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Abstract

Context

Hereditary distal renal tubular acidosis caused by SLC4A1 gene mutation (SLC4A1-dRTA) is a rare hereditary form of renal tubular acidosis. Rickets or osteomalacia is a common complication of SLC4A1-dRTA and seriously affects patients’ daily lives. However, studies on the bone microstructure in SLC4A1-dRTA are limited.

Objective

This work aimed to evaluate the bone microstructure of SLC4A1-dRTA patients, compared to age- and sex-matched healthy controls and X-linked hypophosphatemic rickets (XLH) patients.

Methods

This was a retrospective study of 11 SLC4A1-dRTA patients. Clinical manifestations and biochemical and radiographical examinations were characterized. Bone microstructure was examined in 7 SLC4A1-dRTA patients, 7 healthy controls, and 21 XLH patients using high-resolution peripheral quantitative computed tomography.

Results

Skeletal symptoms, including fracture, bone pain, and lower limb deformity, were present in 72.7% of SLC4A1-dRTA patients. Short stature was present in 63.6% of the patients. SLC4A1-dRTA patients had significantly lower volumetric bone mineral density in the distal tibia and more severe deteriorated trabecular bone in the distal radius and tibia than healthy controls. SLC4A1-dRTA patients had significantly more severely deteriorated trabecular bone in the distal radius and distal tibia compared to XLH patients. With long-term alkaline therapy, SLC4A1-dRTA patients had alleviated bone pain and increased height.

Conclusion

Skeletal lesions were common clinical manifestations in SLC4A1-dRTA patients. Compared with XLH, another common type of rickets, SLC4A1-dRTA patients had more severe trabecular bone microstructure damage, further supporting the necessity of early diagnosis and timely treatment of the disease.

renal tubular acidosis, SLC4A1, X-linked hypophosphatemic rickets, bone microarchitecture, volumetric bone mineral density

Primary distal renal tubular acidosis (dRTA) is a rare hereditary form of renal tubular acidosis, with an approximate incidence of less than 1:100 000. Primary dRTA impairs the ability of the kidney to maximally acidify the urine and leads to normal serum anion gap hyperchloremic metabolic acidosis (1, 2). The main genetic basis of dRTA includes mutations in the ATP6V1B1, ATP6V0A1, and SLC4A1. The SLC4A1 gene encodes the anion exchanger member 1 protein channel, expressed by alpha-intercalated cells in the kidney and erythrocytes (3). Long-term complications of primary dRTA include nephrocalcinosis and urolithiasis, bone mineralization disorder, severe hypokalemia, and progressive kidney failure (4). Metabolic acidosis causes the release of bicarbonates and phosphates from the bones, leading to inadequate bone mineralization and dysfunction in osteocytes (5, 6). Bone mineralization disorder mainly manifests as rickets or osteomalacia, with clinical symptoms of bone pain, fragility fractures, skeletal deformities, and growth retardation. The clinical manifestations of rickets and osteomalacia seriously reduce the life quality of dRTA patients and may also lead to psychological problems due to growth impairment.

However, analysis of the characteristics of bone mineral density (BMD) and bone microstructure in dRTA patients in previous studies is insufficient. Few studies have described alterations of BMD in dRTA patients (7-9), and the changes of bone microarchitecture have never been examined in dRTA patients. Dual-energy X-ray absorptiometry (DXA), the most widely used method to evaluate areal BMD, fails to evaluate bone microstructure and may overestimate BMD because of fractures or surgical implants. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a noninvasive technique, which has advantages in evaluating bone geometry, volume BMD (vBMD), trabecular and cortical microstructure parameters noninvasively, with low-dose radiation and high resolution (10). Until now, HR-pQCT has been applied in many metabolic bone diseases (10-12), but still not in the bone evaluation of dRTA patients.

In this study, we summarized the skeletal manifestations in 11 dRTA patients with mutations in SLC4A1 (SLC4A1-dRTA). We then compared HR-pQCT-measured vBMD and bone microstructure in 7 SLC4A1-dRTA patients with age- and sex-matched X-linked hypophosphatemic rickets (XLH) patients, another common type of rickets, and healthy controls. We aimed to study the characteristics of the skeletal lesions in SLC4A1-dRTA patients, observe the effect of alkaline treatment on the skeletal lesions, and understand the differences in bone microstructure between SLC4A1-dRTA and XLH patients.

Methods and Material

Subjects

Eleven SLC4A1-dRTA patients from Peking Union Medical College Hospital (PUMCH) in Beijing, China, were enrolled in this study from 2013 to 2023. The diagnosis of dRTA was based on the inability to acidify urine (pH >5.5) in the setting of a normal anion gap and spontaneous metabolic acidosis. The patients with dRTA caused by SLC4A1 mutation were included based on genetic analysis. The exclusion criteria included (1) patients with rheumatoid diseases, Sjogren syndrome, hematological diseases (ie, sickle cell disease); (2) patients using medications that cause dRTA (ie, amphotericin B, lithium); and (3) patients with primary dRTA caused by other gene mutations, such as ATP6V0A4 and ATP6V1B1. The clinical manifestations of 2 patients were previously published (13).

The study protocol was approved by the ethics committee of PUMCH (Ethical approval number: I-23PJ2019). Informed consent for the blood collection and genetic analysis was obtained from the patients or their parents.

Clinical and Biomedical Analyses

The clinical data were retrospectively collected, including general characteristics (eg, age, gender, age at diagnosis, age at onset, duration of disease), clinical manifestations, birth history, family history, and treatment protocol. Height and weight were measured. All biochemical parameters were measured at the department of clinical laboratory of PUMCH. Quality control was conducted every day and was within the allowable range of detection kits. Blood pH and bicarbonate were measured by Automatic Blood Gas System (ABL800; Radiometer, Denmark). Urine pH was measured by automated urine chemistry analyzer (UC3500; Sysmex Europe, Germany). Serum sodium, chloride, potassium, creatinine, phosphate, total calcium, alkaline phosphatase, and 24-hour urine excretion of calcium and phosphate were determined with a Beckman automatic biochemical analyzer (AU5800; Beckman Coulter, USA). Serum intact PTH (iPTH), total 25-hydroxyvitamin D (25OHD), and β-isomerized C-terminal telopeptide of type I collagen (β-CTX) were measured by an electrochemiluminescence immunoassay (E170; Roche Diagnostics, Switzerland). The intra-assay and inter-assay coefficients of variations (CVs) of the main measurements were < 1% for blood pH and bicarbonate. The intra-assay and inter-assay CVs of serum sodium and chloride were all < 1.5%. The intra-assay and inter-assay CVs of serum potassium were < 2.5%. The intra-assay and inter-assay CVs of serum alkaline phosphatase were < 5%. The CVs varied in creatinine were < 4%. The intra-assay CVs in 25OHD and iPTH were 5.9 and 2.6%, with inter-assay CVs 6.5 and 5.8%, respectively. The β-CTX CVs varied < 10%. The intra-assay and inter-assay CVs of other biochemical parameters were all < 1.5%.

Genetic Analysis

Peripheral blood was collected from patients. Genomic DNA was extracted from white blood cells using DNA extraction kit (QIAGEN, Germany). A custom-designed gene panel was conducted by the Nimblegen SeqCap EZ system (Roche, Beijing, China) to capture all exons and 30-bp flanking intron sequences of 19 genes for hereditary kidney disease. Targeted next-generation sequencing was performed at the BGI Corporation (Tianjin, China) and sequenced on the HiSeq 2500 Sequencing System (Illumina, San Diego, CA, USA). The coverage of the target regions of all samples was 99%, and the average sequencing depth on the target of all samples was 250×. The mutations were filtered according to the population frequency < 1% (the single nucleotide polymorphism database and databases of BGI Corporation), and potential functional variations that affect protein-coding sequences. The mutations in the SLC4A1 gene were further identified by Sanger sequencing.

DXA and X-ray

Areal BMD in the lumbar spine (L1-L4), femoral neck, and total hip were assessed by DXA (Lunar, GE Healthcare, USA). For the adult patients, the Z-score was calculated according to the mean and SD of the age- and gender-matched normal Chinese population from the reference database provide by the GE-lunar DXA manufacturer. For patients aged <19 years, we calculated the Z-score manually using the sex- and age-specific reference for Chinese adolescents (14). The CV% values for BMD were 1.0%, 1.6% and 0.7% for the lumbar spine, femoral neck, and total hip, respectively. Morphology of lower limbs and thoracic and lumbar vertebrae were evaluated by full lower limbs X-films, X-rays from frontal and lateral positions in the thoracic and lumbar spine, respectively.

HR-pQCT

HR-pQCT was performed in 7 patients with SLC4A1-dRTA, 7 age- and sex-matched healthy control subjects, and 21 age- and sex-matched patients with XLH. The healthy control subjects were drawn from a cohort of 979 healthy people to establish HR-pQCT reference data in the Chinese population (15). XLH patients were drawn from a cohort of 261 XLH patients in our institution with PHEX gene mutation (16).

