Radiographic imaging, densitometry and disease severity in Autosomal dominant osteopetrosis type 2

Abstract

Objective: To characterize relationships between quantitative computed tomography bone mineral density measurements and other qualitative and quantitative imaging measures, as well as clinical metrics, in patients with autosomal dominant osteopetrosis type 2 (ADO2).

Materials and methods: Clinical and radiologic parameters of 9 adults and 3 children with autosomal dominant osteopetrosis type 2 were assessed including lumbar spine quantitative computed tomography (QCT), radiographic skeletal survey (skull base thickening; Erlenmeyer flask deformity; endobone pattern; and spine density pattern (endplate sclerosis, "anvil" appearance, or diffuse sclerosis)), dual-energy x-ray absorptiometry (DXA), tibial peripheral quantitative computed tomography (pQCT) volumetric bone mineral density (vBMD), bone turnover markers, and bone marrow failure or visual impairment.

Results: The skeletal parameter most divergent from normal was lumbar spine QCT Z-score (+ 3.6 to + 38.7). Lumbar QCT Z-score correlated positively with pQCT tibial diaphysis vBMD (Pearson correlation r = 0.73, p = 0.02) and pQCT tibial metaphysis vBMD (r = 0.87, p < 0.01). A trend towards positive lumbar QCT Z-score correlation with serum P1NP/CTX ratio (r = 0.54, p = 0.10) and lumbar DXA Z-score (r = 0.55, p = 0.10) were observed. Bone marrow failure and vision impairment occurred in those with most severe quantitative and qualitative measures, while those with less severe radiographic features had the lowest QCT Z-scores.

Conclusion: Lumbar spine QCT provided the most extreme skeletal assessment in ADO2, which correlated positively with other radiologic and clinical markers of disease severity. Given the quantification of trabecular bone and greater variation from normal with wider range of values, lumbar QCT Z-scores may be useful to determine or detect impact of future treatments.

Keywords: ADO2; Osteoclast; Osteopetrosis; Quantitative computed tomography.

Fig. 1

Lumbar QCT measurement technique with elliptical region of interest (ROI) manually drawn within the L1 vertebral body and circular ROIs within each of the three components of the calibration phantom.

Fig. 2

A young adult male with ADO2 demonstrates all classic radiograph features of the disease. (a) AP chest radiograph with diffuse sclerosis of the ribs (long white arrows), clavicles (short white arrow), vertebral bodies (short black arrow), coracoids (thin black arrow), and proximal humerus (dashed black arrow). (b) Lateral skull radiograph with skull base thickening (black arrows). (c) AP distal femur radiograph with Erlenmeyer flask deformity (abnormal width of distal femoral metadiaphysis, double headed arrow; expected shape of distal femur, dashed black line). (d) AP pelvis radiograph with endobone (bone-within-bone) appearance (dashed arrows). (e) AP lumbar spine radiograph with dense sclerotic bands at the vertebral body endplates (“rugger jersey” spine, white arrows).

Fig. 3

Example radiographs and CT images of each vertebral body sclerosis pattern, including (a) a middle-aged woman with the classic “rugger jersey” pattern of vertebral body sclerosis (parallel bands of increased density at the vertebral body endplates, white arrows), (b) a young adult woman with the “anvil” pattern of vertebral body sclerosis (dense sclerotic bands at the vertebral body endplates with additional central vertebral body intramedullary density, dotted outline), and (c) a middle-aged man with diffuse vertebral body sclerosis.

Fig. 4

pQCT comparison of the tibial diaphysis and distal tibia in a healthy young adult control on left, and a teenage female ADO2 patient on the right, demonstrating cortical thickening and limited marrow cavity space in the osteopetrosis patient.

Fig. 5

Scatter plots of lumbar spine QCT Z-score (y-axis) versus: (a) lumbar spine DXA Z-score, (b) tibial diaphysis pQCT total volumetric bone mineral density (vBMD, g/cm3), (c) distal tibial pQCT total vBMD (g/cm3), and (d) serum P1NP/CTX ratio. The data point labels of clinical metrics include anemia (A), vision impairment (V), and child (C). The solid line in (a) is the identity line that y=x, which shows that QCT Z-scores were higher than DXA Z-scores for majority of the data points.