Individualized Management of Osteoarthritis: The Role of Pharmacogenomics to Optimize Pain Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

• Abstract: The sentence “In the absence of Disease Modifying Antirheumatic Drugs (DMARs) for OA, current treatment strategies largely focus on symptom relief rather than disease modification and often fail to account for the substantial inter-individual variability in drug response.” is too long and not clear. Please rephrase and divide.
• I recommend replacing the “Clinical pharmacology” subtitles with “Pharmacokinetics” as it is more accurate for describing the metabolism, elimination half-lives and drug dosing.
• I recommend to add 2-3 illustrating graphs to summarize some parts of the review such as the mechanism of actions. This will enrich the review and make it more interesting for readers.
• While the potential of PGx is well-articulated, the review could briefly touch upon the current barriers to widespread PGx implementation in OA management (e.g., cost of testing, clinician education, integration into electronic health records, turn-around time for results, and the need for more OA-specific PGx studies).
• The abstract mentions "While PGx data is not currently embedded in OA clinical treatment guidelines...". It might be beneficial to reiterate in the conclusion that a key future step is the integration of robust PGx evidence into OA-specific treatment guidelines.
• Ensure all abbreviations are defined at first use (e.g., ADR, ACR, CPIC, QoL are well-handled).
• Line 126: "Beyond a therapeutic dose, APAP is mostly converted..." This sentence structure is a bit confusing. It likely means "At therapeutic doses (less than 4 grams daily), APAP is mostly converted to..." or "When APAP doses exceed the therapeutic range (e.g., >4 grams daily), the proportion metabolized via CYP enzymes to NAPQI increases as glucuronidation and sulfation pathways become saturated." The subsequent sentences clarify, but this initial one could be rephrased.
• The abstract might imply a similar level of CPIC-guided actionability to the rest of review. Perhaps slightly rephrasing in the abstract, e.g., "...actionable genetic variants like CYP2D6 and CYP2C9, and important metabolizing genes such as CYP2E1 and UGT1A6."
• Page 5, lines 195-197: "Patients who are rapid metabolizers or ultra-rapid metabolizers of CYP2E1 (i.e., higher transcriptional activity) may be at higher risk for APAP toxicity..." This is a plausible hypothesis. However, the next sentence rightly states, "Nonetheless, there is limited data to substantiate the effect of CY2E1 phenotype on drug-induced liver injury." Given the limited direct evidence for phenotype-based risk stratification for APAP via CYP2E1 (as opposed to known induction by alcohol/isoniazid), the initial statement could be slightly softened or more explicitly framed as a potential concern requiring further research.

 

