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issn:0171-967
1.  [No title available] 
PMCID: PMC3949118  PMID: 24077875
2.  Cellular complexity of the bone marrow hematopoietic stem cell niche 
Calcified tissue international  2013;94(1):112-124.
The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells every day. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices, which include quiescence, self-renewal, differentiation and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.
doi:10.1007/s00223-013-9805-8
PMCID: PMC3936515  PMID: 24101231
3.  Molecular Mechanisms of Osteoblast/Osteocyte Regulation by Connexin43 
Calcified tissue international  2013;94(1):55-67.
Osteoblasts, osteocytes and osteoprogenitor cells are interconnected into a functional network by gap junctions formed primarily by connexin43 (Cx43). Over the past two decades, it has become clear that Cx43 is important for the function of osteoblasts and osteocytes. This connexin contributes to the acquisition of peak bone mass and it is a major modulator of cortical modeling. We review key data from human and mouse genetics on the skeletal consequences of ablation or mutation of the Cx43 gene (Gja1), and the molecular mechanisms by which Cx43 regulates the differentiation, function and survival of osteogenic lineage cells. We also discuss putative second messengers that are communicated by Cx43 gap junctions, the role of hemichannels, and the function of Cx43 as a scaffold for signaling molecules. Current knowledge demonstrates that Cx43 is more than a passive channel; rather, it actively participates in generation and modulation of cellular signals driving skeletal development and homeostasis.
doi:10.1007/s00223-013-9742-6
PMCID: PMC3815501  PMID: 23754488
Cx43; gap junction; bone; signal transduction; Runx2; Osterix
4.  Control of Bone Remodeling by the Peripheral Sympathetic Nervous System 
Calcified tissue international  2013;94(1):140-151.
The skeleton is no longer seen as a static, isolated, and mostly structural organ. Over the last two decades, a more complete picture of the multiple functions of the skeleton has emerged, and its interactions with a growing number of apparently unrelated organs have become evident. The skeleton not only reacts to mechanical loading and inflammatory, hormonal, and mineral challenges, but also acts of its own accord by secreting factors controlling the function of other tissues, including the kidney and possibly the pancreas and gonads. It is thus becoming widely recognized that it is by nature an endocrine organ, in addition to a structural organ and site of mineral storage and hematopoiesis. Consequently and by definition, bone homeostasis must be tightly regulated and integrated with the biology of other organs to maintain whole body homeostasis, and data uncovering the involvement of the central nervous system (CNS) in the control of bone remodeling support this concept. The sympathetic nervous system (SNS) represents one of the main links between the CNS and the skeleton, based on a number of anatomic, pharmacologic, and genetic studies focused on β-adrenergic receptor (βAR) signaling in bone cells. The goal of this report was to review the data supporting the role of the SNS and βAR signaling in the regulation of skeletal homeostasis.
doi:10.1007/s00223-013-9752-4
PMCID: PMC3883940  PMID: 23765388
Bone turnover; Remodeling; Mouse genetics/transgenetics; Neurotransmitters; Signal transduction
5.  Osteocytes: Master Orchestrators of Bone 
Osteocytes comprise the overwhelming majority of cells in bone and are its only true “permanent” resident cell population. In recent years, conceptual and technological advances on many fronts have helped to clarify the role osteocytes play in skeletal metabolism and the mechanisms they use to perform them. The osteocyte is now recognized as a major orchestrator of skeletal activity, capable of sensing and integrating mechanical and chemical signals from their environment to regulate both bone formation and resorption. Recent studies have established that the mechanisms osteocytes use to sense stimuli and regulate effector cells (e.g. osteoblasts and osteoclasts) are directly coupled to the environment they inhabit – entombed within the mineralized matrix of bone and connected to each other in multicellular networks. Communication within these networks is both direct (via cell-cell contacts at gap junctions) and indirect (via paracrine signaling by secreted signals). Moreover, the movement of paracrine signals is dependent on movement of both solutes and fluid through the space immediately surrounding the osteocytes (i.e. the Lacunar-Canalicular System, LCS). Finally, recent studies have also shown that the regulatory capabilities of osteocytes extend beyond bone to include a role in endocrine control of systemic phosphate metabolism. This review will discuss how a highly productive combination of experimental and theoretical approaches has managed to unearth these unique features of osteocytes and bring to light novel insights into the regulatory mechanisms operating in bone.
doi:10.1007/s00223-013-9790-y
PMCID: PMC3947191  PMID: 24042263
Osteocytes; Biomechanics; Mechanotransduction; Intercellular communication
6.  Notch signaling in Skeletal Stem Cells 
Calcified tissue international  2013;94(1):68-77.
