Restoration of proximal periprosthetic bone loss by denosumab in cementless total hip arthroplasty

Summary

Denosumab contributed to the restoration of proximal periprosthetic bone loss around the femoral stem that were measured using a DEXA, especially in zone 7, at 1 year after cementless THA in elderly osteoporotic patients.

Introduction

Although bone quality is an important issue in elderly osteoporotic patients who underwent total hip arthroplasty (THA) with a cementless stem, periprosthetic bone mineral density (BMD) in the proximal femur has been reported to be decreased by 15–40% postoperatively. Some authors have examined the use of several types of bisphosphonates to prevent decreases in BMD in the proximal femur after cementless THA; however, few reports have demonstrated success in restoring BMD in the proximal medial femoral bone, such as zone 7.

Methods

We conducted prospective study comparing patients who underwent cementless THA administered with denosumab (10 patients) and without denosumab (10 patients). BMD around the femoral stem were measured using a DEXA immediately after surgery, and at 6 months and at 1 year after surgery. No difference was found between the two groups referred to the patient’s demographic data.

Results

We found that denosumab displayed definitive effects in increasing the % change in periprosthetic BMD at zone 7 by an average of 7.3% in patients with cementless THA, compared to control group who were given only vitamin D.

Conclusion

Denosumab is one of a number of anti-osteoporotic agents to have a definitive effect on the restoration of proximal periprosthetic bone loss, especially in zone 7, after cementless THA. Denosumab contributed to the restoration of decreased periprosthetic BMD to normal levels. As the decrease in BMD in the proximal femur after THA is considered to be apparent at 6–12 months after surgery, it is believed that prevention of the deterioration of bone quality is important in the proximal femur immediately after cementless THA for elderly female patients with osteoporosis.

     

Effect of Twice‐Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial

We conducted an open‐label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3–5.9%) in 46 patients in the denosumab group and decreased by ?0.5% (95% CI ?1.8% to 0.9%) in 44 patients in the control group (between‐group difference 5.1% [95% CI 3.1–7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1–3.7%; p = 0.035) over that in the control group at 12 months. High‐resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C‐terminal telopeptide of type I collagen, procollagen type I N‐terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.     

Discontinuation of denosumab and associated fracture incidence: Analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial

Osteoporosis is a chronic disease and requires long‐term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off‐treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off‐treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T‐scores. During treatment, more placebo‐treated subjects as compared with denosumab‐treated subjects sustained a fracture and had significant decreases in BMD. During the off‐treatment period (median 0.8 years per subject), 42% versus 28% of placebo‐ and denosumab‐treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject‐years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49–1.38), adjusted for age and total hip BMD T‐score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off‐treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off‐treatment period for up to 24 months. © 2013 American Society for Bone and Mineral Research.     

Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.     

Female patients with low systemic BMD are prone to bone loss in Gruen zone 7 after cementless total hip arthroplasty: A 2-year DXA follow-up of 39 patients

Background and purpose Factors that lead to periprosthetic bone loss following total hip arthroplasty (THA) may not only depend on biomechanical implant-related factors, but also on various patient-related factors. We investigated the association between early changes in periprosthetic bone mineral density (BMD) and patient-related factors.Patients and methods 39 female patients underwent cementless THA (ABG II) with ceramic-ceramic bearing surfaces. Periprosthetic BMD in the proximal femur was determined with DXA after surgery and at 3, 6, 12, and 24 months. 27 patient-related factors were analyzed for their value in prediction of periprosthetic bone loss.Results Total periprosthetic BMD was temporarily reduced by 3.7% at 3 months (p < 0.001), by 3.8% at 6 months (p < 0.01), and by 2.6% at 12 months (p < 0.01), but recovered thereafter up to 24 months. Preoperative systemic osteopenia and osteoporosis, but not the local BMD of the operated hip, was predictive of bone loss in Gruen zone 7 (p = 0.04), which was the only region with a statistically significant decrease in BMD (23%, p < 0.001) at 24 months. Preoperative serum markers of bone turnover predicted the early temporary changes of periprosthetic BMD. The other patient-related factors failed to show any association with the periprosthetic BMD changes.Interpretation Female patients with low systemic BMD show greater bone loss in Gruen zone 7 after cementless THA than patients with normal BMD. Systemic DXA screening for osteoporosis in postmenopausal patients before THA could be used to identify patients in need of prophylactic anti-resorptive therapy.     

Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo‐Controlled FREEDOM Trial and Its Extension

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above‐baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant‐years during the on‐treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant‐years). Among participants with ≥1 off‐treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1–7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3–1.9) times higher with each additional year of off‐treatment follow‐up; among participants with available off‐treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1–1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant‐years) of nonvertebral fractures during the off‐treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov : NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.     

地舒单抗对绝经后骨质疏松性股骨颈骨折全髋关节置换术后股骨近端假体周围骨密度的影响

目的:研究地舒单抗对绝经后骨质疏松性股骨颈骨折患者全髋关节置换术后(total hip arthroplasty,THA)股骨近端假体周围骨密度的影响。方法:选取2020年10月至2021年10月绝经后女性骨质疏松性股骨颈骨折行THA术后54例,治疗组25例接受地舒单抗治疗,年龄(74.3±6.2)岁;对照组29例未接受地舒单抗治疗,年龄(75.2±4.8)岁。术后1周及3、6及12个月各个时间点,通过双能X线骨密度仪(DEXA型)测定股骨近端假体周围骨密度,并在不同时间点测量骨转换各项指标。结果:术后3、6及12个月对照组的抗酒石酸酸性磷酸酶(tartrate resistant acid phosphatase,TRACP-5b)高于治疗组(P<0.05);对照组术后12个月骨特异性碱性磷酸酶(bone-specific alkaline phosphatase,BALP)高于治疗组(P<0.05)。两组患者Gruen 1、7区的骨密度在术后3、6及12个月较术后1周(基线)均下降(P<0.05);对照组Gruen 7区术后各时间点比较,差异有统计学意义(P<0.05);治疗组各时间点比较,差异无统计学意义(P>0.05)。两组术后3个月Gruen 1、7区比较,差异无统计学意义(P>0.05);术后6个月Gruen 1、7区和术后12个月Gruen 1、7区,治疗组骨密度均明显高于对照组(P<0.05)。两组术后3个月Gruen 1、7区骨密度下降百分比比较,差异无统计学意义(P>0.05)。对照组术后6个月Gruen 1、7区,术后12个月Gruen 1、7区骨密度下降百分比明显高于治疗组(P<0.05)。提示在使用地舒单抗6个月后,即可降低骨密度丢失幅度,并且该效应可达至术后12个月。结论:绝经后骨质疏松性股骨颈骨折患者在THA术后,使用地舒单抗可减少股骨近端假体周围骨密度丢失,有效抑制骨吸收。     

Changes of femoral periprosthetic bone mineral density 6 years after treatment with alendronate following total hip arthroplasty

Earlier osteodensitometric results of femoral periprosthetic bone showed that postoperative antiresorptive treatment with alendronate following total hip arthroplasty (THA) reduces the periprosthetic bone loss that commonly occurs in the first months after surgery. However, whether alendronate can prevent periprosthetic bone loss over the long term, or if bone loss occurs after discontinuing alendronate is unknown. Femoral periprosthetic bone mineral density (BMD) was assessed in 49 patients 6 years after cementless total hip arthroplasty using dual energy X‐ray absorptiometry. Twenty‐nine patients were treated postoperatively with alendronate and 20 control patients received no treatment. All patients were followed up at 12 months after surgery in a prospective randomized study. The bone mineral density was evaluated in 7 regions of interest according to the Gruen protocol. Six years after total hip arthroplasty, no significant changes were detected in femoral periprosthetic BMD when compared with results at 1 year, and the bone loss in patients with postoperative alendronate treatment was still significantly less than those without treatment. These results suggest that the prevention of femoral periprosthetic bone loss following THA achieved by postoperative antiresorptive treatment with alendronate is of long‐standing effect, and further bone loss does not occur after the first postoperative year. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:183–188, 2009     

Efficacy of Zoledronic Acid in Maintaining Areal and Volumetric Bone Density After Combined Denosumab and Teriparatide Administration: DATA-HD Study Extension

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high-turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA-HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15-month study, women were invited to enroll in the DATA-HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty-three women enrolled in the DATA-HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, −4.0% to −2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20-μg and 40-μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA-HD Extension regimen may be an effective strategy in the long-term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Monitoring of periprosthetic BMD after uncemented total hip arthroplasty with dual-energy X-ray absorptiometry--a 3-year follow-up study.

