Persistence and compliance with osteoporosis therapies among postmenopausal women in the UK Clinical Practice Research Datalink.

Gaining full benefits from osteoporosis medications requires long-term treatment. Investigating the real-world persistence of women receiving osteoporosis medications in the UK, we found that most patients stop treatment within a year. To prevent osteoporotic fragility fractures, long-term treatment persistence must be improved. INTRODUCTION: Persistence with osteoporosis therapies has historically been poor. To treat this chronic and progressive disease, it is essential that patients receive the full benefit of these medications. We estimated persistence and compliance with osteoporosis therapies in a large sample of postmenopausal women in the UK. METHODS: Data were obtained from the Clinical Practice Research Datalink for all women aged 50 years and over or women with early menopause, who received at least one prescription in primary care for any licensed osteoporosis therapy between January 1, 2010 and December 31, 2015. Persistence and compliance at 24 months (primary objective) and at 5 years (exploratory objective) were estimated in three patient cohorts: "All Patients," "Naïve Patients," and "Drug-Specific." RESULTS: The All Patients cohort included 72,256 women. Persistence with any therapy was 56.1%, 43.6%, 36.4%, and 31.0% at 6, 12, 18, and 24 months, respectively, and 23.2% and 13.1% at 3 years and 5 years, respectively. Patients were generally more persistent and compliant if evaluated from their first exposure to osteoporosis therapy (Naïve Patients cohort). In the drug-specific analysis, 64% of patients receiving denosumab (administered subcutaneously every 6 months) were persistent at 24 months compared with 28% and 23% of those taking oral bisphosphonates and intravenous bisphosphonates, respectively. CONCLUSIONS: Only about one in three patients who received osteoporosis therapy continued to be on treatment after 2 years. There is a need to improve persistence with osteoporosis therapy, especially for high-risk patients.

Risk factors for poor health-related quality of life in cancer survivors with multiple chronic conditions: exploring the role of treatment burden as a mediator.

PURPOSE: The purpose of this study was to identify risk factors for poor health-related quality of life (HRQL) in multi-morbid adult cancer survivors and explore whether perceived treatment and self-management burden mediate any of these relationships. METHODS: Ninety-one multi-morbid cancer survivors (median age: 65 years) completed surveys at baseline and 6 months. Demographic, psychosocial, and health care-related factors were assessed as were perceived treatment burden and general HRQL (physical and mental health). Data on medical diagnoses and cancer treatment were extracted from the medical record. Bivariate correlations screened for associations between predictors and outcomes, with significant predictors entered into multivariable linear regressions to identify unique risk factors for greater treatment burden and poorer HRQL. Follow-up regressions examined whether treatment burden mediated any of the risk factor-outcome relationships. RESULTS: Factors that correlated with higher baseline treatment burden included: having more diagnoses, less formal education, having seen more physicians in the past 6 months, having a mental health diagnosis, not having a set routine for one's self-management, low health literacy, low self-efficacy for self-management, and low social support (Ps <0.05). Among these, factors that also correlated with worse 6-month HRQL outcome included: having more diagnoses, having seen more physicians in the past 6 months, having a mental health diagnosis, not having a set routine for one's self-management, low health literacy, low self-efficacy, and low social support (Ps <0.05). Multivariable regressions showed that some of these factors independently predicted higher treatment burden and/or worse HRQL. Low self-efficacy was the most robust independent risk factor for poor HRQL (bs: 0.34-0.49, Ps <0.005), with evidence supporting that the relationships were partially mediated by treatment burden. CONCLUSION: Monitoring of psychosocial and health care-related risk factors for high treatment burden and poor HRQL can identify multi-morbid cancer survivors in need of extra support and could inform a more personalized treatment approach.

Comorbidities, bone-sparing agent prescription history and their determinants among postmenopausal women in UK primary care settings: a retrospective database study.

SUMMARY: Distinguishing oral bisphosphonates from other bone-sparing therapies, this retrospective observational study, first, characterized treated osteoporosis patients in the UK, and secondly, explored factors associated with the risk of discontinuation or switching between therapies. The latter should be considered when evaluating real-world data. PURPOSE: This retrospective observational study evaluated the characteristics of women with postmenopausal osteoporosis, including comorbidities and determinants of treatment patterns with bone-sparing agents. METHODS: The UK Clinical Practice Research Datalink was used to identify postmenopausal women (aged ≥50 years) treated with a bone-sparing agent or diagnosed with osteoporosis between 1 January 1993 and 31 December 2008. Two non-mutually-exclusive subpopulations were defined: (1) patients active in the database on 31 December 2008; (2) patients treated with a bone-sparing agent since 1 January 1993. Subpopulation 1 was used to describe patient comorbidities and osteoporosis treatment history, and subpopulation 2 was used to explore the characteristics associated with bone-sparing treatment patterns use via multivariable regression for repeated multinomial responses. RESULTS: A total of 62,657 individuals met the inclusion criteria; subpopulation 1 comprised 38,469 women (61.4%), of whom 21,687 received a bone-sparing agent in 2008 (99.7% oral bisphosphonates and the remainder other agents). Those receiving other agents were more likely to have had previous treatment with bone-sparing agents, to have experienced previous fractures, and to have visited their doctor more frequently. Analyses also identified several comorbidities associated with an increased risk of discontinuation of bone-sparing agents, including heart disease, gastrointestinal disease, and renal failure. Anticonvulsant use was associated with a dramatic increase in the risk of switching. CONCLUSIONS: Several patient characteristics were associated with discontinuation of, or switching between, bone-sparing treatments. Patients receiving bone-sparing medication other than oral bisphosphonates were more likely to have comorbid conditions and a history of fracture and to have taken an oral bisphosphonate previously.