The skeleton is originated from stem cells residing in the sclerotome and neural crest that undergo proliferation, migration and commitment. The development of the skeletal stem cells is influenced by many signaling pathways that govern cell fate determination, proliferation, differentiation and apoptosis. This review will focus on Notch signaling functions in regulating different cells types forming the skeletal system as well as the interplay between them to maintain homeostasis. Osteochondroprogenitors require Notch signaling to maintain the multipotency and to prevent from premature differentiation into osteoblast. Subsequently, over-activation of Notch signaling suppresses osteoblast maturation. Moreover, Notch signaling in osteochondroprogenitors is required for chondrocyte proliferation, hypertrophy and suppresses terminal differentiation. Translational studies demonstrated a crucial role of Notch signaling in osteosarcoma and osteoarthritis, where concepts derived from developmental pathways are often recapitulated. This brings hope of taking advantages of the molecular mechanisms learned from development to approach the pathological processes underlying abnormal bone/cartilage metabolism or tumorigenesis. Pharmacological agents that target Notch receptors or ligands in a tissue specific fashion would offer new opportunities for treating bone/cartilage diseases caused by dysregulation of Notch signaling.
doi:10.1007/s00223-013-9773-z
PMCID: PMC3947214  PMID: 23963632
Notch signaling; osteoblast differentiation; chondrogenesis; osteoclastogenesis
7.  Osteocyte-Driven Bone Remodeling 
Calcified tissue international  2013;94(1):25-34.
Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and it is downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet to be identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone resorbing osteoclasts. Osteocytes are also the source of molecules that regulate generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function, or to altered expression of either molecule in osteocytes, markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling.
doi:10.1007/s00223-013-9774-y
PMCID: PMC3947228  PMID: 24002178
osteocyte; osteoclast; osteoblast; bone remodeling; RANKL; OPG; Sost
8.  Inflammation, telomere length and grip strength: a 10 year longitudinal study 
Calcified tissue international  2014;95(1):54-63.
Background
Telomere attrition has been associated with age related diseases although causality is unclear and controversial; low grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between ageing, telomere length (TL) and inflammaging is hence essential to the understanding of ageing and management of age-related diseases. This longitudinal study explores whether telomere attrition is a cause or consequence of ageing and whether inflammaging explains some of the associations between TL and one marker of ageing, grip strength.
Methods
We studied 253 Hertfordshire Ageing Study participants at baseline and 10 year follow up (mean age at baseline 67.1years). Participants completed a health questionnaire and had blood samples collected for immune-endocrine and telomere analysis at both time points. Physical ageing was characterised at follow-up using grip strength (GS).
Findings
Faster telomere attrition was associated with lower GS at follow-up (β=0.98, p=0.035). This association was completely attenuated when adjusted for inflammaging burden (p=0.86) over the same period. Similarly, greater inflammaging burden was associated with lower GS at follow-up (e.g. interleukin1β (IL-1β): β=−2.18, p=0.001), however, these associations were maintained when adjusted for telomere attrition (IL-1β, p=0.006).
Interpretation
We present evidence that inflammaging may be driving telomere attrition and in-part explains the associations which have previously been reported between TL and grip strength. Thus biomarkers of physical ageing, such as inflammaging, may require greater exploration. Further work is now indicated.
doi:10.1007/s00223-014-9862-7
PMCID: PMC4098723  PMID: 24858709
Telomere; epidemiology; sarcopenia; inflammation; ageing; osteoporosis; grip strength
9.  Cadherin-Mediated Cell-Cell Adhesion and Signaling in the Skeleton 
Calcified tissue international  2013;94(1):46-54.
