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`Nexus Pharmaceuticals v. Exela Pharma Sciences
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`PGR2024-00016
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`EXELA 2010
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`ALUMINUMIN INFANT BONE DISEASE
`
`401
`
`TABLE1. Initial evaluation of patient with total
`parenteral nutrition—associated metabolic bone disease
`Value Normalrange(ref.)
`Serum parameter
`Total calcium (mg/dl)
`
`
`
`8.5
`
`9.0-11.5
`(with normal albumin)
`4.50-5.50
`4.0-7.0
`1.8-3.0
`<1.0
`3.0-5.0
`
`<1
`
`9-52
`
`14-80
`<10
`110-175
`
`4.82
`3.7
`2.1
`0.6
`2.8
`
`3:5
`
`20
`
`150
`182
`121
`
`Ionized calcium (mg/dl)
`Phosphorus(mg/dl)
`Magnesium (mg/dl)
`Creatinine (mg/dl)
`Albumin (g/dl)
`Parathyroid hormone
`(ng/ml) (midregion assay)
`25-Hydroxyvitamin D
`(ng/ml)
`1,25-Dihydroxyvitamin D
`(pg/ml)
`Aluminum (yg/L)
`Copper(g/dl)
`Urine parameter
`Calcium/creatinine (mg/mg)
`Al/creatinine (ug/mg)
`TmP/GFR? (mg/dl)
`* SD.
`» Based on a constant infusion of phosphate per day and no
`oral intake.
`
`this
`4 months necrotizing enterocolitis recurred,
`time with intestinal perforation. She underwent co-
`lon resection and ileostomy and wastreated exclu-
`sively with continuous TPN for 24 h/day. At age 7
`months she wasnoted to have osteopenia, perios-
`teal resorption, and cupping on x-ray film, sugges-
`tive of rickets (Fig. 1). Results of aninitial biochem-
`ical evaluation were compatible with nutritional
`rickets (Table 1).
`The TPN solution contained elemental calcium
`33-36 mg/kg/day, phosphorus 31-40 mg/kg/day,
`copper30 wg/kg/day, and vitamin D, 5 g/day. This
`was the maximum amountthat could be added to
`the solution without calcium phosphate precipita-
`tion. The patient was given supplemental vitamin
`D, 125 wg i.m. each week beginning 6 weeksprior to
`diagnosis and therapy for aluminum overload and
`was maintained on this dose throughout her course.
`This was done even thoughthe patient had no bio-
`chemical evidence of vitamin D deficiency because
`of a previous report that rickets occurring in infants
`receiving chronic TPN therapy improved following
`high-dose vitamin D supplementation (5).
`Aspart of the evaluation, serum Al concentration
`wasfound to be 182 pg/L (normal <10 pg/L) (2) and
`urinary Al/creatinine 0.7 .g/mg [normal 0.06 + 0.08
`(SD) pg/mg] (3). The TPN solution initially con-
`tained 229 pg Al/L, providing the patient with 22
`wg/kg/day. Because of these high Al levels and be-
`cause no additional calcium or phosphate could be
`added to the TPN solution, she was given deferox-
`amine, an agent used to chelate Al from bone in
`patients with dialysis osteomalacia (6). The purpose
`
`0.013
`0.70
`3.4
`
`0.12 + 0.027 (10)
`0.055 + 0.0467 (3)
`4.2-8.0 (11)
`
`of this treatment was to attempt to improve the
`bone mineralization. During this therapeutic trial,
`all nutrients came exclusively from TPN.
`
`METHODS
`
`Calcium, phosphorus, andcreatinine levels in se-
`rum and urine were analyzed by standard auto-
`mated methods; ionized calcium levels in serum
`were ascertained byion-selective electrode analysis
`
`
`
`FIG. 1. Roentgenograph of femurs, illustrating osteopenia and periosteal resorption.
`
`J Pediatr Gastroenterol Nutr, Vol. 9, No. 3, 1989
`
`2
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`

`

`402
`
`G. L. KLEIN ET AL.
`
`using a Radiometer A-1 electrode. Serum levels of
`magnesium weredetermined colorimetrically on an
`Ektachem 400 (Kodak, Rochester, NY, U.S.A.)
`and albumin levels were determined by serum pro-
`tein electrophoresis on a cellulose-acetate gradient.
`Serum levels of 25-hydroxy- and 1,25-
`dihydroxyvitamin D were performed at Mayo Med-
`ical Laboratories (Rochester, MN, U.S.A.) using
`dual-cartridge extraction and a radioreceptorassay,
`with interassay variations of 10 and 15%, respec-
`tively (7). Analyses of sera for immunoreactive
`parathyroid hormone (PTH)levels were performed
`utilizing an antibody to the midmolecular region,
`with intraassay variation of 5% andinterassay vari-
`ation of 10% (8). Aluminum levels were determined
`utilizing flameless atomic absorption spectroscopy
`as previously described (9).
`
`RESULTS
`
`The patient was given deferoxamine 20 mg/kg i.v.
`over 2 h 3 evenings during week 1, but the dose was
`reduced to 10 mg/kg once weekly thereafter. Peak
`serum Al during the first week of therapy was 73
`g/L andthis level fell over 6 weeks to 26 pg/L (Fig.
`2). Urine Al/creatinine rose by ~350% 24 h follow-
`ing each administration of deferoxamine. Unex-
`
`pectedly, total serum calcium levels fell by the
`fourth dose of deferoxamine and reached 6.5 mg/dl
`with serum ionized calcium 3.95 mg/dl by the be-
`ginning of the third week of therapy (Fig. 2). During
`this time she continued to receive calcium in her
`TPN, 33-36 mg/kg/day, as well as the phosphorus
`and vitamin D doses mentioned above. Thereafter,
`serum calcium levels fluctuated but remained low.
