Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions.

Cirrhosis predisposes to abnormalities in energy, hormonal, and immunological homeostasis. Disturbances in these metabolic processes create susceptibility to sarcopenia or pathological muscle wasting. Sarcopenia is prevalent in cirrhosis and its presence portends significant adverse outcomes including the length of hospital stay, infectious complications, and mortality. This highlights the importance of identification of at-risk individuals with early nutritional, therapeutic and physical therapy intervention. This manuscript summarizes literature relevant to sarcopenia in cirrhosis, describes current knowledge, and elucidates possible future directions.

Erectile Dysfunction in Cirrhosis: Its Prevalence and Risk Factors.

Background: Erectile dysfunction (ED) is common in men with cirrhosis. The aim of this study was to assess the prevalence of ED and the factors associated with ED in men with cirrhosis. Methods: 400 men with cirrhosis [Child-Turcotte-Pugh (CTP) class A, 44.0%; CTP class B, 41.0%; and CTP class C, 15.0%] having high Karnofsky performance score, and living in a stable monogamous relationship with a female partner were included in the study. International Index of Erectile Function (IIEF) questionnaire, and Short-Form (36) Health Survey (SF-36) were used to assess erectile function and the health-related quality of life (HRQOL), respectively. Results: ED was found in 289 (72.3%) patients. Patients with ED reported significantly lower SF-36 scores across all the eight domains of SF-36 (i.e., physical functioning score, role physical score, bodily pain score, general health perception score, vitality score, social functioning score, role emotional score, and mental health score); physical component summary score, and mental physical component summary score, compared with those without ED. On multivariate analysis, factors associated with ED were older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher hepatic venous pressure gradient (HVPG), presence of generalized anxiety disorder (GAD), presence of major depression, and lower appendicular skeletal muscle index measured by dual-energy X-ray absorptiometry (DEXA ASMI). Conclusion: ED is common in men with cirrhosis, and men with ED have poor HRQOL compared with those without ED. Older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher HVPG, presence of GAD, presence of major depression, and lower DEXA ASMI are associated with ED.

High Prevalence of Hormonal Changes and Hepatic Osteodystrophy in Frail Patients with Cirrhosis-An Observational Study.

Background/Aim: Hormonal changes and hepatic osteodystrophy are less often studied complications of cirrhosis. This study describes the variance in hormones and osteodystrophy between Frail and Not frail patients with cirrhosis. Methods: 116 outpatients with cirrhosis were prospectively enrolled in this study. Frailty assessment was done using Liver Frailty Index (LFI). Sociodemographic assessment, anthropometry, nutritional assessment, hormone profile, and dual-energy X-ray absorptiometry scan were done in all patients. Results: 116 patients, predominantly males (100 (86.2%) with mean age of 50.16 years (95% CI, 48.43-51.89) were included. Malnutrition was more common in Frail group as compared to Not frail group. Subjective global assessment (SGA) class-B patients were significantly more in Frail group (37 (74%) vs 3 (4.5%), P = 0.001). The prevalence of lower parathyroid hormone (PTH) (14 (28%) vs 2 (3%)), testosterone (33 (66%) vs 15 (22.7%)), vitamin D3 (44 (88%) vs 39 (59.1%)), and cortisol (37 (74%) vs 37 (56.1) levels was higher in Frail group (P < 0.05). The number of patients diagnosed with osteodystrophy (34 (68%) vs 21 (31.8%), P = 0.001) was significantly higher in Frail group. The marker of osteoclastic activity, ß-cross laps, was significantly elevated in the Frail group both in males (736 (655-818) vs 380 (329-432), P = 0.001) and (females 619 (479-758) vs 313 (83-543), P = 0.02). Bone mineral density (BMD) at lumbar spine (LS) and neck of femur (NF) had significant correlation with LFI (ρ = 0.60, P = 0.001 for LS and ρ = 0.59, P = 0.001 for NF), serum testosterone (ρ = 0.58, P = 0.001 for LS and ρ = 0.53, P = 0.001 for NF), ß-cross laps (ρ = 0.38, P = 0.001for LS and ρ = 0.35, P = 0.000 for NF), vitamin D3 (ρ = 0.23, P = 0.04 for LS and ρ = 0.25, P = 0.01 for NF), PTH (ρ = 0.52, P = 0.001 for LS and ρ = 0.48. P = 0.001 for NF), and cortisol (ρ = 0.50, P = 0.001 for LS and ρ = 0.45, P = 0.001 for NF) levels. Conclusion: This is the first study that highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis and opens a new dimension for research and target of therapy in this field.

