Showing papers in "Calcified Tissue International in 2019"
University of Liège1, University of Toulouse2, Heidelberg University3, University of Erlangen-Nuremberg4, University of Oxford5, University of Southampton6, King Saud University7, World Health Organization8, Vrije Universiteit Brussel9, Catholic University of the Sacred Heart10, University of Milan11, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico12, Tufts University13, University of Sheffield14, Australian Catholic University15, Ghent University Hospital16, Medical University of Graz17, Public Health Research Institute18, Geneva College19
TL;DR: An overview of different methods available and applicable in clinical settings and the use of grip strength to measure muscle strength and theUse of 4-m gait speed or the Short Physical Performance Battery test to measure physical performance in daily practice are proposed.
Abstract: It is well recognized that poor muscle function and poor physical performance are strong predictors of clinically relevant adverse events in older people. Given the large number of approaches to measure muscle function and physical performance, clinicians often struggle to choose a tool that is appropriate and validated for the population of older people they deal with. In this paper, an overview of different methods available and applicable in clinical settings is proposed. This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were organized afterwards where the whole group could amend and discuss the recommendations further. Several characteristics should be considered when choosing a tool: (1) purpose of the assessment (intervention, screening, diagnosis); (2) patient characteristics (population, settings, functional ability, etc.); (3) psychometric properties of the tool (test–retest reliability, inter-rater reliability, responsiveness, floor and ceiling effects, etc.); (4) applicability of the tool in clinical settings (overall cost, time required for the examination, level of training, equipment, patient acceptance, etc.); (5) prognostic reliability for relevant clinical outcomes. Based on these criteria and the available evidence, the expert group advises the use of grip strength to measure muscle strength and the use of 4-m gait speed or the Short Physical Performance Battery test to measure physical performance in daily practice. The tools proposed are relevant for the assessment of muscle weakness and physical performance. Subjects with low values should receive additional diagnostic workups to achieve a full diagnosis of the underlying condition responsible (sarcopenia, frailty or other).
239 citations
TL;DR: In this article, the authors estimated the excess economic burden for individuals with muscle weakness regarding the provision of health and social care among 442 men and women who participated in the Hertfordshire Cohort Study (UK).
Abstract: Sarcopenia and muscle weakness are responsible for considerable health care expenditure but little is known about these costs in the UK. To address this, we estimated the excess economic burden for individuals with muscle weakness regarding the provision of health and social care among 442 men and women (aged 71–80 years) who participated in the Hertfordshire Cohort Study (UK). Muscle weakness, characterised by low grip strength, was defined according to the Foundation for the National Institutes of Health criteria (men < 26 kg, women < 16 kg). Costs associated with primary care consultations and visits, outpatient and inpatient secondary care, medications, and formal (paid) as well as informal care for each participant were calculated. Mean total costs per person and their corresponding components were compared between groups with and without muscle weakness. Prevalence of muscle weakness in the sample was 11%. Mean total annual costs for participants with muscle weakness were £4592 (CI £2962–£6221), with informal care, inpatient secondary care and primary care accounting for the majority of total costs (38%, 23% and 19%, respectively). For participants without muscle weakness, total annual costs were £1885 (CI £1542–£2228) and their three highest cost categories were informal care (26%), primary care (23%) and formal care (20%). Total excess costs associated with muscle weakness were £2707 per person per year, with informal care costs accounting for 46% of this difference. This results in an estimated annual excess cost in the UK of £2.5 billion.
93 citations
TL;DR: The present article reports and summarizes the main recommendations included in this 2018 guidance document, and updates the previous guidelines document, published in 2013 and is written in a European perspective.
Abstract: A guidance on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis was recently published in Osteoporosis International as a joint effort of the International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (Kanis et al. in Osteoporos Int https://doi.org/10.1007/s00198-018-4704-5 , 2018). This manuscript updates the previous guidelines document, published in 2013 (Kanis et al. in Osteoporos Int 24:23-57, 2013) and is written in a European perspective. The present article reports and summarizes the main recommendations included in this 2018 guidance document.
81 citations
University of California, San Francisco1, Yale University2, Seoul National University3, Johns Hopkins University School of Medicine4, University of Sheffield5, Osaka City University6, Indiana University7, Ohio State University8, University of Tokyo9, University of Oxford10, Royal National Orthopaedic Hospital11, Osaka University12, University College London13, University of Southern California14, University of Edinburgh15, Duke University16, Asan Medical Center17
TL;DR: Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity as discussed by the authors.
Abstract: Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.
73 citations
TL;DR: The known literature on CNO/CRMO is reviewed and areas of interest are proposed as well as possible ways to make current diagnostic criteria more detailed, including unifocal cases of the jaw to be a possible sub-type that may need its own set of criteria.
