Decreased risk of breast cancer associated with oral bisphosphonate therapy

Figures & data

Figure 1 Potential confounding role of low bone mineral density in the relationship between bisphosphonate use and breast cancer incidence.

Notes: Low bone mineral density could result in bisphosphonate use. It is also known that low bone mineral density is associated with a decreased incidence of breast cancer. Therefore, the relationship between bisphosphonate use and breast cancer risk could be influenced by confounding with low bone mineral density.

Table 1 Types of bisphosphonates

Types	Non-nitrogenous bisphosphonates	Nitrogenous bisphosphonates
Mechanism of action	After uptake into osteoclasts, the drug metabolizes to hydrolysis-resistant analogs of ATP and leads to apoptosis	After uptake into osteoclasts, the drug inhibits mevalonate pathway in cholesterol synthesis (important for cell growth signaling) thereby resulting in apoptosis
Examples	Clodronate, Etidronate	Alendronate, risedronate, pamidronate, zoledronate
Administration	Clodronate – po and iv (not available in US) Etidronate – po	Alendronate – po Risedronate – po Pamidronate and zoledronate – iv

Abbreviations: ATP, adenosine triphosphate; po, by mouth; iv, intravenous.

Table 2 Indications for bisphosphonate use

Treatment of osteoporosis

Treatment of hypercalcemia

Prevention of skeletal-related events in bone metastasis

Prevention of chemotherapy-induced bone loss

Table 3 Possible mechanisms for the antitumor effects of bisphosphonates

Inhibit cancer cell adhesion to extracellular matrix proteins

Inhibit cancer cell proliferation and induce apoptosis

Inhibit cancer cell migration and invasion

Inhibit angiogenesis

Table 4 Observational studies on oral bisphosphonate use in decreasing breast cancer risk

Study and location	Population	Conclusions	Comments
Newcomb et al^Citation26 USA	2936 breast cancer patients and 2975 population controls	OR:a 0.67 (95% CI: 0.51–0.89)	• Case-control study design. • Interview-based, hence, more risk for recall bias. • Significant dose-response relationship was identified with increasing use of the drug (P-trend = 0.01). • Unable to adjust for low BMD.
Rennert et al^Citation27 Israel	1832 patients with postmenopausal breast cancer and 2207 age-, clinic-, ethnicity-matched controls	OR:b 0.80 (95% CI: 0.65–0.99)	• Case-control study design • Drug use was assessed from pharmacy database, hence, more reliable. However, other variables are still prone for recall bias. • Drug use for less than 1 year had no association with breast cancer incidence. • Compliance with daily use was 72% and with weekly use was 88%. • Unable to adjust for low BMD.
Chlebowski et al^Citation31 USA	154,768 participants of the Women’s Health Initiative cohort	HR:c 0.68 (95% CI: 0.52–0.88)	• Nested case-control design within a cohort of postmenopausal women. • Data were prospectively collected. Hence, recall bias is minimized. However, drug use was ascertained by questionnaire methods. • Nearly 5156 women were diagnosed with breast cancer of whom 1120 were diagnosed with DCIS. • Used a surrogate marker for BMD – 5-year hip fracture risk score. There still might have been some significant residual confounding with low BMD. • Study found an increased risk for DCIS in drug users.
Cardwell et al^Citation33 UK	41,826 bisphosphonate users and 41,826 age-, sex- and practice-matched controls	HR:d 0.75; (95% CI: 0.63–0.89)	• Nested case-control design within the General Practice Research Database that includes nearly 6% of the UK population. • Most of the data were prospectively collected. However, drug use was ascertained from prescriptions. • Cancers were ascertained from diagnostic codes in patient files and not from cancer registries. • Other exposure variables such as smoking status, BMI, and alcohol use were ascertained from diagnostic codes and chart review – all subject to inaccuracies. • An exploratory analysis was conducted to adjust for confounding with low BMD. However, sample size for the analysis is small, at 25 in each group. Therefore, residual confounding might have influenced the results.

Notes:

a Adjusted for age at first birth, family history of breast cancer, body mass index, menopausal status, age at menopause, diagnosis of osteoporosis, smoking, and number of mammograms;

b analysis was done for any bisphosphonate use. Similar results were obtained when analysis was done for bisphosphonate use > 1 year. However, no statistically significant association was observed in patients with <1 year of bisphosphonate use. Adjusted for age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnicity, body mass index, use of calcium, hormone replacement therapy, number of pregnancies, months of breast-feeding, and age at first pregnancy;

c adjusted for age, ethnicity, smoking, alcohol use, physical activity, body mass index, mammogram in last 2 years, prior hormone replacement therapy or oral contraceptive use, calcium and vitamin D levels, 5-year hip fracture risk score, and Gail breast cancer risk score;

d adjusted for potential risk and confounding factors such as body mass index, smoking, alcohol use, and nonsteroidal anti-inflammatory drug or steroid use of calcium and vitamin D, and hormone replacement therapy use.

Abbreviations: OR, odds ratio; CI, confidence interval; BMD, bone mineral density; HR, hazard ratio; DCIS, ductal carcinoma in situ; BMI, body mass index.

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