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The Evolving Role of Bisphosphonates for Cancer Treatment-Induced Bone Loss

  • Authors: Chairperson: Robert E. Coleman, MD, FRCP; Faculty: Richard L. Theriault, DO, MBA; Matthew R. Smith, MD, PhD; Lee S. Rosen, MD
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Target Audience and Goal Statement

The target audience for this educational program includes healthcare professionals involved in the treatment and management of cancer treatment-induced bone loss, specifically including medical oncologists, urologists and oncology nurses.

Cancer treatment-induced bone loss is an emerging problem in patients with breast cancer or prostate cancer receiving long-term hormonal therapy. In these patients, bone loss associated with hormonal therapy or chemotherapy can result in skeletal morbidity that substantially reduces quality of life.

Recently, however, several studies have shown that bisphosphonates play a vital role in this setting by preserving or even improving bone mineral density. These studies suggest that bisphosphonates can maintain bone health when introduced early in the continuum of cancer care. This educational activity will provide oncologists and other healthcare professionals with the information necessary to make informed treatment decisions to maintain bone health in their patients.

Upon completion of this activity, participants will be able to:

  1. Identify the prevalence of cancer treatment-induced bone loss associated with hormonal therapy and chemotherapy in patients with breast or prostate cancer.
  2. Discuss the pathophysiology of cancer treatment-induced bone loss.
  3. Identify the role of bisphosphonates in the management of cancer treatment-induced bone loss and maintenance of bone health.
  4. Discuss information based on recent clinical trials that demonstrate the efficacy and safety of a new generation of bisphosphonates across a range of primary malignancies to prevent skeletal complications associated with bone metastases.
  5. Describe the clinical utility of bisphosphonates in earlystage disease to prevent cancer treatment-induced bone loss and improve long-term bone health.
  6. Discuss the clinical utility of bisphosphonates across the continuum of care for patients with cancer.
  7. Identify at least 2 ways to improve the quality of care for patients with advanced cancer.


  • Robert E Coleman, MD, FRCP

    Professor of Medical Oncology, Academic Unit of Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, England, UK


    Disclosure: Grants/Research Support: Novartis Pharmaceuticals;
    Consultant: Novartis Pharmaceuticals;
    Speakers' Bureau: Novartis Pharmaceuticals, Roche, Schering Pharmaceuticals.

  • Lee Rosen, MD

    Director of Research, Premiere Oncology, Santa Monica, California


    Disclosure: Grants/Research Support: Novartis Pharmaceuticals.

  • Matthew R Smith, MD, PhD (Chair)

    Assistant Professor of Medicine, Harvard Medical School; Assistant Physician, Massachusetts General Hospital, Boston, Massachusetts


    Disclosure: Grants/Research Support: Novartis Pharmaceuticals;
    Consultant: Novartis Pharmaceuticals.

  • Richard L Theriault, DO, MBA

    Professor of Medicine, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA


    Disclosure: Grants/Research Support: Novartis Pharmaceuticals;
    Speakers' Bureau: Novartis Pharmaceuticals.

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The Evolving Role of Bisphosphonates for Cancer Treatment-Induced Bone Loss

Authors: Chairperson: Robert E. Coleman, MD, FRCP; Faculty: Richard L. Theriault, DO, MBA; Matthew R. Smith, MD, PhD; Lee S. Rosen, MDFaculty and Disclosures


Pathophysiology of Cancer Treatment-Induced Bone Loss, Presented by Richard L. Theriault, DO, MBA

Bone Turnover, Bone Remodeling

  • It's my role to review the pathophysiology of bone diseases and specifically relate that to cancer treatments, including chemotherapy, hormonal therapy, and others.

  • Pathophysiology of Cancer Treatment-Induced Bone Loss

    Slide 1.

    Pathophysiology of Cancer Treatment-Induced Bone Loss

    (Enlarge Slide)
  • We will begin by looking at bone remodeling.

