Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.

In brief: This study describes a novel autosomal dominant form of primary osteoporosis caused by SGMS2 mutations in six families. A recurrent mutation p.Arg50* led to primary osteoporosis in four families, whereas missense mutations p.Ile62Ser and p.Met64Arg caused a much more severe bone phenotype with spondylometaphyseal dysplasia and neonatal fractures.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Therapy of Osteoporosis and Bone Mineralization. The ongoing resorption and subsequent formation of bone based on the activity of the bone cells (the bone turnover) and the time course of mineral accumulation in the newly formed matrix (the mineralization kinetics) are causing a specific heterogeneity of bone matrix mineralization. The assessment of the bone mineralization density distribution (BMDD), which is revealing the degree and the distribution of the calcium concentrations, is one technique to quantify this mineralization pattern. Based on the analysis of transiliac bone biopsy samples, it was shown that the reduction of bone turnover after antiresorptive therapy was associated with an increase in the degree (shift of the BMDD peak to higher calcium concentrations) and a reduction in the heterogeneity of mineralization (narrowing of the BMDD peak) in the bone matrix. Vice versa, after anabolic therapy the BMDD peak was shifted to lower calcium concentrations and got broader. The measurement of the BMDD in transiliac bio psy samples is not only important for the monitoring and safety aspects of therapies but it is essentially contributing to the understanding of the mechanisms of action of different therapies. In particular, changes in BMDD are an important information for the interpretation of changes in bone mineral density (by DEXA) during therapies. J Miner Stoffwechs Muskuloskelet Erkrank 2016; 23 (Pre-Publishing Online).

Therapy of Osteoporosis and Bone Mineralization. The ongoing resorption and subsequent formation of bone based on the activity of the bone cells (the bone turnover) and the time course of mineral accumulation in the newly formed matrix (the mineralization kinetics) are causing a specific heterogeneity of bone matrix mineralization. The assessment of the bone mineralization density distribution (BMDD), which is revealing the degree and the distribution of the calcium concentrations, is one technique to quantify this mineralization pattern. Based on the analysis of transiliac bone biopsy samples, it was shown that the reduction of bone turnover after antiresorptive therapy was associated with an increase in the degree (shift of the BMDD peak to higher calcium concentrations) and a reduction in the heterogeneity of mineralization (narrowing of the BMDD peak) in the bone matrix. Vice versa, after anabolic therapy the BMDD peak was shifted to lower calcium concentrations and got broader. The measurement of the BMDD in transiliac bio psy samples is not only important for the monitoring and safety aspects of therapies but it is essentially contributing to the understanding of the mechanisms of action of different therapies. In particular, changes in BMDD are an important information for the interpretation of changes in bone mineral density (by DEXA) during therapies. J Miner Stoffwechs Muskuloskelet Erkrank

Background The classical role of the calcium-sensing receptor (CaSR), an extracellular G protein-coupled receptor, is regulation of calcium homeostasis. In addition, it is involved in several cellular processes such as proliferation, differentiation, and apoptosis. The CaSR has been suggested to mediate the effects of calcium in delaying the onset of colorectal cancer (CRC). We have previously demonstrated that CaSR expression is downregulated in CRC, leading us to hypothesize that loss of CaSR might provide a growth advantage to transformed cells, conferring them resistance to calciummediated growth inhibition. Therefore the aim of the study was to understand the consequences of losing CaSR expression in CRC. Methods and Results We analysed mRNA (qRT-PCR) and protein (immunofluorescence) expression of CaSR in two CRC cell lines: Caco-2/15 (well-differentiated adenocarcinoma) and HT-29 (moderately differentiated adenocarcinoma). HT-29 cells showed lower CaSR levels when compared with Caco-2/15 cells (30-fold lower mRNA expression), similar to our CRC patient cohort (n = 60), where we found significantly less CaSR expression in tumours compared with respective adjacent mucosa (p < 0.001). To investigate the possible impact of CaSR on growth, we used a

