S. Bours

Contributors to Secondary Osteoporosis and Metabolic Bone Diseases in Patients Presenting with a Clinical Fracture

BACKGROUND Previously undetected contributors to secondary osteoporosis and metabolic bone diseases (SECOB) are frequently found in patients with osteoporosis, but the prevalence in patients at the time they present with a clinical fracture is unknown. METHODS All consecutive patients with a recent clinical vertebral or nonvertebral fracture, who were able and willing to be investigated (n = 626: 482 women, 144 men, age range 50-97 yr) had bone mineral density and laboratory investigations (serum calcium, inorganic phosphate, 25-hydroxyvitamin D, creatinine, intact PTH, TSH, free T(4), serum and urine protein electrophoresis, and in men also serum testosterone). RESULTS Known SECOB contributors were present in 23.0% of patients and newly diagnosed SECOB contributors in 26.5%: monoclonal proteinemia (14 of 626), renal insufficiency grade III or greater (54 of 626), primary (17 of 626) and secondary (64 of 626) hyperparathyroidism, hyperthyroidism (39 of 626), and hypogonadism in men (12 of 144). Newly diagnosed SECOBs, serum 25-hydroxyvitamin D less than 50 nmol/liter (in 63.9%), and dietary calcium intake less than 1200 mg/d (in 90.6%) were found at any age, in both sexes, after any fracture (except SECOB in men with finger and toe fractures) and at any level of bone mineral density. CONCLUSION At presentation with a fracture, 26.5% of patients have previously unknown contributors to SECOB, which are treatable or need follow-up, and more than 90% of patients have an inadequate vitamin D status and/or calcium intake. Systematic screening of patients with a recent fracture identifies those in whom potentially reversible contributors to SECOB and calcium and vitamin D deficiency are present.

Serum 25(OH)D response to vitamin D3 supplementation: A meta-regression analysis

OBJECTIVE The aim of this study was to review factors that influence serum 25(OH)D when patients are given vitamin D supplements. METHODS From a comprehensive search of all randomized controlled clinical trials with vitamin D3 supplementation available on PubMed up to November 2011, we selected 33 with 43 treatment arms that included at least 30 adult participants. The achieved pooled mean difference (PMD) and 95% confidence intervals (CIs) were calculated using the random-effects models. Meta-regression and subgroup analyses were performed for prespecified factors, including dose, duration, baseline serum 25(OH)D, and age. RESULTS With a mean baseline serum 25(OH)D of 50.4 nmol/L, PMD was 37 nmol/L (95% CI, 33-41) with significant heterogeneity among studies. Dose (slope: 0.006; P < 0.001), trial duration (slope: 0.21; P < 0.001), baseline serum 25(OH)D (slope: -0.19; P < 0.001), and age (slope: 0.42; P < 0.001) independently influenced vitamin D response. Similar results were found in studies with a mean baseline serum 25(OH)D <50 nmol/L. In subgroup analyses, the PMD was higher with doses ≥800 IU/d (39.3 nmol/L) after 6 to 12 mo (41.7 nmol/L), with baseline 25(OH)D <50 nmol/L (39.6 nmol/L), and in adults aged >80 y (40.5 nmol/L). CONCLUSION This meta regression indicates that a higher increase in serum levels of 25(OH)D in adults is found with a dose of ≥800 IU/d, after at least 6 to 12 mo, and even when baseline 25(OH)D is low and in adults >80 y.

