Heikki Kröger

Predictive Value of BMD for Hip and Other Fractures.

The relationship between BMD and fracture risk was estimated in a meta‐analysis of data from 12 cohort studies of ∼39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score.

WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta

This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.

Alendronate Reduces Periprosthetic Bone Loss After Uncemented Primary Total Hip Arthroplasty: A Prospective Randomized Study

Periprosthetic bone loss, especially in the proximal part of the femur, is common after cemented and uncemented total hip arthroplasty (THA). Bone loss can be progressive and, in the extreme, may threaten survival of the prosthesis. To study whether alendronate therapy can reduce bone loss adjacent to prostheses, 13 uncemented primary THA patients were randomized to the study. They received 10 mg alendronate + 500 mg calcium (n = 8) or 500 mg calcium only (n = 5) daily for 6 months follow‐up after THA. Periprosthetic bone mineral density (BMD) was measured with dual energy X‐ray absorptiometry (DXA). Decreases in periprosthetic BMD in the alendronate‐treated group were lower compared with the changes in the calcium‐only group in the same regions of interest at the same follow‐up time. In the proximal femur, the mean BMD decrease was 17.1% in the calcium‐only group, whereas in the alendronate‐treated group the decrease was only 0.9% (p = 0.019). The mean periprosthetic BMD change was also significantly different in the total periprosthetic area between the study groups at the end of the follow‐up (calcium‐only group −9.9% vs. alendronate‐treated group −2.6%; p = 0.019). Alendronate therapy led to a significant reduction in periprosthetic bone loss after primary uncemented THA compared with the changes found in patients without therapy. This kind of bone response may improve the support of the prosthesis and may result in better survival of the prosthesis. However, in this study the follow‐up time was too short and the study population was too small to make any long‐term conclusions as to the prognosis for THA patients treated with alendronate.

Relationship between postmenopausal osteoporosis and the components of clinical sarcopenia

PURPOSE The aim of the study was to determine the relationship between the components of clinical sarcopenia and osteoporosis in postmenopausal women. METHODS A population-based cohort of 590 Finnish postmenopausal women (mean age 67.9; range 65-72) was selected from the Osteoporosis Fracture Prevention (OSTPRE-FPS) study in 2002. Bone mineral density (BMD) and lean tissue mass were assessed by dual X-ray absorptiometry (DXA). The study sample was divided into three categories according to the WHO BMD classification: normal, osteopenia and osteoporosis. The study sample was divided into non-sarcopenic, presarcopenic, sarcopenic and non-classified groups according to quartiles of RSMI i.e. relative skeletal muscle index (appendicular muscle mass (kg)/square of height (m)), hand grip strength (kPa) and walking speed. RESULTS In logistic regression analysis sarcopenic women had 12.9 times higher odds of having osteoporosis (p ≤ 0.001, OR=12.9; 95% CI=3.1-53.5) in comparison to non-sarcopenic women. In comparison to women in the highest grip strength quartile, women within the lowest quartile had 11.7 times higher odds of having osteoporosis (p=0.001, OR=11.7; 2.6-53.4). Sarcopenic women had 2.7 times higher odds of having fractures than their non-sarcopenic counterparts (p=0.005, OR=2.732; 1.4-5.5). Sarcopenic women had also 2.1 times higher risk of falls during the preceding 12 months compared to non-sarcopenic women (p=0.021, OR=2.1; 1.1-3.9). Adjustment for age, body mass index (BMI), physical activity and hormone therapy (HT) did not significantly alter these results. CONCLUSIONS The components of clinical sarcopenia are strongly associated with osteoporosis. Grip strength is the most significant measurement to reveal the association between sarcopenia and osteoporosis, falls and fractures.

Adenovirus-mediated VEGF-A gene transfer induces bone formation in vivo.

