Periprosthetic fractures are osteoporotic fractures: missed opportunities for osteoporosis diagnosis.

Joint replacement surgery is common in older adults, leading to increasing periprosthetic fracture (PPFx) occurrence. We reviewed all PPFx seen over a 4-year period at an academic hospital. Clinical osteoporosis could be diagnosed based on existing data in 104 (67%) at the time of PPFx. Periprosthetic fractures are generally osteoporosis-related. PURPOSE: Periprosthetic fractures (PPFx) cause morbidity, mortality, and cost. This study's purpose was to describe osteoporosis-related data available at the time of PPFx. METHODS: The electronic medical record (EMR) of PPFx patients seen over 4 years in a university orthopedic practice were reviewed. Demographic data and osteoporosis relevant parameters were collected. Prior DXA studies were reviewed, and L1 Hounsfield unit (HU) measurements were performed on CT scans obtained within 2 years before PPFx. Clinical osteoporosis was defined as prior diagnosis, prescribed osteoporosis treatment, T-score ≤ - 2.5, HU ≤ 100, or prior fracture. RESULTS: Records of 156 PPFx patients (115 F/41 M), mean (SD) age 75.4 (11.9), were reviewed. Almost all 153/156 (98%) of these fractures were femoral. Falls caused 139 (89%); 12 (8%) were spontaneous. Mean time post-arthroplasty was 7.9 (6.3) years. Prior fragility fracture(s) occurred in 72 (46%); 14 were PPFx. Osteoporosis was previously diagnosed in 45 (29%) and medications prescribed in 41 (26%). Prior to PPFx, DXA data were available in 62, mean (SD) lowest T-score was - 1.9 (0.9) and was ≤ - 2.5 in 19. CT data were available in 46; mean (SD) L1 HU was 79.0 (29.4) and was ≤ 100 in 35. Based on existing data, clinical osteoporosis could have been diagnosed in 104 (67%) at the time of PPFx. CONCLUSION: Periprosthetic fractures are osteoporosis-related. They occur in older adults, often female, and result from falls; BMD, when assessed, is low. Data available at the time of PPFx often allows osteoporosis diagnosis; this should prompt evaluation and pharmacologic treatment consideration.

Intraoperative physician assessment of bone: correlation to bone mineral density.

This study evaluated the intraoperative physician assessment (IPA) of bone status at time of total knee arthroplasty. IPA was highly correlated with distal femur and overall bone mineral density. When IPA identifies poor bone status, formal bone health assessment is indicated. PURPOSE: Intuitively, intraoperative physician assessment (IPA) would be an excellent measure of bone status gained through haptic feedback during bone preparation. However, no studies have evaluated the orthopedic surgeon's ability to do so. This study's purpose, in patients undergoing total knee arthroplasty (TKA), was to relate IPA with (1) the lowest bone mineral density (BMD) T-score at routine clinical sites; and (2) with distal femur BMD. METHODS: Seventy patients undergoing TKA by 3 surgeons received pre-operative DXA. Intraoperatively, bone quality was assessed on a 5-point scale (1 excellent to 5 poor) based on tactile feedback to preparation. Demographic data, DXA results, and IPA score between surgeons were compared by factorial ANOVA. Lowest T-score and distal femur BMD were associated with IPA using Spearman's correlation. RESULTS: The mean (SD) age and BMI were 65.8 (7.6) years and 31.4 (5.1) kg/m2, respectively. Patient demographic data, BMD, and IPA (mean [SD] = 2.74 [1.2]) did not differ between surgeons. IPA correlated with the lowest T-score (R = 0.511) and distal femur BMD (R = 0.603-0.661). Based on the lowest T-score, no osteoporotic patients had an IPA above average, and none with normal BMD was classified as having poor bone. CONCLUSIONS: IPA is highly correlated with local (distal femur) and overall BMD. This study supports the International Society for Clinical Densitometry position that surgeon concern regarding bone quality should lead to bone health assessment. As IPA is comparable between surgeons, it is logical this can be widely applied by experienced orthopedic surgeons. Future studies evaluating IPA at other anatomic sites are indicated.

Femur and Tibia BMD Measurement in Elective Total Knee Arthroplasty Candidates.

Distal femur BMD declines ∼20% following total knee arthroplasty (TKA) potentially leading to adverse outcomes. BMD knowledge before and following TKA might allow interventions to optimize outcomes. We hypothesized that distal femur and proximal tibial BMD could be reproducibly measured with existing DXA technology. Elective TKA candidates were enrolled and standard clinical DXA plus bilateral PA and lateral knee scans acquired. Manual regions of interest (ROIs) were placed at distal femur and proximal tibia sites based on required TKA machining and periprosthetic fracture location. Intra- and inter-rater BMD reliability was assessed by intra-class correlation (ICC). Custom and standard proximal femur BMD were correlated by linear regression and paired t test evaluated BMD differences between planned surgical and contralateral side. One hundred subjects (68F/32M), mean (SD) age and BMI of 67.2 (7.7) yr and 30.8 (4.8) kg/m2 were enrolled. Lowest clinical BMD T-score was < -1.0 in 65% and ≤ -2.5 in 16%; 34 had prior fracture. BMD reproducibility at all custom ROIs was excellent; ICC > 0.96. Mean BMD at custom ROIs ranged from 0.903 to 1.346 g/cm2 in the PA projection and 0.891 to 1.429 g/cm2 in the lateral. Lower BMD values were observed at the proximal tibia, while the higher measurements were at the femur condyle. Custom knee ROI BMD was highly correlated (p < 0.0001) with total and femur neck with better correlation at ROIs adjacent to the joint (R2 = 0.62-0.67, 0.49-0.55 respectively). In those without prior TKA (n = 76), mean BMD was lower (2.8%-6.6%; p < 0.05) in the planned surgical leg at all custom ROIs except the PA tibial regions. Individual variability was present with 82% having a custom ROI with lower BMD (up to 53%) in the planned operative leg. Distal femur and proximal tibial BMD can be measured using custom ROIs with good reproducibility. Suboptimal bone status is common in TKA candidates and distal femur/proximal tibia BMD is often lower on the planned operative side. Routine distal femur/proximal tibial BMD measurement might assist pre-operative interventions, surgical decision-making, subsequent care and outcomes. Studies to evaluate these possibilities are indicated.

A pilot study comparing daily teriparatide with monthly cycles of teriparatide and raloxifene.

This 6-month pilot study in osteoporotic postmenopausal women evaluated cyclic TPD/RLX compared to daily subcutaneous TPD with the concept of optimizing bone formation. Compared to daily subcutaneous TPD, cyclic therapy showed comparable increase in spine BMD and favorable effects on total proximal femur BMD and cortical thickness. PURPOSE: There is no cure for osteoporosis; better medications or different approaches with current agents are needed. We hypothesized that monthly cycles of teriparatide (TPD) followed by raloxifene (RLX) might promote ongoing bone formation. Additionally, as TPD might initially adversely affect hip BMD, such effects may be mitigated by a cyclic approach. Therefore, this 6-month pilot study evaluated the effect of cyclic TPD/RLX compared to daily subcutaneous TPD on bone markers, BMD, trabecular bone score (TBS), and hip parameters assessed by 3D modeling. METHODS: Postmenopausal osteoporotic women (n=26) were randomized to open-label TPD 20 daily or alternating monthly cycles of TPD followed by monthly RLX 60 mg daily. BMD was measured at the lumbar spine (LS), femur, and radius by DXA. To further assess LS BMD, QCT and opportunistic CT (L1 Hounsfield units [HU]) were performed. LS TBS and hip cortical and trabecular parameters were assessed using DXA. Baseline group comparisons were performed by unpaired T-test with change over time evaluated by repeated measures ANOVA. RESULTS: Participant mean age, BMI, and lowest T-score were 67.0 years, 26.0 kg/m2, and -2.7; no between-group differences in serum chemistries, 25(OH)D, or BMD were observed. LS-BMD increased (p<0.001) with TPD or TPD/RLX as measured by DXA (4.8%/5.2%), QCT (13%/9.4%), or HU (15.6%/10.2%) with no between-group difference. TPD/RLX produced beneficial between-group differences in total proximal femur BMD (1.5%, p<0.05) and cortical thickness (1.6%, p<0.05). CONCLUSION: Compared with daily TPD, cyclic TPD/RLX comparably increased spine BMD and might have favorable effects on proximal femur BMD and cortical thickness.

"Effect of very dense artifacts on Hologic and general electric bone densitometry results".

