Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro‐osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age‐dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age‐dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age‐dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.

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Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (n = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound. Additionally, histomorphometric analyses are reported on six subjects seen at the UCLA Bone and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5 to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean bone mineral density (BMD) Z-scores were decreased in the femoral neck, total hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present in 46% of subjects. Twenty-seven percent of subjects reported one or more long bone fractures. Thirty-two percent of subjects had incidental vertebral fractures, which were unrelated to transplant status. Long-bone deformity/bowing was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21% of evaluated subjects. Risk factors included CKD, phosphate wasting, hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy. Sixty-one percent of the non-transplanted subjects had ultrasonographic evidence of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed impaired mineralization in four of six studied subjects. We conclude that skeletal deformities, decreased bone mass, and vertebral fractures are common and relevant complications of nephropathic cystinosis, even before renal transplantation. Efforts to minimize risk factors for skeletal disease include optimizing mineral metabolism and hormonal status, combined with monitoring for nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work and is in the public domain in the USA.

Fibrous dysplasia (FD) is a mosaic disorder of benign fibro-osseous lesions, which may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). Cranial base abnormalities, including Chiari I malformation (CM1), in which the cerebellum extends below the foramen magnum, and secondary basilar invagination (BI), in which the odontoid prolapses into the posterior cranial fossa, are potentially serious complications of metabolic bone disorders. The purpose of this study was to determine the prevalence, natural history, and risk factors for CM1 and BI in patients with FD/MAS, and to determine mechanisms of cranial base deformities. Clinical and radiographic data from subjects in an FD/MAS natural history study were evaluated and compared to normal controls. In 158 patients with craniofacial FD, 10 (6.3%) cases of CM1 and 12 (7.6%) cases of BI were diagnosed. No cranial base abnormalities were identified in 10 control subjects. Craniomorphometric and volumetric analyses identified cranial constriction and cranial settling as the primary mechanisms of cranial base abnormalities, whereas intracranial hypertension was a contributing factor in a minority of subjects. Longitudinal analyses found progression of odontoid position with age, but no progression of tonsillar position. No endocrinopathies were associated with CM1. MAS endocrinopathies associated with BI included hyperthyroidism (odds ratio [OR] 12.0; 95% confidence interval [CI], 2.9 to 55.6; p < 0.01), precocious puberty (OR 5.6; 95% CI, 1.2 to 26.0; p < 0.05), and hypophosphatemia (OR 7.7; 95% CI, 1.9 to 27.0; p < 0.01). Scoliosis was associated with both CM1 (OR 4.8; 95% CI, 1.1 to 22.8; p < 0.05) and BI (OR = infinity; 95% CI, 4.7 to infinity; p < 0.01). This study successfully characterized cranial base abnormalities in FD/MAS and the pathophysiological connection between them. These findings support routine screening for cranial base abnormalities in patients with craniofacial FD, as well as aggressive management of contributory risk factors. © 2018 American Society for Bone and Mineral Research.

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equivalent* and uI = 0.5 for fluorine, we calculate that the inductive effect alone of a 9 fluorine would result in a rate increase of lo5; hence, the ?r-conjugation effect actually results in a millionfold rate decrease.By contrast, two a fluorines increase the LiCHAcatalyzed exchange of toluene by a factor of >104.'j (6) D. J. Cram, "Fundamentals of Carbanion Chemistry," Academic Press Inc., New York, N. Y . , 1965, p 59, reports that all four hydrogens of m-methylbenzal fluoride undergo hydrogen-deuterium exchange at comparable rates with potassium t-butoxide in t-butyl alcohol-d. This corresponds to a far slower relative rate for the difluoromethyl hydrogen than we have found, but this apparent discrepancy may very well be due to extensive internal return in the t-butyl alcohol system.(7) On leave from the Institute

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