Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation.

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus (R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution (R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.

Outcomes following intravenous bisphosphonate infusion in pediatric patients: A 7-year retrospective chart review.

INTRODUCTION: Intravenous bisphosphonates (IV BP) have been used to treat children with osteoporosis for many years. Favorable side effect profile and improvements in bone mineral density (BMD) have been demonstrated in patients with osteogenesis imperfecta (OI), a primary form of osteoporosis in pediatrics. Less is known about the safety of IV BP in children with secondary osteoporosis or glucocorticoid-induced osteoporosis (GIO). We aimed to determine the prevalence of both acute and long-term side effects and assess the efficacy of IV BP treatment to increase bone mineral density in pediatric patients with varying presentations of compromised bone health. METHODS: We conducted a retrospective chart review of pediatric patients (<21 years old) treated for osteoporosis with intravenous pamidronate (PAM) or zoledronic acid (ZA) at Cincinnati Children's Hospital Medical Center from 2010 to 2017. Patient demographics, diagnosis, infusion type and dose, acute phase reactions (APR), electrolyte abnormalities, and bone density measurements were collected from the electronic medical records. Diagnoses were grouped into 3 categories: primary osteoporosis, secondary osteoporosis, and GIO. Descriptive characteristics and adverse events were compared among categories. Change in bone mineral density (BMD) over time was compared among groups. RESULTS: 123 patients (56% male) received 942 infusions (83% PAM and 17% ZA). APR was reported in 7% of all infusions and more common in secondary osteoporosis (16%, p < 0.0001). There was a higher percentage of acute adverse events after the first infusion (27% vs 5%, p < 0.0001). Hypocalcemia following IV BP infusions occurred in 7% (27/379) of infusions and was significantly associated with ZA use (p = 0.04). Severity of hypocalcemia was generally mild, requiring intravenous calcium in 3% (13/379) of infusions. Hypophosphatemia occurred frequently, however rarely required intravenous supplementation. In 468 patient years of IV BP exposure, there were no reports of osteonecrosis of the jaw (ONJ) nor atypical femoral fracture (AFF). Lumbar spine (LS) aBMD Z-score 1 year after IV BP initiation increased overall for all groups (p < 0.0001) but did not significantly differ for those who did or did not fracture following IV BP treatment. CONCLUSIONS: APR due to intravenous BP treatment for pediatric osteoporosis were infrequent and generally mild. APR were more likely to occur in patients with secondary osteoporosis, a group who may require closer monitoring. A higher proportion of hypophosphatemia occurred in the patients with GIO. Long-term serious adverse events including ONJ and AFF were not identified in our patient population. LS aBMD Z-score increased following initiation of IV BP. However, the change in BMD was not associated with risk of fracture during the follow-up interval. These data provide reassurance and suggest that IV BP can be safely used in pediatric patients with osteoporosis.

Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children.

OBJECTIVE: Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS: A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS: Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION: The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

Two Case Reports of FGF23-Induced Hypophosphatemia in Childhood Biliary Atresia.

Cholestatic liver disease has long been associated with childhood rickets, secondary to impaired absorption of fat-soluble vitamin D. Elevated serum levels of fibroblast growth factor 23 (FGF23), secondary to genetic defects or tumor-induced osteomalacia, causes hypophosphatemic rickets in childhood. We present 2 infants with end-stage liver disease due to biliary atresia (BA) who developed hypophosphatemia with renal phosphate wasting. Serum FGF23 levels were elevated more than 8 times the upper limit of normal, and the older infant showed radiographic evidence of rickets. Both infants required large supplements of phosphate in addition to calcitriol. Following liver transplantation, FGF23 normalized in both patients and phosphate and calcitriol supplementation were discontinued. Immunohistochemistry revealed ectopic overexpression of FGF23 by hepatocytes in the BA liver. These observations highlight a unique cause of hypophosphatemic rickets in childhood and suggest the need for further investigation into the relationship between BA and other cholestatic disorders, and bone metabolism.