Comparison of Anthropometry, Bioelectrical Impedance, and Dual-energy X-ray Absorptiometry for Body Composition in Cirrhosis.

Background & aims: This study was planned to evaluate triceps skinfold thickness (TSFT), mid-arm muscle circumference (MAMC) and bioelectrical impedance analysis (BIA) for assessing body composition using dual-energy X-ray absorptiometry (DEXA) (reference) and to predict fat mass (FM) and fat-free mass (FFM) in patients with cirrhosis. Methods: FM and FFM were assessed by using DEXA and BIA. Skin-fold calliper was used for measuring TSFT, and MAMC was calculated. Bland-Altman plot was used to determine agreement and linear regression analysis for obtaining equations to predict FM and FFM. Results: Patients with cirrhosis (n = 302, 241 male, age 43.7 ± 12.0 years) were included. Bland-Altman plot showed very good agreement between BIA and DEXA for the estimation of FM and FFM. Majority of patients were within the limit of agreement: FM (98%) and FFM (96.4%). BIA shows a positive correlation with DEXA:FM (r = 0.73, P ≤ 0.001) and FFM (r = 0.86, P ≤ 0.001). DEXA (FM and FFM) shows a positive correlation with TSFT (r = 0.69, P ≤ 0.01) and MAMC (r = 0.61, P ≤ 0.01). The mean difference between the observed and predicted value of FM and FFM by BIA in the developmental set was 0.01 and 0.05, respectively; whereas in the validation set, it was -0.13 and 0.86, respectively. The mean difference between the observed and predicted value of TSFT and MAMC in the developmental set was 0.43 and 0.07; whereas, in the validation set, it was 0.16 and 0.48, respectively. Conclusion: Anthropometry (TSFT and MAMC) and BIA are simple and easy to use and can be a substitute of DEXA for FM and FFM assessment in routine clinical settings in patients with cirrhosis.

Treatment of osteoporotic fractures in alkaptonuria by teriparatide stimulates bone formation and decreases fracture rate - A report of two cases.

Two cases of advanced alkaptonuria (AKU) with co-existing osteoporosis are described. Case 1 developed multiple non-vertebral fragility fractures, while Case 2 developed vertebral fragility fractures, both refractory to bisphosphonates. Difficulties in diagnosing osteoporosis in AKU complicated by extensive calcifying and ossifying spondylosis are discussed. Both patients continued to fracture despite nitisinone therapy for metabolic control of AKU, as well as bisphosphonate antiresorptive therapy for osteoporosis. Subsequently the patients were treated with teriparatide 20 µg subcutaneous injections daily for two years, leading to reduction in fractures soon after commencing therapy in both cases. Markers of bone remodelling P1NP and CTX were stimulated. No complications due hypercalcaemia or calcification were encountered in either case. We conclude that teriparatide is an effective adjunct in the treatment of AKU when bisphosphonates prove ineffective.

Histomorphometric and microarchitectural analysis of bone in metastatic breast cancer patients.

BACKGROUND: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm "Bordier" core needle. We examined the feasibility of using a 2 mm "Jamshidi™" core needle as a more practical and less invasive technique. METHODS: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry. RESULTS: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (<3 lesions) and 7 had extensive bone metastases (ESM) (>3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size. DISCUSSION: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses.

A dynamic association between myosteatosis and liver stiffness: Results from a prospective interventional study in obese patients.

