Two studies have provided additional evidence that use of bisphosphonates to treat osteoporosis may reduce the risk of invasive breast cancer in postmenopausal women. The results of these studies were published in the Journal of Clinical Oncology.

Bisphosphonates are a class of drugs used to prevent and treat osteoporosis and to reduce the risk of bone complications from bone metastases or multiple myeloma. Studies have suggested that in addition to their effects on bone, bisphosphonates may also have certain anticancer effects.

Two studies published in the same issue of the Journal of Clinical Oncology reported on the relationship between bisphosphonate use and risk of postmenopausal breast cancer. The first study evaluated information from more than 150,000 participants in the Women’s Health Initiative studies. http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_edn1 - [1] The studies enrolled postmenopausal women between the ages of 50 and 70.

The focus of the analysis was oral bisphosphonate use. Of the more than 150,000 study participants, 2,816 were users of oral bisphosphonates at the time of study entry. The most commonly used oral bisphosphonate was Fosamax® (alendronate).

After an average of more than seven years of follow-up, risk of invasive breast cancer was 32% lower among bisphosphonate users. A reduced risk was observed for both estrogen receptor (ER)-positive as well as ER-negative cancers, although the result for ER-negative cancers did not meet the criteria for statistical significance (suggesting that it could have occurred by chance alone). Risk of ductal carcinoma in situ (DCIS) was higher in bisphosphonate users; the researchers note that the clinical significance of this finding is uncertain.

The second study involved the Breast Cancer in Northern Israel Study. http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_edn2 - [2] The study collected information for 4,039 postmenopausal women with and without breast cancer.

The results indicated that use of bisphosphonates for more than one year reduced the risk of breast cancer by 39%. Breast cancers in bisphosphonate users were more likely to be ER-positive and less likely to be poorly differentiated.

These studies provide additional evidence that bisphosphonates may reduce the risk of invasive breast cancer. An accompanying editorial notes: “At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone protecting effects, when evaluating treatment options in women with postmenopausal osteoporosis, especially considering that bisphosphonates are generally well tolerated in this population.” http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_edn3 - [3]  

Like most drugs, bisphosphonates carry a risk of side effects. Women who are considering bisphosphonate use to manage osteoporosis are advised to talk with their doctor about the risks and benefits.

References: 

http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_ednref1 - [1] Chlebowski RT, Chen Z, Cauley JA et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. Journal of Clinical Oncology [early online publication]. June 21, 2010.

http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_ednref2 - [2] Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. Journal of Clinical Oncology [early online publication]. June 21, 2010

http://www.stlcancer.com/cancernews.aspx?section=cancernews&id=44990#_ednref3 - [3] Gnant M. Can oral bisphosphonates really reduce the risk of breast cancer in healthy women? Journal of Clinical Oncology [early online publication]. June 21, 2010

Among patients with multiple myeloma or bone metastases from breast cancer, prostate cancer, or other solid tumors, denosumab was more effective than Zometa® (zoledronic acid) at delaying or preventing bone complications such as fracture. Results from an integrated analysis of Phase III clinical trials were presented at the 35th European Society for Medical Oncology (ESMO) Congress.

Metastatic cancer refers to cancer that has spread to distant sites in the body. Several types of cancer—including breast and prostate cancer—have a tendency to spread to the bone. Bone metastases can lead to serious problems such as fracture and spinal cord compression and may require treatment with surgery or radiation therapy.

In multiple myeloma, plasma cells infiltrate the bone marrow, spreading into the cavities of all the large bones of the body. In a majority of patients with multiple myeloma, the bones develop multiple holes, referred to as osteolytic lesions, that cause the bones to be fragile and subject to fracture.

Zometa is a bisphosphonate drug that is commonly used to reduce the risk of bone complications from bone metastases or multiple myeloma. Researchers continue, however, to explore new approaches to treatment.

Denosumab is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Denosumab has been approved for the treatment of postmenopausal osteoporosis and has also shown promising results in the management of bone metastases and treatment-related bone loss.

