Pediatric solid organ transplantation and osteoporosis: a descriptive study on bone histomorphometric findings

Authors

Inari S. Tamminen, Helena Valta, Hannu Jalanko, Sari Salminen, Mervi K. Mäyränpää, Hanna Isaksson, Heikki Kröger, Outi Mäkitie

Abstract

Background

Organ transplantation may lead to secondary osteoporosis in children. This study characterized bone histomorphometric findings in pediatric solid organ transplant recipients who were assessed for suspected secondary osteoporosis.

Methods

Iliac crest biopsies were obtained from 19 children (7.6–18.8 years, 11 male) who had undergone kidney (n = 6), liver (n = 9), or heart (n = 4) transplantation a median 4.6 years (range 0.6–16.3 years) earlier. All patients had received oral glucocorticoids at the time of the biopsy.

Results

Of the 19 patients, 21 % had sustained peripheral fractures and 58 % vertebral compression fractures. Nine children (47 %) had a lumbar spine BMD Z-score below −2.0. Histomorphometric analyses showed low trabecular bone volume (< −1.0 SD) in 6 children (32 %) and decreased trabecular thickness in 14 children (74 %). Seven children (37 %) had high bone turnover at biopsy, and low turnover was found in 6 children (32 %), 1 of whom had adynamic bone disease.

Conclusions

There was a great heterogeneity in the histological findings in different transplant groups, and the results were unpredictable using non-invasive methods. The observed changes in bone quality (i.e. abnormal turnover rate, thin trabeculae) rather than the actual loss of trabecular bone, might explain the increased fracture risk in pediatric solid organ transplant recipients.

Link To Article

http://dx.doi.org/10.1007/s00467-014-2771-1

Deferoxamine Enhances Bone Regeneration in Mandibular Distraction Osteogenesis

Authors

Farberg, Aaron S. M.D.; Sarhaddi, Deniz B.A.; Donneys, Alexis M.D.; Deshpande, Sagar S. B.S.; Buchman, Steven R. M.D.

Abstract

Background: Distraction osteogenesis is a powerful reconstructive technique for bone growth and repair. An angiogenic means of enhancing the efficacy of this metabolically demanding procedure would be beneficial in expanding its therapeutic potential. The authors posit that the angiogenic effect of deferoxamine, an iron chelator that has been shown to increase angiogenesis, will improve bone regeneration by means of augmentations in quality and quantity of bone and bone-producing cells.

Methods: Two groups of rats (n = 12) underwent surgical external fixation and subsequent distraction. During the distraction stage, the experimental deferoxamine group (n = 5) was treated with injections into the distraction gap. After 28 days of consolidation, mandibles were harvested and prepared for histologic analysis.

Results: The authors found a proliferation of osteocytes in the deferoxamine-treated group when compared with the regenerate of the control group. Deferoxamine effected a significant increase in osteocytes and an increase in bone volume fraction, with subsequent decreased osteoid volume fraction. The data also demonstrated no significant difference in empty lacunae.

Conclusions: The authors’ study demonstrates the effectiveness of deferoxamine treatment to enhance the number of osteocytes within the regenerate in a murine mandibular distraction osteogenesis model. Maintenance of full lacunae supports the authors’ finding of a robust cellular response to deferoxamine therapy. These results suggest that the angiogenic capabilities of deferoxamine translate into an increase in the number of bone-forming cells in the regenerate. Deferoxamine may have utility in optimizing bone formation in distraction osteogenesis and lead to superior reconstructive capabilities for craniofacial surgeons in the future.

Link To Article

http://dx.doi.org/10.1097/01.prs.0000438050.36881.a9

Japanese Medaka: A Non-Mammalian Vertebrate Model for Studying Sex and Age-Related Bone Metabolism In Vivo

Authors

Admane H. Shanthanagouda, Bao-Sheng Guo, Rui R. Ye, Liang Chao, Michael W. L. Chiang, Gopalakrishnan Singaram, Napo K. M. Cheung, Ge Zhang, Doris W. T. Au

Abstract

Background

In human, a reduction in estrogen has been proposed as one of the key contributing factors for postmenopausal osteoporosis. Rodents are conventional models for studying postmenopausal osteoporosis, but the major limitation is that ovariectomy is needed to mimic the estrogen decline after menopause. Interestingly, in medaka fish (Oryzias latipes), we observed a natural drop in plasma estrogen profile in females during aging and abnormal spinal curvature was apparent in old fish, which are similar to postmenopausal women. It is hypothesized that estrogen associated disorders in bone metabolism might be predicted and prevented by estrogen supplement in aging O. latipes, which could be corresponding to postmenopausal osteoporosis in women.

Principal findings

In O. latipes, plasma estrogen was peaked at 8 months old and significantly declined after 10, 11 and 22 months in females. Spinal bone mineral density (BMD) and micro-architecture by microCT measurement progressively decreased and deteriorated from 8 to 10, 12 and 14 months old, which was more apparent in females than the male counterparts. After 10 months old, O. latipes were supplemented with 17α-ethinylestradiol (EE2, a potent estrogen mimic) at 6 and 60 ng/mg fish weight/day for 4 weeks, both reduction in spinal BMD and deterioration in bone micro-architecture were significantly prevented. The estrogenic effect of EE2 in O. latipes was confirmed by significant up-regulation of four key estrogen responsive genes in the liver. In general, bone histomorphometric analyses indicated significantly lowered osteoblasts and osteoclasts numbers and surfaces on vertebrae of EE2-fed medaka.

Significance

We demonstrate osteoporosis development associated with natural drop in estrogen level during aging in female medaka, which could be attenuated by estrogen treatment. This small size fish is a unique alternative non-mammalian vertebrate model for studying estrogen-related molecular regulation in postmenopausal skeletal disorders in vivo without ovariectomy.

Link To Article

http://dx.doi.org/10.1371/journal.pone.0088165

WNT7B Promotes Bone Formation in part through mTORC1

Authors

Jianquan Chen, Xiaolin Tu, Emel Esen, Kyu Sang Joeng, Congxin Lin, Jeffrey M. Arbeit, Markus A. Rüegg, Michael N. Hall, Liang Ma, Fanxin Long

Abstract

WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation.

Link To Article

http://dx.doi.org/10.1371/journal.pgen.1004145

RANKL Inhibition Blocks Osteolytic Lesions and Reduces Skeletal Tumor Burden in Models of Non-Small-Cell Lung Cancer Bone Metastases

Authors

Miller RE, Jones JC, Tometsko M, Blake ML, Dougall WC

Abstract

INTRODUCTION:

Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression.

METHODS:

We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses.

RESULTS:

OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts.

CONCLUSIONS:

These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.

Link To Article

http://www.ncbi.nlm.nih.gov/pubmed/24496001

1,25(OH)2D3 Induces a Mineralization Defect and Loss of Bone Mineral Density in Genetic Hypercalciuric Stone-Forming Rats

Authors

Adeline H. Ng, Kevin K. Frick, Nancy S. Krieger, John R. Asplin, Madison Cohen-McFarlane, Christopher D. Culbertson, Kelly Kyker-Snowman, Marc D. Grynpas, David A. Bushinsky

Abstract

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague–Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)2D3 (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats. To examine the effect of the increased VDR on the osseous response to 1,25D, we fed GHS and SD rats an ample Ca diet and injected either 1,25D [low dose (LD) 12.5 or high dose (HD) 25 ng/100 g body weight/day] or vehicle (veh) daily for 16 days. Femoral areal bone mineral density (aBMD, by DEXA) was decreased in GHS+LD and GHS+HD relative to GHS+veh, while there was no effect on SD. Vertebral aBMD was lower in GHS compared to SD and further decreased in GHS+HD. Both femoral and L6 vertebral volumetric BMD (by μCT) were lower in GHS and further reduced by HD. Histomorphometry indicated a decreased osteoclast number in GHS+HD compared to GHS+veh or SD+HD. In tibiae, GHS+HD trabecular thickness and number increased, with a 12-fold increase in osteoid volume but only a threefold increase in bone volume. Bone formation rate was decreased in GHS+HD relative to GHS+veh, confirming the mineralization defect. The loss of BMD and the mineralization defect in GHS rats contribute to increased hypercalciuria; if these effects persist, they would result in decreased bone strength, making these bones more fracture-prone. The enhanced effect of 1,25D in GHS rats indicates that the increased VDRs are biologically active.

Link To Article

http://dx.doi.org/10.1007/s00223-014-9838-7