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
Introduction: Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone structure. Its treatment is directed at the processes of bone formation or resorption,... Show moreIntroduction: Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone structure. Its treatment is directed at the processes of bone formation or resorption, that are of utmost importance in fracture healing. We provide a comprehensive review of the literature aiming to summarize and clarify the effects of osteoporosis and its treatment on fracture healing.Material and methods: A literature search was conducted in PubMed and Embase (OVID version). In vivo animal and human studies on long bone fractures were included. A total of 93 articles were included for this review; 23 studies on the effect of osteoporosis (18 animal and 5 clinical studies) and 70 studies on the effect of osteoporosis treatment (41 animal, 26 clinical studies and 3 meta-analyses) on fracture healing.Results: In animal fracture models osteoporosis was associated with decreased callus formation and bone growth, bone mineral density, biomechanical strength and delayed cellular and differentiation processes during fracture healing. Two large databases identified osteoporosis as a risk factor for non-union whereas three other studies did not. One of those three studies however found a prolonged healing time in patients with osteoporosis. Antiosteoporosis medication showed inconsistent effects on fracture healing in both non-osteoporotic and osteoporotic animal models. Only the parathyroid hormone and anti-resorption medication were related to improved fracture healing and delayed remodelling respectively. Clinical studies performed in predominantly hip and distal radius fracture patients showed no effect of bisphosphonates on fracture healing. Parathyroid hormone reduced time to union in several clinical trials performed in mainly hip fracture patients, but this did not result in decreased delayed or non-union rates.Conclusion: Evidence that substantiates the negative influence of osteoporosis on fracture healing is predominantly from animal studies and to a lesser extent from clinical studies, since convincing clinical evidence lacks. Bisphosphonates and parathyroid hormone may be used during fracture healing, since no clear negative effect has been shown. Parathyroid hormone might even decrease time to fracture union, without decreasing union rate. Show less
Abdelrahman, S.; Ireland, A.; Winter, E.M.; Purcell, M.; Coupaud, S. 2021
Osteoporosis is a long-term consequence of spinal cord injury (SCI) that leads to a high risk of fragility fractures. The fracture rate in people with SCI is twice that of the general population.... Show moreOsteoporosis is a long-term consequence of spinal cord injury (SCI) that leads to a high risk of fragility fractures. The fracture rate in people with SCI is twice that of the general population. At least 50% of these fractures are associated with clinical complications such as infections. This review article presents key features of osteoporosis after SCI, starting with its aetiology, a description of temporal and spatial changes in the long bones and the subsequent fragility fractures. It then describes the physical and pharmacological approaches that have been used to attenuate the bone loss. Bone loss after SCI has been found to be highly site-specific and characterised by large inter-variability and site-specific changes. The assessment of the available interventions is limited by the quality of the studies and the lack of information on their effect on fractures, but this evaluation suggests that current approaches do not appear to be effective. More studies are required to identify factors influencing rate and magnitude of bone loss following SCI. In addition, it is important to test these interventions at the sites that are most prone to fracture, using detailed imaging techniques, and to associate bone changes with fracture risk. In summary. bone loss following SCI presents a substantial clinical problem. Identification of at-risk individuals and development of more effective interventions are urgently required to reduce this burden. 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
Acute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism... Show moreAcute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). ZOL, however, has also been reported to inhibit the proliferation of regulatory T cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a negative regulator of T cell activation that is increased in patients with autoimmune diseases. There are, however, no data on the relationship between ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations or in vitro with the use of assays relevant to the mechanism of action of N-BPs. The objectives of the present study were firstly, to characterize the ZOL-induced APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship with changes in circulating sCTLA-4 and secondly, to investigate the effects of ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous ZOL 5 mg. Five women experienced APR (APR + ) associated with significant decreases in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 values were increased in all patients before ZOL administration and decreased significantly 72 h after the ZOL infusion (from 30.0 +/- 2.9 to 6.3 +/- 1.8 ng/ml; p < 0.001) with no differences between APR + and APR- patients. Consistent with the results of the in vivo study, ZOL (1 mu M) decreased the production of sCTLA-4 by 87% and 57% after 3 and 5 days in cultures of peripheral blood mononuclear cells (PBMCs) in vitro, respectively, and inhibited the expression of both cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel immunoregulatory action of ZOL that is not related to its action on bone resorption but might be associated with reported clinically significant extraskeletal outcomes of ZOL treatment. Show less
Bruggen, W. van der; Hagelstein-Rotman, M.; Geus-Oei, L.F. de; Smit, F.; Dijkstra, P.D.S.; Appelman-Dijkstra, N.M.; Vriens, D. 2020
Purpose To quantify (NaF)-F-18-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing... Show morePurpose To quantify (NaF)-F-18-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of (NaF)-F-18-PET/CT uptake parameters in HB and FD. Relating (NaF)-F-18 uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). Methods In a prospective cohort study (n = 20), (NaF)-F-18-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. Results Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R-2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R-2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R-2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R-2 = 0.596, p = 0.007 and R-2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R-2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R-2 = 0.518, p = 0.024), higher TLF (R-2 = 0.478, p = 0.036), and higher levels of FGF-23 (R-2 = 0.567, p = 0.034). Conclusions Individualized (NaF)-F-18-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with (NaF)-F-18-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on (NaF)-F-18-PET/CT was higher in baseline patients using bisphosphonates. This makes (NaF)-F-18-PET/CT a promising tool to quantitatively measure treatment efficacy in FD. 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
Hellemond, I.E.G. van; Smorenburg, C.H.; Peer, P.G.M.; Swinkels, A.C.P.; Seynaeve, C.M.; Sangen, M.J.C. van der; ... ; Dutch Breast Canc Res Grp BOOG 2020
Purpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the... Show morePurpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. Methods We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan-Meier methods and Cox proportional hazards models were used for analyses. Results Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45-1.49), osteoporosis HR 1.10 (95% CI 0.26-4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40-1.42), osteoporosis HR 1.86 (95% CI 0.43-8.01)]. Moreover, bisphosphonate use did not impact DRFS. Conclusion No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS. Show less
Meent, M.M. van de; Wetselaar-Glas, M.J.M.; Fiocco, M.; Appelman-Dijkstra, N.M.; Merkesteyn, J.P.R. van 2019
This thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about... Show moreThis thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about neoadjuvant endocrine therapy, and discusses the optimal duration of this treatment and the information on treatment efficacy that aromatase-inhibitor specific adverse events may provide. Show less