The current analysis was based on information from three Phase III clinical trials that directly compared denosumab to Zometa among patients with bone metastases or multiple myeloma. http://stlcancer.com/cancernews.aspx?section=cancernews&id=45129#_edn1 - [1] Together, the studies enrolled more than 5,700 patients. The studies assessed the frequency and timing of bone complications such as fracture, radiation to the bone, surgery to the bone, and spinal cord compression.

• Patients treated with denosumab remained free of bone complications longer than patients treated with Zometa. Median time to first on-study bone complication was 27.7 months among patients treated with denosumab compared with 19.5 months among patients treated with Zometa.
• Overall survival and time to cancer progression were similar among patients treated with Zometa and patients treated with denosumab.
• Osteonecrosis of the jaw (an uncommon but serious side effect) occurred in 1.8% of patients treated with denosumab and 1.3% of patients treated with Zometa. This difference between study groups was not statistically significant, suggesting that it could have occurred by chance alone.

In a separate analysis of the Phase III clinical trials, researchers reported that denosumab delayed the worsening of pain to a greater extent than Zometa. http://stlcancer.com/cancernews.aspx?section=cancernews&id=45129#_edn2 - [2]

These results suggest that denosumab may be more effective than Zometa at delaying or preventing skeletal complications in patients with bone metastases or multiple myeloma.

References

http://stlcancer.com/cancernews.aspx?section=cancernews&id=45129#_ednref1 - [1] Lipton A, Siena S, Rader M et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials. Presented at the 35th European Society for Medical Oncology (ESMO) Congress, Milan, Italy, October 8-12, 2010. Abstract 1249P.

http://stlcancer.com/cancernews.aspx?section=cancernews&id=45129#_ednref2 - [2] Cleeland CS, Patrick DL, Fallowfield L et al. Effects of denosumab vs zoledronic acid (ZA) on pain in patients (pts) with advanced cancer and bone metastases: An integrated analysis of 3 pivotal trials. Presented at the 35th European Society for Medical Oncology (ESMO) Congress, Milan, Italy, October 8-12, 2010. Abstract 1248P.

SAN ANTONIO (EGMN) – In sharp contrast with previous findings, zoledronic acid failed to improve disease-free survival when added to adjuvant chemotherapy for women with stage II/III breast cancer in a highly anticipated phase III trial.

“In terms of primary analysis and primary end point, this is a negative trial,” Dr. Robert Coleman said during a press briefing on Dec. 8 at the annual San Antonio Breast Cancer Symposium. “It is highly unlikely that this conclusion will change with further follow-up.”

The Endocrine Society's 93rd Annual Meeting was the site of a presentation on June 6, 2011 of the finding of Richard Bockman, PhD and his associates at Hospital for Special Surgery of a better response to treatment with bisphosphonate drugs among women whose vitamin D levels were higher than the range of 20 to 30 nanograms per milliliter considered adequate by the Institute of Medicine (IOM).

The current study included 160 women with osteoporosis who had been using alendronate, residronate, ibandronate or zolendronate for 18 months or more and who had received two or more bone mineral density scans separated by 18 months to 5 years. Eighty-nine of the participants were classified as responders to bisphosphonates, and 71 were nonresponders, which included 42 women with low bone mineral density, 17 who experienced a fracture, and 12 having a persistently low T-score. "The way the data are expressed for a bone density is how many standard deviations are you away from the normal," Dr Bockman explained. "One standard deviation from the normal is a T score of one. Two standard deviations is a T score of two. Below the normal, it is a minus two and above the normal is a plus two. If your bone density is more than 2.5 standard deviations below the normal, that defines a low bone mass that is considered to be osteoporosis."

