Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: population based retrospective cohort study

Dear Editor,
Thank you for providing the opportunity to respond to the comments made to our paper describing the association between bisphosphonate use and implant survival after arthroplasty of the knee or hip [1].

It has been suggested that it might be of interest to explore the effect of post-operative use of bisphosphonates on implant survival within our data. We agree that timing and duration of bisphosphonate therapy in relation to primary arthroplasty at the hip and/or knee is an essential issue to address in further research. Unfortunately, even withstanding our substantial sample size, we lacked statistical power to explore this question specifically as of the 741 (38.7%) bisphosphonate users in our data who initiated therapy after their operation, only 4 out of them (0.5%) underwent revision surgery during the observation period.

Professor Cobb commented on the fact that our paper did not explore the potential effect of bisphosphonate therapy on fractures post-surgery. In previous publications we have explored the association of bisphosphonate therapy on post-surgical fracture within this GPRD cohort. Our analyses suggest that fracture risk is increased after total hip and knee arthroplasty, and that bisphosphonate use is associated with a significant reduction in fracture risk in this population [2,3,4]. Osteoporotic patients and those with a fragility fracture before undergoing total joint arthroplasty are of special interest, as they might benefit further (or not) from bisphosphonate therapy. However, due to the lack of accurate information on indication for surgery within GPRD, we could not explore this issue in our data. This should be explored in future analyses.

We agree that sub-trochanteric atypical fractures are a potential consequence of bisphosphonate therapy, but acknowledge a direct causal association remains unproven [5]. These fractures are considered rare, at an estimated rate of 5 per 10,000 [6]. However, these rates are derived largely from bisphosphonate therapy in patients with osteoporosis and the rate in non-osteoporotic populations is not known, requiring further study.

We would like to clarify that we used a retrospective cohort study design for this analysis – not a case-control study as suggested in responses to the paper. We used propensity score adjustment to control for confounding by indication not propensity score matching. Hence the sample size used in analysis was actually the 41,995 patients. Although matching on propensity scores is a perfectly valid method, adjustment for this variable has also been shown to be useful to reduce confounding by indication in observational pharmaco-epidemiological studies such as ours [7]. We were re-assured that the direction of effect was similar in unadjusted vs. adjusted models and further there was only a modest attenuation of effect of 0.41 to 0.54 with propensity score adjustment. We agree that the range of 95% confidence intervals may indicate small to large effects, but the current balance of evidence supports the observed effect size and suggests these findings require replication.

We agree that screening strategies are required to identify patients at highest risk of revision before pharmacological therapies are conducted and this issue is being addressed as part of the ongoing NIHR-funded COAST Study. The potential effect of calcium and vitamin D supplements on implant survival is now the focus of ongoing work. Although we have not performed a formal cost effectiveness evaluation, we do wish to point out that now bisphosphonates are generic, they have fallen in price to 14 – 20 pounds per year of therapy and therefore would not classify them as expensive. We have been open in our declarations and leave to the reader to assess the potential for publication bias.

Finally, we were judicious in our conclusions of this study given the observational nature of the data and documented limitations. We specifically did not recommend prescribing of bisphosphonate in this patient group based solely on our findings instead highlighting the need for an experimental study.

REFERENCES
1.- Prieto-Alhambra D, Javaid MK, Judge A, Murray D, Carr A, Cooper C, Arden NK. Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: population based retrospective cohort study. BMJ. 2011 Dec 6;343:d7222. doi: 10.1136/bmj.d7222.
2.- Prieto-Alhambra D, Javaid MK, Maskell J, Judge A, Nevitt M, Cooper C, Arden NK. Changes in hip fracture rate before and after total knee replacement due to osteoarthritis: a population-based cohort study. Ann Rheum Dis. 2011 Jan;70(1):134-8.
3.- Prieto-Alhambra D, Javaid MK, Judge A, Maskell J, Kiran A, Cooper C, Arden NK. Bisphosphonate use and risk of post-operative fracture among patients undergoing a total knee replacement for knee osteoarthritis: a propensity score analysis. Osteoporos Int. 2011 May;22(5):1555-71.
4.- Prieto-Alhambra D, Javaid MK, Judge A, Maskell J, Kiran A, de Vries F, Cooper C, Arden NK. Fracture risk before and after total hip replacement in patients with osteoarthritis: potential benefits of bisphosphonate use. Arthritis Rheum. 2011 Apr;63(4):992-1001.
5.- Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010 Nov;25(11):2267-94.
6.- Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011 May 5;364(18):1728-37.
7.- Austin PC. The performance of different propensity-score methods for estimating differences in proportions (risk differences or absolute risk reductions) in observational studies. St