Kurt Lippuner

The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation

Introduction.  Vitamin D is essential for calcium metabolism as well as for fracture prevention, and a recent review suggested that the optimal serum 25(OH)D lies in the region of 50–80 nmol L−1 (20–32 ng mL−1). A high prevalence of inadequacy has been reported in many studies but the prevalence of inadequacy amongst women with osteoporosis in different regions of the world has not been well characterized.

The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long‐term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly–Pivotal Fracture Trial (HORIZON‐PFT) was extended to 6 years. In this international, multicenter, double‐blind, placebo‐controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent‐to‐treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN‐BMD remained constant in Z6 and dropped slightly in Z3P3 (between‐treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment. (ClinicalTrials.gov identifier: NCT00145327).

Fracture risk and zoledronic acid therapy in men with osteoporosis

BACKGROUND Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis. METHODS In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months. RESULTS The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%). CONCLUSIONS Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00439647.).

Compressive strength of interbody cages in the lumbar spine: the effect of cage shape, posterior instrumentation and bone density

Abstract One goal of interbody fusion is to increase the height of the degenerated disc space. Interbody cages in particular have been promoted with the claim that they can maintain the disc space better than other methods. There are many factors that can affect the disc height maintenance, including graft or cage design, the quality of the surrounding bone and the presence of supplementary posterior fixation. The present study is an in vitro biomechanical investigation of the compressive behaviour of three different interbody cage designs in a human cadaveric model. The effect of bone density and posterior instrumentation were assessed. Thirty-six lumbar functional spinal units were instrumented with one of three interbody cages: (1) a porous titanium implant with endplate fit (Stratec), (2) a porous, rectangular carbon-fibre implant (Brantigan) and (3) a porous, cylindrical threaded implant (Ray). Posterior instrumentation (USS) was applied to half of the specimens. All specimens were subjected to axial compression displacement until failure. Correlations between both the failure load and the load at 3 mm displacement with the bone density measurements were observed. Neither the cage design nor the presence of posterior instrumentation had a significant effect on the failure load. The loads at 3 mm were slightly less for the Stratec cage, implying lower axial stiffness, but were not different with posterior instrumentation. The large range of observed failure loads overlaps the potential in vivo compressive loads, implying that failure of the bone-implant interface may occur clinically. Preoperative measurements of bone density may be an effective tool to predict settling around interbody cages.

A Meta‐Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX

Trabecular bone score (TBS) is a gray‐level textural index of bone microarchitecture derived from lumbar spine dual‐energy X‐ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)‐independent predictor of fracture risk. The objective of this meta‐analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual‐level data from 17,809 men and women in 14 prospective population‐based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow‐up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35–1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10‐year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24–1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65–1.87 versus 1.70, 95% CI 1.60–1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.

Incidence and Direct Medical Costs of Hospitalizations due to Osteoporotic Fractures in Switzerland

Abstract: The objective of this study was to estimate the annual direct medical costs of hospitalizations due to osteoporotic fractures in Switzerland. Days of hospital stay in 1992 were quantified using the casuistic of the medical statistics department of VESKA (Vereinigung Schweizerischer Krankenhäuser, the Swiss Hospital Association), which covers 43% of all hospital beds of that country. Number and incidence of total hospitalizations due to fractures were calculated by extrapolating to 100% the 43% VESKA-selected sample. To estimate number and incidence of hospitalizations due to osteoporotic fractures, internationally accepted age-specific osteoporosis attribution rates were applied. According to the latter the probability of a fracture being causes by osteoporosis increases with age. Mean length of stay for all fractures was calculated (= total hospital days divided by number of cases). By multiplying these mean lengths of stay by the number of osteoporosis-related fracture cases, the number of bed-days due to osteoporotic fractures was calculated. To compare the direct medical costs of hospitalization due to osteoporosis with those due to other frequent diseases, days of hospital stay caused by chronic obstructive pulmonary disease (COPD), stroke, acute myocardial infarction and breast cancer were estimated using the same methodology. A total estimate of 63 170 (f: 33 596, m: 29 574) hospitalizations due to fractures (and other osteoporosis-related diagnoses) was calculated, thus leading to overall annual incidence rates of hospitalizations for fractures of 950/100 000 women and 877/100 000 men. In women, 548 615 hospital days were found to be caused by osteoporosis, 353 654 days by COPD, 352 062 days by stroke, 200 669 days by breast carcinoma and 131 331 days by myocardial infarction. In men, COPD caused more hospitalization days (537 164) than myocardial infarction (196 793), stroke (180 524) or osteoporosis (152 857). Taking a mean price for a hospital day in Switzerland of 845 Swiss francs, the annual costs of acute hospitalizations due to osteoporosis and its complications were approximately 600 million Swiss francs (f: 464, m: 130 million Swiss francs) in 1992. We conclude that there is enough economic evidence to justify wide-scale interventions against osteoporosis in Switzerland.

