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Osteoporosis is a metabolic bone disease with low bone mineral density (BMD) and high incidence of vertebral fractures (VFs). Postmenopausal women with osteoporosis have decreased total fat and lean mass. This study aimed to investigate the associations between body composition and VF risk and explore the potential predictor of VF risk in postmenopausal women. Enrolled 731 postmenopausal women were referred by various departments and outpatient clinics to assess vertebral status between October 2016 and November 2017. The main measures were total body lean mass, fat mass, and BMD. Patients were divided into osteopenia, osteoporosis, and normal groups based on T-scores. Logistic regression analyses were performed to evaluate associations between body composition parameters and VF. VF was significantly associated with increased age, lower height, and lighter weight in all participants, and higher BMI was observed in VF participants. Participants in the osteoporosis group were older and had lower height, weight, and BMD than those in normal and osteopenia groups. Femoral and total hip T-scores as well as T-scores for lumbar spine were significantly lower in participants with VF than in non-VF participants. Percentage of bone mass was also significantly lower in VF participants compared to that of non-VF participants. Women with increased BMD and lower bone mass had reduced odds for VF occurrence. Bone mass was significantly able to identify VF occurrence. Body composition analysis discerns differences in the bone status of postmenopausal women with and without VF. The cutoff value of the bone mass might be used effectively as an indicator of risk for VF occurrence.

Light chain (AL) amyloidosis is the result of a clonal plasma cell disorder which causes organ damage by deposition of misfolded light chains. Kidney is a common site of amyloid deposition. Proteinuria, usually in nephrotic range and unexplained renal insufficiency are the main manifestations of renal injury. We report a unique case of renal involvement by AL amyloidosis masquerading as metabolic bone disease. 38 year old male patient presented with progressively increasing diffuse bony pains, low backache and proximal weakness of both lower limbs since two years. On investigation, he was detected to have hypophosphatemic osteomalacia due to renal phosphate loss which was fibroblast growth factor 23 (FGF23)- independent. He also had nephrotic range low molecular weight proteinuria. Renal biopsy to ascertain the aetiology revealed deposition of amyloid fibrils in the glomerular mesangium on electron microscopy. Its characterization by immunofluorescence (IF) was consistent with immunoglobulin light chain (AL) amyloidosis. In the absence of a demonstrable plasma cell clone on bone marrow biopsy, we made a diagnosis of monoclonal gammopathy of renal significance (MGRS). He was treated with chemotherapy following which there was symptomatic improvement and reduction in phosphaturia. This case describes a unique presentation of renal injury due to AL amyloidosis masquerading as hypophosphatemic osteomalacia. The aim of this report is to highlight that hypophosphatemia in adults is usually acquired and treatment of underlying etiology results in cure, unlike in children where genetic counseling and phosphate replacement is the mainstay of treatment.

Osteoporosis is a metabolic bone disease with a high prevalence that affects the population worldwide, particularly the elderly. It is often due to fractures associated with bone fragility that the diagnosis of osteoporosis becomes clinically evident. However, early diagnosis would be necessary to initiate therapy and to prevent occurrence of further fractures, thus reducing morbidity and mortality. X-ray-based imaging plays a key role for fracture risk assessment and monitoring of osteoporosis. Whereas over decades dual-energy X-ray absorptiometry (DXA) has been the main method used and still reflects the reference standard, another modality reemerges with quantitative computed tomography (QCT) because of its three-dimensional advantages and the opportunistic exploitation of routine CT scans. Against this background, this article intends to review and evaluate recent advances in the field of X-ray-based quantitative imaging of osteoporosis at the spine. First, standard DXA with the recent addition of trabecular bone score (TBS) is presented. Secondly, standard QCT, dual-energy BMD quantification, and opportunistic BMD screening in non-dedicated CT exams are discussed. Lastly, finite element analysis and microstructural parameter analysis are reviewed.

We describe a novel disease of diffuse skeletal histiocytosis associated with multiple fragility fractures and high osteoclast activity. Clinical, radiographic, biochemical, genetic, and histopathological investigations were performed to characterize the diagnosis of an Asian man who presented with hip fracture and diffuse skeletal lytic lesions. After excluding malignancy and other common metabolic bone diseases, open bone biopsy yielded several pathological samples all showing extensive skeletal histiocytosis likely to explain the diffuse axial and appendicular lytic lesions. Rare disorders such as Langerhans histiocytosis, Erdheim-Chester disease, and diffuse cystic skeletal angiomatosis were excluded through careful pathological examination and lack of CD1a and S-100 staining. Whole exome sequencing did not yield diagnostic findings to explain this likely acquired disease. High markers of osteoclast activity suggested excessive focal bone resorption but normalized after zoledronic acid treatment. A novel disease of skeletal histiocytosis with high bone turnover is differentiated from other histiocytic and lytic skeletal diseases.

