Osteoporosis: A Long-Term and Late-Effect of Breast Cancer Treatments
Round 1
Reviewer 1 Report
This is an excellent review covering one of the most common short- and long-term side effects of breast cancer therapy. The author is one of the most prominent researchers in the field. It was a pleasure to review this manuscript. All relevant aspects are covered and the structure of the text reveals not only exceptional knowledge but also excellent teaching skills. I have nothing to add and recommend publication of the manuscript in the present form.
Author Response
I thank reviewer for his/her favorable comments
Reviewer 2 Report
This article attempts to review to common problem of osteoporosis experienced by female breast cancer patients treated with hormone deprivation therapies. This is not a novel concept and for many years women experiencing bone loss as a result of their cancer treatments have been administered bisphosphonates. Furthermore, due to more recent findings that adjuvant bisphosphonates have anti-metastatic properties, increasing survival in post menopausal women, both European and US guidelines now recommend that post menopausal women receive adjuvant zoledronic acid for 3-5 years. These new updates are barely mentioned in the review. In it's current format it is unclear how this piece of work adds to current understanding or could be used to guide decision making in any way.
Specific concerns:
- The first line of the abstract is poorly constructed, please address this.
- Please add a concluding sentence to the abstract stating the purpose of this review
- Line 29 and in the corresponding figure, the author talks about the 'mechanical forces of gravity' the forces that act on bone are more complex than just gravity and also include physical exercise as well as stresses and strains due to everyday activity. These combination of mechanical forces regulate osteoblast differentiation and activity and should be discussed more widely in this section.
- Homeostatic regulation of bone remodelling is poorly described, please provide more detail in the text.
- Figure 1 and subsequent figures, should be able to be interpreted independently of the text. Please provide a description of what is happening in the figure within the legend. It is also not clear why zoledronic acid and denosumab are included in this figure as they are not discussed until much later in the manuscript, maybe this could be clarified in an updated figure legend. Also in this figure estrogens are mentioned separately to hormones (why)? As not all hormones affect bone, this label needs to be more specific.
- Throughout the manuscript authors refer to estrogen receptors as a collective, please specify differences between ER alpha and beta (these have different regulatory effects).
- Line 40 "are" is missing between receptors and located. "preserve" should be 'preserves' - please check the grammar throughout the manuscript.
- Line 47 "osteoporosis is an equation" is incorrect terminology - can say "osteoporosis can be calculated using an equation, although I think the author mean due to an imbalance in equilibrium??
- Table 1. Please provide references for the individual risk factors presented to allow readers to locate the original study.
- Line 63 "these risk factors also promote overall health" is an oxymoron, please rephrase.
- Data presented in figure 2 is 18 years old! Please provide up to date data.
- Line 83, please provide information showing how much bone loss is induced by tamoxifen in pre-menopausal women.
- When discussing AI, GnRH agonist and CIOF (lines 83-85) please provide clarity on whether these data are from pre- or post-menopausal women. Separate data form both groups would be ideal.
- Please provide a link between the osteoporosis section and oral and intravenous bisphosphonates and RANKL inhibitor section.
- Figure 5 in a copy from a book or paper and appears to serve no particular purpose? Either make an original figure which is meaningful for the text or remove.
- It is unclear why a description for the machoism of action for NBPs is given without a direct link to which of these are used as treatments for osteoporosis and/or cancer induced bone disease. Importantly, the mevalonate pathway is ubiquitous to all cells, bisphosphonates carry out their primary function in bone because they are calcium collators and bind to hydroxyapatite. During bone resorption osteoclasts take up bone bound bisphosphonates leading to high concentrations and inhibition of the mevalonate pathway in this cell type. This message of why BPs affect ostoclasts rather than all cells is completely missing.
- The description of the mechanism of action of denosumab is poor. Other RANKL inhibitors are starting to be used, these new drugs should also be mentioned.
- Authors site the half life of zoledronic acid as 188 days, it should be highlighted that this is just in the bone as half life in the blood is ~2.5 hours.
- Section 8 needs to be corrected and updated, please include the updated reference: Coleman et al. Lancet Onc. 2014. Note that in clinical trials, adding adjuvant zoledronic acid to standard of care reduced bone metastasis in both pre- and post-menopausal women. However, in post-menopausal women this treatment resulted in reduced soft tissue metastasis and increased DSF and overall survival, whereas, pre-menopausal women experience increased soft tissue metastasis and reduced DSF.