Treatment with Denosumab Reduces the Incidence of New Vertebral and Hip Fractures in Postmenopausal Women at High Risk

CONTEXT The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.

The relative importance of vertebral bone density and disc degeneration in spinal flexibility and interbody implant performance. An in vitro study.

Study Design An in vitro biomechanical investigation in the human lumbar spine focuses on the functional significance of vertebral bone density and intervertebral disc degeneration. Objective To determine the interrelationship between vertebral bone density and intervertebral disc degeneration, their effect on normal spine motion, and their significance in the biomechanical performance of interbody fixation techniques. Summary of Background Data A relationship between vertebral bone density and intervertebral disc degeneration has been suggested, but a definitive relationship has not been established. The effect of vertebral bone density and intervertebral disc degeneration on interbody stabilization remains unknown despite the rapidly increasing use of this surgical method for patients with chronic low back pain. Methods The vertebral bone density and intervertebral disc degeneration of 72 functional spinal units were determined using dual energy x‐ray absorptiometry scans and macroscopic grading, respectively. A three‐dimensional flexibility test was performed on 24 functional spinal units in the intact and stabilized conditions. The compressive behavior of the bone‐implant interface was evaluated in 48 functional spinal units. Results The vertebral bone density in moderately degenerated discs was significantly lower than at all other levels of intervertebral disc degeneration. Increasing intervertebral disc degeneration resulted in more axial rotation and less lateral bending. In flexion‐extension and lateral bending, better vertebral bone resulted in significantly better stabilization. This trend was observed also in axial compression, in which higher failure loads were observed with greater bone densities. Conclusion The authors conclude a significant relationship exists between bone density and disc degeneration, bone density is a highly important factor in the performance of interbody stabilization, and disc degeneration is of moderate importance in spinal motion.

Eccentric Exercise in Coronary Patients: Central Hemodynamic and Metabolic Responses

PURPOSE With lengthening (eccentric) muscle contractions, the magnitude of locomotor-muscle mass and strength increase has been demonstrated to be greater compared with shortening (concentric) muscle contractions. In healthy subjects, energy demand and heart rate responses with eccentric exercise are small relative to the amount of muscle force produced. Thus, eccentric exercise may be an attractive alternative to resistance exercise for patients with limited cardiovascular exercise tolerance. METHODS We tested the cardiovascular tolerance of eccentric exercise in 13 coronary patients (ages 40-66) with preserved and/or mild reduced left ventricular function. Patients were randomly assigned to either an eccentric (ECC; N = 7) or a concentric (CON; N = 6) training group and trained for 8 wk. Training workload was increased progressively (from week 1 to 5) to an intensity equivalent to 60% [OV0312]O(2peak). RESULTS On average, maximum power output achieved with ECC was fourfold compared with CON (357 +/- 96 W vs 97 +/- 21 W; P < 0.005), whereas measures of oxygen uptake and blood lactate were significantly lower (P < 0.05 each), and ratings of perceived exertion were similar for ECC and CON. During a 20-min session of ECC and CON, central hemodynamics was measured by means of right heart catheterization. During ECC, responses of mean arterial blood pressure, systemic vascular resistance, pulmonary capillary pressure, cardiac index, and stroke work of the left ventricle on average were in the normal range of values and similar to those observed during CON. Compared with baseline, after 8 wk of training, echocardiographic left ventricular function was unchanged. CONCLUSION The results indicate uncoupling of skeletal muscle load and cardiovascular stress during ECC. For low-risk patients with coronary heart disease without angina, inducible ischemia, or left ventricular dysfunction, ECC can be recommended as a safe new approach to perform high-load muscular exercise training with minimal cardiovascular stress.

Prediction of Hip Fracture Risk by Quantitative Ultrasound in More Than 7000 Swiss Women ≥70 Years of Age: Comparison of Three Technologically Different Bone Ultrasound Devices in the SEMOF Study†‡

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women ≥70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not.