Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution.

Effects of Orthogeriatric Care Models on Outcomes of Hip Fracture Patients: A Systematic Review and Meta-Analysis.

Orthogeriatrics is increasingly recommended in the care of hip fracture patients, although evidence for this model is conflicting or at least limited. Furthermore, there is no conclusive evidence on which model [geriatric medicine consultant service (GCS), geriatric medical ward with orthopedic surgeon consultant service (GW), integrated care model (ICM)] is superior. The review summarizes the effect of orthogeriatric care for hip fracture patients on length of stay (LOS), time to surgery (TTS), in-hospital mortality, 1-year mortality, 30-day readmission rate, functional outcome, complication rate, and cost. Two independent reviewers retrieved randomized controlled trials, controlled observational studies, and pre/post analyses. Random-effects meta-analysis was performed. Thirty-seven studies were included, totaling 37.294 patients. Orthogeriatric care significantly reduced LOS [mean difference (MD) - 1.55 days, 95% confidence interval (CI) (- 2.53; - 0.57)], but heterogeneity warrants caution in interpreting this finding. Orthogeriatrics also resulted in a 28% lower risk of in-hospital mortality [95%CI (0.56; 0.92)], a 14% lower risk of 1-year mortality [95%CI (0.76; 0.97)], and a 19% lower risk of delirium [95%CI (0.71; 0.92)]. No significant effect was observed on TTS and 30-day readmission rate. No consistent effect was found on functional outcome. Numerically lower numbers of complications were observed in orthogeriatric care, yet some complications occurred more frequently in GW and ICM. Limited data suggest orthogeriatrics is cost-effective. There is moderate quality evidence that orthogeriatrics reduces LOS, in-hospital mortality, 1-year mortality, and delirium of hip fracture patients and may reduce complications and cost, while the effect on functional outcome is inconsistent. There is currently insufficient evidence to recommend one or the other type of orthogeriatric care model.

Natural history of mineral metabolism, bone turnover and bone mineral density in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol.

The skeletal effects of renal transplantation are not completely understood, especially in patients managed with a steroid minimization immunosuppressive protocol and long term. We enrolled 69 adult transplant recipients (39 males; ages 51.1 ± 12.2 years), free of antiresorptive therapy and managed with a steroid minimization immunosuppressive protocol, into a 5-year prospective observational study to evaluate changes in areal bone mineral density (aBMD), mineral metabolism and bone remodelling. Dual energy X-ray absorptiometry, laboratory parameters of mineral metabolism (including parathyroid hormone, sclerostin and fibroblast growth factor 23) and non-renal cleared bone turnover markers (BTMs) (bone-specific alkaline phosphatase, trimeric N-terminal propeptide and tartrate-resistant acid phosphatase 5b) were assessed at baseline and 1 and 5 years post-transplantation. The mean cumulative methylprednisolone exposure at 1 and 5 years amounted to 2.5 ± 0.8 and 5.8 ± 3.3 g, respectively. Overall, bone remodelling activity decreased after transplantation. Post-transplant aBMD changes were minimal and were significant only in the ultradistal radius during the first post-operative year {median -2.2% [interquartile range (IQR) -5.9-1.2] decline, P = 0.01} and in the lumbar spine between Years 1 and 5 [median 1.6% (IQR -3.2-7.0) increase, P = 0.009]. BTMs, as opposed to mineral metabolism parameters and cumulative corticosteroid exposure, associated with aBMD changes, both in the early and late post-transplant period. Most notably, aBMD changes inversely associated with bone remodelling changes. In summary, in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol, BMD changes are limited, highly variable and related to remodelling activity rather than corticosteroid exposure.

Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates.

BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.

Bone mineral density, bone turnover markers, and incident fractures in de novo kidney transplant recipients.

