For Physicians
Pathophysiology and Treatment of Malignant Skeletal Disease
Bisphosphonates are the most commonly prescribed drugs for the treatment and prevention of osteoporosis. Long term studies lasting 7 to 10 years have demonstrated their safety and effectiveness1, although patients need to be monitored for adverse events which occur in some individuals. This class of drugs targets the process of bone resorption by inhibiting osteoclast function. The first generation, etidronate and clodronate (Didronel®, Bonefos®) lack nitrogen, adhere to bone, and are metabolized by osteoclasts causing mitochondrial dysfunction and apoptosis. The second generation contains nitrogen, is internalized by osteoclasts and then inhibits an enzyme crucial for cellular vesicle transport, without which osteoclasts cannot form the tight sealing zones or ruffled borders at the bone surface required for bone resorption. These drugs include pamidronate, zoledronic acid, risendronate, and ibandronate (Aredia®, Zometa®, Actonel®, Boniva® respectively)5.
Bisphosphonates are the most commonly prescribed drugs for the treatment and prevention of osteoporosis. Long term studies lasting 7 to 10 years have demonstrated their safety and effectiveness1, although patients need to be monitored for adverse events which occur in some individuals. This class of drugs targets the process of bone resorption by inhibiting osteoclast function. The first generation, etidronate and clodronate (Didronel®, Bonefos®) lack nitrogen, adhere to bone, and are metabolized by osteoclasts causing mitochondrial dysfunction and apoptosis. The second generation contains nitrogen, is internalized by osteoclasts and then inhibits an enzyme crucial for cellular vesicle transport, without which osteoclasts cannot form the tight sealing zones or ruffled borders at the bone surface required for bone resorption. These drugs include pamidronate, zoledronic acid, risendronate, and ibandronate (Aredia®, Zometa®, Actonel®, Boniva® respectively)5.
Pathophysiology of metastatic bone diseaseThe central process in metastatic bone disease is the uncoupling of bone remodeling by means of increased osteoclast-mediated skeletal lysis and suppressed bone mineralization by osteoblasts. Invading tumor cells and marrow stromal cells have a direct effect by secreting factors that directly upregulate a broad spectrum of cytokines, chemokines, and hormone-like proteins (e.g.PTH-like protein) that stimulate osteoclast formation and activity. The indirect effect tumor cells have on RANK ligand (RANKL), a membrane bound protein found on marrow stromal cells, synovial fibroblasts, and osteoblasts, and also secreted by activated T lymphocytes, probably is more important. Normally, RANKL binds to RANK, a transmembrane signaling receptor found on the surface of osteoclasts and their precursors, and the resultant signaling induces osteoclast formation, activation, and survival. An important regulator of osteoclastogenesis is osteoprotegerin (OPG), a soluble decoy receptor of RANKL produced by osteoblasts and stromal cells. Under normal conditions OPG blocks the interaction of RANKL with RANK, limiting and regulating osteoclastic activity. However, invading tumor cells stimulate the production of RANKL and simultaneously suppress OPG. Therefore, in malignant bone disease the upregulation of RANKL and suppression of OPG leads to an imbalance in osteoclastic activity resulting in increased bone lysis, bone pain, and fracture4,5.
Bisphosphonate Therapy and CancerNew and important indications for bisphosphonate therapy in oncology have emerged during the past few years. Bisphosphonates have been found to be very effective as adjunctive drugs in the treatment of a variety of malignancies with skeletal metastases, and also have been used with great success for hypercalcemia. In breast cancer and multiple myeloma, several of these drugs have been shown to delay the onset of skeletal related events (SRE), defined as pathologic fracture, spinal cord compression, hypercalcemia, radiation therapy for pain, and bone surgery. Therapeutic benefit usually is not evident until 6-12 months of treatment. Even though quality of life may have been unequivocally improved by bisphosphonate treatment, overall survival benefit in metastatic disease has not been documented10 . The two drugs studied most frequently have been pamidronate (Aredia®) and zoledronic acid (Zometa®), and head-to-head comparisons of the two indicate that zoledronic acid (ZOL), is more potent and superior13.
Results of clinical trials in metastatic prostate cancer were quite similar. Although many bisphosphonates consistently improve BMD in men on gonadotropin hormone releasing agonists (GnRH-agonists)9, BMD alone is not always a reliable predictor of reduced skeletal morbidity. Once again, ZOL seemed to be better than other bisphosphonates, as fewer patients treated with ZOL versus placebo had skeletal related events, the annual incidence of SREs was much lower, and clinical benefits were sustained at 24 month follow-up11. ZOL has become the standard of care for men with advanced prostate cancer and bone metastases9. Despite improved quality of life, there has been no documentation of improvement in survival for men with metastatic disease.
