Key messages
• Giving medicines that slow down bone breakdown (bone-modifying medicines) likely helps make bones stronger and lowers the chance of fractures, but it might also lead to more unwanted effects.
• Because each treatment has its own benefits and drawbacks, it is difficult to determine which medicine is the best option.
• We need more studies where these medicines are compared directly to each other.
What is bone loss and why do people with cancer develop it?
Bone loss means that more old bone is broken down than new bone is formed, causing an imbalance. Bone-modifying medicines called bisphosphonates or denosumab can help by slowing down the breakdown of bone. Women with breast cancer are especially prone to bone loss because cancer treatments can weaken bones, making them more susceptible to fractures.
What did we want to find out?
We wanted to identify which medicines work best for reducing bone loss in women with breast cancer and if they have any unwanted effects. We wanted to know whether these medicines:
• make bones stronger ('bone density');
• improve how women feel and function in their daily lives;
• lower the chance of having fractures;
• increase how long women live; and
• have unwanted effects such as damage to the jaw bone ('osteonecrosis of the jaw') or kidney issues.
What did we do?
We looked for studies that compared different bone-modifying medicines for reducing bone loss resulting from early or locally advanced breast cancer. We compared their findings, summarised the results, and assessed how confident we were in the evidence, based on how the studies were done and how many people took part. We used statistics to compare multiple treatments against each other and rank them based on how well they worked and any unwanted effects.
What did we find?
We found 47 studies involving 35,163 people at different ages and with different stages of breast cancer. They received either bone-modifying medicines (bisphosphonates or denosumab) or placebo/no treatment, alongside cancer treatment. Cancer treatment may include chemotherapy, endocrine therapy and/or radiotherapy.
Thirty-four studies involving 33,793 people reported data that could be included in this review. These studies compared eight different bone-modifying agents to reduce bone loss.
Most bone-modifying medicines (except alendronate and pamidronate) seem to improve bone density (9 trials; 1166 people) and lower the risk of fractures (16 trials; 19,492 people).
Bone-modifying medicines do not seem to have an impact on quality of life (only three studies; no quantitative analysis).
This review suggests that these medicines might not affect survival when including both pre and postmenopausal women (17 trials; 30,991 people).
These medicines can cause more unwanted effects such as osteonecrosis of the jaw (12 trials; 23,527 people). The bisphosphonate, clodronate, and denosumab, might not affect kidney function, while ibandronate and zoledronic acid could increase the risk of kidney problems compared to no treatment or placebo (12 trials; 22,469 people).
What are the limitations of the evidence?
Overall, we are moderately confident in the evidence that one treatment is better or worse than another. Our confidence is limited because we sometimes observe conflicting results for the same treatments.
We did not have enough evidence to reach a firm conclusion on which treatments are the best. This is because not all the studies provided the information we needed, so we could not compare every treatment for each outcome.
How up-to-date is the evidence?
The evidence is up-to-date until January 2023.
When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.
Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women.
To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs).
We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.
We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases.
Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings.
Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options).
Bone mineral density
We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty).
Quality of life
No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined.
Overall fracture rate
We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty).
Overall survival
We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty).
Osteonecrosis of the jaw
We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty).
Renal impairment
We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty).