The HEP Score: A Nomogram-Derived Hematoma Expansion Prediction Scale.

BACKGROUND: Identification of intracerebral hemorrhage (ICH) patients at risk of substantial hematoma expansion (SHE) could facilitate the selection of candidates likely to benefit from therapies aiming to minimize ICH growth. We aimed to develop a grading tool that can be quickly used during the hyperacute phase to predict the risk of SHE. METHODS: We reviewed data from 237 spontaneous ICH patients who had baseline head CT scan within 12 h of symptom onset and follow-up CT during the following 72 h. We performed logistic regression analyses to determine the predictors of SHE (defined as an absolute increase in ICH volume >6 ml or an increase >33% on follow-up CT). We identified 6 predictors; each was assigned a point in the graphic interface of a nomogram which was used to construct a scoring system-The Hematoma Expansion Prediction (HEP) Score, varying from 0 to 18 points. We evaluated the ability of the model to predict the probability of SHE using c-statistics. RESULTS: SHE occurred in 74 patients (31.2%). The final model to predict SHE included 6 variables: time from onset to baseline CT (<3 vs. 3-12 h), history of dementia, current smoking, antiplatelet use, Glasgow Comma Scale score, and the presence of subarachnoid hemorrhage on baseline scan. The model had satisfactory discrimination ability with a bootstrap corrected c-index of 0.76 (95% CI 0.69-0.83) and good calibration. Patients with a total HEP score >3 were at greatest risk for SHE. CONCLUSIONS: We developed and internally validated a novel nomogram and an easy to use score which accurately predict the probability of SHE based on six easily obtainable parameters. This could be useful for treatment decision and stratification. External prospective validation of the HEP score is warranted before its application to other populations.

Day-night variability of hematoma expansion in patients with spontaneous intracerebral hemorrhage.

The levels of several coagulation factors, able to influence hemostatic balance, display circadian variations. We hypothesized that the onset and extent of hematoma expansion (HE) following intracerebral hemorrhage (ICH) also display diurnal patterns. We reviewed clinical, laboratory, and radiological data from 111 consecutive patients with spontaneous ICH who had baseline head computed tomography (CT) scans within 3 h of ICH onset and follow-up CT during the following 72 h. We defined any HE (AHE) as any increase in hematoma volume from baseline to follow-up CT and significant HE (SHE) as an absolute increase in hematoma volume >6 mL or relative increase >33%. We categorized the patients into 2 groups based on the timing of the initial CT scans--day group (from 0800 to 2000 h) and night group (from 2000 to 0800 h)--and performed logistic regression analyses. We also analyzed the differences in the rates of HE between the groups during six 4-h periods spanning 24 h, using χ(2) tests. We found that the rates of AHE and SHE were higher in the day versus night group (75% vs. 48%; p = 0.009 for AHE and 47.6% vs. 25.9%; p = 0.047 for SHE). On multivariable logistic regression, day group assignment was independently associated with AHE (adjusted odds ratio = 3.53; p = 0.008) but not with SHE. Both AHE and SHE peaked in the early afternoon (1200-1600 h) and reached a nadir during the 2000 to 2400 h time period, and they were significantly different between the time periods (0000-0400, 0400-0800, 0800-1200, 1200-1600, 1600-2000, and 2000-2400 h); p = 0.002 and 0.029, respectively. These exploratory findings support the presence of a daily pattern in the occurrence of HE, with a higher risk during the day hours. Our results could have implications for future therapeutic efforts targeting HE in ICH and for the triage of ICH patients. They require further validation.

Teriparatide (PTH 1-34) treatment increases peripheral hematopoietic stem cells in postmenopausal women.

