Utility of PINP to monitor osteoporosis treatment in primary care, the POSE study (PINP and Osteoporosis in Sheffield Evaluation).

PURPOSE: In Sheffield (UK), we introduced the PINP monitoring algorithm for the management of osteoporosis treatment delivered in primary care. Our aims were to evaluate whether this algorithm was associated with better osteoporosis outcomes and was cost-effective compared to standard care. METHODS: Inclusion criteria were referral from Sheffield GPs, BMD scans performed between 2012 and 2013 and a report advising initiation of oral bisphosphonate and PINP monitoring. 906 patients were identified and retrospectively divided into Group A (intention to monitor, with baseline PINP, n = 588) and Group B (no intention to monitor, without baseline PINP, n = 318). The model described by Davis and colleagues was used to extrapolate life-time costs and quality-adjusted life-years (QALYs). RESULTS: No differences were found in baseline characteristics between groups (age, gender, BMI, BMD and major risk factors for fractures). More patients in Group A started oral treatment (77.4% vs 49.1%; p < 0.001), but there were no differences between groups in the presence of a gap in treatment >3 months or in treatment duration. Patients in Group A were more likely to have follow-up DXA scan at 4-6 years from baseline (46.9% vs 29.2%; p < 0.000) and had a greater increase in total hip BMD (+2.74% vs + 0.42%; p value = 0.003). Fewer new fractures occurred in Group A but this was not statistically significant, but the numbers of fractures were small. Patients in Group A were more likely to change management (p = 0.005) including switching to zoledronate (p = 0.03). The PINP measurement and increased prescribing in Group A resulted in increases in both costs (£30.19) and QALYs (0.0039) relative to Group B, giving an incremental cost effectiveness ratio (ICER) of £7660 in the probabilistic sensitivity analysis. CONCLUSIONS: Patients monitored with PINP are more likely to start oral bisphosphonate treatment, switch to zoledronate, have follow-up DXA scans and a greater increase of hip BMD. PINP monitoring has the potential to be cost-effective in a UK NHS setting given that interventions with an ICER under £20,000 are generally considered to be cost-effective.

Real-world bone turnover marker use: impact on treatment decisions and fracture.

The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice. INTRODUCTION: The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database. METHODS: Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture. RESULTS: Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88). CONCLUSION: In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.

Adherence to raloxifene therapy: assessment methods and relationship with efficacy.

UNLABELLED: Response to therapy depends on patient compliance but accurate assessment is difficult and adequate levels of adherence are uncertain. Adherence to raloxifene treatment may be assessed more accurately by electronic monitoring than by counting returned tablets. The level of adherence is positively associated with the degree of bone response. INTRODUCTION: Adherence to study medication is usually estimated by counting returned tablets. This method relies on subjects' honesty and may be inaccurate. We aimed to assess adherence more accurately, and examine its effect on measures of bone response, by using electronic monitoring. METHODS: Osteopenic women, ages 50 to 80, were prescribed daily raloxifene for 2 years. Electronic bottle caps (Medication Event Monitoring System (MEMS), Aardex) recorded the date and time on opening. Returned tablets were also counted. We measured bone mineral density (BMD) in duplicate at the spine and hip at baseline and 2 years. We also measured urinary N-terminal cross-linked telopeptide of type I collagen (NTX) at baseline, 1 and 2 years. We calculated the percentage changes in BMD and NTX from mean baseline to mean follow up measurements. Percentage adherence was assessed by both methods for 71 subjects that completed the study. RESULTS: The two methods correlated significantly (p <0.001, Spearman's rho = 0.73) but the tablet count showed a higher median adherence than the MEMS caps (95.7 vs. 85.0%, p <0.001), with greater divergence at lower adherence levels. MEMS adherence in 65 subjects with complete data correlated with NTX response (p <0.01, rho = -0.33) but with BMD response only at the femoral neck. However, adherence in the lowest quartile was associated with poorer BMD response at all sites (p <0.05). CONCLUSION: Tablet counts may give similar results overall but conceal substantial individual non-adherence. Monitoring caps may assess adherence more accurately than tablet counts and would be the preferred method in clinical trials. The degree of adherence is associated with both bone turnover and BMD responses to anti-resorptive therapy.