Direct cell-to-cell interactions via cell adhesion molecules, in particular cadherins, are critical for morphogenesis, tissue architecture, and cell sorting and differentiation. Partially overlapping, yet distinct roles of N-cadherin (cadherin-2) and cadherin-11 in the skeletal system have emerged from mouse genetics and in vitro studies. Both cadherins are important for precursor commitment to the osteogenic lineage, and genetic ablation of Cdh2 and Cdh11 results in skeletal growth defects and impaired bone formation. While Cdh11 defines the osteogenic lineage, persistence of Cdh2 in osteoblasts in vivo actually inhibits their terminal differentiation and impairs bone formation. The action of cadherins involves both cell-cell adhesion and interference with intracellular signaling, and in particular the Wnt/β-catenin pathway. Both cadherin-2 and cadherin-11 bind to β-catenin, thus modulating its cytoplasmic pools and transcriptional activity. Recent data demonstrate that cadherin-2 also interferes with Lrp5/6 signaling by sequestering these receptors in inactive pools via axin binding. These data extend the biologic action of cadherins in bone forming cells, and provide novel mechanisms for development of therapeutic strategies aimed at enhancing bone formation.
doi:10.1007/s00223-013-9733-7
PMCID: PMC4272239  PMID: 23657489
Cadherins; cell-cell adhesion; osteoblast differentiation; Wnt/β-catenin signaling; bone formation
10.  1,25(OH)2D3 Induces a Mineralization Defect and Loss of Bone Mineral Density in Genetic Hypercalciuric Stone-Forming Rats 
Calcified tissue international  2014;94(5):531-543.
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 (VDR) 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 (12.5 (LD) or 25 (HD) ng/100 g body wt/d) or vehicle (veh) daily for 16d. 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 3-fold 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 indicates that the increased VDR are biologically active.
doi:10.1007/s00223-014-9838-7
PMCID: PMC4276134  PMID: 24481706
vitamin D; calcium; reabsorption; bone quality
11.  Increased Bone Mineral Density with Monthly Intravenous Ibandronate Contributes to Fracture Risk Reduction in Patients with Primary Osteoporosis: Three-Year Analysis of the MOVER Study 
Calcified Tissue International  2014;95(6):557-563.
The relationship between gains in bone mineral density (BMD) in the hip and the incidence of vertebral fractures in the MOVER study was examined. Japanese patients from the ibandronate and risedronate treatment groups whose hip BMD had increased during the 3-year treatment period were classified into those with or without vertebral fractures. In both the ibandronate group and the risedronate group, hip BMD gains in the patients who had developed no vertebral fractures during the treatment period were greater than in the patients who developed vertebral fractures. We categorized the gains in hip BMD at 6 months into 3 groups (≤0, >0 to ≤3, and >3 %), and used logistic regression analysis to estimate odds ratios and the probabilities of incidence of vertebral fractures at 12, 24, and 36 months. The current study demonstrated that greater gains in hip BMD during the first 6 months of treatment were associated with a reduction in the risk of subsequent vertebral fractures during the duration of treatment, and suggested that measurement of hip BMD gain at that time could lead to a prediction of the risk of the future vertebral fracture incidence.
doi:10.1007/s00223-014-9927-7
PMCID: PMC4239781  PMID: 25377907
Ibandronate; Vertebral fracture; Hip BMD change; Osteoporosis; MOVER study
12.  Efficacy of reversal of aortic calcification by chelating agents 
Calcified tissue international  2013;93(5):10.1007/s00223-013-9780-0.
Elastin specific medial vascular calcification, termed Monckeberg’s sclerosis has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA) and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium (Ca) from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly (lactic-co-glycolic acid) (PLGA) nanoparticles regressed elastin specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.
doi:10.1007/s00223-013-9780-0
PMCID: PMC3809012  PMID: 23963635
Elastin; Demineralization; Calcium; Arteriosclerosis; Chelating complexes
13.  The Role of Phosphatases in the Initiation of Skeletal Mineralization 
Calcified tissue international  2012;93(4):299-306.
Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene cause hypophosphatasia, a heritable form of rickets and osteomalacia, caused by an arrest in the propagation of hydroxyapatite (HA) crystals onto the collagenous extracellular matrix due to accumulation of extracellular inorganic pyrophosphate (PPi), a physiological TNAP substrate and a potent calcification inhibitor. However, TNAP knockout (Alpl−/−) mice are born with a mineralized skeleton and have HA crystals in their chondrocyte- and osteoblast-derived matrix vesicles (MVs). We have shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHOSPHO1 and TNAP have nonredundant functional roles during endochondral ossification. Double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality, despite normal systemic phosphate and calcium levels. This strongly suggests that the Pi needed for initiation of MV-mediated mineralization is produced locally in the perivesicular space. As both TNAP and nucleoside pyrophosphohydrolase-1 (NPP1) behave as potent ATPases and pyrophosphatases in the MV compartment, our current model of the mechanisms of skeletal mineralization implicate intravesicular PHOS-PHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP and NPP1 in the extravesicular progression of mineralization.
doi:10.1007/s00223-012-9672-8
PMCID: PMC3594124  PMID: 23183786
Biomineralization; Bone and cartilage development; Metabolic bone disease; Animal model
14.  The Relation between Bone and Stone Formation 
Calcified tissue international  2012;93(4):374-381.
Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total body calcium. The source of this additional urine calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD) which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover, as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone we utilized our genetic hypercalciuric stone-forming (GHS) rats which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and their bones are more fracture prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve bone health of patients with kidney stones.
doi:10.1007/s00223-012-9686-2
PMCID: PMC3625692  PMID: 23247537
nephrolithiasis; hypercalciuria; bone density
15.  Vascular Calcification: an Update on Mechanisms and Challenges in Treatment 
Calcified tissue international  2013;93(4):365-373.
Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a non-occlusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification will also be reviewed.
doi:10.1007/s00223-013-9712-z
PMCID: PMC3714357  PMID: 23456027
Vascular calcification; Treatments; MicroRNA; Osteoclasts; RANK/RANKL/OPG; Osteoporosis
16.  Biomineralization Mechanisms: A new paradigm for crystal nucleation in organic matricies 
Calcified tissue international  2012;93(4):307-315.
There is substantial practical interest in the mechanism by which the carbonated apatite of bone mineral can be initiated specifically in a matrix. The current literature is replete with studies aimed at mimicking the properties of vertebrate bone, teeth and other hard tissues by creating organic matrices that can be mineralized in vitro, and either functionally substitute for bone on a permanent basis, or serve as a temporary structure that can be replaced by normal remodeling processes. A key element in this is mineralization of an implant with the matrix and mineral disposed in the proper orientations and relationships. This review examines the pathway to crystallization from a supersaturated calcium phosphate solution in vitro, focusing on the basic mechanistic questions concerning mineral nucleation and growth. Since bone and dentin mineral forms within collagenous matricies we consider how the in vitro crystallization mechanisms might or might not be applicable to understanding the in vivo processes of biomineralization in bone and dentin. We propose that the pathway to crystallization from the calcium phosphate supersaturated tissue fluids involves the formation of a dense liquid phase of first-layer bound-water hydrated calcium and phosphate ions in which the crystallization is nucleated. SIBLING proteins and their in vitro analogs such as polyaspartic acids, have similar dense liquid first-layer bound water surfaces which interact with the dense liquid calcium phosphate nucleation clusters and modulate the rate of crystallization within the bone and dentin collagen fibril matrix.
doi:10.1007/s00223-012-9678-2
PMCID: PMC3726565  PMID: 23241924
17.  Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta 
Calcified tissue international  2013;93(4):338-347.
Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90% of OI cases. Since then a growing list of mutant genes causing the 5–10% of recessive cases has rapidly emerged. They include CRTAP, LEPRE1 and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode respectively lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPIN H1, which encodes the collagen chaperone HSP47; SERPIN F1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include over-mineralization or under-mineralization defects as well as abnormal collagen post-translational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen.
These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen post-translational modification, chaperoning of newly synthesized collagen chains into native molecules or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on post-translational features of bone collagen that have evolved to optimize it as a biomineral template.
doi:10.1007/s00223-013-9723-9
PMCID: PMC3758449  PMID: 23508630
Collagen; Bone; Cross-Linking; Osteogenesis Imperfecta; Post-Translational modifications
18.  Evaluation of Compressive Strength Index of the Femoral Neck in Caucasians and Chinese 
Calcified tissue international  2010;87(4):324-332.
Compressive strength index (CSI) of the femoral neck is a parameter that integrates the information of bone mineral density (BMD), femoral neck width (FNW), and body weight. CSI is considered to have the potential to improve the performance of assessment for hip fracture risk. However, studies on CSI have been rare. In particular, few studies have evaluated the performance of CSI, in comparison with BMD, FNW, and bending geometry, for assessment of hip fracture risk. We studied two large populations, including 1683 unrelated U.S. Caucasians and 2758 unrelated Chinese adults. For all the study subjects, CSI, femoral neck BMD (FN_BMD), FNW, and bending geometry (section modulus [Z]) of the samples were obtained from dual-energy X-ray absorptiometry scans. We investigated the age-related trends of these bone phenotypes and potential sex and ethnic differences. We further evaluated the performance of these four phenotypes for assessment of hip fracture risk by logistic regression models. Chinese had significantly lower FN_BMD, FNW, and Z, but higher CSI than sex-matched Caucasians. Logistic regression analysis showed that higher CSI was significantly associated with lower risk of hip fracture, and the significance remained after adjusting for covariates of age, sex, and height. Each standard deviation (SD) increment in CSI was associated with odds ratios of 0.765 (95% confidence interval, 0.634, 0.992) and 0.724 (95% confidence interval, 0.569, 0.921) for hip fracture risk in Caucasians and Chinese, respectively. The higher CSI in Chinese may partially help explain the lower incidence of hip fractures in this population compared to Caucasians. Further studies in larger cohorts and/or longitudinal observations are necessary to confirm our findings.
doi:10.1007/s00223-010-9406-8
PMCID: PMC4176885  PMID: 20814670
Osteoporosis; Bone mineral density; Compressive strength index; Femoral neck width; Section modulus; Hip fracture
19.  91 Osteoporosis Patients Affected with Bisphosphonate Related Osteonecrosis of the Jaw: A Case Series 
Calcified tissue international  2013;93(3):241-248.
PURPOSE
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents with necrotic bone in the mouth in the setting of bisphosphonate (BP) exposure. It has been studied in cancer patients taking high-dose BP, but BRONJ has also been noted in patients taking lower dose BP for osteoporosis. The purpose of this study is to characterize the phenotypes and outcomes in a large series of patients with osteoporosis and BRONJ in the setting of BP exposure.
METHODS
The investigators conducted a retrospective case series. The sample was composed of subjects with BRONJ and osteoporosis. Subjects with a history of BP treatment for myeloma or metastatic cancer to the bones were excluded. Descriptive statistics were computed for the study variables.
RESULTS
Ninety one cases of BRONJ met the inclusion criteria. Subjects had a median age of 71 years and were predominately female (94.5%). The median time of BP exposure was 60 months and ranged from 2 to 120 months. Most subjects were treated with alendronate (82.4%). The mandible was involved more frequently (58.2%) than the maxilla (37.3%). Subjects commonly (65.9%) but not universally reported pain. For subjects with treatment outcome data (n = 40), most reported improvement (80.0%).
CONCLUSION
Although BRONJ is an uncommon condition, the absolute number of cases is fairly large due to the very large number of patients taking BPs for osteoporosis. The findings of this study confirm that BRONJ primarily affects the mandible, a substantial minority present without pain and that patients typically improve with treatment.
doi:10.1007/s00223-013-9747-1
PMCID: PMC3744621  PMID: 23756612
Osteoporosis; bisphosphonate; osteonecrosis of the jaw; risk factors
20.  Adaptation of Tibial Structure and Strength to Axial Compression Depends on Loading-History in Both C57BL/6 and BALB/C Mice 
Calcified tissue international  2013;93(3):211-221.
