Comparative effectiveness of denosumab, teriparatide, and zoledronic acid among frail older adults: a retrospective cohort study.

The comparative effects of zoledronic acid, denosumab, and teriparatide for preventing hip fractures in frail older adults, especially those in nursing homes, were unknown. We found that denosumab and zoledronic acid may be as effective as teriparatide for hip fracture prevention in nursing home residents. INTRODUCTION: Several non-oral drugs exist for osteoporosis treatment, including zoledronic acid (ZA), denosumab, and teriparatide. Little data exist on the comparative effectiveness of these drugs for hip fracture prevention in frail older adults. We examined their comparative effectiveness in one of the frailest segments of the US population-nursing home (NH) residents. METHODS: We conducted a national retrospective cohort study of NH residents aged ≥ 65 years using 2012 to 2016 national US Minimum Data Set clinical assessment data and linked Medicare claims. New parenteral ZA, denosumab, and teriparatide use was assessed via Medicare Parts B and D; hip fracture outcomes via Part A; and 125 covariates for confounding adjustment via several datasets. We used inverse probability weighted (IPW) competing risk regression models to compare hip fracture risk between groups with teriparatide as the reference. RESULTS: The study cohort (N = 2019) included 1046 denosumab, 578 teriparatide, and 395 ZA initiators. Mean age was 85 years, 90% were female, and 68% had at least moderate functional impairment. Seventy-two residents (3.6%) had a hip fracture and 1100 (54.5%) died over a mean follow-up of 1.5 years. Compared to teriparatide use, denosumab use was associated with a 46% lower risk of hip fracture (HR 0.54, 95% CI 0.29-1.00) and no difference was observed for ZA (HR 0.70, 95% CI 0.26-1.85). CONCLUSIONS: Denosumab and ZA may be as effective as teriparatide for hip fracture prevention in frail older adults. Given their lower cost and easier administration, denosumab and ZA are likely preferable non-oral treatments for most frail, older adults.

Genetic correlations of milk fatty acid contents predicted from milk mid-infrared spectra in New Zealand dairy cattle.

The objective of this study was to estimate genetic correlations among milk fatty acid (FA) concentrations in New Zealand dairy cattle. Concentrations of each of the most common FA, expressed as a percentage of the total FA, were determined by gas chromatography on a specific cohort of animals. Using this data set, prediction equations were derived using mid-infrared (MIR) spectroscopy data collected from the same samples. These prediction equations were applied to a large data set of MIR measurements in 34,141 milk samples from 3,445 Holstein-Friesian, 2,935 Jersey, and 3,609 crossbred Holstein-Friesian × Jersey cows, sampled an average of 3.42 times during the 2007-2008 season. Data were analyzed using univariate and bivariate repeatability animal models. Heritability of predicted FA concentration in milk fat ranged from 0.21 to 0.42, indicating that genetic selection could be used to change the FA composition of milk. The de novo synthesized FA (C6:0, C8:0, C10:0, C12:0, and C14:0) showed strong positive genetic correlations with each other, ranging from 0.24 to 0.99. Saturated FA were negatively correlated with unsaturated (-0.93) and polyunsaturated (-0.84) FA. The saturated FA were positively correlated with milk fat yield and fat percentage, whereas the unsaturated FA were negatively associated with fat yield and fat percentage. Our results indicate that bovine milk FA composition can be changed through genetic selection using MIR as a phenotypic proxy.

Widespread prevalence of a CREBRF variant amongst Maori and Pacific children is associated with weight and height in early childhood.

OBJECTIVE: Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with body mass index in Samoans. METHODS: A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Maori, Pacific, European and Asian individuals in the cohort. RESULTS: We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Maori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129). CONCLUSIONS: We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.

Defining hip fracture with claims data: outpatient and provider claims matter.

