Effect of Alendronate Treatment on the Clinical Picture and Bone Turnover Markers in Chronic Idiopathic Hyperphosphatasia

Demir, Ercan; Bereket, Abdullah; Özkan, Behzat; Topçu, Meral

doi:10.1515/jpem.2000.13.2.217

Cited by 25 publications

(8 citation statements)

References 10 publications

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“…Treatment with a bisphosphonate has been helpful for patients with the other disorders that activate the RANK/RANKL/OPG signaling pathway . Riches and colleagues described the clinical and biochemical response to bisphosphonate therapy in 3 patients with PDB2 and found that treatment with aminobisphosphonates resulted in greater suppression of bone turnover markers and a more durable response than treatment with the first‐generation bisphosphonate etidronate .…”

Section: Discussionmentioning

confidence: 99%

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Schafer

Mumm

El‐Sayed

et al. 2013

Journal of Bone and Mineral Research

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Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow-legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF-κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12-base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes and genetic basis of the mendelian disorders of RANK signaling activation.

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Section: Discussionmentioning

confidence: 99%

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Schafer

Mumm

El‐Sayed

et al. 2013

Journal of Bone and Mineral Research

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“…Patients presenting in infancy typically develop severe deformity and may never become ambulant, or if they do, walking is delayed and lost in early childhood (2–4) . Others are not recognized until later childhood but may nonetheless become severely disabled, because deformity can progress particularly during the pubertal growth spurt (5–7) . In contrast, some patients have relatively mild deformity even after growth is completed (8,9) .…”

Section: Introductionmentioning

confidence: 99%

“…(2)(3)(4) Others are not recognized until later childhood but may nonetheless become severely disabled, because deformity can progress particularly during the pubertal growth spurt. (5)(6)(7) In contrast, some patients have relatively mild deformity even after growth is completed. (8,9) Biochemical studies indicate that bone turnover is greatly accelerated.…”

Section: Introductionmentioning

confidence: 99%

Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype

Chong

Hegde

Fawkner

et al. 2003

Journal of Bone and Mineral Research

115

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Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function.Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. Materials and Methods:We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships.

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“…There are two case reports of children treated with bisphosphonates for familial idiopathic hyperphosphatasia. Cassinelli et al [16] treated a child with familial idiopathic hyperphosphatasia with intravenous pamidronate (0.75 mg/kg per day for 5 days) followed by oral pamidronate (8 mg/kg per day) for 1 year and Demir et al [22] treated their patient with oral alendronate for 10 weeks. Both treatments resulted in clinical improvement and a decrease in serum alkaline phosphatase and urinary hydroxyproline.…”

Section: Familial Idiopathic Hyperphosphatasiamentioning

confidence: 99%

The role of bisphosphonates in diseases of childhood

Srivastava

Alon

2003

European Journal of Pediatrics

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Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. In recent years, bisphosphonates have been used in children for treatment of a growing number of disorders associated primarily with generalized or localized osteoporosis, metabolic bone diseases, heterotopic calcification in soft tissues, and for resistant hypercalcemia. In the present review we discuss the pharmacological aspects of bisphosphonates and related bone pathophysiology, review the pediatric literature on the role of bisphosphonates in childhood diseases and our experience with these drugs. The theoretical concerns of possible adverse effects of these drugs on the growing skeleton have not materialized in the limited pediatric clinical experience. Bisphosphonates provide the pediatrician with an opportunity to treat mineral and bone disorders of childhood which until recently did not have satisfactory therapy, at the same time, being aware of the theoretical concerns on microdamage accumulation in bone, bone quality and teratogenic potential of these drugs.

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Effect of Alendronate Treatment on the Clinical Picture and Bone Turnover Markers in Chronic Idiopathic Hyperphosphatasia

Cited by 25 publications

References 10 publications

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype

The role of bisphosphonates in diseases of childhood

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