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Idiopathic osteoporosis (IOP) in premenopausal women is characterized by fragility fractures at low or normal bone mineral density (BMD) in otherwise healthy women with normal gonadal function. Histomorphometric analysis of transiliac bone biopsy samples has revealed microarchitectural deterioration of cancellous bone and thinner cortices. To examine bone material quality, we measured the bone mineralization density distribution (BMDD) in biopsy samples by quantitative backscattered electron imaging (qBEI), and mineral/matrix ratio, mineral crystallinity/maturity, relative proteoglycan content, and collagen cross-link ratio at actively bone forming trabecular surfaces by Raman microspectroscopy and Fourier transform infrared microspectroscopy (FTIRM) techniques. The study groups included: premenopausal women with idiopathic fractures (IOP, n = 45), or idiopathic low BMD (Z-score ≤ -2.0 at spine and/or hip) but no fractures (ILBMD, n = 19), and healthy controls (CONTROL, n = 38). BMDD of cancellous bone showed slightly lower mineral content in IOP (both the average degree of mineralization of cancellous bone [Cn.Ca(Mean) ] and mode calcium concentration [Cn.Ca(Peak) ] are 1.4% lower) and in ILBMD (both are 1.6% lower, p < 0.05) versus CONTROL, but no difference between IOP and ILBMD. Similar differences were found when affected groups were combined versus CONTROL. The differences remained significant after adjustment for cancellous mineralizing surface (MS/BS), suggesting that the reduced mineralization of bone matrix cannot be completely accounted for by differences in bone turnover. Raman microspectroscopy and FTIRM analysis at forming bone surfaces showed no differences between combined IOP/ILBMD groups versus CONTROL, with the exceptions of increased proteoglycan content per mineral content and increased collagen cross-link ratio. When the two affected subgroups were considered individually, mineral/matrix ratio and collagen cross-link ratio were higher in IOP than ILBMD. In conclusion, our findings suggest that bone material properties differ between premenopausal women with IOP/ILBMD and normal controls. In particular, the altered collagen properties at sites of active bone formation support the hypothesis that affected women have osteoblast dysfunction that may play a role in bone fragility.

Bisphosphonate zählen heute zu den wichtigsten Medikamenten zur Behandlung von Knochenerkrankungen, die mit einer erhöhten Osteoklastenaktivität und damit einer erhöhten Knochenresorption verbunden sind: Osteoporose (Knochenbruch-Krankheit), Knochenmetastasen, tumorindizierte Hyperkalzämie und seltenere Erkrankungen wie Morbus Paget, fibröse Dysplasie oder Osteogenesis Imperfekta. Bei der postmenopausalen Osteoporose gelten die Bisphosophonate als „first line“-Therapie. Sie sind laut einer US-Studie aus dem Jahr 2008 die Osteoporosebehandlung mit dem günstigsten Kosten-Nutzen Verhältnis. Da die Bisphopsphonate die am häufigsten angewendete Therapie bei postmenopausaler Osteoporose darstellen, ist der Fokus dieses Artikels aufihre Wirkung bei Osteoporose gelegt.

During embryogenesis, urorectal septal formation occurs around the same time that VATER association develops. Axial mesodermal dysplasia spectrum is thought to arise as a consequence of aberrant mesodermal migration during early development, resulting in bronchial, pulmonary, cardiovascular, gastrointestinal, renal, urogenital and skeletal abnormalities. Congenital vertebral defects that result from disruption of the induction and formation of the axial skeleton include, spondylocostal dysostosis, Jarcho-Levin syndrome, Klippel-Feil anomaly and a wide range of syndromic malformation complex such as VATER and VACTERL association (David A et al. Am J Med Genet 1996; 62: 1 – 5). VACTERL association is a well-known association of abnormalities including vertebral anomalies, anal atresia, tracheo-esophageal fistula, renal abnormalities and limb abnormalities. VACTERL association sometimes termed VATER association depending on the clinical criteria used for the diagnosis. VATER is used to describe the association of Vertebral defects, Anal atresia or stenosis, Tracheo-Esophageal fistula, Radial defects and Renal anomalies (Endoh N et al. Cogen Anoms 2003; 43: 180 – 183). Recently, VATER association and persistent cloaca have been proposed to represent a continuous spectrum of anomalies, but the pathophysiology concerning the continuity of the development and the clinical condition are still unclear (Mori M et al. Tohoku J Exp Med 2007; 213: 291 – 295). The importance of recognising the full extent of spinal abnormalities lies in pre-empting the complications that might ensue.