Author Response

• Abstract: The sentence “In the absence of Disease Modifying Antirheumatic Drugs (DMARs) for OA, current treatment strategies largely focus on symptom relief rather than disease modification and often fail to account for the substantial inter-individual variability in drug response.” is too long and not clear. Please rephrase and divide.
• I appreciate the detailed responses and suggestions. I have divided this statement into two sentences for better clarity and readability. Please see lines 11-14 for changes.
• I recommend replacing the “Clinical pharmacology” subtitles with “Pharmacokinetics” as it is more accurate for describing the metabolism, elimination half-lives and drug dosing.
• Thank you for your suggestion, we agree that pharmacokinetics is an appropriate title for the section; however, additional information has been presented in the section that goes above and beyond just pharmacokinetics. We believe that clinical pharmacology is a more representative title for these sections for that reason.
• I recommend adding 2-3 illustrating graphs to summarize some parts of the review such as the mechanism of actions. This will enrich the review and make it more interesting for readers.
• Thank you for the suggestion. We agree that visuals can make the paper more interesting and visually appealing; however, we believe that a reference summary table, such as Table 1, could serve the article more effectively and facilitate our goal of writing the paper to serve as guidance for clinicians managing patients with OA.
• While the potential of PGx is well-articulated, the review could briefly touch upon the current barriers to widespread PGx implementation in OA management (e.g., cost of testing, clinician education, integration into electronic health records, turn-around time for results, and the need for more OA-specific PGx studies).
• Thank you for the thoughtful idea. It is easy to lose sight of this, as it is very important to think about the practicality of PGx testing. Please see section 3 on page 15 for challenges and opportunities.
• The abstract mentions "While PGx data is not currently embedded in OA clinical treatment guidelines...". It might be beneficial to reiterate in the conclusion that a key future step is the integration of robust PGx evidence into OA-specific treatment guidelines.
• Thank you, this suggestion is valuable and will enhance the overall conclusion of the paper. Please see the updated conclusion starting on page 16 for the inclusion of your comment.
• Ensure all abbreviations are defined at first use (e.g., ADR, ACR, CPIC, QoL are well-handled).
• Thank you for the thorough review of the manuscript. We ensured every abbreviation is now defined when first mentioned.
• Line 126: "Beyond a therapeutic dose, APAP is mostly converted..." This sentence structure is a bit confusing. It likely means "At therapeutic doses (less than 4 grams daily), APAP is mostly converted to..." or "When APAP doses exceed the therapeutic range (e.g., >4 grams daily), the proportion metabolized via CYP enzymes to NAPQI increases as glucuronidation and sulfation pathways become saturated." The subsequent sentences clarify, but this initial one could be rephrased.
• Thank you for this level of detail. I agree that the sentence was confusing and slightly inaccurate. This section has been updated to say “at” rather than “beyond”. I hope you find this clearer now that edits have been made.  Please see lines 132, 138-140 for this correction.
• The abstract might imply a similar level of CPIC-guided actionability to the rest of review. Perhaps slightly rephrasing in the abstract, e.g., "...actionable genetic variants like CYP2D6 and CYP2C9, and important metabolizing genes such as CYP2E1 and UGT1A6."
• Thank you, please see line 21 for the changed phrasing.
• Page 5, lines 195-197: "Patients who are rapid metabolizers or ultra-rapid metabolizers of CYP2E1 (i.e., higher transcriptional activity) may be at higher risk for APAP toxicity..." This is a plausible hypothesis. However, the next sentence rightly states, "Nonetheless, there is limited data to substantiate the effect of CY2E1 phenotype on drug-induced liver injury." Given the limited direct evidence for phenotype-based risk stratification for APAP via CYP2E1 (as opposed to known induction by alcohol/isoniazid), the initial statement could be slightly softened or more explicitly framed as a potential concern requiring further research.
• Great point, we appreciate the feedback on this. We agree that the statement could be softened slightly. Please see lines 211-212 for edits.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript titled "Individualized Management of Osteoarthritis: The Role of Pharmacogenomics to Optimize Pain Therapy" offers a timely and in-depth review of how pharmacogenomic insights can enhance pharmacological treatment of osteoarthritis (OA)-related pain. The authors provide a detailed, well-structured analysis that aligns with the growing emphasis on personalized medicine. However, several aspects could be improved to enhance clarity, consistency, and completeness:

Major Suggestions:

1. Define All Abbreviations Upon First Use:
   Abbreviations such as NSAIDs (line 17), COX (line 93), GG (line 292), GI (line 304), SNRI and SSRI (line 349), 5-HT (line 364), HTR2A and SLC6A4 (line 383), CrCl (line 523), and WOMAC (line 560) should be spelled out at first mention to ensure clarity for all readers.
2. Expand Abbreviations in Table 1:
   Include the full definitions of dosing frequency abbreviations (e.g., QID = four times daily, BID = twice daily, TID = three times daily, QD = once daily) and clarify that OAT1/3 refers to organic anion transporters.
3. Avoid Redundant Definitions and Ensure Consistency:
   Delete repeated full terms for abbreviations (e.g., "nonsteroidal anti-inflammatory drugs" in lines 97 and 213, "cyclooxygenase enzyme" in line 236, and "osteoarthritis" in line 550). Also, standardize terminology—e.g., use CYP450 instead of "cytochrome P450 (CYP)" on line 250.
4. Correct Formatting Issues:
   Ensure uniformity in font and font size throughout the text, particularly in lines 69–70, 80–81, and 195–197, where inconsistencies were noted.
5. Reference Formatting in Tables:
   Replace informal in-text citations in Tables 2 and 3 ("Theken et al., 2020" and "Crews et al., 2021") with proper numbered references (37 and 72, respectively) to maintain consistency with the rest of the manuscript.
6. Clarify Medical Terminology (INR):
   In line 183, define INR (International Normalized Ratio) and briefly explain its relationship with warfarin’s anticoagulant effect to provide context for the subsequent discussion.
7. Revise Misclassified Items in Table 1:
   The following entries under “major metabolizing enzymes” are not enzymes and should be removed or reclassified:

        Flurbiprofen: list enterohepatic circulation under a separate column.

