Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

European survey showed wide variations in diagnostic procedures and management strategies for metabolic bone disease of prematurity in 22 countries.

AIM: The aim of this study was to evaluate the clinical relevance, diagnostic procedures and treatment strategies for metabolic bone disease in preterm infants across Europe. METHODS: An e-survey was distributed by email to 545 neonatal units in 38 European countries between July and October 2021. The protocol was based on the Checklist for Reporting Results of Internet E-Surveys. RESULTS: In total, 76 neonatal units (14%) from 22 European countries (58%) completed the e-survey. In the 12 months prior to the survey, 29% of 76 units reported at least one symptomatic case of fracture associated with metabolic bone disease of prematurity, and 18% of 76 units reported at least one case of craniofacial deformity. Most centres followed local guidelines for diagnosis (77% of 73 units) and treatment (63% of 72 units). Alkaline phosphatase was the blood marker most used for treatment indication (81% of 72 units), and phosphate supplementation was the treatment most used (82% of 71 units). CONCLUSION: Metabolic bone disease of prematurity remains clinically relevant. Wide variations in diagnostic procedures and management strategies were observed in European neonatal units. Evidence-based consensus guidelines appear urgently needed to reduce the number of symptomatic cases.

Skeletal consequences of preterm birth in pigs as a model for preterm infants.

Preterm birth affects about 10% of all live births with many resultant health challenges, including metabolic bone disease of prematurity (MBDP) which is characterized by elevated alkaline phosphatase, suppressed phosphate, and deficient skeletal development. Because of the lack of an animal model, very little is known about bone structure, strength, and quality after preterm birth. This study investigated the utility of a pig model to replicate clinical features of preterm birth, including MBDP, and sought to determine if early postnatal administration of insulin-like growth factor (IGF)-1 was an effective treatment. Preterm pigs, born by caesarean section at 90% gestation, were reared in intensive care facilities (respiratory, thermoregulatory and nutritional support) and compared with sow-reared term pigs born vaginally. Preterm pigs were systemically treated with vehicle or IGF-1 (recombinant human IGF-1/BP-3, 2.25 mg/kg/day). Tissues were collected at postnatal days 1, 5, and 19 (the normal weaning period in pigs). Most bone-related outcomes were affected by preterm birth throughout the study period whereas IGF-1 supplementation had almost no effect. By day 19, alkaline phosphatase was elevated, phosphate and calcium were reduced, and the bone resorption marker CTX-1 was elevated in preterm pigs compared to term pigs. Preterm pigs also had decrements in femoral cortical cross-sectional properties, consistent with reduced whole-bone strength. Thus, the preterm pig model replicates many features of preterm bone development in infants, including features of MBDP, and allows for direct interrogation of skeletal tissues, enhancing the field's ability to examine underlying mechanisms.

Premature birth interrupts a critical period of skeletal development as the majority of fetal bone mineral accumulation occurs during the last gestational trimester, leaving preterm infants at increased risk for low bone mineral density and fractures. While there are some data on growth in bone mass in preterm infants, very little is known about bone structural properties, quality, and strength during development after preterm birth. In this study we sought to evaluate the pig as a model for postnatal skeletal development after premature birth. Preterm pigs born after approximately 90% of the full gestation period were compared to full-term control pigs through day 19 of life. Levels of two blood markers used to diagnose osteoporosis of prematurity were replicated in the pig model. Bone properties related to strength were reduced even when accounting for their smaller body size, possibly suggesting elevated fracture risk in preterm infants. Based on the similarities between the preterm pig model and preterm human infants, the pig model may prove to be useful to study factors and interventions affecting postnatal bone development after preterm birth.

Sodium Glycerophosphate Use in Parenteral Nutrition Improves Mineral Metabolism in Extremely Low Birth Weight Infants.

OBJECTIVE: To evaluate the clinical effect of sodium glycerophosphate (NaGP) in parenteral nutrition solutions on mineral metabolism in extremely low birth weight (ELBW) infants. STUDY DESIGN: NaGP was introduced for use in place of potassium phosphate (K3PO4) in January 2018; this retrospective cohort study included 95 ELBW infants treated with K3PO4 between January 2015 and December 2017 and 77 infants treated with NaGP between August 2018 and January 2021. Mineral intake over the first 14 days; changes in serum calcium, phosphorus, sodium, and alkaline phosphatase (ALP) levels over the first 1-3 months; and the rates of electrolyte imbalance and clinical morbidity were compared. High-risk infants who had nil per os (NPO) status for >14 days and prolonged parenteral nutrition exposure were further analyzed as a subgroup. RESULTS: The use of NaGP instead of K3PO4 significantly increased Ca and P intake, but intakes remained below the recommended range (Ca, 64-140 mg/kg/day; P, 50-108 mg/kg/day). Compared with levels in the K3PO4 group, the NaGP group had significantly higher serum Ca and P levels after day 14 and lower ALP levels after day 56. In the subgroup analysis, the NaGP group had significantly lower incidences of hypophosphatemia, hyponatremia, bronchopulmonary dysplasia, and ALP >500 IU/L. CONCLUSIONS: Although the administration of NaGP instead of K3PO4 in parenteral nutrition regimens still did not provide adequate Ca and P intake for ELBW infants, higher intake significantly improved serum Ca and P levels, especially in ELBW infants with prolonged parenteral nutrition exposure.

A Multidisciplinary and a Comprehensive Approach to Reducing Fragility Fractures in Preterm Infants.

With advances in neonatal care, bone fractures prior to discharge from the hospital in preterm infants receiving contemporary neonatal care, are rare. Nevertheless, such fractures do occur in very low birth weight and extremely low birth weight infants who go on to develop metabolic bone disease of prematurity (MBDP), with or without secondary hyperparathyroidism. MBDP is a multifactorial disorder arising from the disruption of bone mass accrual due to premature birth, postnatal immobilisation, and loss of placental oestrogen resulting in bone loss, inadequate provision of bone minerals from enteral and parenteral nutrition, and medications that leach out bone minerals from the skeleton. All of these factors lead to skeletal demineralisation and a decrease in bone strength and an increased risk of fractures of the long bones and ribs. Secondary hyperparathyroidism resulting from phosphate supplements, or enteral/parenteral feeds with a calcium-to-phosphate ratio of < 1.3:1.0 leads to subperiosteal bone resorption, cortical thinning, and further skeletal weakening. Such fractures may occur from routine handling and procedures such as cannulation. Most fractures are asymptomatic and often come to light incidentally on radiographs performed for other indications. In 2015, we instituted a comprehensive and multidisciplinary Neonatal Bone Health Programme (NBHP), the purpose of which was to reduce fragility fractures in high-risk neonates, by optimising enteral and parenteral nutrition, including maintaining calcium-to-phosphate ratio ≥1.3:1, milligram to milligram, biochemical monitoring of MBDP, safe-handling of at-risk neonates, without compromising passive physiotherapy and skin-to-skin contact with parents. The at-risk infants in the programme had radiographs of the torso and limbs at 4 weeks and after 8 weeks from enrolment into the program or before discharge. Following the introduction of the NBHP, the bone fracture incidence reduced from 12.5% to zero over an 18-month period.

Factors Affecting Metabolic Bone Disease of Prematurity: Is Hypothyroxinemia Included?

Objectives: The association between transient hypothyroxinemia of prematurity (THOP) and metabolic bone disease of prematurity (MBD) is not clearly known. We aimed to evaluate the effects of THOP and other risk factors on MBD in very low birth weight infants. Methods: This study included infants born at <30 weeks gestational age and <1500 g birth weight who were hospitalized between July 2016 and December 2019. The following information was obtained from medical records: Demographic characteristics; clinical follow-up data; morbidities; initial thyroid function tests; and calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) levels at postnatal 4-6 weeks. Newborns with an ALP level >500 IU/L were diagnosed with MBD. Patients without MBD were defined as Group 1 and patients with MBD were defined as Group 2. Results: Our study enrolled 145 infants who met the inclusion criteria. The incidences of MBD and THOP were 16.5% and 56.5%, respectively. Gestational age and birth weight were significantly lower in Group 2 than in Group 1. It was observed that these infants received total parenteral nutrition for a longer period of time and had a longer transition period to full enteral feeding. In addition, duration of non-invasive mechanical ventilation, duration of oxygen treatment, frequencies of moderate-severe bronchopulmonary dysplasia, and postnatal steroid use were found to be significantly higher in babies in Group 2 compared to babies in Group 1. There was no significant difference between the groups in terms of THOP. However, multivariate logistic regression analysis revealed no risk factors for the development of MBD. The presence of MBD and Ca, P, and ALP levels did not differ significantly between patients with and without THOP. Conclusion: Our study reveals that MBD is a multifactorial disease and THOP is not a risk factor for the development of MBD.

Extrapulmonary complications of bronchopulmonary dysplasia in premature infants / 中国小儿急救医学

Bronchopulmonary dysplasia(BPD)is a common chronic lung disease that occurs in preterm infants.The infant who with BPD has the feature of small gestational age, low birth weight and immature development of various organ systems.During hospitalization, it is easy to combine with brain injury in premature infant, metabolic bone disease of prematurity, retinopathy of prematurity and cholestasis syndrome, which seriously affect the survival rate and life quality of premature infants.This article reviewed the extrapulmonary complications of BPD in premature infants.

Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.

Metabolic bone disease of prematurity (MBDP) is characterised by skeletal demineralisation, and in severe cases it can result in fragility fractures of long bones and ribs during routine handling. MBDP arises from prenatal and postnatal factors. Infants who are born preterm are deprived of fetal mineral accumulation, 80% of which occurs in the third trimester. Postnatally, it is difficult to maintain a comparable intake of minerals, and medications, such as corticosteroids and diuretic therapy, lead to bone resorption. With improvements in neonatal care and nutrition, the incidence of MBDP in preterm infants appears to have decreased, although the recent practice of administering phosphate supplements alone will result in secondary hyperparathyroidism and associated bone loss, worsening MBDP. Postnatal immobilisation and loss of placental supply of oestrogen also contribute to skeletal demineralisation. There is no single diagnostic or screening test for MBDP, with pitfalls existing for most radiological and biochemical investigations. By reviewing the pathophysiology of calcium and phosphate homeostasis, one can establish that plasma parathyroid hormone is important in determining the aetiology of MBDP - primarily calcipaenia or phosphopaenia. This will then direct treatment with the appropriate supplements while considering optimal physiological calcium to phosphate ratios.

Acetylcholinesterase activity and bone biochemical markers in premature and full-term neonates.

Background Almost 30% of the premature infants have low body weight and bone mineral density due to prematurity. There is no consensus of screening premature neonates for metabolic bone disease; therefore, it is important to investigate the use of bone biochemical parameters. Latest studies involved the activity of acetylcholinesterase as a mediator in bone remodeling. It is hypothesized that there is a possible correlation of bone biochemical biomarkers and acetylcholinesterase (AChE) activity in premature infants. Methods We studied 50 neonates (26 preterm with gestational age <32 weeks, 24 full-term). Clinical data (sex, gestational week) and anthropometric parameters (body weight) were recorded. We directly measured the bone biochemical markers in serum such as alkaline phosphatase (ALP), calcium (Ca), phosphorus (P), magnesium (Mg) and parathyroid hormone (PTH). In addition, we measured the AChE activity. Results ALP and parathyroid hormone levels were higher, but Ca, P and AChE were lower in premature neonates group compared with full-term ones. There is a significant positive correlation of gestational age with body weight, Ca and AChE. A significant negative correlation was observed for ALP and PTH with gestational age. Conclusions We found a gestational age-related increase of AChE activity. There were significant relationships between AChE activity with P and PTH.

Mineral status of premature infants in early life and linear growth at age 3.

BACKGROUND: Preterm infants are at significant risk of reduced bone mineral content and subsequent bone disease (metabolic bone disease of prematurity, MBDP). MBDP is frequently found in very low-birthweight (VLBW) infants, but long-term height prognosis is not well known. METHODS: VLBW infants from two major neonatal intensive care units were studied. Medical records were reviewed. A total of 143 subjects were analyzed after excluding subjects who died, or who had severe complications that could affect linear growth, Silver-Russell syndrome, severe cholestasis, and/or chromosomal abnormality. The relationship between MBDP and height at age 3 was investigated. RESULTS: Height standard deviation score (SDS) at age 3 negatively correlated with peak serum alkaline phosphatase (ALP) activity in early life (r = -0.30, P = 0.0003) and positively correlated with serum phosphorus (P) at peak ALP (r = 0.33, P = 0.0002). In addition, serum P independently affected height SDS at 3 years of age (ß = 0.19, P = 0.018), and was significantly different between infants with and without catch-up growth in height (difference: 0.23 mmol/L, 95%CI: 0.09-0.36, P = 0.0010). CONCLUSIONS: MBDP, particularly hypophosphatemia in the early period of life, is associated with linear growth until 3 years of age in VLBW infants.

Enfermedad metabólica ósea del prematuro: informe de un caso y revisión de la literatura / Metabolic bone disease of prematurity: Case report and review

Se comunica el caso de una paciente con enfermedad metabólica ósea del prematuro, que nació luego de 26 semanas de gestación y de 62 días de vida extrauterina, que estuvo internada desde su nacimiento en un hospital de 3er nivel en la ciudad de Oruro, donde estuvo conectada a presión positiva nasal (CPAP) por varios días, además de recibir tratamiento antibiótico con varios esquemas de amplio espectro por haber cursado con sepsis neonatal y enterocolitis necrosante (ECN) grado II; además recibió metilxantinas por presentar periodos de apnea y hasta su ingreso a nuestro hospital permanecía dependiente de oxígeno, con muy poca ganancia de peso e hipoactividad. Fue transferida para valoración oftalmológica por sospecha de retinopatía del prematuro. A su ingreso se hizo un examen clínico minucioso y se realizaron varios exámenes de laboratorio y gabinete con los cuales se demostró una osteopenia del prematuro, que respondió en forma favorable al tratamiento.

We describe a 26 weeks old premature baby with metabolic bone disease. She was transferred to our hospital at 62 days of age for ophthalmologic evaluation. She was treated in the primary hospital with CPAP, different antibiotics for sepsis and NEC. She also received methylxanthines for neonatal apnea. When she arrived to our hospital she was oxygen dependent and with little weight increase. During her stay at our neonatal unit we performed a complete physical exam and several diagnostic tests, showing metabolic bone disease which favorable response to specific treatment.