Leanne M. Ward

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism

The osteocyte, a terminally differentiated cell comprising 90%–95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (Pi) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

Type V Osteogenesis Imperfecta: A New Form of Brittle Bone Disease

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age‐matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N‐telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect.

Osteogenesis imperfecta (OI) is a heritable disease of bone in which the hallmark is bone fragility. Usually, the disorder is divided into four groups on clinical grounds. We previously described a group of patients initially classified with OI type IV who had a discrete phenotype including hyperplastic callus formation without evidence of mutations in type I collagen. We called that disease entity OI type V. In this study, we describe another group of 8 patients initially diagnosed with OI type IV who share unique, common characteristics. We propose to name this disorder “OI type VI.” Fractures were first documented between 4 and 18 months of age. Patients with OI type VI sustained more frequent fractures than patients with OI type IV. Sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. All patients had vertebral compression fractures. No patients showed radiological signs of rickets. Lumbar spine areal bone mineral density (aBMD) was low and similar to age‐matched patients with OI type IV. Serum alkaline phosphatase levels were elevated compared with age‐matched patients with type IV OI (409 ± 145 U/liter vs. 295 ± 95 U/liter; p < 0.03 by t‐test). Other biochemical parameters of bone and mineral metabolism were within the reference range. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations, and type I collagen protein analyses were normal. Qualitative histology of iliac crest bone biopsy specimens showed an absence of the birefringent pattern of normal lamellar bone under polarized light, often with a “fish‐scale” pattern. Quantitative histomorphometry revealed thin cortices, hyperosteoidosis, and a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. We conclude that type VI OI is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralization defect, in the absence of a disturbance of mineral metabolism. The underlying genetic defect remains to be elucidated.

Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease.

Osteogenesis imperfecta (OI) is a heritable disease of bone with low bone mass and bone fragility. The disease is generally classified into four types based on clinical features and disease severity, although recently fifth and sixth forms have also been reported. Most forms of OI are autosomal dominant. Rarely, autosomal recessive disease has been described. We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec. In keeping with the established numeric classification for OI forms, we have called this form of the disease OI type VII. The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. Rhizomelia is a prominent clinical feature. Histomorphometric analyses of iliac crest bone samples revealed findings similar to OI type I, with decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. The disease has subsequently been localized to chromosome 3p22-24.1, which is outside the loci for type I collagen genes. The underlying genetic basis for the disease remains to be determined.

Consensus Statement: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

BACKGROUNDnVitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication.nnnEVIDENCEnA systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence.nnnPROCESSnThirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus.nnnRESULTSnThis consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts.nnnCONCLUSIONnRickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Alendronate for the Treatment of Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study

CONTEXTnInformation on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited.nnnOBJECTIVEnThe objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI.nnnDESIGN AND PARTICIPANTSnWe conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater.nnnMAIN OUTCOME MEASURESnSpine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured.nnnRESULTSnALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups.nnnCONCLUSIONSnOral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Advanced Vertebral Fracture among Newly Diagnosed Children with Acute Lymphoblastic Leukemia: Results of the Canadian STeroid-associated Osteoporosis in the Pediatric Population (STOPP) Research Program

Vertebral compression is a serious complication of childhood acute lymphoblastic leukemia (ALL). The prevalence and pattern of vertebral fractures, as well as their relationship to BMD and other clinical indices, have not been systematically studied. We evaluated spine health in 186 newly diagnosed children (median age, 5.3 yr; 108 boys) with ALL (precursor B cell: N = 167; T cell: N = 19) who were enrolled in a national bone health research program. Patients were assessed within 30 days of diagnosis by lateral thoraco‐lumbar spine radiograph, bone age (also used for metacarpal morphometry), and BMD. Vertebral morphometry was carried out by the Genant semiquantitative method. Twenty‐nine patients (16%) had a total of 75 grade 1 or higher prevalent vertebral compression fractures (53 thoracic, 71%; 22 lumbar). Grade 1 fractures as the worst grade were present in 14 children (48%), 9 patients (31%) had grade 2 fractures, and 6 children (21%) had grade 3 fractures. The distribution of spine fracture was bimodal, with most occurring in the midthoracic and thoraco‐lumbar regions. Children with grade 1 or higher vertebral compression had reduced lumbar spine (LS) areal BMD Z‐scores compared with those without (mean ± SD, −2.1 ± 1.5 versus −1.1 ± 1.2; p < 0.001). LS BMD Z‐score, second metacarpal percent cortical area Z‐score, and back pain were associated with increased odds for fracture. For every 1 SD reduction in LS BMD Z‐score, the odds for fracture increased by 80% (95% CI: 10–193%); the presence of back pain had an OR of 4.7 (95% CI: 1.5–14.5). These results show that vertebral compression is an under‐recognized complication of newly diagnosed ALL. Whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined.

Prevalent Vertebral Fractures among Children Initiating Glucocorticoid Therapy for the Treatment of Rheumatic Disorders

Vertebral fractures are an under‐recognized problem in children with inflammatory disorders. We studied spine health among 134 children (87 girls) with rheumatic conditions (median age 10 years) within 30 days of initiating glucocorticoid therapy.

Maternal and Fetal Outcome After Long-Term Pamidronate Treatment Before Conception: A Report of Two Cases†

The pregnancies of two women with osteogenesis imperfecta who received intravenous pamidronate before conception are reported. The mothers suffered no ill effects. One baby had transient asymptomatic hypocalcemia and one had bilateral talipes equinovarus.