Parathyroid Hormone as a Functional Indicator of Vitamin D Sufficiency in Children

There has been debate on what constitutes physiologically normal 25-hydroxyvitamin D serum levels in children. The Institute of Medicine and the American Academy of Pediatrics have recommended that 25-hydroxyvitamin D levels in children be more than 50 nmol/L.¹ The Canadian Paediatric Society has suggested that 25-hydroxyvitamin D levels be more than 75 nmol/L.² Given the long time course for the development of chronic health outcomes that may be related to low vitamin D levels in children, physiological indicators of vitamin D sufficiency would be helpful.

One physiological indicator of bone health is parathyroid hormone (PTH). Studies of adults have identified that PTH levels cease to decline at 25-hydroxyvitamin D levels typically more than 75 nmol/L, suggesting physiological vitamin D sufficiency.³ In children, identifying such a plateau has been elusive. To address this, we conducted a study of healthy young children to determine whether a 25-hydroxyvitamin D plateau exists above which serum PTH is minimized.

Research ethics approval was obtained through The Hospital for Sick Children and all parents of participating children consented to study participation.

In this cross-sectional study, data were prospectively collected from healthy children 1 to 6 years of age recruited during a health maintenance physician’s visit in Toronto, Ontario, Canada (latitude 43.4°N) between December 2008 and June 2011 (www.targetkids.ca).

Nonfasting total 25-hydroxyvitamin D was measured using the DiaSorin LIAISON 25-hydroxyvitamin D TOTAL chemiluminescence assay with an interassay imprecision of 4.9 nmol/L (Diasorin SpA) using the DEQAS quality assessment scheme. Nonfasting PTH was measured using a Roche E170 modular electrochemiluminescence immunoassay with an interassay imprecision of 0.14 pmol/L (Hoffmann–La Roche Ltd). Laboratory tests were performed on a daily basis at the Mount Sinai Services Laboratory (www.mountsinaiservices.com).

To evaluate the relationship between 25-hydroxyvitamin D and PTH, an age- and sex-adjusted restricted cubic spline linear regression model with 3 knots was constructed.⁴ Three knots were chosen because the relationship between PTH and 25-hydroxyvitamin D appeared to be fairly smooth and did not require the flexibility that additional knots provide. A plateau point was estimated by finding the root of the derivative (approximated by the standard limit definition of the derivative) of the predicted mean PTH (from the model) as a function of vitamin D. P values less than .05 (2-tailed) were considered statistically significant.

Data were analyzed using the R project for statistical computing (rms package) (www.r-project.org).

Venous blood sampling was obtained from 1370 children. Mean 25-hydroxyvitamin D level was 86 nmol/L and mean PTH level was 2.67 pmol/L (Table).

The restricted cubic spline regression model identified a nonlinear relationship between 25-hydroxyvitamin D and PTH, with a 25-hydroxyvitamin D plateau at 107 nmol/L (P < .001) (Figure). Age was statistically significant (P = .02) while sex was not (P = .12).

We have identified a 25-hydroxyvitamin D plateau around 100 nmol/L above which PTH is minimized in young children. An ongoing challenge has been developing an evidence-based 25-hydroxyvitamin D threshold that supports healthy growth and development in children. A 25-hydroxyvitamin D PTH plateau could be useful in setting this threshold.

To our knowledge, no study of children has had the statistical power of the present study, which may explain previous inconsistent findings.⁵ Also, our study was conducted in an era in which 55% of these children were receiving a vitamin D supplement, resulting in a mean 25-hydroxyvitamin D level that may have been sufficiently high to demonstrate PTH suppression. Our data provide evidence that 25-hydroxyvitamin D levels higher than currently recommended for young children may be required to minimize PTH. Further research will need to confirm whether minimizing PTH through higher 25-hydroxyvitamin D translates into measureable improvement in health outcomes for young children.

Corresponding Author: Jonathon L. Maguire, MD, MSc, FRCPC, Applied Health Research Centre of the Li Ka Shing Knowledge Institute, St Michael’s Hospital, Departments of Paediatrics and Health Policy Management and Evaluation, Faculty of Medicine, University of Toronto, and Department of Pediatrics, St Michael’s Hospital, 30 Bond St, 15-014 Cardinal Carter, Toronto, ON M5B 1W8, Canada (jonathon.maguire@utoronto.ca).

Published Online: February 17, 2014. doi:10.1001/jamapediatrics.2013.5379.

Author Contributions: Dr Maguire and Mr Thorpe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Maguire, Parkin.

Acquisition of data: Maguire, Parkin.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Maguire.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Thorpe, Sochett.

Obtained funding: Maguire, Birken, Parkin.

Administrative, technical, and material support: Parkin.

Study supervision: Maguire.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the Canadian Institutes of Health Research and the St Michael’s Foundation. The Paediatric Outcomes Research Team is supported by a grant from The Hospital for Sick Children Foundation.

Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The following clinical site investigators participated in the TARGetKids! Collaboration: Tony Barozzino, MD, Gary Bloch, MD, Ashna Bowry, MD, Douglas Campbell, MD, Sohail Cheema, MD, Brian Chisamore, MD, Karoon Danayan, MD, Anh Do, MD, Michael Evans, MD, Mark Feldman, MD, Sloane Freeman, MD, Moshe Ipp, MD, Sheila Jacobson, MD, Tara Kiran, MD, Holly Knowles, MD, Eddy Lau, MD, Fok-Han Leung, MD, Muhammad Mamdani, PharmD, MA, MPH, Julia Morinis, MD, MSc, Sharon Naymark, MD, Patricia Neelands, MD, Michael Peer, MD, Marty Perlmutar, MD, Michelle Porepa, MD, Noor Ramji, MD, Alana Rosenthal, MD, Janet Saunderson, MD, Michael Sgro, MD, Susan Shepherd, MD, Carolyn Taylor, MD, Sheila Wijayasinghe, MD, Ethel Ying, MD, and Elizabeth Young, MD. We also thank Azar Azad, PhD, Tonya D'Amour, Julie DeGroot, MSc, Sharmilaa Kandasamy, Kanthi Kavikondala, Tarandeep Malhi, Magda Melo, MSc, Subitha Rajakumaran, Juela Sejdo, and Laurie Thompson for administrative and technical support for the TARGetKids! program.