The Efficacy of Denosumab for Prevention of Early Periprosthetic Bone Loss After Cementless Total Hip Arthroplasty

We read the recent study by Nyström and colleagues with great interest. Using a prospective, randomized, double-blind, placebo-controlled design, they investigated whether denosumab could inhibit early periprosthetic bone loss after cementless total hip arthroplasty (THA). The results demonstrated that although denosumab is potently effective in preventing early periprosthetic bone loss after cementless THA, the effect diminishes and is even associated with rebound phenomenon after discontinuing treatment. We applaud the authors for their excellent and important work that bridges our knowledge gap in understanding the restorative effect of denosumab in THA. However, we do have two minor points that may help to contextualize findings from this study and contribute to further investigations of denosumab in THA. First, the practice settings and patient population may limit the generalizability of the results. According to the predefined inclusion criteria, this trial only included young and middle-aged patients without osteoporosis, which are not the typical population in whom denosumab is indicated. In comparison with a previous study that only included postmenopausal women, the increments of periprosthetic bone mineral density (BMD) in the present study were more prominent in both Gruen zone 7 (3% versus –5.3% compared with baseline; 32% versus 12.8% compared with the placebo) and in the entire periprosthetic region (11% versus 5.5% compared with the placebo). This may bemainly attributed to thedifferent responses between the young and elderly patients andmay lead to an overestimation of the antiresorptive effect of denosumab in patients with osteoporosis. Second, there are a number of relevant questions that need to be addressed. To prevent early periprosthetic bone loss after uncemented THA, when should denosumab be used? When should denosumab treatment be discontinued? Answers to both questions are likely to be of interest. Adaptive bone remodeling after cemented and cementless THA has long been an interesting subject of many studies with various study designs. Most of them found significant and rapid decreases of periprosthetic BMD within the first year, and the periprosthetic bone remodeling appears to be stabilized from the second year, as only marginal increases or decreases of BMD occurred in all Gruen zones. A number of studies have investigated the efficacy of bisphosphonates for the preservation of periprosthetic BMD after THA, which found that periprosthetic bone loss could be effectively arrested or even reverted. The current limited data demonstrated that denosumab is at least as effective as bisphosphonates in decreasing bone resorption, and denosumab even increases bone mass in some Gruen zones, although the exact BMD changes in each Gruen zone were not given in detail in the present study. However, both studies found that the periprosthetic BMDs of the denosumab group approached the levels of the placebo group after discontinuation of denosumab, although the rebound effect was only observed in the present study and might have been missed in the other study. The rapid reversal after cessation of denosumab has been well documented in previous research, and bisphosphonates are recommended to prevent the subsequent rebound increase in bone resorption, which was confirmed to be valid in a recent study. Based on the current available evidence and the theoretical considerations of the pharmacodynamics of denosumab (as well as of bisphosphonates), at least two injections of denosumab every 6 months after THA should be used for preventing the rapid decreases of periprosthetic BMDwithin the first year. Further, additional bisphosphonate therapy given 6 months after the last denosumab injection should be recommended to maintain the beneficial treatment effects of denosumab. In view of this, this preliminary regimen needs to be confirmed in future well-designed robust trials, and long-term follow-up with further clinically relevant endpoints are recommended.