Effect Of Denosumab Research Articles

OP129 A Cost-Utility Analysis Of Denosumab (Prolia®) For Treating Osteoporosis In Postmenopausal Women: A Swiss Healthcare Payer Perspective

IntroductionOsteoporosis is characterized by decreased bone mass and density, increasing skeletal fragility, and the risk of fragility fracture. Fragility fractures are associated with a high economic burden. Denosumab (Prolia®) is a pharmacological therapy used to treat osteoporosis and reduce the risk of fragility fracture. This study aimed to assess the cost effectiveness of denosumab, compared with other pharmacological therapies (oral bisphosphonates, intravenous [IV] ibandronate, zoledronate, raloxifene, and bazedoxifene) and no treatment, for treating postmenopausal women with osteoporosis.MethodsA discrete event simulation model was developed using a lifetime time horizon. A Swiss healthcare payer perspective was adopted. Time-to-fracture distributions were derived from Swiss-specific Fracture Risk Assessment Tool (FRAX®) probabilities. Reductions in the risk of vertebral and nonvertebral fractures due to treatment were informed by a Bayesian network meta-analysis. Cost-effectiveness frontier analysis was utilized. Pairwise incremental cost-effectiveness ratios (ICERs) between denosumab and each comparator were also estimated. Sensitivity analyses were conducted to identify key drivers and explore the overall certainty of findings.ResultsAt a hypothetical willingness-to-pay (WTP) threshold of CHF100,000 (EUR101,630), IV ibandronate was the most cost-effective therapy in women aged 60 years who had a very high risk of fracture, and in women aged 70 or 80 years of any risk level. In women aged 60 years with a lower risk level, zoledronate was the most cost-effective option. Nevertheless, ICERs from pairwise comparisons between denosumab and some comparators (no treatment, bazedoxifene, raloxifene, and/or zoledronate depending on the cohort’s age and risk profile) were below the hypothetical WTP threshold. Higher intervention costs, smaller reductions in the risk of hip fracture, and shorter duration of residual benefit associated with denosumab contributed to the high ICER values seen in pairwise comparisons with oral bisphosphonates (as a class) and IV ibandronate.ConclusionsThe present evaluation supported the cost effectiveness of denosumab against some, but not all, comparators. Nevertheless, these results should be interpreted cautiously in light of uncertainty in the true effect of treatments on fracture risk.

Current indications for denosumab in benign bone tumours.

Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK-RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a secondary ossification and connective tissue formation. Given its high efficacy, denosumab is the standard treatment of unresectable or metastatic giant cell tumour of bone (GCTB) requiring morbid surgery. Neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases; it should be considered, however, with caution for joint-saving surgery due to high local recurrence rates. In cases of unresectable or metastatic GCTB, however, denosumab treatment should be administered for years or even as a lifelong therapy. This poses many yet unanswered questions concerning the frequency of denosumab treatment as well as the ratio of the adverse events in the following years. Denosumab suppresses, not directly targets, the neoplastic stromal cells of GCTB. Ongoing in vitro studies suggest that other drugs alone or in combination (e.g. sunitinib) with denosumab may target both the neoplastic and the giant cells. Promising results have been reported regarding the off-label use of denosumab in other giant cell-rich tumours/tumour-like lesions, i.e. aneurysmal bone cysts and central giant cell granulomas. Data are derived, however, mostly from case reports and case series. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.

