The Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months... Show moreThe Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab.Purpose In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years.Methods TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months +/- 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 +/- 2.3 years (range 1-10 years). Of these, 38 were treatment naive (group 1) and 21 had received other treatments prior Dmab (group 2).Results Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (r(s) = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites.Conclusion Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption. Show less
Kalisvaart, G.M.; Heijden, L. van der; Cañete, A.N.; Sande, M.A.J. van de; Gelderblom, H.; Langevelde, K. van 2023
Rationale and objectivesDenosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high... Show moreRationale and objectivesDenosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high morbidity. Time intervals for treatment effects to occur are unclear and monitoring tools are limited, complicating optimal drug dose titration. We assessed changes in time intensity curve (TIC) - derived perfusion features on DCE-MRI in GCTB during denosumab treatment and evaluated the duration of treatment effects on tumor perfusion.Materials and methodsPatients with GCTB who underwent dynamic contrast enhanced (DCE) MRI before (t = 0) and after 3 (t = 3), 6 (t = 6) or 12 (t = 12) months of denosumab treatment were retrospectively included in a single center. Regions of interest were placed on tumor compartments with visually most intense enhancement and TICs were created. Time-to-enhancement (TTE), wash-in rate (WIR), maximal relative enhancement (MRE), and area-under-the-curve (AUC) were calculated. Differences in perfusion features were calculated with the Wilcoxon signed-rank test.ResultsIn all 24 patients decreased perfusion on DCE-MRI after start of denosumab treatment was seen. TTE increased between t = 0 and t = 3 (p < 0.001). WIR, MRE and AUC decreased between t = 0 and t = 3 (p < 0.001, p = 0.01 and p = 0.02, respectively). No significant differences in features were found between t = 3 and t = 6 or t = 6 and t = 12. No significant perfusion differences in primary versus recurrent, or axial versus appendicular tumors, were found.ConclusionMRI perfusion significantly changed in GCTB within 3 months of denosumab treatment compared to baseline. No further significant change occurred between 3 and 6, and 6 and 12 months of treatment. These findings suggest that evaluation of treatment response and subsequent consideration of maintenance with lower doses of denosumab, may already be indicated after 3 months. In cases where long term denosumab is the preferred therapy, monitoring change in tumor characteristics on DCE-MRI may aid optimal drug dose titration, minimizing side effects. Show less
Osteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly... Show moreOsteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly recognized. As a result, there is growing interest in its prevention and treatment. Important goals of care are to prevent fractures, increase bone mass and trabecular and cortical thickness, reshape vertebral fractures, prevent (or correct) skeletal deformities, and improve mobility, independence, and quality of life. Secondary pediatric osteoporosis is often of multifactorial origin since affected children frequently have more than one acquired factor that is detrimental to bone health. Typical conditions causing osteoporosis are leukemias, progressive muscle or neurological disorders, as well as chronic inflammatory conditions and their treatment. Management of children with osteoporosis involves a multidisciplinary team involving pediatric experts from different subspecialties. With regard to prevention and early intervention, it is important to provide optimal management of any underlying systemic conditions including avoidance, or dose-reduction, of osteotoxic medications. Basic supporting life-style measures, such as appropriate nutrition, including adequate calcium intake and vitamin D, and physical activity are recommended, where possible. When pediatric treatment criteria for osteoporosis are met, antiresorptive drugs constitute the first pharmacological line treatment. Conclusion: This clinical review focuses on the prevention, treatment, and follow-up of children with, or at risk of developing, osteoporosis and the transition from pediatric to adult care. Show less
Schreuder, W.H.; Lipplaa, A.; Cleven, A.H.G.; Berg, H. van den; Bisschop, P.H.; Jongh, R.T. de; ... ; Lange, J. de 2022
Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of... Show moreBackground: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ).Methods: A retrospective cohort study was conducted compromising patients treated with a 1year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety.Results: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0 -50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity.Conclusion: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
GCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of... Show moreGCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of the receptor activator of nuclear factor Kappa-B ligand (RANKL), a mediator of osteoclast activation. Although the mainstay of treatment is complete tumour removal with preservation of bone, therapy with denosumab, an inhibitor of RANKL, has been introduced for selected cases. Objectives: Denosumab-treated GCTB (DT-GCTB) was reported to show a wide spectrum of histological changes such as depletion of osteoclast-like giant cells and intralesional bone deposition, which may lead to diagnostic difficulties. We investigated clinicopathologic and molecular features of DT-GCTB, matched with pre-therapy samples. Participants: 21 cases were included (13 females, 8 males), aged 15 to 64 (median, 30 years). Results: DT-GCTB showed development of sclerotic neocortex and varying degrees of osteosclerosis radiographically. Marked depletion of giant cells, different degree of ossification, fibrosis, and proliferation of mononuclear cells was observed. Staining for H3.3G34W was positive in mononuclear cells in 19 cases (90.5%), while one negative case was positive for H3.3G34V. H3F3A G34W mutation was confirmed in 17 of 19 cases (89.5%), corresponding to nuclear staining with H3.3 G34W antibody. G34L mutation was detected in one G34W negative case, in which H3.3 G34V nuclear positive staining was observed, possibly due to cross-reaction. Conclusions: Post-therapy tumours still exhibit a similar mutation profile, while significantly differing from classic GCTB morphologically. Correlation with history of denosumab administration, awareness of features of DT-GCTB, IHC and molecular studies for histone H3 mutations are important in its assessment. Show less
Meier, M.E.; Bruggen, W. van der; Sande, M.A.J. van de; Appelman-Dijkstra, N.M. 2021
We present two patients with fibrous dysplasia who showed a decrease in lesional size and activity after denosumab therapy. Both patients also experienced a reduction in pain and bone turnover... Show moreWe present two patients with fibrous dysplasia who showed a decrease in lesional size and activity after denosumab therapy. Both patients also experienced a reduction in pain and bone turnover markers, which had not been accomplished during previous bisphosphonate therapy. These cases highlight the potential of denosumab to decrease lesional size in fibrous dysplasia. This finding has been reported in mice, but not in humans. Denosumab may be considered when bisphosphonates are not tolerated or not effective (enough), or in severe cases as neoadjuvant therapy to improve surgical possibilities and outcome. In addition, these results show that Na[F-18]F PET-CT is suitable for detecting change in each fibrous dysplasia lesion distinctively. Show less
Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a... Show morePrimary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naive 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia. Show less
Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection.... Show moreDiscontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures. Trial Registration: NCT02499237; July 16, 2015 Show less
This thesis aimed to provide more insight in the diagnosis of MRONJ and to study the best treatment for MRONJ. In order to give more insight in the different aspects of the diagnosis of MRONJ, part... Show moreThis thesis aimed to provide more insight in the diagnosis of MRONJ and to study the best treatment for MRONJ. In order to give more insight in the different aspects of the diagnosis of MRONJ, part I focuses on origin, clinical and radiological features with a special interest for dental implants. This thesis therefore shows that MRONJ is precipitated by dental pathology, a dental/surgical procedure or a pressure sore. Therefore, there should be a more prominent role for prevention of MRONJ. For dental clinicians, but also for the prescribing doctors (e.g. internists such as oncologist and hematologists, general practitioners) this would mean a focus on informing patients of the possible disease and dose depending risks for MRONJ. Dental check-ups before initiation of the anti-resorptive therapy might be advisable and maintenance of a good dental hygiene is of upmost importance. Consequently, dental hygiene should be optimal in patients using anti-resorptive medication and eligible for implants to prevent development of peri-implantitis, which can lead to MRONJ. In addition the decision for insertion of implants should be made on an individual level and preferably in a specialised centre because of the increased risk of development of MRONJ in long term users.A combination of clinical and radiological examination should dictate the diagnosis and treatment. DRONJ may unintentionally be undertreated because it does not present itself as clearly as BRONJ as this thesis shows. Part II focuses on the surgical treatment of MRONJ. Surgical treatment of BRONJ and DRONJ is challenging since no consensus is found in the literature. This thesis shows that treatment according to our surgical technique has a high success rate in all stages of MRONJ. The technique is based on a few relatively simple surgical principles comprising extensive saucerization and rounding off in combination with primary closure. In literature this technique is in line with others, with comparable success rates. Show less
Introduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two... Show moreIntroduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 +/- 0.2 years of denosumab therapy.Methods: We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM.Results: LS-BMD did not change significantly at year 3 compared to year 2 (-1.35 +/- 1.1%, p = 1.00) and compared to baseline ( -1.96 +/- 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years.Conclusions: A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment. Show less
Giant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign classification, GCTB may be... Show moreGiant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign classification, GCTB may be locally aggressive with local recurrence as a challenging issue. Denosumab is a human monoclonal antibody that inhibits osteolysis via the RANK-RANK ligand pathway. There is currently no consensus on optimal treatment duration or imaging modality for monitoring patients on denosumab therapy. This review illustrates the radiological findings of GCTB on denosumab treatment seen on plain radiographs, CT, MRI, PET-CT and DEXA, with reference to the current literature. Recognizing imaging features indicative of a positive response to denosumab is important for therapeutic decision-making. Imaging findings with respect to duration of denosumab treatment, tumour upregulation during treatment, tumour recurrence and malignant transformation are discussed. The development of a sclerotic neocortex and varying degrees of matrix osteosclerosis are seen on plain radiographs. Reconstitution of subarticular bone and articular surface irregularity are optimally evaluated on CT which can also quantify tumour density. MRI demonstrates heterogeneous low signal matrix and is useful to assess decrease in size of cystic and/or soft tissue components of GCTB. A fat-suppressed fluid-sensitive MR sequence is important to detect tumour reactivation. Reduction in F-18-FDG-PET avidity represents an early sensitive sign of response to denosumab treatment. Regardless of imaging modality, close follow-up in a specialist centre and careful evaluation of nonresponders is necessary as local recurrence after cessation of denosumab treatment and malignant transformation of GCTB have been described. Show less
Effects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values.... Show moreEffects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values. Antiresorptive treatment, in contrast to vitamin D +/- calcium treatment alone, induced BMD-independent increases in bone material strength index, measured by IMI, the magnitude of which depended on pretreatment values.Introduction Bone material strength index (BMSi), measured by IMI in vivo, is reduced in patients with fragility fractures, but there is no information about changes in values during long-term therapy. In the present study, we assessed changes in BMSi in patients receiving antiosteoporotic treatments for periods longer than 12 months.Methods We included treatment-naive patients with low bone mass who had a BMSi measurement with OsteoProbe (R) at presentation and consented to a repeat measurement after treatment. Results We studied 54 patients (34 women), median age 58 years, of whom 30 were treated with bisphosphonates or denosumab (treatment group) and 24 with vitamin D +/- calcium alone (control group). There were no differences in clinical characteristics between the two groups with the exception of a higher number of previous fragility fractures in the treatment group. Baseline hip BMD and BMSi values were lower in the treatment group. After 23.1 +/- 6.6 months, BMSi increased significantly in the treatment group (82.4 +/- 4.3 vs 79.3 +/- 4.1;p < 0.001), but did not change in the control group (81.5 +/- 5.2 vs 82.2 +/- 4.1;p = 0.35). Changes in BMSi with antiresorptives were inversely related with baseline values (r = - 0.43;p = 0.02) but not with changes in BMD. Two patients in the control group with large decreases in BMSi values sustained incident fractures.Conclusion In patients at increased fracture risk, antiresorptive treatments induced BMD-independent increases in BMSi values, the magnitude of which depended on pretreatment values. Show less