        Ketoprofen, Etodolac: move hydroxylation & glucuronidation to a new column titled "       Metabolism Pathways."

        Nabumetone, Sulindac, Ketorolac: similarly, adjust placement of glucuronidation and enterohepatic circulation to avoid misclassification.

       8. Include a Comparative Summary Table:
Consider adding a new table summarizing pharmacogenomic implications, key enzymes, common variants, and clinical recommendations for each discussed drug. This would be especially useful for clinicians seeking a quick-reference guide.

       9. Clarify Future Perspectives Section:
The section discussing emerging therapies (e.g., Botulinum Toxin A and Resiniferatoxin) is informative but could benefit from clearer integration with the manuscript's central theme of pharmacogenomics. For example, consider discussing how PGx might influence responses to these novel treatments or how future trials might incorporate genetic stratification.

Conclusion:

This manuscript is a valuable and timely contribution to the literature on OA pain management and precision medicine. Addressing the points above will enhance its clarity, consistency, and practical applicability. With these minor revisions, the manuscript will be well-suited for publication.

Recommendation: Accept after Minor Revisions

Author Response

The manuscript titled "Individualized Management of Osteoarthritis: The Role of Pharmacogenomics to Optimize Pain Therapy" offers a timely and in-depth review of how pharmacogenomic insights can enhance pharmacological treatment of osteoarthritis (OA)-related pain. The authors provide a detailed, well-structured analysis that aligns with the growing emphasis on personalized medicine. However, several aspects could be improved to enhance clarity, consistency, and completeness:

Major Suggestions:

• Define All Abbreviations Upon First Use:
  Abbreviations such as NSAIDs (line 17), COX (line 93), GG (line 292), GI (line 304), SNRI and SSRI (line 349), 5-HT (line 364), HTR2A and SLC6A4 (line 383), CrCl (line 523), and WOMAC (line 560) should be spelled out at first mention to ensure clarity for all readers.
• Great detailed observation, thank you, we appreciate the time and effort it took to identify these suggestions. We have updated accordingly throughout the paper. Of note, GG is the name of the genotype, HTR2A is the name of a gene, as well as SLC6A4, not an abbreviation. Thank you. All other abbreviations have been updated.
1. Updated line numbers for your reference: NSAIDs (line 17), COX (line 100, GI (line 320), SNRI and SSRI (line 366-367), 5-HT (line 382),  CrCl (line 543), and WOMAC (line 605)
• Expand Abbreviations in Table 1:
  Include the full definitions of dosing frequency abbreviations (e.g., QID = four times daily, BID = twice daily, TID = three times daily, QD = once daily) and clarify that OAT1/3 refers to organic anion transporters.
• Thank you. We have added definitions for the abbreviations below the table. We hope that adds additional clarification. See table 1 starting on line 274.
• Avoid Redundant Definitions and Ensure Consistency:
  Delete repeated full terms for abbreviations (e.g., "nonsteroidal anti-inflammatory drugs" in lines 97 and 213, "cyclooxygenase enzyme" in line 236, and "osteoarthritis" in line 550). Also, standardize terminology—e.g., use CYP450 instead of "cytochrome P450 (CYP)" on line 250.
• Thank you for the detailed feedback. The entire paper has been reviewed and updated to not include duplicative full terms after abbreviations have been defined. All are highlighted in yellow (line 233, 240, 241, 242, 595)
• Correct Formatting Issues:
  Ensure uniformity in font and font size throughout the text, particularly in lines 69–70, 80–81, and 195–197, where inconsistencies were noted.
• Thank you for the observation. All font sizes and font types have been updated for consistent sizing and font type.
• Reference Formatting in Tables:
  Replace informal in-text citations in Tables 2 and 3 ("Theken et al., 2020" and "Crews et al., 2021") with proper numbered references (37 and 72, respectively) to maintain consistency with the rest of the manuscript.
• Thank you for the comment. Tables 3 and 4 have been updated to be consistently cited. See page 9 line 315 and page 13 line 521.
• Clarify Medical Terminology (INR):
  In line 183, define INR (International Normalized Ratio) and briefly explain its relationship with warfarin’s anticoagulant effect to provide context for the subsequent discussion.
• Thank you for the suggestion. Please see page 5 for added lines 194-199 to better define and expand upon INR.
• Revise Misclassified Items in Table 1:
  The following entries under “major metabolizing enzymes” are not enzymes and should be removed or reclassified:

        Flurbiprofen: list enterohepatic circulation under a separate column.

