International Osteoporosis Foundation Working Group provides guidance; urges caution in the diagnosis and treatment of osteoporosis in adults under 50 years of age
Much of the research defining osteoporosis and fracture risk has focused on older adults, i.e. postmenopausal women and men over the age of 50. While older adults are at highest risk of osteoporosis and related fractures, the disease can also affect younger adults between 20 and 50 years of age. However, the diagnosis and management of osteoporosis in young adults is complicated by special challenges, including a complex pathophysiology and the related fact that there is no clear definition of osteoporosis, or of intervention thresholds, in this age group.
An International Osteoporosis Foundation scientific working group has now published a review which outlines the pathophysiology, diagnosis and management of osteoporosis in young adults, providing a clear screening strategy that includes the use of clinical and laboratory exams.
Dr. Serge Ferrari of the University of Geneva and chair of the IOF Working Group on Osteoporosis Pathophysiology, explains the diagnostic challenge faced by clinicians, ‘Low bone mass in this age group may not necessarily represent a pathological condition, but result instead from low peak bone mass in relation to body size, late puberty, or genetic and environmental background.’
On the other hand, there are young adults who may truly have osteoporosis with bone fragility at a young age. This may result from altered bone modelling and/or remodelling during growth or later due to a chronic disorder or a genetic or idiopathic condition. Typical examples would be inflammatory bowel diseases, particularly Crohn’s disease. These diseases impair bone mass gain and/or accelerate bone loss because of mal-absorption and poor nutrient intake. In addition, low levels of physical activity, secondary amenorrhea, and in many cases the effects of corticosteroid treatment, can have an impact on bone mass.
Distinguishing between these two situations can be all the more difficult because up to 30% of young women and 50% of young men have had fractures during childhood and adolescence, usually traumatic. These are not necessarily associated with skeletal fragility.
An apparently low areal bone mineral density (T-score < -2.5 at spine or hip by DXA) must be interpreted with caution in young adults of small body size (constitutionally lean) and/or stunted growth. Inaccurate ‘diagnosis’ of osteoporosis in young subjects can lead to anxiety, unnecessary drug prescriptions, and in some countries potential restrictions of insurance coverage. Individuals with low bone mass, although possibly deserving investigation depending on the context (for instance to rule out vitamin D deficiency) should not automatically be classified as osteoporotic. This diagnosis only applies when there is evidence of skeletal fragility. Nevertheless, a truly low BMD and/or unusual fractures (such as low-trauma, multiple and vertebral) should prompt investigation for secondary causes of osteoporosis. Careful medical history, clinical and laboratory investigations can reveal an underlying disease that requires specific medical intervention, which in turn will improve bone mass. Bisphosphonates may improve BMD in young subjects with osteoporosis due to various disorders, however the evidence is scarce so far and there are no data on their anti-fracture efficacy. In any case, the indications and duration of anti-resorptive treatment in the young should be as restrictive as possible, particularly in the absence of secondary causes, multiple and/or fragility (vertebral) fractures, and high bone turnover accompanied by documented bone loss. Professor Cyrus Cooper, chair of the IOF Committee of Scientific Advisors, concluded, 'This review will be of assistance to clinicians managing this important problem. The clinical relevance of low bone mineral density in young adults is less well understood than is the case in postmenopausal women and older men. Furthermore, many treatment modalities licensed for use in postmenopausal osteoporosis have not been carefully evaluated in younger adults. Clear guidance as to the interpretation of BMD and the appropriate use of treatments is therefore most timely.' International Osteoporosis Foundation

