Can vertebral body compression fractures regenerate spontaneously?

Osteoporosis in childhood and adolescence

Summary

Osteoporosis is a disease of the skeletal system that leads to an increased bone fracture rate by impairing the bone microarchitecture. While osteoporosis is a common diagnosis in older adults, osteoporosis in children and adolescents has only recently become increasingly important. A distinction is generally made between two different forms of the disease: Primary osteoporosis is caused by genetic changes in genes relevant to the skeleton, the most common group of diseases is osteogenesis imperfecta with causative mutations in the collagen-1 gene. Internal measures include functional therapeutic measures as well as pharmacological therapies with bisphosphonates. Secondary osteoporosis as a symptom of chronic underlying diseases or pharmacological interventions has a significantly higher prevalence than the primary forms of osteoporosis. Depending on the pathomechanism and course of the underlying disease, there are osteoporotic symptoms of the most varied of severity. The therapy concepts must be adapted to the individual symptoms, the data situation on the use of bisphosphonates is significantly lower than for osteogenesis imperfecta. The aim of this article is to provide an overview of the diagnosis and therapy of the very different forms of pediatric osteoporosis as well as an insight into recent developments for primary and secondary care.

Abstract

Osteoporosis is defined as a pathologic condition of the skeleton with impaired bone microarchitecture and increased bone fragility. In contrast to the well-established standards of care for adult-onset types of osteoporosis, such as postmenopausal osteoporosis, specific guidelines on diagnostics and treatments in pediatric populations have emerged just in recent years. Two major types of pediatric osteoporosis can be distinguished: Primary osteoporosis is caused by mutations in structural or regulatory genes of the skeleton, such as collagen 1A1 / 2. The resulting qualitative or quantitative deficits in bone structure lead to a broad spectrum of bone frailty and soft tissue affection as observed in the different types of osteogenesis imperfecta. Specialized pediatric care involves multidisciplinary management including functional therapy and pharmacologic treatment with bisphosphonates. Secondary osteoporosis as a symptom of nonprimary bone-related conditions represents a much more prevalent condition as compared to primary osteoporosis. Due to the diverse etiologies and underlying pathomechanisms, clinical features vary from case to case and data on specific therapeutic measures is sparse. Patient management has to be tailored to the individual need of the patient and can include bisphosphonate treatment and induction of puberty besides optimization of the underlying condition and functional therapeutic measures. This review aims to provide an overview on diagnostics and current therapeutic options for pediatric osteoporosis and to give insights into recent developments with relevance for primary and secondary care.

Osteoporosis in childhood and adolescence

The skeletal apparatus is a complex organ system that has to meet different demands in the course of life. In child development, the bony portion experiences a significant increase in mineral content, especially during the adolescent growth spurt, which leads to a peak in bone density and fracture resistance up to young adulthood. A pathological structural change in this vulnerable phase can lead to long-term impairment of the quality of life and independence up to permanent health impairments for the affected patients regardless of the cause.

The definition of pediatric osteoporosis is fundamentally different from the criteria for adults and was defined by the International Society for Clinical Densitometry (ICSD) [1] as follows:

  • Non-traumatic vertebral compression fracture

    OR

  • Bone densityFootnote 1 Z ‑ Score ≤ −2 SDS AND relevant fracture historyFootnote 2,Footnote 3

  • Normal bone density does NOT rule out the presence of childhood osteoporosis

As can be seen from the definition, the diagnostic focus of children and adolescents is on recording clinical symptoms in terms of the tendency to fracture and, as in adults, is not based solely on findings from bone density measurements. An important point of criticism of the currently valid definition is the need for recurrent fracturing, which, especially in children and adolescents with a high risk of osteoporosis, often leads to a delay in the diagnosis and thus also to a delayed initiation of therapeutic measures. Furthermore, in the current definition, frequent fractures such as forearm fractures in healthy children and adolescents are not sufficiently differentiated from fractures such as femoral fractures, which are rare in healthy people. Correspondingly, diagnostic instructions for the clarification of pediatric osteoporosis have recently been propagated, which include not only bone density, but also the character of the fracture and the clinical context (Fig. 1; [4]).

In childhood and adolescence, the osteoporotic changes are divided into two large groups, which differ in etiology and therapy:

Primary osteoporosis

Primary osteoporosis is defined by rare diseases that, due to genetic changes, lead to structural weakness of the bone and thus to an increased tendency to fracture. The most common forms of primary osteoporosis are known as osteogenesis imperfecta, around 80% of which are caused by changes in the genes Col1A1 and Col1A2, the gene coding for the main collagen in bone. Depending on the genetic change, the course can vary from perinatally lethal symptoms to largely asymptomatic patients. Accordingly, four subgroups of osteogenesis imperfecta are divided according to Sillence [5]. Although the original classification is still widespread in the clinic, the genetic diversity and new insights into pathomechanisms can only be partially mapped [6]. In addition to further approaches to the classification, the updated version of the Sillence classification was published in 2014, which represents a continuum to the widespread typification as well as an overview of the genetic cause and clinical course of the individual forms (Tab. 1).

The most common types of osteogenesis imperfecta are type I with a moderate tendency to fracture without a progressive-deforming course and type 3 with congenital fractures and deformities. Typical accompanying symptoms in both types are blue-grayish sclera, caused by the altered refraction of light due to the disturbed collagen structure arise.

Other symptoms include enamel defects (dentinogenesis imperfecta), slack ligaments and joints, slight hematoma formation, hearing impairment, and rare symptoms such as basilar vagination and cardiac abnormalities. Especially in the case of severe forms of the disease, interdisciplinary patient care by specialized facilities for pediatric orthopedics and osteology is essential in order to enable a coordinated approach to pharmacological therapies as well as corrective and stabilizing surgical interventions. The aim is to achieve the least possible restricted mobility as well as independent everyday and professional ability, which can be achieved for most patients. For patients with a mild form of the disease, everyday life as normal as possible with a high level of participation and activity is aimed for, whereby sporting restrictions can often be largely avoided through the use of protective clothing (shin guards, back protectors) and coordination training. When dealing with children and adolescents with osteogenesis imperfecta, the self-assessment and pain perception of the patients is important information for supervising institutions such as kindergartens, schools and carers, which should be taken seriously and should not be ignored. Multidisciplinary medical care by a specialized team from pediatrics, pediatric orthopedics, functional therapy and skeletal radiology forms the basis of care and coordination of patient care.

Secondary osteoporosis

For a long time, osteoporosis was mainly viewed as a disease of late adulthood, which is of little importance in childhood and adolescence. It is only recently that the pediatric forms of acquired osteoporosis have received greater scientific attention. Due to the vulnerability during skeletal maturation, pathological effects on the skeletal system can be associated with irreversible, long-term consequences and corresponding consequences for the quality of life. The awareness of the supervising disciplines and thus early diagnosis and therapy are therefore of great importance. A recent consensus of the Spanish Society for Pediatric Rheumatology gives a good overview of common causes and diagnostic approaches for osteoporotic changes in children and adolescents; a modified overview can be found in Table 2 [8]. Common etiologies of secondary pediatric osteoporosis are described as examples in the following paragraphs.

Glucocorticode-induced osteoporosis

Long-term treatment with glucocorticoids is one of the most common risk factors for pediatric osteoporosis and, in combination with the existing underlying disease, can lead to a pronounced phenotype. Despite the increasing use of biologicals, glucocorticoids are still an essential treatment option for a large number of inflammatory diseases. By changing the ratio of osteoprotegerin to receptor activator of nuclear factor-kappa-B ligand (RANKL), glucocorticoids lead directly to a strong stimulation of the bone-degrading osteoclast activity. In addition to specific risk factors for the underlying diseases (such as cytokine production in rheumatoid diseases or malnutrition in inflammatory bowel diseases), the development of osteoporotic symptoms is potentiated.

Since the course of the underlying disease is decisive for the total exposure to bone-impairing substances, the inclusion criteria influence the outcome of clinical studies, especially in the case of glucocorticoid-induced osteoporosis. In specific patient groups, such as juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE), a high rate of vertebral body fractures of 6–28% has been described, although the composition of the collectives makes it difficult to compare the studies [9]. Recent data from a randomized study on oral bisphosphonate therapy in patients with JIA found a significant increase in bone density, but a reduction in the fracture rate could not be proven in a sample of 217 patients [10].

Neuromuscular diseases / muscular dystrophies

Muscular dystrophies such as Duchenne muscular dystrophy (DMD) result in both inactivity osteoporosis and the inflammatory component in an impairment of the bone. In addition, long-term treatment with glucocorticoids is a common and life-prolonging measure that is associated with a vertebral fracture rate of 30–50%. Study data suggest that patients with DMD will survive longer on bisphosphonate therapy, which is attributed, among other things, to the delay in the onset of fractures that restrict mobilization [11]. In the current consensus guidelines, bisphosphonate therapy is recommended for vertebral body fractures or fractures of long tubular bones following inadequate trauma, with screening for asymptomatic vertebral compression fractures being anchored since 2018 [12].

Leukemic Diseases

Acute lymphoblastic leukemia (ALL) is the most common oncological disease in children and adolescents. Canadian data show a high prevalence of vertebral body fractures at diagnosis of 16% and a 6 ‑ year probability of 36% [13]. In contrast to other forms of secondary osteoporosis, patients with successful treatment of ALL often have a high potential for skeletal regeneration. A re-erection of compressed vertebral bodies has been described both spontaneously and with bisphosphonate therapy [13, 14].

Immobilization

The skeletal apparatus is subject to constant adaptation to mechanical influences and loads from muscles and shear forces. This so-called mechanosensing is mainly ensured by network-like connected osteocytes, the numerically most frequent bone cells, and represents a fundamental prerequisite for the coordinated activity of the osteoblasts. A reduction in these mechanical influences leads to a change in bone metabolism and a breakdown of bone substance. The most common diagnoses of immobilization in children and adolescents include infantile cerebral palsy and spinal cord injuries. In addition to the mechanical components, there are often additional risk factors such as malnutrition, low exposure to the sun, low vitamin D levels and low calcium intake, as well as co-medication with classic anti-epileptic drugs. As early as the age of 9, patients with infantile cerebral palsy show almost 100% reduced bone density and fracture prevalence by 26% [15]. The distal femur and the proximal tibia are frequent sites of fractures without or after minimal trauma. The overlap of the immobilization with other specific risk factors of the underlying disease, such as muscular dystrophies or severe forms of osteogenesis imperfecta, adds to the complexity and necessity of individualized therapy at. Therapy concepts such as whole-body vibration therapy can lead to improvements in muscular function [16]. Similar to other forms of secondary osteoporosis, attempts at therapy with bisphosphonates have increased bone density, but there are no clear data on reducing the incidence of fractures.

A special form of secondary osteoporosis is increased bone resorption with severe burn injuries: the massive release of cytokines and endogenous glucocorticoids together with immobilization often leads to massive muscle and bone loss, which leads to a fracture in up to 15% of the children affected [17]. Bisphosphonates were able to efficiently prevent the loss of mineral substance in a placebo-controlled, randomized study [18]; recent in vitro data also support the hypotheses of positive effects of bisphosphonates on muscle catabolism in burned patients [19].

Prevention

In children and adolescents at risk of developing osteoporosis, prevention is of paramount importance. Adequate intake of calcium and vitamin D, along with adequate calorie and protein intake and normalization of the BMI, is often the first step towards minimizing risk factors. In addition to optimizing possible underlying diseases, therapeutic approaches that save glucocorticoids are often important steps in avoiding osteoporotic changes. In the case of delayed puberty development as a common symptom of chronically ill children, initiation of puberty at an appropriate age should be considered in order to enable physiological bone maturation and an increase in mineral content. Physical activity, functional therapies and, if necessary, pain therapies are essential to avoid immobilization (Table 3).

Functional therapy concepts

Improving mobility and maintaining independence are important therapy goals aimed at by strengthening the musculoskeletal apparatus. In both primary and secondary osteoporosis, there is often hypotonia; after fractures or operations, learning a new sequence of movements can be essential for maintaining function. In addition, fear of movement and learned inactivity often have to be overcome through targeted and supportive training. Functional therapy by an experienced team is an integral part of patient care, especially for patients with previous fractures, operations or bone pain.

Targeted rehabilitation concepts, based on whole-body vibration training and various cycles of functional-therapeutic interventions, were able to increase both motility and bone density in patients with severe osteogenesis imperfecta [20]. The establishment of specific rehabilitation programs, however, requires a high degree of interdisciplinary cooperation, resource allocation and scientific support in order to be able to achieve the best possible outcome for the patient.

