Commentary (Lipton): The Multidisciplinary Approach to Bone Metastases

The most common malignant tumors frequently metastasize to the skeleton. Although bone metastases occur frequently with nearly all tumors, some cancers (eg, breast and prostate cancer) have a special predilection for the skeleton. Complications associated with skeletal metastases substantially erode the patient's quality of life. These skeletal-related events (SREs) include spinal cord compression, fracture, surgery, radiation therapy, and hypercalcemia. On average, patients with bone metastases experience three to four SREs per year (one every 3 to 4 months). In addition, they frequently have pain and require narcotics, which erode their quality of life.

Cancers cause two distinct (but overlapping) types of skeletal lesions on x-ray. Most common is the destructive osteolytic lesion seen in patients with multiple myeloma and renal cell cancer. Tumor products affect the normal remodeling sequence, and there is an increase in osteoclast activity. The secondary osteoblast response seen in normal bone remodeling is impaired, so that the lesion is predominantly osteolytic.

Less common is the predominantly osteoblastic response seen most often in prostate cancer. Recent studies suggest that this is associated with significant osteolytic activity, but at the time of clinical detection, the blastic lesions predominate on x-ray. Finally, mixed osteolytic/osteoblastic lesions are seen in many patients with metastatic breast cancer.

Treatment of Bone Metastases

In the late 1960s, Fleisch et al described the potent effects of bisphos- phonates on bone, inhibition of osteoclast activity, binding to calcium and hydroxyapatite, and inhibition of bone resorption.[1] The development of bisphosphonates has followed a generational path-etidronate (Didronel) and clodronate, the first-generation non- amino-containing agents followed by the nitrogen-containing agents characterized by pamidronate (Aredia) and the more chemically complex agents such as zoledronate (Zabel, Zometa), which has a heterocyclic side chain containing two nitrogens.

The potency of bisphosphonates has been assessed by their relative ability to inhibit osteoclast function. A ranking of anti-osteoclast activity indicates zoledronate is more potent than pamidronate, which is more potent than clodronate or etidronate. Bisphosphonates are poorly absorbed when administered orally and are associated with gastrointestinal side effects including esophageal reflux and/or ulceration.

The article by Dr. Blum and colleagues provides an excellent overview of the role of bisphosphonates in the treatment of skeletal metastases. Bisphosphonates have become the mainstay of treatment of hypercalcemia and bone metastases, with SREs reduced by 30% to 50% in multiple myeloma, breast cancer, prostate cancer, and other solid tumors.

Unanswered Questions About Bisphosphonates

The oral bisphosphonate clodronate is employed by many physicians in Canada and Western Europe. The question of the relative efficacy of an oral agent like clodronate compared with intravenous pamidronate or zoledronate remains unanswered. No prospective data are available to compare clodronate with pamidronate or zoledronate using SREs as an end point.

Many questions also remain regarding optimal bisphosphonate therapy. The first is: Do all patients respond equally, or do some patients derive little benefit? (The percentage of patients who experienced an SRE decreased from 56% on placebo to 44% on zoledronate in the breast cancer trial.) What is the optimal timing for the administration of a bisphosphonate? (The maximum effect of pamidronate's inhibition of bone resorption occurs 14 days after treatment.)

Would more frequent administration of a bisphosphonate be more advantageous? Would higher doses of zoledronate result in a greater clinical benefit? (Data from a phase I trial of zoledronate suggested increased inhibition of bone-resorption markers with the use of 8 and 16 mg of this new potent agent.) Would these high doses administered over a longer period of time result in a greater decrease in the incidence of SREs and less renal toxicity?

Can the markers of bone resorption (eg, serum or urine N-telopeptide) be used to guide the initiation and stopping of bisphosphonate therapy? When should treatment with a bisphosphonate be stopped? (All the randomized trials stopped treatment at approximately 2 years, and patients were not followed for SREs after discontinuation of bisphosphonate therapy.) Finally, little prospective data exist on the cost-effectiveness of bisphosphonate therapy.

Bisphosphonates as Adjuvant Therapy

Three studies have been reported on the use of clodronate for the prevention of bone metastases in patients with early-stage breast carcinoma at high risk of developing recurrent disease.[ 2-4] Two studies suggest that adjuvant therapy with clodronate decreases the number of patients who develop skeletal metastases. Contrary results were reported in a third study. In that study, more patients who received clodronate developed bone metastases (21% vs 17%; P = NS), but the incidence of visceral metastases (37% vs 22%; P = .008) was higher with clodronate, and there were more deaths (42 vs 24 patients; P = .01). The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant clodronate trial are eagerly awaited, as are the results of adjuvant trials of zoledronate.

The Future

Studies conducted over the past 20 years have established bisphosphonates as the treatment of choice for hypercalcemia and bone metastases. Skeletal complications have been reported to have decreased by 30% to 50%. Nevertheless, there remains much room for improvement. The impact on time to progression of skel- etal metastases has been slight and on overall survival, nonexistent.

The future is bright, with many new classes of agents on the horizon and the methodology established for performing clinical trials in these patients. New classes of drugs that inhibit osteoclast activity are being tested. These include anti-osteoclast agents (nonbisphosphonates) such as osteoprotegerin (OPG) or an antibody to OPG ligand, antibody to parathyroid hormone-related protein, Src tyrosine kinase pathway inhibitors, vacuolar proton ATPases, p38 MAPKinase inhibitors, prostaglandin E2 inhibitors, calcitonin-receptor blockers, and inhibitors of osteoclast cathepsin K.

The challenge is to learn how to integrate these new agents with bisphosphonate therapy. It is likely that, in the future, bone metastases will be treated with the combination of a bis- phosphonate plus one or more of these new agents. Better palliation and, hopefully, prevention of bone metastases may soon be achieved.

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.

Fleisch H, Russell RGG, Francis MD:Diphosphonates inhibit hydroxyapatite dissolutionin vitro and bone resorption in tissue cultureand in vivo. Science 165:1262-1264, 1969.

2.

Diel IJ, Solomayer EF, Costa SD, et al:Reduction in new metastases in breast cancerwith adjuvant clodronate treatment. N Engl JMed 339:357-363, 1998.

3.

Powles T, Paterson S, Kanis JA, et al:Randomized, placebo-controlled trial of clodronatein patients with primary operable breastcancer. J Clin Oncol 20:3219-3224, 2002.

4.

Saarto T, Blomqvist C, Virkkunen P, etal: Adjuvant clodronate treatment does not reducethe frequency of skeletal metastases innode-positive breast cancer patients: 5-year resultsof randomized clinical trial. J Clin Oncol19:10-17, 2001.