Kidney transplant recipients are at increased risk of fractures. This prospective observational study investigated whether areal bone mineral density (aBMD) as assessed by dual-energy x-ray absorptiometry can predict incident fragility fractures in de novo kidney transplant recipients and whether bone turnover markers increase diagnostic accuracy. Parameters of bone mineral metabolism including parathyroid hormone (PTH), fibroblast growth factor 23, sclerostin, calcidiol and calcitriol, and bone turnover markers were assessed in blood samples collected immediately prior to kidney transplantation in 518 adult recipients. aBMD was measured at several skeletal sites within 14 days posttransplant. Thirty patients had a history of a fragility fracture at the time of transplantation, and osteopenia or osteoporosis at the femoral neck was observed in 77%. Bone turnover markers were inversely correlated with aBMD at all skeletal sites. Low aBMD and low PTH were associated with history of fragility fracture at the time of transplantation, independent of age, gender, and comorbidity. During a median post-transplant follow-up of 5.2 years, 38 patients sustained a fragility fracture, corresponding to a fracture incidence of 14.1 per 1000 person-years. Low aBMD at the hip and lumbar spine were associated with incident fractures, independent of classical determinants, including history of fracture. PTH and bone turnover markers at the time of transplantation failed to predict incident fractures. In conclusion, aBMD is low, correlates inversely with bone turnover, and predicts incident fractures in de novo kidney transplant recipients.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Glycemia but not the Metabolic Syndrome is Associated with Cognitive Decline: Findings from the European Male Ageing Study.

OBJECTIVE: Previous research has indicated that components of the metabolic syndrome (MetS), such as hyperglycemia and hypertension, are negatively associated with cognition. However, evidence that MetS itself is related to cognitive performance has been inconsistent. This longitudinal study investigates whether MetS or its components affect cognitive decline in aging men and whether any interaction with inflammation exists. METHODS: Over a mean of 4.4 years (SD ± 0.3), men aged 40-79 years from the multicenter European Male Ageing Study were recruited. Cognitive functioning was assessed using the Rey-Osterrieth Complex Figure (ROCF), the Camden Topographical Recognition Memory (CTRM) task, and the Digit Symbol Substitution Test (DSST). High-sensitivity C-reactive protein (hs-CRP) levels were measured using a chemiluminescent immunometric assay. RESULTS: Overall, 1,913 participants contributed data to the ROCF analyses and 1,965 subjects contributed to the CTRM and DSST analyses. In multiple regression models the presence of baseline MetS was not associated with cognitive decline over time (p > 0.05). However, logistic ordinal regressions indicated that high glucose levels were related to a greater risk of decline on the ROCF Copy (ß = -0.42, p < 0.05) and the DSST (ß = -0.39, p < 0.001). There was neither a main effect of hs-CRP levels nor an interaction effect of hs-CRP and MetS at baseline on cognitive decline. CONCLUSION: No evidence was found for a relationship between MetS or inflammation and cognitive decline in this sample of aging men. However, glycemia was negatively associated with visuoconstructional abilities and processing speed.

A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ∼10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.-Dubois, V., Laurent, M. R., Sinnesael, M., Cielen, N., Helsen, C., Clinckemalie, L., Spans, L., Gayan-Ramirez, G., Deldicque, L., Hespel, P., Carmeliet, G., Vanderschueren, D., and Claessens, F. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

Development and validation of an eight-item calcium screener to assess daily calcium intake of patients with osteoporosis in clinical practice.

