ABSTRACT
Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.
Subject(s)
Hypophosphatasia , Adult , Child , Humans , Adolescent , Hypophosphatasia/diagnosis , Hypophosphatasia/genetics , Alkaline Phosphatase/genetics , Europe , Prevalence , MutationABSTRACT
Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.
Subject(s)
Hypophosphatasia , Infant , Adult , Infant, Newborn , Humans , Hypophosphatasia/diagnosis , Hypophosphatasia/epidemiology , Hypophosphatasia/genetics , Alkaline Phosphatase/genetics , Mutation , PrevalenceABSTRACT
BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
Subject(s)
Hypophosphatasia , Adult , Child , Humans , Hypophosphatasia/diagnosis , Hypophosphatasia/genetics , Mutation , Retrospective Studies , Alkaline Phosphatase/genetics , Genotype , PhenotypeABSTRACT
Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. INTRODUCTION: Fragility fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). METHODS: This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). RESULTS: Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. CONCLUSION: Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.
Subject(s)
Fractures, Bone , Muscular Dystrophy, Duchenne , Osteoporosis , Spinal Fractures , Male , Adolescent , Humans , Child, Preschool , Child , Young Adult , Adult , Glucocorticoids/adverse effects , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/drug therapy , Cross-Sectional Studies , Spinal Fractures/etiology , Spinal Fractures/complications , Fractures, Bone/complications , Osteoporosis/etiology , Osteoporosis/chemically induced , Bone Density , Risk Factors , Lumbar VertebraeABSTRACT
Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.
Subject(s)
Bone Density Conservation Agents , Hypercalcemia , Osteogenesis Imperfecta , Child , Male , Humans , Osteogenesis Imperfecta/drug therapy , Osteogenesis Imperfecta/genetics , Denosumab , Hypercalcemia/drug therapy , Calcium/pharmacology , Bone Density , Zoledronic Acid/therapeutic useABSTRACT
Vitamin D deficiency (VitDD) rickets and other manifestations of severe VitDD, such as cardiomyopathy and hypocalcemic seizures, continue to be diagnosed in Canada. Breastfed Indigenous infants, particularly those living in northern communities, are disproportionately impacted, although formula-fed infants are not exempt in cases where the mother's vitamin D status is critically low. This statement deals with the prevention of rickets and hypocalcemia due to VitDD for Indigenous children, and revises an earlier document from the Canadian Paediatric Society. An assessment of the risk for VitDD is recommended for each maternal-infant dyad because of the link between maternal and infant VitDD. Along with supports for enhanced adherence, additional VitD supplementation is recommended for prenatal women and infants deemed at high risk and, in certain situations, intermittent higher dose supplementation may be required. Food insecurity can also contribute to rickets, so advocacy is required to prevent VitDD rickets in Indigenous children.
ABSTRACT
Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.
Subject(s)
Familial Hypophosphatemic Rickets , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Child , Familial Hypophosphatemic Rickets/drug therapy , Humans , Patient Reported Outcome MeasuresABSTRACT
PURPOSE OF REVIEW: Part 1 of this review on secondary osteoporosis of childhood was devoted to understanding which children should undergo bone health monitoring, when to label a child with osteoporosis in this setting, and how best to monitor in order to identify early, rather than late, signs of bone fragility. In Part 2 of this review, we discuss the next critical step in deciding which children require bisphosphonate therapy. This involves distinguishing which children have the potential to undergo "medication-unassisted" recovery from secondary osteoporosis, obviating the need for bisphosphonate administration, from those who require anti-resorptive therapy in order to recover from osteoporosis. RECENT FINDINGS: Unlike children with primary osteoporosis such as osteogenesis imperfecta, where the potential for recovery from osteoporosis without medical therapy is limited, many children with secondary osteoporosis can undergo complete recovery in the absence of bisphosphonate intervention. Over the last decade, natural history studies have unveiled the spectrum of this recovery, which spans overt deterioration (i.e., incident vertebral and non-vertebral fractures and declines in bone mineral density (BMD)), to spectacular reclamation of BMD, and complete restoration of normal vertebral dimensions after spine fractures. The fact that reshaping of vertebral bodies following fractures is growth-dependent underscores the need to identify and treat those at risk for permanent vertebral deformity in a timely fashion. The decision to treat a child with a bisphosphonate hinges on distinguishing bone fragility from typical childhood fractures, and determining the potential for medication-unassisted recovery following an osteoporotic fragility fracture. While improvements in BMD are a well-known sign of recovery, restitution of bone structure is also a key indicator of recuperation, one that is unique to childhood, and that plays a pivotal role in the decision to intervene or not.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Chronic Disease , Diphosphonates/therapeutic use , Osteoporosis/prevention & control , Bone Density , Child , Humans , Osteoporotic Fractures/prevention & control , Secondary PreventionABSTRACT
PURPOSE OF THE REVIEW: Underlying conditions which adversely affect skeletal strength are one of the most common reasons for consultations in pediatric bone health clinics. The diseases most frequently linked to fragility fractures include leukemia and other cancers, inflammatory disorders, neuromuscular disease, and those treated with osteotoxic drugs (particularly glucocorticoids). The decision to treat a child with secondary osteoporosis is challenged by the fact that fractures are frequent in childhood, even in the absence of risk factors. Furthermore, some children have the potential for medication-unassisted recovery from osteoporosis, obviating the need for bisphosphonate therapy. RECENT FINDINGS: Over the last decade, there have been important advances in our understanding of the skeletal phenotypes, fracture frequencies, and risk factors for bone fragility in children with underlying disorders. With improved knowledge about the importance of fracture characteristics in at-risk children, there has been a shift away from a bone mineral density (BMD)-centric definition of osteoporosis in childhood, to a fracture-focused approach. As a result, attention is now drawn to the early identification of fragility fractures, which includes asymptomatic vertebral collapse. Furthermore, even a single, long bone fracture can represent a major osteoporotic event in an at-risk child. Fundamental biological principles of bone strength development, and the ways in which these go awry in chronic illnesses, form the basis for monitoring and diagnosis of osteoporosis in children with underlying conditions. Overall, the goal of monitoring is to identify early, rather than late, signs of osteoporosis in children with limited potential to undergo medication-unassisted recovery. These are the children who should undergo bisphosphonate therapy, as discussed in part 1 (monitoring and diagnosis) and part 2 (recovery and the decision to treat) of this review.