Tibial compression can increase murine bone mass. However, loading protocols and mouse strains differ between studies which may contribute to conflicting results. We hypothesized that bone accrual is influenced more by loading history than by mouse strain or animal handling. The right tibiae of 4-month C57BL/6 and BALB/c mice were subjected to axial compression (10 N, 3 days/week, 6 weeks). Left tibiae served as contralateral controls to calculate relative changes [(Loaded-Control)/Control]. The WashU protocol applied 60 cycles/day, at 2 Hz, with 10 s rest-insertion between cycles; the Cornell/HSS protocol applied 1200 cycles/day, at 6.7 Hz, with 0.1 s rest-insertion. Because sham loading, sedation and transportation did not affect tibial morphology, unhandled mice served as age-matched controls (AC). Both loading protocols were anabolic for cortical bone, but Cornell/HSS loading elicited a more rapid response that was greater than WashU loading by 13%. By 6 weeks, cortical bone volume of each loading group was greater than of AC (avg. +16%) and not different from each other. Ultimate displacement and energy-to-fracture were greater in tibiae loaded by either protocol and ultimate force was greater with Cornell/HSS loading. At 6 weeks, independent of mouse strain, the WashU protocol produced minimal trabecular bone and the trabecular bone volume fraction of Cornell/HSS tibiae was greater than of AC by 65% and of WashU by 44%. We concluded that tibial adaptation to loading was more influenced by waveform than mouse strain or animal handling and therefore may have targeted similar osteogenic mechanisms in C57BL/6 and BALB/c mice.
doi:10.1007/s00223-013-9744-4
PMCID: PMC3748612  PMID: 23708853
Biomechanics; Bone Architecture/Structure; Mechanical Loading; Exercise; Bone Strength
21.  Interactions Between B Lymphocytes and the Osteoblast Lineage in Bone Marrow 
Calcified tissue international  2013;93(3):261-268.
The regulatory effects of the immune system on the skeleton during homeostasis and activation have been appreciated for years. In the past decade it has become evident that bone tissue can also regulate immune cell development. In the bone marrow, the differentiation of hematopoietic progenitors requires specific microenvironments, called niches, provided by various subsets of stromal cells, many of which are of mesenchymal origin. Among these stromal cell populations, cells of the osteoblast lineage serve a supportive function in the maintenance of normal hematopoiesis, and B lymphopoiesis in particular. Within the osteoblast lineage, distinct differentiation stages exert differential regulatory effects on hematopoietic development. In this review we will highlight the critical role of osteoblast progenitors in the perivascular B lymphocyte niche.
doi:10.1007/s00223-013-9753-3
PMCID: PMC3762579  PMID: 23839529
22.  Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia 
Calcified tissue international  2013;93(2):155-162.
X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which increase circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Since XLH is a dominant disease, one mutant allele is sufficient for manifestation of the disease. However, dosage effect of a PHEX mutation in XLH is not completely understood. To examine the effect of Phex genotypes, we compared serum biochemistries and skeletal measures between all five possible genotypes of a new murine model of XLH (PhexK496X or PhexJrt). Compared to sex-matched littermate controls, all Phex mutant mice had hypophosphatemia, mild hypocalcemia, and increased parathyroid hormone and alkaline phosphatase levels. Furthermore, mutant mice had markedly elevated serum Fgf23 levels due to increased Fgf23 expression and reduced cleavage of Fgf23. Although females with a homozygous Phex mutation were slightly more hypocalcemic and hypophosphatemic than heterozygous females, the two groups had comparable intact Fgf23 levels. Similarly, there was no difference in intact Fgf23 or phosphorus concentrations between hemizygous males and heterozygous females. Compared to heterozygous females, homozygous counterparts were significantly smaller and had shorter femurs with reduced bone mineral density, suggesting the existence of dosage effect in the skeletal phenotype of XLH. However, overall phenotypic trends in regards to mineral ion homeostasis were mostly unaffected by the presence of one or two mutant Phex allele(s). The lack of gene dosage effect on circulating Fgf23 (and thus, phosphorus) levels suggests that a Phex mutation may create the lower set point for extracellular phosphate concentrations.
doi:10.1007/s00223-013-9736-4
PMCID: PMC3742319  PMID: 23700148
gene dosage effect; Fgf23; phosphate; Phex; X-linked hypophosphatemia
23.  Obesity, Healthcare Utilization and Health-Related Quality of Life after Fracture in Postmenopausal Women: Global Longitudinal Study of Osteoporosis in Women (GLOW) 
Calcified tissue international  2014;94(2):223-231.
