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• Response to Lack of data/evidence to back recommendations for significant change of practice
  Raja Padidela
  Published on: 10 June 2021
• Lack of data/evidence to back recommendations for significant change of practice
  Minesh Khashu
  Published on: 1 August 2019

• Published on: 10 June 2021

  Response to Lack of data/evidence to back recommendations for significant change of practice

  • Raja Padidela, Paediatric Endocrinologist Royal Manchester Children’s Hospital

  Dear Editors,

  Archives of Disease in Childhood

  We thank Dr. Khashu for his comments on our article Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.

  Below we provide responses to his comments.

  1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.

  Response: Our suggested approach on management of Metabolic Bone Disease of Prematurity (MBDP) is underpinned by pathophysiology of this disorder. The case discussed is not an anecdotal case but represents many such cases referred to our service. In all age groups calcipaenic state (Calcium deficiency) causes increase in PTH secretion while phosphopaenic states (inadequate Phosphate absorption from diet or primary urinary phosphate leak) do not. Therefore our approach is to measure PTH to guide mineral supplementation and more specifically to maintain appropriate oral Calcium (Ca) to Phosphate (PO₄) ratio for adequate mineralisation of bones. It is our observation that PTH is not routinely measured in MBDP but, there are publications where PTH has been measured...

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  Dear Editors,

  Archives of Disease in Childhood

  We thank Dr. Khashu for his comments on our article Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.

  Below we provide responses to his comments.

  1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.

  Response: Our suggested approach on management of Metabolic Bone Disease of Prematurity (MBDP) is underpinned by pathophysiology of this disorder. The case discussed is not an anecdotal case but represents many such cases referred to our service. In all age groups calcipaenic state (Calcium deficiency) causes increase in PTH secretion while phosphopaenic states (inadequate Phosphate absorption from diet or primary urinary phosphate leak) do not. Therefore our approach is to measure PTH to guide mineral supplementation and more specifically to maintain appropriate oral Calcium (Ca) to Phosphate (PO₄) ratio for adequate mineralisation of bones. It is our observation that PTH is not routinely measured in MBDP but, there are publications where PTH has been measured and was found to be useful, both in diagnosis and management of MBDP^1-5. Besides us Moreira et al have also demonstrated usefulness of PTH measurement and treatment using oral calcium supplements². Oral phosphate supplementation reduces ionized calcium and therefore increases parathyroid hormone concentration. This pathophysiological concept is further elucidated in recent published case in Archives of Disease in Childhood education and practice section where pharmacological dose of oral phosphate in MBDP caused hypocalcaemia⁶. Our advice is to maintain oral Ca to PO₄ ratio as unopposed supplementation with PO₄ can cause secondary hyperparathyroidism and worsening of MBDP.

  2. The review recommends measurement of plasma parathromone as a critical initial step and most of the subsequent practice is dictated by this. The authors state “measurement of plasma PTH both for screening and diagnosis is crucially important". In the very next line they however state "the reference range of plasma PTH in neonates is not well established" They then go to talk about a very small study of 20 preterm neonates. It does not make much sense to recommend a major change of practice without any data to back it up and then highlight plasma PTH as a critical investigation for decision making when we don't really have any robust normative data. Should we not instead be generating prospective data based on current practice and if there is evidence of secondary hyperparathyroidism to change treatment accordingly? Also should we not be generating normative data for various gestations and postnatal ages to be confident about the plasma PTH values?

  Response: We agree that data on normal ranges of PTH in preterm infants was derived from 20 preterm neonates but, with 134 separate measurements⁷. This study is well conducted and in healthy neonates, PTH concentration using third-generation immunoassays demonstrated values similar to adult reference ranges with authors concluding that values above this should be considered as secondary hyperparathyroidism. Unlike serum PO₄, Ca concentration is tightly maintained within a narrow range in all age groups and it would therefore appear that PTH, which is the primary hormone for Ca homeostasis, is also maintained within the normal range in all age groups. We believe therefore that current reference ranges of PTH in combination with measurement of serum Ca, PO4 and Alkaline Phosphatase are sensitive indicator of MBDP and will allow us to guide management with appropriate mineral supplementation. Of course a larger study will be most welcome specially looking at various gestational ages and corrected ages in premature infants taking into consideration infant’s dietary Ca intake and serum Vitamin D concentration.

  3. In figure 1, the first part shows a right humerus at 3 months of age but the subsequent picture at 5 months which supposedly is to demonstrate healing following vitamin D and calcium therapy is of the left arm. Before and after pics ideally need to be same side and similar resolution to clearly demonstrate the change.

  Response: The purpose of these images was to demonstrate consequences of secondary hyperparathyroidism when Ca to PO₄ mineral ratio is not maintained. These manifestations are generalised and affects all long bones of infant. Through these images we have demonstrated improvement in bone mineralisation, healing of periosteal elevation and rickets following treatment with oral calcium and vitamin D supplementation. Even though, these images are of different arms, healing of above manifestations of MBDP are clearly demonstrated.  

