Low Bone Density in Fabry Tied to High Levels of Calciprotein Particles
High levels of calciprotein particles (CPP) — tiny structures that transport excess minerals in the bloodstream — were found in adults with Fabry disease who have a low bone mineral density (BMD), a study revealed for the first time.
The hip bone and the top of the upper leg bone (femoral neck) were most affected.
In addition, elevated CPP was higher in men with Fabry than in women, a difference not seen in healthy individuals.
Further research is needed to understand the relevance of sex-related differences and determine whether CPP measurements may help assess bone disease in Fabry, the researchers noted.
The study, “Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease,” was published in the journal Osteoporosis International.
Fabry disease is a genetic condition marked by the accumulation of fatty molecules, mainly globotriaosylceramide (Gb3 or Gl-3), inside cells. Their buildup triggers immune responses and leads to chronic inflammation. Over time, the condition damages tissues, including the heart and kidneys, and the brain and spinal cord.
The genetic defect occurs on the X chromosome — one of the two sex chromosomes, of which women have two and men one; men also have a Y chromosome. Given the defect’s location, the disease is typically more severe in males than females, as women can carry a healthy gene copy that partially compensates for the defective copy.
Studies have indicated that people with Fabry, particularly men, also have higher rates of diseases characterized by bone mineral density loss, such as osteoporosis or osteopenia. However, the biological mechanisms by which the bone mineral density is lower in Fabry patients have not been fully explored.
Investigating CPP Levels in Fabry
CPPs are tiny structures that form outside cells and facilitate the transport and clearance of excess minerals from the bloodstream. They consist of a protein that carries clusters of calcium and phosphate — two minerals that largely occur in bones and teeth.
The levels of CPP in the bloodstream have correlated with disease-related processes related to chronic kidney disease, a common feature in Fabry. High levels of circulating CPPs also have been reported in other chronic inflammatory disorders such as inflammatory bowel disease and inflammatory joint conditions.
These findings prompted researchers based at the University of Melbourne, in Australia, to explore the relationship between CPP in the bloodstream and bone mineral density in adults with Fabry. The study enrolled 37 women and 22 men, who were matched in age and body fat content per height (BMI).
In the body, CPP can form as single units. Still, CPPs primarily form as large, multi-unit spherical structures (CPP-I) and even larger, more elongated secondary particles containing crystalline calcium phosphate (CPP-II).
Patients’ blood tests revealed that CPP-I was the most abundant, making up 88.6% of CPP types. CPP-I levels correlated strongly with CPP-II levels.
The absolute levels of both CPP-I and CPP-II were higher in Fabry patients than an age-matched group of 28 healthy individuals, who also had more abundant CPP-I (87.9%) — “implying no disturbance in the tendency for particle transformation,” the team wrote.
The median levels of CPP-I and CPP-II were higher in men with Fabry than they were in females. Notably, the team did not find such sex-related differences in CPP among the control group.
Neither CPP-I nor CPP-II levels were related to disease severity, advanced damage to the heart or kidneys, other mineral metabolism markers, and heart function measures. Consistent with more medication use by men, CPP-I and CPP-II levels were higher in patients prescribed enzyme replacement therapy, immunosuppressants, and spironolactone to treat fluid buildup due to kidney disease.
A pronounced reduction in bone mineral density, as measured by lower T-scores — the bone mineral density value compared with that of a healthy 30-year-old of the same sex — was found for men at all bone sites measured.
In males compared with females, osteopenia (T-score −1.0 to −2.5) and osteoporosis (T-score −2.5 or less) were found in the lower (lumbar) spine (54.5% vs. 28%), the total hip (68% vs. 32%), and the femoral neck (82% vs. 46%). Low bone mineral density at these three sites correlated with lower BMI and higher calcium levels in the blood, but not disease severity or heart measures.
Elevated CPP-I and CPP-II were significantly related to lower bone mineral density across all Fabry participants in the total hip and femoral neck but not the lumbar spine. CPP-II levels were consistently higher than those for CPP-I, “indicating a more robust association of CPP-II with [bone mineral density] at these sites,” the researchers wrote.
A sex-specific analysis found that CPP-II was associated with raw bone mineral density measurements and T-scores only in female Fabry disease patients in the femoral neck region. After adjusting for sex, CPP-I levels were not associated with bone mineral density at any body site measure.
“We have uncovered a novel association between low [bone mineral density] and high circulating CPP levels in a cohort of patients with Fabry disease,” the researchers concluded. “Our work contributes to the knowledge surrounding the relatively newly described CPP and how their presence, particularly as CPP-II, can be indicative of a pathological [disease] state.”
These findings “should lead to future mechanistic studies to increase our understanding of the CPP-bone relationship in Fabry disease,” the team added.