We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

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The data derived from osteons (as the basic structural units of the cortical bone) in different skeletal conditions can be employed to highlight structural factors contributing to the fracture susceptibility of various groups of individuals.

IV.

SUMMARYResearch in the last decade has revealed that bone is not only a target tissue for numerous circulating hormones but functions as an endocrine organ itself. As a recent study demonstrated a stimulatory effect of the osteoblast-derived hormone osteocalcin (OCN) on testosterone production in mice, we investigated whether such an association can be replicated in humans. We used data from 1338 men (25-86 years) in the population-based epidemiological Study of Health in Pomerania and from 110 male outpatients with bone disorders (18-85 years) for the study. We analysed cross-sectional associations between OCN and total testosterone serum concentrations (TT), as well as associations between further markers of bone turnover [bone-specific alkaline phosphatase (BAP), serum C-terminal telopeptides of Type I collagen (CTX), urinary deoxypyridinoline] and TT using ordinary least square (OLS) regression models. Multivariable OLS models revealed a positive association between OCN and TT in the population-based (b coefficients for a one standard deviation increase, 0.590; standard error (SE), 0.175; p-value, <0.01) and patient-based (b coefficient, 0.575; SE, 0.132; pvalue, <0.01) samples even after adjustment for age and body mass index (both samples), and time of blood sampling (populationbased sample only). Furthermore, we observed positive associations between BAP and TT (b coefficient, 0.403; SE, 0.170; p-value, 0.02) as well as between CTX and TT (b coefficient, 0.733; SE, 0.172; <0.01) in men from the general population. The present investigation shows that OCN is associated with TT in the general population and in patients with bone disorders, and may thus indicate general male health status. Additional longitudinal observational studies are warranted to confirm our findings and future experimental research is necessary to elucidate potential mechanisms underlying the observed associations.

Background: We developed a quadriceps-tendon graft technique using a double-layered, partial-thickness, soft tissue quadriceps tendon graft (dlQUAD) for anterior cruciate ligament reconstruction (ACLR). This technique allows simple femoral loop button fixation and a limited harvest depth of the quadriceps tendon. Purpose: To evaluate the outcome of patients undergoing revision ACLR using the dlQUAD technique compared with a hamstring tendon graft (HT). Study Design: Cohort study; Level of evidence, 3. Methods: A total of 114 patients who underwent revision ACLR between 2017 and 2018 were included in this retrospective case series. At a mean follow-up of 26.9 ± 3.7 months (range, 24-36), 89 patients (dlQUAD: n = 43, HT: n = 46) were clinically examined. In addition, patients completed the Lysholm score, Tegner activity scale, subjective International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score, and visual analog scale (VAS) for pain. Postoperative failure of the revision ACLR was defined as a side-to-side difference (SSD) in Rolimeter testing ≥5 mm or a pivot-shift grade of 2 or 3. Results: Nine patients (10.1%) were identified with a failed revision ACLR. There was a significantly lower failure rate with dlQUAD versus the HT group (2.3% vs 17.4%; P = .031). The mean postoperative SSD was significantly less in the dlQUAD group (1.3 ± 1.3 mm [range, 0-5] vs 1.8 ± 2.2 mm [range, 0-9]; P = .043). At the latest follow-up, Tegner and IKDC scores significantly improved in the dlQUAD group compared with the HT group (Tegner: 5.8 ± 1.8 vs 5.6 ± 1.5; P = .043; IKDC: 83.8 ± 12.2 vs 78.6 ± 16.8; P = .037). The pain VAS score was also significantly reduced in the dlQUAD group compared with the HT group (0.9 ± 1.1 vs 1.6 ± 2.0; P = .014). Conclusion: The dlQUAD and HT techniques both demonstrated significant improvement of preoperative knee laxity and satisfactory patient-reported outcome measures after revision ACLR. Compared with the HT grafts, the dlQUAD technique showed lower failure rates and small increases in Tegner and IKDC scores.

Purpose The purpose of this study was to investigate specific risk factors, common fracture locations and possible sexspecific differences in elderly patients with stress fractures. Methods This analysis enrolled 105 patients (83 women, 22 men) with stress fractures. For the analysis of possible risk factors related to increasing age, data from 82 patients (67 women, 15 men) aged 40 years and older (mean age of 57.4 ± 11.0 years) were compared with that from a younger control group [23 patients (16 women, seven men), mean age 28.4±6.7 years]. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry bone densitometry (DXA) and blood samples were taken. Results A total of 211 stress fractures were found. Of these, 177 were found in the study group, of which 90.4 % were located in the lower limb. Lumbar and femoral BMD was significantly lower in elderly patients; however, the BMD of most patients was within the osteopenic or normal range. Within the study group, a total of 83.8 % had a vitamin D insufficiency (<30 μg/ l); 75.5 % were not engaged in regular physical activity more than once a week. Overweight patients within the study group had significantly more stress fractures compared to normal weight patients (2.6±1.7 vs. 1.9±1.1, p<0.05). Conclusions A similar contribution of risk factors has been found for stress fractures in elderly patients and younger controls of the general population. Stress fracture incidence seems to be rather multifactorial and not based on osteoporotic changes alone. A balanced calcium and vitamin D metabolism seems to be of paramount importance for stress fracture prevention in elderly patients.