The impact of teriparatide adherence and persistence on fracture outcomes.

UNLABELLED: The study investigated the real-world relationship between teriparatide adherence and persistence and fracture outcomes in a US claims database. Fracture risk was estimated to decrease as adherence and persistence increased for any clinical, vertebral, and non-vertebral fractures. Greater emphasis on programs to increase patient adherence may improve clinical outcomes. INTRODUCTION: Adherence to osteoporosis treatment is essential for achieving optimal therapeutic outcomes. Previous findings from clinical trials and observational studies demonstrate that longer teriparatide (TPTD) exposure is associated with fewer fractures. The study aim was to investigate real-world relationships between TPTD adherence and persistence and fracture outcomes. METHODS: The Thomson Reuters MarketScan® database, 2004-2008, was used to identify TPTD users with continuous enrollment 12 months pre- and 24 months post-TPTD initiation. Post-index fractures included vertebral and non-vertebral. Adherence (medication possession ratio, MPR) groups were defined as high (MPR ≥ 0.80), medium (0.5 ≤ MPR < 0.8), and low (MPR < 0.5). Persistence groups were defined by periods 1-6, 7-12, 13-18, and 19-24 months. Logistic regressions modeled fracture risk for any clinical, hip, vertebral, and non-vertebral fractures, controlling for patient characteristics, insurance and healthcare provider types, Charlson comorbidity index, bone mineral density screening, medication use, and fracture history. RESULTS: Among 3,587 TPTD patients (mean age 68.9 years; 91% female), fracture risk was lowest in high MPR patients in all models except hip (OR = 1.17; p = 0.64). Medium versus high MPR was a significant risk factor for any fracture (OR = 1.49; p = 0.004) and non-vertebral fracture (OR = 1.45; p = 0.014); low-MPR was a significant risk factor for any fracture (OR = 1.64; p < 0.01), vertebral fracture (OR = 2.56; p = 0.001), and non-vertebral fracture (OR = 1.44; p = 0.013). Persistence of 1-6 months versus 19-24 months was associated with higher risk for any clinical (OR = 1.88, p < 0.001), vertebral (OR = 3.69; p < 0.001), and non-vertebral fracture (OR = 1.51; p = 0.011), but not hip (OR = 1.93; p = 0.08). CONCLUSIONS: Fracture risk decreased as TPTD adherence and persistence increased for any clinical, vertebral, and non-vertebral fractures.

Adherence and persistence with teriparatide among patients with commercial, Medicare, and Medicaid insurance.

UNLABELLED: Adherence to, and persistence with, treatments for osteoporosis are low. Adherence with teriparatide decreases over time. Higher copayments in the commercial/Medicare population were associated with worse persistence. Understanding factors such as prior screening, prior treatment history, and out of pocket costs that influence persistence with teriparatide may help clinicians make informed decisions. INTRODUCTION: The purpose of this study was to evaluate adherence and persistence with teriparatide. METHODS: Beneficiaries with at least one claim for teriparatide in 2003 or 2004 and continuous enrollment in the previous 12 months and subsequent 6 months were identified in a national commercial/Medicare and Medicaid administrative claims database (MarketScan®). Adherence was assessed through calculation of the medication possession ratio (MPR). Persistence was measured by time until discontinuation and time until first 60-day gap in treatment. Factors associated with persistence were assessed using Cox proportional hazards models. RESULTS: The average MPR at 6 months was 0.74 (N=2,218) and at 12 months, was 0.66 (N=1,303). At 6 months, 64.6% of patients remained on therapy and at 12 months, 56.7% remained. Bone mineral density screening and use of antiresorptive therapy within the 12 months pre-period, and lower patient copayments were associated with increased persistence. CONCLUSION: Patients appear to have good adherence with teriparatide over the first 6 months which declines over time. Prior screening and treatment of osteoporosis and out of pocket costs appear to impact persistence. To optimize patient outcomes, clinicians should consider clinical factors that impact persistence, while healthcare decision makers should consider the negative effect of higher patient copayments on persistence.

Characteristics of patients initiating teriparatide for the treatment of osteoporosis.

UNLABELLED: The demographic and clinical characteristics of patients initiating teriparatide were compared with those of patients initiating bisphosphonates for the treatment of osteoporosis. In these samples of commercially insured, Medicare, and Medicaid patients, patients initiating teriparatide were older, in poorer health, and appeared to have more severe osteoporosis than patients initiating bisphosphonates. INTRODUCTION: The demographic and clinical characteristics of patients initiating teriparatide are compared with those of patients initiating bisphosphonates. METHODS: Beneficiaries (45 years and older) with at least one claim for teriparatide or a bisphosphonate from 2003 to 2005 and continuous enrollment in the previous 12 months and subsequent 6 months were identified from commercial, Medicare, and Medicaid administrative claims databases. Patients initiating teriparatide (commercial/Medicare (N = 2,218); Medicaid (N = 824)) were compared to patients initiating bisphosphonates (commercial/Medicare (N = 97,570); Medicaid (N = 77,526)) in terms of age, provider specialty, comorbidities, prior use of osteoporosis medications, fractures, BMD screening, health status, and resource utilization. RESULTS: Teriparatide patients were older and in poorer health than bisphosphonate patients. Approximately 38% of teriparatide patients in both groups had fractured in the pre-period compared to 16% of commercial/Medicare and 15% of Medicaid bisphosphonate patients. Teriparatide patients were more likely to have used osteoporosis medications in the pre-period (79.9% versus 32.1% (commercial/Medicare); 82.2% versus 19.6% (Medicaid)). CONCLUSIONS: In these samples of patients, those initiating teriparatide differed from those initiating bisphosphonates. Teriparatide patients were older, in poorer health, and appeared to have more severe osteoporosis than bisphosphonate patients. Comparisons of treatment outcomes should take these differences in patient characteristics into consideration.