    As we sit here our bones are remodeling and it is estimated it takes about 36 months to replace our skeletons; about every 3 years you get a new inside and, fortunately, that holds you up.

    Bone remodeling is characterized by 2 major activities: osteoblastic rebuilding of bone, and resorption of bone by osteoclasts.

  • Bone Turnover

    Slide 2.

    Bone Turnover

    (Enlarge Slide)
  • Usually, these are interrelated; they are coupled and balanced. If we look at coupling, with normal bone osteoclast comes along and remodels the surface as it needs to; osteoblasts come in and rebuild the bone. The amount of bone removed is equivalent to the amount of bone replaced and they are anatomically distributed appropriately.

    If they are coupled with imbalance, then there is either excessive osteoblastic activity or excessive osteoclastic activity, but the amount of bone made is the same; they are coupled but unbalanced.

    A third possibility is uncoupled but balanced. You may have osteoclastic activity of the surface of the bone and make an osteoclastic lacuna at the bone, but then osteoblastic activity occurs at a remote site or not in the site necessary to replace the bone that has been removed.

    The last possibility is uncoupled and imbalanced. This is the predominant phenomenon in cancer. You not only have excessive osteoclastic activity with destruction of bone, you have an imbalance in production of bone. You may have too much, in which case we have perhaps a radiographic appearance of osteoblastic disease, or you may have too little, in which case we have an appearance of osteolytic or osteoporotic bones. These are the 4 bone remodeling paradigms that one can think of as we look at bone remodeling in cancer.

  • Bone Remodeling Cancer Effects

    Slide 3.

    Bone Remodeling Cancer Effects

    (Enlarge Slide)
  • A number of markers are available to measure whether there is a predominant osteolytic or osteoblastic component to bone disease. In osteoporotic bone disease, the primary event is degradation of bone and the biochemical markers of that include calcium/creatinine ratio and hydroxyproline/creatinine ratio, which are very rarely used, and perhaps the best is N-telopeptide, an amino terminal peptide of collagen crosslinks. C-telopeptide is also measured. These are all urine tests that can be ordered. At our institution we use N-telopeptide.

  • Biochemical Markers of Bone Turnover (1)

    Slide 4.

    Biochemical Markers of Bone Turnover (1)

    (Enlarge Slide)
  • As serum markers, both N-telopeptide and C-telopeptide are available. Bone sialoprotein is measured at some sites. Markers of bone formation, osteoblastic activity, consist primarily of fractionation of the bone alkaline phosphatase measured in normal blood, and osteocalcin, which can be measured also in normal blood.

  • Biochemical Markers of Bone Turnover (2)

    Slide 5.

    Biochemical Markers of Bone Turnover (2)

    (Enlarge Slide)

Bone Loss in Breast Cancer and Prostate Cancer: The Similarities

  • Breast cancer and prostate cancer have a lot in common. Women don't have prostates and most men don't get breast cancer; nevertheless, they have a lot in common. Primarily they cause bone metastases and that treatment results in a decrease in gonadal steroids, which results in decrease of bone mineral density. And decrease in bone mineral density results in increased fracture risk.

    They also have in common the observation that hormone replacement therapy, giving women with breast cancer estrogen or men with prostate cancer testosterone, is relatively, if not absolutely, contraindicated. There are very limited prospective data on preventive measures for bone treatment, and treatment for bone loss as a consequence of metastatic disease or primary breast and prostate cancer.

  • Breast Cancer and Prostate Cancer: Common Skeletal Themes

    Slide 6.

    Breast Cancer and Prostate Cancer: Common Skeletal Themes

    (Enlarge Slide)
  • What induces the bone loss? On the left is breast cancer. First is cytotoxic chemotherapy, and there are 2 mechanisms of cytotoxic chemotherapy inducing bone loss. First, there is a direct negative effect of the cytotoxic therapy on bone cells, predominantly osteoblasts and, second, many women who are premenopausal have cytotoxic therapy effects on ovarian function, which results in gonadal loss as well.