BACKGROUND & AIMS: Retrospective cross-sectional studies linked sarcopenia and myosteatosis with metabolic dysfunction-associated fatty liver disease (MAFLD). Here, we wanted to clarify the dynamic relationship between sarcopenia, myosteatosis, and MAFLD. METHODS: A cohort of 48 obese patients was randomised for a dietary intervention consisting of 16 g/day of inulin (prebiotic) or maltodextrin (placebo) supplementation. Before and after the intervention, we evaluated liver steatosis and stiffness with transient elastography (TE); we assessed skeletal muscle index (SMI) and skeletal muscle fat index (SMFI) (a surrogate for absolute fat content in muscle) using computed tomography (CT) and bioelectrical impedance analysis (BIA). RESULTS: At baseline, sarcopenia was uncommon in patients with MAFLD (4/48, 8.3%). SMFI was higher in patients with high liver stiffness than in those with low liver stiffness (640.6 ± 114.3 cm2/ Hounsfield unit [HU] vs. 507.9 ± 103.0 cm2/HU, p = 0.001). In multivariate analysis, SMFI was robustly associated with liver stiffness even when adjusted for multiple confounders (binary logistic regression, p <0.05). After intervention, patients with inulin supplementation lost weight, but this was not associated with a decrease in liver stiffness. Remarkably, upon intervention (being inulin or maltodextrin), patients who lowered their SMFI, but not those who increased SMI, had a 12.7% decrease in liver stiffness (before = 6.36 ± 2.15 vs. after = 5.55 ± 1.97 kPa, p = 0.04). CONCLUSIONS: Myosteatosis, but not sarcopenia, is strongly and independently associated with liver stiffness in obese patients with MAFLD. After intervention, patients in which the degree of myosteatosis decreased reduced their liver stiffness, irrespective of body weight loss or prebiotic treatment. The potential contribution of myosteatosis to liver disease progression should be investigated. CLINICAL TRIALS REGISTRATION NUMBER: NCT03852069. LAY SUMMARY: The fat content in skeletal muscles (or myosteatosis) is strongly associated with liver stiffness in obese patients with MAFLD. After a dietary intervention, patients in which the degree of myosteatosis decreased also reduced their liver stiffness. The potential contribution of myosteatosis to liver disease progression should be investigated.

Chondrodysplasia, enchondromas and a chest deformity causing severe pulmonary morbidity in a boy with a PTHLH duplication: A case report.

Parathyroid hormone-like hormone (PTHLH) plays an important role in bone formation. Several skeletal dysplasias have been described that are associated with disruption of PTHLH functioning. Here we report on a new patient with a 898 Kb duplication on chromosome 12p11.22 including the PTHLH gene. The boy has multiple skeletal abnormalities including chondrodysplasia, lesions radiographically resembling enchondromas and posterior rib deformities leading to a severe chest deformity. Severe pulmonary symptoms were thought to be caused by limited mobility and secondary sputum evacuation problems due to the chest deformity. Imaging studies during follow-up revealed progression of the number of skeletal lesions over time. This case extends the phenotypic spectrum associated with copy number variation of PTHLH.

Wavelet transform-based photoacoustic time-frequency spectral analysis for bone assessment.

In this study, we investigated the feasibility of using photoacoustic time-frequency spectral analysis (PA-TFSA) for evaluating the bone mineral density (BMD) and bone structure. Simulations and ex vivo experiments on bone samples with different BMDs and mean trabecular thickness (MTT) were conducted. All photoacoustic signals were processed using the wavelet transform-based PA-TFSA. The power-weighted mean frequency (PWMF) was evaluated to obtain the main frequency component at different times. The y-intercept, midband-fit, and slope of the linearly fitted curve of the PWMF over time were also quantified. The results show that the osteoporotic bone samples with lower BMD and thinner MTT have higher frequency components and lower acoustic frequency attenuation over time, thus higher y-intercept, midband-fit, and slope. The midband-fit and slope were found to be sensitive to the BMD; therefore, both parameters could be used to distinguish between osteoporotic and normal bones (p < 0.05).

Nutrition in Chronic Liver Disease: Consensus Statement of the Indian National Association for Study of the Liver.