 Ketoprofen, Etodolac: move hydroxylation & glucuronidation to a new column titled "       Metabolism Pathways."

    Nabumetone, Sulindac, Ketorolac: similarly, adjust placement of glucuronidation and enterohepatic circulation to avoid misclassification.

• Thank you for your observation. I appreciate the thorough review. Table 2 has been updated to state “major metabolic pathway” and “minor metabolic pathway”. This has allowed us to keep all metabolic pathways in the same column and eliminate the need for a new column.

• Include a Comparative Summary Table:
  Consider adding a new table summarizing pharmacogenomic implications, key enzymes, common variants, and clinical recommendations for each discussed drug. This would be especially useful for clinicians seeking a quick-reference guide.
  • Thank you for the suggestion. We agree this will add to the paper and serve as a quick reference guide. Please see Table 1 for this addition.

9. Clarify Future Perspectives Section:
   The section discussing emerging therapies (e.g., Botulinum Toxin A and Resiniferatoxin) is informative but could benefit from clearer integration with the manuscript's central theme of pharmacogenomics. For example, consider discussing how PGx might influence responses to these novel treatments or how future trials might incorporate genetic stratification.

• Thank you for the thoughtful idea. We agree this section could have been more well-rounded. Please see the additional paragraph starting on line 610 for additional content. Also, please review the newly added section “Challenges and Opportunities”. We believe this section touches on the comments the reviewer raised.

Conclusion:

This manuscript is a valuable and timely contribution to the literature on OA pain management and precision medicine. Addressing the points above will enhance its clarity, consistency, and practical applicability. With these minor revisions, the manuscript will be well-suited for publication.

Recommendation: Accept after Minor Revisions

• We thank the reviewer for their meticulous review of the manuscript and thoughtful suggestions provided. We believe the manuscript greatly benefited from this reviewer’s comments.

Reviewer 3 Report

Comments and Suggestions for Authors

So far, pharmacogenetic (PG) data is not currently embedded in osteoarthritis (OA) clinical treatment. In this review the authors describe the potential modification by PGs of the presently used drugs by genetic variants of metabolizing enzymes such as CYP2D6, CYP2C9, 20 CYP2E1, and UGT1A6. For the currently used drugs the involvement of these Phase I and Phase II enzymes in their metabolism is described including the clinical consequences of genetically determined differences in their activity. Finally, the current clinical studies on long lasting pain relief of Botulinum Toxin A and Resiniferatoxin, as well as the angiopoistin-like 3 signaling pathway to regenerate and preserve cartilage are addressed.

Overall, the manuscript reviews existing knowledge and does not provide new information. It is an excellent chapter for a textbook of pharmacology or clinical pharmacology, rather than a research paper.

Minor point:

In case of acetaminophen it should be clearly stated that hepatotoxicity occures when both glucuronidation and sulfation are overwhelmed at high doses.

Author Response

So far, pharmacogenetic (PG) data is not currently embedded in osteoarthritis (OA) clinical treatment. In this review the authors describe the potential modification by PGs of the presently used drugs by genetic variants of metabolizing enzymes such as CYP2D6, CYP2C9, 20 CYP2E1, and UGT1A6. For the currently used drugs the involvement of these Phase I and Phase II enzymes in their metabolism is described including the clinical consequences of genetically determined differences in their activity. Finally, the current clinical studies on long lasting pain relief of Botulinum Toxin A and Resiniferatoxin, as well as the angiopoistin-like 3 signaling pathway to regenerate and preserve cartilage are addressed.

Overall, the manuscript reviews existing knowledge and does not provide new information. It is an excellent chapter for a textbook of pharmacology or clinical pharmacology, rather than a research paper.

• Thank you so much for your review and comments. We appreciate your dedication and time. This paper aims to serve as a clinician resource and comprehensive review rather than a research paper. To our knowledge, no such comprehensive review exists that specifically would serve as a resource for the treatment of OA utilizing PGx. For that reason, we do feel the paper is worthy of publication and to be used as a clinical guide for implementing PGx into OA treatment.

