Aortitis in COVID-19.

Corona Virus Disease of 2019 (COVID-19) pandemic has affected more than 67.9 million individuals world-wide and led to more than 15.5 million Deaths. In the initial studies from China, 88.7 % of the patient were noted to have fever, 67 % of the patient had cough and 56.4 % had ground glass changes on the chest imaging. With time, the presentation of patients has been found to be highly variable and unpredictable. COVID-19 is reported to present with various complications, ranging from gastrointestinal (GI) manifestations, such as loss of sensation of taste, abdominal pain, diarrhea, vomiting, pancreatitis and hepatobiliary disease, to neurological manifestations of encephalitis and stroke, and cardiovascular manifestations like myocarditis, heart failure and arrythmia. We report a rare case of COVID-19 presenting with abdominal pain from aortitis.

Regulation of circulating sclerostin levels by sex steroids in women and in men.

Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone-resorption, but not bone-formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C-terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption.

Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy.

Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.

Use of DXA-based structural engineering models of the proximal femur to discriminate hip fracture.

Several DXA-based structural engineering models (SEMs) of the proximal femur have been developed to estimate stress caused by sideway falls. Their usefulness in discriminating hip fracture has not yet been established and we therefore evaluated these models. The hip DXA scans of 51 postmenopausal women with hip fracture (30 femoral neck, 17 trochanteric, and 4 unspecified) and 153 age-, height-, and weight-matched controls were reanalyzed using a special version of Hologic's software that produced a pixel-by-pixel BMD map. For each map, a curved-beam, a curved composite-beam, and a finite element model were generated to calculate stress within the bone when falling sideways. An index of fracture risk (IFR) was defined over the femoral neck, trochanter, and total hip as the stress divided by the yield stress at each pixel and averaged over the regions of interest. Hip structure analysis (HSA) was also performed using Hologic APEX analysis software. Hip BMD and almost all parameters derived from HSA and SEM were discriminators of hip fracture on their own because their ORs were significantly >1. Because of the high correlation of total hip BMD to HSA and SEM-derived parameters, only the bone width discriminated hip fracture independently from total hip BMD. Judged by the area under the receiver operating characteristics curve, the trochanteric IFR derived from the finite element model was significant better than total hip BMD alone and similar to the total hip BMD plus bone width in discriminating all hip fracture and femoral neck fracture. No index was better than total hip BMD for discriminating trochanteric fractures. In conclusion, the finite element model has the potential to replace hip BMD in discriminating hip fractures.

Comparison of densitometric and radiographic vertebral fracture assessment using the algorithm-based qualitative (ABQ) method in postmenopausal women at low and high risk of fracture.

UNLABELLED: Using ABQ diagnosis, the sensitivity to detect VF of densitometric versus radiographic assessment in 755 postmenopausal women was 71-81% and specificity was 97%. Misdiagnosis was influenced by image quality and was more common for mild deformities. INTRODUCTION: Using densitometric vertebral fracture assessment (VFA), prevalent fractures are identified when vertebral height appears reduced by >or=20%. However, this approach does not discriminate between osteoporotic vertebral fracture (VF) and nonosteoporotic deformity, which increases the false-positive rate. Algorithm-based qualitative diagnosis (ABQ) focuses on vertebral endplate fracture to exclude these deformities but has not been applied in VFA. We wished to determine whether densitometric image quality is adequate for ABQ assessment. Our aims were to (1) calculate agreement between VFA and radiography using ABQ to identify prevalent VF and (2) identify the primary reasons for any discordant diagnosis. METHODS: Radiographic and densitometric spine images for postmenopausal women at low risk (LR; n = 459) and high risk (HR; n = 298) of VF were assessed using ABQ. Agreement between imaging modalities for VF diagnosis was assessed by kappa statistics using ABQ radiographic readings as the gold standard. RESULTS: The prevalence of VF was 11-29% (radiography) and 9-26% (VFA) in the LR and HR groups, respectively. Agreement between imaging modalities was good or very good (kappa = 0.62-0.81 in the LR and HR populations). The sensitivity to detect women with VF by VFA was 71% and 84% in the LR and HR populations, respectively, and specificity was 97%. Fifty-two (77%) and 60 (61%) of vertebrae misclassified by VFA in the LR and HR populations were mild fractures and 37 (54%) and 62 (63%) were wedge fractures. One third of fractures missed by VFA were related to poor or unreadable image quality (n = 27 and 28 vertebrae in the LR and HR populations, respectively). CONCLUSIONS: There was good agreement between VFA and radiography using ABQ to identify prevalent VF in women at LR or HR of osteoporotic VF. Vertebrae misclassified by VFA were primarily mild fractures or deformities, and two thirds of all fractures missed by VFA were related to poor or unreadable image quality.

