Synthetic human growth hormone for treating X-linked hypophosphatemia (or vitamin D-resistant rickets) in children

Review question

Can human growth hormone lead to improved clinical outcomes (such as increased growth and bone mineral density, as well as better kidney and hormone function) without side effects in children with X-linked hypophosphataemia?


X-linked hypophosphataemia is a genetic disorder which causes abnormal levels of phosphate in the body. This can lead to short stature and rickets. Standard treatment of X-linked hypophosphatemia can heal rickets, but does not always raise the level of phosphates in the blood or return growth levels to normal. It is unclear whether combining human growth hormone therapy with standard treatment improves the phosphate levels, growth rates and bone mineral density.

Search date

The evidence is current to: 12 January 2021

Study characteristics

We included two small studies with a total of 20 children aged between 2.5 and nine years old in this review.  There were equal numbers of boys and girls. Both trials were randomised so that participants had an equal chance of being put in the growth hormone group or the control group (children in the control group either got no additional treatment or a placebo (sham) treatment). One (parallel) trial compared children given the growth hormone to children who did not have any treatment for three years. The second trial was a cross-over trial, so to start with one group of children were given human growth hormone therapy and the second group were given a placebo for a year and then the groups were given the opposite treatment for a further year.


The parallel trial found no difference in height scores after treatment with growth hormone compared to no additional treatment. No serious side effects were seen in either of the trials. In the cross-over trial, human growth hormone therapy improved the height standard deviation score (z score), and temporarily increased blood phosphate levels. 

We found no conclusive evidence that shows that human growth hormone treatment works for this condition. There have not been enough studies of human growth hormone treatment for this condition and more research is needed. This is an updated version of a previously published review.

Quality of the evidence

We mostly graded the certainty of the evidence as low or very low. This was because the trials were very small and only included a few children. We were also concerned that there might have been some bias in the results because of the design of the smaller cross-over trial.

Authors' conclusions: 

We do not have enough high-certainty evidence to recommend the use of recombinant human growth hormone therapy in children with X-linked hypophosphatemia.

Read the full abstract...

Conventional treatment of X-linked hypophosphatemia with oral phosphate and calcitriol can heal rickets, but it does not always raise serum phosphate concentrations significantly, nor does it always normalize linear growth. Some clinical trials suggest that combining recombinant human growth hormone therapy with conventional treatment improves growth velocity, phosphate retention, and bone mineral density, but some clinical trials suggest that it appears to aggravate the pre-existent disproportionate stature of such children. This is an updated version of a previously published review.


To determine whether recombinant human growth hormone therapy for children with X-linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine function, renal function, bone mineral density, body proportions, and also with any adverse effects.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. In addition, we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE and the reference lists of identified trials and other reviews. We also undertook some additional handsearching of relevant journals and conference proceedings.

Date of the most recent search: 12 January 2021

Selection criteria: 

All randomized controlled studies or quasi-randomized controlled studies comparing growth hormone (alone or combined with conventional treatment) with either placebo or conventional treatment alone in children with X-linked hypophosphatemia.

Data collection and analysis: 

Two authors independently assessed studies for risk of bias and extracted data from eligible studies. GRADE criteria were used to assess the certainty of the evidence for each outcome.

Main results: 

We included two studies (20 participants) in the review. In one cross-over study, results showed that recombinant human growth hormone therapy may improve the height standard deviation (SDS) score (z score), but we are unsure whether the intervention was the reason behind a transient increase in serum phosphate and tubular maximum for phosphate reabsorption. In the second, parallel study, treatment may also have improved the height SDS from baseline in the rhGH group compared to the control group, although no significant difference was seen between groups after three years, MD 0.50 SDS (95 % CI -0.54 to 1.54) (low-certainty evidence). The treatment was possibly well-tolerated during both studies with only transient adverse effects seen in three participants (low-certainty evidence). We are uncertain whether growth hormone improves serum phosphate levels or change in TmP/GFR (very low-certainty evidence). The treatment may make little or no difference to alkaline phosphatase levels (low-certainty evidence).