Minor point:

In case of acetaminophen it should be clearly stated that hepatotoxicity occures when both glucuronidation and sulfation are overwhelmed at high doses.

• Great additional detail to add. Thank you for your thorough review. See page 4 for additional lines 155-157 regarding saturation of sulfation and glucuronidation.

Reviewer 4 Report

Comments and Suggestions for Authors

I have read with interest the manuscript titled “Individualized Management of Osteoarthritis: The Role of Pharmacogenomics to Optimize Pain Therapy” by Isabella M. Sturgeon et al., and I hereby inform you that I accept it for publication in future pharmacology, albeit after a number of revisions, which I classify as major.

The role of pharmacogenomics is a very modern, important, and consequently, highly interesting approach in the field of pain therapy optimization. As the authors themselves point out, it offers a promising direction in the personalization of OA treatment.

The manuscript is well-written and reads smoothly. Nevertheless, it contains several fundamental shortcomings.

The first and foremost issue is the lack of clear conclusions. Dear authors, sentences such as “Integrating pharmacogenomics into OA management presents an opportunity to refine pain management strategies by aligning drug selection and dosing with a patient’s genetic profile” or “Pharmacogenomic data, particularly for enzymes such as CYP2D6, CYP2C9, and UGT1A6, offer insights that can guide safer and more effective use of analgesics” refer to knowledge that has been established for quite some time. Therefore, they cannot serve as a sufficient answer to the core question posed in the manuscript title: “The Role of Pharmacogenomics to Optimize Pain Therapy.” Please revise this section thoroughly so that a clear and direct answer to this question is presented.

Secondly, in a review article, one would expect an analysis of the most recent findings - ideally covering the last 4–5 years. Given the pace at which new publications appear in the scientific literature, such a timeframe seems reasonably acceptable. However, the authors of this paper did not avoid the mistake of referencing sources that fall outside of this range. Several references stand out in this regard. For example:

[3] “Biologic basis of osteoarthritis: state of the evidence” from 2015—does this really reflect the current state of knowledge?

[8] “Osteoarthritis: an overview of the disease and its treatment strategies” from 2005—is this indicative of modern therapeutic strategies for the disease?

[11] “Pharmacogenetics of analgesic drugs” from 2013—have there been no advances since then?

[16] “Mechanism of Action of Acetaminophen: Is There a Cyclooxygenase 3?” from 2000—please forgive the jest, but has the scientific community still not answered this question?

Similar concerns apply to references [6, 19, 22, 23, 24, 25, 27, 28, 30, 32, 33, 34, 35], and continue in the same tone through the rest of the References section. I urge the authors to undertake a critical review of the cited literature with this issue in mind.

 

As for minor issues:

Reference [17] lacks the publication year.

Affiliations: Does the journal require the inclusion of academic titles and professional degrees?

 

kind regards,

 

Author Response

I have read with interest the manuscript titled “Individualized Management of Osteoarthritis: The Role of Pharmacogenomics to Optimize Pain Therapy” by Isabella M. Sturgeon et al., and I hereby inform you that I accept it for publication in future pharmacology, albeit after a number of revisions, which I classify as major. The role of pharmacogenomics is a very modern, important, and consequently, highly interesting approach in the field of pain therapy optimization. As the authors themselves point out, it offers a promising direction in the personalization of OA treatment. The manuscript is well-written and reads smoothly. Nevertheless, it contains several fundamental shortcomings.

The first and foremost issue is the lack of clear conclusions. Dear authors, sentences such as “Integrating pharmacogenomics into OA management presents an opportunity to refine pain management strategies by aligning drug selection and dosing with a patient’s genetic profile” or “Pharmacogenomic data, particularly for enzymes such as CYP2D6, CYP2C9, and UGT1A6, offer insights that can guide safer and more effective use of analgesics” refer to knowledge that has been established for quite some time. Therefore, they cannot serve as a sufficient answer to the core question posed in the manuscript title: “The Role of Pharmacogenomics to Optimize Pain Therapy.” Please revise this section thoroughly so that a clear and direct answer to this question is presented.