Association between incident and baseline vertebral fractures in European women: vertebral fracture assessment in the Osteoporosis and Ultrasound Study (OPUS).

UNLABELLED: Vertebral fracture assessment (VFA) with densitometric devices uses less radiation than spinal radiography. We assessed risk of new vertebral fracture (VF) in women with baseline fracture identified on VFA using algorithm-based qualitative diagnosis. Women with VF had significantly greater risk of VF after 6 years compared to those without baseline fracture. INTRODUCTION: Prevalent VFs predict future fracture and are identifiable on vertebral fracture assessment (VFA) using bone densitometry devices. We have previously performed cross-sectional, but not longitudinal, VFA using the algorithm-based qualitative method (ABQ). We aimed to examine the prevalence and incidence of VF and test the association between prevalent and incident VF identified by ABQ VFA. METHODS: We used ABQ to assess vertebral images obtained at baseline and 6 years (Hologic devices) in 674 women at ages 39 to 80 years participating in the Osteoporosis and Ultrasound Study. Criteria for prevalent and incident VF were endplate fracture, with/without cortical fracture. We compared proportions (chi-squared test) and characteristics (two-sample t tests and analysis of variance) of women with and without VF and calculated odds ratios for incident VF in women with prevalent VF (logistic regression). RESULTS: Prevalent VF was identified in one premenopausal woman and 41 postmenopausal women. Incident VF was identified in 18 postmenopausal women. Odds ratios (95% CI) for incident VF in postmenopausal women with prevalent VF were 7.8 (2.8, 22.1) (unadjusted) and 4.3 (1.4, 13.7) (adjusted for age and bone mineral density, BMD). Women with prevalent or incident VF were older (P < 0.01), with lower hip BMD (P < 0.001) compared to women without VF. CONCLUSIONS: Population-based postmenopausal women had relatively low prevalence and incidence of VF analysed with the ABQ method applied to VFA. Women with prevalent fracture had a significantly greater risk of incident VF than women without prevalent fracture.

The role of bone turnover markers and risk factors in the assessment of osteoporosis and fracture risk.

The clinical evaluation of osteoporosis in individual patients involves confirmation of the diagnosis, the investigation of secondary causes of osteoporosis and the evaluation of subsequent fracture risk. Optimum clinical assessment involves bone mineral densitometry with the treatment thresholds modified by clinical risk factors for individual patients. Bone turnover markers and clinical risk factors can be used to identify patients at risk of osteoporotic fracture and those who have secondary osteoporosis. Risk assessment should involve the evaluation of absolute rather than relative risk. Further work is required to improve the integration of clinical risk factors, bone turnover markers and bone densitometry into appropriate models to enable the assessment of the absolute risk of fracture for individual patients.

Identification of vertebral deformities in women: comparison of radiological assessment and quantitative morphometry using morphometric radiography and morphometric X-ray absorptiometry.

Our aim was to compare normal vertebral reference values for morphometric radiography (MRX) and morphometric X-ray absorptiometry (MXA) and to compare these methods for the identification of vertebral deformities. We calculated MXA reference values (Hologic QDR 4500 A) for 327 women (ages 22-88 years) randomly selected from local General Practice lists in Sheffield, U.K. MRX reference values were calculated from spinal radiographs for 123 of these subjects (ages 56-88 years). We used these reference values to identify deformities in the MRX and MXA reference populations and in 83 women with osteoporosis (ages 49-87 years). We observed differences in mean deformity of vertebral height ratios measured by MRX and MXA, especially for the mid-to-posterior ratio. We compared agreement between quantitative methods (MRX and MXA) and qualitative radiological assessment. Severity of deformity was defined by semiquantitative (SQ) assessment. Agreement was moderate for MRX (k = 0.59; 95% CI = 0.43-0.77) and for MXA (k = 0.47; 95% CI = 0.29-0.66) in the reference population. Agreement was good for MRX (k = 0.86; 95% CI = 0.82-0.89) and MXA (k = 0.71; 95% CI = 0.66-0.75) in the osteoporotic population. MRX and MXA correctly identified a greater proportion of moderate or severe deformities compared with mild deformities. Sensitivity, specificity, predictive values, and accuracy were slightly better for MRX than for MXA. Although MXA agrees well with qualitative radiological assessment, the large proportion of vertebrae excluded from analysis because of poor image quality limits the diagnostic value of the technique. Reference intervals should be technique specific.