In vitro reconstitution and analysis of the chain initiating enzymes of the R1128 polyketide synthase.

Biosynthesis of the carbon chain backbone of the R1128 substances is believed to involve the activity of a ketosynthase/chain length factor (ZhuB/ZhuA), an additional ketosynthase (ZhuH), an acyl transferase (ZhuC), and two acyl carrier proteins (ACPs; ZhuG and ZhuN). A subset of these proteins initiate chain synthesis via decarboxylative condensation between an acetyl-, propionyl-, isobutyryl-, or butyryl-CoA derived primer unit and a malonyl-CoA derived extender unit to yield an acetoacetyl-, beta-ketopentanoyl-, 3-oxo-4-methylpentanoyl-, or beta-ketohexanoyl-ACP product, respectively. To investigate the precise roles of ZhuH, ZhuC, ZhuG, and ZhuN, each protein was expressed in Escherichia coli and purified to homogeneity. Although earlier reports had proposed that ZhuC and its homologues played a role in primer unit selection, direct in vitro analysis of ZhuC showed that it was in fact a malonyl-CoA:ACP malonyltransferase (MAT). The enzyme could catalyze malonyl transfer but not acetyl- or propionyl-transfer onto R1128 ACPs or onto ACPs from other biosynthetic pathways, suggesting that ZhuC has broad substrate specificity with respect to the holo-ACP substrate but is specific for malonyl-CoA. Thus, ZhuC supplies extender units to both the initiating and elongating ketosynthases from this pathway. To interrogate the primer unit specificity of ZhuH, the kinetics of beta-ketoacyl-ACP formation in the presence of various acyl-CoAs and malonyl-ZhuG were measured. Propionyl-CoA and isobutyryl-CoA were the two most preferred substrates of ZhuH, although acetyl-CoA and butyryl-CoA could also be accepted and elongated. This specificity is not only consistent with earlier reports demonstrating that R1128B and R1128C are the major products of the R1128 pathway in vivo, but is also in good agreement with the properties of the ZhuH substrate binding pocket, as deduced from a recently solved crystal structure of the enzyme. Finally, to investigate the molecular logic for the occurrence of not one but two ACP genes within the R1128 gene cluster, the inhibition of ZhuH-catalyzed formation of beta-ketopentanoyl-ACP was quantified in the presence of apo-ZhuG or apo-ZhuN. Both apo-proteins were comparable inhibitors of the ZhuH catalyzed reaction, suggesting that the corresponding apo-proteins can be used interchangeably during chain initiation. Together, these results provide direct biochemical insights into the mechanism of chain initiation of an unusual bacterial aromatic PKS.

Alkali metal cation-pi interactions observed by using a lariat ether model system.

The Na(+) or K(+) cation-pi interaction has been experimentally probed by using synthetic receptors that comprise diaza-18-crown-6 lariat ethers having ethylene sidearms attached to aromatic pi-donors. The side chains are 2-(3-indolyl)ethyl (7), 2-(3-(1-methyl)indolyl)ethyl (8), 2-(3-(5-methoxy)indolyl)ethyl (9), 2-(4-hydroxyphenyl)ethyl (10), 2-phenylethyl (11), 2-pentafluorophenylethyl (12), and 2-(1-naphthyl)ethyl (13). Solid-state structures are reported for six examples of alkali metal complexes in which the cation is pi-coordinated by phenyl, phenol, or indole. Indole-containing crown, 7, adopts a similar conformation when bound by NaI, KI, KSCN, or KPF(6). In each case, the macroring and both arenes coordinate the cation; the counteranion is excluded from the solvation sphere. NMR measurements in acetone-d(6) solution confirm the observed solid-state conformations of unbound 7 and 7.NaI. In 7.Na(+) and 7.K(+), the pyrrolo, rather than benzo, subunit of indole is the pi-donor for the alkali metal cation. Cation-pi complexes were also observed for 10.KI and11.KI. In these cases, the orientation of the cation on the aromatic ring is in accord with the binding site predicted by computational studies. In contrast to the phenyl case (11) the pentafluorophenyl group of 12 failed to coordinate K(+). Solid-state structures are also reported for 7.NaPF(6), 10.NaI, 11.NaI, 13.KI, 13.KPF(6), and 9.NaI, in which cation-pi complexation is not observed. Steric and electrostatic considerations in the pi-complexation of alkali metal cations by these lariat ethers are thought to account for the observed complexation behavior or lack thereof.

Synthetic receptors as models for alkali metal cation-pi binding sites in proteins.

The alkali metal cations Na(+) and K(+) have several important physiological roles, including modulating enzyme activity. Recent work has suggested that alkali metal cations may be coordinated by pi systems, such as the aromatic amino acid side chains. The ability of K(+) to interact with an aromatic ring has been assessed by preparing a family of synthetic receptors that incorporate the aromatic side chains of phenylalanine, tyrosine, and tryptophan. These receptors are constructed around a diaza-18-crown-6 scaffold, which serves as the primary binding site for an alkali metal cation. The ability of the aromatic rings to coordinate a cation was determined by crystallizing each of the receptors in the presence of K(+) and by solving the solid state structures. In all cases, complexation of K(+) by the pi system was observed. When possible, the structures of the unbound receptors also were determined for comparison. Further proof that the aromatic ring makes an energetically favorable interaction with the cation was obtained by preparing a receptor in which the arene was perfluorinated. Fluorination of the arene reverses the electrostatics, but the aromaticity is maintained. The fluorinated arene rings do not coordinate the cation in the solid state structure of the K(+) complex. Thus, the results of the predicted electrostatic reversal were confirmed. Finally, the biological implications of the alkali metal cation-pi interaction are addressed.