Suboptimal effect of different vitamin D3 supplementations and doses adapted to baseline serum 25(OH)D on achieved 25(OH)D levels in patients with a recent fracture: a prospective observational study

OBJECTIVE Guidelines on the need for dose adaptation of vitamin D3 supplementation according to baseline serum 25(OH)D are inconclusive. The effects of increasing doses of vitamin D3 at lower baseline serum 25(OH)D values on the serum 25(OH)D after 4.2 and 11 months were determined in an observational study. DESIGN A prospective observational study. METHODS Out of 1481 consecutive women and men with a recent clinical fracture, 707 had a baseline 25(OH)D level <50 nmol/l and were supplemented with increasing doses of vitamin D3 (400, 800, 1700, and ≥3500 IU/day) according to the lower baseline 25(OH)D. Final analysis was restricted to the 221 participants who had full follow-up data available for 11 months. RESULTS Serum 25(OH)D ≥50 nmol/l was achieved in 57-76% of patients after 4.2 months and in 73-79% after 11 months. These percentages were similar for all doses (P=0.06 and P=0.91 respectively). The mean achieved 25(OH)D was similar for all dose groups (56.1-64.0 nmol/l after 4.2 months and 60.2-76.3 nmol/l after 11 months). With multivariate analysis, the increase in 25(OH)D (17±32.0 after 4.2 months and 24.3±34.0 nmol/l after 11 months) was dependent on the baseline 25(OH)D (P<0.001), not on supplementation dose, season, age, BMI, or gender. CONCLUSIONS The increase in serum 25(OH)D was significantly larger with higher vitamin D3 supplementation doses. However, this dose-effect response was mainly explained by the baseline 25(OH)D, not the supplementation dose, with a greater magnitude of response at lower baseline 25(OH)D concentrations. In 21-27% of patients, serum 25(OH)D3 levels did not reach 50 nmol/l after 11 months, at any dose. Further studies are needed to identify possible causes of suboptimal response such as non-compliance, undiagnosed malabsorption syndromes, or variability in cholecalciferol content of the vitamin D supplements.

Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.

Purpose of reviewThe purpose of this review is to provide guidance to clinicians about which laboratory tests should be performed in patients with osteoporosis or with a recent fracture. Recent findingsNewly diagnosed secondary osteoporosis and other metabolic bone diseases (SECOB) have been found in 5–48% of patients with osteoporosis. In patients with a recent fracture, new SECOB is found in 10–47% of patients with osteoporosis, and in 26–51% if all patients with a fracture regardless of bone mineral density (BMD) are screened. More than one SECOB can be found in the same patient, even when they have already known SECOB. In primary hyperparathyroidism, hyperthyroidism, hypercortisolism, and multiple myeloma, both SECOB and its treatment have an impact on BMD and fractures. For other SECOBs, no treatment is available, or there are no data about the effect of treatment of the SECOB on BMD and fractures. SummaryWe recommend performing the following tests in all patients with osteoporosis or a recent clinical fracture: calcium, phosphate, creatinine, albumin, erythrocyte sedimentation rate in all patients, 24 h urine calcium in men and serum testosterone in men less than 70 years. On indication, additional tests can be performed.

The risks of sarcopenia, falls and fractures in patients with type 2 diabetes mellitus

Fracture risk in patients with type 2 diabetes mellitus (T2DM) is increased, and the mechanism is multifactorial. Recent research on T2DM-induced bone fragility shows that bone mineral density (BMD) is often normal or even slightly elevated. However, bone turnover may be decreased and bone material and microstructural properties are altered, especially when microvascular complications are present. Besides bone fragility, extra-skeletal factors leading to an increased propensity to experience falls may also contribute to the increased fracture risk in T2DM, such as peripheral neuropathy, retinopathy and diabetes medication (e.g. insulin use). One of the probable additional contributing factors to the increased fall and fracture risks in T2DM is sarcopenia, the age-related decline in skeletal muscle mass, quality and function. Although the association between sarcopenia, fall risk, and fracture risk has been studied in the general population, few studies have examined the association between T2DM and muscle tissue and the risks of falls and fractures. This narrative review provides an overview of the literature regarding the multifactorial mechanisms leading to increased fracture risk in patients with T2DM, with a focus on sarcopenia and falls.