Insertion of a metallic implant into the femur changes bone loading conditions and results in remodeling of femoral bone. To quantify changes in bone mass after uncemented total hip arthroplasty (THA), we monitored femoral bone with dual-energy X-ray absorptiometry (DXA). The periprosthetic bone mineral density (BMD) was measured with Lunar DPX densitometry in seven Gruen zones and the total periprosthetic area at scheduled time intervals in 22 patients during a 3-year follow-up. BMD decreased significantly almost in all Gruen zones during the first 3 months, ranging from 3.4% to 14.4% (p < 0.05 top < 0.001). At the end of the first year, the most remarkable decrease in BMD was found in the calcar (zone 7; -22.9%). During the second postoperative year, a slight restoration of periprosthetic bone mass was recorded. During the third year, no significant changes in BMD were found. The preoperative BMD was the only factor that was significantly related to the periprosthetic bone loss. Clearly, the early periprosthetic bone loss noticed during the 3 months after THA is caused by mainly limited weight bearing to the operated hip and stress shielding. We suggest that the restoration of bone mass is a sign of successful osteointegration between bone and metallic implant. DXA is a suitable tool to follow the bone response to prosthetization and will increase our knowledge on the behavior of bone after THA.     

Periprosthetic bone loss after cemented total hip arthroplasty

In this prospective 5-year study, we determined the periprosthetic bone loss after cemented total hip arthroplasty (THA) in 15 patients using dual energy X-ray absorptiometry (DXA). A reduction in the periprosthetic bone mineral density (BMD) of 5-18% occurred in all Gruen regions, or regions of interest (ROI), during the first 3 months after THA. The bone loss continued up to 6 months in almost all ROIs. From 1 to 5 years, we found only minor changes in BMD in periprosthetic bone. After the follow-up, the mean greatest bone loss (26%) was seen in the femoral calcar area. The reduction in mean BMD was 5% in men, and 16% in women. The lower the preoperative BMD, the higher was the postoperative bone loss. We found that after the phase of acute bone loss, further loss was minimal, reflecting merely the normal ageing of bone after uncomplicated THA.     

A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains

Discontinuation of denosumab is associated with a rapid return of bone mineral density (BMD) to baseline and an increased risk of multiple vertebral fractures. No subsequent treatment regimen has yet been established for preventing either loss of BMD or multiple vertebral fractures after denosumab discontinuation. The aim of this 8-year observational study was to investigate the effect of a single zoledronate infusion, administered 6 months after the last denosumab injection, on fracture occurrence and loss of BMD. We report on 120 women with postmenopausal osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration 3 years) and then 5 mg zoledronate 6 months after the last denosumab injection. All patients were evaluated clinically, by dual-energy X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), before the first and after the last denosumab injection and at 2.5 years (median) after denosumab discontinuation. During this off-treatment period, 3 vertebral fractures (1.1 per 100 patient-years) and 4 nonvertebral fractures (1.5 per 100 patient-years) occurred. No patients developed multiple vertebral fractures. Sixty-six percent (confidence interval [CI] 57% to 75%) of BMD gained with denosumab was retained at the lumbar spine and 49% (CI 31% to 67%) at the total hip. There was no significant difference in the decrease of BMD between patients with BMD gains of >9% versus <9% while treated with denosumab. Previous antiresorptive treatment or prevalent fractures had no impact on the decrease of BMD, and all bone loss occurred within the first 18 months after zoledronate infusion. In conclusion, a single infusion of 5 mg zoledronate after a 2- to 5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment. © 2020 American Society for Bone and Mineral Research.     

Periprosthetic bone loss after cemented total hip arthroplasty: a prospective 5-year dual energy radiographic absorptiometry study of 15 patients

In this prospective 5-year study, we determined the periprosthetic bone loss after cemented total hip arthroplasty (THA) in 15 patients using dual energy X-ray absorptiometry (DXA). A reduction in the periprosthetic bone mineral density (BMD) of 5-18% occurred in all Gruen regions, or regions of interest (ROI), during the first 3 months after THA. The bone loss continued up to 6 months in almost all ROIs. From 1 to 5 years, we found only minor changes in BMD in periprosthetic bone. After the follow-up, the mean greatest bone loss (26%) was seen in the femoral calcar area. The reduction in mean BMD was 5% in men, and 16% in women. The lower the preoperative BMD, the higher was the postoperative bone loss. We found that after the phase of acute bone loss, further loss was minimal, reflecting merely the normal ageing of bone after uncomplicated THA.     

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized,Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ ?2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.     