Malnutrition and sarcopenia are common in patients with chronic liver disease and are associated with increased risk of decompensation, infections, wait-list mortality and poorer outcomes after liver transplantation. Assessment of nutritional status and management of malnutrition are therefore essential to improve outcomes in patients with chronic liver disease. This consensus statement of the Indian National Association for Study of the Liver provides a comprehensive review of nutrition in chronic liver disease and gives recommendations for nutritional screening and treatment in specific clinical scenarios of malnutrition in cirrhosis in adults as well as children with chronic liver disease and metabolic disorders.

Quantification of epicardial fat using non contrast cardiac CT in an HIV population: Reproducibility and association with other body fat indices.

PURPOSE: To assess the reproducibility of different epicardial fat measurement and their association with other adiposity measurements in HIV-infected and non-HIV-infected patients. METHODS AND MATERIALS: In this cross-sectional study, 167 HIV-infected and 58 non-HIV-infected consecutive participants (200 males; mean age 56 years) with low/intermediate cardiovascular risk were recruited between 2012 and 2017 from a large prospective cohort and underwent non-contrast cardiac CT. Two independent observers measured epicardial fat volume, area and thickness in all participants. For intra-observer agreement, one observer did a second assessment in a subset of 40 patients. Agreement was assessed with the intraclass correlation coefficient (ICC). Pearson's correlation was estimated to assess the association between epicardial fat, body-mass index (BMI) and dual-energy x-ray absorptiometry (DEXA) derived percentage of body fat. RESULTS: Inter-observer agreement was excellent for epicardial fat volume (ICC 0.75) and area (ICC 0.95) and good for epicardial fat thickness (ICC near the left anterior descending artery (LAD) 0.64, ICC near right coronary artery (RCA) 0.64). Intra-observer agreement was excellent for epicardial fat volume (ICC 0.97), area (ICC 0.99), thickness at LAD (ICC 0.71) and good for epicardial fat thickness at RCA (ICC 0.68). Epicardial fat volume had a better correlation to total body fat (r = 0.28, p < 0.001) and trunk fat (r = 0.37, p < 0.001), in comparison to other epicardial fat indices. CONCLUSION: Assessment of epicardial fat volume is highly reproducible in both HIV-infected and non-HIV-infected patients and shows a superior correlation with DEXA-based body and trunk fat measurements. Epicardial fat volume should be considered over other CT assessment methods when quantifying epicardial fat in HIV patients.

Pelvic region bone density, soft tissue mass, and injury frequency in female professional ballet dancers and soccer athletes.

We recently observed a high prevalence of low pelvic bone mineral density (BMD) in female professional ballet performers. Because this population is susceptible to musculoskeletal overuse injuries, we aimed to determine which regions of the pelvis may be at greatest risk compared to general population females (GENPOP) as well as professional female soccer players (SOCCER, a comparison to other elite athletes regularly subjected to high degrees of loading). Three groups of age-matched females [(GENPOP; n = 38, 27±1yrs), (BALLET; single company, n = 36, 26±3yrs), (SOCCER; single NWSL® club, n = 34, 25±1yrs)] consented to have their BMD and body composition assessed (DEXA, GE®). In addition to soft tissue and total and regional BMD analyses, a segmental analysis of the pelvis was performed to determine site-specific BMD for the iliac fossa, iliac fossa/iliac crest/ilium combined, pubic bone, ischium, and sacrum. A mixed-model ANOVA followed by a Tukey's post-hoc test was used to compare the groups (Type-I error; α = 0.05). The BALLET group had lower pelvic BMD for all measures (Avg.%Diff. = 15%-27%, p<0.001) compared to the SOCCER group and for the ischium (Avg.%Diff.= 8%; p=0.007) and sacrum (Avg.%Diff. â€‹= â€‹7%; p = 0.028) compared to the GENPOP group. The BALLET group had lower lean mass for all measures compared to the other groups (Avg.%Diff. = 12%-18%; p < 0.01). Professional ballet performers exhibit reduced pelvic region soft tissue and site-specific BMD not previously detected using standard DEXA analyses. These findings highlight which pelvic regions may benefit from preventative strength training and/or nutritional interventions.

