Rate Of Bone Remodeling Research Articles

Editorial: Molecular Endocrinology Articles in the Spotlight for January 2012

Beginning with this issue of Molecular Endocrinology, we’ll be highlighting three articles that should be of special interest to our readers. Although all manuscripts accepted for publication in Molecular Endocrinology have a high degree of scientific merit, the three selected for an editorial highlight are meant to showcase particularly novel and significant findings reflective of others that can be found throughout the issue. This first issue of 2012 includes the following articles that are excellent examples of the relevance of basic science findings to clinical management of endocrine disorders. The first, “Reduced bone turnover in mice lacking the P2Y13 receptor of ADP” by Alison Gartland and colleagues, addresses the issue of osteoporosis and the need for drugs that provide alternative treatment for osteoporosis. The authors show that deletion of the P2Y13 receptor, a G protein-coupled receptor for extracellular ADP, leads to a reduction in trabecular bone mass, reduction in osteoblast and osteoclast numbers and an overall reduction in the rate of bone remodeling in mice. They also find that P2Y13R( / ) mice are protected from ovariectomyinduced bone loss. Therefore, the P2Y13 receptor may provide a new therapeutic target that confers a protective advantage in conditions of accelerated bone turnover such as estrogen deficiency-induced osteoporosis. This would be a tremendous benefit to the one third of all women and one fifth of all men over fifty who will experience an osteoporotic fracture in their lifetime. “FXR protects lung from LPS-induced acute injury”, by Wendong Huang and colleagues, is another article in the spotlight this month. This research addresses acute lung injury, which is associated with 17,000–43,000 deaths each year. In one of the important findings of this study, Huang et al. demonstrate that expression of a constitutively active FXR repressed the expression of proinflammatory genes and improved lung permeability and lung regeneration in FXR / mice. Therefore, FXR may be an ideal target for drug development as novel and safe FXR ligands may be effective for the treatments of lung injury and other related diseases. Finally, Signe Altmae and colleagues bring us a Research Resource contribution, “Interactome of human embryo implantation: identification of gene expression pathways, regulation, and integrated regulatory networks.” This study helps us to better understand the complex genetic network that leads to successful embryo implantation and will be relevant to the development of future strategies to alleviate human infertility. The authors are the first to perform thorough computational analysis to identify the potential molecular interactions between implantation-stage endometrium and the embryo. I hope you enjoy these articles, as well as the rest of the exceptional articles in this issue. With best wishes for 2012— Donald B. DeFranco, Editor-in-Chief

Effects of Kalsis, A Dietary Supplement, on Bone Metabolism in the Ovariectomized Rats

We studied the ability of Kalsis, a food supplement that contains selenium, citric acid, and vitamin E, to prevent the effects of ovariectomy on bone loss. Six-month-old, Wistar female rats were studied. Groups (n = 12): SHAM: sham-operated rats; OVX: ovariectomized rats, treated with vehicle; OVX + Kalsis: ovariectomized rats treated with Kalsis (25 mg/kg/day) for 3 months. Bone mineral density (BMD) was determined by DXA in lumbar spine and femur. Computerized microtomography (μCT) in femur and serum osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), β-isomer of carboxyterminal telopeptide of collagen I (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase (TRAP) were performed. Treatment with Kalsis prevented BMD loss in OVX group. μCT showed a decrease in BV/TV, and trabecular number, and an increase in trabecular separation in OVX rats. Kalsis administration attenuated partially bone loss observed by μCT due to ovariectomy. BGP, PINP, and the resorption index (CTX/TRAP) were increased in OVX group. Treatment with Kalsis maintained this increase. The mechanism of action of this supplement is not through a decrease in bone remodelling rate. The antioxidant action of this food supplement, due to the synergism of all its components, as a cause of its beneficial effect is suggested.

P2-19-01: Impact of Zoledronic Acid on Fractures, Bone Mineral Density and Bone Remodeling in the AZURE Trial (BIG 01–04).