Effects of denosumab on bone mineral density around proximal femoral prosthesis after total hip replacement in postmenopausal osteoporotic patients

To evaluate the effect of denosumab on bone mineral density around proximal femoral prosthesis after total hip arthroplasty(THA) in the postmenopausal osteoporotic patients. Fifty-four consecutive patients underwent unilateral primary THA were included in this retrospective study. Twenty-five patients received denosumab for osteoporosis as the treatment group, and the twenty-nine without denosumab were the control group. At 1 week, 3month, 6 months, and 12 months after THA, bone turnover markers and proximal femoral periprosthetic bone mineral density (BMD) were measured. At 3, 6 and 12 months after operation, the level of TRACP-5b in the control group was significantly higher than that in the treatment group (P<0.05);the level of bone-specific alkaline phosphatase (BALP) between two groups showed significant difference in 12 months after operation (control group was higher than treatment group, P<0.05). The BMD of Gruen 1 and Gruen 7 decreased at 3, 6 and 12 months after operation compared with 1 week after operation. Comparing the treatment group and the control group, the differences of the the decrease of BMD in Gruen 1 and Gruen 7 were no significant at 3 months after surgery. In Gruen 1, Gruen 7 at 6 months after operation and Gruen 1, Gruen 7 at 12 months after operation, the decrease of BMD in the control group was significantly higher than that in the treatment group(P<0.05). It is suggested that desudumab could inhibit the loss of BMD after 6 months, and continuously show a protective effect on bone mass at 12 months after operation. After THA in postmenopausal patients with osteoporotic femoral neck fracture, Desuzumab can reduce the loss of BMD around the proximal femoral prosthesis and effectively inhibit bone resorption.

Effect of denosumab in treatment of unresectable spine and sacrum giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a rare tumor of the bone that is locally invasive. Surgery is the primary treatment that is usually done by intralesional curettage. In pelvis and spine surgery may be associated with high rate of complications, recently, Denosumab has been proposed for the treatment of these tumors in latter anatomical regions. Denosumab may be administered alone or as an adjuvant to surgery. This study aimed to assess the treatment effects of Denosumab in patients with unresectable GCTB. This study was a case series. Patients with unresectable GCTB of vertebra and sacrum were enrolled in this study. Patients received 120mg of monthly Denosumab and additional doses on days 8th and 15th of treatment. Images of patients before and after treatment were evaluated. Nine patients with a median age of 30 years with spine and sacrum GCTB were included in this study. The median time of treatment with denosumab was 28 months (range: 3-67). Tumor control was seen in all patients. According to Inverse Choi density/size (ICDS), criteria objective response (complete response and partial response) was seen in 8 patients, and one had stable disease. Based on CT scan images, in 4 patients (44.44%), less than 50% of the transverse diameter of the tumor became ossified, and in the other five patients (55.55%), more than 50% of the tumor's transverse diameter became ossified. The median tumor volume before treatment was 829 cm3, and after treatment was 504cm3 which was significantly reduced (P = 0.005). No complication related to therapy was seen. Tumor response was seen in all patients, and tumor control according to ICDS criteria was evident in all cases. This finding was in line with previous studies. Clinical improvement of signs and symptoms was also seen in all patients. Generally, our study demonstrates a sustained clinical benefit and tumor response with Denosumab, as tumor response ≥ 24 weeks was evident in all cases. No side effects were seen in patients despite long-term treatment with Denosumab.

Effect of Denosumab on Bone Density in Postmenopausal Osteoporosis: A Comparison with and without Calcium Supplementation in Patients on Standard Diets in Korea.

The side effects and safety issues tied to calcium supplementation raise questions about its necessity in osteoporosis treatment. We retrospectively evaluated 189 postmenopausal osteoporosis patients treated with denosumab for 12 months. Patients exhibited neither renal dysfunction nor compromised general dietary intake. Patients were divided into three groups as follows: group A, weekly vitamin D 7000 IU; group B, daily vitamin D 1000 IU with elemental calcium 100 mg; and group C, daily vitamin D 1000 IU with elemental calcium 500 mg. All groups showed significant increases in bone density: +6.4 ± 4.7% for the lumbar spine, +2.2 ± 3.5% for the femoral neck, and +2.4 ± 3.8% for the total hip in group A; +7.0 ± 10.9% for the lumbar spine, +2.3 ± 5.2% for the femoral neck, and +2.4 ± 3.8% for the total hip in group B; and + 6.7 ± 8.7% for the lumbar spine, +2.5 ± 8.4% for the femoral neck, and +2.3 ± 4.0% for the total hip in group C. Serum calcium levels increased over time in all three groups with no significant difference. Changes in CTX and P1NP levels did not differ between the groups (all p > 0.05). With regular dietary intake, calcium supplementation levels showed no significant effect on bone density, bone marker changes, or hypocalcemia incidence during denosumab treatment.