Drug therapy options

Bisphosphonates

Bisphosphonates are derivatives of pyrophosphate with a high affinity for the hydroxyapatite of the bone. By inhibiting the mevalonate signaling pathway, ostoclastogenesis is inhibited, which leads to a reduction in absorption and bone remodeling.Both parenteral and enteral formulations are available, but oral administration is limited by the risk of esophagitis due to incorrect use in younger patients. The most common i.v. Preparations in the DACH region are zoledronate, neridronate and pamidronate, while the oral preparations are mainly risedronate and alendronate. By publishing a consensus of the Australasian Pediatric Endocrine Group A structured review article on the use of bisphosphonates in children and adolescents for clinical use in primary and secondary osteoporosis has been available since 2018 [21].

Bisphosphonates in osteogenesis imperfecta

The broadest experience regarding the use of bisphosphonates in pediatric osteoporosis is in patients with osteogenesis imperfecta, in whom this group of substances has been used for several decades. With the publication of a Cochrane review, improvements in bone density were reported, but a general statement on the fracture rate, pain or growth could not be given due to insufficient data [22]. Any differences with regard to the effectiveness on vertebral changes make intravenous administration the preferred treatment option in the case of corresponding symptoms. Therapy is usually indicated by a fracture rate of two long bones per year, a singular vertebral body fracture or chronic bone pain.

Bisphosphonates in secondary osteoporosis

The use of bisphosphonates in secondary osteoporosis should only ever take place under the condition that the risk factors have been optimized, as indicated above. In particular, a vitamin D deficiency must be compensated for before therapy is initiated, otherwise severe hypocalcemia is possible. The data on drug therapy for children and adolescents with secondary osteoporosis is usually relatively small, as randomized placebo-controlled studies are rarely carried out in these cohorts. The relevant factor is the characteristic of the underlying cause: while in children and adolescents with leukemic diseases there is a rather temporary course with a high endogenous recovery probability, diseases such as muscular dystrophies usually have a progressively worsening course. Accordingly, it is important to be able to offer a therapy to those patients who benefit most from the therapy in the risk-benefit assessment.

Side effects

The most common therapy-associated side effect - especially with the first administration of bisphosphonate therapy - is an acute phase reaction with fever, bone pain and nausea, which occurs in up to 80% of patients. Due to the generally good response to anti-inflammatory drugs, this symptom, which usually occurs 1–2 days after administration, can be discussed with the families in advance and managed well. A dose reduction at the first dose is recommended in most therapy regimens. The inhibition of osteoclast activity can lead to a therapy-associated decrease in serum calcium. Correspondingly, a sufficient 25-OH vitamin D status at the start of therapy as well as an adequate calcium and phosphate supply must be ensured. Bisphosphonate-induced osteonecrosis of the jawbone as a typical complication in adults has not yet been observed in children and adolescents. A safety interval for invasive maxillofacial surgery of 6–12 months is nevertheless recommended. Esophagitis represents a rare but threatening complication of oral bisphosphonates, which must be taken through the esophagus as quickly as possible. Together with the unclear data situation regarding the effect on vertebral body fractures, the indication for oral administration in the pediatric field is severely limited. Due to possible effects on fracture healing, the development of a callus formation before administration is generally recommended. The data on delayed healing after osteotomies is not clear; if necessary, an adaptation of the administration is indicated in order to avoid effects on the healing process. Contraindications are pregnancy, renal insufficiency, florid rickets and hypophosphatasia (inhibiting ALPLMutations with reduced alkaline phosphatase activity).

Perspectives of drug therapy

The use of specific anti-osteoporotic biologics has been established for years in the adult sector thanks to the approval of the monoclonal RANKL antibody denosumab, but has only been tested in case series in the pediatric sector. Strong fluctuations in the serum calcium level, rebound hypercalcemia after the end of therapy and the observation of a loss of effectiveness during long-term treatment currently only permit use outside of study protocols in individual cases. Data from a multicenter study on the treatment of pediatric patients with osteogenesis imperfecta are expected in 2023 [23].

