine in metastatic breast cancer patients–preliminary results

BackgroundBone-targeted agents are widely used for the treatment of osteoporosis, the prevention of cancer-therapy induced bone loss, and for reducing the risk of skeletal related events in patients with metastatic disease. Despite widespread use, relatively little is known about the in vivo effect of these agents on bone homeostasis, bone quality, and bone architecture in humans. Traditionally bone quality has been assessed using a transiliac bone biopsy with a 7mm “Bordier” core needle. We examined the possibility of using a 2mm “Jamshidi” core needle as a more practical and less invasive method to assess bone turnover and potentially other tumor effects. MethodsA pilot study on the feasibility of assessing bone quality and microarchitecture and tumor invasion using a 2mm bone marrow trephine was conducted. Patients underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for bone microarchitecture, bone density, and histomorphometry. The study plan was to accrue three patients with advanced breast cancer to assess the feasibility of the study before enrolling more patients. ResultsThe procedure was well tolerated. The sample quality was excellent to analyze bone trabecular microarchitecture using both microCT and histomorphometry. Intense osteoclastic activity was observed in a patient with extensive tumor burden in bone despite intravenous bisphosphonate therapy. DiscussionGiven the success of this study for assessing bone microarchitecture, bone density, and histomorphometry assessment using a 2mm needle the study will be expanded beyond these initial three patients for longitudinal assessment of bone-targeted therapy.

Protection of bone in premenopausal women with breast cancer: focus on zoledronic acid

Maintaining bone health is important for patients with breast cancer (BC), the most commonly diagnosed cancer in American women. Indeed, bone loss is common throughout the BC disease continuum. In the metastatic BC setting, patients are likely to develop bone metastases, a painful complication that can lead to potentially debilitating skeletal-related events. Bone health is equally important for patients with early BC. During adjuvant therapy for early BC, the largest challenge to bone health is from accelerated bone mineral density (BMD) loss. Although decreased BMD is well recognized in older, postmenopausal women, it may be underestimated in younger, premenopausal women undergoing endocrine therapy for BC. The rate and extent of cancer therapy-induced bone loss (from chemotherapy or endocrine therapy) are substantially greater than normal decreases in BMD during menopause. Bisphosphonates such as zoledronic acid (ZOL) are antiresorptive agents indicated for the treatment of bone metastases from BC. Clinical trials over the past few years suggest that, although not yet approved for this indication, ZOL can prevent cancer therapy-induced bone loss and improve BMD in premenopausal women receiving adjuvant (endocrine or chemo-) therapy for BC. Furthermore, the benefits of ZOL therapy may go beyond maintaining bone health and include potential anticancer benefits together with favorable tolerability and cost/benefit profiles. This review will focus specifically on the role of ZOL in preserving the bone health of premenopausal women with BC.

Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors

Development of bone metastasis is common among patients with advanced cancer. Improvements in chemotherapeutic agents have allowed these patients to live longer with metastatic-stage disease. Thus, treatments to prevent skeletal complications of metastatic bone disease, such as skeletal-related events and pain, are increasingly important. As the skeletal damage with bone metastases is largely caused by increased osteoclast activity, antiresorptive agents (denosumab or bisphosphonates) are recommended for use in these patients. Denosumab, a fully human monoclonal antibody to RANKL, a key mediator of osteoclast activity, was shown to be superior to zoledronic acid for the prevention of skeletal-related events in patients with solid tumors and bone metastases. In addition, denosumab is the only agent currently approved for the treatment of bone loss in patients with breast or prostate cancer receiving hormone-ablation therapy. Denosumab is also being evaluated in several other indications, including adjuvant treatment of breast cancer and giant cell tumor of the bone.