For each participant, the nondominant distal radius and left distal tibia were scanned by HR-pQCT (Xtreme CT II; Scanco Medical AG, Brüttisellen, Switzerland). The detailed protocol is described in a previous study (15). For segmentation of the cortical and trabecular compartments, the built-in software was used, and default settings of the threshold were applied to discriminate the trabecular bone and cortical bone. The lower and upper thresholds for the trabecular bone were 320 mg HA/ccm and 3000 mg HA/ccm, respectively. The lower and upper thresholds for the cortical bone were 450 mg HA/ccm and 3000 mg HA/ccm, respectively. The vBMD of total compartments (Tt.vBMD), trabecular bone (Tb.vBMD), cortical bone, and the cross-sectional area of all compartments, trabecular bone, and cortical bone were directly measured after compartment segmentation. And other trabecular bone parameters, including cortical porosity (Ct.Po), cortical thickness, trabecular bone volume fraction (Tb.BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and trabecular number (Tb.N), were calculated directly.

Statistical Analysis

Quantitative parameters were presented as mean ± SD or median (25th percentile, 75th percentile) as appropriate. Count parameters were presented as counts/percentage. Because of the small sample size, comparisons of continuous variables between the 2 groups were assessed using the Mann–Whitney U test, and comparisons of count variable was assessed with the chi-square test. P < .05 was considered statistically significant. All statistical analyses were performed using SPSS statistical software (version 19.0, Chicago, USA).

Results

Demographic and Clinical Characteristics of Patients With SLC4A1-dRTA

Eleven SLC4A1-dRTA patients (8 males and 3 females) were enrolled, with median age of 9.0 (5.0, 25.0) years, and median age at diagnosis of 7.0 (4.0, 25.0) years (Table 1). They presented a median height of 119.0 (105.0, 148.0) cm on the first visit to our center. Skeletal symptoms, including fracture, bone pain, and lower limb deformity, were present in 72.7% of patients. Short stature (63.6%) and weakness (54.5%) were also common clinical manifestations. Nephrocalcinosis was detected by abdominal ultrasound in 90.9% of patients, and 27.3% of the patients presented with urolithiasis. The median Z-score at L1-L4, femoral neck, and total hip of the patients were −0.3 (−2.9, 0.8), −0.9 (−2.4, 0.3), and −1.1 (−3.3, 0.5), respectively. Severe bilateral bowing of lower limbs was seen in SLC4A1-dRTA patients (Fig. 1A). X-ray films revealed sparse and blurry bone trabeculae in the thoracic and lumbar spine, lumbar vertebrae biconcave deformities, and multiple calcifications around renal pyramids (Fig. 1B-D). The detailed clinical characteristics of 11 patients are presented in Supplementary Table S1 (17).

Representative radiographs of patients with SLC4A1-dRTA. (A) X-ray films revealed the severe bilateral bowing of lower limbs. (B, C) X-ray films revealed sparse and blurry bone trabeculae in the thoracic and lumbar spine and lumbar vertebrae biconcave deformities. (D) X-ray films revealed the multiple calcifications around renal pyramids
Figure 1.

Representative radiographs of patients with SLC4A1-dRTA. (A) X-ray films revealed the severe bilateral bowing of lower limbs. (B, C) X-ray films revealed sparse and blurry bone trabeculae in the thoracic and lumbar spine and lumbar vertebrae biconcave deformities. (D) X-ray films revealed the multiple calcifications around renal pyramids

Abbreviation: dRTA, distal renal tubular acidosis.

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Table 1.
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Demographic and clinical characteristics of the dRTA patients with SLC4A1 gene mutation in our center

 Patients with dRTA (n = 11)Reference range
Male/female8/3—
Age, y9.0 (5.0, 25.0)—
Age at diagnosis, y7.0 (4.0, 25.0)—
Height, cm119.0 (105.0, 148.0)—
Height, Z score−2.3 (−4.4, −1.5)—
Clinical manifestation—
 Skeletal symptoms, n/%8/72.7%—
  Fracture, n/%4/50.0% (n = 8)—
  Bone pain, n/%5/62.5% (n = 8)—
  Lower limb deformity, n/%4/50.0% (n = 8)—
 Short stature, n/%7/63.6%—
 Weakness, n/%6/54.5%
Blood pH7.30 (7.25, 7.35)7.35-7.45
Blood bicarbonate, mmol/L15.9 (12.7, 17.2)22.0-27.0
Urine pH7.3 (7.0, 7.5)5.0-8.0
Serum sodium, mmol/L140.0 (138.0, 143.0)135-145
Serum chloride, mmol/L113.0 (111.0, 116.0)96-111
Serum potassium, mmol/L3.9 (3.3, 4.1)3.5-5.5
Serum ALP, U/L192.0 (186.0, 564.0)a
Serum β-CTX, ng/mL1.49 (0.97, 2.72) (n = 9)b
Serum creatinine, µmol/L45.0 (36.0, 68.0)18-88
Renal ultrasound
 Nephrocalcinosis, n/%10/90.9%—
 Urolithiasis, n/%3/27.3%—
Areal BMD by DXA (n = 6)
 Lumbar spine1-4 BMD, g/cm20.684 (0.596, 0.803)—
 Lumbar spine1-4, Z score−0.3 (−2.9, 0.8)−2∼2
 Femoral neck BMD, g/cm20.593 (0.539, 0.791)—
 Femoral neck Z score−0.9 (−2.4, 0.3)−2∼2
 Total hip BMD, g/cm20.584 (0.462, 0.849)—
 Total hip Z score−1.1 (−3.3, 0.5)−2∼2
 Patients with dRTA (n = 11)Reference range
Male/female8/3—
Age, y9.0 (5.0, 25.0)—
Age at diagnosis, y7.0 (4.0, 25.0)—
Height, cm119.0 (105.0, 148.0)—
Height, Z score−2.3 (−4.4, −1.5)—
Clinical manifestation—
 Skeletal symptoms, n/%8/72.7%—
  Fracture, n/%4/50.0% (n = 8)—
  Bone pain, n/%5/62.5% (n = 8)—
  Lower limb deformity, n/%4/50.0% (n = 8)—
 Short stature, n/%7/63.6%—
 Weakness, n/%6/54.5%
Blood pH7.30 (7.25, 7.35)7.35-7.45
Blood bicarbonate, mmol/L15.9 (12.7, 17.2)22.0-27.0
Urine pH7.3 (7.0, 7.5)5.0-8.0
Serum sodium, mmol/L140.0 (138.0, 143.0)135-145
Serum chloride, mmol/L113.0 (111.0, 116.0)96-111
Serum potassium, mmol/L3.9 (3.3, 4.1)3.5-5.5
Serum ALP, U/L192.0 (186.0, 564.0)a
Serum β-CTX, ng/mL1.49 (0.97, 2.72) (n = 9)b
Serum creatinine, µmol/L45.0 (36.0, 68.0)18-88
Renal ultrasound
 Nephrocalcinosis, n/%10/90.9%—
 Urolithiasis, n/%3/27.3%—
Areal BMD by DXA (n = 6)
 Lumbar spine1-4 BMD, g/cm20.684 (0.596, 0.803)—
 Lumbar spine1-4, Z score−0.3 (−2.9, 0.8)−2∼2
 Femoral neck BMD, g/cm20.593 (0.539, 0.791)—
 Femoral neck Z score−0.9 (−2.4, 0.3)−2∼2
 Total hip BMD, g/cm20.584 (0.462, 0.849)—
 Total hip Z score−1.1 (−3.3, 0.5)−2∼2

Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; dRTA, distal renal tubular acidosis; DXA, dual energy X-ray absorptiometry; β-CTX, C-terminal telopeptide of type I collagen.

aThe reference range of ALP (U/L): 0-15 years, 42-390; 16-18 years, 52-171; adult male individual: ≥ 19 years, 45-125; adult female individual: 19-49 years, 35-100; ≥ 50 years, 50-135.

bThe reference range of β-CTX (ng/mL): adult female, 0.21-0.44; adult male, 0.26-0.51; pediatric male individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.435-2.924; pediatric female individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.242-1.291.