Sedentary behaviour and bone health in children, adolescents and young adults: a systematic review-supplementary presentation

Background: Sedentary behaviour (SB) is a potential risk factor for suboptimal bone deposition in youth. Results: Total SB was negatively associated with lower extremity bone outcomes, while no association was observed with total body bone outcomes. Insufficient evidence was found for an association between total SB and lumbar spine bone outcomes. Conclusion: This review highlights the heterogeneity of the available evidence and emphasizes the need for well-designed studies.

Contra-lateral bone loss at the distal radius in postmenopausal women after a distal radius fracture: A two-year follow-up HRpQCT study

Opposite to the fracture side, bone mineral density (BMD) measured by DXA at the contra-lateral side does not change after a distal radius fracture. However, it is unknown if also bone micro-architecture and strength at the contralateral side are unaffected. Therefore, the aim of this study was to assess BMD, micro-architecture and bone mechanical properties at the contra-lateral side during two years follow-up after a distal radius fracture using high resolution peripheral quantitative computed tomography (HRpQCT). The contra-lateral distal radius of 15 postmenopausal women (mean age 64±8years) with a distal radius fracture treated by cast immobilization was scanned by HRpQCT at baseline, 3months and 2years post-fracture. BMD and cortical and trabecular micro-architecture were measured and biomechanical parameters were estimated using micro finite element analysis (μFEA). Additionally, markers of bone resorption and formation were measured at each visit. Bone parameters and turnover markers across the three visits were analysed using a linear mixed-effect model with Bonferroni correction. Two years post-fracture, a significant decrease from baseline was found in cortical BMD (-4.2%, p<0.001), failure load (-6.1%, p=0.001), stiffness in compression (-5.7%, p=0.003) and bending (-6.4%, p=0.008), and bone formation (-47.6%, p=0.010). No significant changes from baseline were observed in total and trabecular BMD, nor in cortical or trabecular micro-architecture and neither in bone resorption. Results were similar between patients with or without adequate anti-osteoporosis drug treatment. We found a significant decline in BMD in the cortical but not the trabecular region, and a reduction in bone strength and stiffness at the contra-lateral side two years after a distal radius fracture. These changes exceeded the changes that may be expected due to aging, even in the presence of adequate anti-osteoporosis treatment.

SAT0512 Fracture Healing of Distal Radius Fractures Assessed by High-Resolution Peripheral Quantitative Computed Tomography, Bone Strength Analysis and Biomarkers

Background Fracture healing is a dynamic process, in which an inflammatory reaction induces bone resorption and formation in order to repair the fracture and restore bone strength. In contrast to plain radiographs, high resolution peripheral quantitative computed tomography (HR-pQCT) allows to visualize trabecular and cortical bone three dimensionally. From these 3D images bone strengths based on µFEA can be calculated. Objectives Evaluate the different stages of bone formation and bone resorption during the fracture healing process and relate the pattern of bone formation and resorption to the HR-pQCT derived bone parameters. Methods 18 women, aged 64±8 years, with a stable distal radius fracture were included and underwent HR-pQCT scanning (XtremeCT, Scanco Medical, Switzerland) of the fractured radius at 1-2 weeks post-fracture (baseline) and 3-4 weeks, 6-8 weeks and 12 weeks post-fracture. From the HR-pQCT images bone mineral density was assessed for the trabecular and the cortical region and using the 3D models, trabecular thickness and bone stiffness were calculated. Blood samples were collected at each visit for measurement of PINP, ICTP and hs-CRP. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant changes from baseline. Correlations between the HR-pQCT parameters and the biomarkers were calculated using the Spearman’s correlation coefficient. Results During the fracture healing period, trabecular density and thickness and bone stiffness increased by 20%, 28% and 33%, respectively (all p<0.01), while cortical density decreased by 2.9% (p<0.05). Mean hs-CRP was 3.78±6.33 mg/L and was correlated negatively with the increase in trabecular density (r=-0.78, p<0.001) and PINP (r=-0.321, p<0.01). PINP temporarily increased and PINP and ICTP were intercorrelated at visit 1 and 2 (r=0.48, p<0.001). No significant correlations were found between the HR-pQCT parameters and the biomarkers. Conclusions These results open the perspective that a combination of HRpQCT and markers of inflammation and bone remodeling allow to study in detail the factors that are involved in normal and impaired fracture healing, and potentially also the effects of medications in optimizing the natural process of fracture healing. Disclosure of Interest J. de Jong: None Declared, S. Bours: None Declared, P. Willems: None Declared, J. Arts: None Declared, T. van Geel: None Declared, P. Brink: None Declared, B. van Rietbergen Consultant for: Scanco Medical AG, P. Menheere: None Declared, J. van den Bergh: None Declared, P. Geusens: None Declared

