With age, both men and women experience a decline of sex-hormones and impaired bone repair. This study examined whether bone healing could be improved by combined treatment with the selective androgen and estrogen receptor modulators ostarine (Ost) and raloxifene (Ral), and compared its efficacy with monotherapy in female and male rat models. Three‑month‑old female (Experiment 1, n = 15/group) and 8‑month‑old male (Experiment 2, n = 15/group) Sprague–Dawley rats were either intact (healthy control) or ovariectomized/orchiectomized (Ovx/Orx). Ovx/Orx rats received daily either no treatment, Ost, Ral, or combined Ost + Ral at the respective monotherapy doses. Eight weeks after Ovx or 12 weeks after Orx, rats underwent bilateral metaphyseal osteotomy of the tibia with plate fixation. Healing was assessed five in females or 6 weeks in males later by micro‑CT, biomechanics, and histology. Increased total, callus, and cortical densities as well as bone volume fraction were observed in the Ost + Ral group, accompanied by reduced callus volume and surface area, indicating advanced healing. The effect of Ost + Ral was stronger than that of Ral, whereas Ost alone did not alter bone parameters. Biomechanical properties were improved in the Ral and Ost + Ral groups relative to Ovx/Orx controls. Uterus weight was lowest in Ovx and Ovx + Ral groups and enhanced by Ost and Ost + Ral. Prostate weight was lowest in Orx and Orx + Ral rats and increased by Ost. The combination with Ral reduced the androgenic effect of Ost on prostate. Combined treatment may represent a promising approach for osteoporotic bone repair in both sexes, though potential side effects of Ost require consideration.

Importance: Costal cartilage calcification (CCC) of the cartilage graft, commonly used in reconstruction of nasal/auricular deformities, can cause poor surgical outcome, but structural and quantitative analyses are lacking. Objective: To compare the prevalence, amount, and structural pattern of CCC from individuals by gender and age, as measured by digital contact radiography. Design, Setting, and Participants: This is a cross-sectional cadaveric study (n = 92) of the seventh rib cartilage. CCC prevalence/amount/structural pattern (central [c]/peripheral [p]/diffuse [d]) was analyzed within three age groups: I (<40 years), II (40-70 years), and III (>70 years). Main Outcomes and Measures: Qualitative and quantitative CCC analyses were set in relation to gender/structural pattern/age. Results: CCC prevalence was gender independent (96.7%) and occurred in c/p/d: 12.4%/22.4%/65.2%. Structural CCC pattern differed between age groups (I: 80%; c/p/d: 26.7%/46.6%/6.7%; II: 100%; c/p/d: 18.0%/30.8%/51.2%; III: 100%; p/d: 2.6%/97.4%). The mean CCC amount (9.1%) was gender independent and showed a significant correlation with age (p = 0.001). The mean amount showed a significant difference between the structural pattern [d/p: 3.3 times higher (p = 0.006), d/c: 7.7 times higher (p < 0.001)] and age groups (I/II/III: 6.4/8.5%/10.9%), whereby the amount was higher in groups II (factor: 7.4; p < 0.001) and III (factor: 16.5; p < 0.001) compared with group I. Conclusions: These data show an age-/gender-independent high CCC prevalence in the general population (96.7%). CCC already occurred in young donors (<40 years) with a not negligible amount (6.4%). CCC increased with age and structural analysis showed a gender-/age-specific pattern, whereby males were prone to peripheral/females to central CCC. Diffuse CCC was observed as an age-independent sign for high CCC levels.

Introduction: Previously, we have shown that hyponatremia (HypoNa) impairs bone tissue to a similar extent as estrogen deficiency and that both factors have a synergistic adverse effect on bone healing.The present study investigated whether HypoNa worsens the effect of estrogen depletion on bone in an ovariectomized rat model for postmenopausal osteoporosis.

Background and Objectives: Hyponatremia is the most common electrolyte disorder in elderly and associated with increased risk of falls. Clinical studies as well as small animal experiments suggested an association between chronic hyponatremia and osteoporosis. Furthermore, it has been assumed that subtle hyponatremia may be an independent fracture risk in the elderly. Therefore, this study was designed to evaluate the possible influence of chronic hyponatremia on osteoporosis and low-energy fractures of the spine. Materials and Methods: 144 patients with a vertebral body fracture (mean age: 69.15 ± 16.08; 73 females and 71 males) due to low-energy trauma were treated in a level one trauma center within one year and were included in the study. Chronic hyponatremia was defined as serum sodium < 135 mmol/L at admission. Bone mineral density (BMD) of the spine was measured using quantitative computed tomography in each patient. Results: Overall, 19.44% (n = 28) of patients in the low-energy trauma group had hyponatremia. In the group with fractures caused by low-energy trauma, the proportion of hyponatremia of patients older than 65 years was significantly increased as compared to younger patients (p** = 0.0016). Furthermore, there was no significant gender difference in the hyponatremia group. Of 28 patients with chronic hyponatremia, all patients had decreased bone quality. Four patients showed osteopenia and the other 24 patients even showed osteoporosis. In the low-energy trauma group, the BMD correlated significantly with serum sodium (r = 0.396; p*** < 0.001). Conclusions: The results suggest that chronic hyponatremia affects bone quality. Patients with chronic hyponatremia have an increased prevalence of fractures after low-energy trauma due to a decreased bone quality. Therefore, physicians from different specialties should focus on the treatment of chronic hyponatremia to reduce the fracture rate after low-energy trauma, particularly with elderly patients.