Characterization of circulating osteoblast lineage cells in humans.

We recently identified circulating osteoblastic cells using antibodies to osteocalcin (OCN) or alkaline phosphatase (AP). We now provide a more detailed characterization of these cells. Specifically, we demonstrate that 46% of OCN positive (OCN(pos)) cells express AP, and 37% also express the hematopoietic/endothelial marker CD34. Using two different anti-OCN antibodies and forward/side light scatter characteristics by flow cytometry, we find that OCN(pos) cells consist of two distinct populations: one population exhibits low forward/side scatter, consistent with a small cell phenotype with low granularity, and a second population has higher forward/side scatter (larger and more granular cell). The smaller, low granularity population also co-expresses CD34, whereas the larger, more granular cells are CD34 negative. Using samples from 26 male subjects aged 28 to 68 years, we demonstrate that the concentration of circulating OCN(pos) cells increases as a function of age (R=0.59, P=0.002). By contrast, CD34(pos) cells tend to decrease with age (R=-0.31, P=0.18); as a consequence, the ratio of OCN(pos):CD34(pos) cells also increase significantly with age (R=0.54, P=0.022). These findings suggest significant overlap between circulating cells expressing OCN and those expressing the hematopoietic/endothelial marker CD34. Further studies are needed to define the precise role of circulating OCN(pos) cells not only in bone remodeling but rather also potentially in the response to vascular injury.

The role of the immune system in the pathophysiology of osteoporosis.

The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses on our current understanding of how the components of this complex-interlinked system are regulated and how these fit with previous models of senile and postmenopausal osteoporosis. There is certainly substantial evidence that bone remodeling is a tightly regulated, finely balanced process influenced by subtle changes in proinflammatory and inhibitory cytokines as well as hormones and cellular components that act primarily but not exclusively through the receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin system. In addition, an acute or chronic imbalance in the system due to infection or inflammation could contribute to systemic (or local) bone loss and increase the risk of fracture. Although significant progress has been made, there remains much to be done in unraveling this complex interaction between the immune system and bone.

The discriminative ability of peripheral and axial bone measurements to identify proximal femoral, vertebral, distal forearm and proximal humeral fractures: a case control study.

Previous studies evaluating peripheral bone measurement devices have often used discontinued technologies, compared single devices, only evaluated a single fracture syndrome or failed to make a comparison with central densitometry, which is currently the gold standard for fracture discrimination. We have used a case control study to evaluate the ability of different peripheral and central bone techniques to discriminate between fracture cases and controls, determine the impact of different measurement sites, evaluate the role of measuring the cortical or trabecular envelopes using quantitative computed tomography (QCT) and determine the impact of using combinations of sites and techniques on fracture discrimination. We recruited postmenopausal women with proximal femoral (n=53), vertebral (n=73), distal forearm (n=78) or proximal humeral (n=75) fractures, and 500 population-based women (age 55-80 years). All subjects had measurements of the spine, total hip and distal forearm with dual-energy X-ray absorptiometry (DXA), distal forearm QCT and quantitative ultrasound (QUS) of the heel (four devices), finger (two devices), radius and metatarsal. The association of each device with fracture was expressed as the age-adjusted standardized odds ratios (sOR) per 1-SD decrease of population variance. The association of bone measurements with fracture was site-specific. We found the hip (sOR up to 3.40) and vertebral (sOR up to 4.67) fractures were more closely associated with central bone measurements than upper limb fractures (sOR 1.96 and 2.05). The performance of heel broadband ultrasound attenuation (sOR 2.09-2.41), heel speed of sound (sOR 1.79-2.28) and peripheral BMD (sOR 2.07 and 2.24) was comparable with total hip (sOR 2.46) and lumbar spine DXA (sOR 2.31) in discriminating all types of osteoporotic fracture. In general, measuring cortical or trabecular envelopes did not increase sOR. However, combining different measurement sites or technologies provided additional information, which was independent of total hip BMD. The ability of different bone measurements to discriminate between fracture cases and controls is device- and site-specific, with additional information obtained by combining measurement sites and technologies.

The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial.