Fractures in obese postmenopausal women may be associated with higher morbidity than in non-obese women. We aimed to compare healthcare utilization, functional status, and health-related quality of life (HRQL) in obese, non-obese and underweight women with fractures. Information from GLOW, started in 2006, was collected at baseline and at 1, 2 and 3 years. In this subanalysis, self-reported incident clinical fractures, healthcare utilization, HRQL and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 non-obese and 941 obese women with ≥1 incident clinical fracture during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities and fracture type, was significantly greater in obese than non-obese women (6 vs. 5 days, P = 0.017). Physical function and vitality score were significantly worse in obese than in non-obese women, both before and after fracture, but changes after fracture were similar across groups. Use of anti-osteoporosis medication was significantly lower in obese than in non-obese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than non-obese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.
doi:10.1007/s00223-013-9801-z
PMCID: PMC3917823  PMID: 24077896
Fractures; Healthcare utilization; Functional status; Quality of life; Obesity
24.  Impact of Dietary Aromatic Amino Acids on Osteoclastic Activity 
Calcified Tissue International  2014;95(2):174-182.
We had shown that aromatic amino acid (phenylalanine, tyrosine, and tryptophan) supplementation prevented bone loss in an aging C57BL/6 mice model. In vivo results from the markers of bone breakdown suggested an inhibition of osteoclastic activity or differentiation. To assess osteoclastic differentiation, we examined the effects of aromatic amino acids on early /structural markers as vitronectin receptor, calcitonin receptor, and carbonic anhydrase II as well as, late/functional differentiation markers; cathepsin K and matrix metalloproteinase 9 (MMP-9). Our data demonstrate that the aromatic amino acids down-regulated early and late osteoclastic differentiation markers as measured by real time PCR. Our data also suggest a link between the vitronectin receptor and the secreted cathepsin K that both showed consistent effects to the aromatic amino acid treatment. However, the non-attachment related proteins, calcitonin receptor, and carbonic anhydrase II, demonstrated less consistent effects in response to treatment. Our data are consistent with aromatic amino acids down-regulating osteoclastic differentiation by suppressing remodeling gene expression thus contributing initially to the net increase in bone mass seen in vivo.
doi:10.1007/s00223-014-9878-z
PMCID: PMC4104004  PMID: 25000990
Osteoclast; Amino acids; Cathepsin K; Carbonic anhydrase II; Calcitonin receptor
25.  Influence of lifestyle factors on quantitative heel ultrasound measurements in middle-aged and elderly men 
Calcified tissue international  2010;86(3):211-219.
We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men, and looked at the influence of lifestyle factors on the occurrence of these parameters.
Men aged between 40 and 79 years were recruited from eight European centres and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance and quantitative ultrasound (QUS) of the calcaneus (Hologic - SAHARA). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, centre and weight.
3,258 men, mean age 60.0 years were included in the analysis. A higher PASE score (upper vs lower tertile) was associated with higher BUA (β coefficient = 2.44 dB/Mhz), SOS (β coefficient = 6.83 m/s) and QUI (β coefficient = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (β coeff =3.71 dB/Mhz), SOS (β coeff = 6.97 m/s) and QUI (β coeff = 4.50). A longer time to walk 50 feet was linked with lower BUA (β coeff = −0.62 dB/Mhz), SOS (β coeff = −1.06 m/s) and QUI (β coeff = −0.69). Smoking was associated with a reduction in BUA, SOS and QUI. There was a U shaped association with frequency of alcohol consumption.
Modification of lifestyle, including increasing physical activity and stopping smoking may help optimise bone strength and reduce the risk of fracture in middle aged and elderly European men.
PMCID: PMC4080706  PMID: 20205346
Epidemiology; Ultrasound; Bone mineral density; Risk factors; Exercise

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