Romosozumab in patients who experienced an on-study fracture: post hoc analyses of the FRAME and ARCH phase 3 trials.

Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or alendronate. Recurrent fracture risk was also lower in romosozumab­treated patients, and there were no fracture­related complications. Results support continuing romosozumab treatment post­fracture. PURPOSE: Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate post­fracture period, in the FRAME and ARCH phase 3 trials. METHODS: In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatment­emergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible. RESULTS: Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% [2/56] and 1.8% [1/56] versus 9.2% [7/76] and 3.9% [3/76]; ARCH, 10.0% [7/70] and 5.7% [4/70] versus 12.6% [12/95] and 8.4% [8/95], respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% [0/17] and 0.0% [0/17] versus 11.9% [7/59] and 8.5% [5/59]; ARCH, 9.0% [6/67] and 7.5% [5/67] versus 15.0% [15/100] and 16.0% [16/100], respectively). In patients with fracture by Month 12, no fracture­related complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators. CONCLUSION: Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture. TRIAL REGISTRATIONS: NCT01575834; NCT01631214.

A genome-wide genomic score added to standard recommended stratification tools does not improve the identification of patients with very low bone mineral density.

The role of integrating genomic scores (GSs) needs to be assessed. Adding a GS to recommended stratification tools does not improve the prediction of very low bone mineral density. However, we noticed that the GS performed equally or above individual risk factors in discrimination. PURPOSE: We aimed to investigate whether adding a genomic score (GS) to recommended stratification tools improves the discrimination of participants with very low bone mineral density (BMD). METHODS: BMD was measured in three thoracic vertebrae using CT. All participants provided information on standard osteoporosis risk factors. GSs and FRAX scores were calculated. Participants were grouped according to mean BMD into very low (<80 mg/cm3), low (80-120 mg/cm3), and normal (>120 mg/cm3) and according to the Bone Health and Osteoporosis Foundation recommendations for BMD testing into an "indication for BMD testing" and "no indication for BMD testing" group. Different models were assessed using the area under the receiver operating characteristics curves (AUC) and reclassification analyses. RESULTS: In the total cohort (n=1421), the AUC for the GS was 0.57 (95% CI 0.52-0.61) corresponding to AUCs for osteoporosis risk factors. In participants without indication for BMD testing, the AUC was 0.60 (95% CI 0.52-0.69) above or equal to AUCs for osteoporosis risk factors. Adding the GS to a clinical risk factor (CRF) model resulted in AUCs not statistically significant from the CRF model. Using probability cutoff values of 6, 12, and 24%, we found no improved reclassification or risk discrimination using the CRF-GS model compared to the CRF model. CONCLUSION: Our results suggest adding a GS to a CRF model does not improve prediction. However, we noticed that the GS performed equally or above individual risk factors in discrimination. Clinical risk factors combined showed superior discrimination to individual risk factors and the GS, underlining the value of combined CRFs in routine clinics as a stratification tool.

Incident peptic ulcers and concomitant treatment of direct oral anticoagulants and oral bisphosphonates-a real-world cohort study.