• Thank you for your comment. We revised the conclusion and addressed your comments throughout the manuscript, and created a new section describing the challenges and opportunities of our proposed approach. We believe these edits have greatly improved the cohesion of the manuscript and facilitated the primary objective of the paper.

Secondly, in a review article, one would expect an analysis of the most recent findings - ideally covering the last 4–5 years. Given the pace at which new publications appear in the scientific literature, such a timeframe seems reasonably acceptable. However, the authors of this paper did not avoid the mistake of referencing sources that fall outside of this range. Several references stand out in this regard. For example:

[3] “Biologic basis of osteoarthritis: state of the evidence” from 2015—does this really reflect the current state of knowledge?

• Thank you for the thorough review of the manuscript and the references. We agree that a review article should include the most recent and contemporary level of evidence when possible. We recognize that some of our references are outside this time range. However, these papers were used because either the field has progressed that much, or the same papers are considered seminal papers in their respective field. This reference was used in combination with references 1,2, 3, and 7, which are all written in the last 5 years and have no significant changes from the evidence presented in the 2015 reference you are referring to. We felt that, because there have been no significant changes in the past 10 years, it is pertinent to include older references to demonstrate the lack of scientific updates in this area. While we agree that it may not be best practice to utilize older references due to the lack of significant updates, this reference is still valid and reasonable to include in the paper.

[8] “Osteoarthritis: an overview of the disease and its treatment strategies” from 2005—is this indicative of modern therapeutic strategies for the disease?

• Again, this was used in combination with several updated resources. See references 7, 9, and 10, which are more recent and again do not provide any significant updates. We have carefully selected the references used for their validity and lack of significant updates. It is important to note that the ACR guidelines for the treatment of OA are six years old, further demonstrating the lack of updates in treatment strategies.

[11] “Pharmacogenetics of analgesic drugs” from 2013—have there been no advances since then?

• Thank you for your suggestion. See references 12,13,14 for additional supportive references that are more timely.

[16] “Mechanism of Action of Acetaminophen: Is There a Cyclooxygenase 3?” from 2000—please forgive the jest, but has the scientific community still not answered this question?

• We completely understand the concern with using some references outside of the typical window of 4-5 years; however, this question still remains unanswered. We have added supplemental references that are more updated to further illustrate the lack of scientific updates for the APAP mechanism. While its functional role in humans remains a subject of debate, ongoing research continues to explore its potential as a therapeutic target, particularly in the context of inflammation and pain management.
• Please also see references 36, 37 for confirmatory and more recent studies regarding APAP impact on INR.

Similar concerns apply to references [6, 19, 22, 23, 24, 25, 27, 28, 30, 32, 33, 34, 35], and continue in the same tone through the rest of the References section. I urge the authors to undertake a critical review of the cited literature with this issue in mind.

• Thank you for your comments regarding the publication dates of referenced materials. We have made great efforts to ensure that the data presented in this paper is the most up-to-date and current. Unfortunately, the scientific community has not progressed at the pace we would hope for in these areas. The particular call-outs you have made are supplements that further enhance the points and are not the sole resource used.
• Please see highlighted references for additional, more timely references that are now in the paper. Overall, there were limited updates; therefore, the newer resources we have now added only further support claims in the paper and have not led to any content changes or major edits.

As for minor issues:

Reference [17] lacks the publication year.

• Thank you for the observation. I believe our referencing software formatted this reference without including the year of publication, which is 2021. Please see reference 20 now, as this has been corrected.

Affiliations: Does the journal require the inclusion of academic titles and professional degrees?

• It’s unlikely, but we added our professional degrees to our names.

kind regards,

Thank you for your time and effort in reviewing our manuscript. 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Based on a detailed description of genetically dependent metabolic variations of pharmaceuticals used in the clinical treatment of osteoarthritis (OA), the authors present evidence that such information will enable clinicians to select the most appropriate initial pharmacotherapy and minimizing the risk of adverse effects.

Although the manuscript presents existing although very specific knowledge it may be beneficial to clinicians who are not aware of the wide variations of drug metabolism within the human population.

By adding additional information and a table which summarizes information, whether or not Phase I and Phase II enzyme variations affect efficiency of drug used in OA therapy and modifications of the text the message becomes even more substantiated.

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you for the corrections you made to the manuscript. I accept the publication in its present form.