Table 1.
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Demographic and clinical characteristics of the dRTA patients with SLC4A1 gene mutation in our center

 Patients with dRTA (n = 11)Reference range
Male/female8/3—
Age, y9.0 (5.0, 25.0)—
Age at diagnosis, y7.0 (4.0, 25.0)—
Height, cm119.0 (105.0, 148.0)—
Height, Z score−2.3 (−4.4, −1.5)—
Clinical manifestation—
 Skeletal symptoms, n/%8/72.7%—
  Fracture, n/%4/50.0% (n = 8)—
  Bone pain, n/%5/62.5% (n = 8)—
  Lower limb deformity, n/%4/50.0% (n = 8)—
 Short stature, n/%7/63.6%—
 Weakness, n/%6/54.5%
Blood pH7.30 (7.25, 7.35)7.35-7.45
Blood bicarbonate, mmol/L15.9 (12.7, 17.2)22.0-27.0
Urine pH7.3 (7.0, 7.5)5.0-8.0
Serum sodium, mmol/L140.0 (138.0, 143.0)135-145
Serum chloride, mmol/L113.0 (111.0, 116.0)96-111
Serum potassium, mmol/L3.9 (3.3, 4.1)3.5-5.5
Serum ALP, U/L192.0 (186.0, 564.0)a
Serum β-CTX, ng/mL1.49 (0.97, 2.72) (n = 9)b
Serum creatinine, µmol/L45.0 (36.0, 68.0)18-88
Renal ultrasound
 Nephrocalcinosis, n/%10/90.9%—
 Urolithiasis, n/%3/27.3%—
Areal BMD by DXA (n = 6)
 Lumbar spine1-4 BMD, g/cm20.684 (0.596, 0.803)—
 Lumbar spine1-4, Z score−0.3 (−2.9, 0.8)−2∼2
 Femoral neck BMD, g/cm20.593 (0.539, 0.791)—
 Femoral neck Z score−0.9 (−2.4, 0.3)−2∼2
 Total hip BMD, g/cm20.584 (0.462, 0.849)—
 Total hip Z score−1.1 (−3.3, 0.5)−2∼2
 Patients with dRTA (n = 11)Reference range
Male/female8/3—
Age, y9.0 (5.0, 25.0)—
Age at diagnosis, y7.0 (4.0, 25.0)—
Height, cm119.0 (105.0, 148.0)—
Height, Z score−2.3 (−4.4, −1.5)—
Clinical manifestation—
 Skeletal symptoms, n/%8/72.7%—
  Fracture, n/%4/50.0% (n = 8)—
  Bone pain, n/%5/62.5% (n = 8)—
  Lower limb deformity, n/%4/50.0% (n = 8)—
 Short stature, n/%7/63.6%—
 Weakness, n/%6/54.5%
Blood pH7.30 (7.25, 7.35)7.35-7.45
Blood bicarbonate, mmol/L15.9 (12.7, 17.2)22.0-27.0
Urine pH7.3 (7.0, 7.5)5.0-8.0
Serum sodium, mmol/L140.0 (138.0, 143.0)135-145
Serum chloride, mmol/L113.0 (111.0, 116.0)96-111
Serum potassium, mmol/L3.9 (3.3, 4.1)3.5-5.5
Serum ALP, U/L192.0 (186.0, 564.0)a
Serum β-CTX, ng/mL1.49 (0.97, 2.72) (n = 9)b
Serum creatinine, µmol/L45.0 (36.0, 68.0)18-88
Renal ultrasound
 Nephrocalcinosis, n/%10/90.9%—
 Urolithiasis, n/%3/27.3%—
Areal BMD by DXA (n = 6)
 Lumbar spine1-4 BMD, g/cm20.684 (0.596, 0.803)—
 Lumbar spine1-4, Z score−0.3 (−2.9, 0.8)−2∼2
 Femoral neck BMD, g/cm20.593 (0.539, 0.791)—
 Femoral neck Z score−0.9 (−2.4, 0.3)−2∼2
 Total hip BMD, g/cm20.584 (0.462, 0.849)—
 Total hip Z score−1.1 (−3.3, 0.5)−2∼2

Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; dRTA, distal renal tubular acidosis; DXA, dual energy X-ray absorptiometry; β-CTX, C-terminal telopeptide of type I collagen.

aThe reference range of ALP (U/L): 0-15 years, 42-390; 16-18 years, 52-171; adult male individual: ≥ 19 years, 45-125; adult female individual: 19-49 years, 35-100; ≥ 50 years, 50-135.

bThe reference range of β-CTX (ng/mL): adult female, 0.21-0.44; adult male, 0.26-0.51; pediatric male individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.435-2.924; pediatric female individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.242-1.291.

Bone vBMD and Bone Microarchitecture of Patients With SLC4A1-dRTA

HR-pQCT parameters of patients with SLC4A1-dRTA and sex- and age-matched XLH and controls are shown in Table 2, Table 3 and Fig. 2.

Bone geometry, vBMD, and microarchitectures of HR-pQCT at the distal radius and tibia in patients with SLC4A1-dRTA, patients with XLH and sex- and age-matched control. Compared to healthy controls, SLC4A1-dRTA patients showed deterioration in microstructure, including lower Tb.BV/TV, lower Tb.N, and higher Tb.Sp, compared to the healthy control group. Compared to healthy controls, XLH patients also had significantly lower Tt.vBMD, lower Tb.N, and higher Tb.Sp at the distal tibia. Compared with XLH patients, SLC4A1-dRTA patients also showed more severe deterioration in microstructure.
Figure 2.

Bone geometry, vBMD, and microarchitectures of HR-pQCT at the distal radius and tibia in patients with SLC4A1-dRTA, patients with XLH and sex- and age-matched control. Compared to healthy controls, SLC4A1-dRTA patients showed deterioration in microstructure, including lower Tb.BV/TV, lower Tb.N, and higher Tb.Sp, compared to the healthy control group. Compared to healthy controls, XLH patients also had significantly lower Tt.vBMD, lower Tb.N, and higher Tb.Sp at the distal tibia. Compared with XLH patients, SLC4A1-dRTA patients also showed more severe deterioration in microstructure.

Abbreviations: BV/TV, bone volume fraction; Ct.Po, cortical porosity; dRTA, distal renal tubular acidosis; Sp, separation; Tb, trabecular; Th, thickness; Tt, total; vBMD, volumetric bone mineral density; XLH, X-linked hypophosphatemia.

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Table 2.
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Comparison of bone geometry, vBMD, and microstructure at the distal radius evaluated by HR-pQCT among dRTA, XLH, and control groups

Radius
 Control (n = 7)dRTA (n = 7)XLH (n = 21)P1P2P3
Male/female6/16/118/3———
Age, y11.0 (5.0, 29.0)7.0 (5.0, 29.0)7.0 (5.5, 29.0).805.796.917
Height, cm138.0 (120.0, 169.0)114.3 (105.0, 163.0)111.5 (104.0, 151.9).259.071.836
Weight, kg28.5 (22.5, 65.0)22.5 (19.0, 75.0)22.0 (18.0, 61.3).535.249.836
Treatmenta, n/%—2/28.6%9/42.9%——.503
Geometry
 Tt.Ar, mm2193.2 (104.8, 301.1)143.3 (100.9, 314.9)204.1 (118.3, 370.9)1.000.568.466
 Tb.Ar, mm2164.0 (77.2, 192.2)122.8 (79.0, 242.0)174.6 (93.9, 305.9)1.000.348.435
 Cr.Ar, mm229.8 (24.9, 75.4)24.1 (20.3, 75.7)37.7 (27.6, 58.4).535.836.466
 Ct.Pm, mm56.3 (40.1, 75.3)57.1 (41.2, 85.5)56.8 (43.6, 77.9).902.640.876
Volumetric density
 Tt.vBMD, mg HA/cm3304.3 (186.6, 349.5)241.0 (233.0, 259.0)267.6 (244.3, 312.1).209.466.140
 Tb.vBMD, mg HA/cm3136.4 (116.3, 226.3)122.5 (100.1, 147.6)185.3 (115.6, 241.9).318.604.062
 Ct.vBMD, mg HA/cm3769.5 (608.4, 920.0)619.8 (516.2, 885.4)664.6 (598.5, 846.6).259.376.568
Microstructure
 Tb.BV/TV, %18.7 (14.4, 34.0)13.7 (10.6, 19.5)25.4 (18.1, 34.3).097.272.002b
 Tb.N, 1/mm1.398 (1.358, 1.608)1.218 (1.034, 1.299)1.544 (1.000, 1.887).026b.756.272
 Tb.Th, mm0.199 (0.196, 0.277)0.206 (0.193, 0.221)0.250 (0.233, 0.263).805.071<.001b
 Tb.Sp, mm0.682 (0.537, 0.728)0.830 (0.731, 1.004)0.598 (0.484, 0.983).038b.917.249
 Ct.Th, mm0.855 (0.495, 1.103)0.707 (0.436, 1.055)0.804 (0.657, 0.920).710.466.717
 Ct.Po, %0.2 (0.1, 1.1)0.3 (0.2, 0.5)1.4 (0.3, 2.0)0.805.036b.020b
Radius
 Control (n = 7)dRTA (n = 7)XLH (n = 21)P1P2P3
Male/female6/16/118/3———
Age, y11.0 (5.0, 29.0)7.0 (5.0, 29.0)7.0 (5.5, 29.0).805.796.917
Height, cm138.0 (120.0, 169.0)114.3 (105.0, 163.0)111.5 (104.0, 151.9).259.071.836
Weight, kg28.5 (22.5, 65.0)22.5 (19.0, 75.0)22.0 (18.0, 61.3).535.249.836
Treatmenta, n/%—2/28.6%9/42.9%——.503
Geometry
 Tt.Ar, mm2193.2 (104.8, 301.1)143.3 (100.9, 314.9)204.1 (118.3, 370.9)1.000.568.466
 Tb.Ar, mm2164.0 (77.2, 192.2)122.8 (79.0, 242.0)174.6 (93.9, 305.9)1.000.348.435
 Cr.Ar, mm229.8 (24.9, 75.4)24.1 (20.3, 75.7)37.7 (27.6, 58.4).535.836.466
 Ct.Pm, mm56.3 (40.1, 75.3)57.1 (41.2, 85.5)56.8 (43.6, 77.9).902.640.876
Volumetric density
 Tt.vBMD, mg HA/cm3304.3 (186.6, 349.5)241.0 (233.0, 259.0)267.6 (244.3, 312.1).209.466.140
 Tb.vBMD, mg HA/cm3136.4 (116.3, 226.3)122.5 (100.1, 147.6)185.3 (115.6, 241.9).318.604.062
 Ct.vBMD, mg HA/cm3769.5 (608.4, 920.0)619.8 (516.2, 885.4)664.6 (598.5, 846.6).259.376.568
Microstructure
 Tb.BV/TV, %18.7 (14.4, 34.0)13.7 (10.6, 19.5)25.4 (18.1, 34.3).097.272.002b
 Tb.N, 1/mm1.398 (1.358, 1.608)1.218 (1.034, 1.299)1.544 (1.000, 1.887).026b.756.272
 Tb.Th, mm0.199 (0.196, 0.277)0.206 (0.193, 0.221)0.250 (0.233, 0.263).805.071<.001b
 Tb.Sp, mm0.682 (0.537, 0.728)0.830 (0.731, 1.004)0.598 (0.484, 0.983).038b.917.249
 Ct.Th, mm0.855 (0.495, 1.103)0.707 (0.436, 1.055)0.804 (0.657, 0.920).710.466.717
 Ct.Po, %0.2 (0.1, 1.1)0.3 (0.2, 0.5)1.4 (0.3, 2.0)0.805.036b.020b

