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      Neonatal Hypercalcemia Secondary to Subcutaneous Fat Necrosis Successfully Treated with Pamidronate: A Case Series and Literature Review

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          Abstract

          Subcutaneous fat necrosis (SCFN) is a noninfectious panniculitis that occurs in term infants who experience significant distress in the 1st weeks of life, including hypoxic ischemic encephalopathy (HIE). Since the introduction of therapeutic hypothermia for HIE, there have been a few published case reports of SCFN, following this modality of treatment. Although, most cases of SCFN resolve spontaneously, SCFN may be associated with hypercalcemia, which may sometimes reach dangerous levels. Approaches used for the management of this potentially life-threatening condition, include hyperhydration, calciuric diuretics, corticosteroids, and in more resistant cases pamidronate, a bisphosphonate. We report our experience on the use of pamidronate in two cases of severe hypercalcemia associated with SCFN following therapeutic hypothermia for HIE. We believe that with increasing use of therapeutic hypothermia for HIE, clinicians are likely to encounter this condition more frequently.

          Most cited references19

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          Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.

          It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonates were found to inhibit osteoclast-mediated bone resorption in vitro by inhibiting farnesyl diphosphate synthase, thereby preventing protein prenylation in osteoclasts. In this study, we examined the potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate (YM-529). We found a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The activity of recombinant human farnesyl diphosphate synthase was inhibited at concentrations > or = 1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximately equal to minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of antiresorptive potency. Furthermore, minor changes to the structure of the R(2) side chain of heterocycle-containing bisphosphonates, giving rise to less potent inhibitors of bone resorption in vivo, also caused a reduction in potency up to approximately 300-fold for inhibition of farnesyl diphosphate synthase in vitro. These data indicate that farnesyl diphosphate synthase is the major pharmacological target of these drugs in vivo, and that small changes to the structure of the R(2) side chain alter antiresorptive potency by affecting the ability to inhibit farnesyl diphosphate synthase.
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            Bisphosphonates: from the laboratory to the clinic and back again.

            Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occuring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains. Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures. The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid-associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradual
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              Subcutaneous fat necrosis after moderate therapeutic hypothermia in neonates.

              Therapeutic moderate hypothermia in newborns with hypoxic-ischemic encephalopathy is rapidly becoming standard clinical practice. We report here 12 cases of subcutaneous fat necrosis among 1239 cases registered with a national registry of newborns treated with moderate whole-body hypothermia. All the infants suffered from perinatal asphyxia and hypoxic-ischemic encephalopathy. Moderate-to-severe hypercalcemia was identified in 8 of 10 infants with blood calcium measurements. In all cases the skin lesions appeared after completion of the cooling treatment. Our data suggest that prolonged moderate hypothermia is an actual risk factor for subcutaneous fat necrosis. Because the lesions often develop several days after birth, physicians need to be aware of this condition as a possible complication in infants treated with moderate hypothermia after asphyxia. Blood calcium levels need to be monitored in affected infants.
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                Author and article information

                Journal
                AJP Rep
                AJP Rep
                10.1055/s-00000169
                AJP Reports
                Thieme Medical Publishers (333 Seventh Avenue, New York, NY 10001, USA. )
                2157-6998
                2157-7005
                19 November 2014
                November 2014
                : 4
                : 2
                : e93-e96
                Affiliations
                [1 ]Section of Neonatology, Peter Lougheed Centre, Calgary, Alberta, Canada
                [2 ]Section of Neonatology, University of Calgary, Calgary, Alberta, Canada
                [3 ]Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
                Author notes
                Address for correspondence Essa Hamdan Al Awad MD Section of Neonatology, Peter Lougheed Centre 3500 – 26 Ave NE , Calgary AB , T1Y 6J4Canada Veronica.Samedi@ 123456albertahealthservices.ca essa.alawad@ 123456albertahealthservices.ca
                Article
                140039
                10.1055/s-0034-1395987
                4239139
                35b1397c-0f4f-438c-98de-56d87439d520
                © Thieme Medical Publishers
                History
                : 23 July 2013
                : 01 October 2014
                Categories
                Article

                hypercalcemia,therapeutic hypothermia,newborn,pamidronate,subcutaneous fat necrosis

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