Abstract 2065: Loss of Nrf2 increases susceptibility to radiation induced bone loss

Abstract A fundamental clinical complication in the treatment of patients with metastatic breast cancer is severe bone loss. Patients with breast cancer routinely received both chemotherapy and radiotherapy, both are known to increase oxidative stress and bone loss. Underlying mechanism of cancer therapy induced bone loss is poorly understood. We have previouslyreported that treatment with radiation (RT) increases TGFβ1 levels in mice. TGFβ1 increases oxidative stress by induction of reactive oxygen species (ROS). TGFβ1 increases oxidative stress by induction of reactive oxygen species (ROS). TGFβ1/Smad3 signaling suppresses Nrf2 (Nuclear factor erythroid-derived 2), a master transcription factor that positively regulates induction of antioxidant gene expression resulting in elevated ROS levels. Our objective is to test the hypothesis whether loss of Nrf2 gene increases the radiation induced bone loss. We have used age matched wild type control and Nrf2-/- mice. Mice were irradiated (single dose, 20 Gy) on the hind legs and microCT analysis was done to measure the overall bone loss. A similar increase in bone loss was noted in mice following histological analysis of the long bones. Additionally, reduction in osteoblast colony forming units and osteoblast differentiation were also noted. We have seen a higher number of osteoclasts in Nrf2-/- mice compared to wild type control and following radiation, the trend remains same. We conclude that, loss of Nrf2 leads to incraesed susceptibility to the radiation induced bone damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2065. doi:1538-7445.AM2012-2065

The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer

Breast cancer is the second most common cancer among American women and has a high rate of metastasis to bone. Patients regularly undergo adjuvant therapy (chemotherapy or hormonal therapy) following surgical resection of the tumor. In addition to potential direct effects on bone cells, both chemotherapy and hormonal therapy induce ovarian dysfunction and dramatically decrease estrogen levels in both pre- and postmenopausal women. This leads to decreased bone mineral density and increased fracture risk. Antiresorptive therapies (e.g, zoledronic acid and denosumab) have demonstrated efficacy in preventing cancer therapy-induced bone loss in patients with breast cancer and are approved for the prevention of skeletal-related events in patients with bone metastases from breast cancer. This review will focus on the evolving role of these antiresorptive therapies in the care of women with early or metastatic breast cancer.

Bisphosphonate Therapy for Skeletal Malignancies and Metastases: Impact on Jaw Bones and Prosthodontic Concerns

Healthy jawbones ensure better tooth anchorage and the ability to masticate and maintain metabolism. This is achieved by a delicate balance between bone formation and resorption in response to functional demands. An imbalance in the expression of receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) and osteoprotegerin (OPG) or osteoclastogenesis inhibitory factor (OCIF) is believed to be the underlying mechanism of osteolysis in metastases, multiple myelomas, and cancer therapy-induced bone loss in patients. Considered mainly as bone-specific agents to treat postmenopausal osteoporosis, bisphosphonates, in combination with certain chemotherapeutic agents have proved to be effective in prevention of tumor formation and metastatic osteolysis in bone tissue. Osteonecrosis of the jaws associated with them has, however, been of grave concern to the prosthodontist, as it predisposes patients to a bone-deficient basal seat for dental prostheses. This manuscript reviews available information over the past 13 years on possible mechanisms of bone loss, bisphosphonate-induced osteonecrosis of jaw bones, and prosthodontic concerns.

New role for an established drug? Bisphosphonates as potential anticancer agents

As a result of their ability to effectively reduce the risk of skeletal-related events, bisphosphonates (BPs) were incorporated into clinical practice over a decade ago, leading to a new treatment paradigm for patients with skeletal involvement from advanced cancer. BPs are now a well-established treatment option in this setting. Our review of the literature found that in addition to maintaining bone health in patients with malignant bone lesions and patients at risk for cancer therapy-induced bone loss, emerging preclinical and clinical data suggest that BPs may also have anticancer activity. Later generation, nitrogen-containing BPs (N-BPs), such as zoledronic acid (ZOL), inhibit the mevalonate pathway, subsequently inhibiting a number of cellular functions in bone-resorbing osteoclasts. In addition, N-BPs inhibit cancer cell proliferation, viability, motility, invasion and angiogenesis; induce cancer cell apoptosis; and act in synergy with antineoplastic agents. N-BPs, especially ZOL, may be useful as anticancer agents. As evidence continues to emerge, another shift in cancer treatment paradigms, in which N-BPs are considered for their anticancer activity as well as palliative effects, may be approaching.