- The conclusions need to provide some insight into which patients should receive anti-resporptive therapies and which drugs should be selected.
Author Response
This article attempts to review to common problem of osteoporosis experienced by female breast cancer patients treated with hormone deprivation therapies. This is not a novel concept and for many years women experiencing bone loss as a result of their cancer treatments have been administered bisphosphonates. Furthermore, due to more recent findings that adjuvant bisphosphonates have anti-metastatic properties, increasing survival in post -menopausal women, both European and US guidelines now recommend that post- menopausal women receive adjuvant zoledronic acid for 3-5 years. These new updates are barely mentioned in the review. In it's current format it is unclear how this piece of work adds to current understanding or could be used to guide decision making in any way.
Response: I respectfully disagree with reviewer’s 2 take the on the use zoledronic acid as anti-cancer drug. The major guideline societies like the joint Cancer Ontario and ASCO, and NCCN guidelines both recommend consider the use adjuvant ZA in high-risk postmenopausal women and adjuvant endocrine therapy. Not mandate zoledronic acid use. Whereas ESMO and to lesser extent St. Gallens/Vienna are more in favor of adjuvant ZA. See point 19, section 8. There is sufficient uncertainty and several unanswered questions. Only 43% of oncologist’s routinely prescribe zoledronic acid for the anti-tumor effect.
Specific concerns:
1. The first line of the abstract is poorly constructed, please address this.
Response: This has been edited.
2. Please add a concluding sentence to the abstract stating the purpose of this review
Response: The last sentence of abstract now states the purpose of this review
3. Line 29 and in the corresponding figure, the author talks about the 'mechanical forces of gravity' the forces that act on bone are more complex than just gravity and also include physical exercise as well as stresses and strains due to everyday activity. These combination of mechanical forces regulate osteoblast differentiation and activity and should be discussed more widely in this section.
Response: This has been addressed in text
4. Homeostatic regulation of bone remodeling is poorly described, please provide more detail in the text.
Response: As this is a narrative review, and in view of the intended audience (not experts in bone metabolism), I think there is sufficient detail.
5. Figure 1 and subsequent figures, should be able to be interpreted independently of the text. Please provide a description of what is happening in the figure within the legend. It is also not clear why zoledronic acid and denosumab are included in this figure as they are not discussed until much later in the manuscript, maybe this could be clarified in an updated figure legend. Also, in this figure estrogens are mentioned separately to hormones (why)? As not all hormones affect bone, this label needs to be more specific.
Response: A figure legend that describes the Figures has been added. Estrogens are highlighted because this a breast cancer review, and estrogens are central to breast cancer. The specificity of hormones that affect bone is in text. ZA and DEN are now included in the legend
6. Throughout the manuscript authors refer to estrogen receptors as a collective, please specify differences between ER alpha and beta (these have different regulatory effects).
Response: References and text has been to section 1 that details ER alpha and beta actions
7. Line 40 "are" is missing between receptors and located. "preserve" should be 'preserves' - please check the grammar throughout the manuscript.
Response: Line 40 is corrected
8. Line 47 "osteoporosis is an equation" is incorrect terminology - can say "osteoporosis can be calculated using an equation, although I think the author mean due to an imbalance in equilibrium??
Response: The text now reads “One can think of osteoporosis as an equation.”
9. Table 1. Please provide references for the individual risk factors presented to allow readers to locate the original study.
Response: The individual risk factors are now referenced.
10. Line 63 "these risk factors also promote overall health" is an oxymoron, please rephrase
Response: The sentence has been revised to
“These lifestyle modifications also promote overall health.”
11. Data presented in figure 2 is 18 years old! Please provide up to date data.
Response: This is classic paper despite being 18 years old. Since it illustrates the point, I will keep it.
12. Line 83, please provide information showing how much bone loss is induced by tamoxifen in pre-menopausal women.
Response: The data for bone loss with tamoxifen in premenopausal women is now provided.
13. When discussing AI, GnRH agonist and CIOF (lines 83-85) please provide clarity on whether these data are from pre- or post-menopausal women. Separate data form both groups would be ideal.