Efficacy and Side Effects of Denosumab for Stage 3b-4 CKD Patients with Osteoporosis: An Open-Label, Prospective Pilot Clinical Study

Efficacy and Side Effects of Denosumab for Stage 3b-4 CKD Patients with Osteoporosis: An Open-Label, Prospective Pilot Clinical Study

THU448 Multiple Non-traumatic Vertebral Fractures After Discontinuation Of Denosumab

Abstract Disclosure: S. Riahi: None. A.R. Crawford: None. U. Gruntmanis: None. Background: In multiple studies, including a post-hoc analysis of the FREEDOM trial1, an increased risk of vertebral fractures has been demonstrated in patients after discontinuation of denosumab. Clinical Case: A 65-year-old female presented to the endocrinology clinic for evaluation of severe osteoporosis. She was diagnosed with osteoporosis in 2017 after a DXA scan demonstrated a lumbar spine T-score of −3.5. She was started on denosumab therapy by her primary care provider to treat her osteoporosis and received a total of 10 injections over 5 years, during which time she experienced no fractures. Her lumbar spine T-score improved to −2.6 in March of 2021. She received her last injection of denosumab in December of 2021 and was told that she no longer needed denosumab therapy. She began to develop severe pain in her back in October of 2022 and noticed a 3-inch height loss. X-rays done in November of 2022 demonstrated a new compression fracture in L2. Due to persistent debilitating pain, patient had repeat X-rays performed 1 week later which demonstrated multiple age indeterminate compression fractures which MRI was able to confirm at T5, T7, and T9-T12. Repeat DXA scan in December of 2022 demonstrated a lumbar spine T-score of −3.1. Serum C-Telopeptide (CTX) was 1060pg/mL. Patient had adequate calcium and vitamin D intake, and secondary causes of osteoporosis were excluded. Conclusion: This case report highlights the rapid reversibility of the beneficial effects of denosumab on bone density and bone remodeling after discontinuation of the drug (evidenced by the significantly elevated CTX), the importance of close follow up, and the use of transition therapy in patients after discontinuation of denosumab to attenuate the risks associated with stopping the medication. It also places import on the use of MRI imaging, especially in the cases of rebound associated vertebral fractures secondary to denosumab discontinuation2 for those patients in whom you have high suspicion to better characterize compression fractures when x-ray findings are not felt to be sufficient.