`Urinary calcium/creatinine was lowinitially (Table
`1) (10) and did not change significantly when re-
`peated during week 3, 0.04 mg/mg. Serum levels of
`PTH and 1,25-dihydroxyvitamin D did not change
`from baseline following reevaluation during the
`third week of deferoxamine therapy. Deferoxamine
`therapy was discontinued by week 6 owingto re-
`peated episodes of gram-negative bacterial sepsis
`and difficulty in maintaining central venous cathe-
`ters. No roentgenographic improvement wasseen.
`The patient was ultimately discharged, receiving
`parenteral nutrition at home. She subsequently died
`at home andpermission for an autopsy wasrefused.
`
`DISCUSSION
`
`SERUMCa(etotal aionized)
`MMMMEE
`LLMLULCLTLLTOLLTETPEELEA
`
`
` mgdt
`
`'
`
`SERUM ALBUMIN
`LLLLLLLLLELLL
`*+i—
`
`Our patient developed sustained hypocalcemiain
`responseto deferoxamine given to reduce the body
`burden of Al incurred as a result of chronic TPN
`therapy. The cause of the hypocalcemia is uncer-
`tain, but it occurred despite constant calcium infu-
`sion in the TPN solution and sustained elevation of
`serum levels of PTH and 1,25-dihydroxyvitamin D,
`hormones that should increase bone resorption to
`sustain serum calcium levels (11). Urine calcium
`excretion did not increase during deferoxamine
`therapy and ostomy calcium output was not mea-
`sured. The affinity of deferoxamine for calcium is
`AgmL
`SERUM P
`substantially lower than that for aluminum,
`LLILMLELLLLMLE7Ds
`K, = 10? vs. 10?! (12). Inasmuch as deferoxamine
`5 {4A]
`'
`a
`2
`did not increase urinary calcium excretion and at
`e
`0
`least 70% of deferoxamine is excreted in the urine
` {2LLL2
`(12),
`it
`is unlikely that deferoxamine therapy in-
`creased ostomy calcium excretion. Although uri-
`nary calcium/creatinine may vary overthe course of
`a day, the patient received a continuousinfusion of
`calcium in the TPN solution and received nothing
`by mouth. Thus, conditions were such as to mini-
`mize any variability that might occur. However,the
`lack of elevated urinary calcium excretion is con-
`sistent with this patient’s hyperparathyroidism.
`Onecan speculate that if calcium excretion was
`not increased, a likely explanation for the low se-
`
`SERUM PTH
`
`LILLE
`
`4
`
`2o
`
`gat
`
`nN
`
`SERUM At
`
`DEFEROXAMINE
`‘
`20 mg/kg/dose 10 mg/kg __
`|
`_t
`;ttt +
`—_t
`3
`0
`1
`2
`WEEKS OF DEFEROXAMINE
`
`wt
`4
`
`_—t
`5
`
`,
`6
`
`FIG. 2. Serial serum levels of calcium (total and ionized),
`albumin, parathyroid hormone (PTH), phosphorus, and alu-
`minum during the course of deferoxamine therapy. Arrows
`indicate days on which deferoxamine was given. Each circle
`represents an individual determination. Normal serum levels
`are defined by the hatched areas.
`
`J Pediatr Gastroenterol Nutr, Vol. 9, No. 3, 1989
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`ALUMINUMIN INFANTBONE DISEASE
`
`403
`
`rum calcium would be deposition in the patient’s
`demineralized bone, the chief repository of body
`calcium. It is known from previous studies that Al
`accumulates at
`the mineralization front of bone
`both in infants (4) and in adults (1) receiving TPN
`therapy. Administration of deferoxamine to our pa-
`tient resulted in a significant increase in urinary Al
`and a fall in serum Al. This would suggest chelation
`of Al from bone, one of the major repositories of
`parenterally administered Al (1-5). Chelation of Al
`from bone followed by increased bone calcium de-
`position suggests that Al deposited in bone may im-
`pair bone calcium uptake.
`Reduction of serum calcium has also been de-
`scribed during deferoxamine treatment for Al-
`associated dialysis osteomalacia (6,13—-16), includ-
`ing a preliminary report of a series of 51 patients
`(16). Lack of roentgenographic improvementin our
`patient may be explained by a duration of deferox-
`amine therapy of <4 months, the minimum needed
`to show improvementin dialysis patients (6), the
`constant resupply of Al
`in the TPN solution, and
`lack of adequate provision of calcium and/or phos-
`phate.
`Inadequate provision of calcium and/or phos-
`phate in TPN solutions has been most frequently
`implicated in the pathogenesis of what may well be
`multifactorial metabolic TPN-related bone disease
`in infants (17-19). Lack of calcium and/or phos-
`phate mayhave been a primary pathogenic factorin
`the bone demineralization observed in our patient.
`However, the amount of Al received by our pa-
`tient in her TPN solution is similar to amounts pre-
`viously reported to result in bone Al accumulation
`in infants 10-fold greater than in normal
`infants
`(3,4). Thus, Al in amounts currently contaminating
`TPN solutions may contribute to the pathogenesis
`or exacerbation of TPN-related bone disease in in-
`fants.
`
`to Nancy Alcock,
`Acknowledgment: We are grateful
`Ph.D., Department of Preventive Medicine and Commu-
`nity Health, University of Texas Medical Branch at
`Galveston, for the determination of serum copper con-
`centration and to Wilma Nance and Rosa Jaramillo for
`manuscript preparation.
`
`REFERENCES
`
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`ciated with low bone formationin patients receiving chronic
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`J Pediatr Gastroenterol Nutr, Vol. 9, No. 3, 1989
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