Medicare claims are commonly used to identify hip fractures, but there is no universally accepted definition. We found that a definition using inpatient claims identified fewer fractures than a definition including outpatient and provider claims. Few additional fractures were identified by including inconsistent diagnostic and procedural codes at contiguous sites. INTRODUCTION: Medicare claims data is commonly used in research studies to identify hip fractures, but there is no universally accepted definition of fracture. Our purpose was to describe potential misclassification when hip fractures are defined using Medicare Part A (inpatient) claims without considering Part B (outpatient and provider) claims and when inconsistent diagnostic and procedural codes occur at contiguous fracture sites (e.g., femoral shaft or pelvic). METHODS: Participants included all long-stay nursing home residents enrolled in Medicare Parts A and B fee-for-service between 1/1/2008 and 12/31/2009 with follow-up through 12/31/2011. We compared the number of hip fractures identified using only Part A claims to (1) Part A plus Part B claims and (2) Part A and Part B claims plus discordant codes at contiguous fracture sites. RESULTS: Among 1,257,279 long-stay residents, 40,932 (3.2%) met the definition of hip fracture using Part A claims, and 41,687 residents (3.3%) met the definition using Part B claims. 4566 hip fractures identified using Part B claims would not have been captured using Part A claims. An additional 227 hip fractures were identified after considering contiguous fracture sites. CONCLUSIONS: When ascertaining hip fractures, a definition using outpatient and provider claims identified 11% more fractures than a definition with only inpatient claims. Future studies should publish their definition of fracture and specify if diagnostic codes from contiguous fracture sites were used.

Diuretic initiation and the acute risk of hip fracture.

SUMMARY: We found the risk of hip fracture was transiently elevated around twofold shortly after initiation of a loop or thiazide diuretic drug in a case-crossover and case-control study. No statistical association was found following the initiation of a comparator medication: ACE inhibitors. Awareness of these short-term risks may reduce hip fractures. INTRODUCTION: Little is known about the acute effects of initiating a diuretic drug on risk of fracture. We evaluated the relationship between initiating a diuretic drug and the occurrence of hip fracture. METHODS: The study sample included 2,118,793 persons aged ≥50 years enrolled in The Health Improvement Network (THIN) between 1986 and 2010. The effect of a new start of a diuretic drug or comparator medication (ACE inhibitor) on risk of hip fracture was assessed using a case-crossover and case-control study during the 1-7, 8-14, 15-21, and 22-28 days following drug initiation. RESULTS: Included were 28,703 individuals with an incident hip fracture over a mean of 7.9 years follow-up. In the case-crossover study, the risk of experiencing a hip fracture was increased during the first 7 days following loop diuretic drug initiation (OR = 1.8; 95 % CI, 1.2, 2.7). The elevated risk did not continue during the 8-14, 15-21, or 22-28 days following drug initiation. For thiazide diuretics, the risk of hip fracture was elevated 8-14 days after drug initiation (OR = 2.2; 95 % CI, 1.2, 3.9). No such association was observed in the 1-7, 15-21, or 22-28 days following thiazide drug initiation. ACE inhibitor initiation was not associated with a statistically significant increased risk of hip fracture. Similar results were observed using a case-control study. CONCLUSIONS: The risk of hip fracture was transiently elevated around twofold shortly after the new start of a loop or thiazide diuretic drug. Awareness of these short-term risks may reduce hip fractures and other injurious falls in vulnerable adults.

Does dietary protein reduce hip fracture risk in elders? The Framingham Osteoporosis Study.

UNLABELLED: Association between dietary protein and fracture risk is unclear. We examined association between energy-adjusted protein intake and hip fracture risk in elders. The risk of hip fracture was reduced in upper quartiles of protein intake when compared with lowest quartile. INTRODUCTION: Studies of the association between dietary protein intake and hip fracture risk are conflicting. Therefore, we examined protein intake and hip fracture risk in a population-based group of elderly men and women. METHODS: Five hundred seventy-six women and 370 men from the Framingham Osteoporosis Study with no previous history of hip fracture completed Food Frequency Questionnaires. Energy-adjusted protein intake was evaluated as a continuous variable and as quartiles. Incidence rates and hazard ratios were calculated, adjusting for age, BMI, sex, and energy intake. RESULTS: Among 946 participants (mean age 75 years), mean protein intake was found to be 68 gm/d. Increased protein intake was associated with a decreased risk of hip fracture compared to those in the lowest quartile of protein intake (Q2 HR = 0.70, Q3 HR = 0.56, and Q4 HR = 0.63; all p values ≥ 0.044), p for trend was 0.07. When a threshold effect was considered (Q2-4 vs Q1), intakes in the higher quartiles combined were associated with a significantly lower risk for hip fracture (HR = 0.63; p = 0.04). CONCLUSION: Our results are consistent with reduced risk of hip fracture with higher dietary protein intake. Larger prospective studies are needed to confirm and extend this finding in elderly men and women.

Mutation in bovine beta-carotene oxygenase 2 affects milk color.

beta-Carotene biochemistry is a fundamental process in mammalian biology. Aberrations either through malnutrition or potentially through genetic variation may lead to vitamin A deficiency, which is a substantial public health burden. In addition, understanding the genetic regulation of this process may enable bovine improvement. While many bovine QTL have been reported, few of the causative genes and mutations have been identified. We discovered a QTL for milk beta-carotene and subsequently identified a premature stop codon in bovine beta-carotene oxygenase 2 (BCO2), which also affects serum beta-carotene content. The BCO2 enzyme is thereby identified as a key regulator of beta-carotene metabolism.

Application of the National Osteoporosis Foundation Guidelines to postmenopausal women and men: the Framingham Osteoporosis Study.

UNLABELLED: We applied the 2008 National Osteoporosis Foundation (NOF) Guidelines to Framingham Osteoporosis Study participants and found nearly one half of Caucasian postmenopausal women and one sixth of men aged 50 years and older would be recommended for osteoporosis treatment. Given the high proportion of persons recommended for treatment, NOF Guidelines may need to be re-evaluated with respect to budget impact. INTRODUCTION: Little is known about the public health impact of the NOF Guidelines. Therefore, we determined the proportion of US Caucasians recommended for treatment of osteoporosis according to NOF Guidelines (2003 and 2008). METHODS: One thousand nine hundred and forty-six postmenopausal women and 1,681 men aged > or =50 years from the Framingham Study with information on bone mineral density (1987-2001) were included. Information on clinical predictors was used to estimate the 10-year probability of hip and major osteoporotic fracture by FRAX (version 3.0). RESULTS: Overall proportion of women meeting treatment criterion was less when the 2008 NOF Guidelines were applied (41.1%) compared with 2003 Guidelines (47.8%). The proportion of women aged <65 years meeting treatment criterion was much less when applying 2008 Guidelines (23.1% in 2003, 8.3% in 2008), whereas the proportion of women aged >75 years increased slightly (78.3% in 2003, 86.0% in 2008). Seventeen percent of men aged > or =50 years met treatment criterion (2.5% aged 50-64 years, 49.8% aged >75 years). CONCLUSIONS: Nearly one half of Caucasian postmenopausal women and one sixth of men aged 50 years and older would be recommended for osteoporosis treatment according to 2008 NOF Guidelines. Given the high proportion of persons recommended for treatment, NOF Guidelines may need to be re-evaluated with respect to budget impact.

Within-field damage and distribution patterns of the stalk borer, Eldana saccharina (Lepidoptera: Pyralidae), in sugarcane and a comparison with nematode damage.

The occurrence of Eldana saccharina (Lepidoptera: Pyralidae) was monitored in grids represented by plots in 12 nematicide trials in South African sugarcane fields. The trials encompassed a total of eight plant cane crops and 22 ratoon crops and were situated within commercial cane fields. Several measurements were made to characterize the damage caused by E. saccharina. These included the number of internodes per stalk, the percentage of internodes damaged and the percentage of stalks damaged. The mapping of E. saccharina infestation in plant crops of sugarcane showed that the borders of the trials were as infested as the centre, indicating invasion from outside the field plus internal spread within the field. Ratoon crops were less infested than plant crops. This could be explained by a shorter ratoon crop cycle and by the fields having areas that were more suitable for the borer than elsewhere. The location of these preferred areas could be predicted from one ratoon crop to the next but was not related to the distribution of the borer in the plant crop. This situation was thought to explain the apparent stabilization of E. saccharina infestation in ratoon cane. Because the borer was found at harvest only in stalks with more than 14 to 16 internodes, it appeared that the oldest shoots, or the shoots with the greatest growth potential, attracted the insect, possibly due to their higher nitrogen content, which would stimulate growth. All the trials were on sandy soil, and crop loss from nematodes was greater than that caused by E. saccharina.