Response: These data are now provided.
14. Please provide a link between the osteoporosis section and oral and intravenous bisphosphonates and RANKL inhibitor section.
Response: A one sentence link between the osteoporosis and drugs to prevent or treat osteoporosis is now inserted.
16 Figure 5 in a copy from a book or paper and appears to serve no particular purpose? Either make an original figure which is meaningful for the text or remove.
Response: Respectfully, I disagree with reviewer 2 assessment of Figure 5. This figure illustrates the major n-amino bisphosphonates in use today.
17. it is unclear why a description for the machoism of action for NBPs is given without a direct link to which of these are used as treatments for osteoporosis and/or cancer induced bone disease. Importantly, the mevalonate pathway is ubiquitous to all cells, bisphosphonates carry out their primary function in bone because they are calcium collators and bind to hydroxyapatite. During bone resorption osteoclasts take up bone bound bisphosphonates leading to high concentrations and inhibition of the mevalonate pathway in this cell type. This message of why BPs affect osteoclasts rather than all cells is completely missing.
Response: This was an oversight and I am grateful to reviewer 2 for pointing this out. The connection between the amino bisphosphonates, bone mineral matrix, and osteoclast inhibition is now clarified.
18. The description of the mechanism of action of denosumab is poor. Other RANKL inhibitors are starting to be used, these new drugs should also be mentioned.
Response: Again, this is narrative for a non-expert audience. I included references on newer RANKL inhibitors
19. Authors site the half -life of zoledronic acid as 188 days, it should be highlighted that this is just in the bone as half-life in the blood is ~2.5 hours.
Response: This has been added to the table.
20. Section 8 needs to be corrected and updated, please include the updated reference: Coleman et al. Lancet Onc. 2014. Note that in clinical trials, adding adjuvant zoledronic acid to standard of care reduced bone metastasis in both pre- and post-menopausal women. However, in post-menopausal women this treatment resulted in reduced soft tissue metastasis and increased DSF and overall survival, whereas, pre-menopausal women experience increased soft tissue metastasis and reduced DSF.
Response: The reference has been included. The statement that reduced skeletal metastases in pre and postmenopausal women is not correct. There are no data in premenopausal women that show benefit in EBCTCG meta-analysis and individual randomized trials including the reference I included. I still feel this is a controversial area, where the US societies say consider adding adjuvant ZA in high risk of relapse patients, and the European societies are more in favor. I will treatment my postmenopausal multiply node-positive, or genomically-defined high risk patients. But I don’t add adjuvant ZA to postmenopausal node-negative or low genomic risk patients.
21. The conclusions need to provide some insight into which patients should receive anti-resorptive therapies and which drugs should be selected.
Response: The conclusion now contains which patients should be selected, and which drugs selected.
Reviewer 3 Report
Structure of the discussion is somewhat difficult to follow because it jumps back and forth between osteoporosis in the general population and osteoporosis in breast cancer patients/survivors.
Numerous errors in grammar, sentence structure, missing words, and incomplete sentences.
"Anti-Osteoporosis Drugs and their Anti-Cancer Activity" section: SWOG S0307 was a "negative" trial for the comparison between 3 different bisphosphonates. It had no ability to address the question of whether bisphosphonates impact recurrence/survival since all patients received a bisphosphonate.
Author Response
Reviewer 3
- Structure of the discussion is somewhat difficult to follow because it jumps back and forth between osteoporosis in the general population and osteoporosis in breast cancer patients/survivors.
Response: It is unclear where the discussion is in this narrative review. There is no section labeled “Discussion.”
- Numerous errors in grammar, sentence structure, missing words, and incomplete sentences.
Response: I have put the paper through “Grammarly” program correcting grammar, missing words and incomplete sentences.
- "Anti-Osteoporosis Drugs and their Anti-Cancer Activity" section: SWOG S0307 was a "negative" trial for the comparison between 3 different bisphosphonates. It had no ability to address the question of whether bisphosphonates impact recurrence/survival since all patients received a bisphosphonate.
Response: SWOG S0307 has an analysis by age, 55 years and under versus greater than 55. One might expect to see less skeletal mets or increased survival in over 55 years old group.
Round 2
Reviewer 2 Report
The authors have addressed concerns and added relevant information to this review as requested.