OA11 Osteoporosis, denosumab, and hypocalcaemia in multimorbid renal impairment

Abstract Introduction Osteoporosis affects approximately 30% of patients with chronic kidney disease (CKD) at stages 3-5, with 10% of women and 5% of men experiencing a fragility fracture within a given three-year follow up period. First-line management of osteoporosis with bisphosphonates is often precluded in CKD, with alendronate and zoledronate being contraindicated in creatinine clearances of &amp;lt; 35mL/min, and risedronate if &amp;lt; 30mL/min. Denosumab, a RANK-ligand inhibiting monoclonal antibody, can be used in cases of poorer renal function, however causes hypocalcaemia more commonly than bisphosphonates. Concomitant CKD compounds this risk if creatinine clearance falls below 30mL/min, presenting additional challenges for management. Case description A 75-year old woman with known osteoporosis and chronic kidney disease secondary to hypertension and a pauci-immune necrotising glomerulonephritis was found to have a serum calcium of 2.08mmol/L approximately three months after commencing six-monthly denosumab. Her lumbar spine T-score on dual x-ray absorptiometry showed severe osteoporosis at −2.9, with a fragility fracture of the humerus sustained four years prior. Her baseline eGFR was 23mL/min/1.73m2, and creatinine clearance was 22mL/min. Her past medical history was extensive and included secondary hyperparathyroidism due to CKD and resulting vitamin D deficiency, with a PTH of 23.0pmol/L, serum calcium of 2.26mmol/L, and a serum 25-OH vitamin D3 level of 33.5nmol/L four months prior to denosumab therapy. The history also included Sjögren’s syndrome on long-term daily prednisolone 7.5mg, alternate-day hydroxychloroquine 200mg, and daily leflunomide 10mg for accompanying synovitis of the hands, hypothyroidism controlled with daily levothyroxine 50mcg, hypertension controlled with daily 2.5mg bisoprolol, peripheral neuropathy secondary to vitamin B12 deficiency on three-monthly hydroxocobalamin, myocardial infarction with percutaneous coronary intervention to three arteries, diverticular disease with abscess perforation requiring laparotomy and intensive care admission, and a previous deep vein thrombosis on long-term anticoagulation with apixaban. The patient had received risedronate in the past while her creatinine clearance still permitted this. Her vitamin D deficiency had been managed orally with Adcal-D3 and colecalciferol 800IU once daily, which was uptitrated to 1600IU once daily prior to commencing denosumab. However, despite the patient’s serum vitamin D levels rising from 33.5 to 37.2nmol/L in the months preceding her first denosumab infusion, serum calcium had fallen below normal range on post-infusion blood tests. Serum phosphate returned at 0.91mmol/L, and vitamin D had fallen to 23.1nmol/L in the three months following denosumab treatment. Consequently, the patient was commenced on longer term intensive vitamin D supplementation. Discussion This case raises the issue of multifactorial hypocalcaemia against a backdrop of osteoporosis, persistent vitamin D deficiency, and medical comorbidity limiting management options. The significance of CKD in this case highlights the importance of monitoring and replacing vitamin D. While the hypocalcaemia detected at three months post-infusion may have occurred in part due to the direct effect of denosumab, the patient’s vitamin D deficiency no doubt also played a role in this, and failing to detect the deficiency may have resulted in premature termination of denosumab treatment. This case also highlights the extended timeframe in which such hypocalcaemia may present. Case-series literature describes hypocalcaemia manifesting at, on average, eight days post-infusion in patients with CKD-associated hyperparathyroidism. However we demonstrate here that extended lag times up to twelve weeks are possible; the patient was symptomatic with leg cramping at the time of clinic follow up. Future practice may benefit from establishing monitoring regimes for those with CKD and osteoporosis receiving denosumab, or bisphosphonates toward the lower end of permitted renal function. Key learning points Chronic kidney disease both limits available management options in osteoporosis, and increases the likelihood of complications from the remaining available agents – illustrated here with hypocalcaemia. Hypocalcaemia in a patient with chronic kidney disease and osteoporosis may be driven by several factors: hyperphosphataemia, vitamin D deficiency, and the effect of denosumab to prevent mobilisation of calcium from bone to serum can all be culprits. Calcium, phosphate, and vitamin D all need to be tightly monitored in medically complex patients on treatment for osteoporosis.

Effect of agents affecting bone homeostasis on short- and long-term implant failure.

To review the current evidence on the relationship between agents that affect bone homeostasis and dental implant failures. Electronic searches for bisphosphonates, denosumab, methotrexate, corticosteroids, romosozumab, sunitinib, and bevacizumab were performed using PubMed, MEDLINE (OVID), EMBASE (OVID), Cochrane Central Register of Controlled Trials (Cochrane Library), Cochrane Oral Health Group Trials Register (Cochrane Library) and Web of Science (Thomson Reuters). Manual searches were also conducted to complement the digital searches for recent issues. Previous publications suggested that bisphosphonates do not compromise the survival of dental implants. However, one study documented an increased risk of implant failure in patients who had received high-dose of intravenous bisphosphonate therapy after implant rehabilitation. There has been an issue of MRONJ around implants in patients who have successfully received implant therapy before and after antiresorptive therapy, leading to late implant failure. Despite evidence on the detrimental effects of denosumab, methotrexate and corticosteroids on bone metabolism, their role in implant survival is not conclusive. At present, there is insufficient evidence to establish a potential connection between agents that affects bone homeostasis and implant failure. However, some studies have reported negative results for implant therapy. In addition, implant-related sequestration in patients who received anti-resorptive therapy, despite of successful osseointegration, is also noticeable. Although limited studies are available at present, clinicians should still carefully consider the potential hazards and take appropriate precautions to minimize the risks associated with the medications and implant therapy.