Abstract Background: The AZURE trial was designed to determine whether the addition of zoledronic acid (ZOL) to standard adjuvant therapy improves disease free survival (DFS) in patients (pts) with stage II/III breast cancer. Although in a recent analysis after 752 events and a median follow-up of 59 months no difference in overall DFS was seen between ZOL and control pts, significant benefits were seen in women >5years post menopause. Here, we report the impact of ZOL on fractures in the main study, and on bone mineral density (BMD) and bone remodeling evaluated within a sub-study. Materials and methods: 3360 pts were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy with (n=1681) or without (n=1678) up to 19 doses of ZOL 4mg over 5 years. Pts with osteoporosis and those using bisphosphonates, either at baseline or in the previous year, were excluded from study entry. BMD was assessed in 228 patients within a sub-study; 40 of these also underwent quantitative bone scanning (QBS), a novel imaging technique that yields values for 99mTc-MDP/HMDP whole skeleton plasma clearance (Kbone) as a surrogate for the rate of bone remodeling and enables assessment of specific regions of interest within the skeleton. Results: Fractures occurred in 152 (4.5%) pts; 60 (3.6%) ZOL pts compared with 92 (5.5%) control (CTRL) pts (difference −1.9%; 95%CI −3.3%, −0.5%). The difference in fracture incidence appeared early and persisted throughout the follow-up period. Fifty-six (86.2%) of the fractures in the ZOL group and 68 (61.8%) in the CTRL group occurred in the absence of, or prior to a DFS event. The fracture rates before disease recurrence were similar at 3.0% (51 pts) in the ZOL group and 3.4% (57 pts) in the CTRL group (difference −0.4%; 95%CI −1.6%, 0.8%). In contrast, 2.1% (8 ZOL pts) and 9.1% (34 CTRL pts) experienced a fracture after a DFS event (difference −6.9%; 95% CI −10.2%, −3.7%). For pts with a DFS event, the majority of fractures occurred after a skeletal recurrence; 87.5% (7 of 8) ZOL and 88.2% (30 of 34) CTRL pts. BMD Z-scores at completion of protocol treatment were higher in patients treated with ZOL. Kbone was lower in ZOL patients (26.5 vs 29.8 ml min−1 using 99mTc-MDP and 34.3 vs 39.3 ml min−1 with 99mTc-HMDP). Expressed as a percentage of whole skeleton clearance, regional values in the mandible were similar 1.15% (ZOL) vs. 1.22% (CTRL). Conclusions: Adjuvant ZOL given in the schedule studied in AZURE reduced the fracture rate in patients who developed recurrence of breast cancer. BMD was higher and the rate of bone remodeling less in patients treated with ZOL. Further follow-up will determine the duration and clinical relevance of these effects on bone health. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-01.

Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6mice were ovariectomized (OVX, n=11) or sham-operated (SHM, n=9) and monitored with in vivo μCT on the day of surgery and every 2weeks after, up to 12weeks. There was a significant decrease in bone volume fraction for OVX (-35%) compared to SHM (+16%) in trabecular bone (P<0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P<0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (-16%) compared to SHM (+11%, P<0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P<0.001) and a delayed increase in bone formation rate (P<0.001). Monitoring transient bone biology is a promising method for future research.

Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture.

Reduced Bone Turnover in Mice Lacking the P2Y13 Receptor of ADP

Osteoporosis is a condition of excessive and uncoupled bone turnover, in which osteoclastic resorption exceeds osteoblastic bone formation, resulting in an overall net bone loss, bone fragility, and morbidity. Although numerous treatments have been developed to inhibit bone loss by blocking osteoclastic bone resorption, understanding of the mechanisms behind bone loss is incomplete. The purinergic signaling system is emerging to be a pivotal regulator of bone homeostasis, and extracellular ADP has previously been shown to be a powerful osteolytic agent in vitro. We report here that deletion of the P2Y(13) receptor, a G protein-coupled receptor for extracellular ADP, leads to a 40% reduction in trabecular bone mass, 50% reduction in osteoblast and osteoclast numbers in vivo, as well as activity in vitro, and an overall 50% reduction in the rate of bone remodeling in mice in vivo. Down-regulation of RhoA/ROCK I signaling and a reduced ratio of receptor activator of nuclear factor κB ligand/osteoprotegerin observed in osteoblasts from P2Y(13)R(-/-) mice might explain this bone phenotype. Furthermore, because one of the main causes of osteoporosis in older women is lack of estrogen, we examined the effect of ovariectomy of the P2Y(13)R(-/-) mice and found them to be protected from ovariectomy-induced bone loss by up to 65%. These data confirm a role of purinergic ADP signaling in the skeleton, whereby deletion of the P2Y(13) receptor leads to reduced bone turnover rates, which provide a protective advantage in conditions of accelerated bone turnover such as oestrogen deficiency-induced osteoporosis.

Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and DXA BMDa of the hip and spine in middle-aged and elderly European men: the European Male Ageing Study (EMAS)

To assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men. A cross-sectional population-based survey. Men aged 40-79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β C-terminal cross-linked telopeptide (β-cTX)), total testosterone, total oestradiol (E(2)), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres. A total of 3120, mean age 59.9 years (s.d.=11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E(2) were negatively associated with β-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both β-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine. E(2), SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.

Discontinuous Release of Bone Morphogenetic Protein-2 Loaded Within Interconnected Pores of Honeycomb-Like Polycaprolactone Scaffold Promotes Bone Healing in a Large Bone Defect of Rabbit Ulna

The choice of an appropriate carrier and its microarchitectural design is integral in directing bone ingrowth into the defect site and determining its subsequent rate of bone formation and remodeling. We have selected a three-dimensional polycaprolactone (PCL) scaffold with an interconnected honeycomb-like porous structure to provide a conduit for vasculature ingrowth as well as an osteoconductive pathway to guide recruited cells responding to a unique triphasic release of osteoinductive bone morphogenetic proteins (BMP) from these PCL scaffolds. We hypothesize that the use of recombinant human bone morphogenetic protein 2 (rhBMP2)-PCL constructs promotes rapid union and bone regeneration of a large defect. Results of our pilot study on a unilateral 15 mm mid-diaphyseal segmental rabbit ulna defect demonstrated enhanced bone healing with greater amount of bone formation and bridging under plain radiography and microcomputed tomography imaging when compared with an empty PCL and untreated group after 8 weeks postimplantation. Quantitative measurements showed significantly higher bone volume fraction and trabecular thickness, with lower trabecular separation in the rhBMP2-treated groups. Histology evaluation also revealed greater mature bone formation spanning across the entire scaffold region compared with other groups, which showed no bone regeneration within the central defect zone. We highlight that it is the uniqueness of the scaffold having a highly porous network of channels that promoted vascular integration and allowed for cellular infiltration, leading to a discontinuous triphasic BMP2 release profile that mimicked the release profile during natural repair mechanisms in vivo. This study serves as preclinical evidence demonstrating the potential of combining osteoinductive rhBMP2 with our PCL constructs for the repair of large defects in a large animal model.

Achyranthes bidentata root extract prevent OVX-induced osteoporosis in rats

AimThe objective of the present study was to systematically investigate the effects of Achyranthes bidentata root extract (ABRE) on postmenopausal osteoporosis. Materials and methodsEighty 3-month-old female Sprague–Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17β-ethinylestradiol (E2, 25μg/kg/day); OVX with ABRE of graded doses (100, 300, or 500mg/kg/day). Daily oral administration of ABRE or E2 started on week 4 after OVX for 16 weeks. Bone mass, bone turnover and strength were analyzed by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by microcomputed tomography (μCT). Results16 weeks treatment of ABRE slowed down the body weight gain and prevented the loss of bone mass induced by the OVX. The prevention effect on bone loss was due to altering the rate of bone remodeling, which could be inferred from the decreased level of bone turnover markers, such as serum alkaline phosphatase (ALP), osteocalcin (OC) and urinary deoxypyridinoline (DPD). The changes of urinary calcium and phosphorus excretion provided the same evidence. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. ConclusionsWe conclude that 16 weeks of ABRE treatment improve bone biomechanical quality through modifications of bone mineral density (BMD), and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis.