Prescribed vitamin D and calcium preparations in patients treated with bone remodelling agents in primary care: a report of a pilot study.

BACKGROUND: Recent guidelines recommend that patients receiving treatment for osteoporosis should also receive supplementation with calcium and vitamin D unless they are calcium and vitamin D replete. Given that the majority of elderly patients have inadequate levels of vitamin D and that determining nutritional status is time-consuming and costly, it seems prudent to ensure that the majority of patients aged over 65 and receiving medication for osteoporosis should receive supplementation as a matter of course. OBJECTIVES: To determine the level of co-prescription of calcium and vitamin D in patients receiving treatment for osteoporosis with bisphosphonates, teriparatide, raloxifene or strontium. STUDY DESIGN AND METHODS: A pilot audit of nine general practices covering a population of 61 202. RESULTS: Overall, 1.1% (n = 662) of patients were receiving treatment for osteoporosis; of those, only 34.1% of patients were co-prescribed calcium or calcium and vitamin D. Levels of co-prescription varied considerably across practices from 74.0% to 12.2%. CONCLUSIONS: Despite national guidelines, co-prescription of calcium and vitamin D with treatment for osteoporosis remains sub-optimal with considerable variation between practices. Strategies should be adopted to increase physician awareness of widespread vitamin D inadequacy, the rationale for supplementation and poor compliance.

Progenitor cell yield in sequential blood stem cell mobilization in the same patients: insights into chemotherapy dose escalation and combination of haemopoietic growth factor and chemotherapy.

Between April 1988 and March 1994 a total of 23 patients with haematological or non-haematological malignancies received serial peripheral blood stem cell (PBSC) mobilization to attain sufficient harvest for PBSC transplant at our institution. There was no improvement in yield with the second mobilization for group A patients (n = 12) who had the same dose of cyclophosphamide twice as mobilizing agent. For group B patients (n = 6). who had a higher dose of cyclophosphamide with the second mobilization, there was significant increase in CFU-GM yield. CD34+ cell yield was not measured. For group C patients, who received interleukin-3 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with the first mobilization and chemotherapy plus GM-CSF with the second, there was significant increase in CFU-GM as well as CD34+ cell yield. Our results demonstrate that, at the doses studied, chemotherapy dose escalation and combining haemopoietic growth factor with chemotherapy improve progenitor cell yield in PBSC mobilization.

An incremental response to high-dose therapy in multiple myeloma.

Results of conventional chemotherapy for multiple myeloma are disappointing. High-dose chemoradiotherapy with auto-transplantation is increasingly reported and some results are encouraging. We report the results of peripheral blood stem cell transplantation (PBSCT) for multiple myeloma at a single institution over a 6-year period. Forty patients, including 18 de novo patients, received debulking chemotherapy consisting of vincristine, adriamycin, and dexamethasone or methyl-prednisolone followed by stem cell mobilization with high-dose cyclophosphamide. Twenty-nine patients received PBSCT following high-dose chemoradiotherapy. Following PBSCT 92% of evaluable patients obtained at least a partial remission and 29% reached complete remission. Objective treatment responses, defined as at least a 50% reduction in serum paraprotein or marrow plasma cells, were observed following each treatment step of debulking chemotherapy, mobilization and PBSCT in 50, 42 and 71% of patients, respectively. The median overall survival from diagnosis in patients transplanted was 50 months and the median overall and progression-free survivals following transplant were 26 and 18 months, respectively. Median follow-up was 28 months. Overall treatment-related mortality was 20% but was significantly lower in de novo vs previously treated patients at 6 and 33% respectively (P = 0.027). De novo patients were more likely to obtain complete remission and had a longer overall survival following transplant but overall survival from diagnosis was similar to previously treated patients. A low serum B2M before mobilization predicted a longer progression-free survival. PBSCT needs to be considered early following diagnosis to maximise treatment response and reduce the high treatment-related mortality seen in heavily pretreated patients. In this treatment program a dose response effect in multiple myeloma was observed possibly suggesting that more intensive therapy than a single transplant may effect greater disease response.

Collection efficiency on the Fenwal CS3000 when using filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) as a peripheral blood stem cell mobilization agent.

