Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

Abstract

Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets.

A Digital Model to Simulate Effects of Bone Architecture Variations on Texture at Spatial Resolutions of CT, HR-pQCT, and μCT Scanners

“…The main aim of a texture analysis is to provide information on trabecular structure in addition to BMD, which alone can easily be quantified by DXA and QCT. That implies the question of how strong texture parameters depend on BV/TV, which is the main determinant of BMD as newly formed bone mineralizes up to 70% of its final value within a few days [ 37 , 38 ]. A strong dependence would limit the additional value of a texture analysis.…”

Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization

“…(26,36,37) In particular, FGF23 and sclerostin expression are increased, while DMP1 expression is lower in transplant recipients than in children with CKD who did not receive (26) Excessive FGF23 expression may contribute to altered mineralization kinetics. (17,35,38) DMP1 is widely expressed throughout mineralized bone and decreased expression may result in impairments in skeletal mineralization. (39) Overall, although a direct effect of aberrant osteocytic protein expression on bone mineralization per se has yet to be established, these data suggest that abnormal osteocytic protein expression and local impairments in skeletal mineralization co-occur and may be linked.…”

“…In consequence, “younger” or newly formed bone packets are less mineralized relative to “older” ones . However, the mineralization kinetics, ie, the time course of mineral deposition in the bone matrix, might be disturbed in pathological situations . Mineralization does not only require the presence of adequate calcium and phosphate levels but is also locally controlled by bone cell derived proteins, such as sclerostin, and by the organic matrix composed of collagen and noncollagenous matrix proteins, such as dentin matrix protein 1 (DMP1) …”

“…(14,15) However, the mineralization kinetics, ie, the time course of mineral deposition in the bone matrix, might be disturbed in pathological situations. (16,17) Mineralization does not only require the presence of adequate calcium and phosphate levels but is also locally controlled by bone cell derived proteins, such as sclerostin, and by the organic matrix composed of collagen and noncollagenous matrix proteins, such as dentin matrix protein 1 (DMP1). (18)(19)(20) The degree of bone matrix mineralization can be quantified in bone biopsy samples as bone mineralization density distribution (BMDD) by evaluating the entire cross-sectioned area of the biopsy sample by quantitative backscattered electron imaging (qBEI).…”

Mineral density differences between femoral cortical bone and trabecular bone are not explained by turnover rate alone

“…Shifts of BMDDs and of average bone mineral densities towards higher and lower mineral densities have previously been attributed to lower and higher birth rates of basic multicellular units (BMUs), respectively [6, 46], and acceleration and deceleration of mineral accumulation in specific bone diseases [50]. Mineralisation kinetics, i.e.…”