Using the Mann–Whitney U test or chi-square test to compare the control and dRTA group, control, and XLH group, dRTA, and XLH group. P value in bold represents a statistically significant difference. p1 : control vs dRTA ; p2: control vs XLH; p3: dRTA vs XLH.

Abbreviations: Ct.Ar, cortical bone area; Ct.Pm, cortical perimeter; Ct.Po, cortical porosity; Ct.Th, cortical thickness; Ct.vBMD, cortical volumetric bone mineral density; dRTA, distal renal tubular acidosis; HA, hydroxyapatite; Tb.1/N.SD, trabecular inhomogeneity; Tb.Ar, trabecular bone area; Tt.Ar, total bone area; Tb.BV/TV, trabecular bone volume to total volume ratio, or trabecular fraction; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Tb.vBMD, trabecular volumetric bone mineral density; Tt.vBMD, total volumetric bone mineral density; XLH, X-linked hypophosphatemia.

aTreatment with citrate salts and/or sodium bicarbonate therapy for dRTA patients; treatment with phosphate salts and active vitamin D for XLH patients.

bP < .05.

Table 2.
Open in new tab

Comparison of bone geometry, vBMD, and microstructure at the distal radius evaluated by HR-pQCT among dRTA, XLH, and control groups

Radius
 Control (n = 7)dRTA (n = 7)XLH (n = 21)P1P2P3
Male/female6/16/118/3———
Age, y11.0 (5.0, 29.0)7.0 (5.0, 29.0)7.0 (5.5, 29.0).805.796.917
Height, cm138.0 (120.0, 169.0)114.3 (105.0, 163.0)111.5 (104.0, 151.9).259.071.836
Weight, kg28.5 (22.5, 65.0)22.5 (19.0, 75.0)22.0 (18.0, 61.3).535.249.836
Treatmenta, n/%—2/28.6%9/42.9%——.503
Geometry
 Tt.Ar, mm2193.2 (104.8, 301.1)143.3 (100.9, 314.9)204.1 (118.3, 370.9)1.000.568.466
 Tb.Ar, mm2164.0 (77.2, 192.2)122.8 (79.0, 242.0)174.6 (93.9, 305.9)1.000.348.435
 Cr.Ar, mm229.8 (24.9, 75.4)24.1 (20.3, 75.7)37.7 (27.6, 58.4).535.836.466
 Ct.Pm, mm56.3 (40.1, 75.3)57.1 (41.2, 85.5)56.8 (43.6, 77.9).902.640.876
Volumetric density
 Tt.vBMD, mg HA/cm3304.3 (186.6, 349.5)241.0 (233.0, 259.0)267.6 (244.3, 312.1).209.466.140
 Tb.vBMD, mg HA/cm3136.4 (116.3, 226.3)122.5 (100.1, 147.6)185.3 (115.6, 241.9).318.604.062
 Ct.vBMD, mg HA/cm3769.5 (608.4, 920.0)619.8 (516.2, 885.4)664.6 (598.5, 846.6).259.376.568
Microstructure
 Tb.BV/TV, %18.7 (14.4, 34.0)13.7 (10.6, 19.5)25.4 (18.1, 34.3).097.272.002b
 Tb.N, 1/mm1.398 (1.358, 1.608)1.218 (1.034, 1.299)1.544 (1.000, 1.887).026b.756.272
 Tb.Th, mm0.199 (0.196, 0.277)0.206 (0.193, 0.221)0.250 (0.233, 0.263).805.071<.001b
 Tb.Sp, mm0.682 (0.537, 0.728)0.830 (0.731, 1.004)0.598 (0.484, 0.983).038b.917.249
 Ct.Th, mm0.855 (0.495, 1.103)0.707 (0.436, 1.055)0.804 (0.657, 0.920).710.466.717
 Ct.Po, %0.2 (0.1, 1.1)0.3 (0.2, 0.5)1.4 (0.3, 2.0)0.805.036b.020b
Radius
 Control (n = 7)dRTA (n = 7)XLH (n = 21)P1P2P3
Male/female6/16/118/3———
Age, y11.0 (5.0, 29.0)7.0 (5.0, 29.0)7.0 (5.5, 29.0).805.796.917
Height, cm138.0 (120.0, 169.0)114.3 (105.0, 163.0)111.5 (104.0, 151.9).259.071.836
Weight, kg28.5 (22.5, 65.0)22.5 (19.0, 75.0)22.0 (18.0, 61.3).535.249.836
Treatmenta, n/%—2/28.6%9/42.9%——.503
Geometry
 Tt.Ar, mm2193.2 (104.8, 301.1)143.3 (100.9, 314.9)204.1 (118.3, 370.9)1.000.568.466
 Tb.Ar, mm2164.0 (77.2, 192.2)122.8 (79.0, 242.0)174.6 (93.9, 305.9)1.000.348.435
 Cr.Ar, mm229.8 (24.9, 75.4)24.1 (20.3, 75.7)37.7 (27.6, 58.4).535.836.466
 Ct.Pm, mm56.3 (40.1, 75.3)57.1 (41.2, 85.5)56.8 (43.6, 77.9).902.640.876
Volumetric density
 Tt.vBMD, mg HA/cm3304.3 (186.6, 349.5)241.0 (233.0, 259.0)267.6 (244.3, 312.1).209.466.140
 Tb.vBMD, mg HA/cm3136.4 (116.3, 226.3)122.5 (100.1, 147.6)185.3 (115.6, 241.9).318.604.062
 Ct.vBMD, mg HA/cm3769.5 (608.4, 920.0)619.8 (516.2, 885.4)664.6 (598.5, 846.6).259.376.568
Microstructure
 Tb.BV/TV, %18.7 (14.4, 34.0)13.7 (10.6, 19.5)25.4 (18.1, 34.3).097.272.002b
 Tb.N, 1/mm1.398 (1.358, 1.608)1.218 (1.034, 1.299)1.544 (1.000, 1.887).026b.756.272
 Tb.Th, mm0.199 (0.196, 0.277)0.206 (0.193, 0.221)0.250 (0.233, 0.263).805.071<.001b
 Tb.Sp, mm0.682 (0.537, 0.728)0.830 (0.731, 1.004)0.598 (0.484, 0.983).038b.917.249
 Ct.Th, mm0.855 (0.495, 1.103)0.707 (0.436, 1.055)0.804 (0.657, 0.920).710.466.717
 Ct.Po, %0.2 (0.1, 1.1)0.3 (0.2, 0.5)1.4 (0.3, 2.0)0.805.036b.020b

Using the Mann–Whitney U test or chi-square test to compare the control and dRTA group, control, and XLH group, dRTA, and XLH group. P value in bold represents a statistically significant difference. p1 : control vs dRTA ; p2: control vs XLH; p3: dRTA vs XLH.

Abbreviations: Ct.Ar, cortical bone area; Ct.Pm, cortical perimeter; Ct.Po, cortical porosity; Ct.Th, cortical thickness; Ct.vBMD, cortical volumetric bone mineral density; dRTA, distal renal tubular acidosis; HA, hydroxyapatite; Tb.1/N.SD, trabecular inhomogeneity; Tb.Ar, trabecular bone area; Tt.Ar, total bone area; Tb.BV/TV, trabecular bone volume to total volume ratio, or trabecular fraction; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Tb.vBMD, trabecular volumetric bone mineral density; Tt.vBMD, total volumetric bone mineral density; XLH, X-linked hypophosphatemia.

aTreatment with citrate salts and/or sodium bicarbonate therapy for dRTA patients; treatment with phosphate salts and active vitamin D for XLH patients.

bP < .05.