To scan novel candidate genes associated with osteoporosis, a two-stage transcriptome-wide association study (TWAS) of bone mineral density (BMD) was conducted. The BMD-associated genes identified by TWAS were then compared with the gene expression profiling of BMD in bone cells, B cells, and mesenchymal stem cells. We identified multiple candidate genes and gene ontology (GO) terms associated with BMD. Osteoporosis (OP) is a metabolic bone disease characterized by decrease in BMD. Our objective is to scan novel candidate genes associated with OP. A transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study (GWAS) summary of bone mineral density (BMD) with two pre-computed mRNA expression weights of peripheral blood and muscle skeleton. Then, another independent GWAS data of BMD was used to verify the discovery results. The BMD-associated genes identified between discovery and replicate TWAS were further subjected to gene ontology (GO) analysis implemented by DAVID. Finally, the BMD-associated genes and GO terms were further compared with the mRNA expression profiling results of BMD to detect the common genes and GO terms shared by both DNA-level TWAS and mRNA expression profile analysis. TWAS identified 95 common genes with permutation P value

Postmenopausal osteoporosis is a major health problem with important genetic factors in postmenopausal women. We explored the relationship between SQRDL and osteoporosis in a cohort of 1006 patients and 2027 controls from Han Chinese postmenopausal women. Our evidence supported the significant role of SQRDL in the etiology of postmenopausal osteoporosis. Postmenopausal osteoporosis (PMOP) is a metabolic bone disease leading to progressive bone loss and the deterioration of the bone microarchitecture. The sulfide-quinone reductase-like protein is an important enzyme regulating the cellular hydrogen sulfide levels, and it can regulate bone metabolism balance in postmenopausal women. In this study, we aimed to investigate whether SQRDL is associated with susceptibility to PMOP in the Han Chinese population. A total of 3033 postmenopausal women, comprised of 1006 cases and 2027 controls, were recruited in the study. Twenty-two SNPs were selected for genotyping to evaluate the association of SQRDL gene with BMD and PMOP. Association analyses in both single marker and haplotype levels were performed for PMOP. Bone mineral density (BMD) was also utilized as a quantitative phenotype in further analyses. Bioinformatics tools were applied to predict the functional consequences of targeted polymorphisms in SQRDL. The SNP rs1044032 (P = 6.42 × 10−5, OR = 0.80) was identified as significantly associated with PMOP. Three SNPs (rs1044032, rs2028589, and rs12913151) were found to be significantly associated with BMD. Although limited functional significance can be obtained for these polymorphisms, significant hits for association with PMOP were found. Moreover, further association analyses with BMD identified three SNPs with significantly independent effects. Our evidence supported the significant role of SQRDL in the etiology of PMOP and suggest that it may be a genetic risk factor for BMD and osteoporosis in Han Chinese postmenopausal women.

In this study, label-free-based quantitative subcellular proteomics integrated with network analysis highlighted several candidate genes including P4HB, ITGB1, CD36, and ACTN1 that may be involved in osteoporosis. All of them are predicted as significant membrane proteins with high confidence and enriched in bone-related biological process. The results were further verified in transcriptomic and genomic levels. Osteoporosis is a metabolic bone disease mainly characterized by low bone mineral density (BMD). As the precursors of osteoclasts, peripheral blood monocytes (PBMs) are supported to be important candidates for identifying genes related to osteoporosis. We performed subcellular proteomics study to identify significant membrane proteins that involved in osteoporosis. To investigate the association between monocytes, membrane proteins, and osteoporosis, we performed label-free quantitative subcellular proteomics in 59 male subjects with discordant BMD levels, with 30 high vs. 29 low BMD subjects. Subsequently, we performed integrated gene enrichment analysis, functional annotation, and pathway and network analysis based on multiple bioinformatics tools. A total of 1070 membrane proteins were identified and quantified. By comparing the proteins’ expression level, we found 36 proteins that were differentially expressed between high and low BMD groups. Protein localization prediction supported the notion that the differentially expressed proteins, P4HB (p = 0.0021), CD36 (p = 0.0104), ACTN1 (p = 0.0381), and ITGB1 (p = 0.0385), are significant membrane proteins. Functional annotation and pathway and network analysis highlighted that P4HB, ITGB1, CD36, and ACTN1 are enriched in osteoporosis-related pathways and terms including “ECM-receptor interaction,” “calcium ion binding,” “leukocyte transendothelial migration,” and “reduction of cytosolic calcium levels.” Results from transcriptomic and genomic levels provided additional supporting evidences. Our study strongly supports the significance of the genes P4HB, ITGB1, CD36, and ACTN1 to the etiology of osteoporosis risk.