The Effect of Denosumab in Elderly Patients Regarding Bone Density and Fracture Risk.

With an aging population, the importance of treating and diagnosing osteoporosis is increasing. Osteoporosis, previously known as a resorptive change primarily related to endocrinological mechanisms, is also being approached as a phenomenon of senile change. Denosumab is gaining popularity among osteoporosis medications due to its ability to increase bone mineral density (BMD) and the economic benefit arising from the 6-month cycle. In line with previous literature, this study aimed to examine the BMD-augmenting effect of denosumab through which it reduces fracture risk in individuals aged over 80 years. We reviewed patients who received denosumab between 2018 and 2022 with a minimum clinical observation period of 12 months. BMD was measured every 12 months, and patients were classified per their period of denosumab use. Fracture risk was evaluated using the fracture risk assessment tool (FRAX) and fracture incidence during the observation period were assessed. Among 155 patients, a significant increase in BMD was observed at 3 sites: the lumbar spine, femoral neck, and total hip (p<0.001, p<0.001, and p=0.001, respectively). The patients were divided according to the length of clinical follow-up they received, and similar results were found in all subgroups. Fracture risk assessment was performed using FRAX and the incidence of fracture events during follow-up. FRAX significantly decreased in all subgroups except those who received 24 months of follow-up (p=0.003, p=0.41, p=0.001 in the 12, 24, and ≥36 months groups, respectively). Denosumab use resulted in long-term BMD increase and reduced fracture risk in individuals aged 80 and above.

Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. 241 consecutive women (median age 58years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24months of follow-up. During the study period, 139 women (57.7%) received denosumab 60mg every 6months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

Comparison of anti-fracture effectiveness of zoledronate, ibandronate and alendronate versus denosumab in a registry-based cohort study

SummaryThis registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.PurposeTo analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting.MethodsThis registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting.ResultsA total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab.ConclusionsWhen adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.

Meta-analysis of the effects of denosumab and romosozumab on bone mineral density and turnover markers in patients with osteoporosis.

To assess the alterations in bone mineral density and bone turnover marker concentrations following the administration of denosumab and romosozumab therapies in patients with osteoporosis. PubMed was searched for studies published until January 28, 2023, that investigated the clinical efficacy and bone turnover marker changes of denosumab and romosozumab in the treatment of osteoporosis, with a minimum follow-up of 3 months in each study. Studies were screened, and data on changes in bone mineral density (BMD), P1NP, and TRACP-5b levels after treatment were extracted and included in the analysis. Six studies were analyzed. At 3 months after treatment, the romosozumab group showed greater changes in lumbar BMD and bone turnover markers. BMD of total hip and femoral neck was relatively delayed. Beginning at 6 to 12 months, romosozumab showed greater changes in bone mineral density and markers of bone turnover. Both romosozumab and denosumab have antiosteoporotic effects, with greater effects on BMD and bone turnover markers observed within 12 months of romosozumab treatment. https://www.crd.york.ac.uk/prospero, identifier CRD42023395034.

Denosumab use in osteogenesis imperfecta: an update on therapeutic approaches.

