Invited Mini Review Metabolic Bone Disease of Prematurity: Overview and Practice Recommendations

Abstract

Metabolic bone disease of prematurity (MBDP) is defined by undermineralization of the preterm infant skeleton arising from inadequate prenatal and postnatal calcium (Ca) and phosphate (PO4) accretion. Severe MBDP can be associated with rickets and fractures. Despite advances in neonatal nutrition, MBDP remains prevalent in premature infants due to inadequate mineral accretion ex utero. There also remain significant knowledge gaps regarding best practices for monitoring and treatment of MBDP among neonatologists and pediatric endocrinologists. Preventing and treating MBDP can prevent serious consequences including rickets or pathologic fractures. Postnatal monitoring to facilitate early recognition of MBDP is best done by first-tier laboratory screening by measuring serum Ca, phosphorus, and alkaline phosphatase to identify infants at risk. If these laboratories are abnormal, further studies including assessing parathyroid hormone and/or tubular resorption of PO4 can help differentiate between Ca and PO4 deficiency as primary etiologies to guide appropriate treatment with mineral supplements. Additional research into optimal mineral supplementation for the prevention and treatment of MBDP is needed to improve long-term bone health outcomes and provide a fuller evidence base for future treatment guidelines. Metabolic bone disease of prematurity (MBDP) is defined by undermineralization of the preterm infant skeleton arising from inadequate prenatal and postnatal calcium (Ca) and phosphate (PO4) accretion. Severe MBDP can be associated with rickets and fractures. Despite advances in neonatal nutrition, MBDP remains prevalent in premature infants due to inadequate mineral accretion ex utero. There also remain significant knowledge gaps regarding best practices for monitoring and treatment of MBDP among neonatologists and pediatric endocrinologists. Preventing and treating MBDP can prevent serious consequences including rickets or pathologic fractures. Postnatal monitoring to facilitate early recognition of MBDP is best done by first-tier laboratory screening by measuring serum Ca, phosphorus, and alkaline phosphatase to identify infants at risk. If these laboratories are abnormal, further studies including assessing parathyroid hormone and/or tubular resorption of PO4 can help differentiate between Ca and PO4 deficiency as primary etiologies to guide appropriate treatment with mineral supplements. Additional research into optimal mineral supplementation for the prevention and treatment of MBDP is needed to improve long-term bone health outcomes and provide a fuller evidence base for future treatment guidelines.

Keywords: Metabolic bone disease; Nutrition; Phosphate; Prematurity; Rickets.

Fig. 1.

Screening and management algorithm for premature infants at risk for metabolic bone disease. *If available, oral solutions compounded from intravenous products are preferred. Potassium PO4 may be preferred if the patient is on diuretic or requires potassium supplementation. Recommend to start with low doses of oral phosphorus supplements and titrate up as needed to prevent diarrhea. May transition to PO4 tablets or packets after discharge. ALP, alkaline phosphatase; BID, twice daily; Ca, calcium; Ca/Cr, calcium/creatinine; cGA, corrected gestational age; MBDP, metabolic bone disease of prematurity; QID, four times daily; P, phosphorus; PO4, phosphate; PTH, parathyroid hormone; TPN, total parenteral nutrition; TRP, tubular reabsorption of phosphate; 25OHD, 25 hydroxy vitamin D.

Fig. 2.

Ca and PO4 homeostasis in MBDP. There is a complex interplay among 1,25(OH)₂D, PTH, and fibroblast growth factor 23 (FGF23) to maintain mineral homeostasis [69]. Phosphorus deficiency leads to low FGF 23 levels (mechanism not completely understood) which causes increased 1,25(OH)₂D production, resulting in increased absorption of both Ca and phosphorus from the gut and increased phosphorus reabsorption from the kidneys. This is in contrast to conditions with FGF-23-mediated hypophosphatemia (like X-linked hypophosphatemic rickets) which have elevated FGF 23 levels causing decreased 1,25(OH)₂D production. In primary Ca and/or vitamin D deficiency, PTH level increases which activates 25OHD to 1,25(OH)₂D which in turns increases absorption of Ca and phosphorus from gut. Elevated PTH also increases bone resorption with release of Ca and phosphorus as well as increases renal Ca reabsorption and renal phosphorus excretion. The net effect is normal serum Ca, low serum phosphorus, and elevated ALP level. All the above lead to decreased mineralization of growth plate and bone, resulting in MBDP. Since the serum chemistry panel can be similar in both Ca and PO4 deficiency states, if PO4 is supplemented alone in a Ca deficiency state, it can exacerbate hyperparathyroidism and cause further bone resorption. Hence, it is important to understand the pathophysiology to treat appropriately. ALP, alkaline phosphatase; Ca, calcium; P, phosphorus; PO4, phosphate; PTH, parathyroid hormone; TPN, total parenteral nutrition; TRP, tubular reabsorption of phosphate; 1,25(OH)2D, 1,25 dihydroxy vitamin D.