    In addition, in premenopausal women, surgery (oophorectomy) or radiation therapy to the ovary, a good therapy in the adjuvant setting, also results in bone loss. Hormone therapy, tamoxifen in premenopausal women, and the aromatase inhibitors result in bone loss, as well as gonadotropin-releasing hormone (GnRH) antagonists/agonists, which shut off ovarian function. All of these result in estrogen depletion.

    In prostate cancer, the list is nearly the same. Cytotoxic therapy again has a negative effect not only on testicular function but also on bone. Surgical therapy. Hormone therapy, including antiandrogens and GNRH agonists/antagonists, results in androgen depletion.

    The final common pathway, estrogen and androgen depletion, is the result of bone mineral density being decreased.

  • Cancer Treatment-Induced Bone Loss (CTIBL) in Breast and Prostate Cancer

    Slide 7.

    Cancer Treatment-Induced Bone Loss (CTIBL) in Breast and Prostate Cancer

    (Enlarge Slide)
  • In the bone microenvironment a lot of things are going on. There are both cellular functions and cytokine functions that help maintain bone integrity. Here we have a normal bone environment and we have pre-B cells, which produce receptor activator of nuclear factor-kappa beta ligand (RANKL). RANKL, when it binds to the receptor on osteoclasts, increases osteoclastogenesis, a recruitment from the monocyte and macrophage cell line of osteoclasts, and activates osteoclast precursors into active or mature osteoclasts, which then work on the site of bone and degrade the bone.

    Osteoprotegerin, which is produced by osteoblasts, is in circulation and acts as a decoy receptor of RANKL. This is the inhibitory component to shut off osteoclastic function. Ordinarily there's a balance so that bones are remodeled and there's coupling and balance between function of osteoblasts and osteoclasts. This would be the normal bone microenvironment.

  • Bone Microenvironment

    Slide 8.

    Bone Microenvironment

    (Enlarge Slide)
  • In an estrogen-depleted state, pre-B cells expand in number, activity of RANKL is increased, stromal cell production of RANKL is increased and, as a consequence, osteoclastic precursors and osteoclastogenesis are increased, resulting in more mature osteoclasts and excessive bone breakdown.

    This is augmented by interleukin-6 production, which occurs as a consequence of estrogen depletion and may also occur as a consequence of prostaglandin E2, interleukin-1, and tumor necrosis factor alpha production, especially in metastatic disease to bone.

  • Bone Microenvironment: Estrogen Depletion

    Slide 9.

    Bone Microenvironment: Estrogen Depletion

    (Enlarge Slide)
  • The consequences, bioavailable estradiol concentrations, are dramatically reduced. On the left are premenopausal women and the level is more than 200. Postmenopausal women levels are dramatically less. Even in men estradiol levels are higher until there is androgen depletion. So once androgen is depleted, once estrogen is depleted, that pathway of increased RANKL production, osteoclastogenesis, and osteoclast activation occurs.

  • Bioavailable Estradiol Concentrations

    Slide 10.

    Bioavailable Estradiol Concentrations

    (Enlarge Slide)
  • Hypogonadism then occurs as a result of natural menopause, increased osteoclast formation, and survival, and leads to 5% to 10% loss of cortical bone within the first year to 2 years after menopause. Trabecular bone is lost at a greater percentage and trabecular bone, unlike cortical bone, is not reconstituted very well. Cancer treatment-related bone loss increases loss of cortical and trabecular bone both through the agents we talked about cytotoxic wise and because of hypogonadism.

  • CTIBL Exacerbates Bone Loss in Postmenopausal Women

    Slide 11.