Medial septal lesions retard classical conditioning of the nicitating membrane response in rabbits.

Lesions of the medial septum were produced in 7 of 14 rabbits prior to classical conditioning of the nictitating membrane response. Lesions significantly altered the hippocampal electroencephalogram, attenuated conditioned hippocampal unit responses, and slowed the behavioral rate of acquisition. The contrast of the behavioral results with those of studies of massive septal or hippocampal ablation suggests a functional subdivision of the septo-hippocampal system in learning.

Prediction of learning rate from the hippocampal electroencephalogram.

Samples of spontaneous electroencephalographic (EEG) activity from the dorsal hippocampus of rabbits were recorded immediately before classical conditioning of the nictitating membrane response. Computer analysis revealed a significant predictive relationship between EEG frequency characteristics and the subsequent rate of learning.

Changes in bone mineral density (BMD): a longitudinal study of osteoporosis patients in the real-world setting.

In clinical practice, the frequency of patients achieving improved T-scores and the expected change in bone mineral density (BMD) according to osteoporosis drugs is unknown. We found that osteoporosis medications infrequently achieve improved femoral neck T-scores over 1.2 years. BMD increases were more often seen with IV bisphosphonates and denosumab. PURPOSE: To determine the frequency of osteoporosis patients achieving improvement in T-scores and quantify the change in bone mineral density (BMD) over time according to osteoporosis medication use. METHODS: The study included all patients receiving clinical care at United Osteoporosis Centers, Gainesville, GA, 1995-2015, who had at least two measures of femoral neck BMD (N = 1232). We evaluated successive pairs of BMD tests to describe the distribution of transitions between T-score categories. Generalized estimating equations were used to estimate %BMD change between successive pairs of BMD tests according to osteoporosis medication, adjusted for age, sex, height, weight, baseline BMD, previous fracture, and follow-up time. RESULTS: Mean (±SD) age was 68 (±10) years, and 90% of patients were women. Mean baseline T-score was - 2.04 (± 0.85). In total, 1232 patients had 4918 pairs of successive BMD tests, with a mean 1.2 years (± 0.9) between assessments. Frequency of transition to an improved T-score category was 41% when prior T-score ≤ - 3.5, and 15% when prior T-score - 1.99 to - 1.50. Most individuals (69%) remained in the same T-score category. BMD increased 0.54% (95% CI 0.23-0.85%) with IV bisphosphonates and 1.23% (95% CI 0.56-1.90%) with denosumab, whereas no significant change was seen with oral bisphosphonates, teriparatide, or raloxifene. CONCLUSIONS: Osteoporosis patients are unlikely to improve femoral neck T-scores over 1.2 years. Additional studies are needed to determine the optimal time to repeat BMD testing while receiving osteoporosis treatment and to determine whether fracture risk is reduced in patients who achieve target T-scores.

Ovarian and IGF-I axis control of mammary development in prepubertal heifers.