SAT0372 Comparing tolerability and efficacy of generic versus brand alendronate. A cross-over study in postmenopausal women with osteoporosis

Background During recent years an increasing amount of generic alendronate formulations has become available. Although expected to have the same tolerability and efficacy, head-to head comparison of generic and brand alendronate was never performed. Objectives Therefore, the objective of our study was to compare tolerability and efficacy of generic (GAln) and brand alendronate (BAln). Methods A randomized double-blinded single-centre cross-over study in postmenopausal women with osteoporosis using GAln and BAln in a cross-over setting, each for a period of 12 weeks with visits at baseline, week 4, 12, 16 and 24. Tolerance was evaluated by the Gastro-Intestinal Symptom Rating Scale (GSRS) and by self-reported side effects. Efficacy was assessed by bone turnover markers (CTX and PINP). Results 37 women (age; 65,4±6,4 years) were enrolled. Abdominal pain score at wk4 and wk16 was higher after GAln compared to BAln (B: 0,24; CI: 0,07- 0,4). After wk4 upper gastro-intestinal side effects (B: 0,20; CI: 0,03-0,33) and dyspepsia (B: 0,15; CI:0,02-0,28), were more reported after GAln. After adjustments for tolerance, BAln demonstrated a lower level of CTX than GAln at wk4 (B: 121,3;CI:51,98-190,5), but not at wk12 (B: 53,6; CI:-3,71-111). PINP was lower for women who received BAln at wk12 (B: 8,93;CI: 0,35-17,5). Conclusions In postmenopausal women with osteoporosis, generic alendronate caused significantly more gastro-intestinal side-effects during the first weeks of treatment. Markers of bone resorption and formation were significantly higher at week 4 and 12 with generic alendronate. Generic alendronate may not have the same tolerability and efficacy as branded alendronate. Disclosure of Interest None Declared

SAT0373 The role of the combination of bone and fall related risk factors on short-term subsequent fracture risk

Background Bone- and fall-related risk factors contribute to subsequent NVF risk and mortality Objectives We analysed whether a combination of bone-related and fall-related risk factors (RFs) in patients with a recent non-vertebral fracture (NVF) contributed to subsequent NVF risk and mortality during 2-years in patients who were offered after a mean of 3 months fall and fracture prevention according to their baseline risk and guidelines. Methods 834 consecutive patients aged ≥50 years with a recent NVF who were able and willing to participate were extensively evaluated for the presence of bone and fall RFs. We compared the yearly re-fracture risk and mortality in subgroups of patients according to the presence of bone RFs and/or fall RFs. Results Fifty seven patients (6.8%) had a subsequent NVF and 29 (3.5%) died within 2-years. During the first year the odds ratio for a subsequent fracture was 4.2 (95%CI:1.2-14.3) in patients with a combination of bone and fall RFs compared to patients with only bone RFs, and 2.8 (95%CI:1.4-5.8) compared to all patients without this combination. No differences in subsequent fracture risk were found in the second year. No significant differences in mortality were found between patients with or without bone and/or fall RFs. Conclusions Evaluation of fall RFs contributes to identifying patients with bone RFs at highest immediate risk of subsequent NVF. It should be further studied whether fall prevention immediately after a NVF can decrease fracture risk on top of anti-osteoporosis treatment in patients with a combination of bone and fall RFs. Disclosure of Interest None Declared