Medical Management for Fracture Prevention in Children with Osteogenesis Imperfecta.

There are no licensed treatments for children with osteogenesis imperfecta. Children currently receive off-label treatment with bisphosphonates, without any consistent approach to dose, drug or route of administration. Meta-analyses suggest that anti-fracture efficacy of such interventions is equivocal. New therapies are undergoing clinical trials, and it is likely that one or more will receive marketing authorisation within the next three to five years. The long-term outcome from such interventions will need to be studied carefully well beyond the period over which the clinical trials are conducted, and a consistent approach to the collection of data in this regard will be needed as a major collaborative effort.

Maternal pregnancy vitamin D supplementation increases offspring bone formation in response to mechanical loading: Findings from a MAVIDOS Trial sub-study.

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.

High-resolution peripheral quantitative computed tomography in children with osteogenesis imperfecta.

Bone health in children with osteogenesis imperfecta is monitored using radiographs and dual-energy X-ray absorptiometry, which have limitations. High-resolution peripheral quantitative CT can non-invasively derive bone microarchitectural data. Children with severe osteogenesis imperfecta have fragile deformed bones, and positioning for this scan can be difficult. We assessed the feasibility of high-resolution peripheral quantitative CT in nine children aged 9-15 years with osteogenesis imperfecta and compared results with dual-energy X-ray absorptiometry and with healthy controls. All nine recruited children were successfully scanned and showed no preference for either modality. It therefore appears feasible to perform high-resolution peripheral quantitative CT in children with osteogenesis imperfecta aged 9 years and older. Future studies should focus on understanding the clinical implications of the technology in this patient cohort.

Effect of vitamin D supplementation on free and total vitamin D: A comparison of Asians and Caucasians.

OBJECTIVES: It is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men. DESIGN: Prospective, single-centre clinical trial. PARTICIPANTS: Sixty young men (18-25 year) of Asian (n = 30) and Caucasian (n = 30) origin. MEASUREMENTS: We measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks. RESULTS: At baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (≈56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians. CONCLUSIONS: Asian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency.

Estimating bone mass in children: can bone health index replace dual energy x-ray absorptiometry?

BACKGROUND: Bisphosphonates have been shown to increase metacarpal cortical width. Bone health index is computed from hand radiographs by measuring cortical thickness, width and length of the three middle metacarpals, and may potentially help predict fracture risk in children. OBJECTIVE: To compare bone health index with bone mineral density as measured from dual energy X-ray absorptiometry scans in patients with and without bisphosphonate treatment. MATERIALS AND METHODS: Two hundred ninety-three Caucasian patients (mean age: 11.5±3.7 years) were included. We documented absolute values and z-scores for whole-body less head and lumbar spine bone mineral density then correlated these with the bone health index, which were acquired on the same day, in different patient groups, depending on their ethnicity and diagnosis. RESULTS: Bone health index showed moderate to strong correlation with absolute values for whole-body (r=0.52) and lumbar spine (r=0.70) bone mineral density in those not treated with bisphosphonates and moderate correlation absolute values for whole-body (r=0.54) and lumber spine (r=0.51) bone mineral density for those treated with bisphosphonates. There was weak correlation of z-scores, ranging from r=0.11 to r=0.35 in both groups. CONCLUSION: The lack of a strong correlation between dual energy X-ray absorptiometry and bone health index suggests that they may be assessing different parameters.

Type V osteogenesis imperfecta undergoing surgical correction for scoliosis.

PURPOSE: The objective of this article is to report a case of type V osteogenesis imperfecta (OI) undergoing posterior instrumented fusion for scoliosis. Type V OI is a moderately severe dysplasia causing primary defects in endochondral bone ossification or mineralisation. It is characterised by hyperplastic callus (HPC) formation, interosseous membrane calcifications, poor bone quality and spinal deformities including scoliosis. Data on the surgical management of spinal deformities in this patient group are lacking. CASE REPORT: A 16-year-old patient with a confirmed diagnosis of type V OI presented with a progressive scoliosis. The patient underwent a T3-L4 posterior instrumented correction and fusion utilising pedicle screws, pedicle hooks and sub-laminar wiring. At 4 months after surgery, the pedicle hooks pulled out and required partial metalwork removal after CT scanning confirmed bony union and no evidence of HPC formation. The patient was successfully discharged with satisfactory correction, confirmed bony union, no neurologic complication and absence of any hyperplastic callus formation. CONCLUSION: Type V OI patients requiring surgical intervention for scoliosis correction can safely undergo posterior instrumented fusion using sublaminar wiring and pedicle hook/screw constructs without apparent risk of HPC formation around neural elements. Surgery in this patient group remains challenging due to the associated poor bone quality. LEVEL OF EVIDENCE: V.

Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.

Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.

Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL.

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.

Bone strength in children: understanding basic bone biomechanics.

The term 'bone strength' is often used to explain why some children's bones fracture while others do not. Bone strength describes the general integrity of bone; a complex organ with multiple structural levels and an array of biomechanical properties. Key biomechanical properties of bone include stiffness, toughness, ductility and mechanical strength. When measured in bone tissue, these properties are known as the intrinsic biomechanical properties of bone, while the extrinsic biomechanical properties reflect the structural behaviour of a whole bone. The fine balance between various and often opposing intrinsic and extrinsic biomechanical properties of bone is crucial for fracture resistance. When clinically evaluating a child with a fracture, an understanding of basic bone biomechanics helps determine the likely mechanism of injury and whether underlying reduced fracture resistance exists.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Clinical management of hypophosphatasia.

HPP is a rare disease that manifests in different ways across the life course. Accurate diagnosis depends upon the use of appropriate age-related normative data. A new therapy is undergoing clinical trials; the preliminary published data is encouraging, but the scope of clinical application remains to be determined.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions.

The ISCD 2007 Pediatric Official Positions define osteoporosis in children on the basis of fracture history and low bone density, adjusted as appropriate for age, gender, and body size. The task force on fracture prediction and osteoporosis definition has reviewed these positions and suggests modifications with respect to vertebral fracture and the definition of a significant fracture history and draws attention to the need to consider degree of trauma as a factor that may modify fracture risk prediction.

Endoscopic endonasal resection of the odontoid peg for paediatric basilar invagination.

Osteogenesis imperfecta (OI) is a genetic disorder whose primary manifestations are fractures, bone deformity and bone pain. Brainstem compression due to basilar invagination is a rare and potentially life-threatening complication of OI. Children with this condition often require significant medical input and multiple admissions to hospital. Traditionally, anterior decompression is carried out through an open trans-oral route. We describe an endoscopic endonasal approach for resection of the peg in a child with OI and basilar invagination. We believe this approach provides an excellent alternative with minimal morbidity and decreased length of stay especially in the paediatric population.

Bisphosphonate Treatment Alters the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta: A Pilot Study.