Although much is known about the endocrine control of bovine mammary development, most heifer work has focused on periods near the time of puberty or during gestation. However, we have found that ovariectomy in the prepubertal period also markedly impacts mammary development well before the onset of estrus would have normally occurred. Interactions between the pituitary and ovary to control udder development are mediated at least in part via alteration in concentrations of local IGF-I axis molecules within the developing mammary gland. For example, in heifers treated with growth hormone or estrogen, expression of IGF-I binding proteins (IGFBP-3) protein was reduced, thus effecting an increase in free IGF-I. Ovariectomized heifers had reduced rates of epithelial cell proliferation, fewer IGF-I receptors, and less local IGF-I. Mammary tissue expression of fibronectin was increased in ovariectomized heifers, but laminin expression was higher in controls. Thus, alterations in specific extracellular matrix proteins likely impact heifer mammary development. As a result, we have initiated calfhood studies. At 30 days of age, it is difficult to detect parenchymal tissue in the udder. Only a thin cord of parenchymal tissue (150 mg per gland) is discernible. By 75 days of age, a rounded, walnut-like mass of mammary parenchymal tissue becomes very evident and at 90 days of age, this mass of tissue has grown to approximately 10 g, a approximately 60-fold increase. At 2 months of age, most proliferating epithelial cells (>92%) are confined to a population of light and intermediate-staining parenchymal cells. Between 2 and 5 months of age, a dark-staining cell population markedly emerges, but these dark cells were rarely labeled with bromodeoxyuridine (BrdU) and are likely to represent a more differentiated or committed cell lineage. The coordinated change in the proportions of each cell type suggests a progression from light-, to intermediate-, to dark-staining cell phenotypes. We are currently focusing on the importance of the ovary and mammary tissue synthesis of estrogens on emergence of specific populations of putative mammary stem cells.

Delayed acquisition of behavioral and hippocampal responses during jaw movement conditioning in aging rabbits.

Young (3-7 months; n = 7) and aging (40-49 months; n = 7) rabbits (Oryctolagus cuniculus) were classically conditioned in a trace jaw movement paradigm (300 ms tone, 450 ms trace, 200 ms intraoral water) after implantation of electrodes into area CAI of dorsal hippocampus. Aging rabbits took significantly more trials to reach a behavioral criterion of 8 conditioned responses in any 9 consecutive trials than young rabbits (p = 0.04), and their conditioned, but not unconditioned, jaw movement responses were of a lower frequency than those of young rabbits (p = 0.02). Early in training, aging rabbits' hippocampal responses were significantly smaller just before water onset than corresponding responses of young rabbits (p = .03). The magnitude of this response was negatively correlated with trials to criterion (r = -0.60, p = 0.03). These results are interpreted in terms of age-related differences in the hippocampal contribution to jaw movement learning.

Hippocampal age differences reoccur after modification of stimulus configurations in rabbit jaw movement conditioning.

Rabbits of two age groups, young (3-7 months; n = 7) and aging (40-49 months; n = 7), were implanted with chronic recording electrodes in area CA1 of dorsal hippocampus and trained in a delay conditioned jaw movement (CJM) paradigm (after previously reaching criterion in a trace CJM paradigm with the same conditioned stimulus and unconditioned stimulus). Unlike results from the trace experiment, there was no significant difference in trials to behavioral criterion between the two age groups. There were large, but temporary, differences in the magnitude of conditioning-related hippocampal neural responses early in delay training. Aging rabbits' hippocampal responses were significantly smaller on Day 2 of delay training than corresponding responses of young rabbits (p = 0.0008). It is important to note that neural differences were not observed on Days 1 and 3 of delay training or at criterion performance in the prior trace conditioning. These results are interpreted in terms of age-related differences in hippocampal responsiveness to changes in biologically significant stimulus configurations.

Interactions between the ovary and the local IGF-I axis modulate mammary development in prepubertal heifers.

