Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

Barvencik, Florian; Beil, Frank Timo; Gebauer, Matthias; Busse, Björn; Koehne, Till; Seitz, Sebastian; Zustin, Josef; Pogoda, Pia; Schinke, Thorsten; Amling, Michael

doi:10.1007/s00198-011-1528-y

Cited by 65 publications

(46 citation statements)

References 36 publications

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“…Alpl encodes tissue-nonspecific alkaline phosphatase, which is responsible for the hydrolysis PP i , (50) and Alpl expression has been shown previously to be regulated by extracellular adenosine. (27) In humans, disruption of ALPL causes hypophosphatasia, characterized by skeletal hypomineralization (56) and presumably a result of excessive accumulation of PP i . Thus, decreased Alpl expression in the spinal tissues of ENT1 -/-mice would be expected to increase extracellular PP i levels, counteracting the decrease in PP i arising from changes in Enpp1 and Ank expression.…”

Section: Discussionmentioning

confidence: 99%

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory spondyloarthropathy, characterized by ectopic calcification of spinal tissues. Symptoms include spine pain and stiffness, and in severe cases dysphagia and spinal cord compression. The etiology of DISH is unknown and there are no specific treatments. Recent studies have suggested a role for purine metabolism in the regulation of biomineralization. Equilibrative nucleoside transporter 1 (ENT1) transfers hydrophilic nucleosides, such as adenosine, across the plasma membrane. In mice lacking ENT1, we observed the development of calcified lesions resembling DISH. By 12 months of age, ENT1 -/-mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro-computed tomography (mCT) revealed ectopic mineralization of paraspinal tissues in the cervical-thoracic region at 2 months of age, which extended to the lumbar and caudal regions with advancing age. Energy-dispersive X-ray microanalysis of lesions revealed a high content of calcium and phosphorus with a ratio similar to that of cortical bone. At 12 months of age, histological examination of ENT1 -/-mice revealed large, irregular accumulations of eosinophilic material in paraspinal ligaments and entheses, intervertebral discs, and sternocostal articulations. There was no evidence of mineralization in appendicular joints or blood vessels, indicating specificity for the axial skeleton. Plasma adenosine levels were significantly greater in ENT1 -/-mice than in wild-type, consistent with loss of ENT1-a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1 -/-mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1 -/-mice indicated generalized disruption of pyrophosphate homeostasis. This is the first report of a role for ENT1 in regulating the calcification of soft tissues. Moreover, ENT1 -/-mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders. ß

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Section: Discussionmentioning

confidence: 99%

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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“…The adult form of hypophosphatasia is mainly characterized by osteomalacia, pseudofractures, and pathologic fractures after minimal trauma, as well as by muscle and joint pain (55). In addition, a study demonstrated that histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia confirmed the expected enrichment of non-mineralized osteoid, but also showed an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix (56). Hypophosphatemic nephrolithiasis/osteoporosis-1 (NPHLOP1) is caused by heterozygous mutation in the sodium/phosphate cotransporter type 2 (SLC34A1) gene (prevalence <1/1.000.000).…”

Section: Metabolic Bone Diseasementioning

confidence: 92%

“…The pathogenesis of osteoporosis in this disease is not clear, however increased bone turnover and impaired trabecular bone microarchitecture have been described (64). The risk of fractures seems correlate with acromegaly activity, its duration, coexistent hypogonadism, diabetes mellitus, and glucocorticoid therapy (56). There are no specific recommendations, but screening with thoracic and lumbar vertebral radiographs is indicated in patients affected by acromegaly (64).…”

Section: Acromegalymentioning

confidence: 99%

Rare causes of osteoporosis

Marcucci

Brandi

2015

ccmbm

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SummaryOsteoporosis is a metabolic bone disease characterized by loss of bone mass and strength, resulting in increased risk of fractures. It is classically divided into primary (postmenopausal or senile), secondary and idiopathic forms. There are many rare diseases, that cause directly or indirectly osteoporosis. The identification and classification of most of these rare causes of osteoporosis is crucial for the specialists in endocrinology and not, in order to prevent this bone complication and to provide for an early therapy. Several pathogenic mechanisms are involved, including various aspects of bone metabolism such as: decreased bone formation, increased bone resorption, altered calcium, phosphorus and/or vitamin D homeostasis, and abnormal collagen synthesis. In this review, less common forms of primary and secondary osteoporosis are described, specifying, if applicable: genetic causes, epidemiology, clinical features, and pathogenic mechanisms causing osteoporosis. A greater awareness of all rare causes of osteoporosis could reduce the number of cases classified as idiopathic osteoporosis and allow the introduction of appropriate and timely treatments.

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“…Common disease manifestations of HPP in adults are, in particular, metatarsal and femoral stress fractures or pseudofractures, pathological fractures after minimal trauma, muscle and joint pain, and osteomalacia (18,19). However, the incidence and clinical manifestation of the latter may also be complicated by an additional vitamin D deficiency, which is frequently seen in HPP patients (20).…”

Section: Introductionmentioning

confidence: 99%

“…However, the incidence and clinical manifestation of the latter may also be complicated by an additional vitamin D deficiency, which is frequently seen in HPP patients (20). In addition to the above clinical symptoms, the diagnosis of HPP is based on low serum ALP enzyme activity, high endogenous levels of TNSALP substrates, and ultimately mutations in the ALPL gene (9,18).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Seefried

Baumann

Hemsley

et al. 2017

Journal of Clinical Investigation

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BACKGROUND. Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme. METHODS.In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up. RESULTS.Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient.CONCLUSION. BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP. TRIAL REGISTRATION. Clinicaltrials.gov NCT01406977. FUNDING.

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Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

Abstract: Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.

Cited by 65 publications

References 36 publications

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Rare causes of osteoporosis

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

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