A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update.

In the UK, over 250 000 patients take continuous oral glucocorticoids (GCs), yet no more than 14% receive any therapy to prevent bone loss, a major complication of GC treatment. Bone loss is rapid, particularly in the first year, and fracture risk may double. This review, based wherever possible on clinical evidence, aims to provide easy-to-use guidance with wide applicability. A treatment algorithm is presented for adults receiving GC doses of 7.5 mg day(-1) or more for 6 months or more. General measures, e.g. alternative GCs and routes of administration, and therapeutic interventions, e.g. cyclical etidronate and hormone replacement, are recommended.

Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels.

The cellular mechanisms for bone loss in type I (postmenopausal) osteoporosis are highly controversial. We attempted to resolve this by assessing rates of formation and resorption of iliac cancellous bone by a new histomorphometric method in 89 women with osteoporosis (mean age +/- SD, 66 +/- 6 years) and in 32 carefully selected normal postmenopausal women (64 +/- 6 years). In the osteoporotic women, bone resorption rate was increased by 39% (P less than 0.05) at the cellular level and by 67% (P less than 0.05) at the tissue level, whereas bone formation was unchanged at the tissue level but decreased by 14% (P less than 0.01) at the cellular (osteoblast) level. This pronounced remodeling imbalance (P less than 0.001) was probably exacerbated by a 45% increase (P less than 0.1) in activation frequency of new remodeling foci. These abnormalities were associated with a high rate of cancellous bone loss (median, 5.8%/year versus 0.1% year in controls). Thus, accelerated loss of cancellous bone in type I osteoporosis results from the combination of increased bone resorption and inadequate compensation by bone formation.

Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers.

In 12 younger (age, 30-41 yr) and 11 older (age, 55-73 yr) normal women we assessed bone formation rate using multiple methods. Bone formation (mean +/- SE) was higher in the older women than in the younger women, based on measurements of serum bone Gla-protein (1.67 +/- 0.07 vs. 1.14 +/- 0.10 nmol/L; P less than 0.01), serum bone-specific alkaline phosphatase activity (388 +/- 42 vs. 223 +/- 22 nanokatal/L, P less than 0.01), and bone formation rate by histomorphometry of iliac biopsy (31.1 +/- 4.9% vs. 15.1 +/- 2.7%/yr; P less than 0.01), but was similar in the two groups when accretion rates were assessed by calcium kinetics (5.9 +/- 1.0 vs. 7.5 +/- 1.2; P = NS). This latter discrepancy may have been caused by several age-related factors, especially reduced mineralization of completed osteons, and by not correcting for the decrease in total skeletal calcium in the older group. Our data call into question the traditional belief that bone turnover decreases in older women.

The assessment of postmenopausal osteoporosis by total body neutron activation analysis.

Total body calcium (TBCa) was measured using a cyclotron for in vivo neutron activation analysis (IVNAA) in 20 healthy women, 15 women with vertebral compression fractures, and 8 women with wrist fractures. The precision of the technique, using phantoms, was 1.8% for a dose of 13 mSv. A formula for predicted TBCa (TBCap) was derived from the 20 normal women based on span and years postmenopause. The coefficient of variation of TBCa after normalization in the normal women was 6.6%. The mean TBCa values for the vertebral and wrist fracture groups were 69% and 84% of TBCap for women at the time of the menopause. The low TBCa in the wrist fracture group was attributable to post-menopausal bone loss. Of the low TBCa in the vertebral fracture group, about half the loss could be attributed to postmenopausal age and half to other factors.