Very dense artifacts confound bone density measurement. Hologic and GE densitometers exclude artifact density and GE also excludes associated area. Consequently, BMD is decreased with Hologic software. Despite different manufacturers' approaches, when dense artifacts overlay the spine, the affected vertebral body should be excluded from the reported BMD. PURPOSE: Very dense objects, such as lead bullets are described as "black hole" artifacts on Hologic densitometers. Whether similar results occur on GE scanners is not reported. We hypothesized that dense artifacts confound both brands of densitometers. METHODS: Three lead bullets of varying size were placed overlying or adjacent to L3 on anthropomorphic and encapsulated aluminum spine phantoms. Three scans were acquired with and without projectiles on a Hologic Discovery W, GE iDXA, and Prodigy densitometer. RESULTS: Lead bullets are measured as having high bone mineral content (BMC); they appear black in dual-energy mode on Hologic scanners and are colored blue on GE scanners. On Hologic scanners, BMC of a dense artifact over bone is excluded, but the bone area is not altered. Consequently, bone mineral density (BMD) of the affected vertebra, and of L1-4, is decreased. For example, a .45 caliber bullet over L3 decreased BMD (p < 0.05) by 48.3% and L1-4 by 9.1%. GE scanners excluded associated BMC and area covered by the artifact, thereby minimizing impact on BMD. Dense artifacts over soft tissue on a phantom do not substantially affect BMD on either manufacturer's densitometer when scanned. CONCLUSION: Densitometer manufacturers handle very dense artifacts differently. GE software removes artifact BMC and area with resultant minimal impact on BMD, Hologic removes only BMC, not area, thereby decreasing BMD. Regardless of this difference, when dense artifacts overlay the spine, it is best to exclude the affected vertebral body. Finally, the BMD stability observed with artifacts over soft tissue may not be replicated in humans.

DOES VITAMIN D METABOLITE MEASUREMENT HELP PREDICT 25(OH)D CHANGE FOLLOWING VITAMIN D SUPPLEMENTATION?

OBJECTIVE: Variability in 25-hydroxyvitamin D (25(OH)D) change following vitamin D supplementation exists. Vitamin D metabolite measurement might assist in predicting 25(OH)D response and also contribute to defining vitamin D adequacy. This study assessed utility of vitamin D metabolite measurements to predict 25(OH)D response and explored the relationship between parathyroid hormone (PTH) and a "vitamin D composite index" comprised of the sum of serum 25(OH) D, cholecalciferol (vitamin D3) and 24,25 dihydroxyvitamin D (24,25(OH)2D). METHODS: Sixty-two postmenopausal women were randomized to daily vitamin D3 1,800 IU or placebo for 4 months. Blood was drawn at baseline and after 1 and 4 months. Serum 25(OH)D, vitamin D3, and 24,25(OH)2D were measured by liquid chromatography tandem mass spectroscopy. Free 25(OH)D and PTH were measured by enzyme-linked immunosorbent assay. Repeated measures analysis of variance and regression analyses were performed. RESULTS: Baseline 25(OH)D was positively correlated (P<.05) with vitamin D3, 24,25(OH)2D and free 25(OH) D. Daily vitamin D supplementation increased all metabolites (P<.001). Substantial individual variability in 25(OH) D change at 4 months was observed but was unrelated to baseline vitamin D3, 25(OH)D or 24,25(OH)2D. Only body mass index, body weight, and body fat mass was associated with 25(OH)D change at 4 months. The vitamin D composite score was associated with serum PTH, but this association was similar to that observed with 25(OH) D alone. CONCLUSION: This study does not support measurement of vitamin D metabolites in a composite index to assist in prediction of 25(OH)D response to supplementation. Overweight individuals have less robust 25(OH) D response to supplementation, but variability precludes prediction of the result following daily supplementation. ABBREVIATIONS: BMI = body mass index DXA = dual-energy X-ray absorptiometry LC-MS/MS = liquid chromatography tandem mass spectroscopy 25(OH)D = 25-hydroxyvitamin D 24,25(OH)2D = 24,25 dihydroxyvitamin D PTH = parathyroid hormone vitamin D3 = cholecalciferol.

The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge.

It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5(TFP) and TRIM5(CypA) alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.

The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers.

The role of CD4(+) T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4(+) T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4(+) T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4(+) T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4(+) T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.

Molecular typing of major histocompatibility complex class I alleles in the Indian rhesus macaque which restrict SIV CD8+ T cell epitopes.