Bone remodeling surrounding primary teeth in skeletally immature dogs

To quantify remodeling in the bone surrounding fully erupted primary teeth and to compare bone remodeling in the primary and permanent dentitions. Two bone sections were obtained bilaterally from the maxilla and mandible of the primary molar region of approximately 5-month-old male beagle dogs. Histomorphometric methods were used to estimate the osteonal remodeling in the alveolar and basal regions of the tooth supporting bone. The following variables were calculated: mineral apposition rate (MAR, µm/d), mineralizing surface/bone surface (MS/BS, %), bone formation rate (BFR, %/y), and erosion surface/bone surface (ES/BS, %). Comparisons were made between jaws (maxilla vs mandible) and bone types (alveolar vs basal), and data analyzed by analysis of variance (ANOVA) and Tukey-Kramer tests. Remodeling (BFR) surrounding primary teeth was compared to existing data from bone surrounding permanent teeth. The mean and standard deviation BFR values (%/y) were as follows: mandibular alveolar, 44.10 (±26.89); maxillary alveolar, 3.54 (±3.57); mandibular basal, 22.65 (±14.65); and maxillary basal, 12.33 (±7.11). The mandibular BFR was significantly (P < .05) higher than the maxillary bone. The BFR of the alveolar bone of primary teeth was not significantly (P = .48) different from the alveolar bone supporting permanent teeth. The remodeling rate of alveolar bone in skeletally immature dogs was greater in the mandible than in the maxilla and remained unaltered between primary and permanent dentitions.

Does the cortical bone resorption rate change due to 90Sr-radiation exposure? Analysis of data from Techa Riverside residents

The Mayak Production Association released large amounts of (90)Sr into the Techa River (Southern Urals, Russia) with peak amounts in 1950-1951. Techa Riverside residents ingested an average of about 3,000 kBq of (90)Sr. The (90)Sr-body burden of approximately 15,000 individuals has been measured in the Urals Research Center for Radiation Medicine in 1974-1997 with use of a special whole-body counter (WBC). Strontium-90 had mainly deposited in the cortical part of the skeleton by 25 years following intake, and (90)Sr elimination occurs as a result of cortical bone resorption. The effect of (90)Sr-radiation exposure on the rate of cortical bone resorption was studied. Data on 2,022 WBC measurements were selected for 207 adult persons, who were measured three or more times before they were 50-55 years old. The individual-resorption rates were calculated with the rate of strontium recirculation evaluated as 0.0018 year(-1). Individual absorbed doses in red bone marrow (RBM) and bone surface (BS) were also calculated. Statistically significant negative relationships of cortical bone resorption rate were discovered related to (90)Sr-body burden and dose absorbed in the RBM or the BS. The response appears to have a threshold of about 1.5-Gy RBM dose. The radiation-induced decrease in bone resorption rate may not be significant in terms of health. However, a decrease in bone remodeling rate can be among several causes of an increased level of degenerative dystrophic bone pathology in exposed persons.

Modeling of biological doses and mechanical effects on bone transduction

Shear stress, hormones like parathyroid and mineral elements like calcium mediate the amplitude of stimulus signal, which affects the rate of bone remodeling. The current study investigates the theoretical effects of different metabolic doses in stimulus signal level on bone. The model was built considering the osteocyte as the sensing center mediated by coupled mechanical shear stress and some biological factors. The proposed enhanced model was developed based on previously published works dealing with different aspects of bone transduction. It describes the effects of physiological doses variations of calcium, parathyroid hormone, nitric oxide and prostaglandin E2 on the stimulus level sensed by osteocytes in response to applied shear stress generated by interstitial fluid flow. We retained the metabolic factors (parathyroid hormone, nitric oxide and prostaglandin E2) as parameters of bone cell mechanosensitivity because stimulation/inhibition of induced pathways stimulates osteogenic response in vivo. We then tested the model response in terms of stimulus signal variation versus the biological factors doses to external mechanical stimuli. Despite the limitations of the model, it is consistent and has physiological bases. Biological inputs are histologically measurable. This makes the model amenable to experimental verification.

