Bone Metabolic Disorders in Premature and Full-Term Neonates - A Detailed Overview

Introduction:

Reduced bone mineral content (BMC) impairs skeletal mineralization and is linked to metabolic bone disease (MBD) in neonates. It is often referred to as osteopenia of infancy and frequently occurs in premature babies due to several dietary and biomechanical variables. BMC is negatively correlated with gestational age and birth weight and is regulated by calcium and phosphorus. In addition, rachitic alterations (rickets) may or may not occur.

What Is Metabolic Bone Disorder (MBD)?

Reduced bone mineralization in newborns, when compared to in-utero or ex-utero (outside the uterus) bone mineral density of newborns with equivalent gestational age or birth weight, as well as biochemical evidence and radiographic abnormalities, is known as MBD. This disorder is frequently seen in neonates with very low birth weights (VLBW: 3.30 pounds), with an increased incidence in those with extremely low birth weights (ELBW: 2.20 pounds).

What Are the Causes of MBD?

Intrauterine growth restriction, extended parenteral nutrition (PN) (without phosphate), and postponed enteral nutrition are the main reasons for insufficient mineralization. When exposed to prolonged periods of immobility, newborns with inadequate calcium, phosphorus, and vitamin D consumption are at increased risk of developing MBD. Between the sixth and sixteenth week of life, or at 40 weeks of corrected age, MBD begins to manifest. However, it may not be apparent until a considerable demineralization has occurred (loss of 20 to 40 % of BMC). The various other causes are

In-Utero:

• Deficient maternal calcium and phosphorus stores.

• Maternal vitamin D deficiency.

• Accelerated physiological fetal growth in 3rd trimester.

Ex-Utero:

1. Maternal:

• Inadequate nutritional supplementation to lactating mother (calcium, phosphorus, vitamin D).

2. Neonatal:

• Insufficient supplementation of calcium, phosphorus, and vitamin D.

• Excessive fluid restriction in VLBW neonates.

• Urinary calcium wasting (phosphorus deficiency).

• Use of term formula in preterm infants.

• Use of soy-based or lactose-free formula.

Neonatal Cholestasis - Have exaggerated malabsorption and impaired 25(OH)D, which further aggravates osteopenia.

• Hereditary Pseudovitamin D Deficiency: Type 1 (abnormal or absent 1-α-hydroxylase activity) or type 2 (1,25-dihydroxy vitamin D resistance in tissues).

• Medications: Furosemide, steroids, Methylxanthines, Phenobarbitone, Phenytoin - Enhance osteoclastic (bone destruction) activity, decrease osteoblastic (bone formation) proliferation, reduce calcium absorption and promote renal calcium wasting may lead to osteopenia (reduced bone mineral content).

How Is a Metabolic Bone Disorder Caused?

The disease-related physiological processes that are out of balance to cause metabolic bone disorders are

• Calcium and Phosphorus Homeostasis - Bone integrity is greatly influenced by the homeostasis of calcium, phosphorus, and magnesium, which comprise most of the skeletal system's structural matrix. Ninety-nine percent of the calcium and eighty percent of the phosphorus in the human body are found in the bone as microcrystalline hydroxyapatite. The extracellular fluids and soft tissues contain the body's calcium (1 %). Only 50 % of the total calcium in serum is physiologically active because it is in the ionized state. Calcium that is still present is 40 % attached to proteins (albumin and globulin) and 10 % to organic and inorganic acids. Similarly, the bone matrix contains a significant amount of magnesium (60 %). Calcium and phosphorus homeostasis is influenced by various variables, including vitamin D, parathyroid hormone (PTH), calcitonin, dietary calcium and phosphorus content, intestinal absorption, bone deposition and resorption, and rate of urine excretion.

• Role of Parathyroid Hormone - There is a drop in calcium levels shortly after birth, regardless of gestational age and ongoing mineral requirements, with a minimum reached at 24 to 30 hours after delivery in preterm newborns. PTH levels increase as a result. PTH causes urinary phosphate wasting and increases calcium reabsorption in the kidney. PTH activates renal 25(OH)D3-1-alpha-hydroxylase, which enhances intestinal calcium and phosphate absorption, helping to produce calcitriol [1,25(OH)2D]. PTH encourages the release of calcium and phosphate after bone resorption has taken place. Overall, PTH has the most significant impact on calcium metabolism in the kidney. These metabolic alterations continue when calcium intake is inadequate for an extended length of time, as is the case in MBD.

• Fetal Bone Homeostasis - Depending on the baby's age, different amounts of minerals are needed for the appropriate development of the skeleton. The fetus grows more rapidly in its skeleton, especially in the final trimester. Osteoblasts create the osteoid or organic bone matrix that contains calcium and phosphate hydroxyapatite. Between 24 and 37 weeks of pregnancy, this osteoblastic activity grows dramatically and accounts for 80 % of mineral deposition. As calcium is actively transferred transplacentally with the help of a calcium pump located in the basement membrane, the placenta plays a crucial role in forming the fetal skeleton.

• Additionally, the placenta is where vitamin D is activated to 1,25-dihydroxycholecalciferol, which is crucial for transplacental phosphate transfer. Thus, higher estrogen levels cause a hypercalcemic state in fetal life, which enhances bone modeling and endocortical bone growth. Preterm newborns have interruptions in all these processes, making them more likely to have under-mineralized bones. Additionally, persistent placental inflammatory disease (chorioamnionitis) or placental insufficiency, as seen by intrauterine development retardation, limits the transplacental transfer of calcium and phosphorus, generating an osteopenic environment in the uterus. Because maternal dietary calcium intake affects placental calcium levels and fetal bone deposition, pregnant women who receive a calcium supplement of 0.004 pounds on or after week 22 of gestation see an increase in neonatal BMC.

• Neonatal Bone Homeostasis - In term newborns, the physical bone density decreases by a third from birth to six months. This happens because the bone marrow cavity preferentially widens quickly compared to the cortical surface area. Contrary to preterm newborns, term neonates typically maintain bone integrity. After delivery, serum calcium levels and transplacentally transferred estrogens decline, increasing PTH. However, during the first 48 hours of life, decreasing serum calcium levels do not coincide with an increase in serum PTH levels, which then causes serum calcium levels to fall. The type and quantity of calcium consumption, gastrointestinal function, particularly calcium active and passive transport, and maternal vitamin D levels all affect calcium absorption in postnatal life. Preterm neonates with low nutrient intake and ineffective gastrointestinal absorption of calcium and phosphorus are at a double disadvantage and more likely to develop MBD. When preterm newborns experience large gastric aspirates, vomiting, abdominal distension, and constipation, oral calcium absorption is impaired. In addition to dietary supplementation, physical activity during fetal life, such as quickening against the uterine wall, is another crucial component regulating osteoblastic activity. This activity may be lost in ill, premature neonates who are less active in postnatal life. Reduced physical activity causes urinary calcium waste and bone resorption by increasing osteoclastic activity and inhibiting osteoblastic activity.

What Are the Clinical Features of MBD?

The various features of metabolic bone disorders are

• Arrested growth velocity - Reduced linear growth with normal head growth.

• Features of hypocalcemia - Low calcium levels in the blood (jitteriness and tetany).

• Features of rickets.

• Spontaneous fractures of ribs and long bones.

• Pain while handling - Seen in cases of pathological fractures.

• Respiratory distress.

• Deranged pulmonary function.

• Difficulty in weaning from a ventilator.

What Are the Risk Factors of MBD?

The risk factors causing metabolic bone disorders are

1. Antenatal (Before Birth)

   • Placental insufficiency.

   • Preeclampsia - High blood pressure during pregnancy.

   • Chorioamnionitis - A bacterial infection occurring during pregnancy.

   • Neuromuscular disorders.

   • Intraventricular hemorrhage - Bleeding into the fluid-filled areas of the brain.

   • Periventricular leukomalacia - Death of brain tissue around the fluid-filled areas of the brain called ventricles.

   • Genetic polymorphisms - Vitamin D receptor, collagen alpha I, estrogen.

   • Male gender.

2. Postnatal (After Birth)

   • Prolonged total parenteral nutrition of more than four weeks.

   • Bronchopulmonary Dysplasia - Chronic lung disease causing damage to bronchi (airway), leading to tissue destruction in the alveoli.

   • Necrotizing enterocolitis - Causes inflammation of the baby's intestines resulting in perforation through which bacteria can enter the bloodstream.

   • Liver disease.

   • Renal disease.

   • Medications like loop diuretics, Methylxanthines, and glucocorticoids.

How Is MBD Diagnosed?

The various diagnostic methods for metabolic bone disorders are

1. Biochemical Findings

   • Decreased serum phosphorus levels [ less than 3.5 to 4 mg/dL (1.1 to 1.3 mmol/L)].

   • Increased serum alkaline phosphatase levels.

   • Elevated bone isoenzymes of alkaline phosphatase.

   • Low or normal serum calcium levels.

   • Low or normal serum 25(OH)D levels.

   • Elevated serum PTH levels (often variable).

   • Low urinary calcium and phosphorus levels.

2. Radiological Findings

   • Radiograph of a long bone - Widening of epiphyseal growth plates; metaphysis rarefaction, cupping, fraying, subperiosteal new bone formation, and osteopenia.

   • Radiograph of the skull, spine, and scapula - Demonstration of osteopenia.

   • Radiograph of the chest - Osteopenia and rachitic changes, pathologic fractures in ribs.

   • DEXA (dual-energy X-ray absorptiometry) - reduced bone mineral content.

   • Quantitative ultrasound - reduced bone SOS (speed of sound).

How Is MBD Managed?

The various types of management in MBD include

• Early enteral feeding.

• Fortified human milk.

• Premature formulas.

• Adequate calcium and phosphorus intake.

• Vitamin D supplementation of 400 IU/day (ensures sufficient vitamin D stores).

• Preferable use of thiazide diuretics over furosemide.

• Assisted with physical exercises.

• Avoid forceful chest physiotherapy.

• Calcitriol (exceptional circumstances).

Conclusion:

It is important to promptly recognize the metabolic anomalies indicative of MBD to initiate treatment interventions and avoid spontaneous or pathological fractures. Estimating the risk of osteopenia and determining the effectiveness of treatment requires a regular calculation of phosphate and alkaline phosphatase concentrations. Similar to DEXA, quantitative ultrasonography helps in nutritional rehabilitation by allowing the measurement of bone mineralization. Another critical MBD prevention technique is maternal vitamin D supplementation.