  4. We don’t know what proportion of such preterms have secondary hyperparathyroidism and the case discussed in your paper may be a small minority. Rather than advising a significant change of practice would it not be more appropriate to actually prove presence or absence of sec hyperparathyroidism in a larger dataset and develop normative values for PTH for various gestations/postnatal age ranges etc?

  Response: Please also refer to our response to comment 2. We agree that a larger dataset in preterm neonates would be appropriate. Given challenges of undertaking this study in sick preterm infants, we would have to rely on above mentioned well conducted study⁷ which has demonstrated that adult normative ranges are applicable in preterm neonates. In our clinical practise we have always found measurement of PTH extremely useful in diagnosis and monitoring of treatment in all cases of MBDP. Our clinical approach of maintaining oral Ca to PO₄ ratio in management of rickets has allowed normalisation of serum PTH, PO₄ and ALP, healing of rickets and prevented secondary hyperparathyroidism and associate complications such as hypocalcaemia and fractures.

   

  References:

  1. Lothe A, Sinn J, Stone M. Metabolic bone disease of prematurity and secondary hyperparathyroidism. J Paediatr Child Health. 2011;47(8):550–553.
  2. Moreira A, February M, Geary C. Parathyroid hormone levels in neonates with suspected osteopenia. J Paediatr Child Health. 2013;49(1):E12–E16.
  3. Yes¸iltepe Mutlu G, Kırmızıbekmez H, Ozsu E, et al. Metabolic bone disease of prematurity: report of four cases. J Clin Res Pediatr Endocrinol. 2014;6(2):111–115.
  4. Dowa Y, Kawai M, Kanazawa H, et al. Screening for secondary hyperparathyroidism in preterm infants. Pediatr Int. 2016;58(10):988–992.
  5. Patel M, Housley D, Ossuetta I. Serial serum parathormone (PTH) as a marker for monitoring metabolic bone disease of prematurity. Arch Dis Child. 2008;93:ps323.
  6. Liddicoat INM, Tighe MP. Supplementation in hypophosphataemic rickets: the bare bones of management. Arch Dis Child Educ Pract Ed 2019;104:207-210. Matejek T ,
  7. Navratilova M , Zaloudkova L , et al. Parathyroid hormone - reference values and association with other bone metabolism markers in very low birth weight infants - pilot study. J Matern Fetal Neonatal Med 2018:1–8.

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  Conflict of Interest:
  None declared.

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• Published on: 1 August 2019

  Lack of data/evidence to back recommendations for significant change of practice

  • Minesh Khashu, Neonatologist Poole Hospital NHS Foundation Trust

  I read with interest this review by Dr Padidela et al.

  I would like the authors to comment on the following issues:

  1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.

  2. The review recommends measurement of plasma parathromone as a critical initial step and most of the subsequent practice is dictated by this. The authors state " measurement of plasma PTH both for screening and diagnosis is crucially important". In the very next line they however state "the reference range of plasma PTH in neonates is not well established" They then go to talk about a very small study of 20 preterm neonates.
  It does not make much sense to recommend a major change of practice without any data to back it up and then highlight plasma PTH as a critical investigation for decision making when we don't really have any robust normative data.
  Should we not instead be generating prospective data based on current practice and if there is evidence of secondary hyperparathyroidism to change treatment accordingly? Also should we not be generating normative data for various gestati...

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  I read with interest this review by Dr Padidela et al.

  I would like the authors to comment on the following issues:

  1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.

  2. The review recommends measurement of plasma parathromone as a critical initial step and most of the subsequent practice is dictated by this. The authors state " measurement of plasma PTH both for screening and diagnosis is crucially important". In the very next line they however state "the reference range of plasma PTH in neonates is not well established" They then go to talk about a very small study of 20 preterm neonates.
  It does not make much sense to recommend a major change of practice without any data to back it up and then highlight plasma PTH as a critical investigation for decision making when we don't really have any robust normative data.
  Should we not instead be generating prospective data based on current practice and if there is evidence of secondary hyperparathyroidism to change treatment accordingly? Also should we not be generating normative data for various gestations and postnatal ages to be confident about the plasma PTH values?

  3. In figure 1, the first part shows a right humerus at 3 months of age but the subsequent picture at 5 months which supposedly is to demonstrate healing following vitamin D and calcium therapy is of the left arm. Before and after pics ideally need to be same side and similar resolution to clearly demonstrate the change.

  4. We don’t know what proportion of such preterms have secondary hyperparathyroidism and the case discussed in your paper may be a small minority. Rather than advising a significant change of practice would it not be more appropriate to actually prove presence or absence of sec hyperparathyroidism in a larger dataset and develop normative values for PTH for various gestations/postnatal age ranges etc?

  Best Wishes

  Dr. Minesh Khashu

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  Conflict of Interest:
  None declared.

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