The clinical utility of TRACP-5b to monitor anti-resorptive treatments of osteoporosis.

TRACP-5b can be used to monitor the response of treatments in osteoporosis. We investigated the effect of feeding on levels of TRACP-5b and how these markers perform in a clinical setting. After feeding, there was no effect on levels TRACP-5b. It has similar diagnostic accuracy to CTX and PINP. INTRODUCTION: Bone turnover markers (BTMs) can be used to monitor response to osteoporosis treatment. However, some are affected by food intake and are not suitable to measure in a clinical setting. An assay is available which is capable of detecting the active isoform 5b of tartrate resistance acid phosphatase (TRACP-5b) and it may have minimal biological variation. Our aims were to investigate the effect of feeding on levels of TRACP-5b and compare this to CTX and PINP and then to compare the diagnostic accuracy of TRACP-5b to CTX and PINP in patients with osteoporosis given commonly used treatments. METHODS: Eighteen patients were recruited to investigate the effect of feeding on BTMs. Ninety-seven patients (74 females and 23 males) receiving 5 mg annual intra-venous zoledronate (mean age 70) and 97 patients receiving no treatment were recruited as group-matched controls. Sixteen patients receiving 60 mg subcutaneous denosumab every 6 months, (mean age 76) and 16 matched controls were recruited. Seventy-six patients were receiving oral bisphosphonates: 70 mg alendronate weekly, 35 mg risedronate and 150 mg monthly ibandronate (4%). Thirty of these patients had BMD measured at the total hip and lumbar spine. An estimate of compliance was not determined. Eighty patients receiving no treatment were recruited as group-matched controls. TRACP-5b (ELISA, Nittobo) and CTX and PINP were measured in serum in the non-fasting state between 0800 and 1700. RESULTS: After feeding, there was no effect on levels TRACP-5b and significant reductions in CTX and PINP, 29% and 10%, respectively (p < 0.001). In the zoledronate and denosumab groups, there were no differences in the areas under the curves (AUCs) between TRACP-5b, PINP and CTX. In the oral bisphosphonates group, the AUCs between TRACP-5b and PINP and TRACP-5b and CTX were significantly different, p < 0.01 and p = 0.001, respectively. TRACP-5b was negatively correlated with BMD. CONCLUSION: TRACP-5b is not affected by food intake, unlike CTX and PINP. All three BTMs correlate with change in BMD at the lumbar spine and total hip. TRACP-5b has similar diagnostic accuracy to CTX and PINP with commonly used treatments for osteoporosis with the exception of oral bisphosphonate therapy.

Evaluation of estimated glomerular function (eGFR) versus creatinine clearance (CrCl) to predict acute kidney injury when using zoledronate for the treatment of osteoporosis.

Zoledronate could be contributing to the development of acute kidney injury in a small number of patients. Since estimated glomerular function (eGFR) is simpler to obtain and at least as good a predictor as creatinine clearance (CrCl), it should be used in everyday practice. INTRODUCTION: Zoledronate is widely used for the treatment of osteoporosis. A potential side effect is acute kidney injury (AKI). Advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 2019 stated that CrCl and not estimated glomerular filtration rate (eGFR) should be used and that treatment should not be given if CrCl < 35 ml/min. The objective of this study was to compare our current method of assessing renal function (eGFR) with the method proposed by the MHRA (CrCl) for predicting AKI after zoledronate infusions. METHODS: The evaluation was performed at the Metabolic Bone Centre in Sheffield Teaching Hospitals, UK. Data on all the patients who had zoledronate from 1/09/2015 to 1/10/2020 were included. RESULTS: Data on 4405 patients were retrieved (total number of infusions 7660). Creatinine in the 14 days post-infusion was available for a total of 969 infusions and AKI was observed within 14 days following 45 infusions (4.6%). One patient died due to pneumonia. One patient needed continued haemodialysis. Severe AKI (threefold in creatinine and/or eGFR < 15 ml/min/173 m2) was observed within 1 year following 24 infusions. If the MHRA recommendations had been followed, 996 infusions with baseline CrCl < 35 ml/min would not have been given. Of these, follow-up data on serum creatinine within 14 days were available for 142 infusions, showing AKI in only four (2.8%). Logistic regression showed that both CrCl and eGFR were significant factors in predicting AKI within 14 days, but that the current recommended cut-off of CrCl 35 ml/min had poor sensitivity. CONCLUSION: Since eGFR is at least as good a predictor of AKI as CrCl, and permits the treatment of more patients at high fracture risk, we recommend that eGFR is used to determine renal function for zoledronate treatment. We suggest that the infusion is given over 30 min in patients with eGFR < 50 ml/min/1.73 m2.