Oral bisphosphonates and direct oral anticoagulants are related to upper gastrointestinal ulcers. The present study investigated whether concomitant use of these drugs increase the risk of upper gastrointestinal ulcers and report no increased risk of upper gastrointestinal ulcers compared to the use of either drug alone, when individuals with previous upper gastrointestinal ulcers are excluded. INTRODUCTION: This study examines whether concomitant use of oral bisphosphonates (oBP) and direct oral anticoagulants (DOAC) increases the risk of peptic ulcers more than any drug alone. METHODS: A population-based cohort study was performed. We sampled a cohort of oBP and DOAC users from a sample of 2,622,742 individuals, consisting of diabetes patients and age- and gender-matched controls, obtained from the Danish National Patient Register. The exposures were concomitant use of oBP and DOAC and single use of DOAC and single use of oBP. The primary endpoint was the first incident peptic ulcer. Information on exposure and outcome were collected from national registries. The period of observation was from 01.01.2008 until 31.12.2018. Unadjusted and adjusted Cox regressions were performed. RESULTS: 8077 individuals received concomitant treatment with DOAC and oBP; 96,451 individuals used DOAC and no oBP; and 118,675 used oBP and no DOAC. The mean duration of follow-up was 1.9 years for concomitant users, 2.5 years for DOAC users, and 4.5 years for oBP users. A total of 4742 individuals with incident peptic ulcers were collected. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to single DOAC treatment in the adjusted analysis (HR = 1.23, 95% CI: 1.03; 1.48). However, the effects were abolished when excluding individuals with a previous ulcer. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to users of oBP in the adjusted model (HR = 1.34, 95% CI: 1.11; 1.63). CONCLUSION: Based on our results, concomitant use of oBP and DOAC is associated with a slight increase in the risk of peptic ulcers compared to either drug alone. The prescribing physician should weigh the slight increased risk of ulcer in concomitant users of oBP and DOAC with beneficial reductions in stroke and fractures.

Socio-economic inequalities in fragility fracture incidence: a systematic review and meta-analysis of 61 observational studies.

Individuals with low socio-economic status (SES) have a more than 25% higher risk of fragility fractures than individuals with high SES. Body mass index and lifestyle appear to mediate the effect of SES on fracture risk. Strategies to prevent fractures should aim to reduce unhealthy behaviours through tackling structural inequalities. INTRODUCTION: This systematic review and meta-analysis aimed to evaluate the impact of socio-economic status (SES) on fragility fracture risk. METHODS: Medline, Embase, and CINAHL databases were searched from inception to 28 April 2021 for studies reporting an association between SES and fragility fracture risk among individuals aged ≥50 years. Risk ratios (RR) were combined in meta-analyses using random restricted maximum likelihood models, for individual-based (education, income, occupation, cohabitation) and area-based (Index of Multiple Deprivation, area income) SES measures. RESULTS: A total of 61 studies from 26 different countries including more than 19 million individuals were included. Individual-based low SES was associated with an increased risk of fragility fracture (RR 1.27 [95% CI 1.12, 1.44]), whilst no clear association was seen when area-based measures were used (RR 1.08 [0.91, 1.30]). The strength of associations was influenced by the type and number of covariates included in statistical models: RR 2.69 [1.60, 4.53] for individual-based studies adjusting for age, sex and BMI, compared with RR 1.06 [0.92, 1.22] when also adjusted for health behaviours (smoking, alcohol, and physical activity). Overall, the quality of the evidence was moderate. CONCLUSION: Our results show that low SES, measured at the individual level, is a risk factor for fragility fracture. Low BMI and unhealthy behaviours are important mediators of the effect of SES on fracture risk. Strategies to prevent fractures and reduce unhealthy behaviours should aim to tackle structural inequalities in society thereby reducing health inequalities in fragility fracture incidence.

Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal. INTRODUCTION: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. METHODS: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). RESULTS: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). CONCLUSION: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

Fracture rates in patients discontinuing alendronate treatment in real life: a population-based cohort study.

In this nationwide register-based cohort study, we found no difference in the risk of fractures in patients discontinuing versus continuing alendronate (ALN) treatment after 5 years. INTRODUCTION: Information on fracture risk in patients discontinuing ALN in a real-life setting is sparse. We aimed to examine ALN discontinuation patterns, compare fracture rates in patients discontinuing versus continuing ALN after 5 years of treatment, and define determinants of fractures in ALN discontinuers. METHODS: A nationwide population-based cohort study using Danish health registry data. Our source population was individuals who had redeemed ≥ 2 ALN prescriptions between January 1, 1995, and September 1, 2017. RESULTS: We found that 25% of all ALN initiators used ALN for less than 1 year and 43% continued treatment for at least 5 years. We classified n = 1865 as ALN discontinuers and n = 29,619 as ALN continuers. Using Cox proportional hazards regression analysis and an "as-treated" approach, we observed no increased risk of any fracture (incidence rate ratio (IRR) 1.06, 95% CI 0.92-1.23), vertebral fracture (IRR 0.59, 95% CI 0.33-1.05), hip fracture (IRR 1.04, 95% CI 0.75-1.45), or major osteoporotic fracture (IRR 1.05, 95% CI 0.88-1.25) in the ALN discontinuers compared to continuers during a follow-up time of 1.84 ± 1.56 years (mean ± SD) and 2.51 ± 1.60 years, respectively. ALN re-initiation was a major determinant of follow-up among the discontinuers. Old age (> 80 vs. 50-60 years, unadjusted IRR 2.92, 95% CI 1.18-7.24) was the strongest determinant for fractures following ALN discontinuation. CONCLUSION: In a real-world setting, less than 50% continued ALN treatment for 5 years. We found no difference in the risk of fractures in patients discontinuing versus continuing ALN after 5 years.

The predictive value of bone turnover markers during discontinuation of alendronate: the PROSA study.

In patients discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years), BMD decreased, and bone turnover markers increased within the premenopausal reference range over 2 years. Increased p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD is dependent on continued suppression of bone turnover. INTRODUCTION: It is unknown how to monitor patients discontinuing alendronate (ALN) after more than 5 years. We investigated if BTM measured before or during treatment discontinuation with ALN predict bone loss after 1 or 2 years. METHODS: PROSA was a cohort study conducted at Aarhus University Hospital including postmenopausal women and men above 50 years treated with ALN ≥ 5 years who had osteopenia at the hip and BMD T-score at the lumbar spine > - 4. ALN was discontinued and BTMs were measured at baseline, months (M) 1, 3, 6, and 12, and DXA was performed at baseline, M6, and M12. We extended the study and measured BTMs and performed DXA at M24. The primary endpoint was if changes in p-CTX at M3 or M6 predict changes in THBMD after 1 year ( Clinicaltrials.gov : NCT03051620). RESULTS: We enrolled 136 participants discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years) in PROSA and 124 participants in PROSA Extension. There was a significant decrease in LSBMD - 0.74% ± 0.27, THBMD - 2.65% ± 0.39, FNBMD - 2.35% ± 0.33, and trabecular bone score - 0.97% ± 0.35 and an increase in p-CTX by 61.1% ± 4.7 (p < 0.05 for all) after 24 months. Increase in p-CTX at M3 was associated with bone loss at the hip sites at M12 and M24. CONCLUSION: In patients discontinuing ALN, BMD decreased significantly and BTMs increased within the reference range over 2 years. An increase in p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD during treatment discontinuation is dependent on continued suppression of bone turnover.

Fragility fractures and health-related quality of life: does socio-economic status widen the gap? A population-based study.

Studying 12,839 fracture cases and 91,426 controls, we found that fractures of the spine and hip are associated with clinically important HRQoL deficits up to 5 years post-fracture. Fracture cases with a low educational attainment are more likely to report very low HRQoL due to a low pre-fracture HRQoL. INTRODUCTION: The aim of this study was to explore the short-term and long-term impact of fractures on health-related quality of life (HRQoL) and to study the effect of educational attainment as a proxy for socio-economic status (SES) on post-fracture HRQoL. METHODS: In a population-based survey including 12,839 fracture cases and 91,426 controls, HRQoL was measured using the physical component score (PCS) and the mental component score (MCS) of the 12-Item Short Form Health Survey (SF-12). Information about fractures, age, sex, ethnicity, comorbidity and SES was obtained from national registers. Multiple regression analysis was conducted to measure the mean HRQoL difference, termed deficit, between non-fracture controls and fracture cases (all fractures combined and fractures at six different skeletal sites). RESULTS: PCS and MCS were significantly lower among fracture cases than among controls. Statistically and clinically important PCS deficits (≥ 5 points) were observed among people with fractures of the spine and hip up to 5 years post-fracture and among people with upper arm fractures up to 1 year post-fracture. Greater deficits were observed for MCS but not for PCS in post-fracture HRQoL in the low than in the high SES group. CONCLUSION: Fractures of the spine and hip are associated with clinically important deficits in physical HRQoL up to 5 years post-fracture. Low educational attainment widened the gap in mental but not in physical post-fracture HRQoL. However, due to low pre-fracture PCS and MCS, people with a low educational attainment and fractures were more likely to report very low HRQoL post-fracture.

The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial.

We conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups. INTRODUCTION: Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. METHODS: We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 µg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 µg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. RESULTS: Undercarboxylated osteocalcin decreased in the MK-7-group (- 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (- 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. CONCLUSION: Treatment with MK-7 375 µg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov : NCT01922804 .

Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis.

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Glucose-Lowering Drugs and Fracture Risk-a Systematic Review.

PURPOSE OF REVIEW: Diabetes mellitus (DM) is associated with increased fracture risk. The aim of this systematic review was to examine the effects of different classes of glucose-lowering drugs on fracture risk in patients with type 2 DM. The heterogeneity of the included studies did not allow formal statistical analyses. RECENT FINDINGS: Sixty studies were included in the review. Metformin, dipeptidylpeptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2-inhibitors do not appear to increase fracture risk. Results for insulin and sulphonylureas were more disparate, although there may be an increased fracture risk related to hypoglycemia and falls with these treatments. Glitazones were consistently associated with increased fracture risk in women, although the evidence was sparser in men. New glucose-lowering drugs are continuously being developed and better understanding of these is leading to changes in prescription patterns. Our findings warrant continued research on the effects of glucose-lowering drugs on fracture risk, elucidating the class-specific effects of these drugs.

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated. INTRODUCTION: Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment. METHODS: This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and ß-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS: A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and ß-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and ß-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION: A zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.

Socio-economic inequalities in fragility fracture outcomes: a systematic review and meta-analysis of prognostic observational studies.

Individuals with low socio-economic status (SES) have a higher risk of dying following hip fracture compared with individuals with high SES. Evidence on social inequalities in non-hip fractures is lacking as well as evidence on the impact of SES on health-related quality of life post fracture. INTRODUCTION: Fragility fractures, especially of the hip, cause substantial excess mortality and impairment in health-related quality of life (HRQoL). This systematic review and meta-analysis aimed to investigate the association between socio-economic status (SES) and post-fracture mortality and HRQoL. METHODS: PubMed, EMBASE and CINAHL databases were searched from inception to the last week of November 2018 for studies reporting an association between SES and post-fracture mortality and/or HRQoL among people aged ≥ 50 years. Risk ratios (RRs) were meta-analyzed using a standard inverse-variance-weighted random effects model. Studies using individual-level and area-based SES measures were analyzed separately. RESULTS: A total of 24 studies from 15 different countries and involving more than one million patients with hip fractures were included. The overall risk of mortality within 1-year post-hip fracture in individuals with low SES was 24% higher than in individuals with high SES (RR 1.24, 95% CI 1.19 to 1.29) for individual-level SES measures, and 14% (RR 1.14, 95% CI 1.09 to 1.19) for area-based SES measures. The quality of the evidence for the outcome mortality was moderate. Using individual SES measures, we estimated the excess HRQoL loss to be 5% (95% CI - 1 to 10%) among hip fracture patients with low SES compared with high SES. CONCLUSIONS: We found a consistently increased risk of post-hip fracture mortality with low SES across SES measures and across countries with different political structures and different health and social care infrastructures. The impact of SES on post-fracture HRQoL remains uncertain due to sparse and low-quality evidence.

Treatment with zoledronic acid subsequent to odanacatib prevents bone loss in postmenopausal women with osteoporosis.

Treatment with zoledronic acid 5 mg maintained bone turnover markers in the premenopausal range, increased lumbar spine bone mineral density, and maintained hip bone mineral density in women previously treated with odanacatib 50 mg weekly. INTRODUCTION: The development of odanacatib (ODN), a cathepsin K inhibitor, for treatment of osteoporosis was discontinued due to an increased risk of cardiovascular events. As the treatment is considered reversible, participants from the LOFT trial in Aarhus, Denmark, were offered treatment with zoledronic acid (ZOL). METHODS: Sixty-seven postmenopausal women were treated with ZOL 5 mg and followed for 12 months. Of these, 39 had received ODN for 7 years and 28 had received placebo for 5 years and ODN for 2 years. Bone turnover markers (BTM) were measured 3, 6, and 12 months after ZOL, and DXA of spine and hip were performed at time of ZOL treatment and after 12 months. RESULTS: Within the entire study population, BMD at the lumbar spine increased by 2.8 ± 0.9% (mean ± SEM) (p < 0.01) from baseline to month 12. There was no significant change in BMD at the total hip (p = 0.17) or femoral neck (p = 0.39). There was no difference in the changes in BMD from baseline to 12 months between the two groups at any site (p ≥ 0.20 for all). CTX increased by 107 ± 9% (p < 0.001), PINP by 102 ± 16% (p < 0.001), osteocalcin by 32 ± 6% (p = 0.001) and BSAP by 79 ± 37% (p = 0.001) between 3 and 12 months after ZOL. At month 12, BTM were still within the premenopausal reference range. S-25-hydroxyvitamin D increased (p = 0.059), while PTH (p = 0.007) and eGFR (p = 0.014) decreased during the year following ZOL administration. CONCLUSION: Treatment with ZOL 5 mg maintained BTMs in the premenopausal range and prevented bone loss in women previously treated with ODN.

Do femoral fractures in adult patients with osteogenesis imperfecta imitate atypical femoral fractures? A case series.

Atypical femoral fractures (AFFs) are low-energy femoral fractures with characteristic radiological features and a suspected relation to treatment with bisphosphonate (BP) or denosumab. In osteogenesis imperfecta (OI), BP is currently the drug of choice when medical treatment is indicated. Due to bone deformities, the radiologic appearance of femoral fractures may be different in patients with OI and patients with osteoporosis. We investigated the prevalence and appearance of femoral fractures in a cohort of adult patients with confirmed OI (55 patients, age range 19-69 years, 26 women (47%) and 35 patients (64%) had received BP treatment), who attended the outpatient clinic at Aarhus University Hospital. The fractures were evaluated according to major and minor AFF criteria. In our OI cohort, we found that eight out of 55 patients had suffered a femoral fracture in adult year: five women and three men, aged 25 to 54 years. One patient had OI type I, two had OI type III, four had OI type IV, and one had OI type V. All fractures were associated with no or minimal trauma. Four patients had fractures that fulfilled the criteria of AFFs. Two of the four patients had received long-term BP treatment prior to the fracture and three patients had severe deformities of the femur. Femoral fractures in OI imitate AFFs. This suggests that bone deformity, collagen deficiencies, and alterations in mineralization of bone may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. Bone deformities should be monitored as part of the management of adult patients with OI. Continuous dull or aching pain in the groin or thigh should lead to radiographic examination. The radiologic appearance of femoral fractures may be different in patients with osteogenesis imperfecta (OI) and patients with osteoporosis, thus imitate atypical femoral fractures (AFF). We found that bone deformity, collagen deficiencies, and alterations in bone mineralization may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment.

Comparison of bone turnover markers in peripheral blood and bone marrow aspirate.

BACKGROUND: Bone remodeling takes place in the bone marrow environment. We investigated if levels of bone turnover markers (BTMs) differ between bone marrow and peripheral blood, if the bone marrow is an independent compartment, and how well the measurements in bone marrow correlate with bone mineral density. METHODS: Sixty-six men participated in a placebo controlled study designed to evaluate the effect of 16 weeks supplementation with resveratrol on bone mineral density and BTM. Bone marrow aspirates and blood samples were drawn at baseline and at week 16. Procollagen I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTx), osteocalcin, bone specific alkaline phosphatase (BAP), and osteoprogeterin (OPG) were analyzed. Bland-Altman analysis was used to compare measurements across compartment to detect possible systematic or proportional differences. Paired t-test was performed if no proportional difference was revealed at the difference vs concentration plot. RESULTS: Measurements of PINP, CTx, and BAP differed proportionally between compartments depending on concentration; at low concentrations absolute values were only slightly different, while at higher average concentrations the levels were much higher in bone marrow than blood. Osteocalcin measures in bone marrow were systematically and significantly lower than in blood (mean ±â€¯SD; 14.4 µg/L ±â€¯5.3 µg/L versus 21.7 µg/L ±â€¯6.0 µg/L respectively, p < 0.001). OPG measures were comparable between compartments (p = 0.69). CTx and OPG measured in blood were negatively associated with lumbar spine BMD (ß = -0.22, p = 0.05 and ß = -0.02, p = 0.02, respectively), whereas both markers measured in bone marrow were not (p = 0.60 and p = 0.50 respectively). None of the BTMs, bone marrow or blood, were associated with total hip BMD. DISCUSSION: The levels of most BTMs differed significantly between bone marrow and peripheral blood, while OPG was comparable. Levels of PINP, CTx, and BAP differed between compartments depending on concentration, suggesting bone marrow to represent a compartment separate from the general circulation. Unexpectedly, osteocalcin was lower in the marrow, a gradient that was independent of concentration. BTMs measured in bone marrow did not show any association with bone mineral density. Although further studies are needed to investigate potential explanatory causes of the differences, BTMs in bone marrow do not seem to contribute further to fracture risk assessment.

Osteogenesis imperfecta and the teeth, eyes, and ears-a study of non-skeletal phenotypes in adults.

Osteogenesis imperfecta (OI) is a disease causing bone fragility; however, it potentially affects all organs with a high content of collagen, including ears, teeth, and eyes. The study is cross-sectional and compares non-skeletal characteristics in adults with OI that clinicians should be aware of when caring for patients with OI. INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder. The skeletal fragility is pronounced; however, OI leads to a number of extra-skeletal symptoms related to the ubiquity of collagen type 1 throughout the human body. The vast majority of knowledge is derived from studies performed in the pediatric population. Thus, we aimed to investigate the nature and prevalence of ophthalmologic, odontologic, and otologic phenotypes in an adult population with OI. METHODS: The study population comprises 85 Danish OI patients (age 44.9 ± 15.9 years). Fifty-eight patients had OI type I, 12 OI type III, and 15 OI type IV according to the classification by Sillence. Audiometric evaluations and dental examinations were performed in 62 and 73 patients, respectively. Ophthalmologic investigations were performed in 64 patients, including measurements of the central corneal thickness. RESULTS: All patients, except two, had corneal thickness below the normal reference value. Patients with OI type I and patients with a quantitative collagen defect had thinner corneas compared to patients with OI type III and other patients with a qualitative collagen defect. One patient in this cohort was diagnosed with and treated for acute glaucoma. Dentinogenesis imperfecta was diagnosed in one fourth of the patients, based on clinical and radiographic findings. This condition was predominately seen in patients with moderate to severe OI. Hearing loss requiring treatment was found in 15 of 62 patients, of whom three were untreated. The most prevalent type of hearing loss (HL) was sensorineural hearing loss, whereas conductive HL was solely seen in patients with OI type III. The patients with the most severe degrees of HL were patients with mild forms of OI. Age was associated with increased HL. CONCLUSION: Although significant health problems outside the skeleton are frequent in adult patients with OI, the patients are not consistently monitored and treated for their symptoms. Clinicians treating adult patients with OI should be aware of non-skeletal health issues and consider including regular interdisciplinary check-ups in the management plan for adult OI patients.