Bone Fragility Syndrome: Disease characterization, assessment of cristobalite as an etiologic agent, and evaluation of diagnostic tests

A debilitating bone disease causes horses to develop skeletal abnormalities including scapular bowing, lordosis, and cervical arthropathy. Disease progresses until horses die from a catastrophic fracture or humane euthanasia. There is no age, breed or sex predilection. Some horses also have pulmonary silicosis. Affected horses are geographically clustered and primarily located in California. The goals of this research were to: characterize disease manifestations; determine the nature of the bone disease; investigate possible causes, including silicates; investigate the association between lung and bone diseases; and develop clinically useful diagnostic tests.;The disease characterization was done through a retrospective, pathological based study with 9 affected and 3 unaffected horses. Pathologic, radiographic, histologic, and toxicological examinations were performed. Crystals were identified by x-ray diffraction. All 9 affected horses had osteoporosis; 8 of 9 affected horses had pulmonary silicosis making osteoporosis and silicosis highly correlated (r = 0.8, p < 0.01). Cytotoxic silica dioxide crystals were identified in pulmonary and lymphoid tissues with cristobalite the predominant crystalline structure. There were no abnormalities in heavy metals or trace minerals. These results provided strong circumstantial evidence that the bone disease affecting these horses was a silicate associated osteoporosis (SAO).;Evaluation of cristobalite as a causative agent in SAO was done using 45 mice (23 C57BL/6, 22 DBA/2) that were intratracheally exposed to cristobalite extracted from a horse with severe SAO (treatment) or saline (control). Mice were sacrificed after 16 weeks. Lungs were assessed grossly and histologically; bones were assessed using microcomputed tomography and histology. All 12 treated DBA/2 mice and 9 of 10 treated C57BL/6 mice developed pulmonary silicosis; lymphocytic lesions were predominant in C57BL/6 (p < 0.01) and pyogranulomatous lesions were predominant in DBA/2 (p < 0.01). Both of these predominant lung lesions differed from those in SAO horses, which consist of granulomatous lesions. Skeletal abnormalities were not detected in any mice. The lack of skeletal effects indicated that either there are unknown cofactors necessary for the development of osteoporosis, the syndrome is species specific, the methodology did not replicate natural exposure, or that cristobalite is not an etiologic agent for osteoporosis.;A prospective, clinical trial using 20 diseased and 40 unaffected horses assessed diagnostic tests for detection of bone fragility syndrome (BFS), the clinical syndrome of SAO in the absence of confirmed silicosis. Bone scintigraphy was used as the reference standard to which physical examination, scapular ultrasound, and serum biomarkers (carboxy-terminal telopeptide of collagen crosslinks, bone-specific alkaline phosphatase) were compared for assessing accuracy in BFS diagnosis. A diagnosis was strongly supported on scintigraphy by ≥ 2 regions of increased radiopharmaceutical uptake, including 1 region in the scapular spine; on physical examination by lateral bowing of the scapula(e); and on ultrasound by widening of the scapular spine. None of the tests evaluated were accurate enough to replace scintigraphy for mild disease; physical examination and scapular ultrasound were accurate in moderate to severe BFS. Serum biomarkers were not accurate for diagnosis. Severity indices of disease were created to classify a spectrum of disease allowing for future monitoring of disease progression.;These studies characterized a devastating skeletal disease affecting California horses, generated several hypotheses about mechanisms of disease, and provided clinical tools for disease diagnosis and monitoring. However, the etiopathogenesis for SAO remains unknown. SAO has many similarities to Paget's disease of bone in man - another disease of unknown cause. Several bone disorders in people are associated with chronic lung diseases. Further investigation of equine SAO may elucidate mechanisms of disease shared between man and animals.