Subject(s)
Bone Development , Chronic Disease , Osteoporosis/diagnosis , Osteoporosis/prevention & control , Bone Density , Bone Density Conservation Agents/therapeutic use , Child , Humans , Osteoporotic Fractures/diagnosis , Osteoporotic Fractures/prevention & control , Phenotype , Risk Assessment , Risk Factors , Secondary PreventionABSTRACT
BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Familial Hypophosphatemic Rickets/drug therapy , Immunologic Factors/therapeutic use , Antibodies, Monoclonal, Humanized , Body Height , Child , Child Development , Child, Preschool , Familial Hypophosphatemic Rickets/diagnosis , Female , Fibroblast Growth Factor-23 , Humans , Infant , Male , Severity of Illness Index , Treatment OutcomeABSTRACT
Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signalling pathway. This inhibits chondrocyte differentiation and puts a break on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. A great deal has been learned about complications and consequences of FGFR3 activation and management guidance is evolving aimed to reduce the increased mortality and morbidity in this condition, particularly deaths from spinal cord compression and sleep apnoea in infants and small children. To date, no drugs are licensed for treatment of achondroplasia. Here, we report on the various substances in the drug development pipeline which target elements in molecular disease mechanism such as FGF (fibroblast growth factor) ligands, FGFR3, MAPK signalling as well as the Ctype natriuretic peptide receptor NPRB (natriuretic peptide receptor B).
Subject(s)
Achondroplasia/genetics , Cell Differentiation , Child , HumansABSTRACT
Dual-energy X-ray absorptiometry (DXA) is widely used in the evaluation of bone fragility in children. Previous recommendations emphasized total body less head and lumbar spine DXA scans for clinical bone health assessment. However, these scan sites may not be possible or optimal for all groups of children with conditions that threaten bone health. The utility of DXA scans of the proximal femur, forearm, and radius were evaluated for adequacy of reference data, precision, ability of predict fracture, and applicability to all, or select groups of children. In addition, the strengths and limitations of vertebral fracture assessment by DXA were evaluated. The new Pediatric Positions provide guidelines on the use of these additional measures in the assessment of skeletal health in children.
Subject(s)
Absorptiometry, Photon/standards , Bone Density , Femur/diagnostic imaging , Forearm/diagnostic imaging , Lumbar Vertebrae/diagnostic imaging , Osteoporosis/diagnosis , Spinal Fractures/diagnosis , Child , Consensus Development Conferences as Topic , Humans , Osteoporosis/complications , Spinal Fractures/etiologyABSTRACT
We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Pregnadienediols/pharmacology , Pregnadienediols/therapeutic use , Administration, Oral , Anti-Inflammatory Agents/blood , Biomarkers/blood , Blood Glucose/analysis , Child , Child, Preschool , Humans , Hydrocortisone/blood , Insulin/blood , Male , Muscular Dystrophy, Duchenne/metabolism , Pregnadienediols/bloodABSTRACT
PURPOSE OF REVIEW: Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. RECENT FINDINGS: While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.
Subject(s)
Anabolic Agents/therapeutic use , Androgens/therapeutic use , Antibodies/therapeutic use , Bone Density Conservation Agents/therapeutic use , Human Growth Hormone/therapeutic use , Osteoporosis/drug therapy , Vibration/therapeutic use , Adaptor Proteins, Signal Transducing , Bone Morphogenetic Proteins/antagonists & inhibitors , Bone Morphogenetic Proteins/immunology , Child , Genetic Markers/immunology , Humans , Teriparatide/therapeutic use , Testosterone/therapeutic use , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/immunologyABSTRACT
PURPOSE OF REVIEW: In Duchenne muscular dystrophy (DMD), the progressive skeletal and cardiac muscle dysfunction and degeneration is accompanied by low bone mineral density and bone fragility. Glucocorticoids, which remain the standard of care for patients with DMD, increase the risk of developing osteoporosis. The scope of this review emphasizes the mutual cohesion and common signaling pathways between bone and skeletal muscle in DMD. RECENT FINDINGS: The muscle-bone interactions involve bone-derived osteokines, muscle-derived myokines, and dual-origin cytokines that trigger common signaling pathways leading to fibrosis, inflammation, or protein synthesis/degradation. In particular, the triad RANK/RANKL/OPG including receptor activator of NF-kB (RANK), its ligand (RANKL), along with osteoprotegerin (OPG), regulates bone matrix modeling and remodeling pathways and contributes to muscle pathophysiology in DMD. This review discusses the importance of the muscle-bone unit in DMD and covers recent research aimed at determining the muscle-bone interactions that may eventually lead to the development of multifunctional and effective drugs for treating muscle and bone disorders regardless of the underlying genetic mutations in DMD.
Subject(s)
Bone and Bones/metabolism , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/metabolism , Osteoporosis/metabolism , Osteoprotegerin/metabolism , RANK Ligand/metabolism , Receptor Activator of Nuclear Factor-kappa B/metabolism , Bone Remodeling , Bone and Bones/pathology , Cytokines/metabolism , Fibrosis , Humans , Muscular Dystrophy, Duchenne/complications , Osteoporosis/complications , Signal TransductionABSTRACT
Children with osteogenesis imperfecta (OI) type VI often have high fracture rates despite the current standard treatment with bisphosphonates. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach, but safety data on denosumab in children are limited. Here we describe fluctuations in bone and mineral metabolism during denosumab treatment in four children with OI type VI who started denosumab (basic protocol: 1 mg per kg body mass every 3 months) between 1.9 and 9.0 years of age, after having received intravenous bisphosphonates previously. All four children developed hypercalciuria during active denosumab therapy. In two children aged 3.9 and 4.6 years, episodes of hypercalcemia were observed between 7 and 12 weeks after the preceding denosumab injection. During times when the interval between denosumab injections was increased to 6 months for clinical reasons, lumbar spine bone mineral density z-scores decreased rapidly. It appears that the duration of action of denosumab is short and variable in children with OI type VI. These observations call into question the concept that denosumab can be used as a stand-alone alternative to bisphosphonates to treat children with OI.
Subject(s)
Bone Density Conservation Agents/adverse effects , Bone Density/drug effects , Denosumab/adverse effects , Hypercalcemia/chemically induced , Hypercalciuria/chemically induced , Osteogenesis Imperfecta/drug therapy , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/therapeutic use , Child , Child, Preschool , Denosumab/administration & dosage , Denosumab/therapeutic use , Humans , Infant , Treatment OutcomeABSTRACT
Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Eye Proteins/genetics , Nerve Growth Factors/genetics , Osteogenesis Imperfecta/drug therapy , Osteogenesis Imperfecta/genetics , Serpins/genetics , Adolescent , Blotting, Western , Canada , Child , Child, Preschool , Denosumab/therapeutic use , Female , Humans , Infant , Male , MutationABSTRACT
Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufficiency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual causeheterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and confirmed by quantitative PCR. Array comparative genomic hybridization in DNA of the index patient in each family showed that deletion size varied from 18.5 kb to 2.23 Mb between families, encompassing between 1 and 47 genes (COL1A1 included). The skeletal phenotype of the affected individuals was similar to that of patients with haploinsufficiency caused by COL1A1 stop or frameshift mutations. However, one individual with a deletion that included also DLX3 and DLX4 had tooth discoloration and bone fragility. Three individuals from 2 families had deletions that included also CACNA1G, and these individuals had learning disabilities. These features are not usually observed in COL1A1 haploinsufficiency, but are in accordance with previously described individuals in whom deletions included the same genes. In summary, we found deletions of COL1A1 in 5 out of 161 families (3 %) with OI type I that were evaluated. Deletions encompassing not only COL1A1 but also neighboring genes can lead to contiguous gene syndromes that may include dental involvement and learning disability.
Subject(s)
Collagen Type I/genetics , Gene Deletion , Osteogenesis Imperfecta/genetics , Adolescent , Adult , Child , Child, Preschool , Collagen Type I, alpha 1 Chain , Comparative Genomic Hybridization , Family , Female , Humans , Infant , Male , Osteogenesis Imperfecta/epidemiology , Pedigree , Polymorphism, Genetic , Young AdultABSTRACT
Vertebral fractures (VF) are a frequent complication of acute lymphoblastic leukemia. Some children with VF undergo vertebral body reshaping to the point of complete restoration of normal vertebral dimensions. Others are left with permanent vertebral deformity if the degree of reshaping has been incomplete by the time of final adult height attainment. In this report, we describe three children with painful VF at leukemia diagnosis or during chemotherapy. Each patient highlights different clinical trajectories in their recovery from VF and underscores the need for osteoporosis intervention trials with the goal to prevent permanent vertebral deformity in selected patients.