Osteogenesis imperfecta (OI) is an inherited skeletal disorder that leads to bone fragility and multiple fractures. Given advances in the genetic understanding of existing phenotypes and newly discovered mutations, therapeutic management of OI has become challenging. Denosumab, a monoclonal antibody that inhibits the interaction between the receptor activator of nuclear factor kappa B ligand (RANKL) and its receptor RANK, has been approved to treat postmenopausal osteoporosis and emerged as an important therapy for malignancies and other skeletal disorders, including pediatric skeletal conditions such as OI. This review summarizes information about denosumab therapy in OI by exploring its mechanisms of action, main indications, and safety and efficacy. Several case reports and small series have been published about the short-term use of denosumab in children with OI. Denosumab was considered a strong drug candidate for OI patients with bone fragility and a high risk of fracture, particularly for patients with the bisphosphonate (BP)-unresponsive OI-VI subtype. The evidence for denosumab's effects in children with OI indicates that it effectively improves bone mineral density but not fracture rates. A decrease in bone resorption markers was observed after each treatment. Safety was assessed by tracking the effects on calcium homeostasis and reporting side effects. No severe adverse effects were reported. Hypercalciuria and moderate hypercalcemia were reported, suggesting that BPs be used to prevent the bone rebound effect. In other words, denosumab can be used as a targeted intervention in children with OI. The posology and administration protocol require more investigation to achieve secure efficiency.

Evaluation of the efficacy and tolerability of alendronate versus denosumab in kidney transplant patients with reduced bone mineral density.

To compare the effect of denosumab and alendronate on bone mineral density (BMD) in renal transplant recipients (RTRs) with low bone mass. Patients were randomized to receive either denosumab subcutaneously (60 mg/6 months), oral alendronate (70 mg/week), or no treatment for 1 year. The three groups were prescribed daily calcium and vitamin D. Primary outcome was BMD assessed at lumbar spine, hip, and radius and measured by dual-energy X-ray absorptiometry (DEXA) at baseline and after 6 and 12 months. Adverse events and laboratory assessments (calcium, phosphate, vitamin D, renal functions, and intact parathyroid hormone) were monitored for all patients. Quality of life was assessed at baseline and after 6 and 12 months for all patients. Ninety RTRs were included in the study (30 in each group). Baseline clinical characteristics and BMD values were comparable in the three groups. After 12 months, lumbar spine T-score of patients treated with denosumab and alendronate showed a median increase of 0.5 [95% confidence interval (CI): 0.4-0.6] and 0.5 (95% CI: 0.4-0.8), respectively, and patients in the control group showed a decrease of -0.2 (95% CI: -0.3 to -0.1), p < 0.001. Denosumab and alendronate showed a significant comparable gain in T-scores at hip and radius versus a significant decrease in the control group. Adverse events and laboratory values were similar in the three groups. Both treatments resulted in comparable significant improvement in physical functioning, physical role limitations, vitality, and pain scores. Denosumab and alendronate showed comparable efficacy in improving BMD at all measured skeletal sites and were safe and well-tolerated, with no serious adverse effects reported in RTRs with low bone mass. The study was registered on ClinicalTrials.gov, number NCT04169698.

Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study

IntroductionIncreased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. Materials and methodsWe have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). Results13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (−4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DiscussionThis study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. ConclusionDenosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Effects of denosumab on bone mineral density and bone metabolism in patients with end-stage renal disease: A systematic review and meta-analysis.

The effects of denosumab on bone mineral density (BMD) and metabolism in patients with end-stage renal disease (ESRD) remain controversial. Hence, we performed a systematic review and meta-analysis of observational studies. The MEDLINE, EMBASE, and Cochrane Library databases were searched in June 2022 to identify studies that evaluated the risk of denosumab-associated hypocalcemia and changes in bone metabolism, changes in BMD from baseline to post-treatment in patients with ESRD. Twelve studies with 348 participants were included. The pooled incidence of hypocalcemia during denosumab treatment was 35.0% (95% confidence interval [CI], 25%-46%; I2 = 63.6%). There were no significant changes in either the serum calcium or phosphate levels from the baseline to post-treatment period; the mean differences were 0.04 mg/dL (95% CI, -0.12 to 0.20 mg/dL) and -0.39 mg/dL (95% CI, -0.89 to 0.12 mg/dL). We found significant changes in the alkaline phosphatase and parathyroid hormone levels; the standardized mean differences were -2.98 (95% CI, -5.36 to -0.59) and -3.12 (95% CI: -4.94 to -1.29), respectively. Denosumab may increase BMD, with mean differences of 9.10% (95% CI: 4.07%-14.13%) and 9.00% (95% CI: 5.93%-12.07%) for the femoral neck and lumbar spine, respectively. Denosumab increased the BMDs of the lumbar spine and femoral neck in patients with ESRD. The onset of hypocalcemia must be carefully monitored during denosumab administration.