Osteonic organization of limb bones in mammals, including humans, and birds: a preliminary study.

As it is well known, bone tissue is characterized by a calcified extracellular matrix which makes this tissue suitable to support the body and protect the inner organs. Lamellar bone tissue is organized in lamellae, 3-7 microm in thickness, and arranged concentrically around vascular channels: the basic structure in this type of organization is called Haversian system or osteon and the diameter of osteons depends on the number of lamellae. Shape and regional density of osteons are related to the bone segment and the specific functional requirements to meet. Aim of this study is to correlate the compact bone tissue microstructure in various classes of mammals, including humans, and birds in order to find an adequate identification key. The results of our study show that in bone tissue samples from various classes of mammals, including humans, and birds the osteonic structure shows peculiar features, often depending on the rate of bone remodelling, different in different animal species. We conclude that a careful microscopic analysis of bone tissue and the characterization of distinctive osteonic features could give a major contribution to forensic medicine to obtain a more reliable recognition of bone findings.

Radiocarbon analysis of dental enamel and bone to evaluate date of birth and death: Perspective from the southern hemisphere

Radiocarbon analysis was conducted on dental enamel, cortical bone and trabecular bone from four human adults from Andean Peru with known birth dates and death dates, the latter all falling within the modern bomb-curve period. Radiocarbon results were compared with known tropospheric values from the southern hemisphere. The results demonstrate that dental enamel can provide useful information regarding birth dates in consideration of known formation times of the specific teeth examined if the radiocarbon values fall within the modern bomb-curve period. Trabecular bone radiocarbon values are closer to the tropospheric values at the date of death than are values from cortical bone reflecting relative differences in the rate of bone remodeling in those tissues. Age at death also represents an important factor.

How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis

Oestrogen deficiency increases the rate of bone remodelling which, in association with a negative remodelling balance (resorption exceeding formation), results in impaired bone architecture, mass and strength. Current anti-osteoporotic drugs act on bone remodelling by inhibiting bone resorption or by promoting its formation. An alternative therapeutic approach is based on the concept of inducing opposite effects on bone resorption and formation. One therapeutic agent, strontium ranelate, was shown to induce opposite effects on bone resorption and formation in pre-clinical studies and to reduce fracture risk in postmenopausal osteoporotic patients. How strontium ranelate acts to improve bone strength in humans remains a matter of debate, however. This review of the most recent pre-clinical and clinical studies is a critical analysis of strontium ranelate's action on bone resorption and formation and how it increases bone mass, microarchitecture and strength in postmenopausal osteoporotic women.

Osteogenic Protein-1 Associated with Mesenchymal Stem Cells Promote Bone Allograft Integration

Limited incorporation and modest bone remodeling can cause allograft failure. We investigated whether mesenchymal stem cells (MSCs) and osteogenic protein-1 (OP-1) can improve allograft integration. A 3-cm full-size intercalary bone defect was created in the mid-diaphysis of the metatarsal bone of the sheep and it was replaced with an allograft alone (control group), or with MSCs (MSC group), OP-1 (OP-1 group), or MSCs and OP-1 (MSC + OP-1 group). Radiographic results showed a faster and complete integration of the allograft in the MSC + OP-1 group. Histology demonstrated that the amount of new bone was significantly greater inside the graft and a longer vessel penetration in the MSC + OP-1 group than in others. Mechanical strength of the allograft was not compromised by the high rate of bone remodeling. These results demonstrated that the association of MSCs and OP-1 improve bone allograft integration promoting an almost complete bone restoring.