Table 3.
Open in new tab

Comparison of bone geometry, vBMD, and microstructure at the distal tibia evaluated by HR-pQCT among dRTA, XLH, and control groups

Tibia
 Control (n = 6)dRTA (n = 6)XLH (n = 18)P1P2P3
Male/female5/15/115/3———
Age, y18.0 (6.5, 35.0)16.0 (5.8, 35.0)14.8 (6.0, 29.8).818.770.974
Height, cm149.0 (118.5, 171.3)131.2 (105.8, 164.3)127.2 (105.4, 152.1).394.119.626
Weight, kg39.3 (24.6, 69.3)38.8 (19.1, 77.4)29.3 (19.8, 62.8).818.343.626
Treatmenta, n/%—2/33.3%7/38.9%——.808
Geometry
 Tt.Ar, mm2543.7 (303.7, 727.6)527.0 (267.4, 741.4)578.9 (331.4, 724.2).937.673.770
 Tb.Ar, mm2450.7 (231.9, 574.9)371.2 (213.3, 609.2)459.7 (258.5, 611.1).818.673.537
 Cr.Ar, mm291.2 (70.6, 147.7)72.7 (53.8, 137.4)94.5 (65.4, 134.9).485.871.310
 Ct.Pm, mm90.7 (66.7, 105.7)80.7 (62.5, 106.6)93.6 (72.8, 103.9).818.581.581
Volumetric density
 Tt.vBMD, mg HA/cm3293.2 (267.2, 384.6)226.4 (189.6, 260.4)250.3 (201.7, 280.1).015b.027b.415
 Tb.vBMD, mg HA/cm3157.4 (136.4, 207.7)91.7 (63.0, 112.7)130.2 (87.5, 170.3).015b.090.119
 Ct.vBMD, mg HA/cm3840.0 (787.8, 954.5)863.4 (737.3, 947.5)728.3 (687,9, 934.4).699.137.310
Microstructure
 Tb.BV/TV, %23.9 (20.8, 30.5)14.1 (11.4, 17.5)20.1 (15.8, 24.4).015b.077.040b
 Tb.N, 1/mm1.314 (1.242, 1.372)1.037 (.641, 1.171)0.985 (0.684, 1.098).004b.012b.871
 Tb.Th, mm0.246 (0.232, 0.283)0.235 (0.220, 0.248)0.286 (0.253, 0.311).310.027b<.001b
 Tb.Sp, mm0.736 (0.688, 0.772)0.962 (0.852, 1.611)1.010 (0.922, 1.504).004b.006b.820
 Ct.Th, mm1.283 (1.154, 1.683)1.123 (1.036, 1.454)1.255 (1.025, 1.469).485.721.974
 Ct.Po, %1.7 (0.8, 2.4)1.6 (0.7, 3.3)2.2 (1.5, 3.4).937.280.454
Tibia
 Control (n = 6)dRTA (n = 6)XLH (n = 18)P1P2P3
Male/female5/15/115/3———
Age, y18.0 (6.5, 35.0)16.0 (5.8, 35.0)14.8 (6.0, 29.8).818.770.974
Height, cm149.0 (118.5, 171.3)131.2 (105.8, 164.3)127.2 (105.4, 152.1).394.119.626
Weight, kg39.3 (24.6, 69.3)38.8 (19.1, 77.4)29.3 (19.8, 62.8).818.343.626
Treatmenta, n/%—2/33.3%7/38.9%——.808
Geometry
 Tt.Ar, mm2543.7 (303.7, 727.6)527.0 (267.4, 741.4)578.9 (331.4, 724.2).937.673.770
 Tb.Ar, mm2450.7 (231.9, 574.9)371.2 (213.3, 609.2)459.7 (258.5, 611.1).818.673.537
 Cr.Ar, mm291.2 (70.6, 147.7)72.7 (53.8, 137.4)94.5 (65.4, 134.9).485.871.310
 Ct.Pm, mm90.7 (66.7, 105.7)80.7 (62.5, 106.6)93.6 (72.8, 103.9).818.581.581
Volumetric density
 Tt.vBMD, mg HA/cm3293.2 (267.2, 384.6)226.4 (189.6, 260.4)250.3 (201.7, 280.1).015b.027b.415
 Tb.vBMD, mg HA/cm3157.4 (136.4, 207.7)91.7 (63.0, 112.7)130.2 (87.5, 170.3).015b.090.119
 Ct.vBMD, mg HA/cm3840.0 (787.8, 954.5)863.4 (737.3, 947.5)728.3 (687,9, 934.4).699.137.310
Microstructure
 Tb.BV/TV, %23.9 (20.8, 30.5)14.1 (11.4, 17.5)20.1 (15.8, 24.4).015b.077.040b
 Tb.N, 1/mm1.314 (1.242, 1.372)1.037 (.641, 1.171)0.985 (0.684, 1.098).004b.012b.871
 Tb.Th, mm0.246 (0.232, 0.283)0.235 (0.220, 0.248)0.286 (0.253, 0.311).310.027b<.001b
 Tb.Sp, mm0.736 (0.688, 0.772)0.962 (0.852, 1.611)1.010 (0.922, 1.504).004b.006b.820
 Ct.Th, mm1.283 (1.154, 1.683)1.123 (1.036, 1.454)1.255 (1.025, 1.469).485.721.974
 Ct.Po, %1.7 (0.8, 2.4)1.6 (0.7, 3.3)2.2 (1.5, 3.4).937.280.454

Using the Mann–Whitney U test or chi-square test to compare the control and dRTA group, control and XLH group, dRTA and XLH group. P value in bold represents a statistically significant difference. p1 : control vs dRTA ; p2: control vs XLH; p3: dRTA vs XLH.

Abbreviations: Ct.Ar, cortical bone area; Ct.Pm, cortical perimeter; Ct.Po, cortical porosity; Ct.Th, cortical thickness; Ct.vBMD, cortical volumetric bone mineral density; dRTA, distal renal tubular acidosis; HA, hydroxyapatite; Tb.1/N.SD, trabecular inhomogeneity; Tb.Ar, trabecular bone area; Tt.Ar, total bone area; Tb.BV/TV, trabecular bone volume to total volume ratio, or trabecular fraction; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Tb.vBMD, trabecular volumetric bone mineral density; Tt.vBMD, total volumetric bone mineral density.

aTreatment with citrate salts and/or sodium bicarbonate therapy for dRTA patients; treatment with phosphate salts and active vitamin D for XLH patients.

bP < .05.

Table 3.
Open in new tab

Comparison of bone geometry, vBMD, and microstructure at the distal tibia evaluated by HR-pQCT among dRTA, XLH, and control groups

Tibia
 Control (n = 6)dRTA (n = 6)XLH (n = 18)P1P2P3
Male/female5/15/115/3———
Age, y18.0 (6.5, 35.0)16.0 (5.8, 35.0)14.8 (6.0, 29.8).818.770.974
Height, cm149.0 (118.5, 171.3)131.2 (105.8, 164.3)127.2 (105.4, 152.1).394.119.626
Weight, kg39.3 (24.6, 69.3)38.8 (19.1, 77.4)29.3 (19.8, 62.8).818.343.626
Treatmenta, n/%—2/33.3%7/38.9%——.808
Geometry
 Tt.Ar, mm2543.7 (303.7, 727.6)527.0 (267.4, 741.4)578.9 (331.4, 724.2).937.673.770
 Tb.Ar, mm2450.7 (231.9, 574.9)371.2 (213.3, 609.2)459.7 (258.5, 611.1).818.673.537
 Cr.Ar, mm291.2 (70.6, 147.7)72.7 (53.8, 137.4)94.5 (65.4, 134.9).485.871.310
 Ct.Pm, mm90.7 (66.7, 105.7)80.7 (62.5, 106.6)93.6 (72.8, 103.9).818.581.581
Volumetric density
 Tt.vBMD, mg HA/cm3293.2 (267.2, 384.6)226.4 (189.6, 260.4)250.3 (201.7, 280.1).015b.027b.415
 Tb.vBMD, mg HA/cm3157.4 (136.4, 207.7)91.7 (63.0, 112.7)130.2 (87.5, 170.3).015b.090.119
 Ct.vBMD, mg HA/cm3840.0 (787.8, 954.5)863.4 (737.3, 947.5)728.3 (687,9, 934.4).699.137.310
Microstructure
 Tb.BV/TV, %23.9 (20.8, 30.5)14.1 (11.4, 17.5)20.1 (15.8, 24.4).015b.077.040b
 Tb.N, 1/mm1.314 (1.242, 1.372)1.037 (.641, 1.171)0.985 (0.684, 1.098).004b.012b.871
 Tb.Th, mm0.246 (0.232, 0.283)0.235 (0.220, 0.248)0.286 (0.253, 0.311).310.027b<.001b
 Tb.Sp, mm0.736 (0.688, 0.772)0.962 (0.852, 1.611)1.010 (0.922, 1.504).004b.006b.820
 Ct.Th, mm1.283 (1.154, 1.683)1.123 (1.036, 1.454)1.255 (1.025, 1.469).485.721.974
 Ct.Po, %1.7 (0.8, 2.4)1.6 (0.7, 3.3)2.2 (1.5, 3.4).937.280.454
Tibia
 Control (n = 6)dRTA (n = 6)XLH (n = 18)P1P2P3
Male/female5/15/115/3———
Age, y18.0 (6.5, 35.0)16.0 (5.8, 35.0)14.8 (6.0, 29.8).818.770.974
Height, cm149.0 (118.5, 171.3)131.2 (105.8, 164.3)127.2 (105.4, 152.1).394.119.626
Weight, kg39.3 (24.6, 69.3)38.8 (19.1, 77.4)29.3 (19.8, 62.8).818.343.626
Treatmenta, n/%—2/33.3%7/38.9%——.808
Geometry
 Tt.Ar, mm2543.7 (303.7, 727.6)527.0 (267.4, 741.4)578.9 (331.4, 724.2).937.673.770
 Tb.Ar, mm2450.7 (231.9, 574.9)371.2 (213.3, 609.2)459.7 (258.5, 611.1).818.673.537
 Cr.Ar, mm291.2 (70.6, 147.7)72.7 (53.8, 137.4)94.5 (65.4, 134.9).485.871.310
 Ct.Pm, mm90.7 (66.7, 105.7)80.7 (62.5, 106.6)93.6 (72.8, 103.9).818.581.581
Volumetric density
 Tt.vBMD, mg HA/cm3293.2 (267.2, 384.6)226.4 (189.6, 260.4)250.3 (201.7, 280.1).015b.027b.415
 Tb.vBMD, mg HA/cm3157.4 (136.4, 207.7)91.7 (63.0, 112.7)130.2 (87.5, 170.3).015b.090.119
 Ct.vBMD, mg HA/cm3840.0 (787.8, 954.5)863.4 (737.3, 947.5)728.3 (687,9, 934.4).699.137.310
Microstructure
 Tb.BV/TV, %23.9 (20.8, 30.5)14.1 (11.4, 17.5)20.1 (15.8, 24.4).015b.077.040b
 Tb.N, 1/mm1.314 (1.242, 1.372)1.037 (.641, 1.171)0.985 (0.684, 1.098).004b.012b.871
 Tb.Th, mm0.246 (0.232, 0.283)0.235 (0.220, 0.248)0.286 (0.253, 0.311).310.027b<.001b
 Tb.Sp, mm0.736 (0.688, 0.772)0.962 (0.852, 1.611)1.010 (0.922, 1.504).004b.006b.820
 Ct.Th, mm1.283 (1.154, 1.683)1.123 (1.036, 1.454)1.255 (1.025, 1.469).485.721.974
 Ct.Po, %1.7 (0.8, 2.4)1.6 (0.7, 3.3)2.2 (1.5, 3.4).937.280.454

Using the Mann–Whitney U test or chi-square test to compare the control and dRTA group, control and XLH group, dRTA and XLH group. P value in bold represents a statistically significant difference. p1 : control vs dRTA ; p2: control vs XLH; p3: dRTA vs XLH.

Abbreviations: Ct.Ar, cortical bone area; Ct.Pm, cortical perimeter; Ct.Po, cortical porosity; Ct.Th, cortical thickness; Ct.vBMD, cortical volumetric bone mineral density; dRTA, distal renal tubular acidosis; HA, hydroxyapatite; Tb.1/N.SD, trabecular inhomogeneity; Tb.Ar, trabecular bone area; Tt.Ar, total bone area; Tb.BV/TV, trabecular bone volume to total volume ratio, or trabecular fraction; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Tb.vBMD, trabecular volumetric bone mineral density; Tt.vBMD, total volumetric bone mineral density.

aTreatment with citrate salts and/or sodium bicarbonate therapy for dRTA patients; treatment with phosphate salts and active vitamin D for XLH patients.

bP < .05.

Compared to healthy controls, SLC4A1-dRTA patients had lower Tb.N (1.218 [1.034, 1.299] vs 1.398 [1.358, 1.608] 1/mm, P = 0.026), and higher Tb.Sp (0.830 [0.731, 1.004] vs 0.682 [0.537, 0.728] mm, P = .038) at the distal radius. There was no statistically significant difference between dRTA and healthy control groups in bone geometry and vBMD at the distal radius. Compared to healthy controls, SLC4A1-dRTA patients had significantly lower Tt.vBMD (226.4 [189.6, 260.4] vs 293.2 [267.2, 384.6] mg HA/cm3, P = .015) and Tb.vBMD (91.7 [63.0, 112.7] vs 157.4 [136.4, 207.7] mg HA/cm3, P = .015) at the distal tibia. SLC4A1-dRTA patients also showed deterioration in microstructure at the distal tibia, including lower Tb.BV/TV (14.1 [11.4, 17.5] vs 23.9 [20.8, 30.5]%, P = .015), lower Tb.N (1.037 [0.641, 1.171] vs 1.314 [1.242, 1.372] 1/mm, P = .004), and higher Tb.Sp (0.962 [0.852, 1.611] vs 0.736 [0.688, 0.772] mm, P = .004), compared to the healthy control group.

XLH patients had higher Ct.Po at the distal radius than healthy controls (1.4 [0.3, 2.0] vs 0.2 [0.1, 1.1]%, P = .036). There was no statistical difference between XLH and healthy control groups in bone geometry, vBMD, and trabecular bone microstructure at the distal radius. Compared to healthy controls, XLH patients also had significantly lower Tt.vBMD (250.3 [201.7, 280.1] vs 293.2 [267.2, 384.6] mg HA/cm3, P = .027), lower Tb.N (0.985 [0.684, 1.098] vs 1.314 [1.242, 1.372] 1/mm, P = .012), and higher Tb.Sp (1.010 [0.922, 1.504] vs 0.736 [0.688, 0.772] mm, P = .006) at the distal tibia.

Compared with XLH patients, SLC4A1-dRTA patients had lower Tb.BV/TV (13.7 [10.6, 19.5] vs 25.4 [18.1, 34.3]%, P = .002), thinner Tb.Th (.206 [0.193, 0.221] vs 0.250 [0.233, 0.263] mm, P < .001) and lower Ct.Po (0.3 [0.2, 0.5] vs 1.4 [0.3, 2.0]%, P = .020) at the distal radius. SLC4A1-dRTA patients also showed more severe deterioration in microstructure at the distal tibia, including lower Tb.BV/TV (14.1 [11.4, 17.5] vs 20.1 [15.8, 24.4]%, P = .040), thinner Tb.Th (0.235 [0.220, 0.248] vs 0.286 [0.253, 0.311] mm, P < .001), compared with the XLH group.

The representative 3-dimensional reconstruction images of HR-pQCT of a 6-year-old male patient with SLC4A1-dRTA, a sex- and age-matched XLH patient, and healthy control are shown in Fig. 3. Compared to the healthy control, the bone cortex of the distal radius and tibia were thinner and bone trabeculae were sparser in dRTA and XLH patients.

Representative 3-dimensional reconstruction images of HR-pQCT of a 6-year-old male patient with SLC4A1-dRTA, a sex- and age-matched XLH patient, and healthy control. Compared to the healthy control, the bone cortex of the distal radius and tibia were thinner, and bone trabeculae were sparser in the SLC4A1-dRTA patient and XLH patient.
Figure 3.

Representative 3-dimensional reconstruction images of HR-pQCT of a 6-year-old male patient with SLC4A1-dRTA, a sex- and age-matched XLH patient, and healthy control. Compared to the healthy control, the bone cortex of the distal radius and tibia were thinner, and bone trabeculae were sparser in the SLC4A1-dRTA patient and XLH patient.

Abbreviations: Ct, cortical bone; dRTA, distal renal tubular acidosis; HR-pQCT, high-resolution peripheral quantitative computed tomography; Tb, trabecular bone; XLH = X-linked hypophosphatemia.

Open in new tabDownload slide

Basic Characteristics, Biochemical Indicators, and Bone Density Before and After Treatment

Ten patients received citrate salts or sodium bicarbonate therapy, 4/10 patients were given active vitamin D, and 2/10 patients were given phosphate supplements (Supplementary Table S1) (17). During follow-up, relief of bone pain was reported in 9 patients, and blood pH was increased after alkaline treatment (7.37 [7.35, 7.40] vs 7.26 [7.25, 7.36], P = .017, Table 4). The Z-scores of height were increased from −2.5 (−5.1, −1.5) to −1.7 (−4.0, −0.9) (P = .043). The serum creatinine level after alkaline treatment was also elevated. However, no statistically significant differences in serum alkaline phosphatase and β-CTX levels were observed before and after alkaline treatment.

Table 4.
Open in new tab

Clinical characteristics of the dRTA patients with SLC4A1 gene mutation in our center at baseline and after alkaline treatment

 Before alkaline treatmentAfter alkaline treatmentnReference rangeP
Age, y7.0 (4.0, 25.0)18.0 (5.0, 30.0)11—.027
Height, cm119.5 (108.1, 144.0)142.0 (119.0 160.5)8—.043
Height, Z score−2.5 (−5.1, −1.5)−1.7 (−4.0, −.9)8—.043
Blood pH7.26 (7.25, 7.36)7.37 (7.35, 7.40)97.35-7.45.017
Blood bicarbonate, mmol/L15.9 (11.9, 17.2)18.7 (16.8, 20.8)922.0-27.0.069
Urine pH7.5 (7.0, 8.0)7.5 (7.5, 8.5)55.0-8.0.357
Serum sodium, mmol/L142.0 (137.5, 143.5)141.0 (139.3, 143.0)6135-145.785
Serum potassium, mmol/L3.6 (3.0, 4.1)4.2 (3.6, 4.5)73.5-5.5.173
Serum creatinine, µmol/L48.5 (36.5, 64.5)70.5 (53.3, 117.8)818-88.028
Serum ALP, U/L278.5 (186.3, 519.0)208.0 (92.0, 318.8)8a.310
Serum β-CTX, ng/mL1.48 (0.87, 2.71)1.52 (0.89, 2.92)8b.600
Lumbar spine 1-4 BMD, g/cm20.6461.0141——
0.6151.2801——
Lumbar spine 1-4 Z score0.72.02−2∼2—
−2.72.0−2∼2—
Femoral neck BMD, g/cm20.5870.8942——
0.5981.080—
Femoral neck Z score−1.20.52−2∼2—
−1.81.8−2∼2—
Total hip BMD, g/cm20.5400.8762——
0.4660.990——
Total hip Z score−2.10.82−2∼2—
−3.00.7−2∼2—
 Before alkaline treatmentAfter alkaline treatmentnReference rangeP
Age, y7.0 (4.0, 25.0)18.0 (5.0, 30.0)11—.027
Height, cm119.5 (108.1, 144.0)142.0 (119.0 160.5)8—.043
Height, Z score−2.5 (−5.1, −1.5)−1.7 (−4.0, −.9)8—.043
Blood pH7.26 (7.25, 7.36)7.37 (7.35, 7.40)97.35-7.45.017
Blood bicarbonate, mmol/L15.9 (11.9, 17.2)18.7 (16.8, 20.8)922.0-27.0.069
Urine pH7.5 (7.0, 8.0)7.5 (7.5, 8.5)55.0-8.0.357
Serum sodium, mmol/L142.0 (137.5, 143.5)141.0 (139.3, 143.0)6135-145.785
Serum potassium, mmol/L3.6 (3.0, 4.1)4.2 (3.6, 4.5)73.5-5.5.173
Serum creatinine, µmol/L48.5 (36.5, 64.5)70.5 (53.3, 117.8)818-88.028
Serum ALP, U/L278.5 (186.3, 519.0)208.0 (92.0, 318.8)8a.310
Serum β-CTX, ng/mL1.48 (0.87, 2.71)1.52 (0.89, 2.92)8b.600
Lumbar spine 1-4 BMD, g/cm20.6461.0141——
0.6151.2801——
Lumbar spine 1-4 Z score0.72.02−2∼2—
−2.72.0−2∼2—
Femoral neck BMD, g/cm20.5870.8942——
0.5981.080—
Femoral neck Z score−1.20.52−2∼2—
−1.81.8−2∼2—
Total hip BMD, g/cm20.5400.8762——
0.4660.990——
Total hip Z score−2.10.82−2∼2—
−3.00.7−2∼2—

Abbreviations:24hUCa, 24-hour urinary calcium; 25OHD, 25 hydroxyvitamin D; ALP, alkaline phosphatase; dRTA, distal renal tubular acidosis; β-CTX, C-terminal telopeptide of type I collagen.

aThe reference range of ALP (U/L): 0-15 years, 42-390; 16-18 years, 52-171; adult male individual: ≥ 19 years, 45-125; adult female individual: 19-49 years, 35-100; ≥ 50 years, 50-135.

bThe reference range of β-CTX (ng/mL): adult female, 0.21-0.44; adult male, 0.26-0.51; pediatric male individual: 5-9 years, 0.574-0.849; 10-13 years, 0.519-2.415; 14-17 years, 0.435-2.924; pediatric female individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.242-1.291.

Table 4.
Open in new tab

Clinical characteristics of the dRTA patients with SLC4A1 gene mutation in our center at baseline and after alkaline treatment

 Before alkaline treatmentAfter alkaline treatmentnReference rangeP
Age, y7.0 (4.0, 25.0)18.0 (5.0, 30.0)11—.027
Height, cm119.5 (108.1, 144.0)142.0 (119.0 160.5)8—.043
Height, Z score−2.5 (−5.1, −1.5)−1.7 (−4.0, −.9)8—.043
Blood pH7.26 (7.25, 7.36)7.37 (7.35, 7.40)97.35-7.45.017
Blood bicarbonate, mmol/L15.9 (11.9, 17.2)18.7 (16.8, 20.8)922.0-27.0.069
Urine pH7.5 (7.0, 8.0)7.5 (7.5, 8.5)55.0-8.0.357
Serum sodium, mmol/L142.0 (137.5, 143.5)141.0 (139.3, 143.0)6135-145.785
Serum potassium, mmol/L3.6 (3.0, 4.1)4.2 (3.6, 4.5)73.5-5.5.173
Serum creatinine, µmol/L48.5 (36.5, 64.5)70.5 (53.3, 117.8)818-88.028
Serum ALP, U/L278.5 (186.3, 519.0)208.0 (92.0, 318.8)8a.310
Serum β-CTX, ng/mL1.48 (0.87, 2.71)1.52 (0.89, 2.92)8b.600
Lumbar spine 1-4 BMD, g/cm20.6461.0141——
0.6151.2801——
Lumbar spine 1-4 Z score0.72.02−2∼2—
−2.72.0−2∼2—
Femoral neck BMD, g/cm20.5870.8942——
0.5981.080—
Femoral neck Z score−1.20.52−2∼2—
−1.81.8−2∼2—
Total hip BMD, g/cm20.5400.8762——
0.4660.990——
Total hip Z score−2.10.82−2∼2—
−3.00.7−2∼2—
 Before alkaline treatmentAfter alkaline treatmentnReference rangeP
Age, y7.0 (4.0, 25.0)18.0 (5.0, 30.0)11—.027
Height, cm119.5 (108.1, 144.0)142.0 (119.0 160.5)8—.043
Height, Z score−2.5 (−5.1, −1.5)−1.7 (−4.0, −.9)8—.043
Blood pH7.26 (7.25, 7.36)7.37 (7.35, 7.40)97.35-7.45.017
Blood bicarbonate, mmol/L15.9 (11.9, 17.2)18.7 (16.8, 20.8)922.0-27.0.069
Urine pH7.5 (7.0, 8.0)7.5 (7.5, 8.5)55.0-8.0.357
Serum sodium, mmol/L142.0 (137.5, 143.5)141.0 (139.3, 143.0)6135-145.785
Serum potassium, mmol/L3.6 (3.0, 4.1)4.2 (3.6, 4.5)73.5-5.5.173
Serum creatinine, µmol/L48.5 (36.5, 64.5)70.5 (53.3, 117.8)818-88.028
Serum ALP, U/L278.5 (186.3, 519.0)208.0 (92.0, 318.8)8a.310
Serum β-CTX, ng/mL1.48 (0.87, 2.71)1.52 (0.89, 2.92)8b.600
Lumbar spine 1-4 BMD, g/cm20.6461.0141——
0.6151.2801——
Lumbar spine 1-4 Z score0.72.02−2∼2—
−2.72.0−2∼2—
Femoral neck BMD, g/cm20.5870.8942——
0.5981.080—
Femoral neck Z score−1.20.52−2∼2—
−1.81.8−2∼2—
Total hip BMD, g/cm20.5400.8762——
0.4660.990——
Total hip Z score−2.10.82−2∼2—
−3.00.7−2∼2—

Abbreviations:24hUCa, 24-hour urinary calcium; 25OHD, 25 hydroxyvitamin D; ALP, alkaline phosphatase; dRTA, distal renal tubular acidosis; β-CTX, C-terminal telopeptide of type I collagen.

aThe reference range of ALP (U/L): 0-15 years, 42-390; 16-18 years, 52-171; adult male individual: ≥ 19 years, 45-125; adult female individual: 19-49 years, 35-100; ≥ 50 years, 50-135.

bThe reference range of β-CTX (ng/mL): adult female, 0.21-0.44; adult male, 0.26-0.51; pediatric male individual: 5-9 years, 0.574-0.849; 10-13 years, 0.519-2.415; 14-17 years, 0.435-2.924; pediatric female individual: 5-9 years, 0.574-1.849; 10-13 years, 0.519-2.415; 14-17 years, 0.242-1.291.

Discussion

Summary of the Study

This is the first study using HR-pQCT to investigate the bone geometry, volumetric BMD, and bone microarchitecture in patients with SLC4A1-dRTA. Compared to healthy controls, SLC4A1-dRTA patients had decreased vBMD and deteriorated trabecular bone. Compared with XLH, another common type of rickets, SLC4A1-dRTA patients still had severe bone microstructure damage. Bone pain and growth retardation were common in patients with SLC4A1-dRTA, which were alleviated by long-term alkaline therapy.

Alterations of BMD in SLC4A1-dRTA Patients

Although rickets/osteomalacia is a common manifestation of primary dRTA, in-depth studies in the characteristics of skeletal lesions in SLC4A1-dRTA are extremely rare. Our study showed that SLC4A1-dRTA patients had decreased BMD. HR-pQCT analysis further revealed a trabecular bone dominant involvement of damaged bone microstructure. In a cross-sectional study in Thailand, BMD was measured by DXA and bone histology analysis was assessed in 14 newly diagnosed adult dRTA patients with different etiologies. Compared to healthy controls, patients with dRTA had decreased BMD in DXA and decreased bone formation rate per bone surface and increased osteoid volume and surface in bone histomorphometry (18). Disthabanchong et al enrolled 7 patients with idiopathic dRTA and 28 normal controls. Compared to controls, the basal BMD in all sites of dRTA patients were lower, and there was significant reduction in the mineral apposition rate, mineralizing surface or osteoid surface, adjusted apposition rate, and bone formation rate per bone surface in dRTA patients (19). Animal models of chronic metabolic acidosis showed significantly increased activity of tartrate-resistant acid phosphatase and decreases in cortical bone mass and trabecular number (20). Our data from noninvasive HR-pQCT SLC4A1-dRTA patients, together with previous studies on dRTA patients with other etiologies, further confirmed the negative impact of chronic metabolic acidosis on BMD and bone microstructure.

Alterations of Bone vBMD and Bone Microarchitecture in SLC4A1-dRTA Patients

Notably, we compared SLC4A1-dRTA patients with XLH, another common type of rickets, in bone microstructure and found that SLC4A1-dRTA patients had even lower vBMD and more severe bone microstructure damage than XLH patients. Previous studies showed that XLH patients had decreased vBMD and impaired microarchitecture, with greater effects at the distal tibia than the distal radius (21, 22). Our study also found that XLH patients had lower Tt.vBMD at the tibia and severely affected bone microarchitecture both at the distal radius and tibia in comparison to the healthy controls. As to the more severely impaired HR-pQCT parameters in SLC4A1-dRTA patients than in XLH patients from our study, we speculate that the mechanism is due to the difference in the pathogenesis of rickets in these 2 disorders. XLH, the most common type of hereditary hypophosphatemic rickets, is led by mutations in the PHEX gene, which encodes a cell surface-bound protein-cleavage enzyme. Loss of PHEX function results in enhanced secretion of the phosphaturic hormone FGF23 (23). The skeletal lesions of XLH are mainly caused by renal phosphate wasting with hypophosphatemia and reduced synthesis of active vitamin D (24). SLC4A1-dRTA patients suffer from not only hypophosphatemia, but also chronic metabolic acidosis, both of which harm the bone microstructure. Considering the high prevalence of nephrocalcinosis in these patients (approximately 90% in the present study), correction of acidosis should be a more effective and safer treatment than other agents such as phosphate supplement or calcitriol.

Treatment of Bone Lesions in Hereditary dRTA

In our study, all SLC4A1-dRTA patients received alkaline therapy, except for 1 asymptomatic patient. And 5 cases received alkaline treatment only, and bone pain and fatigue were relieved. Although there were missing data in the longitudinal areal BMD and bone turnover markers (BTMs) after treatment in most of the patients, the areal BMD increased markedly after alkaline treatment in 2 patients whose BMD data were available. Similar findings have also been reported in other studies. Somnuek et al enrolled 10 dRTA patients who had never received alkaline treatment. One year after alkaline treatment, the BMDs at the femoral trochanter and total femur evaluated by DXA were increased (25). Disthabanchong et al enrolled 7 patients with idiopathic dRTA who received alkaline treatment. After 1 year of alkaline therapy, there was significant increase in the BMD of the total hip and trochanter of femur and significant improvement in the mineral apposition rate, bone formation rate per bone surface, and bone formation rate per osteoblast number (19). Hess et al evaluated the effect of alkaline treatment on BMD in osteopenia patients with incomplete dRTA (9). During follow-up, 21 patients who adhered to alkaline treatment had improvement in BMD at the lumbar spine and femoral neck compared to the baseline, whereas 10 nonadherent patients had worsened or unchanged BMD. There is no significant decrease in BTMs after alkaline treatment in our study, which is inconsistent with previous studies. However, there seems to be a decreasing trend in BTMs after alkaline treatment. This may be due to the limited data of our study. In conclusion, our study and previous studies all supported the effectiveness of alkaline therapy in relieving skeletal symptoms, increasing areal BMDs, and improving mineralization in histomorphometry of bone biopsy of such patients, whereas the effect on the impaired bone microstructure indexes discovered by HR-pQCT still needs further confirmation.

In addition, growth retardation is also a common manifestation of primary dRTA, related to metabolic acid-base disorders and rickets. In our study, 8 patients who received acidosis correction therapy instead of the replacement therapy of recombinant GH showed an increase in height. However, those patients’ heights were still lower than that of their peers. This finding is in accordance with previous studies that reported that adult height in dRTA patients could be improved after alkaline treatment but was still below the mean of normal adult height (4, 26, 27). Case reports showed that a combination of alkaline therapy and growth hormone therapy could improve growth velocity (28). Because of the lack of evidence for GH deficiency in primary dRTA patients, it is still not recommended to provide GH replacement therapy routinely (29).

Limitations

First, the small sample was 1 limitation of our study because of the rarity of SLC4A1-dRTA. However, our study provided rich clinical data on skeletal lesions, especially vBMD and bone geometry, and microstructure evaluated by noninvasive methods, for the rare disease. Second, as a retrospective study, missing data is unavoidable. The follow-up data of DXA and HR-pQCT were lacking because most patients are from outside regions. The follow-up system will be improved in the future. Third, for children, the measurement sites were acquired from 9.0 and 22.0 mm proximal to the reference line for the distal radius and tibia, rather than from a constant percentage of the length of the limb. However, there is no consensus on how the measurement site should be selected for children. And it did not influence the comparisons between the 2 groups of dRTA and XLH patients, as their average height was similar (Table 2). Finally, the degree of bone mineralization cannot be differentiated by HR-pQCT, which may affect the results of some bone microstructure parameters. However, there is no consensus on the threshold settings for the correction and reassessment of patients with bone mineralization defects. Therefore, our results may only represent partial changes in the bone microstructure, and the impact of the mineralization deficit needs to be addressed in the future.

Conclusion

Skeletal lesions are common clinical manifestations in patients with SLC4A1-dRTA. Evaluated by HR-pQCT, SLC4A1-dRTA patients were found to have decreased vBMD and deteriorated bone microstructure. Alkaline therapy promotes adolescent growth, improves bone lesions, and elevates BMD in SLC4A1-dRTA patients. Compared to XLH, another common type of rickets, SLC4A1-dRTA patients have more severe trabecular bone microstructure damage at distal radius and tibia. It is necessary to pay attention to skeletal lesions in patients with primary dRTA and provide early diagnosis and timely treatment to reduce the harm caused by metabolic bone disease.

Acknowledgments

We acknowledge Ms. Leigh-Anne Cui for the assistance in language editing of the manuscript.

Funding

This research was supported by the National Key Research and Development Program of China (2021YFC2501700, 2021YFC2501701, 2021YFC2501704), National Natural Science Foundation of China (82100946, 82270938), Young Elite Scientists Sponsorship Program by Beijing Association for Science and Technology (No.BYESS2023171), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-002), National High Level Hospital Clinical Research Funding (2022-PUMCH-D-006), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT320-10).

Disclosures

The authors declare no competing interest.

Data Availability

The data that support the findings of this study are available on request from the corresponding author.

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Abbreviations

     
  • 25OHD

    25-hydroxyvitamin

    •  
  • BMD

    bone mineral density

    •  
  • BTM

    bone turnover marker

    •  
  • Ct.PO

    cortical porosity

    •  
  • CV

    coefficient of variation

    •  
  • dRTA

    distal renal tubular acidosis

    •  
  • DXA

    dual-energy X-ray absorptiometry

    •  
  • HR-pQCT

    high-resolution peripheral quantitative computed tomography

    •  
  • iPTH

    intact PTH

    •  
  • PUMCH

    Peking Union Medical College Hospital

    •  
  • Tb.Bv/TV

    trabecular bone volume fraction

    •  
  • Tb.N

    trabecular number

    •  
  • Tb.Sp

    trabecular separation

    •  
  • Tb.Th

    trabecular thickness

    •  
  • Tb.vBMD

    volumetric bone mineral density of trabecular bone

    •  
  • Tt.vBMD

    volumetric bone mineral density of total compartments

    •  
  • vBMD

    volumetric bone mineral density

    •  
  • XLH

    X-linked hypophosphatemic

    •  
  • β-CTX

    β-isomerized C-terminal telopeptide of type I collagen

Author notes

Rong Chen and Lijia Cui contributed equally to the study.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
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