Recombinant growth hormone therapy for X‐linked hypophosphatemia in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine whether the use of rhGH therapy in children with X‐linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, body proportions, and also with any adverse effects.
Background
X‐linked hypophosphatemia (XLH) is an inherited disorder of phosphate homeostasis characterized by disproportionate short stature, rickets and osteomalazia, hypophosphatemia, aberrant phosphate reabsorption and disturbance of vitamin D metabolism (Rasmussen 1995). XLH is caused by mutations in the PHEX gene, encoding a membrane‐bound endopeptidase. PHEX is expressed in bones and teeth but not in kidney and efforts are underway to elucidate how PHEX function relates to the mutant phenotype (Jan de Beur 2002).
The diagnosis of XLH is based on a consistent medical history and physical examination, radiological evidence of rachitic disease, normal serum calcium, hypophosphatemia caused by selective renal phosphate wasting for which no other etiology is found, and a family history consistent with multigenerational or sporadic (i.e. nonfamilial) occurrence of XLH (Dixon 1998).
Affected individuals have normal intelligence, but they can suffer significant limitation due to the short stature and bone deformities. Conventional treatment of X‐linked hypophosphatemia with oral phosphate and calcitriol raises serum phosphate concentrations and heals rickets, but does not always normalize linear growth and many individuals fail to reach normal adult height (Friedman 1993). Furthermore, the phosphate therapy is often limited by adverse gastrointestinal symptoms and the high doses of calcitriol can lead to hypercalciuria and nephrocalcinosis (Goodyer 1987).
The use of growth hormone increases glomerular filtration rate and effective renal plasma flow in people with hypothalamic growth hormone deficiency (Hirschberg 1988) and it has been found to increase the rate of renal phosphate reabsorption in immature rats (Haramati 1990). Administration of growth hormone to hypophysectomized rats on a phosphate restricted diet results in a significant increase in 1,25‐dihydroxyvitamin D levels (Halloran 1988). In vivo recombinant human growth hormone (rhGH) treatment stimulates osteoblasts and activates bone remodelling (Brixen 1990), which suggest that growth hormone therapy may be beneficial in the treatment of people with XLH. Some observations that administration of exogenous growth hormone increases renal phosphate reabsorption and calcitriol levels (Brixen 1992; Saggese 1995) lead to speculation regarding the role of growth hormone in phosphate homeostasis and the possible beneficial effects of growth hormone therapy in XLH, and one study shows that height z‐score and growth velocity z‐score improve after 12 months of 0.08mg/kg/d rhGH in children with XLH (Seikaly 1997).
Combining rhGH with conventional treatment offers theoretical advantages in poorly growing people with XLH. It is suggested that rhGH improves growth velocity, phosphate retention, and bone mineral density, but some trials suggest that it appears to aggravate the pre‐existent disproportionate stature of such children (Haffner 1995). In addition, rhGH is expensive, with the lifetime incremental cost of treating one child ranging from £43,100 (US$67,700) to £53,400 (US$83,900) (Bryant 2002). In light of this it is important to evaluate it's effectiveness and adverse effects.
Objectives
To determine whether the use of rhGH therapy in children with X‐linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, body proportions, and also with any adverse effects.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) or quasi‐randomised controlled trials(both published and unpublished). Trials in which quasi‐randomised methods such as alternation are used will be included if there is sufficient evidence that the treatment and control groups were similar at baseline.
Types of participants
Children with defined X‐linked hypophosphatemia.
Types of interventions
Growth hormone (given by subcutaneous injection, at any dose, any frequency and any duration) only or combined with conventional treatment (calcitriol and oral phosphate) compared with either placebo or conventional treatment alone.
Types of outcome measures
Primary outcomes
(1) Measures of longitudinal growth: growth velocity z‐score, height z‐score
Secondary outcomes
(1) Measures of mineral metabolism: serum values of phosphate and calcium
(2) Measures of endocrine function: serum values of 1,25‐dihydroxyvitamin D, insulin‐like growth factor I, alkaline phosphatase, osteocalcin, growth hormone
(3) Measures of renal function: urinary calcium/creatinine ratio, maximum rate of renal tubular reabsorption of phosphate normalized to the glomerular filtration rate(TmP/GFR)
(4) Bone mineral density
(5) Body proportions: sitting height z‐score, subischial leg length z‐score
(6) Any adverse effects reported (e.g. transient glucosuria, transient splenomegaly and muscular prominence)
Outcome data will be grouped into those measured at baseline, 6, 12, 18, 24 months and annually thereafter. If outcome data are recorded at other time periods then consideration will be given to examining these as well.
Search methods for identification of studies
Relevant trials will be identified from the inborn errors of metabolism trials register held at the editorial base of the Cochrane Cystic Fibrosis and Genetic Disorders Group.
The inborn errors of metabolism register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (updated each new issue), quarterly searches of MEDLINE and the prospective handsearching of one journal ‐ the Journal of Inherited Metabolic Disease. Unpublished work is identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
Additional trials will be identified from the reference lists of identified trials and other reviews. We also plan to search the Journal of Bone and Mineral Research (1986 to 2003) and proceedings of the American Society for Bone and Mineral Research Annual Meeting (1st to 24th). The companies that market growth hormone will also be contacted for information on unpublished trials.
Data collection and analysis
The two reviewers (YH and WC) will independently select the trials to be included in the review. Each reviewer will assess the methodological quality of each trial. Methodological quality will be assessed based on a method described by Schulz (Schulz 1995). In particular, reviewers will examine details of the randomisation method, the concealment of treatment allocation schedule, whether the trial was blinded and whether intention‐to‐treat analyses were possible from the available data. Each reviewer using standard data acquisition forms will independently extract data. If disagreement arises on the suitability of a trial for inclusion in the review or on its quality, we plan to attempt to reach a consensus by discussion. Where information is unclear or incomplete, we will contact the primary investigator if this is possible.
In order to allow an intention‐to‐treat analysis for binary outcome measures, data will be sought on the number of participants with each outcome event, by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow up. We aim to calculate a pooled estimate of the treatment effect for each outcome across studies, (the odds of an outcome among treatment allocated patients to the corresponding odds among controls). For continuous outcomes, we plan to record either mean change from baseline for each group or mean post‐treatment/intervention values and standard deviation for each group. Then, where appropriate, we will calculate a pooled estimate of treatment effect by calculating the weighted mean difference. Heterogeneity between trial results will be tested for using a standard chi‐squared test. We plan to perform a sensitivity analysis based on the methodological quality of the studies, including and excluding quasi‐randomised studies. If there are sufficient numbers of studies where quasi‐randomisation is used then this group will be analysed separately.
