Definition

1. 
   

   There is no clear definition of this condition.

   
   
2. 
   

   It is referred to by multiple names, most commonly osteopenia of prematurity, metabolic bone disease of prematurity, or rickets of prematurity.

   
   
3. 
   

   Each of these names implies somewhat different characteristics of the clinical (rickets), laboratory (metabolic bone disease), or radiological (osteopenia and rickets) findings.

   
   
4. 
   

   In practical terms, it is the presence of radiological rickets or fractures that determines the clinical symptomatology. However, markedly abnormal laboratory values, including a very high alkaline phosphatase activity are concerning and may require clinical intervention.

Incidence

1. 
   

   As this is not a reportable condition, the incidence is unknown and would depend on which type of definition is used.

   
   
2. 
   

   For example, an elevated alkaline phosphatase, indicative of metabolic bone disease is nearly universal in very low birthweight infants and as such it is not really possible to identify a true upper limit of normal for the serum alkaline phosphatase activity in preterm infants.

   
   
3. 
   

   Clinically apparent fractures are uncommon.

   
   
4. 
   

   In general, it has been suggested that low bone mass is present in about half of all VLBW infants, but true rickets is likely much less common in this population except in infants <600 g birthweight, where it may reach 50%. Using modern nutritional methods of providing minerals to infants, the incidence of clinically significant low bone mass is probably about 10% of VLBW infants but this number cannot readily be verified.

Pathophysiology

1. 
   

   VLBW infants have an extremely high requirement of calcium and phosphorus, the principal components of bone mineral. This need cannot be met using unfortified human milk.

   
   
2. 
   

   Vitamin D deficiency is not a primary cause of LBM in VLBW infants.

   
   
3. 
   

   However, in full-term infants with malabsorptive problems, such as intestinal failure/short gut and/or cholestatic liver disease, vitamin D deficiency may play an important role in inadequate mineral absorption and bone mass growth.

   
   
4. 
   

   The rare preterm infant with significant renal failure may also present with multiple problems related to bone minerals, including low serum calcium, high serum phosphorus, low vitamin D status, and bone demineralization.

Risk factors

1. 
   

   Clinically important risk factors during hospitalization are those that might decrease mineral intake or absorption or increase mineral excretion.

   
   
2. 
   

   Specifically, these primarily include

   
   
   
   
   • 
     

     The use of unfortified or inadequately fortified human milk

     
     
   • 
     

     Frequent use of loop diuretics

     
     
   • 
     

     Use of steroids

     
     
   • 
     

     Fluid restriction

   
   

   It is impossible in many circumstances to be certain about the most important of these factors, but infants in the NICU frequently encounter more than one of these risks.

   
   
3. 
   

   In many cases, it is lower mineral intake, not bioavailability or even increased renal calcium excretion by loop diuretics (eg, furosemide), which is the principal problem.

Clinical presentation

1. 
   

   Signs and symptoms

   
   
   
   
   1. 
      

      There are often few if any clinical signs in high-risk neonates.

      
      
   2. 
      

      Physical signs of rickets or fractures can be present, however, and are similar to those seen in older children. Specifically, bone or joint swelling can occur.

      
      
   3. 
      

      Classic signs such as bowing of the legs, frontal bossing, rachitic rosary, and craniotabes are generally difficult to appreciate in the newborn period, especially in preterm infants.

   
   
2. 
   

   Condition variability

   
   

   There is considerable variability in the severity and course of neonatal bone demineralization, mostly related to the ability to intervene with additional calcium and phosphorus.

Diagnosis

1. 
   

   Biochemical evidence

   
   

   Severe bone loss leading to rickets is generally suggested by an extremely high serum alkaline phosphatase, generally >800 IU/L, which is often accompanied by a low serum phosphorus <3.5 to 4.0 mg/dL. These biochemical findings are not diagnostic, however, and the ultimate determination of severe bone demineralization or rickets must be done radiographically.

   
   
2. 
   

   Radiographic evidence

   
   
   
   
   1. 
      

      Up to about 40% bone loss may not have any clear signs on radiographic examination.

      
      
   2. 
      

      Nonspecific radiological reports using terms such as “washed-out bones” have little if any definitive meaning in patient care.

      
      
   3. 
      

      Radiological rickets can and should be identified when present using wrist or knee films that demonstrate bone changes compatible with rickets that would also be seen in older children.

      
      
   4. 
      

      Consider performing a wrist or knee x-ray if the alkaline phosphatase exceeds 1000 IU/L or there are repeated values above 800 IU/L.

      
      
   5. 
      

