Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Abstract

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14 unaffected first degree family members. pQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in >700 reference participants. We observed 4 fractures (3 femoral shafts) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (-1.51 vs. 0.17, p = 0.002), cortical area (-2.36 vs. 0.37; p < 0.001) and periosteal circumference (-1.86 vs. -0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (-0.69 vs. 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects of bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.

Keywords: Atypical femur fracture; Bone mineral density; OPPG; Osteoporosis pseudoglioma syndrome; pQCT.

Fig. 1

OPPG pedigree — Study participants are indicated by *.

Fig. 2

Longitudinal bone mineral density by DXA in OPPG patients. Fractures are indicated by arrows. 2A. Five OPPG patients with AA genotype treated with bisphosphonates. Fractures included femoral shaft, tibia and fibula fractures. Treatment is indicated by solid bars. BP = bisphosphonates. TER = teriparatide. Patient A1was treated with risedronate from age 8.5–11 years, pamidronate from 11–14.5 years and alendronate from 16–19.5 years. Patient A2 was treated with risedronate from age 5–8.5 years, pamidronate from 8.5–9.5 years and alendronate from 10–12 years and 13.5–14 years. In patients A2 and A3, the pQCT was done when they were ages 14.5 and 8.5 years. pQCT was not performed in A1, C1, C2. 2B. Four OPPG patients with AB genotype never treated pharmacologically. pQCT scans on these participants were 3 years prior to the last DXA.

Fig. 2

Longitudinal bone mineral density by DXA in OPPG patients. Fractures are indicated by arrows. 2A. Five OPPG patients with AA genotype treated with bisphosphonates. Fractures included femoral shaft, tibia and fibula fractures. Treatment is indicated by solid bars. BP = bisphosphonates. TER = teriparatide. Patient A1was treated with risedronate from age 8.5–11 years, pamidronate from 11–14.5 years and alendronate from 16–19.5 years. Patient A2 was treated with risedronate from age 5–8.5 years, pamidronate from 8.5–9.5 years and alendronate from 10–12 years and 13.5–14 years. In patients A2 and A3, the pQCT was done when they were ages 14.5 and 8.5 years. pQCT was not performed in A1, C1, C2. 2B. Four OPPG patients with AB genotype never treated pharmacologically. pQCT scans on these participants were 3 years prior to the last DXA.

Fig. 3

pQCT Z-scores in 6 OPPG and 14 unaffected participants. (A). Trabecular vBMD, cortical area and periosteal circumference Z-scores were significantly lower in the OPPG participants.

Fig. 4

pQCT images in a 14 year old male OPPG participant and an age-, sex-, and tibia length-matched reference participant. The markedly greater cortical area and periosteal circumference at the 38% cortical diaphysis is evident in the reference participant (A) compared with the OPPG (B) participant. The greater trabecular BMD at the 3% metaphysis site is shown in the reference (C) compared with the OPPG (D) participant.