Abstract: Chronic non-bacterial osteomyelitis (CNO) is a rare auto-inflammatory bone disorder, with a prevalence of around one in a million patients. In the more severe form, it is referred to as chronic recurrent multifocal osteomyelitis (CRMO). We present the current knowledge on epidemiology, pathophysiology as well as diagnostic options and treatment regimens. CNO/CRMO most commonly affects children and lesions are often seen in the metaphyseal plates of the long bones, but cases have been described affecting all age groups as well as lesions in almost every bone. It is, therefore, a disease that clinicians can encounter in many different settings. Diagnosis is mainly a matter of exclusion from differential diagnoses such as bacterial osteomyelitis and cancer. Magnetic resonance imaging is the best radiological method for diagnosis coupled with a low-grade inflammation and a history of recurring episodes. Treatment is based on case reports and consists of alleviating symptoms with non-steroidal anti-inflammatory drugs since the disease is often self-limiting. Recently, more active treatments using either bisphosphonates or biological treatment are becoming more common, to prevent long term bone damage. In general, due to its rarity, much remains unclear regarding CNO/CRMO. We review the known literature on CNO/CRMO and propose areas of interest as well as possible ways to make current diagnostic criteria more detailed. We also find unifocal cases of the jaw to be a possible sub-type that may need its own set of criteria.
55 citations
TL;DR: The focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB.
Abstract: Paget’s disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.
49 citations
Heidelberg University1, Tufts University2, University of Sheffield3, Australian Catholic University4, University of Liège5, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico6, University of Lyon7, King Saud University8, Southampton General Hospital9, Ghent University Hospital10, Catholic University of the Sacred Heart11, National Research Council12, University of Bahrain13, Geneva College14, DuPont15, University of Pavia16, Sofia Medical University17, University of Oxford18
TL;DR: There is insufficient evidence to support a discrete clinical entity of osteosarcopenic obesity at this time, and there is a need for consensus on a definition of bone health-based obesity which will allow for identification, further epidemiological studies and comparisons between studies.
Abstract: The co-existence of impaired bone health (osteopenia/osteoporosis), reduced muscle mass and strength (sarcopenia), and increased adiposity (obesity) in middle-aged and older people has been identified in recent studies, leading to a proposal for the existence of "osteosarcopenic obesity" as a distinct entity. Evidence for the pathophysiological overlap of these conditions is mounting, although a causal relationship is yet to be established. Each component condition occurs frequently with increasing age, and with shared risk factors in many instances, thus, an overlap of these three conditions is not surprising. However, whether the concurrent existence of sarcopenia, osteoporosis and obesity leads to an increased risk of adverse musculoskeletal outcomes and mortality above and beyond the risks associated with the sum of the component parts remains to be proven and is a question of research interest. In this article, we review evidence for the existence of osteosarcopenic obesity including the current operational definition of osteosarcopenic obesity, prevalence, pathophysiology, outcomes and exploratory approaches to the management of components. We conclude that, there is insufficient evidence to support a discrete clinical entity of osteosarcopenic obesity at this time. To expand knowledge and understanding in this area, there is a need for consensus on a definition of osteosarcopenic obesity which will allow for identification, further epidemiological studies and comparisons between studies. Additionally, studies should assess whether the clinical outcomes associated with osteosarcopenic obesity are worse than the mere addition of those linked with its components. This will help to determine whether defining a person as having this triad will eventually result in a more effective treatment than addressing each of the three conditions separately.
44 citations
TL;DR: Critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism in the development of potential therapeutic strategies targeting vascular calcification.
Abstract: Osteoporosis (OP) and cardiovascular diseases (CVD) are both important causes of mortality and morbidity in aging patients. There are common mechanisms underlying the regulation of bone remodeling and the development of smooth muscle calcification; a temporal relationship exists between osteoporosis and the imbalance of mineral metabolism in the vessels. Vascular calcification appears regulated by mechanisms that include both inductive and inhibitory processes. Multiple factors are implicated in both bone and vascular metabolism. Among these factors, the superfamily of tumor necrosis factor (TNF) receptors including osteoprotegerin (OPG) and its ligands has been established. OPG is a soluble decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG binds to RANKL and TRAIL, and inhibits the association with their receptors, which have been labeled as the receptor activator of NF-kB (RANK). Sustained release of OPG from vascular endothelial cells (ECs) has been demonstrated in response to inflammatory proteins and cytokines, suggesting that OPG/RANKL/RANK system plays a modulatory role in vascular injury and inflammation. For the development of potential therapeutic strategies targeting vascular calcification, critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism.
38 citations
TL;DR: This review summarizes the current understanding of pathophysiology in fibrous dysplasia, describes key pre-clinical and clinical investigations, and details the current approach to diagnosis and management.