Effect of Risedronate on Osteocyte Viability and Bone Turnover in Paired Iliac Bone Biopsies from Early Postmenopausal Women

It is unclear whether standard clinical doses of risedronate affect osteocyte viability. This study examined osteocyte viability and bone remodeling rate in early postmenopausal women (1-5 years after menopause) who were treated with a standard clinical dose of risedronate (5 mg/day, orally) for 1 year. Paired transiliac bone biopsies were obtained from 19 postmenopausal women at baseline and after 1-year treatment with placebo (n = 8, mean age 52.9 ± 3.4 years) or risedronate 5 mg/day (n = 11, mean age 52.5 ± 3.4 years). In these samples, we measured osteocyte- and bone remodeling-related variables in trabecular bone. In both the placebo and risedronate groups, empty lacunae were significantly decreased after 1-year treatment compared to baseline. There were no significant differences in osteocyte-related variables between placebo and risedronate. Risedronate significantly reduced bone-remodeling indices including mineralizing surface (MS/BS), bone formation rate (BFR/BS), and activation frequency (Ac.f). Risedronate treatment caused significantly lower MS/BS and Ac.f than placebo administration. In conclusion, risedronate 5 mg/day effectively inhibited bone remodeling but did not significantly reduce osteocyte viability in trabecular bone.

Parathyroid hormone and growth in chronic kidney disease

Growth failure is common in children with chronic kidney disease, and successful treatment is a major challenge in the management of these children. The aetiology is multi-factorial with "chronic kidney disease-metabolic bone disorder" being a key component that is particularly difficult to manage. Parathyroid hormone is at the centre of this mineral imbalance, consequent skeletal disease and, ultimately, growth failure. When other aetiologies are treated, good growth can be achieved throughout the course of the disease when parathyroid hormone (PTH) levels are in the normal range or slightly elevated. A direct correlation between PTH levels and growth has not been convincingly established, and the direct effect of PTH on growth has not been adequately described; furthermore, direct actions of PTH on the growth plate are unproven. The effects of PTH on growth stem from the pivotal role that PTH plays in the development of renal osteodystrophy. In severe secondary hyperparathyroidism, the growth plate is altered and growth is affected. At the other end of the spectrum, with an over-suppressed parathyroid gland, the rate of bone turnover and remodelling is markedly diminished, and some data suggest this is associated with poor growth. Most of the data available suggests that avoiding the development of significant bone disease through the strict control of PTH levels permits good growth. Absolute optimal ranges for PTH that maximise growth or minimise growth failure are not yet established.

Cytokine Expression and Accelerated Tooth Movement

It has been shown that inhibiting the expression of certain cytokines decreases the rate of tooth movement. Here, we hypothesized that stimulating the expression of inflammatory cytokines, through small perforations of cortical bone, increases the rate of bone remodeling and tooth movement. Forty-eight rats were divided into 4 groups: 50-cN force applied to the maxillary first molar (O), force application plus soft tissue flap (OF), force application plus flap plus 3 small perforations of the cortical plate (OFP), and a control group (C). From the 92 cytokines studied, the expression of 37 cytokines increased significantly in all experimental groups, with 21 cytokines showing the highest levels in the OFP group. After 28 days, micro-computed tomography, light and fluorescent microscopy, and immunohistochemistry demonstrated higher numbers of osteoclasts and bone remodeling activity in the OFP group, accompanied by generalized osteoporosity and increased rate of tooth movement.

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high-turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n = 11) and patients with renal osteodystrophy (ROD, n = 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate-to-amide I ratio (mineral-to-matrix ratio), carbonate-to-phosphate ratio, and carbonate-to-amide I ratio (turnover rate/remodeling activity), as well as the collagen cross-link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate-to-phosphate (p < .01) and carbonate-to-amide I (p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization (p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone-remodeling activity and number of bone cells and FTIRI-calculated parameters based on carbonate-to-phosphate and carbonate-to-amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone.