Maciej J. K. Simon

Intravenous bisphosphonates and vitamin D in the treatment of bone marrow oedema in professional athletes

INTRODUCTION The goal of this retrospective study was to evaluate the safety and efficacy of ibandronate for bone marrow oedema (BMO) syndrome and stress fracture cases, and to demonstrate an additional field of therapeutic importance-the high-performance athlete. PATIENTS AND METHODS This retrospective study included twenty-five high-performance athletes. Sixty per cent of the athletes were European soccer players and 40.0% other high-class international athletes (3 women and 22 men with an average age of 25.0±4.2), with BMO of the lower trunk or extremity diagnosed by magnetic resonance imaging (MRI). The treatment regimen consisted of high-dose vitamin D supplementation and intravenous ibandronate therapy. RESULTS The time between the onset of pain and proper diagnosis of BMO was 106.3±104.1 days. Excellent pain reduction (pain at rest and under strain) and improved mobility was reported within the first two weeks after the first ibandronate administration by sixteen patients (64%). The time from first treatment until return to competition (RTC) was on average 102.6±65.2 days in total. If the time from onset of pain until diagnosis was within 40 days, the RTC was significantly reduced (p≤0.05) to almost 50% (63.8±48.1 days) when compared to the athletes with later diagnosis (124.4±63.2 days). CONCLUSIONS The here-applied therapy regimen of intravenous BPs application and vitamin D supplementation in BMO syndrome has a beneficial effect for high-performance athletes. An early diagnosis and rapid treatment start can reduce the RTC significantly. An optimal bone metabolism with sufficient daily calcium and vitamin D intake is crucial and should not only be strived for the professional but also for the recreational athlete.

High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep.

SummaryChronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass.IntroductionUnderstanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures.MethodsDorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (μCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy.ResultsThe fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure.ConclusionsOur data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis.

Sheep model for osteoporosis: The effects of peripheral hormone therapy on centrally induced systemic bone loss in an osteoporotic sheep model

Hypothalamic-pituitary disconnection (HPD) leads to low bone turnover followed by bone loss and reduced biomechanical properties in sheep. To investigate the role of peripheral hormones in this centrally induced systemic bone loss model, we planned a hormone replacement experiment. Therefore, estrogen (OHE), thyroxin (OHT) or a combination of both (OHTE) was substituted in ovariectomized HPD sheep, as both hormones are decreased in HPD sheep and are known to have a significant but yet not fully understood impact on bone metabolism. Bone turnover and structural parameters were analyzed in comparison to different control groups - untreated sheep (C), ovariectomized (O) and ovariectomized+HPD sheep (OH). We performed histomorphometric and HR-pQCT analyses nine months after the HPD procedure, as well as biomechanical testing of all ewes studied. In HPD sheep (OH) the low bone turnover led to a significant bone loss. Treatment with thyroxin alone (OHT) mainly increased bone resorption, leading to a further reduction in bone volume. In contrast, the treatment with estrogen alone (OHE) and the combined treatment with estrogen and thyroxin (OHTE) prevented HPD-induced bone loss completely. In conclusion, peripheral hormone substitution was able to prevent HPD-induced low-turnover osteoporosis in sheep. But only the treatment with estrogen alone or in combination with thyroxin was able to completely preserve bone mass and structure. These findings demonstrate the importance of peripheral hormones for a balanced bone remodeling and a physiological bone turnover.

Deterioration of teeth and alveolar bone loss due to chronic environmental high-level fluoride and low calcium exposure

ObjectivesHealth risks due to chronic exposure to highly fluoridated groundwater could be underestimated because fluoride might not only influence the teeth in an aesthetic manner but also seems to led to dentoalveolar structure changes. Therefore, we studied the tooth and alveolar bone structures of Dorper sheep chronically exposed to very highly fluoridated and low calcium groundwater in the Kalahari Desert in comparison to controls consuming groundwater with low fluoride and normal calcium levels within the World Health Organization (WHO) recommended range.Materials and methodsTwo flocks of Dorper ewes in Namibia were studied. Chemical analyses of water, blood and urine were performed. Mineralized tissue investigations included radiography, HR-pQCT analyses, histomorphometry, energy-dispersive X-ray spectroscopy and X-ray diffraction-analyses.ResultsFluoride levels were significantly elevated in water, blood and urine samples in the Kalahari group compared to the low fluoride control samples. In addition to high fluoride, low calcium levels were detected in the Kalahari water. Tooth height and mandibular bone quality were significantly decreased in sheep, exposed to very high levels of fluoride and low levels of calcium in drinking water. Particularly, bone volume and cortical thickness of the mandibular bone were significantly reduced in these sheep.ConclusionsThe current study suggests that chronic environmental fluoride exposure with levels above the recommended limits in combination with low calcium uptake can cause significant attrition of teeth and a significant impaired mandibular bone quality.Clinical relevanceIn the presence of high fluoride and low calcium-associated dental changes, deterioration of the mandibular bone and a potential alveolar bone loss needs to be considered regardless whether other signs of systemic skeletal fluorosis are observed or not.