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.

A Multicenter Study to Evaluate Harmonization of Assays for C-Terminal Telopeptides of Type I Collagen (ß-CTX): A Report from the IFCC-IOF Committee for Bone Metabolism (C-BM).

BACKGROUND: Biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies. METHODS: We describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield UK) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers' instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method, and Concordance correlation coefficient for ß-CTX values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods. RESULTS: We identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum. CONCLUSION: Our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed.

Quantitative computed tomography discriminates between postmenopausal women with low spine bone mineral density with vertebral fractures and those with low spine bone mineral density only: the SHATTER study.

Lumbar spine volumetric bone mineral density (BMD) measured using quantitative computed tomography (QCT) can discriminate between postmenopausal women with low areal BMD with and without vertebral fractures. QCT provides a 3D measure of BMD, excludes the vertebral posterior elements and accounts for bone size. This knowledge could contribute to effective treatment targeting of patients with low BMD. INTRODUCTION: We evaluated the ability of lumbar spine bone mineral apparent density (BMAD), trabecular bone score (TBS) and volumetric bone mineral density (vBMD) to discriminate between postmenopausal women with low areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) with and without vertebral fractures. The discriminatory ability of lumbar spine aBMD was compared with that of BMAD, TBS and vBMD. METHODS: We studied three groups of postmenopausal women, i.e. group 1, aBMD T-score < - 1.0 and ≥ 1 vertebral fracture (n = 39); group 2, aBMD T-score < - 1.0 and no vertebral fracture, age- and aBMD-matched to group 1 (n = 34); group 3, aBMD score > - 1 and no vertebral fracture, age-matched to group 1 (n = 37). Lumbar spine aBMD was measured by DXA. BMAD was calculated using the DXA scan results. TBS was derived following DXA scan image reanalysis. Lumbar spine vBMD was assessed by quantitative computed tomography and Mindways Pro software. Differences in variables between groups 1, 2 and 3 were examined using general linear univariate modelling approaches. Area under the receiver operating characteristic (ROC) curve was calculated for BMAD, TBS and vBMD to determine the ability of lumbar spine measurement variables to discriminate between group 1 and group 2. A comparison of ROCs was performed. RESULTS: Lumbar spine BMAD and TBS measurement variables were similar for groups 1 and 2. However, vBMD was significantly lower in group 1 and could discriminate between those women with low aBMD with (group 1) and without vertebral fractures (group 2). CONCLUSIONS: We conclude that lumbar spine vBMD may discriminate well between postmenopausal women with low aBMD with and without vertebral fractures as it provides a 3D measure of bone mineral density, excludes the posterior elements of the vertebrae and takes into account bone size. A unique feature of the SHATTER study is that groups 1 and 2 were matched for aBMD, thus our study findings are independent of aBMD. Furthermore, we observed that neither BMAD nor TBS could distinguish between women with low aBMD with and without vertebral fractures. The knowledge gained from the SHATTER study will influence clinical and therapeutic decision-making, thereby optimising the care of patients with and without vertebral and other fragility fractures.

Harmonization of commercial assays for PINP; the way forward.

International Federation of Clinical Chemistry and Laboratory Medicine and The International Osteoporosis Foundation Joint Committee on Bone Metabolism believes that the harmonization of PINP assays is an achievable and practical goal. INTRODUCTION: In order to examine the agreement between current commercial assays, a multi-center study was performed for PINP in serum and plasma. METHODS: The automated methods for PINP (Roche Cobas and IDS iSYS) gave similar results. A significant proportional bias was observed between the two automated assays and the Orion radioimmunoassay (RIA) for PINP. RESULTS: Results from other published studies comparing PINP values among these three assays broadly support our findings. Taken together, these results confirm that harmonized PINP measurements exist between the two automated assays (Roche Cobas and IDS iSYS) when the eGFR is > 30 mL/min/1.73m2, but a significant bias exists between the Orion RIA and the two automated assays. CONCLUSION: Therefore, in subjects with normal renal function, PINP results reported by the Roche Cobas and IDS iSYS assays are similar and may be used interchangeably, and similar reference intervals and treatment targets could be applied for the two automated assays. Harmonization between the automated assays and the RIA is potentially possible with the use of common calibrators and the development of a reference method for PINP. This should also help ensure that any new commercial assay developed in the future will attain similar results. IOF and IFCC are committed to working together towards this goal with the cooperation of the reagent manufacturing industry.

Discordant pattern of peripheral fractures in diabetes: a meta-analysis on the risk of wrist and ankle fractures.

To clarify if the peripheral microarchitectural abnormalities described in diabetics have clinical consequences, we evaluated the risk of wrist and ankle fractures. The meta-analysis resulted in an increase in the risk of ankle fractures and a decrease in wrist fractures risk, suggesting that microarchitecture may not be the major fracture determinant. INTRODUCTION: There is evidence for an increase in the risk of hip fractures in diabetes (both in type 1 and 2), but the risk is not established for other skeletal sites. Microarchitecture evaluations have reported a decrease in volumetric bone mineral density and an increase in cortical porosity at the radius and tibia. To investigate if there is a clinical consequence for these microarchitectural abnormalities, we performed a systematic review and meta-analysis on the risk of ankle and wrist fractures in diabetes. METHODS: Medline and Embase were searched using the terms 'diabetes mellitus', 'fracture', 'ankle', 'radius' and 'wrist'. Relative risks and 95% confidence intervals were calculated using random effects model. RESULTS: For ankle fractures, six studies were selected including 2,137,223 participants and 15,395 fractures. For wrist fractures, 10 studies were eligible with 2,773,222 subjects and 39,738 fractures. The studies included men and women, ages 20 to 109 years for the wrist and 27 to 109 years for the ankle. The vast majority of subjects had type 2 diabetes. Diabetes was associated with an increase in the risk of ankle fractures (RR 1.30 95%CI 1.15-1.48) and a decrease in wrist fractures (RR 0.85 95%CI 0.77-0.95). In the studies that reported body mass index (BMI), the mean values were 10% higher in the diabetic groups than controls. CONCLUSION: The risk of fractures is increased in diabetes at the ankle and decreased at the wrist. The same pattern is observed in obesity. Although bone microarchitectural features are different in obesity and diabetes, the epidemiology of peripheral fractures is similar in both diseases suggesting that microarchitecture may not be the major determinant of peripheral fractures in these populations.

Bone turnover markers to explain changes in lumbar spine BMD with abaloparatide and teriparatide: results from ACTIVE.

Early PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents. INTRODUCTION: We evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an "uncoupling index" (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups. METHODS: Blood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient. RESULTS: Early BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P < 0.0001) with abaloparatide (r = 0.561) than teriparatide (r = 0.198). The mean UI at 1 month was greater for abaloparatide versus teriparatide (1.743 and 1.493, respectively; P = 0.03) but was similar at 3 months or later time points. CONCLUSIONS: Early s-PINP changes correlate with percentage change in lumbar spine BMD 18 months after treatment with both abaloparatide and teriparatide, though the correlation with abaloparatide was greater. The UI was similar between abaloparatide and teriparatide suggesting that the balance between formation and resorption markers was similar.

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis.

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment. INTRODUCTION: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD). METHODS: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value. RESULTS: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046). CONCLUSION: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss. METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Association of incident hip fracture with the estimated femoral strength by finite element analysis of DXA scans in the Osteoporotic Fractures in Men (MrOS) study.

Finite element model can estimate bone strength better than BMD. This study used such a model to determine its association with hip fracture risk and found that the strength estimate provided limited improvement over the hip BMDs in predicting femoral neck (FN) fracture risk only. INTRODUCTION: Bone fractures occur only when it is loaded beyond its ultimate strength. The goal of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture as a single condition or with femoral neck (FN) and trochanter (TR) fractures separately in older men. METHODS: This prospective case-cohort study included 91 FN and 64 TR fracture cases and a random sample of 500 men (14 had a hip fracture) from the Osteoporotic Fractures in Men study during a mean ± SD follow-up of 7.7 ± 2.2 years. We analysed the baseline DXA scans of the hip using a validated plane-stress, linear-elastic FE model of the proximal femur and estimated the femoral strength during a sideways fall. RESULTS: The estimated strength was significantly (P < 0.05) associated with hip fracture independent of the TR and total hip (TH) BMDs but not FN BMD, and combining the strength with BMD did not improve the hip fracture prediction. The strength estimate was associated with FN fractures independent of the FN, TR and TH BMDs; the age-BMI-BMD adjusted hazard ratio (95% CI) per SD decrease of the strength was 1.68 (1.07-2.64), 2.38 (1.57, 3.61) and 2.04 (1.34, 3.11), respectively. This association with FN fracture was as strong as FN BMD (Harrell's C index for the strength 0.81 vs. FN BMD 0.81) and stronger than TR and TH BMDs (0.8 vs. 0.78 and 0.81 vs. 0.79). The strength's association with TR fracture was not independent of hip BMD. CONCLUSIONS: Although the strength estimate provided additional information over the hip BMDs, its improvement in predictive ability over the hip BMDs was confined to FN fracture only and limited.

Teriparatide treatment exerts differential effects on the central and peripheral skeleton: results from the MOAT study.

The central and peripheral skeleton was characterised using imaging techniques during 104 weeks of teriparatide treatment. Teriparatide exerts differential effects on the central and the peripheral skeleton. Overall, we did not observe a change in total body bone mineral. Our conclusions are constrained by the study limitations. INTRODUCTION: Teriparatide stimulates bone formation and resorption and therefore can cause bone gain and loss. We simultaneously characterised the central and peripheral skeleton using imaging techniques to better understand the mechanism of action of teriparatide. METHODS: Postmenopausal, osteoporotic women (n = 20, 65.4 ± 5.5 years) were recruited into a 104-week study of teriparatide. Imaging techniques included DXA, quantitative computed tomography (QCT), and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Total lumbar spine areal bone mineral content (aBMC) (+ 11.2%), total lumbar spine areal bone mineral density (aBMD) (+ 8.1%), subregional thoracic spine aBMD (+ 7.5%), lumbar spine aBMC (+ 23.5%), lumbar spine aBMD (+ 11.9%), pelvis aBMC (+ 9.3%), and pelvis aBMD (+ 4.3%) increased. However, skull aBMC (- 5.0%), arms aBMC (- 5.1%), legs aBMC (- 2.9%), and legs aBMD (- 2.5%) decreased. Overall, we did not observe a change in total body bone mineral. Increases in L1-L3 volumetric BMD (vBMD) (+ 28.5%) occurred but there was no change in total proximal femur vBMD. Radius and tibia cortical vBMD (- 3.3 and - 3.4%) and tissue mineral density (- 3.2 and - 3.8%) decreased and there was an increase in porosity (+ 21.2 and + 10.3%). Tibia, but not radius, trabecular inhomogeneity (+ 3.2%), and failure load (+ 0.2%) increased, but cortical thickness (- 3.1%), area (- 2.9%), and pore volume (- 1.6%) decreased. CONCLUSIONS: Teriparatide exerts differential effects on the central and the peripheral skeleton. Central trabecular vBMD (L1-L3) is improved, but there is a concomitant decrease in peripheral cortical vBMD and an increase in porosity. Overall, we did not observe a change in total body bone mineral. We acknowledge that our conclusions may be speculative and are constrained by the technical limitations of the imaging techniques used, the lack of a control group, and the small sample size studied.

Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density.

The antiresorptive potency varies between different bisphosphonates. We investigated the effect of stopping oral bisphosphonate treatment for postmenopausal osteoporosis (ibandronate, alendronate, risedronate) on BTMs and BMD. After stopping treatment, all three groups showed an increase in BTMs and a decrease in hip BMD; however, none returned to pre-treatment baseline values. INTRODUCTION: Bisphosphonates (BPs) continue to suppress bone turnover markers (BTMs) after treatment has stopped, leading to the suggestion that a pause in treatment could be considered for low-risk patients. Indirect comparisons suggest that after cessation of treatment, the effects on bone may differ between drugs. We investigated the effects of stopping oral BP treatments for postmenopausal osteoporosis on BTMs and bone mineral density (BMD). METHODS: We studied postmenopausal osteoporotic women who had previously taken part in a 2-year randomised study of three oral BPs (ibandronate, alendronate, or risedronate). At the end of the study, women with hip BMD T-score > - 2.5 and considered clinically appropriate to discontinue treatment were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: All BTMs increased after treatment withdrawal but remained below the pre-treatment baseline with less suppression of BTMs for the risedronate group compared to alendronate and ibandronate up to 48 weeks. There was no difference between the BP groups 96 weeks after stopping treatment. The change in BMD during the 96 weeks after stopping treatment was - 1.6% (95% CI - 1.9 to - 1.2, P < 0.001) for the total hip and - 0.6% (95% CI - 1.1 to - 0.2, P = 0.17) at the lumbar spine with no difference between the three BP groups (P = 0.85 and P = 0.48, respectively). CONCLUSION: For all treatment groups, there was an increase in BTMs and a decrease in hip BMD after stopping BPs for 2 years; however, none returned to pre-treatment baseline values.

Diagnosis and management of bone fragility in diabetes: an emerging challenge.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users.

Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors. INTRODUCTION: ONJ is a rare event in users of oral bisphosphonates. Our aims were to evaluate if the risk of surgically treated ONJ increases with longer or more compliant treatment with alendronate for osteoporosis and to identify risk factors for surgically treated ONJ. METHODS: Open nationwide register-based cohort study containing one nested case-control study. Patients were treatment-naïve incident users of alendronate 1996-2007 in Denmark, both genders, aged 50-94 at the time of beginning treatment (N = 61,990). Participants were followed to 31 December 2013. RESULTS: Over a mean of 6.8 years, 107 patients received surgery for ONJ or related conditions corresponding to an incidence rate of 2.53 (95% confidence interval (CI) 2.08 to 3.05) per 10,000 patient years. Recent use was associated with an adjusted odds ratio (OR) 4.13 (95% CI 1.94 to 8.79) compared to past use. Similarly, adherent users (medication possession ratio (MPR) >50%) were at two to threefold increased risk of ONJ compared to low adherence (MPR <50%), and long-term (>5 years) use was related with higher risk (adjusted OR 2.31 (95% CI (1.14 to 4.67)) than shorter-term use. History of rheumatoid disorders and use of proton pump inhibitors were independently associated with surgically treated ONJ. CONCLUSIONS: Our data suggest that recent, long-term, and compliant uses of alendronate are associated with an increased risk of surgically treated ONJ. Nevertheless, the rates remain low, even in long-term adherent users. ONJ risk appears higher in patients with conditions likely to indirectly affect the oral mucosa.

Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability.

The National Bone Health Alliance (NBHA) recommends standardized sample handling and patient preparation for C-terminal telopeptide of type I collagen (CTX-I) and N-terminal propeptide of type I procollagen (PINP) measurements to reduce pre-analytical variability. Controllable and uncontrollable patient-related factors are reviewed to facilitate interpretation and minimize pre-analytical variability. INTRODUCTION: The IOF and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group have identified PINP and CTX-I in blood to be the reference markers of bone turnover for the fracture risk prediction and monitoring of osteoporosis treatment. Although used in clinical research for many years, bone turnover markers (BTM) have not been widely adopted in clinical practice primarily due to their poor within-subject and between-lab reproducibility. The NBHA Bone Turnover Marker Project team aim to reduce pre-analytical variability of CTX-I and PINP measurements through standardized sample handling and patient preparation. METHODS: Recommendations for sample handling and patient preparations were made based on review of available publications and pragmatic considerations to reduce pre-analytical variability. Controllable and un-controllable patient-related factors were reviewed to facilitate interpretation and sample collection. RESULTS: Samples for CTX-I must be collected consistently in the morning hours in the fasted state. EDTA plasma is preferred for CTX-I for its greater sample stability. Sample collection conditions for PINP are less critical as PINP has minimal circadian variability and is not affected by food intake. Sample stability limits should be observed. The uncontrollable aspects (age, sex, pregnancy, immobility, recent fracture, co-morbidities, anti-osteoporotic drugs, other medications) should be considered in BTM interpretation. CONCLUSION: Adopting standardized sample handling and patient preparation procedures will significantly reduce controllable pre-analytical variability. The successful adoption of such recommendations necessitates the close collaboration of various stakeholders at the global stage, including the laboratories, the medical community, the reagent manufacturers and the regulatory agencies.

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia.

UNLABELLED: We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary. INTRODUCTION: The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene. METHODS: Fifty postmenopausal osteopenic women (age 51-72 years) were randomised to raloxifene or no treatment for 2 years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40 years). Bone mineral density (BMD) was measured at the spine and hip. RESULTS: There was a decrease in BTM in response to raloxifene treatment, percentage change at 12 weeks: C terminal telopeptide of type I collagen (CTX) -39 % (95 % CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32 % (95 % CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12 weeks was as follows: CTX 38 % and PINP 52 % and at 48 weeks CTX 60 % and PINP 65 %. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40 % and PINP 45 %. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031 g/cm(2) (95 % CI 0.016 to 0.046, P < 0.001). CONCLUSIONS: The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.