Integrative and quantitative bioenergetics: Design of a study to assess the impact of the gut microbiome on host energy balance.

The literature is replete with clinical studies that characterize the structure, diversity, and function of the gut microbiome and correlate the results to different disease states, including obesity. Whether the microbiome has a direct impact on obesity has not been established. To address this gap, we asked whether the gut microbiome and its bioenergetics quantitatively change host energy balance. This paper describes the design of a randomized crossover clinical trial that combines outpatient feeding with precisely controlled metabolic phenotyping in an inpatient metabolic ward. The target population was healthy, weight-stable individuals, age 18-45 and with a body mass index ≤30 kg/m2. Our primary objective was to determine within-participant differences in energy balance after consuming a control Western Diet versus a Microbiome Enhancer Diet intervention specifically designed to optimize the gut microbiome for positive impacts on host energy balance. We assessed the complete energy-balance equation via whole-room calorimetry, quantified energy intake, fecal energy losses, and methane production. We implemented conditions of tight weight stability and balance between metabolizable energy intake and predicted energy expenditure. We explored key factors that modulate the balance between host and microbial nutrient accessibility by measuring enteroendocrine hormone profiles, appetite/satiety, gut transit and gastric emptying. By integrating these clinical measurements with future bioreactor experiments, gut microbial ecology analysis, and mathematical modeling, our goal is to describe initial cause-and-effect mechanisms of gut microbiome metabolism on host energy balance. Our innovative methods will enable subsequent studies on the interacting roles of diet, the gut microbiome, and human physiology. CLINICALTRIALSGOV IDENTIFIER: NCT02939703. The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT02939703.

Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction: Central Role of Adiposity.

The aim of this study was to determine the arteriovenous oxygen content difference (ΔAVo2) in adult subjects with and without heart failure with preserved ejection fraction (HFpEF) during systemic and forearm exercise. Subjects with HFpEF had reduced ΔAVo2. Forearm diffusional conductance for oxygen, a lumped conductance parameter that incorporates all impediments to the movement of oxygen from red blood cells in skeletal muscle capillaries into the mitochondria within myocytes, was estimated. Forearm diffusional conductance for oxygen was not different among adults with HFpEF, those with hypertension, and healthy control subjects; therefore, diffusional conductance cannot explain the reduced forearm ΔAVo2. Instead, adiposity was strongly associated with ΔAVo2, suggesting an active role for adipose tissue in reducing exercise capacity in patients with HFpEF.

How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy.

BACKGROUND: Estimated glomerular filtration (eGFR) results based on serum creatinine are frequently inaccurate with differences against measured GFR (mGFR) often attributed to unmeasured non-functional factors, such as muscle mass. METHODS: The influence of muscle mass (measured by dual-energy x-ray absorptiometry, DEXA) on eGFR error (eGFR-mGFR) was evaluated using isotopic mGFR (Tc99m DTPA plasma clearance) in 137 kidney transplant recipients. Serum creatinine was measured by isotopic-calibrated enzymatic analysis, converted to eGFR using Chronic Kidney Disease EPIdemiology (CKD-EPI) formula, then unindexed from body surface area. FINDINGS: Unindexed CKD-EPI eGFR error displayed absent fixed bias but modest proportional bias against reference mGFR. eGFR error correlated with total lean mass by DEXA (r=-0·350, P<0·001) and appendicular skeletal muscle index (ASMI), a proxy for muscularity (r=-0·420, P<0·001). eGFR was falsely reduced by -5·9 ± 1·4 mls/min per 10 kg lean mass. Adipose mass and percentage fat had no effect on error. Muscle-associated error varied with each eGFR formula and influenced all CKD stages. Systemic eGFR error was predicted by ASMI, mGFR, recipient age, and trimethoprim use using multivariable regression. Residual plots demonstrated heteroscedasticity and greater imprecision at higher mGFR levels (P<0·001), from increased variance corresponding to higher absolute values and unreliable prediction by serum creatinine of high mGFR. Serum creatinine correlated with ASMI independent of mGFR level (r = 0·416, P<0·001). The diagnostic test performance of CKD-EPI eGFR to predict CKD stage 3 (by mGFR) was weakest in cachexia (sensitivity 68·4%) and muscularity (specificity 47·4%, positive predictive value 54·5% for the highest ASMI quartile). INTERPRETATION: Serum creatinine and eGFR are imperfect estimates of true renal function, with systemic errors from muscle mass, tubular secretion, and intrinsic proportional bias; and additional inaccuracy at the extremes of renal function and patient muscularity. Cautious interpretation of eGFR results in the context of body habitus and clinical condition is recommended.