Deficiency of Thrombospondin-4 in Mice Does Not Affect Skeletal Growth or Bone Mass Acquisition, but Causes a Transient Reduction of Articular Cartilage Thickness

Although articular cartilage degeneration represents a major public health problem, the underlying molecular mechanisms are still poorly characterized. We have previously utilized genome-wide expression analysis to identify specific markers of porcine articular cartilage, one of them being Thrombospondin-4 (Thbs4). In the present study we analyzed Thbs4 expression in mice, thereby confirming its predominant expression in articular cartilage, but also identifying expression in other tissues, including bone. To study the role of Thbs4 in skeletal development and integrity we took advantage of a Thbs4-deficient mouse model that was analyzed by undecalcified bone histology. We found that Thbs4-deficient mice do not display phenotypic differences towards wildtype littermates in terms of skeletal growth or bone mass acquisition. Since Thbs4 has previously been found over-expressed in bones of Phex-deficient Hyp mice, we additionally generated Thbs4-deficient Hyp mice, but failed to detect phenotypic differences towards Hyp littermates. With respect to articular cartilage we found that Thbs4-deficient mice display transient thinning of articular cartilage, suggesting a protective role of Thbs4 for joint integrity. Gene expression analysis using porcine primary cells revealed that Thbs4 is not expressed by synovial fibroblasts and that it represents the only member of the Thbs gene family with specific expression in articular, but not in growth plate chondrocytes. In an attempt to identify specific molecular effects of Thbs4 we treated porcine articular chondrocytes with human THBS4 in the absence or presence of conditioned medium from porcine synovial fibroblasts. Here we did not observe a significant influence of THBS4 on proliferation, metabolic activity, apoptosis or gene expression, suggesting that it does not act as a signaling molecule. Taken together, our data demonstrate that Thbs4 is highly expressed in articular chondrocytes, where its presence in the extracellular matrix is required for articular cartilage integrity.

Is centrally induced alveolar bone loss in a large animal model preventable by peripheral hormone substitution

ObjectivesAlveolar bone structures are mostly investigated in small animal models. The majority of these studies examined local influences on the alveolar bone, but only a few examined systemic influencing factors. The hypothalamic-pituitary axis is known to be essential for a vital bone balance. The aim of this study was to analyse the effects that selective hormone treatments have on alveolar bone structure and quality in a sheep model for alveolar bone loss, induced by hypothalamic-pituitary disconnection (HPD).MethodsThirty sheep were randomly selected into six groups of five each: control (C), ovariectomy—OVX (O), O + HPD (OH), OH with oestrogen treatment (OHE), OH with thyroxine (T4) treatment (OHT), and OH with a combined treatment of oestrogen and thyroxine (OHTE). After OVX and HPD procedures and an additional 9-month observation/treatment period, structural bone analyses of the mandible were performed by contact radiography, micro-CT, and static histomorphometry.ResultsThe HPD procedure caused structural alveolar bone parameters to decrease significantly compared to controls (C). Treatment with oestrogen (OHE) was protective and bone structure was maintained at baseline levels. Thyroxine treatment (OHT) promoted significant bone loss, but the combined treatment (OHTE) improved bone structure and volume parameters even above baseline levels.ConclusionsAlveolar bone homeostasis significantly underlies systemic regulatory systems. Centrally induced (HPD) bone loss can be prevented by combined peripheral treatment with oestrogen and thyroxine.Clinical relevanceThese results demonstrate the significance of a balanced hormonal regulatory system for steady bone remodelling and maintenance of healthy alveolar bone.

Low physical performance determined by chair rising test muscle mechanography is associated with prevalent fragility fractures

SummaryThis study examined associations between physical performance assessed by chair rising test muscle mechanography and DXA T-score as well as body composition in a large patient cohort. Next to various significant interrelationships between these muscle and bone parameters, lower physical performance was associated with prevalent fragility fractures.PurposeAlthough the interaction between muscle and bone has been demonstrated in various aspects, the clinical focus in the diagnosis of musculoskeletal disorders mainly lies on the skeletal assessments. Accordingly, the association between muscle function, bone mineral density (BMD), and fragility fractures remains to be further elucidated with a feasible muscle assessment in a clinical setting.MethodsPatient data (2076 patients, 1538 women, 538 men) were evaluated retrospectively from a large dual energy X-ray absorptiometry (DXA) database as well as from chair rising test (CRT) that was performed on a muscle mechanograph. To determine potential predictors of the CRT time and maximum force, a multivariate regression analysis was performed including age, DXA T-score, and body composition indices. Furthermore, CRT results were compared between non-fracture and fracture cases.ResultsWe determined independent predictors for CRT time such as age, femoral DXA T-score, and total fat mass, whereas CRT force was only influenced by total lean mass. Both women and men with previous fragility fractures displayed a longer CRT time (women p = 0.009, men p = 0.001) and lower CRT force (women p < 0.001, men p < 0.001) than those with no fractures, while no clear differences in CRT results could be detected between normal BMD, osteopenia, and osteoporosis based on DXA T-scores.ConclusionsOur study demonstrates that in addition to the associations between chair rising time and femoral T-score assessed by DXA, low muscle strength is associated with previous fragility fractures.