Metabolic bone disease of prematurity (MBDP) is a state of undermineralisation of the skeleton in preterm infants. Like most conditions, there is a spectrum of disease, and at the extreme end, it can be associated with fragility fractures and respiratory compromise due to increased chest wall compliance. MBDP is sometimes referred to in the literature as ‘Rickets of prematurity’ and ‘Osteopaenia of prematurity’.
What causes it?
These infants have not had an adequate supply of calcium and phosphate to successfully mineralise their skeletons and to cover them for the period of increased bone resorption, which occurs after birth.
It’s a condition of premature infants?
That’s right. 80% of foetal bone mineral accretion occurs during the third trimester (specifically between 32 and 36 weeks gestation) to cover for a period of rapid bone growth which usually occurs at this time. Despite advances in neonatal nutritional care, we cannot provide comparable rates of mineral accretion to the placenta. In addition, removal from the placental oestrogen supply has effects similar to those seen in post-menopausal women (stirring a long way back in your memory if you have worked in paediatrics for a long time!) and medications commonly used in very preterm infants such as steroids and diuretics also lead to increased bone resorption. The strongest independent risk factor for MBDP is birth weight, so all infants under 1500g should be screened.
The baby looks fine, so I can relax, right?
Sadly not. Both clinical and radiological features are only detectable late in the disease process, with osteopaenia on x-ray not present until 30-40% of bone mineral has already been lost. Severe MBDP can also cause respiratory difficulties due to excessive chest wall compliance, exacerbating the chronic lung disease it often co-exists with. Therefore, infants who are at risk should have regular screening for early identification.
The basic science
The bones provide a reservoir for calcium and phosphate, which are used for various important intracellular processes (including nerve transmission, muscular contraction, coagulation and more). The body has a homeostatic mechanism for keeping calcium in the normal range but no mechanism for maintaining phosphate within the normal range.
What happens if calcium and / or Vitamin D levels are low?
PTH will detect the low calcium levels and, in response, will mobilise calcium from the bones and cause active phosphate excretion in the urine. Because of the calcium resorption, serum calcium levels will remain normal, but phosphate levels will be low. Increased bone turnover from the resorptive action of PTH on bones will raise alkaline phosphatase, and this becomes a vicious cycle as ongoing bone resorption and skeletal demineralisation worsens rickets.
The treatment is high-dose calcium and vitamin D supplementation to remineralise the bones and normalise the serum calcium levels. This will reduce the PTH concentration, halting the cycle of bone resorption and normalising phosphate levels by reducing renal excretion of phosphate.
What happens if phosphate levels are low?
Because the body doesn’t have a compensatory mechanism to maintain phosphate in the normal range, PTH levels will be normal. However, low serum phosphate results in failure to mineralise bones and is the endpoint causing rickets in metabolic bone disease.
So low phosphate is the endpoint? Shall I just treat with phosphate then?
This may seem logical, and until recently, this was common practice. However, supplemental phosphate will bind with serum-ionised calcium resulting in a calcium-phosphate product. This lowers calcium levels and increases PTH secretion, worsening rickets.
Prevention of MBDP
Prevention is always better than cure! Careful nutritional management, including fortification of breast milk, use of preterm formulas (which have additional mineral levels compared to term formula), and attention to calcium: phosphate ratios in Parenteral Nutrition (ESPGHAN recommends molar ratios of 1.3:1 after the first few days of life) and supplementation of Vitamin D are all important in preventing MBDP. Remember, Vitamin D deficiency is common in pregnant women, with particular risk factors being increased skin pigmentation and BMI > 30 (because Vitamin D is a fat-soluble vitamin). While universal Vitamin D supplementation for preterm or low birth weight infants is practised, remember that this reflects these infants’ higher requirements and will not be sufficient if they were Vitamin D deficient from birth.
Screening for MBDP
Metabolic Bone Disease of Prematurity typically develops between 3 and 12 weeks of age, so high-risk infants should be regularly screened. Screening should consist of fortnightly measurements of alkaline phosphatase, phosphate and adjusted calcium. If alkaline phosphatase is raised (typically three times the upper limit of normal), PTH should be measured.
Raised ALP, low phosphate and normal or raised PTH are consistent with MBDP.
I’ve started calcium supplements and now the levels are high – should I be worried about renal stones?
In the presence of raised PTH, there will be active calcium reabsorption from the glomerular filtrate, so the risk of this is negligible.
Vitamin D levels are 30nmol/L, which our local lab says is normal. Shall I stop high dose Vitamin D supplements?
Elevated PTH in MBDP will cause depletion of vitamin D by converting 25-OH Vitamin D to its active metabolite 1-25-dihydroxy-vitamin D, so high dose vitamin D supplementation should be continued if the vitamin D level is below 50nmol/L.
Administration of supplements
When prescribing calcium and phosphate supplements, they should be written up for different times and not given concurrently. If they are given together, the supplements will precipitate in the feed and not be effective.