Pamidronate has been FDA approved for the prevention of SRE in patients with bone disease from multiple myeloma, and bone metastases from breast cancer, as well as for the hypercalcemia of malignancy. Zoledronic acid was approved for patients with breast cancer, prostate cancer, and other solid tumors with documented skeletal metastases, and for hypercalcemia. Both drugs are meant to be used in conjunction with standard anti-cancer treatment.
Bone Loss from Hormone Treatment of CancerEstrogen and androgen hormones are crucial for the stimulation of bone synthesis; therefore, any cancer therapy that depletes either hormone, especially estrogen, can accelerate bone loss12.
Endocrine therapy for hormone receptor positive (ER+) early breast cancer is used as adjuvant therapy after primary treatment of the tumor. This involves estrogen depletion techniques such as ovarian suppression or ablation if premenopausal, and aromatase inhibitors, which block peripheral estrogen synthesis, if post-menopausal. These modalities accelerate osteoporosis in women. For example, aromatase inhibitors (AI) such as Arimidex® and others reduce circulating estrogen to levels much below those usually observed with natural menopause. Annual bone loss is -2.6% compared to -1% in untreated women, resulting in nearly double the 5 year fracture rate (11% vs. 6.6%). When chemotherapy also is required as adjuvant therapy for premenopausal women, it causes ovarian failure in a high percentage of women >40, and almost all women past 50; this may be accompanied by a precipitous drop of about 7% in bone mineral density during the first year of treatment6.
Treatment of prostate cancer with GnRH-agonists results in hypogonadism, characterized by a decrease in serum testosterone by 95% and estrogen by 80%. Several large retrospective studies have consistently confirmed that men treated with GnRH-agonists or orchiectomy are about 40% more likely to develop fractures. Also, most studies of bone mineral density report a 2-3% annual decrease during GnRH-agonist treatment12.
Prevention of Osteoporosis in Hormone Treated PatientsAn important CALGB study of premenopausal women found bone loss of -9.5% at 12 months with chemotherapy alone, -4.3% with chemotherapy and tamoxifen, but increased bone mineral density (+2.2%) when zoledronic acid was administered concomitantly8. For premenopausal women on estrogen suppression by a GnRH agonist plus tamoxifen or anastrozole, the addition of ZOL prevented bone loss at 4 year follow-up6. These trials and several others documented that accelerated bone loss can be reversed by adding bisphosphonates. Clinical trial results have been similar for postmenopausal women treated with hormone therapy. Instead of the predictable decline, bone mineral density usually increased significantly provided adjuvant bisphosphonates were included. The most impressive results have been obtained from twice yearly infusions of ZOL6.
Regardless of this positive effect on prevention, bisphosphonates are FDA approved only for the treatment of established osteoporosis in women and men, and for prevention of osteoporosis in women with documented increased risk.
Novel Therapy: Denosumab (Prolia®)Denosumab is a human monoclonal antibody that neutralizes RANKL and thereby blocks osteoclastic activity. It was recently FDA approved for treatment of postmenopausal women with osteoporosis or at high risk for it, but is not yet approved as an adjunct to cancer treatment. Nevertheless, phase III trials of Denosumab in breast and prostate cancer are ongoing. A trial in breast cancer patients receiving AIs found it to be highly effective; BMD actually increased by 6.2% at two years6. A similar large trial in prostate cancer patients with osteoporosis or at high risk, found significant increases in BMD at 24 months, and a reduction by 64% of the 3 year incidence of new fractures.
Unexpected Findings: A Possible Role in Cancer PreventionTwo recent epidemiological studies raise the possibility that bisphosphonate therapy may play a role in cancer prevention. A controlled study of 4039 healthy postmenopausal Israeli women found that bisphosphonate therapy for at least one year reduced the relative risk for subsequent breast cancer by 28%2. Data from the Women’s Health Initiative also found that the incidence of invasive breast cancer was 32% lower in bisphosphonate users (90% took alendronate), with a mean follow-up of 7.8 years3. In the laboratory, nitrogen-containing bisphosphonates have demonstrated anti-tumor effects against breast cancer cell lines, and also have been shown to act synergistically with cytotoxic therapy6.
Clinical evidence supporting an antitumor effect was obtained from a trial showing a reduction of micrometastases in the bone marrow of breast cancer patients receiving adjuvant therapy when they were treated concurrently with ZOL6. Further clinical evidence comes from a large (1803 subjects) European trial of premenopausal early breast cancer patients treated with ovarian suppression followed by either tamoxifen or an aromatase inhibitor. The addition of ZOL to endocrine therapy improved disease-free and recurrence-free survivals by 36 and 35% respectively, while also preventing osteoporosis, with a median 4 year follow-up. Thus, twice yearly ZOL effectively improved clinical outcome65. Similar results were obtained in an American study of postmenopausal women on adjuvant endocrine therapy. However, comparable data have not been obtained in studies of metastatic prostate cancer9. Nevertheless, these observations regarding prevention are exciting and have stimulated additional studies regarding a possible anti-tumor effect for zoledronic acid.
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