OBJECTIVE: To validate a short food frequency questionnaire (screener) estimating daily average calcium intake from dietary sources to guide calcium supplementation of patients with osteoporosis in clinical practice. METHODS: An eight-item calcium screener was developed based on existing literature, food consumption data and expert opinion. Convergent validity was determined by comparison with 3-day food records using mean difference, Spearman's correlation coefficients (SCC) and Bland-Altman analysis. Test-retest reliability was assessed by SCC and intraclass correlation coefficients (ICC). We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to identify patients requiring calcium supplementation (<1200 mg dietary calcium intake/day). RESULTS: Fifty-two patients filled out the eight-item calcium screener and the 3-day Food record (mean age of 66.8 ± 12.9 (SD)) and 38 patients filled out the screener twice for reliability analysis (mean age of 65.8 ± 12.8 (SD)). Dietary calcium intake between the calcium screener and food records showed a strong correlation (N = 52 patients, SCC = 0.53, p ≤ 0.001) and mean difference of 21 mg (p = 0.70). Bland-Altman analysis showed agreement within 95% confidence intervals for 49/52 comparisons (94%). Test-retest reliability of the calcium screener was excellent (SCC = 0.96, p ≤ 0.001; ICC = 0.99, p ≤ 0.001). CONCLUSION: The calcium screener shows good convergent validity, reliability and feasibility to estimate daily calcium intake of patients with osteoporosis in routine clinical practice.

Hospitalizations for hip and non-hip osteoporotic fractures in Belgium: nationwide trends between 2010 and 2021.

This study aimed to describe the incidence of hospitalizations for osteoporotic fractures in patients aged 50 years and over in Belgium between 2010 and 2021. A declining trend in crude and age-adjusted hospitalization incidence was observed, however, the absolute number of hospitalisations for osteoporotic fractures increased due to demographic changes. PURPOSE: The secular trends of hospitalizations for hip and other osteoporotic fractures between 2010 and 2021 in patients aged 50 years and over in Belgium are unknown. This study aimed to describe the incidence of hospitalizations for osteoporotic fractures in patients aged 50 years and over in Belgium between 2010 and 2021. METHODS: Population-based, retrospective study based on hospitalization data extracted by the national database NIHDI and demographical data retrieved from the Belgian Federal Bureau for Statistics. Data were combined to determine the crude and age-standardized hospitalization incidence of fractures of the hip, distal femur, pelvis, humerus, wrist, and spine (2010 as the reference year). RESULTS: A total of 445,234 hospitalizations for osteoporotic fractures were reported between 2010 and 2021 (excluding 2015). Hospitalizations increased by 5.8% between 2010 and 2021 (p = 0.013) with a higher increase in men (12.1%; p = 0.001) compared to women (4.1%; p = 0.041). The crude incidence of hospitalizations for all fractures per 100,000 persons per year decreased from 990 to 910 between 2010 and 2021 (p = 0.572). The age-standardized incidence for hospitalizations of any osteoporotic fracture in men declined from 5.30/1,000 to 4.42/1,000 (p = 0.010). In women, a similar decrease was observed (13.84/1,000 to 11.62/1,000; p = 0.003). Both age-standardized hospitalizations for hip and non-hip fractures showed a decrease in both sexes. CONCLUSION: Although a declining trend in the crude incidence per 100,000 and in the age-adjusted incidence of hospitalizations for osteoporotic fractures was observed, the absolute number of hospitalizations for osteoporotic fractures increased due to the demographic change of an ageing population.

Predictors of mortality one year after pelvic fractures in an older population: a retrospective cohort study.

The goal was to investigate if patient characteristics can be used to predict 1-year post-fracture mortality after pelvic fracture. Multivariate logistic regression identified male gender, comorbidities and presence of in-hospital complications as predictors of 1-year mortality. PURPOSE: Osteoporotic pelvic fractures have significant mortality and morbidity in the older population. The aim of this study was to investigate the factors predicting one-year mortality of patients sustaining a low-impact pelvic fracture (pelvic ring and acetabulum). METHODS: A total of 282 patients aged ≥ 65 years presenting with a low-energy pelvic ring (n =254) or acetabular (n =28) fracture to the emergency department at the University Hospitals Leuven were included. Demographic and clinical data were retrospectively collected and predictors for mortality one year after pelvic ring fractures were evaluated. RESULTS: The one-year mortality after osteoporotic pelvic ring fractures and acetabular fractures was respectively 20.4% (95% CI 15.7-26.0) and 14% (95% CI 4.0-32.7). Multivariate logistic regression adjusted for confounders identified male gender (OR 3.18; 95% CI (1.06-9.49), p =0.038), a higher number of comorbidities (OR 1.5; 95% CI (1.16-1.95), p =0.002) and in-hospital complications (OR 5.00; 95% CI (1.39-17.97), p =0.014) as independent predictors of one-year mortality after pelvic ring fractures. CONCLUSION: The one-year mortality after low-energy pelvic is high and can be predicted by different patient characteristics. These findings can guide pelvis fracture treatment decisions in the older population.

Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions.

Androgens increase both the size and strength of skeletal muscle via diverse mechanisms. The aim of this review is to discuss the different cellular targets of androgens in skeletal muscle as well as the respective androgen actions in these cells leading to changes in proliferation, myogenic differentiation, and protein metabolism. Androgens bind and activate a specific nuclear receptor which will directly affect the transcription of target genes. These genes encode muscle-specific transcription factors, enzymes, structural proteins, as well as microRNAs. In addition, anabolic action of androgens is partly established through crosstalk with other signaling molecules such as Akt, myostatin, IGF-I, and Notch. Finally, androgens may also exert non-genomic effects in muscle by increasing Ca(2+) uptake and modulating kinase activities. In conclusion, the anabolic effect of androgens on skeletal muscle is not only explained by activation of the myocyte androgen receptor but is also the combined result of many genomic and non-genomic actions.

Sarcopenia, osteoporosis and frailty.

Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and treatment of osteoporosis are well established in clinical practice, sarcopenia has only been classified internationally as a disease in 2016. Both conditions are associated with an increased risk of adverse health outcomes such as fractures, dysmobility and mortality. Rather than focusing on one dimension of bone or muscle mass or weakness, the concept of musculoskeletal frailty captures the overall loss of physiological reserves in the locomotor system with age. The term osteosarcopenia in particular refers to the double jeopardy of osteoporosis and sarcopenia. Muscle-bone interactions at the biomechanical, cellular, paracrine, endocrine, neuronal or nutritional level may contribute to the pathophysiology of osteosarcopenia. The paradigm wherein muscle force controls bone strength is increasingly facing competition from a model centering on the exchange of myokines, osteokines and adipokines. The most promising results have been obtained in preclinical models where common drug targets have been identified to treat these conditions simultaneously. In this narrative review, we critically summarize the current understanding of the definitions, epidemiology, pathophysiology, and treatment of osteosarcopenia as part of an integrative approach to musculoskeletal frailty.

Skeletal response to teriparatide in real-life setting: effects of age, baseline bone density and prior denosumab use.

OBJECTIVES: Teriparatide (TPD) is an osteoanabolic agent used in patients with high osteoporotic fracture risk. Predictors of therapeutic response to TPD in real-life setting are not well characterised. This study investigated the influence of previous antiresorptive therapy, age and other patient characteristics on the skeletal response to TPD. METHODS: Retrospective study at the metabolic bone clinic, University Hospitals Leuven, Belgium. Patients with osteoporosis and a high fracture burden received TPD for 9-18 months. Bone mineral density (BMD) was measured at baseline, 9 and 18 months at lumbar spine (LS), femoral neck (FN) and total hip (TH). RESULTS: BMD at LS increased at 9 months (change mean (standard error) 6.8 % (0.7) p < 0.001) and at 18 months (8.0 % (0.9) p < 0.001), while BMD at FN and TH did not change significantly. Non-response in BMD change at the LS was seen with prior denosumab use (odds ratio 0.21, 95% confidence interval (CI) 0.049-0.912, p = 0.037). Changes in BMD at TH were significantly greater in younger patients and in patients with a lower baseline BMD. CONCLUSION: TPD-induced changes in BMD at TH might depend on age and baseline BMD and at LS on prior denosumab use. The results suggest that these factors may be relevant for clinical decision making when initiating TPD treatment, although larger studies are needed to confirm these findings.