The collection efficiency (CE) of the Fenwal CS3000 in collecting peripheral blood stem cells during post-chemotherapy recovery phase ranges from 58% to 73%. Recently filgrastim (recombinant methionyl human granulocyte colony-stimulating factor [G-CSF]) has also been shown to be effective as a mobilization agent although mobilization occurs during elevated and not low normal leukocyte counts. We compared the mononuclear cell (MNC) CE and the myeloid progenitor cell (CFU-GM) CE among 11 patients with G-CSF mobilization (33 procedures) and 19 patients during recovery following myelosuppression chemotherapy (93 procedures). Pre-apheresis leukocyte, neutrophil, MNC, and PB CFU-GM counts were significantly higher in the G-CSF group, while the granulocyte percentage in the apheresis products was similar in both groups. Both MNC CE (81.8 +/- 4.5% vs. 64 +/- 2.4%) and CFU-GM CE (79.5 +/- 10.5% vs. 55.8 +/- 3.5%) were higher in the G-CSF group. Only the pre-apheresis MNC count showed an independently significant correlation for both CE (P < .001). The higher CE in the G-CSF group can only be partly explained by a rise in MNC count during apheresis. These data suggest that the blood cell separator works better with leukocytosis, and especially with a higher MNC count. The improvement in CE is another benefit of G-CSF mobilization over chemotherapy mobilization.

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.

A comparison of peripheral blood stem cell mobilisation after chemotherapy with cyclophosphamide as a single agent in doses of 4 g/m2 or 7 g/m2 in patients with advanced cancer.

We used cyclophosphamide at a dose of 7 g/m2 in patients with advanced cancer and compared the efficacy of this treatment to generate peripheral blood stem cells (PBSC) with the previously reported regimen of cyclophosphamide 4 g/m2 in a similar group of patients. None of these patients received haemopoietic growth factors. Twenty-two patients received 7 g/m2 and 37 received 4 g/m2. PBSC were collected by apheresis after the leukocyte count recovered to 1.0 x 10(9)/L. The yield of colony forming unit-granulocyte macrophage (CFU-GM) was higher for the 7 g/m2 group with a median of 35 x 10(4)/kg versus 15 x 10(4)/kg body weight (BW) (p < 0.05) and higher mononuclear cell yield with medians of 4.2 x 10(8)/kg compared with 3.1 x 10(8)/kg BW (p < 0.001). The percentage of patients achieving the minimum safe level of > 15 x 10(4) CFU-GM/kg BW was higher in the 7 g/m2 cyclophosphamide group (82%) than the 4 g/m2 cyclophosphamide group (51%). The duration of significant neutropaenia was a median of 11 compared with nine days (p < 0.004) and all patients receiving 7 g/m2 required admission to hospital and intravenous antibiotic therapy compared with 44% in the 4 g/m2 group. There was one death during the period of neutropaenia after cyclophosphamide in each group. Nineteen per cent of patients required platelet transfusions after cyclophosphamide 7 g/m2 compared with 18% after 4 g/m2. We conclude that the 7 g/m2 cyclophosphamide gives a higher yield of haemopoietic progenitor cells than the 4 g/m2 but at increased clinical toxicity.

Total N-nitroso group analysis of foods. II. Further studies on the precision and sensitivity of the assay.

The total N-nitroso content of foods can be measured by chemical denitrosation with hydrogen bromide and chemiluminescence detection of the cleaved nitric oxide radical. The denitrosation reagent itself causes a significant detector response which has limited the application of the technique to trace analysis. A procedure is described in which the errors associated with this interference are minimized. Application of this method to the trace analysis of aqueous and solid samples is reported together with an investigation of the effects of sample size on the accuracy and sensitivity of the assay as applied to aqueous analytes. The magnitude and significance of the false-positive response from nitrate is discussed in relation to the analysis of cured meats.

Prospective follow-up of growth retarded infants and of those from pregnancies complicated by low oestriol excretion--7 years.

Growth and neurological outcome to 7 years of age were determined in 273 growth retarded infants, 341 infants from pregnancies complicated by subnormal urinary oestriol excretion and 72 control infants. By 1 year of age 80.6% of growth retarded infants were above the 10th percentile for weight. Growth continued so that after 2 years of age only 10.6% were beneath the 10th percentile. A neurological abnormality was detected in 9.5% of growth retarded infants and 8.3% of control infants (P = NS). Only 6 (2.2%) of the growth retarded infants were severely handicapped. A neurological abnormality was detected in 16.4% of infants from pregnancies with low oestriol excretion and although this incidence was higher than that of the control infants (8.3%), the difference failed to achieve statistical significance. The neurological abnormality was severe in only 7 infants (2.1%). The intelligence quotient (IQ) was the same in infants from pregnancies complicated by chronically low oestriol excretion whether hypertonic dextrose (mean IQ 103) had been administered to the mother or not (mean IQ 105). It is concluded that the pregnancy complicated by low oestriol excretion and/or fetal growth retardation should be treated with optimism.