The researchers found that bisphosphonate responders were likelier than nonresponders to have a 25-hydroxyvitamin D level of 33 nanograms per milliliter or higher. Eighty-three percent of those whose vitamin D levels were lowest at less than 20 nanograms per milliliters were nonresponders to bisphosphonates, compared to 24.6 percent of those whose levels were highest at 40 nanograms per milliliter or more. "You are seven times more likely to respond to bisphosphonates if your 25-hydroxyvitamin D level is 33 nanograms/milliliter and above," stated Dr Bockman, who is a professor of medicine at Weill Cornell Medical College. "If you want to see a particular outcome from this treatment, then maybe 20 to 30 is not appropriate. When you see a seven times greater effect, that is pretty impressive."

http://www.lef.org/newsletter/2011/0610_Higher-Vitamin-D-Levels-Improve-Osteoporosis-Drug-Response.htm?source=eNewsLetter2011Wk23-2&key=Article&l=0#article - http://www.lef.org/newsletter/2011/0610_Higher-Vitamin-D-Levels-Improve-Osteoporosis-Drug-Response.htm?source=eNewsLetter2011Wk23-2&key=Article&l=0#article

San Antonio (EGMN) - While treatment with the clodronate does not appear to affect disease-free survival among women with stages I-III breast cancer, the drug does appear to improve certain outcomes for women aged 50 years and older, according to the results of a phase III trial of more than 3,000 patients.

Disease-free survival (DFS) did not differ between women treated with clodronate and those given placebo (hazard ratio, 0.91; P = .27). However, women at least 50 years of age saw benefits in secondary protocol predefined end points, Dr. Alexander H.G. Paterson said at the San Antonio Breast Cancer Symposium.

"This is an easy treatment and it's oral. It seems to have an effect in older women and low toxicity. We've now got four trials [pointing in] the same direction ... that is of a benefit in older patients," said Dr. Paterson, a professor in the departments of medicine and oncology at the University of Calgary in Canada.

In the double-blind, phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 clinical trial, patients with stage I-III breast cancer were randomized to receive oral clodronate 1,600 mg daily for 3 years or placebo, given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy.

The groups were stratified by age (younger than 50 years or at least 50 years), number of positive nodes and estrogen receptor/progesterone receptor (ER/PR) status. The primary end point was disease-free survival, which was defined to include all recurrences, deaths, and second primary cancers. Secondary end points are the incidence of skeletal metastases, overall survival, recurrence-free interval, bone metastasis-free interval, and nonbone metastasis-free interval.

The researchers reported on 3,311 patients (1,656 on placebo and 1,655 on clodronate) with a median of 8 years in the study. Of note, almost two-thirds of patients (64%) were at least 50 years old at the time of enrollment. Three-quarters had pathologically-negative axillary nodes and almost a quarter (22%) had ER-negative or PR-negative breast cancer.

"Compliance was an issue. The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy," said Dr. Paterson. A total of 40% of patients did not complete 3 years of study therapy.

Patients on clodronate had a slightly lower rate of treatment failure at distant sites (5.4% vs. 6.6%). The researchers suspect that the disease-free survival benefit was attenuated due to the equivalent event rates for second primary cancers, contralateral cancers and local/regional relapses.

Overall toxicity was low and comparable for the two groups. There was one case of osteonecrosis of the jaw in the clodronate group.

However, clodronate showed benefit regarding distant metastases in all protocol predefined secondary end points. Hazard reductions ranged from 15% for overall survival to 26% for nonbone metastasis-free interval.

Dr. Paterson noted that secondary protocol predefined end point reductions were even greater among women at least 50 years of age. For these women, there was a 24% reduction in breast cancer recurrence-free interval (P = .05), a 39% reduction in bone metastasis-free interval (P = .024), and a 37% reduction in nonbone metastasis-free interval (P = .015). In addition, women 50 years and older had a 20% reduction in overall survival, though this was not statistically significant (P = 0.1).

"Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates," he said.

Bisphosponates are thought to inhibit the growth of bone metastases by inhibiting osteoclast function and subsequent bone turnover. However, the role of bisphosphonates in preventing or delaying the development of bone (or other) metastases in patients with early breast cancer remains unclear.

The trial received support from the National Cancer Institute and Bayer Schering Pharma Oy. Dr. Paterson disclosed that he is a consultant for GlaxoSmithKline, Amgen, Roche Diagnostics, and Nicomed.

http://www.oncologystat.com/news/Clodronate_Offered_Modest_Benefit_for_Breast_Cancer_Patients_US.html - http://www.oncologystat.com/news/Clodronate_Offered_Modest_Benefit_for_Breast_Cancer_Patients_US.html