    CTIBL Exacerbates Bone Loss in Postmenopausal Women

    (Enlarge Slide)

Breast Cancer Bone Loss

  • In primary breast cancer, bone loss also occurs. Many women with primary breast cancer with estrogen-receptor positive tumors are treated with tamoxifen, and tamoxifen in the premenopausal woman results in bone loss, an opposite effect of what we see in postmenopausal women where bone integrity is maintained. Aromatase inhibitors, by inhibiting the conversion of androstenedione and testosterone to estradiol and estrone, result in further reduction in estrogen even in the postmenopausal woman. So if we look at the levels shown earlier in postmenopausal women, we will reduce it further, 90% or greater, with administration of aromatase inhibitors. This again increases osteoclastic activity.

    Chemotherapy induces ovarian dysfunction that is related to the age of the patient, the type of drug administered, and the total dose of drug administered. If you are over 40 years of age and you receive 3 g of cyclophosphamide, there's a 90% probability you will become menopausal. If you are under 30 years of age and receive 3 g of cyclophosphamide, there's a 90% probability you will not, but if you receive 6 g of cyclophosphamide you will. So drug, dose, and age all impact chemotherapy induced ovarian dysfunction.

    Last on our list we have ovarian ablation, which is still a very good treatment for primary breast cancer; it results in improved, disease-free, and overall survival. There are a number of methods to do this. Surgery, oophorectomy, is the standard, and has been around for a long time; radiation oophorectomy has also been around for a long time. The latest mechanism is the luteinizing hormone-releasing hormone (LH-RH) agonist/antagonist, which is very effective.

  • Bone Loss in Primary Breast Cancer

    Slide 12.

    Bone Loss in Primary Breast Cancer

    (Enlarge Slide)
  • With bone loss in metastatic breast cancer, we have osteoclast activation by treatment, including the aromatase inhibitors, ovarian ablation, and chemotherapy. Chemotherapy has a dual effect, not only affecting ovarian function but also having a negative effect on the osteoblast. Tumor-induced bone loss is related to metastases and up to 80%, perhaps as many as 100%, of patients who develop metastases from primary breast cancer will have bone disease at some point in the clinical course of their disease. All of this results in excessive osteoclastic activity.

  • Bone Loss in Metastatic Breast Cancer

    Slide 13.

    Bone Loss in Metastatic Breast Cancer

    (Enlarge Slide)

Bone Loss During Menopause

  • In terms of bone density in premenopausal women, if you measure lumbar spine bone loss, Shapiro showed that after 6 months of chemotherapy there was a 4% loss of bone density using a dual-energy x-ray absorptiometry (DEXA) technique in the lumbar spine. If you measured it after 12 months there was an additional 3.7% loss for a total loss of between 8% and 10% after 1 year of cyclophosphamide-methotrexate-fluorouracil (CMF) chemotherapy.

    The implications for long-term breast cancer survivors, and fortunately we have many more of those women, are an increase in osteopenia and osteoporosis and an increase in fracture risk.

  • Bone Density With Adjuvant Chemotherapy: Premenopausal Women

    Slide 14.

    Bone Density With Adjuvant Chemotherapy: Premenopausal Women

    (Enlarge Slide)
  • With oophorectomy, up to 20% loss of total bone mass may occur within 18 months. With goserelin, amenorrhea occurs in 95% of women who are premenopausal and, again, is attended by increased bone loss.

  • Oophorectomy: Ovarian Suppression

    Slide 15.

    Oophorectomy: Ovarian Suppression

    (Enlarge Slide)

Diagnostic Tests and Criteria

  • The gold standard for bone mineral density testing is DEXA. Early diagnosis and treatment of bone loss are essential. If we wait until there is fracture or a skeletal event, it's too late. The most sensitive test is DEXA. It is very accurate, more accurate than x-ray or computed tomography (CT) scan. It can be used to measure spine, hip, or total body bone density. There are also peripheral units to measure wrist, heel, and finger bone density as a screening tool.

  • Bone Mineral Density Testing

    Slide 16.