Enobosarm (ostarine, MK-2866, or GTx-024) is a non-steroidal selective androgen receptor modulator. This study evaluated the effect of various regimens of enobosarm (EN) on bone healing in an orchiectomized rat model for aged male osteoporosis and compared it to testosterone (T) treatment. Ninety eight-month-old male Sprague Dawley rats were either orchiectomized (Orx) or left intact (Non-Orx) and divided into groups (n = 15/group): (1) Non-Orx; (2) Orx; (3) Orx+T-th; (4) Orx+EN-th; (5) Orx+T-pr; and (6) Orx+EN-pr. Prophylaxis (Pr) treatments were applied immediately after Orx for up to 18 weeks. Therapy (Th) treatments were applied 12 weeks after Orx for up to 6 weeks. Bilateral tibia osteotomy with plate osteosynthesis was performed 12 weeks after Orx in all groups. EN and T were mixed with the diet; the daily dosage was 0.35 ± 0.06 and 41 ± 8 mg/kg BW, respectively. Both T treatments improved bone healing by increasing callus volume and area, bone volume and density, and cortical width; they had no effect on prostate or levator ani weight. EN-pr increased the callus area and callus density and decreased cortical density, but increased prostate weight. The effect of T-pr and T-th on bone was stronger than EN-pr. EN-th affected bone healing negatively by reducing callus density and area and delaying osteotomy bridging. Levator ani weight was increased in both EN groups. EN treatment after fracture is not advisable in aged males. EN-pr treatment as a therapy for bone healing in men could be further investigated; endocrinological side effects must be closely monitored.

Introduction: We evaluated the prevalence and influence of chronic hyponatremia in patients with low energy trauma. We also investigated the influence of medication and diseases on hyponatremia. Material and methods: This retrospective study included 314 cases of proximal femoral fracture due to low energy trauma. Patients were treated in the University Medical Center Goettingen within 3 years. Hyponatremia was defined as serum sodium <135 mmol/L at admission. Results: Overall, 15.6% of patients in the low energy trauma group had hyponatremia. Among patients older than 80 years, women showed distinctly higher rates of hyponatremia (female: 16.4%; male: 5.9%). In contrast only 4.7% of patients who underwent elective hip arthroplasty showed hyponatremia. Patients on sartanes and aldosterone antagonists showed significantly higher rates of hyponatremia. Alcoholism was significantly associated with hyponatremia. Conclusions: We confirmed a high prevalence of chronic hyponatremia in patients with fractures due to low energy trauma. Our data underscore chronic hyponatremia as a contributing factor to hip fractures. Women older than 80 have a higher risk of developing hyponatremia. Sartanes, aldosterone antagonists, and alcohol disease are associated with hyponatremia. Treating hyponatremia may decrease the risk of fracture after low energy trauma. Therefore, physicians of different specialties should focus on treatment of chronic hyponatremia to reduce the fracture rate associated with low energy trauma.

Non-steroidal selective androgen receptor modulators, including ostarine, have been developed as an alternative to steroidal hormones. Ostarine has shown a beneficial effect on bone in experimental studies, but no data regarding the effect of ostarine on bone healing have yet been reported. We investigated effects of ostarine on bone healing in ovariectomized rats. Sprague-Dawley rats (3 months old) were ovariectomized (Ovx, n = 46) or left intact (Non-Ovx, n = 10). After 8 weeks, an osteotomy of the tibia metaphysis was created in all rats, and the Ovx rats were divided into four groups: untreated Ovx (n = 10) and three Ovx groups (each of 12 rats) treated with ostarine at doses of 0.04, 0.4, or 4 mg/kg BW (OS-0.04, OS-0.4, and OS-4 groups). Five weeks later, bone healing was analyzed. The OS-4 dose enhanced callus formation, increased callus density, accelerated bridging time of the osteotomy, and elevated alkaline phosphatase gene expression in callus and its protein expression in serum. In the Ovx group, most of the callus parameters were diminished. All OS treatments increased the weight of the gastrocnemius muscle, but only partly enhanced uterus weight in OS-0.4 and OS-4. Serum cholesterol level was reduced, and serum phosphorus was elevated in OS-0.04 and OS-4. Ostarine appeared to have a positive effect on early bone healing in ovariectomized rats. Considering its favorable effect on non-osteotomized bone and muscle, this treatment could be further explored as a therapy for osteoporosis. However, possible metabolic side effects should first be evaluated.

