Letter: Bisphosphonate effectiveness in patients with cirrhosis—An emulated clinical trial

Abstract

We read the article by Tapper et al.¹ with great interest and commend the authors for their innovative and clinically valuable research focus. The study, which used US Medicare data and an emulated clinical trial design, provides valuable insights into the role of bisphosphonates in reducing fracture risk in cirrhotic patients. The results suggest that bisphosphonates are effective in reducing fracture risk in cirrhotic patients and highlight the need to monitor osteoporosis in this population. However, several concerns limit the study's applicability.

First, bisphosphonates typically require long-term administration to sustain improvements in bone density and reduce fracture risk.^{2, 3} The effectiveness of bisphosphonates depends largely on patient adherence. Irregular medication intake, early discontinuation, or not following the prescribed dosage can diminish the therapy's benefits, leading to less effective outcomes. The study does not adequately address the role of adherence, which is crucial to determining bisphosphonates effectiveness. This shortcoming limits the applicability of the findings. The inclusion of adherence factors in follow-up design should be conducted to provide more clinically relevant insights into the management of osteoporosis in cirrhotic patients.

Second, the data came entirely from Medicare, a government-funded healthcare program for individuals over 65 with disabilities or haemodialysis. This implies that the study population predominantly consists of elderly individuals. There were significant differences in baseline bone density and fracture recovery between elderlies and younger patients.⁴ Therefore, data on the efficacy of bisphosphonates, particularly in reducing fracture risk, may not be applicable to patients with cirrhosis of the liver in young and middle-aged patients. Future studies should aim to broaden the sample demographic, especially by including young cirrhotic patients, to assess the differential efficacy of bisphosphonates in different age groups. This approach will help determine whether bisphosphonate therapy provides the same fracture prevention benefits for cirrhotic patients in all age groups, enhancing the generalizability and applicability of the results.

Third, cirrhotic patients are often accompanied by multiple comorbidities, such as diabetes, chronic kidney disease, and cardiovascular diseases, and independently increases the risk of fracture.⁵ In addition, these conditions often require drugs such as corticosteroids and proton pump inhibitors, which negatively impact bone metabolism and further increase the risk of fracture.^{6, 7} While the study attempted to adjust to these factors, this adjustment may not fully take into account all comorbidities, especially if there is an interaction between them.

Despite these limitations, the study makes a significant contribution to understanding osteoporosis risk management in elderly cirrhotic patients and highlights bisphosphonates as a potential treatment. To improve the accuracy and clinical relevance of the study, it is necessary to include younger cirrhotic patients in the study population. Additionally, more detailed documentation of comorbidities and medication histories can be more precisely calibrated to reduce residual confounding. The influence of complex comorbidities polypharmacy can be better controlled by using advanced statistical methods such as stratified analysis or propensity score matching. These improvements will improve the external effectiveness of the study and provide stronger guidance for personalised treatment in the clinic.

Mingsi Zhang: Writing – original draft. Yunmeng Nie: Conceptualization; writing – review and editing; supervision.

None.

The authors declare no conflicts of interest.

This article is linked to Tapper et al papers. To view these articles, visit https://doi.org/10.1111/apt.18127 and https://doi.org/10.1111/apt.18259