    Bone Mineral Density Testing

    (Enlarge Slide)
  • For testing, one wants to detect osteopenia or osteoporosis before fracture. The lower the bone density, the greater the fracture risk. And once you've had fracture, it's too late.

    Testing can also be used to determine the rate of bone loss by measuring serially bone mineral density at different time points; baseline, 6 months, 12 months, 2 years. And it can be used to monitor the effects of treatment, whether there's been improvement with whatever intervention we have chosen to use.

  • Bone Mineral Density Testing

    Slide 17.

    Bone Mineral Density Testing

    (Enlarge Slide)
  • The World Health Organization criteria for bone loss use a T-score calculation. T score is the measure of bone in a young, normal person; young determined to be 30 years of age. It is considered to be the optimal or peak bone density. This will vary on the basis of population, race, and ethnicity but that is the normal. The difference between a patient's bone mineral density and that of a healthy young adult is the T score, and for every decrease in 1 standard deviation there's an increase in the relative risk of fracture of 1.5- to 2.5-fold.

    Using these T scores, the World Health Organization has come up with criteria for bone loss to classify people as normal, osteopenic, osteoporotic, or severely osteoporotic. Normal means that your T score is within 1 standard deviation of the normal. Osteopenia is a T score that is -1.0 to -2.5. Osteoporosis is a T score of -2.5 or less (-2.6, -2.7, -3.1, etc). And severe osteoporosis means that you have a fracture.

  • World Health Organization Criteria for Bone Loss: T-Score Calculation

    Slide 18.

    World Health Organization Criteria for Bone Loss: T-Score Calculation

    (Enlarge Slide)

Treatment of Bone Loss

  • The consequences of bone loss include fractured wrists, femurs, and vertebrae. Femoral neck fracture is the most devastating of the 3. Ten percent to 20% of patients require long-term hospital care, an additional 20% of patients require persistent assistance with daily living, and figures of 25% to 30% mortality within the first year of femur fracture are widely reported in the literature.

    Vertebral fracture doesn't have the same mortality risk but it does result in chronic pain, skeletal deformity, loss of mobility, and loss of functional independence; it has a lot of comorbidity associated with it.

  • Consequences of Bone Loss

    Slide 19.

    Consequences of Bone Loss

    (Enlarge Slide)
  • What treatments do we have for these things that occur as a consequence of our treatment for cancer? We can give calcium and vitamin D supplementation and there are standard recommendations about how much one should have. We usually use 1,000 to 1,300 mg/day of calcium. One can expect up to a 4% increase in bone mineral density.

    Hormone replacement therapy, which recently has received a lot of bad press, is still a very effective therapy for osteoporosis, and it will increase bone mineral density.

    Selective estrogen receptor modulators in postmenopausal women have an effect on bone density and maintain the integrity of bone, but are not very good at replenishing bone once lost. In this regard, raloxifene and tamoxifen are the 2 available.

    Calcitonin can be used, and an intranasal preparation is approved for use in patients who are osteopenic.

  • Treatment of Bone Loss (1)

    Slide 20.

    Treatment of Bone Loss (1)

    (Enlarge Slide)
  • Probably the most effective treatments are the bisphosphonates and listed here are alendronate and risedronate in yellow; they are commercially available oral preparations that are approved for the treatment of osteopenia and osteoporosis. The bisphosphonates differ in their potency and these are ranked in order of least to greatest potency, with oral clodronate being the least potent. Unfortunately, it's not available in the United States at present.

    In randomized trials bisphosphonates have been shown to be superior to all other agents in increasing bone mineral density for those patients who have osteopenia or osteoporosis.

  • Treatment of Bone Loss (2)

    Slide 21.

    Treatment of Bone Loss (2)

    (Enlarge Slide)

Treatment With Bisphosphonates

  • The rationale for intravenous (IV) bisphosphonate therapy in cancer treatment-induced bone loss has to do with the importance of maintaining bone health; primary prevention is better than secondary intervention.

