Reply to Denosumab in Prevention of Implant Migration

To the Editor: We appreciate the comments by Aro and colleagues and are thankful for the opportunity to discuss our article. Aro and colleagues correctly observe that implant stability, as measured by radiostereometric analysis (RSA), was not an outcome evaluated in our study. Inhibition of periprosthetic bone resorption by denosumabwas the primary outcome of our study, and implant stability, as measured by plain radiography, was included as a secondary outcome. In our previous prospective study on the same uncemented short femoral stem (the collum femoris preserving [CFP] stem [CFP stem; Waldemar Link GmbH, Hamburg, Germany]), we investigated a cohort of patients with similar age and sex distribution. They were operated by the same two surgeons. Implant fixation was analyzed using RSA and periprosthetic bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The CFP stem provided excellent primary stability at all investigated time points and very little micromotion was observed. Particularly noteworthy, we found no signs of stem subsidence or rotation along the longitudinal axis, but considerable periprosthetic BMD loss of up to nearly 30% in Gruen zone 7. Based on these results, we performed a randomized, doubleblind, placebo-controlled clinical trial (RCT) to investigate whether two injections of denosumab could prevent periprosthetic BMD loss 1 year after surgery. The previous RSA study indicated that a detectable difference in implant micromotion would not be expected, and owing to concerns related to radiation exposure when combining positron emission tomography (PET) with DXA and RSA, we decided not to include an analysis of implant micromotion. An evident strength of our current study is that the power calculations for the subsequent RCT study were based on the results of periprosthetic BMD derived from the previous study. To study systemic and local periprosthetic bone biology we included biochemical markers for bone formation and resorption and [F] sodium fluoride PET-CT (F-PET) as secondary endpoints. F-PET is a technique tomeasure the standardized uptake value of [F], which can indicate periprosthetic osteoblastic activity. Few, if any, RCT studies have included F-PET in their study protocols, rendering our findings rather unique. Finally, there is an advantage to performing an independent RCT without support from or connections with the pharmaceutical industry producing the investigated drug. Aro and colleagues raise concerns about our study cohort. The age span of the investigated study population is relevant for patients with osteoarthritis of the hip (OAH) not only from a Swedish perspective but also from an overall global perspective: 35 to 65 years of age, body weight <110 kg. Thus, the age span is representative of the growing group of younger patients with good bone quality typically operated with uncemented implants. Therefore, our study was explicitly designed to investigate the potential of a potent antiresorptive regimen to prevent periprosthetic BMD loss after total hip arthroplasty (THA) in patients with long life expectancy and high functional demands. Aro and colleagues further claim that the composition of their cohort is more relevant than ours, arguing that the obvious target population is women with low systemic BMD. We do not agree. According to the Annual Report of the Swedish Hip Arthroplasty Registry (2018), only slightly more women (58%) than men are operated with a THA. Moreover, revision surgery is most frequent in younger or middle-aged men. Thus, we fail to see how their cohort would be more representative of patients receiving uncemented implants. In addition, Aro and colleagues claim that low preoperative BMD confers an increased risk for periprosthetic bone loss; however, the cited study by Engh and colleagues was based on the retrospective analysis of plain radiography and not the precise measurement of BMD using DXA. The question concerning the choice of uncemented THA in the elderly is under intense debate. Even in younger patients the use of uncemented stem fixation is associated with a sharply increased risk of early complications (eg, periprosthetic fractures and implant loosening). Such a risk is appreciably increased in the elderly. This issue has been thoroughly analyzed by the Nordic Association of Arthroplasty Registers, to which Finland also reports its results. It is undeniable that the praxis of using cemented THA in the elderly as in Norway and Sweden reduces the risk of early complications. The survival of the implants is lower in Finland. Furthermore, Aro and colleagues are content that their patients have a relatively long life expectancy and will likely benefit from the long-term endurance of the implants. However, we are even more satisfied because our study cohort will have a life expectancy exceeding several decades, substantially longer than