Researchers have identified a potential new pathway in prostate cancer cells by which cancer-driving gene products can be generated, according to a study.
‘Our work shows that cancers have many more tricks than we thought to generate potential cancer-driving genes or gene products,’ said Hui Li, Ph.D., assistant professor of pathology at the University of Virginia in Charlottesville, and a recipient of an Innovative Research Grant from Stand Up To Cancer (SU2C). The AACR is the scientific partner of SU2C.
Gene fusion is a common characteristic of human cancers. In many cases, the protein products of these gene fusions, which are generated via an RNA intermediate, have a key role in the genesis of the cancer. A well-characterised example of this is the protein that drives chronic myeloid leukaemia, BCR-ABL, which is generated via RNA intermediates from a fusion gene formed by chromosomal translocation — an event involving exchange of genomic DNA between two distinct chromosomes.
‘For many years, chromosomal translocation was considered the sole way in which single RNAs consisting of copies of parts of two genes, so-called fusion RNAs, could be generated,’ said Li. ‘We have shown that fusion RNAs can be generated without changes to DNA by a new mechanism that we are calling cis-SAGe [cis-splicing of adjacent genes].’ Recently, a fusion RNA formed from parts of the SLC45A3 and ELK4 genes was identified in prostate cancer cells in the absence of any DNA alterations. Li and his colleagues confirmed in two prostate cancer cells lines that the SLC45A3-ELK4 fusion RNA could be detected even though there was no evidence of genomic DNA rearrangement.
Detailed molecular analysis of the prostate cancer cell lines indicated that the SLC45A3-ELK4 fusion RNA was generated by cis-SAGe. SLC45A3 and ELK4 are neighbouring genes, and cis-SAGe occurred when an RNA that crossed the boundary between the two genes was formed.
The protein CCCTC-binding factor normally acts to insulate SLC45A3 and ELK4 from each other. Li and his colleagues found that levels of this protein at the gene boundary inversely correlated with the amount of SLC45A3-ELK4 fusion RNA generated, providing molecular insight into how the quantity of this fusion RNA could be regulated.
A functional role for the SLC45A3-ELK4 fusion RNA in prostate cancer was suggested by two observations. First, it promoted the growth of the two prostate cancer cell lines in culture. Second, its levels in human prostate samples correlated with prostate cancer disease progression — normal prostate tissue expressed the lowest levels and prostate cancer specimens from men with metastatic disease expressed the highest levels.
‘These data are not sufficient to say that the SLC45A3-ELK4 fusion RNA has a causal role in prostate cancer,’ said Li. ‘But they are highly suggestive, and I am very excited that this high-risk project, which I would not have been able to pursue without the grant from Stand Up To Cancer, has uncovered what seems to be a new way in which cancer can be driven.’ EurekAlert

The use of genome-wide array analysis in parents whose children are suspected of having a genetic disease shows that the parents frequently also have previously undetected genetic abnormalities, a researcher from The Netherlands told the annual conference of the European Society of Human Genetics. Being aware of this is important to parents because it means that their risk of having another affected child is significantly increased.
Dr. Nicole de Leeuw, a clinical laboratory geneticist in the Department of Human Genetics of the Radboud University Nijmegen Medical Centre in Nijmegen, and colleagues performed genome-wide SNP array analysis in 6,500 patients and 1,874 parents. The patients had intellectual disability and/or congenital abnormalities, and the parents of those in whom an aberration was detected were tested in a similar way to determine whether they had the same aberration as their child. Mosaic aberrations, where both genetically normal and abnormal cells are present in an individual, were not only found in one in every 300 patients, but in one in every 270 parents as well. ‘These abnormalities occurred more frequently than we had expected’, said Dr. de Leeuw. ‘Armed with this knowledge, we can try to understand not only why, but also how genetic disease arises in individuals, and this can help us to provide better genetic counselling.’
Analysis of patients’ genomes showed 6.5% de novo (spontaneously arising) genomic imbalances, 9.1% of rare, inherited imbalances, and 0.8% of X-linked abnormalities. Moreover, with the additional data from their SNP array test results, the researchers were able to subsequently find pathogenic mutations in recessive disease genes, uniparental disomies (where a single chromosome is doubled leading to two genetically identical ones), and mosaic aneuploidies (an extra or missing chromosome in some of the cells of the body) in about 30 patients.
‘In at least seven families, these findings meant that what we had thought of as a spontaneously arising, non-inherited genetic abnormality in a child was in fact already present in some form in the parent’, said Dr. de Leeuw. ‘Furthermore, when we tested in different cell lines – for example, DNA from blood and that from a mouth swab – we often found that results varied. This is because mosaic aberrations can occur in cells in some organs and not in others, and underlines the importance of not just relying on one type of cell line for this kind of genetic diagnosis.’
In two cases these tissue-dependent differences changed over time, and the researchers believe that this was due to an attempt by the body to correct and rescue the situation. ‘Such rescue attempts are best known in cases of trisomy, where there are three chromosomes instead of two in a cell, or monosomy, where there is only one. In both these cases, the body may try to correct the situation by respectively deleting or adding (doubling) a chromosome. Such rescue mechanisms may be more common than we expected, and by using genome-wide SNP array analysis it will help us to reveal them. For some patients, it would be particularly interesting if we could test multiple samples of these patients over time’, said Dr. de Leeuw. EurekAlert

Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.
A team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.
De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.
Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analysing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.
‘Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,’ said Gleeson. Realising they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.
The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.
‘We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly,’ said Gleeson. ‘These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.’
The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.
‘Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere,’ said Mathern. ‘Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere.’
But a less-invasive drug therapy would still be more appealing.
‘We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly,’ said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. ‘We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?’ EurekAlert

In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.
AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.
GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.
BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.
In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.
Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.
‘Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD. Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease’ explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, ‘previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.’
Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. ‘These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,’ added Farrer. Boston University Medical Center