Keywords Smallpatellasyndrome.Patellarinstability.Osteoarthritis.RadiographsDiagnosisPatellar instability in a family with small patella syndromeDiscussionSmall patella syndrome is a generalized bone dysplasiawith diagnostic features in the pelvis and knees and subtlechanges in other parts of the skeleton. Scott and Taor [1]reported 12 individuals from an autosomal dominantpedigree with small or absent patellae. Seven individualsalso had abnormalities of the pelvis or upper femoraconsisting of coxa vara, hypoplasia of the lesser trochanter,and abnormal ossification of the ischio-pubic junction.Bernhang and Levine [2] reported bilateral absence of thepatella detected in a 14-year-old child because of a cysticswelling over one knee. This revealed a clear fluid and thecyst had to be surgically excised. Radiologically, other thanthe absent patellae, there were no osseous lesions. Thepatient’s brother was similarly affected. Bongers et al. [3]provided the first evidence for the crucial role of humanTBX4 gene in the skeletal development of the patella,pelvis, and feet. They identified the heterozygosity ofTBX4 mutations in SPS patients, together with the similarskeletal phenotype of animals lacking Tbx4.Patellar stability relies on the limb alignment, theosseous architecture of the patella and the trochlear, theintegrity of the soft tissue constraints, and the interplay ofthe surrounding muscles [4]. Previous reports describedtrochlear dysplasia as an abnormality of the shape anddepth of the trochlear groove, mainly in its proximal extent.This was defined radiologically by Dejour et al. [5] on thebasis of the crossing sign (croisement). If the line of thetrochlear floor crosses the anterior border of one or bothcondyles, the trochlea is said to be flat at that level. Thesame feature was described by Grelsamer and Tedder [6]and called the lateral trochlear sign. Trochlear dysplasiawas further classified by Dejour and Locatelli [7] andTavernier and Dejour [8] on the basis of the CTmorphology of the index scan and the direct lateralradiograph.Small patella syndrome should be differentiated from themore common and better-known nail patella syndrome.Nail patella syndrome is characterized by bilateral dysplasticpatellae,glaucoma,andnephropathy.Iliachornsarepresentinonly approximately 70–80% of cases; they represent apathognomonic radiographic sign [9]. Additional skeletalabnormalities include talipes equinovarus, a malformedcapitellum of the radius, and fibular aplasia. The nails areabnormal from birth and are either absent or small andlongitudinally ridged.

Kidney transplantation is associated with bone loss and a high risk of fractures. Prophylactic treatment of bone is therefore recommended in the early posttransplant period. As a large number of transplant recipients develop adynamic renal osteodystrophy, recombinant parathyroid hormone (rPTH) could be a promising therapeutic option. In a 6-month double-blind, randomized trial, 26 kidney transplant recipients were treated with daily subcutaneous injections of 20 microg teriparatide (PTH 1-34) or placebo. Bone mineral density (BMD) of the femoral neck, lumbar spine and radial bone was measured at transplantation and after 6 months. Paired bone biopsies for histomorphometric analysis were obtained in six, and for measurement of bone matrix mineralization in five patients of each group. Serologic bone markers were measured at baseline and every 3 months. A total of 24 out of 26 patients completed the study. Femoral neck BMD was stable in the teriparatide group, but decreased significantly in the placebo group. Lumbar spine and radial BMD, histomorphometric bone volume and bone matrix mineralization status remained unchanged in both groups. Serologic bone markers were similarly reduced in both groups throughout the study. We conclude that teriparatide does not improve BMD early after kidney transplantation. Neither histological analysis nor bone markers provide evidence of improved bone turnover or mineralization.