Osteoporosis is a major problem in elderly population. We tested the hypothesis whether vascular endothelial growth factor (VEGF‐A) gene transfer is an appropriate way to enhance bone formation and recruitment of osteoblasts in vivo. Adenovirus vectors containing VEGF‐A or lacZ cDNAs (1.4×1010 pfu) were injected locally into right distal femurs of New Zealand White rabbits. Saline was injected into all contralateral distal femurs. One and three weeks after the gene transfers femurs were collected for analyses. X‐Gal staining showed that up to 20% of the bone marrow cells were transfected although gene transfer also resulted in biodistribution of the vector and expression of the transgene in liver and spleen. Trabecular bone hard tissue histomorphometry of the distal femurs was performed to analyze the effect of gene transfer on bone turnover. When compared with unilateral lacZ transfected trabecular bone at one‐week and three‐week time points, VEGF‐A gene transfer significantly increased bone formation parameters, such as osteoblast number, osteoid volume, and bone volume. Also, bone resorption surface was greatly reduced. It is concluded that injection of adenovirus vector can transfect bone marrow cells in vivo with a relatively high efficiency. Our results suggest that adenovirus‐mediated VEGF‐A gene transfer induces bone formation via increasing osteoblast activity and may be useful for the treatment of osteoporosis and other diseases that require efficient osteogenic therapy.

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high‐turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n = 11) and patients with renal osteodystrophy (ROD, n = 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate‐to‐amide I ratio (mineral‐to‐matrix ratio), carbonate‐to‐phosphate ratio, and carbonate‐to‐amide I ratio (turnover rate/remodeling activity), as well as the collagen cross‐link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate‐to‐phosphate (p < .01) and carbonate‐to‐amide I (p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization (p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone‐remodeling activity and number of bone cells and FTIRI‐calculated parameters based on carbonate‐to‐phosphate and carbonate‐to‐amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone.

Longitudinal elastic properties and porosity of cortical bone tissue vary with age in human proximal femur

Tissue level structural and mechanical properties are important determinants of bone strength. As an individual ages, microstructural changes occur in bone, e.g., trabeculae and cortex become thinner and porosity increases. However, it is not known how the elastic properties of bone change during aging. Bone tissue may lose its elasticity and become more brittle and prone to fractures as it ages. In the present study the age-dependent variation in the spatial distributions of microstructural and microelastic properties of the human femoral neck and shaft were evaluated by using acoustic microscopy. Although these properties may not be directly measured in vivo, there is a major interest to investigate their relationships with the linear elastic measurements obtained by diagnostic ultrasound at the most severe fracture sites, e.g., the femoral neck. However, before the validity of novel in vivo techniques can be established, it is essential to understand the age-dependent variation in tissue elastic properties and porosity at different skeletal sites. A total of 42 transverse cross-sectional bone samples were obtained from the femoral neck (Fn) and proximal femoral shaft (Ps) of 21 men (mean±SD age 47.1±17.8, range 17-82years). Samples were quantitatively imaged using a scanning acoustic microscope (SAM) equipped with a 50MHz ultrasound transducer. Distributions of the elastic coefficient (c33) of cortical (Ct) and trabecular (Tr) tissues and microstructure of cortex (cortical thickness Ct.Th and porosity Ct.Po) were determined. Variations in c33 were observed with respect to tissue type (c33Trc33(Ct.Fn)=35.3GPa>c33(Tr.Ps)=33.8GPa>c33(Tr.Fn)=31.9GPa), and cadaver age (R(2)=0.28-0.46, p<0.05). Regional variations in porosity were found in the neck (superior 13.1%; inferior 6.1%; anterior 10.1%; posterior 8.6%) and in the shaft (medial 9.5%; lateral 7.7%; anterior 8.6%; posterior 12.0%). In conclusion, significant variations in elastic coefficients were detected between femoral neck and shaft as well as between the quadrants of the cross-sections of neck and shaft. Moreover, an age-related increase in cortical porosity and a stiffening of the bone tissue were observed. These findings may explain in part the increase in susceptibility to suffer low energy fractures during aging and highlight the potential of ultrasound in clinical osteoporosis diagnostics.