Abstract: Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by structurally unsound fibro-osseous tissue. It is caused by the sporadic post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein signaling in affected tissues. This manifests on a broad clinical spectrum ranging from insignificant solitary lesions to severe disease with deformities, fractures, functional impairment, and pain. Fibrous dysplasia may present in isolation or in association with hyperfunctioning endocrinopathies and cafe-au-lait macules, known as McCune–Albright Syndrome. This review summarizes the current understanding of pathophysiology in fibrous dysplasia, describes key pre-clinical and clinical investigations, and details the current approach to diagnosis and management.
36 citations
TL;DR: A narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.
Abstract: Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.
35 citations
TL;DR: There is an indication that omega-3 may improve BMD, high-quality RCTs are needed to confirm this and effects on other musculoskeletal outcomes, and trials assessing effects of increasing Omega-3, omega-6 and total PUFA on functional status, bone and skeletal muscle strength are limited.
Abstract: We conducted a systematic review and meta-analysis to assess the effects of increasing dietary omega-3, omega-6 and mixed polyunsaturated fatty acids (PUFA) on musculoskeletal health, functional status, sarcopenia and risk of fractures. We searched Medline, Embase, The Cochrane library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) databases for Randomised Controlled Trials (RCTs) of adults evaluating the effects of higher versus lower oral omega-3, omega-6 or mixed PUFA for ≥ 6 months on musculoskeletal and functional outcomes. We included 28 RCTs (7288 participants, 31 comparisons), 23 reported effects of omega-3, one of omega-6 and four of mixed total PUFA. Participants and doses were heterogeneous. Six omega-3 trials were judged at low summary risk of bias. We found low-quality evidence that increasing omega-3 increased lumbar spine BMD by 2.6% (0.03 g/cm2, 95% CI − 0.02 to 0.07, 463 participants). There was also the suggestion of an increase in femoral neck BMD (of 4.1%), but the evidence was of very low quality. There may be little or no effect of omega-3 on functional outcomes and bone mass; effects on other outcomes were unclear. Only one study reported on effects of omega-6 with very limited data. Increasing total PUFA had little or no effect on BMD or indices of fat-free (skeletal) muscle mass (low-quality evidence); no data were available on fractures, BMD or functional status and data on bone turnover markers were limited. Trials assessing effects of increasing omega-3, omega-6 and total PUFA on functional status, bone and skeletal muscle strength are limited with data lacking or of low quality. Whilst there is an indication that omega-3 may improve BMD, high-quality RCTs are needed to confirm this and effects on other musculoskeletal outcomes.
TL;DR: This study is the first to demonstrate that osteoporosis changes collagen/apatite orientation and Young’s modulus in an opposite manner depending on the cause of osteoporeosis in spite of common bone loss.
Abstract: This study revealed the distinguished changes of preferential orientation of collagen and apatite and Young’s modulus in two different types of osteoporotic bones compared with the normal bone. Little is known about the bone material properties of osteoporotic bones; therefore, we aimed to assess material properties in osteoporotic bones. 66 female Sprague–Dawley rats were used. We analyzed the volumetric bone mineral density, collagen/apatite orientation, and Young’s modulus of fifth lumbar vertebral cortex for osteoporotic rats caused by ovariectomy (OVX), administration of low calcium and phosphate content (LCaP) diet, and their combination (OVX + LCaP), as well as sham-operated control. Osteocyte conditions were assessed by hematoxylin and eosin and immunohistochemical (matrix extracellular phosphoglycoprotein (MEPE) and dentin matrix protein 1 (DMP1)) staining. All osteoporotic animals showed bone loss compared with the sham-operated control. OVX improved craniocaudal Young’s modulus by enhancing collagen/apatite orientation along the craniocaudal axis, likely in response to the elevated stress due to osteoporotic bone loss. Conversely, LCaP-fed animals showed either significant bone loss or degraded collagen/apatite orientation and Young’s modulus. Osteocytes in LCaP and OVX + LCaP groups showed atypical appearance and MEPE- and DMP1-negative phenotype, whereas those in the OVX group showed similarity with osteocytes in the control group. This suggests that osteocytes are possibly involved in the osteoporotic changes in collagen/apatite orientation and Young’s modulus. This study is the first to demonstrate that osteoporosis changes collagen/apatite orientation and Young’s modulus in an opposite manner depending on the cause of osteoporosis in spite of common bone loss.
TL;DR: In young men, sclerostin’s response to high-intensity interval exercise is independent of impact and is not related to changes in bone turnover and oxidative stress markers.