Osteomalacia, a metabolic bone disease characterized by the inability to mineralize new osteoid, can be caused by vitamin D deficiency. We report a patient with symptomatic, biochemical, and imaging evidence of osteomalacia due to vitamin D deficiency, who as a result of work up for bone disease was diagnosed with early primary biliary cirrhosis. Osteomalacia was treated with high-dose vitamin D and serial bone density scans showed evidence of increasing bone mineral density suggesting osteoid mineralization in response to treatment. The diagnosis of cholestatic liver disease should be considered in all patients presenting with osteomalacia due to vitamin D deficiency, particularly if other cholestatic liver enzymes are elevated in addition to alkaline phosphatase.

The reference values for bone turnover markers (BTMs) have a significant role in the diagnosis, monitoring, and treatment of metabolic bone disease. This study proposes that the peak value of bone mineral density and the trough value for the BTM curve can be used to determine the reference range of BTM. The aim of this study is to determine the reference intervals of BTMs for adult females in China with an attempt to reference the peak bone mineral density (BMD) with the corresponding BTM valley. This study included 546 premenopausal and 394 postmenopausal women. The levels of several BTMs were determined, and the BMD was measured using a dual-energy X-ray absorptiometry. The BTMs of postmenopausal women were 17–96 % higher than premenopausal women. The change of BTM with age presented an optimal goodness-of-fit according to the cubic regression model (R 2 = 0.074–0.346, all P = 0.000). All kinds of BTM levels were positively correlated with age in premenopausal women aged 27–56 years old (r = 0.167–0.502, P = 0.023–0.000). Except for uCTX, the BTM reference value determined using a curve-fitting valley was significantly lower than the reference values for premenopausal women. The BTM reference values determined in this study were also significantly different from the reference values given by the manufacturers of the reagents used. This study found that the changes of level with age of BTMs in Chinese women present an optimal goodness-of-fit according to the cubic regression model. The fitting valley corresponds to the BMD fitting peak and may possibly be an effective means of determining the BTM reference intervals.

Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AED). Many studies have reported that AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment, and the pathogenesis of AED-associated fractures. Deficits in bone mineral density (BMD) are widely reported in AED-treated patient populations. However, much of the research conducted to date has been limited by factors such as small sample size, potentially biased subject selection, a lack of selection of appropriate control data, and failure to take account of important confounding influences. The pathogenesis of AED-associated fractures is likely to be multifactorial, due to factors including reduced BMD, impaired bone quality (due to osteoporosis and/or osteomalacia), increased propensity to fall, and fractures associated with seizures or loss of consciousness. Patients receiving long-term AED should be monitored for indices of bone health, including BMD and vitamin D status. Lifestyle factors should be optimized, vitamin D status maintained, and fall prevention strategies introduced as appropriate. Good seizure control is important. The use of additional, specific osteoporosis therapy is not evidence-based in this setting, but would appear reasonable in patients with clinically significant decreases in BMD, applying current treatment guidelines for osteoporosis. There is a pressing need for improved understanding of the pathogenesis of AED-associated bone disease, for better definition of the risk associated with specific AED regimens, and for the development of evidence-based preventive and treatment approaches in this common but neglected disorder.

In primary hyperparathyroidism, as is the case for any metabolic bone disease like osteoporosis, bone strength is a function of many variables. In addition to bone density, considerations of bone size, microarchitecture, and dynamic variables related to the evolution of the disease are all likely to influence bone strength. With greater tools to investigate these points and with newly identified cohorts of this disease, some of whom are presenting with the earliest manifestations of abnormal parathyroid function, it is expected that fresh insights will emerge. Greater knowledge of the disease should help in understanding anabolic aspects of PTH when it is used as a treatment for osteoporosis.