Multi-site bone ultrasound measurements in elderly women with and without previous hip fractures

SummaryAbout 75% of patients suffering from osteoporosis are not diagnosed. This study describes a multi-site bone ultrasound method for osteoporosis diagnostics. In comparison with axial dual energy X-ray absorptiometry (DXA), the ultrasound method showed good diagnostic performance and could discriminate fracture subjects among elderly females.IntroductionAxial DXA, the gold standard diagnostic method for osteoporosis, predicts fractures only moderately. At present, no reliable diagnostic methods are available at the primary health care level. Here, a multi-site ultrasound method is proposed for osteoporosis diagnostics.MethodsThirty elderly women were examined using the ultrasound backscatter measurements in proximal femur, proximal radius, proximal and distal tibia in vivo. First, we predicted the areal bone mineral density (BMD) at femoral neck by ultrasound measurements in tibia combined with specific subject characteristics (density index, DI) and, second, we tested the ability of ultrasound backscatter measurements at proximal femur to discriminate between individuals with previously fractured hips from those without fractures. Areal BMD was determined by axial DXA.ResultsCombined ultrasound parameters, cortical thickness at distal and proximal tibia, with age and weight of the subject, provided a significant estimate of BMDneck (r = 0.86, p < 0.001, n = 30). When inserted into FRAX (World Health Organization fracture risk assessment tool), the DI indicated the same treatment proposal as the BMDneck with 86% sensitivity and 100% specificity. The receiver operating characteristic analyses, with a combination of ultrasound parameters and patient characteristics, discriminated fracture subjects from the controls similarly as the model combining BMDneck and patient characteristics.ConclusionsFor the first time, ultrasound backscatter measurements of proximal femur were conducted in vivo. The results indicate that ultrasound parameters, combined with patient characteristics, may provide a means for osteoporosis diagnostics.

Obesity May Impair the Early Outcome of Total Knee Arthroplasty a Prospective Study of 100 Patients

Background and Aims: Obesity has been linked to the development of osteoarthritis of the knee and increases the probability to fall into total knee arthroplasty. In this study we compared short-term outcome of total knee arthroplasty (TKA) in non-obese and obese patients. Material and Methods: A total of 100 patients underwent TKA between October 2006 and March 2007. They were divided into two groups based on the body mass index: 52 of the patients were obese (BMI ≥ 30 kg/m2) and 48 non-obese (BMI < 30 kg/m2). The short-term outcome was studied using clinical, functional and radiological analysis. The mean of the follow-up period was 3 months. Results: There were five complications (2 wound infections, phlebitis, nerve injury and massive edema) in obese patients group compared with no complications in non-obese (p = 0.028). The obese patients had also worse postoperative range of motion (110o̱ vs.118o̱, p = 0.001) than non-obese and the number of technical errors was 17 in obese and 5 in non-obese group, respectively (p = 0.007). Conclusions: We suggest that obesity may impair the early outcome of total knee arthroplasty and obese patients should be informed about the increased risk of complications related to TKA.

Impact of aromatase inhibitor therapy on bone turnover, cortical bone growth and vertebral morphology in pre- and peripubertal boys with idiopathic short stature.

In this randomized placebo-controlled study we examined the influence of aromatase inhibition on bone turnover, cortical bone growth, and vertebral body morphology in peripubertal boys. Thirty peripubertal boys with idiopathic short stature were treated with the aromatase inhibitor letrozole or placebo for 2 years. During treatment and posttreatment follow-up, dual-energy X-ray absorptiometry (DXA)-assessed bone mineral density, metacarpal index (MCI), and markers of bone turnover were examined. Vertebral morphology was examined by DXA after cessation of treatment. In letrozole-treated boys, the concentrations of the bone resorption marker urine aminoterminal telopeptide of type I collagen initially increased and thereafter slowly declined while the concentrations of the bone formation markers serum aminoterminal propeptide of type I collagen and serum alkaline phosphatase remained unchanged or slightly increased, respectively. In placebo-treated boys, all markers of bone turnover increased significantly during treatment. Among those who progressed into puberty, metacarpal index (MCI) increased more in the letrozole-treated than in the placebo-treated boys during treatment (25 vs. 9%, p = 0.007). The change in MCI correlated with the testosterone-to-estradiol ratio (r = 0.59, p = 0.02). Vertebral deformities were detected in 6 out of 13 boys receiving letrozole and in 4 out of 11 receiving placebo (p = 0.70). Aromatase inhibition suppresses bone turnover, possibly through an androgen-mediated effect. In pubertal boys, treatment stimulates cortical bone growth by increasing the testosterone-to-estradiol ratio.