Abstract: This study compared sclerostin’s response to impact versus no-impact high-intensity interval exercise in young men and examined the association between exercise-induced changes in sclerostin and markers of bone turnover and oxidative stress. Twenty healthy men (22.3 ± 2.3 years) performed two high-intensity interval exercise trials (crossover design); running on treadmill and cycling on cycle ergometer. Trials consisted of eight 1 min running or cycling intervals at ≥ 90% of maximal heart rate, separated by 1 min passive recovery intervals. Blood samples were collected at rest (pre-exercise), and 5 min, 1 h, 24 h, and 48 h following each trial. Serum levels of sclerostin, cross-linked telopeptide of type I collagen (CTXI), procollagen type I amino-terminal propeptide (PINP), thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC) were measured. There was no significant time or exercise mode effect for PINP and PC. A significant time effect was found for sclerostin, CTXI, and TBARS with no significant exercise mode effect and no significant time-by-mode interaction. Sclerostin increased from pre- to 5 min post-exercise (47%, p < 0.05) and returned to baseline within 1 h following the exercise. CTXI increased from pre- to 5 min post-exercise (28%, p < 0.05), then gradually returned to baseline by 48 h. TBARS did not increase significantly from pre- to 5 min post-exercise but significantly decreased from 5 min to 48 h post-exercise. There were no significant correlations between exercise-induced changes in sclerostin and any other marker. In young men, sclerostin’s response to high-intensity interval exercise is independent of impact and is not related to changes in bone turnover and oxidative stress markers.
TL;DR: A dynamic relationship between impaired muscle and bone health was observed, with an obvious association between the concomitant incidences of osteoporosis and sarcopenia.
Abstract: The longitudinal relationship between bone health and muscle health is scarcely explored. We aimed to explore the relationship between bone decline and muscle decline over 1 year in older individuals. We used data from the SarcoPhAge cohort, which aims to identify the consequences of sarcopenia. In this way, this study also highlights the yearly changes in muscle mass (by dual-energy absorptiometry), muscle weakness (by grip strength), and/or physical performance (by the short physical performance battery test). Measurements of areal bone mineral density (aBMD), enabling the diagnosis of osteoporosis, and bone microarchitecture (by means of the trabecular bone score) were also performed each year. A 1-year clinically relevant decline in bone and muscle health components was evidenced using the Edwards–Nunnally index. Among the 232 participants with complete data (75.5 ± 5.4 years, 57.8% women), we observed an association between a clinically relevant decline in the skeletal muscle mass index (SMI) and a decrease in aBMD (adjusted OR = 2.12 [1.14–2.51] for the spine, 2.42 [1.10–5.34] for the hip and 2.12 [1.04–5.81] for the neck), as well as a significant association between SMI and deterioration of the skeletal microarchitecture (aOR = 3.99 [2.07–7.70]). A clinically relevant decline in muscle strength was associated with a decrease in spine aBMD (aOR = 2.93 [1.21–7.12]) and hip aBMD (aOR = 3.42 [1.37–7.64]) only. The decline in muscle performance was related to the decline in bone microarchitecture only (aOR = 2.52 [1.23–5.17]). Individuals with incident sarcopenia had an approximately fivefold higher risk of concomitantly developing osteoporosis. A dynamic relationship between impaired muscle and bone health was observed, with an obvious association between the concomitant incidences of osteoporosis and sarcopenia.
TL;DR: The authors' moderate–severe contusion SCI model displayed rapid cancellous bone deterioration and more gradual cortical bone loss and development of whole bone mechanical deficits, which likely resulted from a temporal uncoupling of bone turnover, similar to the sequalae observed in the motor-complete SCI population.
Abstract: To elucidate mechanisms of bone loss after spinal cord injury (SCI), we evaluated the time-course of cancellous and cortical bone microarchitectural deterioration via microcomputed tomography, measured histomorphometric and circulating bone turnover indices, and characterized the development of whole bone mechanical deficits in a clinically relevant experimental SCI model 16-weeks-old male Sprague–Dawley rats received T9 laminectomy (SHAM, n = 50) or moderate–severe contusion SCI (n = 52) Outcomes were assessed at 2-weeks, 1-month, 2-months, and 3-months post-surgery SCI produced immediate sublesional paralysis and persistent hindlimb locomotor impairment Higher circulating tartrate-resistant acid phosphatase 5b (bone resorption marker) and lower osteoblast bone surface and histomorphometric cancellous bone formation indices were present in SCI animals at 2-weeks post-surgery, suggesting uncoupled cancellous bone turnover Distal femoral and proximal tibial cancellous bone volume, trabecular thickness, and trabecular number were markedly lower after SCI, with the residual cancellous network exhibiting less trabecular connectivity Periosteal bone formation indices were lower at 2-weeks and 1-month post-SCI, preceding femoral cortical bone loss and the development of bone mechanical deficits at the distal femur and femoral diaphysis SCI animals also exhibited lower serum testosterone than SHAM, until 2-months post-surgery, and lower serum leptin throughout Our moderate–severe contusion SCI model displayed rapid cancellous bone deterioration and more gradual cortical bone loss and development of whole bone mechanical deficits, which likely resulted from a temporal uncoupling of bone turnover, similar to the sequalae observed in the motor-complete SCI population Low testosterone and/or leptin may contribute to the molecular mechanisms underlying bone deterioration after SCI
TL;DR: The causal inference on an association between smoking and higher fracture risk is strengthened but no linear association of modestly higher alcohol and coffee intake with fracture or BMD is found, however, alcohol dependence may increase fracture risk.