Children with osteogenesis imperfecta (OI) are commonly treated with bisphosphonates. We investigated the skeletal response to mechanical stimulation in children with OI before and after bisphosphonate treatment. Twelve children with OI, naïve to bisphosphonate treatment, stood on a high-frequency (30 Hz), low-amplitude (50 to 200 µ) vibrating platform (Marodyne LivMD) for 10 minutes daily (2.5 minutes × 4 with interspersed 1-minute rest periods) for 7 days (whole body vibration [WBV] 1; day (D) 1-7), followed successively by 5 weeks' monitoring without intervention, 6 weeks' risedronate treatment, 1 week of WBV (WBV2; D85-91), and 1 week without intervention (D92-98). Procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSALP), and carboxy-terminal telopeptide of type I collagen cross-link (CTX) were measured at baseline and intervals bracketing periods of vibration and risedronate treatment. Both P1NP and CTX rose to D8 (18.4%, 13.8%, p < 0.05, respectively), plateaued, then rose again at D43 (19.8%, 19.2%, respectively, p < 0.05 versus baseline). At D85 (after risedronate) both P1NP and CTX had fallen to pre-WBV1 levels. A significantly smaller increase in P1NP was found after WBV2 (D85-91) at D92 (3.5%, 9.2%, respectively) and D99 versus after WBV1 (both p < 0.05). BSALP changed little after WBV1, fell during risedronate, and rose toward baseline after WBV2. We thus showed that WBV increased bone formation and resorption; that increase was attenuated after risedronate. The early increase in P1NP and CTX (D8) after WBV1 suggests increased osteoid formation within existing remodeling units but not increased mineralization. Later increases in P1NP/CTX (D42) suggest increased remodeling cycle initiation after WBV. Risedronate suppressed both biomarkers. The lower increase in P1NP/CTX after WBV2 suggests limited capacity to increase osteoid formation from existing "early stage" osteoblasts and a possible "hangover" effect of risedronate on remodeling activation. These results provide insights into both the response to WBV, ie, mechanical stimulation, and the effect of antiresorptive therapy in children with OI. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Early life vitamin D depletion and mechanical loading determine methylation changes in the RUNX2, RXRA, and osterix promoters in mice.

BACKGROUND: Early life vitamin D exposure is linked to later skeletal health with maternal vitamin D status in pregnancy associated with neonatal bone mass. The MAVIDOS study has demonstrated that vitamin D supplementation leads to reduced RXRA DNA methylation. Mice exposed to early life vitamin D deficiency have reduced bone mass and bone accrual in response to mechanical loading. Using the tibiae of these mice, we have examined the effect of diet and mechanical loading on the DNA methylation of promoters of genetic loci important for bone growth and development and their association with bone strength. RESULTS: Mechanical loading of mouse tibiae leads to a reduction of RXRA DNA methylation. Early life vitamin D deficiency is associated with altered methylation of osterix and Runx2 in these bones. Tibia strength was also demonstrated to be associated with a change in DNA methylation status in CpGs of the vitamin D receptor (VDR), ostrix, and RXRA genes. CONCLUSIONS: We have shown for the first time that mechanical loading of bone and early life vitamin D deficiency leads to changes in the epigenome of this tissue in key genes in the vitamin D and osteoblast differentiation pathway.

The role of bone shape in determining gender differences in vertebral bone mass.

Dual-energy X-ray absorptiometry (DXA) measures of bone mineral density (BMD) in children fail to account for growth because bone depth is unmeasured. While multiple adjustment methods have been proposed using body or bone size, the effect of vertebral shape is relatively unknown. Our study aimed to determine gender differences in vertebral shape and their impact on areal BMD (aBMD). We recruited 189 children, including 107 boys, aged 4-17 years, who attended the emergency department due to trauma. None had fractured. Height, weight, Tanner stage, and DXA measurements of the lumbar spine (LS) and total body were obtained. Cylindrical models were used to predict relationships between vertebral width (VW) and areal density for a given vertebral area assuming uniform volumetric density. The actual relationships between VW, bone area, and aBMD for the LS in the children were then determined. The theoretical models predicted a positive relationship between width and areal density for a constant vertebral area. Actual vertebral measurements demonstrated that boys had greater VW for a given vertebral area but lower aBMD for a given VW than girls at any age. The most likely explanation for the apparent paradox was that vertebral cortical thickness relative to width was greater in girls. This difference remained after adjusting for lean mass, suggesting that bone's response to mechanical stimulation may vary between the sexes during growth with consequent evolutionary advantage for girls approaching reproductive age.

Osteogenesis imperfecta in children.

Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

A total care package.

INPATIENTS OFTEN experience delays in discharge, usually due to a failure to plan for their subsequent care at home and the processes necessary for timely discharge.