Publications by authors named "M Carola Zillikens"

229 Publications

A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders.

Front Endocrinol (Lausanne) 2021 13;12:709711. Epub 2021 Aug 13.

Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using and cell-based techniques, and models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
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http://dx.doi.org/10.3389/fendo.2021.709711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444146PMC
August 2021

The association between hyperkyphosis and fall incidence among community-dwelling older adults.

Osteoporos Int 2021 Sep 8. Epub 2021 Sep 8.

Department of Internal Medicine, Division of Geriatrics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Centre Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Hyperkyphosis, an increased kyphosis angle of the thoracic spine, was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Hyperkyphosis could serve as an indicator of an increased fall risk as well as a treatable condition.

Introduction: Hyperkyphosis is frequently found in adults aged 65 years and older and may be associated with falls. We aimed to investigate prospectively in community-dwelling older adults whether hyperkyphosis or change in the kyphosis angle is associated with fall incidence.

Methods: Community-dwelling older adults (n = 1220, mean age 72.9 ± 5.7 years) reported falls weekly over 2 years. We measured thoracic kyphosis through the Cobb angle between the fourth and 12th thoracic vertebra on DXA-based vertebral fracture assessments and defined hyperkyphosis as a Cobb angle ≥ 50°. The change in the Cobb angle during follow-up was dichotomized (< 5 or ≥ 5°). Through multifactorial regression analysis, we investigated the association between the kyphosis angle and falls.

Results: Hyperkyphosis was present in 15% of the participants. During follow-up, 48% of the participants fell at least once. In the total study population, hyperkyphosis was not associated with the number of falls (adjusted IRR 1.12, 95% CI 0.91-1.39). We observed effect modification by age (p = 0.002). In the oldest quartile, aged 77 years and older, hyperkyphosis was prospectively associated with a higher number of falls (adjusted IRR 1.67, 95% CI 1.14-2.45). Change in the kyphosis angle was not associated with fall incidence.

Conclusions: Hyperkyphosis was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Because hyperkyphosis is a partially reversible condition, we recommend investigating whether hyperkyphosis is one of the causes of falls and whether a decrease in the kyphosis angle may contribute to fall prevention.
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http://dx.doi.org/10.1007/s00198-021-06136-6DOI Listing
September 2021

Skin autofluorescence, a non-invasive biomarker for advanced glycation end-products, is associated with Sarcopenia.

J Clin Endocrinol Metab 2021 Aug 28. Epub 2021 Aug 28.

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: Accumulation of advanced glycation end-products (AGEs) in skeletal muscle has been implicated in development of sarcopenia.

Aim: To obtain further insight in the pathophysiology of sarcopenia we studied its relationship with skin AGEs in the general population.

Methods: In a cross-sectional analysis, 2744 participants of Northern European background, mean age 74.1 years were included from the Rotterdam Study. Skin AGEs were measured using AGE readerTMas Skin autofluorescence (SAF), appendicular skeletal mass index (ASMI) using iDXA, hand grip strength (HGS) using a hydraulic hand dynamometer and in a subgroup gait speed (GS) measured on an electronic walkway (n=2,080). We defined probable sarcopenia (low HGS) and confirmed sarcopenia (low HGS and low ASMI) based on European working group on Sarcopenia revised criteria (EWGSOP2) cut-offs. Multivariate linear and logistic regression were performed adjusting for age, sex, body fat percentage, height, renal function, diabetes and smoking status.

Results: The prevalence of low ASMI was 7.7%, probable sarcopenia 24%, slow GS 3%, confirmed sarcopenia 3.5%. SAF was inversely associated with ASMI (β=-0.062, 95%CI = -0.092 - -0.032), HGS (β=-0.051, 95%CI = -0.075 - -0.026) and GS (β=-0.074, 95% CI = -0.116 - -0.033). One unit increase in SAF was associated with higher odds of probable sarcopenia (OR = 1.36, 95% CI = 1.09 -1.68) and confirmed sarcopenia (OR = 2.01, 95% CI = 1.33- 3.06).

Conclusion: Higher skin AGEs are associated with higher sarcopenia prevalence. We call for future longitudinal studies to explore the role of SAF as a potential biomarker of sarcopenia.
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http://dx.doi.org/10.1210/clinem/dgab632DOI Listing
August 2021

Early-Onset Osteoporosis.

Calcif Tissue Int 2021 Jul 8. Epub 2021 Jul 8.

Department of Internal Medicine, Erasmus University Medical Center, 3015, Rotterdam, The Netherlands.

Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < - 2.0 in growing children and a Z-score ≤ - 2.0 or a T-score ≤ - 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.
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http://dx.doi.org/10.1007/s00223-021-00885-6DOI Listing
July 2021

Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer.

J Bone Oncol 2021 Jun 18;28:100355. Epub 2021 Mar 18.

Bone Centre, Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, the Netherlands.

Introduction: Adjuvant endocrine therapy induces bone loss and increases fracture risk in women with hormone-receptor positive, early-stage breast cancer (EBC). We aimed to update a previous position statement on the management of aromatase inhibitors (AIs) induced bone loss and now included premenopausal women.

Methods: We conducted a systematic literature search of the medical databases from January 2017 to May 2020 and assessed 144 new studies.

Results: Extended use of AIs beyond 5 years leads to persistent bone loss in breast cancer extended adjuvant trials and -analyses. In addition to bone mineral density (BMD), vertebral fracture assessment (VFA) and trabecular bone score (TBS) were shown to independently predict fracture risk in real life prospective studies. FRAX® tool does not seem to be reliable for assessing fracture risk in CTIBL. In premenopausal women, there is strong evidence that intravenous zoledronate prevents bone loss but weak conflicting evidence on reducing disease recurrence from independent randomised controlled trials (RCTs). In postmenopausal women, the strongest evidence for fracture prevention is for denosumab based on a well-powered RCT while there is strong evidence for bisphosphonates (BPs) to prevent and reduce CTIBL but no convincing data on fractures. Adjuvant denosumab has failed to show anticancer benefits in a large, well-designed RCT.

Discussion And Conclusions: Extended use of AIs and persistent bone loss from recent data reinforce the need to evaluate fracture risk in EBC women initiated on AIs. Fracture risk should be assessed with clinical risk factors and BMD along with VFA, but FRAX is not adapted to CTIBL. Anti-resorptive therapy should be considered in those with a BMD T-score < -2.0 SD or with ≥ 2 clinical risk factors including a BMD T-score < -1.0 SD. In premenopausal women, intravenous zoledronate is the only drug reported to prevent bone loss and may have additional anticancer benefits. In postmenopausal women, either denosumab or BPs can be prescribed for fracture prevention with pertinent attention to the rebound phenomenon after stopping denosumab. Adjuvant BPs, in contrast to denosumab, have shown high level evidence for reducing breast cancer recurrence in high-risk post-MP women which should be taken into account when choosing between these two.
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http://dx.doi.org/10.1016/j.jbo.2021.100355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080519PMC
June 2021
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