Abstract: The causal associations of smoking and alcohol and coffee intake with fracture and bone mineral density are unknown. We investigated the associations using Mendelian randomization (MR). Summary-lev ...
TL;DR: In this article, achondroplasia (ACH) patients require various medical interventions throughout the lifetime, such as growth hormone administration and limb lengthening surgeries, but no study focused on the treatment strategy by analyzing HRQoL of ACH patients.
Abstract: Patients with achondroplasia (ACH) require various medical interventions throughout the lifetime. Survey of health-related quality of life (HRQoL) in adult ACH patients is essential for the evaluation of treatment outcomes performed during childhood such as growth hormone administration and limb lengthening surgeries, but no study focused on the treatment strategy by analyzing HRQoL of ACH patients. The purpose of this study was to assess whether final height impacted on HRQoL and to evaluate what kinds of medical interventions were positively or negatively associated with HRQoL. We included 184 ACH patients (10–67 years old) who were registered in the patients’ associations or who had a medical history of the investigators’ institutions, and analyzed HRQoL by using Short Form-36 and patient demographics. Physical component summary (PCS) was significantly lower than the standard values in each age, especially in elderly populations, while mental component summary (MCS) was similar to the standard values. Role/social component summary was deteriorated only in elderly populations. The PCS was improved in the patients who had a height of 140 cm or taller (p < 0.001). The PCS and MCS were strongly associated with the past medical history of spine surgeries (p < 0.001 and p = 0.028, respectively). A treatment strategy would be planned to gain a final height of 140 cm or taller during childhood in combination with growth hormone administration and limb lengthening surgeries. Appropriate medical management for neurological complications of adult ACH patients is required to maintain physical and mental function.
TL;DR: It is demonstrated that Met effectively attenuated the cancellous bone loss induced by KD and maintained the biomechanical properties of long bones, providing evidence for Met as a treatment of by KD-induced osteoporosis in teenage skeleton.
Abstract: Metformin (Met), an anti-diabetes drug, has also shown therapeutic effects for ovariectomy-induced (OVX) osteoporosis. However, similar effects against bone loss induced by a ketogenic diet (KD) have not been tested. This study was aimed to evaluate the microarchitectures and biomechanics of KD-induced osteoporosis with and without administration of Met, and compare the effect of Met on bone loss induced by KD with OVX. Forty female C57BL/6J mice were randomly divided into Sham, OVX, OVX + Met (100 mg/kg/day), KD (3:1 ratio of fat to carbohydrate and protein), and KD + Met (100 mg/kg/day) groups. After 12 weeks, the bone mass and biomechanics were measured in distal cancellous bone and in mid-shaft cortical bone of the femur. The activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), together with immunohistochemistry staining of osteocalcin (OCN) and TRAP, were evaluated. Both OVX and KD induced significant bone loss and compromised biomechanical properties in the cancellous bone, but no effect was found in cortical bone. The administration of Met increased the cancellous bone volume fraction (BV/TV) from 3.78 to 5.23% following the OVX and from 4.04 to 6.33% following the KD, it also enhanced the compressive stiffness from 47 to 160 N/mm following the OVX and from 35 to 340 N/mm with the KD. Met effectively increased serum ALP in the KD group while decreased serum TRAP in the OVX group, but up-regulated expression of OCN and down-regulated expression of TRAP in both OVX and KD groups. The present study demonstrated that Met effectively attenuated the cancellous bone loss induced by KD and maintained the biomechanical properties of long bones, providing evidence for Met as a treatment of by KD-induced osteoporosis in teenage skeleton.
TL;DR: Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.
Abstract: Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.
TL;DR: Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system and the evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare.
Abstract: Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia. The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation. Recessive, loss-of-function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL. Multisystem proteinopathy is a disorder characterised by myopathy and neurodegeneration in which PDB is often an integral component. It may be caused by mutations in several genes including VCP, HNRNPA1, HNRNPA2B1, SQSTM1, MATR3, and TIA1, some of which are involved in classical PDB. The mechanisms of osteoclast activation in these conditions are less clear but may involve NFκB activation through sequestration of IκB. The evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare. Bisphosphonates have been successfully used to gain control of elevated bone remodelling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes.
TL;DR: Swedish 70-year olds with confirmed sarc Openia demonstrate poorer BMD and bone architecture than those with probable and no sarcopenia, and have increased likelihood of incident falls.