Assessing cortical bone mechanical properties using collagen proton fraction from ultrashort echo time magnetization transfer (UTE-MT) MRI modeling.

Cortical bone shows as a signal void when using conventional clinical magnetic resonance imaging (MRI). Ultrashort echo time MRI (UTE-MRI) can acquire high signal from cortical bone, thus enabling quantitative assessments. Magnetization transfer (MT) imaging combined with UTE-MRI can indirectly assess protons in the organic matrix of bone. This study aimed to examine UTE-MT MRI techniques to estimate the mechanical properties of cortical bone. A total of 156 rectangular human cortical bone strips were harvested from the tibial and femoral midshafts of 43 donors (62 ±â€¯22 years old, 62 specimens from females, 94 specimens from males). Bone specimens were scanned using UTE-MT sequences on a clinical 3 T MRI scanner and on a micro-computed tomography (µCT) scanner. A series of MT pulse saturation powers (400°, 600°, 800°) and frequency offsets (2, 5, 10, 20, 50 kHz) was used to measure the macromolecular fraction (MMF) utilizing a two-pool MT model. Failure mechanical properties of the bone specimens were measured using 4-point bending tests. MMF from MRI results showed significant strong correlations with cortical bone porosity (R = -0.72, P < 0.01) and bone mineral density (BMD) (R = +0.71, P < 0.01). MMF demonstrated significant moderate correlations with Young modulus, yield stress, and ultimate stress (R = 0.60-0.61, P < 0.01). These results suggest that the two-pool UTE-MT model focusing on the organic matrix of bone can potentially serve as a novel tool to detect the variations of bone mechanical properties and intracortical porosity.

Evaluation of selected traditional Chinese medical extracts for bone mineral density maintenance: A mechanistic study.

OBJECTIVE: To investigate the development of a minimal traditional Chinese medicine (TCM) formula using selected TCM ingredients and evaluating their biological activity with bone-specific in vitro tests. Finally, determining if the minimal formula can maintain bone mineral density (BMD) in a low bone mass (LBM)/osteoporosis (OP) model system. METHODS AND RESULTS: Sixteen different TCM plant extracts were tested for estrogenic, osteogenic and osteoclastic activities. Despite robust activation of the full-length estrogen receptors α and ß by Psoralea corylifolia and Epimedium brevicornu, these extracts do not activate the isolated estrogen ligand binding domains (LBD) of either ERα or ERß; estrogen (17-ß estradiol) fully activates the LBD of ERα and ERß. E. brevicornu and Drynaria fortunei extracts activated cyclic AMP response elements (CRE) individually and when combined these ingredients stimulated the production of osteoblastic markers Runx2 and Bmp4 in MC3T3-E1 cells. E. brevicornu, Salvia miltiorrhiza, and Astragalus onobrychis extracts inhibited the Il-1ß mediated activation of NF-κß and an E. brevicornu/D. fortunei combination inhibited the development of osteoclasts from precursor cells. Further, a minimal formula containing the E. brevicornu/D. fortunei combination with or without a third ingredient (S. miltiorrhiza, Angelica sinensis, or Lycium barbarum) maintained bone mineral density (BMD) similar to an estradiol-treated control group in the ovariectomized rat; a model LBM/OP system. CONCLUSION: A minimal formula consisting of TCM plant extracts that activate CRE and inhibit of NF-κß activation, but do not behave like estrogen, maintain BMD in a LBM/OP model system.