The utility of the rhesus macaque as an animal model in both HIV vaccine development and pathogenesis studies necessitates the development of accurate and efficient major histocompatibility complex (MHC) genotyping technologies. In this paper, we describe the development and application of allele-specific polymerase chain reaction (PCR) amplification for the simultaneous detection of eight MHC class I alleles from the rhesus macaque (Macaca mulatta) of Indian descent. These alleles were selected, as they have been implicated in the restriction of CD8(+) T cell epitopes of simian immunodeficiency virus (SIV). Molecular typing of Mamu-A 01, Mamu-A 02, Mamu-A 08, Mamu-A 11, Mamu-B 01, Mamu-B 03, Mamu-B 04, and Mamu-B 17 was conducted in a high throughput fashion using genomic DNA. Our amplification strategy included a conserved internal control target to minimize false negative results and can be completed in less than 5 h. We have genotyped over 4,000 animals to establish allele frequencies from colonies all over the western hemisphere. The ability to identify MHC-defined rhesus macaques will greatly enhance investigation of the immune responses, which are responsible for the control of viral replication. Furthermore, application of this technically simple and accurate typing method should facilitate selection, utilization, and breeding of rhesus macaques for AIDS virus pathogenesis and vaccine studies.

Mamu-B*08-positive macaques control simian immunodeficiency virus replication.

Certain major histocompatibility complex (MHC) class I alleles are associated with the control of human immunodeficiency virus and simian immunodeficiency virus (SIV) replication. We have designed sequence-specific primers for detection of the rhesus macaque MHC class I allele Mamu-B*08 by PCR and screened a cohort of SIV-infected macaques for this allele. Analysis of 196 SIV(mac)239-infected Indian rhesus macaques revealed that Mamu-B*08 was significantly overrepresented in elite controllers; 38% of elite controllers were Mamu-B*08 positive compared to 3% of progressors (P = 0.00001). Mamu-B*08 was also associated with a 7.34-fold decrease in chronic phase viremia (P = 0.002). Mamu-B*08-positive macaques may, therefore, provide a good model to understand the correlates of MHC class I allele-associated immune protection and viral containment in human elite controllers.

Introgression of F344 rat genomic DNA on BB rat chromosome 4 generates diabetes-resistant lymphopenic BB rats.

Failure to express the Gimap5 protein is associated with lymphopenia (lyp) and linked to spontaneous diabetes in the diabetes-prone BioBreeding (BBDP) rat. Gimap5 is a member of seven related genes located within 150 Kb on rat chromosome 4. Congenic DR.(lyp/lyp) rats, where BBDP lyp was introgressed onto the diabetes-resistant BBDR background (BBDR.BBDP.(lyp/lyp)), all develop diabetes between 46 and 81 days of age (mean +/- SE, 61 +/- 1), whereas DR.(lyp/+) and DR.(+/+) rats are nonlymphopenic and diabetes resistant. In an intercross between F1(BBDP x F344) rats, we identified a rat with a recombination event on chromosome 4, allowing us to fix 33 Mb of F344 between D4Rat253 and D4Rhw6 in the congenic DR.lyp rat line. Gimap1 and Gimap5 were the only members of the Gimap family remaining homozygous for the BBDP allele. Offspring homozygous for the F344 allele (f/f) between D4Rat253 and D4Rhw6 were lymphopenic (85 of 85, 100%) but did not develop diabetes (0 of 85). During rescue of the recombination, 102 of 163 (63%) rats heterozygous (b/f) for the recombination developed diabetes between 52 and 222 days of age (88 +/- 3). Our data demonstrate that introgression of a 33-Mb region of the F344 genome, proximal to the mutated Gimap5 gene, renders the rat diabetes resistant despite being lymphopenic. Spontaneous diabetes in the BB rat may therefore be controlled, in part, by a diabetogenic factor(s), perhaps unrelated to the Gimap5 mutation on rat chromosome 4.

Physiogenomic resources for rat models of heart, lung and blood disorders.

Cardiovascular disorders are influenced by genetic and environmental factors. The TIGR rodent expression web-based resource (TREX) contains over 2,200 microarray hybridizations, involving over 800 animals from 18 different rat strains. These strains comprise genetically diverse parental animals and a panel of chromosomal substitution strains derived by introgressing individual chromosomes from normotensive Brown Norway (BN/NHsdMcwi) rats into the background of Dahl salt sensitive (SS/JrHsdMcwi) rats. The profiles document gene-expression changes in both genders, four tissues (heart, lung, liver, kidney) and two environmental conditions (normoxia, hypoxia). This translates into almost 400 high-quality direct comparisons (not including replicates) and over 100,000 pairwise comparisons. As each individual chromosomal substitution strain represents on average less than a 5% change from the parental genome, consomic strains provide a useful mechanism to dissect complex traits and identify causative genes. We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation.