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 on bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.

Clinical Response to Treatment with Teriparatide in an Adolescent with Osteoporosis-Pseudoglioma Syndrome (OPPG): A Case Report

“…Streeten et al reported significant increase in the areal BMD in OPPGS patients after treatment with bisphospho-nate, but trabecular volumetric BMD remained low. As a result, during long-term follow-up, there was no significant improvement in bone fractures (12), which was similar to the findings of our study. However, bisphosphonates cannot be considered as an ideal treatment for treatment of OPPG in some patients.…”

“…However, bisphosphonates cannot be considered as an ideal treatment for treatment of OPPG in some patients. Streeten et al reported fractures in three of nine OPPG patients with low-normal hip areal BMD after treatment with bisphosphonates (12). Our patient had multiple bone fractures after about seven years of pamidronate treatment.…”

Lrp5 Mutant and Crispant Zebrafish Faithfully Model Human Osteoporosis, Establishing the Zebrafish as a Platform for CRISPR-Based Functional Screening of Osteoporosis Candidate Genes

“…human subjects, DXA-or pQCT-measured areal BMD, and volumetric BMD of cortical and trabecular bone, are typically expressed as Z-scores, where Z-scores lower than À2 are indicative for osteoporosis. (72)(73)(74) Previous studies using DXA and pQCT scanning in OPPG patients, carrying recessive LRP5 mutations, revealed decreased bone density (vBMD Z-score À1.57) and cortical bone area of the tibia (Z-score À2.19) (75) and decreased BMD of the lumbar spine (Z-scores between À1.2 and À7.8). (76) In addition, dominantly inherited LRP5 mutations were described to result in low bone mass phenotypes in children and adults.…”

Advances in Diagnosis and Management of Childhood Osteoporosis

“…OI or ALL). For example, in children with OPPG (characterised by impaired bone formation resulting in low bone turnover), although bisphosphonates produced an increase in aBMD, several of these children later suffered fractures even with improvement in DXA Z-scores ( 69 ).…”