骨矿改变在人工全髋关节置换术的监测

目的：研究人工全髋关节置换术后髋周骨矿含量的改变。方法：对骨水泥型人工全髋关节置换的25例27髋,在术后不同时段用DEXA测定髋周5个区域的骨矿含量,并与其各自合适的对照作配对样本t检验。结果：术后1个月内（平均23d)测定组显示第4区骨矿量显著增加（P＜0．05）;术后4－6月（平均4．4月）和7－12月测定组显示5个区骨矿量无显著增减（P＞0．05）;术后14－49月（平均27．4月）测定组显示第2区和第5区骨矿量显著降低（P＜0．05）;第1区也有明显降低趋势（P＝0．064）。结论：骨水泥型人工全髋置入后髋周承重部位骨矿量在12月内改变不大;术后约2年在髋臼周围和股骨小粗隆部骨矿明显丢失,与置入假体后产生应力遮挡可能有关。     

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab

Romosozumab is a bone‐forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T‐score changes from baseline over the 2‐year study and contrast these results with the long‐term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab‐treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T‐score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo‐to‐denosumab: 0.38 and 0.17), with the 2‐year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy

Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double‐blind, double‐dummy study in 504 postmenopausal women ≥ 55 years of age with a BMD T‐score of ?2.0 or less and ?4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open‐label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. Copyright © 2010 American Society for Bone and Mineral Research     

Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial

INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass. METHODS: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated. RESULTS: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups. CONCLUSIONS: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.     

Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys

Denosumab is a fully human monoclonal antibody that inhibits RANKL, a protein essential for osteoclast formation, function, and survival. Osteoclast inhibition with denosumab decreased bone resorption, increased bone mineral density (BMD), and reduced fracture risk in osteoporotic women. The effects of 16months of continuous osteoclast inhibition on bone strength parameters were examined in adult ovariectomized (OVX) cynomolgus monkeys (cynos). One month after surgery, OVX cynos (n=14-20/group) were treated monthly with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg). Sham-operated controls were treated with vehicle (n=17). OVX-Veh exhibited early and persistent increases in the resorption marker CTx, followed by similar increases in the formation marker BSAP, consistent with increased bone remodeling. Denosumab reduced CTx and BSAP throughout the study to levels significantly lower than in OVX-Veh or Sham-Veh, consistent with reduced remodeling. Increased remodeling in OVX-Veh led to absolute declines in areal BMD of 4.3-7.4% at the lumbar spine, total hip, femur neck, and distal radius (all p<0.05 vs baseline). Denosumab significantly increased aBMD at each site to levels exceeding baseline or OVX-Veh controls, and denosumab significantly increased cortical vBMC of the central radius and tibia by 7% and 14% (respectively) relative to OVX-Veh. Destructive biomechanical testing revealed that both doses of denosumab were associated with significantly greater peak load for femur neck (+19-34%), L3-L4 vertebral bodies (+54-55%), and L5-L6 cancellous cores (+69-82%) compared with OVX-Veh. Direct assessment of bone tissue material properties at cortical sites revealed no significant changes with denosumab. For all sites analyzed biomechanically, bone mass (BMC) and strength (load) exhibited strong linear correlations (r(2)=0.59-0.85 for all groups combined). Denosumab did not alter slopes of load-BMC regressions at any site, and denosumab groups exhibited similar or greater load values at given BMC values compared with OVX-Veh or Sham. In summary, denosumab markedly reduced biochemical markers of bone remodeling and increased cortical and trabecular bone mass in adult OVX cynos. Denosumab improved structural bone strength parameters at all sites analyzed, and strength remained highly correlated with bone mass. There was no evidence for reduced material strength properties of cortical bone with denosumab over this time period, which approximates to 4years of remodeling in the slower-remodeling adult human skeleton. These data indicate that denosumab increased bone strength by increasing bone mass and preserving bone quality.     

Effects of denosumab on the geometry of the proximal femur in postmenopausal women in comparison with alendronate.

Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, an essential mediator of osteoclast activity and survival. In postmenopausal women with low bone mineral density (BMD), subcutaneous denosumab decreases bone resorption and increases BMD. This post hoc analysis reports on subjects treated for up to 24 months with denosumab 60mg 6 monthly (N=39), placebo (N=39), or open-label alendronate 70mg once weekly (N=38) in a phase 2 study. Hip scans were done by dual-energy X-ray absorptiometry at baseline, 12, and 24 months; these were analyzed with hip structural analysis software to evaluate BMD and cross-sectional geometry parameters at the narrowest segment of the femoral neck, the intertrochanter, and the proximal shaft. Geometric parameters and derived strength indices included bone cross-sectional area, section modulus, and buckling ratio. At 12 and 24 months denosumab and alendronate improved these parameters compared with placebo. Denosumab effects were greater than alendronate at the intertrochanteric and shaft sites. The magnitude and direction of the changes in structural geometry parameters observed in this study suggest that denosumab treatment may lead to improved bone mechanical properties. Ongoing phase 3 studies will determine whether denosumab reduces fracture risk.