Denosumab effect on bone mineral density and urinary-NTX in breast cancer patients receiving aromatase inhibitors.

Aromatase inhibitors are used post-surgical intervention in postmenopausal patients with breast cancer. However, these drugs accelerate decline in bone mineral density (BMD), which is countered by use of denosumab, and the efficacy of the drug can be assessed by bone turnover markers. We investigated the effects of denosumab administration for 2years on BMD and urinary N-telopeptide of type I collagen (u-NTX) levels in breast cancer patients treated with aromatase inhibitors. This was a single-center retrospective study. Postoperative hormone receptor-positive breast cancer patients with low T-scores biannually received denosumab from the time of initiation of aromatase inhibitor therapy for 2years. BMD was measured every 6months, and u-NTX levels were assessed after 1month and thereby every 3months. The median patient age of the 55 patients included in this study was 69 (range: 51-90) years. BMD gradually increased in the lumbar spine and femoral neck and u-NTX levels were lowest at 3months post-initiation of therapy. Patients were divided into two groups based on the change ratio of u-NTX 3months post-denosumab administration. Of these, the group with higher change ratio showed a higher degree of BMD restoration in the lumbar spine and femoral neck 6months post-denosumab treatment. Denosumab increased BMD in patients treated with aromatase inhibitors. The u-NTX level decreased soon after start of denosumab treatment, and its change ratio is predictive of improvement in BMD.

Denosumab for osteoporosis in patients with primary hyperparathyroidism and mild-to-moderate renal insufficiency.

We aimed to assess the efficacy and safety of denosumab in postmenopausal women with primary hyperparathyroidism (PHPT)-related osteoporosis and chronic kidney disease (CKD). Women over 50 years of age with PHPT or postmenopausal osteoporosis (PMO) were retrospectively recruited into this longitudinal study. These PHPT and PMO groups were further categorized into subgroups based on the presence of CKD (Glomerular filtration rate (GFR) < 60 mL/min/1.73 m2). All patients were given denosumab over 24 months due to verified osteoporosis. The primary outcomes were changes in bone mineral density (BMD) and serum calcium levels. 145 postmenopausal women median age 69 [63;77] were recruited and assigned to one of the subgroups: PHPT patients with CKD (n = 22), PHPT patients without CKD (n = 38), PMO patients with CKD (n = 17) and PMO patients without CKD (n = 68). Denosumab treatment significantly increased BMD in patients with PHPT-related osteoporosis and CKD: median T-score L1-L4 from -2.0 to -1.35 (p < 0.001), femur neck from -2.4 to -2.1 (p = 0.012), radius 33% from -3.2 to -3 (p < 0.05)) at 24 months. Changes in BMD were similar in all four studied groups compared to baseline. A marked decline in calcium was noted in the primary study group of PHPT with CKD (median ΔCa = -0.24 mmol/L p < 0.001), compared to PHPT without CKD (median ΔCa = -0.08 mmol/L p < 0.001) and PMO with or without CKD. Denosumab treatment was well-tolerated with no serious adverse events. Denosumab treatment was similarly effective at increasing BMD in patients with PHPT and PMO with and without renal insufficiency. The calcium lowering effects of denosumab were most significant in patients with PHPT and CKD. The safety of denosumab did not differ among participants with and without CKD.