Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review

A systematic review of the literature was performed in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. All publications including data pertaining to the unmet needs of adults with XLH published in English before 19 February 2019 were included. Publications containing information on children and adults were included only if results were presented separately for adults. Case studies, cohort studies, cross-sectional studies, randomized controlled trials and narrative review articles were included.

The systematic review was augmented by a structured Internet search, which was conducted using Google on 8 March 2019. The search terms used in the structured Internet search are presented in Supplementary Table S3. Sources of information on the unmet needs of adults with XLH that were not included in the systematic review were identified from websites captured in the search by a single reviewer, with any uncertainties regarding relevance resolved by a second reviewer. Any data considered by the reviewer to be relevant to the topic of interest were extracted from these sources into an Excel workbook.

Most (n = 48/59) research publications described the clinical manifestations of XLH. Of these, 24 publications covering 20 distinct studies reported the percentage of participants who had experienced specific manifestations (Table 1). The clinical features of XLH in adults reported in these studies comprised musculoskeletal manifestations (such as limb abnormalities, short stature, osteoarthritis, osteomalacia, fractures, muscle weakness, enthesopathy, joint stiffness and spinal stenosis), dental problems, pain, ambulation difficulties (including impaired mobility and gait disturbance), renal complications, fatigue, hyperparathyroidism, loss of balance, hearing loss and tinnitus. Structured assessments of physical performance were not reported. Concerning the musculoskeletal burden of XLH in adults, one cohort study reported a high prevalence of pseudofractures (45%; n = 10/22), as well as a high prevalence of early-onset osteoarthritis and enthesopathy in 55% and 33% of patients younger than 30 years, respectively [36]. In patients 30–66 years of age, the prevalence of osteoarthritis and enthesopathy were as high as 80% and 100%, respectively [36]. Pain was often documented in the studies; the proportion of participants experiencing pain (of any type) varied widely between the studies, ranging from 45 (n = 9/20) in a phase 1/2 clinical trial [50] to 100% (n = 17/17; [38] n = 18/18) [41] in a cohort study and an interview-based study. Hypertension was reported in one research publication; 27% (n = 6/22) of adult patients in that retrospective chart review had a history of hypertension [27]. Few publications discussed differences in disease severity between men and women; however, a retrospective cross-sectional study in 52 adults with XLH rated as good quality found that women had fewer sites of enthesopathy and were less likely to have severe dental disease than men [20]. Available data consistently demonstrated stunted growth in both men and women (Table 1). Limited data were available on body constitution (weight, body mass index [BMI] and body fat percentage); however, when reported, mean or median BMI was over 25 kg/m², suggesting a possible predisposition to adiposity and being overweight (Table 1) [18, 20, 34, 48].

Data on clinical manifestations in 68 adults with XLH were also reported in case study publications, which generally focused on specific manifestations or complications and did not provide comprehensive medical histories. The most frequently reported manifestations were limb deformity (n = 37), pain (n = 30), short stature (n = 30) and impaired mobility (n = 22; Supplementary Fig. S1).

In the research studies with available data on surgical procedures, a high proportion of adults with XLH (≥ 57%) reported a history of orthopaedic surgeries (Table 1). In a phase 3 clinical trial, a history of orthopaedic surgery was reported in 69% (n = 92) of 134 patients (65% female), even though most of them (81%) had received conventional supplementation therapy with phosphate and/or active vitamin D metabolites or analogues during childhood [12]. Data relating to the appropriateness of this therapy in individual patients were not available. In addition, 68% of these patients were receiving analgesics at baseline, and 22% were taking opioids [12]. In a web-based survey of 150 adults with XLH (information on sex was not reported), 65% (n = 97) reported at least one orthopaedic surgery, including osteotomy (63%), knee replacement (12%) and hip replacement (8%) in their medical history [14]. Current phosphate/vitamin D therapy was reported by 62% of the individuals in the study [14].

Several publications that included information relating to clinical management indicated that many adults with XLH stop receiving treatment and may not be followed up after childhood [2, 3, 14, 53]. For example, in a survey of 150 adults with XLH published in 2015, 38% of the respondents were not receiving phosphate/vitamin D at the time of participation in the study, despite 97% of all respondents reporting bone or joint pain [14]. Limited information on the level of awareness of XLH in adults among clinicians was reported in the literature; however, this emerged as a key theme highlighted by numerous authors of publications included in the systematic review [33, 54‐61].

Complications associated with conventional supplementation therapy were reported inconsistently, although hyperparathyroidism and nephrocalcinosis were described in several publications (Fig. 2) [14, 23, 29, 38, 62‐71]. In one example, out of 150 adults with XLH who responded to a web-based survey, hyperparathyroidism and nephrocalcinosis were reported by 33% and 25%, respectively [14]. All of the individuals who reported these conditions were receiving phosphate/vitamin D at the time of the survey [14]. Data on how complications were managed were also sparse. However, six cases of parathyroidectomy being recommended following the development of tertiary hyperparathyroidism were documented in the case studies [53, 62, 63, 65, 69, 70].

Prescription pain medication use by adults with XLH was documented in two research studies, in which approximately 70% of participants were receiving pain medication of some type and 18 to 22% of all participants were taking opioids (Table 1) [12‐14]. The use and effectiveness of supportive treatment measures such as physiotherapy, occupational therapy and exercise interventions were not consistently reported.

A total of 19 web-based sources were identified from the structured Internet search (Supplementary Fig. S2), covering a wide range of topics including clinical manifestations and procedures, lack of disease awareness, complications associated with conventional supplementation therapy, family planning and financial pressure (Supplementary Table S4). These sources were distinct from those in the scientific literature as they contained testimonials from adults who had XLH themselves, as well as additional details from studies identified in the systematic review. For example, a congress poster describing results from a web-based survey included additional analyses to those presented in the published abstract [14, 83]. The poster reported that in 165 adults with XLH (median age [range], 45 [18‐46, 48, 50, 53‐71, 76, 78‐84] years), average scores on the WOMAC were higher for pain (39.4 vs 14.1), stiffness (50.2 vs 20.1) and physical functioning (40.9 vs 15.4) than those reported in the general population, indicating poorer HRQoL [83]. Use of a walking device was reported by 32% of these individuals.