Bone metastases: Zometa to become the gold-standard treatment?

Ever since receiving FDA approval for Aredia in September 1998 Novartis has held the gold standard treatment for bone metastases. In Zometa the Swiss pharmaceutical company possesses a more potent, new generation bisphosphonate capable of taking up market leadership. But with other drugs in this class looking towards market entry nothing is certain.

Datamonitor's Bisphosphonates Update brief examines the current and potential issues surrounding the use of bisphosphonates in bone metastases of breast and prostate cancer. In recent years, the use of bisphosphonates, such as Novartis' Aredia and Zometa, has certainly addressed a significant proportion of unmet needs in the treatment of bone metastases. However, the use of bisphosphonates as preventative agents for bone metastases is controversial and their efficacy remains unproven due to conflicting clinical trial results.

Metastases to the bone, the third most common metastatic site after the lung and brain, occur in up to 75% of patients with breast and prostate cancer. For these patients, symptoms such as hypercalcemia, spinal cord compression, bone fractures and pain severely deteriorate quality of life, and the high incidence of these malignancies means that a significant number of patients are affected by bone metastases.

Maintaining market control

Aredia (pamidronate) was approved by the FDA in September 1998 based on the results of two combined prospective, placebo-controlled, randomized clinical trials of intravenous pamidronate in patients with bone metastases. The study by Hortobagyi et al. showed that fewer patients treated with pamidronate experienced skeletal complications.

Pain and analgesic use were also decreased among the pamidronate patients. On the basis of the trial results, Aredia became the gold standard treatment for bone metastases.

However, in August 2001, Zometa (zoledronate), a more potent, new generation bisphosphonate, also marketed by Novartis, was approved by the FDA for the treatment of hypercalcemia of malignancies and, in February 2002, for the treatment of bone metastases.

Research has however failed to distinguish Zometa as a superior treatment. To date, the drug has shown no statistically significant difference in bone lesion response, time to disease progression or overall survival. Trials have nevertheless reflected that 4mg zoledronate is clinically equivalent to 90mg pamidronate.

Bisphosphonates to rule

Although Novartis will be keen to show that Zometa does indeed have a clear efficacy advantage over pamidronate, the drug still holds a key advantage because of its convenience of administration; 15-minute versus two-hour iv infusion.

Other competition exists in the market however including clodronate, another of the family bisphosphonates. Clodronate remains unavailable in the US despite numerous clinical studies involving the drug for the treatment and prevention of bone metastases. The drug represents a significant opportunity for Schering AG, the marketer of clodronate in Europe, and generic companies marketing clodronate to enter the US bone metastases market

In 1981, concern was expressed in the US when three cases of leukemic reactions in patients treated with clodronate were reported. The following year, a panel of experts reviewed data from all patients receiving the drug in clinical trials, and concluded that the clinical and laboratory data did not support a causal association between treatment with clodronate and the development of leukemia.

Datamonitor believes that positive results in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study, a large-scale study designed to assess the adjuvant role of clodronate, will give Schering AG and generics companies an opportunity to gain patent and approval of clodronate in the US for adjuvant use.

Further indications

If these companies can gain approval of clodronate for this indication before Novartis can with Aredia and Zometa, they can expect a significant proportion of the adjuvant market. The availability of clodronate means that, in Datamonitor's opinion, US physicians are expected to use the drug off-label for the treatment of bone metastases, in direct competition with Novartis drugs.

Whilst clodronate is a potential threat to Novartis drug sales, the Swiss pharmaceutical company should be able to make up this revenue in other areas. Datamonitor believes, for example, that there is significant potential of bisphosphonates for the treatment of hormonal therapy-induced osteoporosis, especially in the prostate cancer market. Cost is however, expected to be a major issue in the uptake of the drugs in European markets.

According to a US opinion leader, "the osteoporosis market for prostate cancer is just beginning to open up". He stated that Novartis, Aventis and Procter & Gamble are actively targeting the market by educating urologists on ADT (androgen deprivation therapy) -induced osteoporosis and conducting large-scale clinical studies. The potential in the market, he believes, is "enormous, if not more so than the bone metastases market".

Zometa looks well set

The key to Novartis' expansion in the breast cancer market for Zometa will be the results of Z-FAST (Zometa-Femara Adjuvant Synergy Trial). Although the trial results will not be available for several years, Datamonitor expects the usage of Zometa with Femara in bone metastases to steadily move into physician prescribing due to Novartis' marketing prowess.

Bisphosphonates sell well, not only because they increase quality of life, but also because they reduce the need for irradiation and surgery by 50%, making them a very effective cost saving treatment.

Novartis' Zometa is, therefore, likely to supersede Aredia but the use of bisphosphonates in the adjuvant setting for the prevention of bone metastases remains controversial due to conflicting results in clinical trials. More studies to determine the efficacy and cost-effectiveness of adjuvant bisphosphonates are needed to gain wider acceptance

Zometa nevertheless looks set to become the gold standard for the treatment of bone metastases in breast cancer due to its clinical efficacy and the vast marketing expertise of Novartis in the oncology market.

If you found this week's Expert View useful, you may be interested in Datamonitor's reports, all available from

· Bisphosphonates Update - The Treatment and Prevention of Bone Metastases in Breast and Prostate Cancer priced $1,600
· Strategic Perspectives: Non-Hodgkin's Lymphoma - A Market Galvanized by the Advent of Innovative Therapies priced $6,400
· Multiple Myeloma Update with ASH Highlights - Increasing the Therapeutic Option priced $1,500

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