In contrast to the antiresorptive character of bisphosphonates and denosumab, osteoanabolic therapeutic agents such as parathyroid hormone (PTH) analogues are potentially significantly more effective substances for the treatment of osteoporosis. However, due to an increased malignancy rate in animal experiments, this group of substances is not available in the pediatric field. With the development and recent approval of a monoclonal sclerostin antibody (romosozumab) for postmenopausal women, there is now the prospect of an osteoanabolic therapy option in the pediatric field. However, data on the use in patients with osteogenesis imperfecta are not expected for the next few years.

Conclusion

The diagnosis and therapy of osteoporosis in children and adolescents is a clinical challenge - clinical algorithms and improved specific diagnostics help in everyday clinical practice to diagnose rare genetic forms and to differentiate them from sporadic fractures in healthy children. Screening examinations using bone density measurements are not indicated. With the steadily growing group of children and adolescents with a chronic underlying disease, growing awareness of the development of osteoporotic changes is essential. Despite the need for improvement, there are now therapy options available for both primary and secondary osteoporosis in pediatric patients with rich empirical values, which can be individually adapted to the patient's needs if necessary. The care provided by multidisciplinary teams, who have pediatric and internal orthopedic expertise as well as pediatric orthopedic expertise, is an important point in patient care, especially when the disease progresses This vulnerable patient cohort hope to be able to increase the quality of life, mobility and independence of children and adolescents with osteoporosis in a more targeted manner.

Left

  • Center for Rare Bone Diseases, Mineralization Disorders and Rare Growth Disorders - Vienna Bone and Growth Center www.knochenzentrum.at

  • Patient organization Osteogenesis imperfecta Austria - OIA www.glasknochen.at

conclusion for practice

Osteoporosis in childhood and adolescence includes both rare genetic diseases and bone changes in chronic diseases. The early initiation of diagnostic measures in the event of symptoms such as back pain, frequent fractures or typical stigmata for osteogenesis imperfecta makes a decisive contribution to optimizing therapy and avoiding long-term effects.

Notes

  1. 1.

    DXA measurement of the lumbar spine and the entire body without including the skull (total body less head, TBLH).

  2. 2.

    Standard deviation from age, body length and gender-adjusted norm collective (height-adjusted Z-score) [2, 3].

  3. 3.

    Fracture ≥2 long tubular bones up to the age of 10 or fracture ≥3 long tubular bones up to the age of 19.

literature

  1. 1.

    2019 ISCD Official Positions ISCD. https://www.iscd.org/official-positions/2019-iscd-official-positions-pediatric/. Accessed: October 5, 2020

  2. 2.

    International Society for Clinical Densitometry International Society for Clinical Densitometry (ISCD) —Pediatric Reference Data. https://www.iscd.org/resources/pediatric-resources/reference-data/. Accessed: October 5, 2020

  3. 3.

    Zemel BS et al (2010) Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 95: 1265-1273

    CASArticle Google Scholar

  4. 4.

    Ward LM, Weber DR, Munns CF, Högler W, Zemel BS (2020) A contemporary view of the definition and diagnosis of osteoporosis in children and adolescents. J Clin Endocrinol Metab 105: e2088 – e2097

    Article Google Scholar

  5. 5.

    Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16: 101-116

    CASArticle Google Scholar

  6. 6.

    Fratzl-Zelman N, Misof BM, Roschger P, Klaushofer K (2015) Classification of osteogenesis imperfecta. Wien Med Wochenschr 165: 264–270

    Article Google Scholar

  7. 7.

    Van Dijk F, Sillence D (2014) Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 164: 1470-1481

    Article Google Scholar

  8. 8.

    Galindo-Zavala R (2020) Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children. Pediatr Rheumatol Online J. https://doi.org/10.1186/s12969-020-0411-9

    ArticlePubMedPubMed Central Google Scholar

  9. 9.

    Rousseau-Nepton I, Lang B, Rodd C (2013) Long-term bone health in glucocorticoid-treated children with rheumatic diseases. Curr Rheumatol Rep 15: 315

    Article Google Scholar

  10. 10.

    Rooney M et al (2019) The prevention and treatment of glucocorticoid-induced osteopaenia in juvenile rheumatic disease: a randomized double-blind controlled trial. EClinicalMedicine 12: 79-87

    Article Google Scholar

  11. 11.

    Gordon KE, Dooley JM, Sheppard KM, MacSween J, Esser MJ (2011) Impact of bisphosphonates on survival for patients with Duchenne muscular dystrophy. Pediatrics 127: e353-e358

    Article Google Scholar

  12. 12.

    Birnkrant DJ et al (2018) Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopedic management. Lancet Neurol 17: 347-361

    Article Google Scholar

  13. 13.

    Ward LM et al (2018) Bone morbidity and recovery in children with acute lymphoblastic leukemia: results of a six-year prospective cohort study. J Bone Miner Res 33: 1435-1443

    CASArticle Google Scholar

  14. 14.

    Pandya N, Meller S, MacVicar D, Atra A, Pinkerton C (2001) Vertebral compression fractures in acute lymphoblastic leukemia and remodeling after treatment. Arch Dis Child 85: 492-493

    CASArticle Google Scholar

  15. 15.

    Bowden SA, Mahan JD (2017) Zoledronic acid in pediatric metabolic bone disorders. Trans Pediatr 6: 256-268

    Article Google Scholar

  16. 16.

    Matute-Llorente Á, González-Agüero A, Gómez-Cabello A, Vicente-Rodríguez G, Mallén JAC (2014) Effect of whole-body vibration therapy on health-related physical fitness in children and adolescents with disabilities: a systematic review. J Adolesc Health 54: 385-396

    Article Google Scholar

  17. 17.

    Mayes T, Gottschlich MM, Khoury J, Kagan RJ (2015) Investigation of bone health subsequent to vitamin D supplementation in children following burn injury. Nutr Clin Pract 30: 830-837

    CASArticle Google Scholar

  18. 18.

    Przkora R, Herndon DN, Sherrard DJ, Chinkes DL, Klein GL (2007) Pamidronate preserves bone mass for at least two years following acute administration for pediatric burn. Bone 41: 297-302

    CASArticle Google Scholar

  19. 19.

    Pin F, Bonetto A, Bonewald LF, Klein GL (2019) Molecular mechanisms responsible for the rescue effects of pamidronate on muscle atrophy in pediatric burn patients. Front endocrinol. https://doi.org/10.3389/fendo.2019.00543

    Article Google Scholar

  20. 20.

    Hoyer-Kuhn H et al (2014) A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. J Musculoskelet Neuronal Interact 14: 445-453

    CASPubMed Google Scholar

  21. 21.

    Simm PJ et al (2018) Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. J Pediatr Child Health 54: 223-233

    Article Google Scholar

  22. 22.

    Dwan K, Phillipi CA, Steiner RD, Basel D (2016) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD005088.pub4

    ArticlePubMedPubMed Central Google Scholar

  23. 23.

    Amgen (2020) Multicenter, single-arm open-label extension study to assess long-term safety and efficacy of current or prior treatment with denosumab in children / young adults with osteogenesis imperfecta. https://clinicaltrials.gov/ct2/show/NCT03638128. Accessed: October 4, 2020

Download references

Funding

Open access funding provided by the Medical University of Vienna.

Author information

Affiliations

  1. Clinical Department for Pediatric Pulmonology, Allergology and Endocrinology, University Clinic for Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Dr. Adalbert Raimann & Gabriele Haeusler

  2. Center for Rare Bone Diseases, Mineralization Disorders and Rare Growth Disorders - Vienna Bone and Growth Center, Vienna, Austria

    Dr. Adalbert Raimann & Gabriele Haeusler

Corresponding author

Correspondence to Dr. Adalbert Raimann.

Ethics declarations

Conflict of interest

A. Raimann and G. Haeusler state that they have no conflict of interest.

The authors did not conduct any human or animal studies for this article. The ethical guidelines given there apply to the studies listed.

additional information

Notice from the publisher

The publisher remains neutral with regard to geographical assignments and area names in published maps and institute addresses.

Rights and permissions

Open Access This article is published under the Creative Commons Attribution 4.0 International License, which permits use, reproduction, editing, distribution and reproduction in any medium and format, provided you properly credit the original author (s) and source, a link to Include a Creative Commons license and indicate whether changes have been made.

The images and other third-party material contained in this article are also subject to the named Creative Commons license, unless otherwise stated in the legend. If the material in question is not under the named Creative Commons license and the action in question is not permitted under statutory provisions, the consent of the respective rights holder must be obtained for the further uses of the material listed above.

For more details on the license, please refer to the license information at http://creativecommons.org/licenses/by/4.0/deed.de.

Reprints and Permissions

About this article