The objective was to determine the effects of ovariectomy and epithelial-stromal interactions on mammary development and local expression of IGF-I and IGF-binding protein (IGFBP) mRNA in prepubertal heifers. An epithelium-free ('cleared') fat pad (CFP) was prepared in two glands in each of 14 Holstein heifers, aged 1-3 Months. Eight of the calves were also ovariectomized. Serum concentrations of GH, IGF-I and prolactin were not affected by ovariectomy. At 6 Months of age, calves were killed to provide mammary samples of parenchyma, CFP and intact fat pad (MFP). Total mammary mass was reduced in ovariectomized calves (130+/-21 g vs 304+/- 25 g; P<0.001), and in several cases parenchymal tIssue was essentially absent. Uterus weight was also reduced by ovariectomy (14.5+/-3.8 g vs 30.4+/-4.5 g; P<0.05). In support of our hypothesis that local IGF-I mediates prepubertal mammary development, mRNA expression of IGF-I was lower in ovariectomized than in control calves (62.1+/-7.8 vs 91.6+/-7.8 arbitrary units; P<0.05). Specific binding of IGF-I to mammary parenchymal microsomes was also reduced by ovariectomy (377+/-142 vs 868+/-82 c.p.m.; P<0.01), suggesting decreased sensitivity to IGF-I. Expression of IGFBP-3 and IGFBP-5 mRNA were not influenced by ovariectomy. Expression of IGF-I, IGFBP-3 and IGFBP-5 mRNA did not differ between CFP and MFP, suggesting that expression of these factors was not influenced by interactions between stroma and developing epithelium. Overall, the data suggested that interactions between the ovary and the local IGF-I axis act to optimize the availability and effectiveness of IGF-I within the gland to stimulate mammary growth.

Water deprivation optimizes hippocampal activity and facilitates nictitating membrane conditioning.

The effects of water deprivation on hippocampal responsiveness and behavior during nictitating membrane (NM) conditioning were assessed in 12 New Zealand White rabbits (Oryctolagus cuniculus). The results showed that water deprivation produced a significant shift in electroencephalographic (EEG) frequencies such that deprived rabbits had a higher proportion of 2-8 Hz activity than did ad-lib controls. In subsequent NM training, the rabbits took significantly fewer trials to reach criterion (M = 66 vs. M = 117). A correlation coefficient quantitatively describing the relation between pretraining EEG patterns and subsequent learning rate was highly significant (r = .84). Multiple-unit analyses indicated that deprivation enhanced hippocampal responsiveness to the conditioning stimuli, especially early in training. It was concluded that the hippocampus is responsive to motivational level and that one role of the hippocampus is in the nonassociative, modulatory processes that affect the rate of conditioning.

Scopolamine disruption of septo-hippocampal activity and classical conditioning.

Sixteen New Zealand White rabbits were implanted with multiple-unit recording electrodes in the hippocampus and lateral septum. Animals received either scopolamine hydrobromide (HBr) or scopolamine methylbromide (MBr, 1.5 mg/kg sc) prior to nictitating membrane conditioning. Slow wave analysis indicated that HBr reduced 5- to 8-Hz and increased 9- to 12-Hz hippocampal activity and increased 1- to 4-Hz activity in both hippocampus and lateral septum. Integrated unit activity from the HBr group showed suppression of responses in septum and hippocampus during learning, whereas the MBr group developed conditioned responses in both structures. Behavioral findings indicated that HBr took longer to reach criterion (M = 329.5 +/- 45.3) than MBr (M = 120.2 +/- 16.0). This experiment showed that centrally active anticholinergic drugs alter the patterns of neuronal activity in the septo-hippocampal region that predict and accompany normal learning. Such drugs delay behavioral acquisition as well, a result suggesting a modulatory role for this brain system in the acquisition phase of classical conditioning.

Medial septal microinfusion of scopolamine disrupts hippocampal activity and trace jaw movement conditioning.

This study investigated the effects of microinfusion of scopolamine into the medial septum (MS Scp) on hippocampal neurophysiology and learning of the rabbit's classically conditioned jaw movement response. The percentage of hippocampal theta slow waves (2-8 Hz) decreased after drug infusion in the MS Scp group but did not change in control groups that received infusion of saline into the MS or scopolamine into the cortex. Unit recordings from the MS Scp group showed significantly smaller conditioning-related hippocampal neural responses than seen in controls, and during conditioning, rabbits in the MS Scp group took significantly longer to reach learning criterion than either control group. Thus, the neural and behavioral impairments previously reported for systemic muscarinic blockade were reproduced by microinfusions restricted to the medial septal nucleus.