Abstract: The aim of this study was to compare bone structure parameters and likelihood of falls across European Working Group on Sarcopenia in Older People (EWGSOP2) sarcopenia categories. 3334 Swedish 70-y ...
TL;DR: The clinical and radiological characteristics as well as the molecular genetics of this condition are discussed, and targeting the type I receptor ameliorates the high bone turnover is shown.
Abstract: Camurati-Engelmann disease or progressive diaphyseal dysplasia is a rare autosomal dominant sclerosing bone dysplasia. Mainly the skull and the diaphyses of the long tubular bones are affected. Clinically, the patients suffer from bone pain, easy fatigability, and decreased muscle mass and weakness in the proximal parts of the lower limbs resulting in gait disturbances. The disease-causing mutations are located within the TGFβ-1 gene and expected to or thought to disrupt the binding between TGFβ1 and its latency-associated peptide resulting in an increased signaling of the pathway and subsequently accelerated bone turnover. In preclinical studies, it was shown that targeting the type I receptor ameliorates the high bone turnover. In patients, treatment options are currently mostly limited to corticosteroids that may relieve the pain, and improve the muscle weakness and fatigue. In this review, the clinical and radiological characteristics as well as the molecular genetics of this condition are discussed.
TL;DR: Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS.
Abstract: Melorheostosis is an exceptionally rare sclerosing hyperostosis that typically affects the appendicular skeleton in a limited segmental fashion. It occasionally occurs on a background of another benign generalised sclerosing bone condition, known as osteopoikilosis caused by germline mutations in LEMD3, encoding the inner nuclear membrane protein MAN1, which modulates TGFβ/bone morphogenetic protein signalling. Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS. Those cases associated with MAP2K1 mutations are more likely to have the classic "dripping candle wax" appearance on radiographs. The relationship between these somatic mutations and those found in a variety of malignant conditions is discussed. There are also similar germline mutations involved in a group of genetic disorders known as the RASopathies (including Noonan syndrome, Costello syndrome and various cardiofaciocutaneous syndromes), successful treatments for which could be applied to melorheostosis. The diagnosis and management of melorheostosis are discussed; there are 4 distinct radiographic patterns of melorheostosis and substantial overlap with mixed sclerosing bone dysplasia. Medical treatments include bisphosphonates, but definitive guidance on their use is lacking given the small number of patients that have been studied. Surgical intervention may be required for those with large bone growths, nerve entrapments, joint impingement syndromes or major limb deformities. Bone regrowth is uncommon after surgery, but recurrent contractures represent a major issue in those with extensive associated soft tissue involvement.
TL;DR: The findings suggest that pharmacological inhibition of the skeletal NFκB signalling pathway reduces prostate cancer related osteolysis, but further studies in the therapeutic implications ofNFκB inhibition in cells of the osteoblastic lineage are needed.
Abstract: NFκB is implicated in cancer and bone remodelling, and we have recently reported that the verified NFκB inhibitor Parthenolide (PTN) reduced osteolysis and skeletal tumour growth in models of metastatic breast cancer. Here, we took advantage of in vitro and ex vivo bone cell and organ cultures to study the effects of PTN on the ability of prostate cancer cells and their derived factors to regulate bone cell activity and osteolysis. PTN inhibited the in vitro growth of a panel of human, mouse and rat prostate cancer cells in a concentration-dependent manner with a varying degree of potency. In prostate cancer cell-osteoclast co-cultures, the rat Mat-Ly-Lu, but not human PC3 or mouse RM1-BT, enhanced RANKL stimulated osteoclast formation and PTN reduced these effects without affecting prostate cancer cell viability. In the absence of cancer cells, PTN reduced the support of Mat-Ly-Lu conditioned medium for the adhesion and spreading of osteoclast precursors, and survival of mature osteoclasts. Pre-exposure of osteoblasts to PTN prior to the addition of conditioned medium from Mat-Ly-Lu cells suppressed their ability to support the formation of osteoclasts by inhibition of RANKL/OPG ratio. PTN enhanced the ability of Mat-Ly-Lu derived factors to increase calvarial osteoblast differentiation and growth. Ex vivo, PTN enhanced bone volume in calvaria organ-Mat-Ly-Lu cell co-culture, without affecting Mat-Ly-Lu viability or apoptosis. Mechanistic studies in osteoclasts and osteoblasts confirmed that PTN inhibit NFκB activation related to derived factors from Mat-Ly-Lu cells. Collectively, these findings suggest that pharmacological inhibition of the skeletal NFκB signalling pathway reduces prostate cancer related osteolysis, but further studies in the therapeutic implications of NFκB inhibition in cells of the osteoblastic lineage are needed.
TL;DR: As a readily available and very cost effective bio-source, ATRA may be a novel therapeutic method to enhance bone consolidation in the clinical setting and promoted osteogenic differentiation of rBMSCs.
Abstract: Distraction osteogenesis (DO) is used to treat specific disorders associated with growth abnormalities and/or loss of bone stock secondary to trauma or disease. However, a high rate of complications and discomfort hamper its further application in clinical practice. Here, we investigated the effects of all-trans retinoic acid (ATRA) on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) and bone consolidation in a rat DO model. Different doses of ATRA were used to treat rBMSCs. Cell viability and osteogenic differentiation were assessed using CCK-8 and alkaline phosphatase staining, respectively. The mRNA expression of osteogenic differentiation-genes (including ALP, Runx2, OCN, OPN, OSX, and BMP2) and angiogenic genes (including VEGF, HIF-1, FLK-2, ANG-2, and ANG-4) were determined by quantitative real-time PCR analysis. Further, we locally injected ATRA or PBS into the gap in the rat DO model every 3 days until termination. X-rays, micro-computed tomography (Micro-CT), mechanical testing, and immunohistochemistry stains were used to evaluate the quality of the regenerates. ATRA promoted osteogenic differentiation of rBMSCs. Moreover, ATRA elevated the mRNA expression levels of osteogenic differentiation-genes and angiogenic genes. In the rat model, new bone properties of bone volume/total tissue volume and mechanical strength were significantly higher in the ATRA-treatment group. Micro-CT examination showed more mineralized bone after the ATRA-treatment, and immunohistochemistry demonstrated more new bone formation after ATRA-treatment than that in the PBS group. In conclusion, as a readily available and very cost effective bio-source, ATRA may be a novel therapeutic method to enhance bone consolidation in the clinical setting.
TL;DR: Changes in bibliometric variables over the last 30 years for four major musculoskeletal science journals are explored, with a specific focus on author gender.
Abstract: This study explored changes in bibliometric variables over the last 30 years for four major musculoskeletal science journals (BONE®), Calcified Tissue International® (CTI®), Journal of Bone and Mineral Research® (JBMR®), and Journal of Orthopaedic Research® (JOR®), with a specific focus on author gender. Bibliometric data were collected for all manuscripts in 1985 (BONE®, CTI®, JOR®), 1986 (JBMR®), 1995, 2005, and 2015; 2776 manuscripts met inclusion criteria. Manuscripts from Europe were more often published in BONE® or CTI®, while those from North America in JBMR® or JOR®. All journals demonstrated an increase over time in the number of authors (3.67–7.3), number of countries (1.1–1.4), number of institutions (1.4–3.1), and number of references (25.1–45.4). The number of manuscript pages increased (6.6–8.9) except for JOR® which showed a decline. CTI® had the lowest number of authors (4.9 vs. 5.6–6.8). There was a change in the corresponding author position from first to last for all journals; this change was highest for CTI® (35%) and lowest for BONE® (14.0%). All journals demonstrated an increase over time in female authors; however, CTI® was the highest amongst these four journals. The percentage of female first authors rose from 24.6 to 44.3% (CTI® 29.1–52.3%). The percentage of corresponding female authors rose from 17.5 to 33.6% (CTI® 22.9–40.0%). The proportion of female authors is increasing, likely reflecting the increasing number of women obtaining doctorates in science, medicine, and engineering.
TL;DR: It is demonstrated that zoledronate infusions given to 11 women after a median delay of 65 days from trial-end substantially preserved BMD, whereas those declining post-trial treatment lost 80–90% of the BMD gained during treatment with romosozumab–denosumab, suggesting sustained protection against rebound bone resorption and the resulting bone loss.
Abstract: Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect, resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation [1]. We found that in women discontinuing long-term treatment with denosumab, zoledronate infusions 6 months after the last dose of denosumab were ineffective in preserving hip BMD and only partially effective at the spine [2]. We hypothesized that this lack of efficacy was contributed to by the very low bone turnover after denosumab treatment, resulting in low skeletal uptake of the bisphosphonate. More recently, we reported data from women followed up for 1 year after the FRAME trial [3]. In that study, osteoporotic women were randomized to romosozumab or placebo for 1 year, and then both groups were provided with open-label denosumab for the subsequent 2 years. Our report demonstrated that zoledronate infusions given to 11 women after a median delay of 65 days from trial-end (i.e., 245 days after the last denosumab injection) substantially preserved BMD, whereas those declining post-trial treatment lost 80–90% of the BMD gained during treatment with romosozumab–denosumab [4]. We have now followed up nine of those zoledronate-treated women for a further year, during which time no further interventions were provided. Figure 1 shows the evolution of BMD over the 2 years from the end of the FRAME study. In the second year, there was minimal further BMD loss at any of the three skeletal sites assessed, such that at the end of follow-up BMD was 10.2% above FRAME baseline at the lumbar spine, 7.6% above baseline at the total hip, and 4.3% at the femoral neck. PINP levels at the end of follow-up were 20–60 μg/L, mean 41 μg/L, slightly lower than levels at 12 months in these women [4] and similar to those seen 18 months post-zoledronate in osteopenic women not previously treated with bone-active drugs [5]. Of the five women taking risedronate in our earlier report, one declined further follow-up, two discontinued risedronate, and two continued that drug. In the latter pair, total hip BMDs 2 years post-FRAME were 6.2% and 8.1% above pre-FRAME values, suggesting satisfactory maintenance of treatment effects. These data suggest that zoledronate administered 7–8 months after the last denosumab injection provides sustained protection against rebound bone resorption and the resulting bone loss. Whether efficacy would be similar after more long-term denosumab treatment and whether zoledronate also protects against rebound fractures now needs to be explored in systematic prospective studies.
TL;DR: Three months of vitamin D3 supplementation improved bone strength and trabecular thickness in tibia, vBMD in the trochanter and femoral neck, but did not affect aBMD.
Abstract: Vitamin D supplementation is often used in the prevention and treatment of osteoporosis, but the role of vitamin D has lately been questioned. We aimed to investigate the effect of 3 months of daily vitamin D3 supplementation (70 µg [2800 IU] vs. placebo) initiated in winter months on bone health. This study is a double-blinded placebo-controlled randomized trial. Bone health was assessed by bone turnover markers, DXA, HRpQCT, and QCT scans. The participants were 81 healthy postmenopausal women with low 25(OH)D ( 6.9 pmol/l) at screening. Vitamin D3 supplementation significantly increased levels of 25(OH)D and 1,25(OH)2D by 59 nmol/l and 19 pmol/l, respectively, whereas PTH was reduced by 0.7 pmol/l (all p < 0.0001). Compared with placebo, vitamin D3 did not affect bone turnover markers, aBMD by DXA or trabecular bone score. Vitamin D3 increased trabecular vBMD (QCT scans) in the trochanter region (0.4 vs. − 0.7 g/cm3) and the femoral neck (2.1 vs. − 1.8 g/cm3) pall < 0.05. HRpQCT scans of the distal tibia showed reduced trabecular number (− 0.03 vs. 0.05 mm−1) and increased trabecular thickness (0.001 vs. − 0.005 mm), as well as an improved estimated bone strength as assessed by failure load (0.1 vs. − 0.1 kN), and stiffness (2.3 vs. − 3.1 kN/mm pall ≤ 0.01). Changes in 25(OH)D correlated significantly with changes in trabecular thickness, stiffness, and failure load. Three months of vitamin D3 supplementation improved bone strength and trabecular thickness in tibia, vBMD in the trochanter and femoral neck, but did not affect aBMD.
TL;DR: HR-pQCT is able to quantify bone repair and progression in patients with rheumatoid arthritis, and was impaired in RA, of which vBMD and micro-structure further deteriorated, particularly in patients on sDMARDs.
Abstract: The study is supported by unrestricted grants from the Weijerhorst foundation (WH-2) and Pfizer (WS2056904).
TL;DR: Low baseline 25OHD levels were associated with unfavorable changes in muscle mass and physical performance, but not with incident sarcopenia, and the role of parathyroid hormone (PTH) therein was examined.
Abstract: Effects of low serum 25OHD on age-related changes in muscle mass and function remain unclear. Our aims were to explore associations of baseline 25OHD levels with prevalent and incident sarcopenia and changes in muscle parameters, and to examine the role of parathyroid hormone (PTH) therein. Cross-sectional (n = 975) and prospective analyses (n = 702) of older adults aged 65–93 years participating in the KORA-Age study. Sarcopenia was defined using the 2010 European Working Group on Sarcopenia in Older People (EWGSOP) criteria as low muscle mass combined with low grip strength or low physical performance. Associations with baseline 25OHD were examined in multiple regression analyses. Low vitamin D status was linked to increased odds of prevalent sarcopenia. Over three years, low baseline 25OHD < 25 vs. ≥ 50 nmol/L were associated with greater loss of muscle mass and increased time for the Timed Up and Go test. The risk for developing incident sarcopenia was not significantly elevated in individuals with low baseline 25OHD but when including death as combined outcome alongside incident sarcopenia, there was a strong positive association in multivariable analysis [OR (95% CI) 3.19 (1.54–6.57) for 25OHD < 25 vs. ≥ 50 nmol/L]. There was no evidence for a PTH-mediating effect. Low baseline 25OHD levels were associated with unfavorable changes in muscle mass and physical performance, but not with incident sarcopenia. Future randomized trials are needed to assess causality and to address the issue of competing risks such as mortality in older cohorts.