Biochemical markers of bone resorption have been used to characterize metabolic bone disease and assess therapeutic response. Most studies have used the urinary measurement of collagen crosslinks, but serum assays have recently been developed that may have less analytic and biologic variability. In the present study, we measured urine and serum N- and C-terminal crosslinked telopeptides of type I collagen (NTX and CTX) and serum bone sialoprotein (BSP) in postmenopausal women with or without hormone replacement therapy (HRT) and in men of similar age. In these populations, the variability of serum and urine markers was similar, except that serum NTX showed somewhat lower variability in postmenopausal women. Urine and serum assays correlated well with one another and were significantly lower in postmenopausal women on HRT compared with untreated women. The difference in women on HRT was similar for sNTX, uNTX and BSP (35-40%) and greater for sCTX and uCTX (52-53%). There was an inverse correlation between markers and bone mineral density, largely attributable to the high correlation in women not on HRT. Fractional excretion of NTX and CTX were estimated at 0.20+/-0.07 and 0.44+/-0.11, respectively. These values were independent of the concentration of the marker or of creatinine in the urine. We conclude that serum markers are useful measures of bone resorption in these populations, in whom the use of such markers is likely to be helpful in the management of osteoporosis.

Long-lasting and severe vitamin D deficiency leads to osteomalacia, a metabolic bone disease characterized by typical biochemical abnormalities (low serum concentrations of calcium and phosphate, increased activity of alkaline phosphatase). Bone histology shows decreased mineralization of bone matrix, increased osteoid volume and decreased bone formation. Vitamin D deficiency can be confirmed by measuring the serum concentration of 25-hydroxyvitamin D (25(OH)D), which is the major circulating metabolite bound with high affinity to a binding protein (DBP) and representing the storage form of vitamin D. In patients with osteomalacia, serum 25(OH)D levels are usually below 5 ng/ml and often undetectable. In contrast, patients with primary osteoporosis usually have serum concentrations of calcium and phosphate within the normal range, and alkaline phosphatase is rarely elevated. Therefore, in the opinion of many authors vitamin D deficiency is not an important pathogenetic factor for the development of osteoporosis. However, growing evidence demonstrates that moderately low levels of vitamin D can already have unfavorable effects on calcium homeostasis leading to bone loss, even if osteomalacia is not present. BargerLux and coworkers [1] showed that 25(OH)D contributes to the stimulation of enteral calcium absorption explaining the secondary increase in parathyroid hormone resulting from vitamin D deficiency, although 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels may still be normal. A vitamin D status insufficient to maintain physiologic calcium homeostasis, but not resulting in overt osteomalacia, is called vitamin D insufficiency or subclinical vitamin D deficiency. Vitamin D insufficiency is a common problem especially in Europe (for reasons explained below), and therefore this paper will review the vitamin D status in different European countries. Definition of ‘Subclinical’ Vitamin D Deficiency

This cross-sectional study investigated bone mineral density (BMD) at the lumbar spine (L2-4) and femoral neck in French Canadian women residing in the Quebec city area. Data collection was initiated in 1988 and completed in 1994. A total of 747 French Canadian Caucasian women (16-79 years of age) with no metabolic bone disease were evaluated. BMD measurements were obtained using dual-photon absorptiometry (DPA) or dual-energy X-ray absorptiometry (DXA). Anthropometric measures such as weight, height and body mass index (BMI) were recorded. Medical files provided information on demographic characteristics, hormonal profile and lifestyle habits. Results show a curvilinear trend of BMD with aging. Furthermore, the peak BMD at the lumbar spine (L2-4) was reached at 29 years followed by a stable phase until 35 years, after which BMD started to decrease. The pattern of bone evolution at the femoral neck was different, peak BMD being achieved earlier, at 21 years, while after age 26 years a significant decrease was already observed. Women older than 60 years showed the lowest BMD. Regression analysis showed that age, weight and height are determinants of BMD at the lumbar spine and explained 33.9% of inter-individual variation. At the femoral neck, 29.1% of variation was explained by age and height only. In conclusion, our data suggest that French Canadian women have a different pattern of bone loss at the femoral neck compared with the lumbar spine, according to their mean BMD values.

Gastric exclusion has been introduced as a surgical treatment for morbid obesity. We describe two women who had undergone gastric bypass for obesity with metabolic bone disease and secondary hyperparathyroidism. In one patient transiliac bone biopsy after double tetracycline labelling demonstrated histologic evidence of hyperparathyroidism with osteitis fibrosa cystica. Six additional women who had undergone gastric exclusion were evaluated. Serum phosphorus, calcium, and creatinine were normal in all but one patient who had hypocalcemia. Serum immunoreactive parathyroid hormone was elevated in seven of eight patients and urinary calcium was less than or equal to 2 mmol/d (80 mg/24 h) in 6 patients. Lumbar spine bone mineral density was 86 +/- 7 (mean +/- SE) per cent of predicted and femoral neck bone mineral density was 89 +/- 6 per cent of predicted. Women who have had gastric exclusion for obesity may develop secondary hyperparathyroidism which could result in loss of bone mass.