Commentary (Berenson): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Oncologists have increasingly recognized that bone loss and its resultant complications have a major impact on the lives of cancer patients. Bone loss in this population may be a consequence of direct cancer involvement in the bone or of treatments that affect gonadal function or otherwise have a negative impact on bone.

Bone Loss in Cancer Patients

Skeletal involvement with metastasis often develops in patients with commonly occurring cancers. In fact, the majority of patients with prostate or breast cancer will develop bone metastasis sometime during the course of the disease. Importantly, cancer patients with metastatic bone disease from these primary tumors often have a longer survival than patients with other sites of metastasis such as the lung or liver. Thus, the "window of opportunity" for bone involvement to have deleterious effects on these patients' quality of life is often long. Patients with metastatic bone disease often develop bone pain, decreased mobility, pathologic fractures, and spinal cord compression. As a result, these patients often require radiotherapy and, less frequently, surgery to prevent or treat these clinical manifestations of bony metastasis.

A growing area of concern for cancer patients is the recognition that therapies frequently used to treat malignancy may lead to major bone loss. Specifically, the use of androgen blockade among men with prostate cancer and aromatase-inhibitor therapy for women with breast cancer leads to clinically significant bone loss in these two large patient populations. In addition, other cancer patients including those receiving glucocorticoids or chemotherapy that impedes gonadal function for prolonged periods of time are also at risk for ongoing bone loss. Other populations at high risk likely include individuals with premalignant disorders such as those with monoclonal gammopathy of undetermined significance.

Drug Therapy for Bone Metastases

Clinical trials in the 1990s clearly demonstrated that monthly infusions of pamidronate (90 mg) reduced skeletal complications in patients with lytic bony involvement from multiple myeloma[1] or breast cancer.[ 2] These trials also showed that chronic administration of this drug was safe and well tolerated. Previous trials involving weaker orally administered bisphosphonates such as etidronate or clodronate in these same patient populations produced variable results. By contrast, there were few supportive clinical results to suggest that any of these drugs (including intravenous pamidronate) were helpful in patients with other can-cers associated with bone metastases or for patients with osteoblastic involvement.

Recently completed placebocontrolled studies of the newer, much more potent bisphosphonate zoledronic acid (Zometa) demonstrate for the first time a clear-cut benefit of this drug given intravenously every 3 weeks in both of these groups of patients.[3,4] Thus, zoledronic acid has received widespread acceptance as the treatment for patients with metastatic bone disease regardless of the primary tumor or type of bone involvement (osteolytic, osteoblastic, or mixed).

Bone Loss Without Metastases

The recent recognition that bone loss due to hormonal manipulation therapies is a major problem among breast or prostate cancer patients without bone metastases has led to a number of clinical trials evaluating bisphosphonates in this setting. Although these trials demonstrate that intravenous bisphosphonates administered every several months to these types of patients prevent bone loss as assessed by bone densitometry, the short duration of these trials has not allowed assessment of clinical end points such as fractures. These data (as well as long-term safety data) will be important to obtain as these agents gain wider use, given their cost and potential long-term toxicities.

More intriguing is the possibility that these agents-particularly the more potent ones such as zoledronic acid- may have antitumor effects. Although these effects have been clearly shown both in vitro and in vivo in preclinical studies, clinical demonstrations have been difficult to find, except in subgroups within large trials.[1] This may be because of the heterogeneous groups of cancer patients enrolled in placebocontrolled bisphosphonate trials as well as the wide variety of other anticancer therapies these individuals were receiving, or from the inability to achieve bisphosphonate concentrations that produce antitumor effects. Newer trials are assessing higher doses of these drugs to determine whether these agents are effective as anticancer therapies.

Renal Effects

The potential deleterious renal effects of bisphosphonates need to be recognized by the treating physician. These mostly relate to the commonly shared backbone of the molecule and are related to the rate of infusion of these agents. Thus, zoledronic acid, which is clinically effective at a dose of only 4 mg, can be given safely much more rapidly (15 minutes) than weaker agents such as pamidronate (at least 120 minutes). Ramaswamy and Shapiro suggest that infusion times shorter than 2 hours (90 minutes) may be safe with prolonged use of the latter agent, but this may eventually lead to renal dysfunction.

Importantly, when pamidronate produces deleterious effects on the kidney, they are often associated with glomerular lesions and resultant albuminuria. In contrast, zoledronic acid more often leads to tubular dysfunction and, as a result, is not associated with albumin in the urine. Although renal dysfunction may result from bisphosphonate therapy, another cause is often the culprit-eg, the patient's cancer (particularly among myeloma and prostate cancer patients), other disorders, or other medications (such as nonsteroidal anti-inflammatory drugs) known to be associated with nephrotoxicity.

Future Directions

Intravenously administered bisphosphonates- especially zoledronic acid- have improved quality of life for patients with bone metastasis, but these patients continue to experience morbidity from this site of involvement. There is a growing list of potential new therapies entering clinical trials to reduce bone loss in these patients, including inhibitors of RANK-RANK-L signaling (ie, receptor activator of nuclear factor-kappa B and the kappa B ligand), parathyroid hormone-related hormone (PTHrP), and cathepsin K. Whether these new therapies will add therapeutic benefit to currently available treatments awaits the results of future clinical trials.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Berenson JR, Lichtenstein A, Porter L, etal: Long-term pamidronate treatment of advancedmyeloma reduces skeletal events. JClin Oncol 6:593-602, 1998.

2.

Hortobagyi GN, Theriault R, Porter L, etal: Efficacy of pamidronate in reducing skeletalcomplications of breast cancer and lytic bonemetastases. N Engl J Med 335:1785-91, 1996.

3.

Saad F, Gleason DM, Murray R, et al: Arandomized, placebo-controlled trial ofzoledronic acid in patients with hormone-refractorymetastatic prostate carcinoma. J NatlCancer Inst 94:1458-68, 2002.

4.

Rosen LS, Gordon D, Tchekmedyian S,et al: Zoledronic acid significantly reducesskeletal related events in patients with bonemetastases from solid tumors (abstract 1179).Proc Am Soc Clin Oncol 21:295a, 2002.