    Early-generation oral bisphosphonates have proven efficacy in prevention of osteoporosis but for some patients they are not the best. The oral agents are poorly absorbed, up to only 6% absorbed, and they require certain maneuvers, such as standing upright for a prolonged period of time after taking them. Occasionally they are associated with gastrointestinal toxicity, which may be severe.

    Cancer treatment-induced bone loss is more rapid than the usual osteoporosis. Per Shapiro's data, within 6 months 4% of bone may be lost by bone mineral density. An effective treatment therefore may require a more potent agent, IV administered, than the oral agents.

    There are also potential additional clinical benefits related to the potential reduction in risk of the development of bone metastases.

  • Rationale for IV Bisphosphonate Therapy for CTIBL

    Slide 22.

    Rationale for IV Bisphosphonate Therapy for CTIBL

    (Enlarge Slide)
  • How do these work? We're going to focus on aminobisphosphonates because they have the greatest activity. They work in many ways, but there are 2 predominant ways. One is they block the accession of monocyte macrophage osteoclast precursors into osteoclastogenesis; instead of recruiting a lot of cells to become osteoclasts, that is blocked.

    Secondly, mature osteoclasts, once they are active, have their function impeded by a number of mechanisms. One is this ruffled border where the cell kind of suction cups onto the bone is interrupted and cells cannot attach to bone very well. Intracellularly, liposomal activity of osteoclast is also inhibited and the low pH required at the cell surface for bone absorption is destroyed.

    In addition, there are data showing that at least the aminobisphosphonates can result in osteoclastic cell apoptosis through activation of capsaicis.

  • Rationale for Bisphosphonate Inhibition of CTIBL

    Slide 23.

    Rationale for Bisphosphonate Inhibition of CTIBL

    (Enlarge Slide)
  • Zoledronic acid is the most potent bisphosphonate we have, and it has an unusual structure. It's this heterocyclic diamino structure. There is a great deal of information indicating that structure function relationships exist with bisphosphonates, and this structure is important for the activity. It's considered a third-generation bisphosphonate, 100 to 850 times more potent than pamidronate using a rat model of hypercalcemia, and it has been shown to increase bone mineral density in postmenopausal women with osteoporosis.

    In prostate cancer, it can prevent cancer treatment-induced bone loss.

  • Zoledronic Acid

    Slide 24.

    Zoledronic Acid

    (Enlarge Slide)
  • These are from Reid's paper in the New England Journal of Medicine showing the difference in lumbar spine and femoral neck bone mineral density with the administration of zoledronic acid compared with placebo. Bone mineral density increases approximately 5% in lumbar spine and 2% in the femoral neck by 12 months after administration of zoledronic acid. So it has a very positive effect on bone mineral density in women with osteoporosis.

  • Zoledronic Acid Increases BMD in Postmenopausal Women With Low BMD

    Slide 25.

    Zoledronic Acid Increases BMD in Postmenopausal Women With Low BMD

    (Enlarge Slide)


  • What can we conclude from this limited amount of information? Cancer treatment compromises bone integrity. Those treatments, including chemotherapy, surgery, radiation therapy, and hormonal therapy, all result in estrogen and androgen depletion and activation of osteoclasts. And activation of osteoclast results in bone destruction and increased fracture risk.

    The size of this problem is not insignificant. In the 1990s, approximately 1.8 million women were diagnosed with breast cancer. Merely by being diagnosed with breast cancer, one is at increased risk of osteopenia and osteoporosis, and if one is diagnosed with metastatic breast cancer to bone, that risk is dramatically increased around 27- to 35-fold. One and a half million men were diagnosed with prostate cancer in the 1990s; 1.5 million men in all of our treatments that can result in bone loss, osteoporosis, and fracture risk. Because of this, there is a strong rationale for developing a potent IV bisphosphonate to prevent or to treat cancer treatment-induced bone loss.

  • Conclusions

    Slide 26.


    (Enlarge Slide)