Long-term adherence and persistence with any therapy are very poor ( approximately 50%). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were randomized to 1) no monitoring, 2) nurse-monitoring, or 3) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff reviewed subjects in the monitored (nurse-monitoring or marker-monitoring) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density (BMD) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57% compared with no monitoring (P = 0.04). There was a trend for the monitored group to persist with therapy for 25% longer compared with no monitoring (P = 0.07). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip (BMD) (r = 0.28; P = 0.01) and percent change in uNTX (r = -0.36; P = 0.002). In conclusion, monitoring of patients increased adherence to therapy by 57% at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points.

Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption.

Previous immunoassays developed for the measurement of serum tartrate-resistant acid phosphatase (TRACP) have lacked specificity for osteoclastic TRACP, TRACP 5b, or have not shown satisfactory clinical performance. The aim of this study was to evaluate the clinical performance of a novel immunocapture activity assay for TRACP 5b, in comparison to telopeptide fragments of type I collagen. Within-subject variability and the effect of feeding on TRACP 5b and telopeptides of type I collagen were assessed in 20 healthy premenopausal women. Diurnal variation of TRACP 5b and serum beta C-terminal cross-linked telopeptide of type I collagen (sbetaCTX) was assessed in 12 healthy postmenopausal women. Renal clearance was assessed in 19 end stage renal failure patients undergoing routine haemodialysis. Response to antiresorptive treatment and calcium supplementation was assessed in osteoporotic postmenopausal women treated with alendronate and calcium (n = 16) or with calcium alone (n = 7) for 24 weeks.Within-subject variability (CVi) of TRACP 5b was 6.6%, lower than CVi of urinary and serum telopeptides. TRACP 5b decreased by 2.4 +/- 0.8%, in response to feeding (P < 0.05) compared to 7.0 +/- 2.6% to 7.9 +/- 3.7% for urinary telopeptides (P < 0.05 to < 0.01) and 8.5 +/- 1.7% to 17.8 +/- 2.6% for serum telopeptides (P < 0.0001). The amplitude of the diurnal rhythm for TRACP 5b was small compared to that of sbetaCTX, 14 +/- 4% vs. 137 +/- 14%. Haemodialysis did not have a significant effect on TRACP 5b but reduced sbetaCTX by 46 +/- 4% (P < 0.0001). In response to alendronate, TRACP 5b decreased by 39 +/- 4% compared to 49 +/- 4% to 69 +/- 5% for urinary telopeptides and 75 +/- 8% for sbetaCTX. We conclude that TRACP 5b shows an attenuated response to antiresorptive therapy in comparison with other markers of bone resorption, but that this may be offset by lower biological variability. TRACP 5b may provide useful additional information about bone resorption.

Octreotide abolishes the acute decrease in bone turnover in response to oral glucose.

Feeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P < 0.001). At 120 min serum C-terminal telopeptide decreased by 45 +/- 2%, urinary N-terminal telopeptide by 31 +/- 7%, osteocalcin by 16 +/- 1%, and procollagen type I N-terminal propeptide by 8 +/- 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P < 0.05) and PTH (P < 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.

Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies.

Bone turnover is acutely suppressed after feeding or oral glucose. Insulin infusion suppresses bone turnover and might mediate this effect, but this is confounded by a possible direct effect of hypoglycemia. We examined the effect of euglycemic hyperinsulinemia and hypoglycemic hyperinsulinemia on bone turnover using an insulin clamp. Sixteen men participated in this double-blind crossover study. Clamp induction involved infusion of insulin (80 mU/m(2).min) while maintaining euglycemia (5 mmol/liter) for 40 min with a variable rate dextrose infusion. Glucose was lowered to 2.5 mmol/liter (hypoglycemic clamp) or maintained at 5 mmol/liter (euglycemic clamp) for a further 105 min. Nine controls received a matched saline infusion. Measurements included serum C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide, osteocalcin, and PTH. Induction of hyperinsulinemia resulted in a reduction in PTH (27% +/- 5; P < 0.01), but no significant change in bone turnover from baseline. Hypoglycemic clamp resulted in suppression of serum C-terminal telopeptide of type I collagen by 34% +/- 3, procollagen type I N-terminal propeptide by 15% +/- 1, osteocalcin by 5% +/- 1, and PTH by a further 12% +/- 5 (all P < 0.05). By contrast, there was no significant change in any marker of bone turnover during euglycemic clamp. Postprandial hyperinsulinemia is unlikely to explain the acute suppression of bone turnover with feeding. The reduction in bone turnover during hypoglycemia may be related to hypoglycemia itself, acute changes in PTH, or other hormones released in response to hypoglycemia.