Objective: In aging population, postmenopausal osteoporosis and decline of musculoskeletal function, referred to as “frailty syndrome” lead to loss of bone and muscle, causing falls, and fall-related injuries. To limit the impact of this portentous duo, simultaneous treatment of both is needed. Urocortin (UCN) has been reported to improve osteoporotic bone properties while its effect on muscle has not been addressed yet. Design and Methods: We aimed to investigate the effect of urocortin in vivo on skeletal muscle structure in osteopenic rats. Sixty Sprague-Dawley rats were divided into five groups: four were ovariectomized (OVX) and one underwent sham operation (SHAM). One ovariectomized group was left untreated (OVX), while one was treated with urocortin s.c. in 3 μg/kg body weight (bw) (OVX+UCN low), one with 30 μg/kg (OVX+UCN high), while one group was treated with estradiol orally (OVX+E: 0.2 mg/kg bw), each for 35 days. Mm. gastrocnemius, longissimus, and soleus were isolated and capillary density as well as diameters of type I and II fibers were measured. In addition, we examined the effect of UCN on tibia using biomechanical, micro-CT and ashing analysis and investigated the blood serum. Results: We demonstrated a positive effect of UCN on M. soleus, in which fiber diameter was positively influenced. The biomechanical and structural parameters of bone were not changed in UCN treated rats. The higher cholesterol, glucose and triglyceride levels in the “UCN high” group raise concern about this treatment. Conclusions: Our results portray urocortin as a substance that can be assessed for future therapeutic treatments of estrogen deficiency. New and Noteworthy: Urocortin has a positive effect on M. soleus (diameter). Urocortin raises serum cholesterol and triglyceride levels. Bone tissue was not affected by UCN.

BackgroundOsteoporosis is one of the world's major medical burdens in the twenty-first century. Pharmaceutical intervention currently focusses on decelerating bone loss, but phytochemicals such as baicalein, which is a lipoxygenase inhibitor, may rescue bone loss. Studies evaluating the effect of baicalein in vivo are rare.MethodsWe administered baicalein to sixty-one three-month-old female Sprague-Dawley rats. They were divided into five groups, four of which were ovariectomized (OVX) and one non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, bilateral tibial osteotomy with plate osteosynthesis was performed and bone formation quantified. Baicalein was administered subcutaneously using three doses (C1: 1mg/kg BW; C2: 10mg/kg BW; and C3: 100mg/kg BW) eight weeks after ovariectomy for four weeks. Finally, femora and tibiae were collected. Biomechanical tests, micro-CT, ashing, histological and gene expression analyses were performed.ResultsBiomechanical properties were unchanged in tibiae and reduced in femora. In tibiae, C1 treatment enhanced callus density and cortical width and decreased callus area. In the C3 group, callus formation was reduced during the first 3weeks after osteotomy, correlating to a higher mRNA expression of Osteocalcin, Tartrate-resistant acid phosphatase and Rankl. In femora, baicalein treatments did not alter bone parameters.ConclusionsBaicalein enhanced callus density and cortical width but impaired early callus formation in tibiae. In femora, it diminished the biomechanical properties and calcium-to-phosphate ratio. Thus, it is not advisable to apply baicalein to treat early bone fractures. To determine the exact effects on bone healing, further studies in which baicalein treatments are started at different stages of healing are needed.

Osteoporosis is one of the most common diseases worldwide. In osteoporosis, vertebral fractures represent a major burden. Lipoxygenase (LOX) inhibitors such as baicalein and zileuton may represent a promising therapeutic option owing to their antioxidative effects and suppression of various inflammatory processes in muscle and bone. The effect of these LOX inhibitors on the spine was studied in osteopenic rats. Female Sprague-Dawley rats were divided two times into five groups: four groups each were ovariectomized (OVX) and one control group was non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, three concentrations of baicalein (1mg/kg body weight [BW], 10mg/kgBW, and 100mg/kgBW) were administered subcutaneously daily in three OVX groups for 4weeks. Similarly, zileuton was administered in three concentrations via food for 5weeks. In vivo computed tomography (pQCT) of the spine was performed before the treatments and at the end of the experiment. Lumbar vertebrae were subjected to a compression test, micro-CT, and ashing analyses. After baicalein treatment, cortical bone mineral density (BMD) was improved; trabecular connectivity and trabecular BMD were diminished at high dose. After zileuton treatment, the total BMD, anorganic weight, trabecular nodes, and trabecular area were improved. The in vivo stress-strain index was increased and alkaline phosphatase activity in serum was enhanced after both treatments. A dose-dependent effect was not clearly observed after both treatments. The treatments using baicalein for 4 and zileuton for 5weeks were not sufficient to change the biomechanical properties and bone volume fraction (BV/TV). Overall, baicalein improved the cortical bone parameters whereas zileuton had a favorable effect on the trabecular structure. Moreover, both treatments increased the bone formation rate. Longer trials, a combination of both LOX inhibitors, and their effect at the cellular and molecular levels should be investigated in further studies.