Cells of the osteoblast lineage play an important role in regulating the hematopoietic stem cell (HSC) niche and early B-cell development in animal models, perhaps via parathyroid hormone (PTH)-dependent mechanisms. There are few human clinical studies investigating this phenomenon. We studied the impact of long-term daily teriparatide (PTH 1-34) treatment on cells of the hematopoietic lineage in postmenopausal women. Twenty-three postmenopausal women at high risk of fracture received teriparatide 20 mcg sc daily for 24 months as part of a prospective longitudinal trial. Whole blood measurements were obtained at baseline, 3, 6, 12, and 18 months. Flow cytometry was performed to identify hematopoietic subpopulations, including HSCs (CD34+/CD45(moderate); ISHAGE protocol) and early transitional B cells (CD19+, CD27-, IgD+, CD24[hi], CD38[hi]). Serial measurements of spine and hip bone mineral density (BMD) as well as serum P1NP, osteocalcin, and CTX were also performed. The average age of study subjects was 64 ± 5 years. We found that teriparatide treatment led to an early increase in circulating HSC number of 40% ± 14% (p = 0.004) by month 3, which persisted to month 18 before returning to near baseline by 24 months. There were no significant changes in transitional B cells or total B cells over the course of the study period. In addition, there were no differences in complete blood count profiles as quantified by standard automated flow cytometry. Interestingly, the peak increase in HSC number was inversely associated with increases in bone markers and spine BMD. Daily teriparatide treatment for osteoporosis increases circulating HSCs by 3 to 6 months in postmenopausal women. This may represent a proliferation of marrow HSCs or increased peripheral HSC mobilization. This clinical study establishes the importance of PTH in the regulation of the HSC niche within humans. © 2014 American Society for Bone and Mineral Research.

Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial.

BACKGROUND: Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone. METHODS: From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 µg teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380. FINDINGS: 94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9·1%, [SD 3·9]) than in the teriparatide (6·2% [4·6], p=0·0139) or denosumab (5·5% [3·3], p=0·0005) groups. Femoral-neck BMD also increased more in the combination group (4·2% [3·0]) than in the teriparatide (0·8% [4·1], p=0·0007) and denosumab (2·1% [3·8], p=0·0238) groups, as did total-hip BMD (combination, 4·9% [2·9]; teriparatide, 0·7% [2·7], p<0·0001; denosumab 2·5% [2·6], p=0·0011). INTERPRETATION: Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture. FUNDING: Amgen, Eli Lilly, National Center for Research Resources.

Acute decline in serum sclerostin in response to PTH infusion in healthy men.

CONTEXT: Animal models suggest that the osteoblast-stimulating actions of PTH are mediated by acute suppression of sclerostin, an inhibitor of the anabolic Wnt pathway. The immediate physiological changes in serum sclerostin in response to PTH infusion have not been reported in human studies. OBJECTIVE: We sought to determine the acute physiological effects of PTH infusion on serum sclerostin and bone turnover markers in healthy adult men. DESIGN, SETTING, AND PARTICIPANTS: Fifty-three healthy adult men underwent an 18-h iv infusion of human PTH(1-34) at a dose of 0.55 U/kg · h. OUTCOMES: Serum levels of ionized calcium, sclerostin, and markers of bone formation (osteocalcin and amino-terminal propeptide of type I procollagen) and bone resorption (C-telopeptide and N-telopeptide) were obtained at 0, 6, 12, and 18 h. RESULTS: Serum ionized calcium, C-telopeptide, and N-telopeptide increased, and osteocalcin and amino-terminal propeptide of type I procollagen fell linearly throughout the PTH infusion (P < 0.001 for all). Average ± sem sclerostin levels declined from 936 ± 65 to 813 ± 63 pg/ml at 6 h (P < 0.001) and remained stably suppressed for the duration of the PTH infusion. There were no significant correlations between change in sclerostin and change in bone markers. CONCLUSIONS: Serum sclerostin declined in response to acute PTH infusion within 6 h in healthy adult men. The early plateau in sclerostin suppression may indicate that maximal stimulation of the Wnt pathway is achieved quickly after exposure to PTH. Our findings support the hypothesis that PTH may mediate its anabolic effects in part via suppression of sclerostin.