      The use of bone ultrasound or bone mineralization techniques remains experimental at this time for preterm infants and newborns.

   
   
3. 
   

   Consider alternative diagnoses

   
   
   
   
   1. 
      

      Rarely another diagnosis may be considered in very preterm infants that is not the typical low mineral intake form of low bone mass or rickets.

      
      
   2. 
      

      Preterm infants can also have osteogenesis imperfecta, hyperparathyroidism, or any of several genetic syndromes associated with low bone mass.

      
      
   3. 
      

      These are usually considered when there are multiple fractures or severe rickets without a typical history of low mineral intake.

      
      
   4. 
      

      It may occasionally be of value to obtain a screening serum parathyroid level, although these can be difficult to interpret as normal values are not well established in infants.

Management

1. 
   

   Medical

   
   

   Medical management relies on (a) improving nutrient intake relative to key minerals and (b) decreasing losses of key nutrients.

   
   
   
   
   1. 
      

      First, consider improving nutrient intake.

      
      
      
      
      • 
        

        Liberalize TPN and feeding volumes as tolerated to reach nutritional needs.

        
        
      • 
        

        Determine if an infant is receiving maximum calcium and phosphorus in intravenous nutrition (TPN), usually 2 mmol/kg/d of each, and via the diet. In general, this means using specially designed fortifiers for human milk or formulas designed for preterm infants. In some cases, infants with intestinal problems, such as short gut syndrome, may only tolerate formulas not designed for preterm infants. This may need to be directly supplemented with vitamins and minerals.

        
        
      • 
        

        Table 21-1a describes three commonly used formulas designed for preterm infants and two human milk fortifiers designed for preterm infants. The amount of calcium, phosphorus, and vitamin D in these three products is described.

        
        
      • 
        

        As further discussed below, a vitamin D intake of 400 IU/dshould be provided. In the presence of cholestasis, up to 1000 IU/d of vitamin D should be given with monitoring of the serum 25-hydroxyvitamin D level every 1 to 2 months. Vitamin D₃ (cholecalciferol) is generally preferredto vitamin D₂ (ergocalciferol), but clinically, little distinction likely exists related to management of preterm infants.

        
        
      • 
        

        There are no currently available forms of vitamin D drops available for use in the United States that only provide vitamin D and iron, a combination often of value in this setting. As such, either a multivitamin with iron or separate vitamin D and iron need to be given.

      
      
   2. 
      

      Secondly, consider decreasing nutrient losses or accommodating for them.

      
      
      
      
      • 
        

        Account for magnesium and zinc losses. This is usually primarily a problem in infants with intestinal diseases including small bowel ostomies and thus may require supplemental minerals in the diet.

        
        
      • 
        

        With regard to preventing mineral losses, careful consideration of the need for loop diuretics, such as furosemide, and the need for steroids. Adding a thiazide diuretic to furosemide may decrease calcium excretion in the urine, but this is unproven in the newborn period. Similarly, there is minimal evidence to support the use of intermittent (such as every other day) furosemide dosing in order to prevent the bone loss.

   
   
2. 
   

   Surgical

   
   

   There is no role for surgical intervention in the management of bone demineralization or fractures in otherwise healthy preterm or full-term infants. Orthopedic consultation may be obtained for splinting/casting long-bone fractures but these are not treated surgically in this population.

Early developmental/therapeutic interventions

1. 
   

   The relationship between rickets in any child and developmental outcome is poorly described.

   
   
2. 
   

   In preterm or other high-risk neonates, low bone mass is usually associated with other better-defined causes of delayed development and it is relatively unlikely that the bone health issues are a significant independent factor. However, infants who have poor bone health often have had substantial problems with other aspects of their nutrition and this may serve as a marker of a need for close follow-up.

   
   
3. 
   

   Additionally, care should be provided regarding the handling of babies with severe bone demineralization to limit trauma that might lead to increased fractures. Physical therapy may be undertaken in at-risk infants but should be done cautiously, especially if mineral intake is limited (eg, long-term TPN, fluid restriction).

Prognosis

1. 
   

   Early predictors and outcomes

   
   
   
   
   1. 
      

      Even in the presence of significant rickets and fractures, the overall prognosis for neonatal bone loss is excellent.

      
      
   2. 
      

      Recovery of full bone mass and healing of fractures is universal when the etiology is nutritional and a more optimal mineral intake is achieved.

   
   

   (This section does not include a description of very rare endocrine-related causes of bone demineralization or genetic disorders such as osteogenesis imperfecta. The prognosis for bone health in these disorders is much more variable.)