Decreased Bone Mineral Density Research Articles

Changes in bone density and structure of proximal humerus with aging in Chinese women

AimsThis study aimed to investigate age- and menopause-related differences in bone mineral density (BMD), bone structure and estimated bone strength at surgical neck of humerus in Chinese female sample. MethodsWe conducted a cross-sectional cohort study of 171 Chinese women. Bone mass, indices of geometric properties and estimated mechanical strength of the surgical neck were evaluated by quantitative computed tomography (QCT). Comparisons were performed across menstrual status categories. Age-related changes in QCT-derived bone parameters were calculated. ResultsThe age-related difference of BMD and cortical thickness was 40.25 % and 32.86 % between the age of 20 and 86 years. Progressive periosteal and endosteal expansion was associated linearly with age. Estimated mechanical strength indexes showed significant quadratic associations with age, with their peak occurred at the age of 46–55 years. The quartile of women with the greatest medullary diameter also had the lowest valve of BMD and cortical thickness and the greatest in skeletal width. Compared to premenopausal individuals, perimenopausal women were distinguished by lower cortical thickness (18.63 %) and BMD (20.05 %). The continued decrease in cortical thickness and BMD was noted after menopause. The medullary and periosteal diameter increased by 17.98 % and 9.34 % respectively in perimenopausal period, but not after menopause. The accelerated loss of the maximum and polar section modulus was observed in late postmenopausal women. ConclusionsThe increase in bone size only occurred during the menopause transition. Obvious loss of resistance to bending was in late postmenopausal period.

The Effects of Tai Chi Rouli Ball Exercise on Bone Mineral Content and Bone Metabolism Indicators in Perimenopausal Women

Background Perimenopause is associated with a decline in estrogen levels, leading to decreased bone mineral density (BMD) and altered bone metabolism, increasing the risk of osteoporosis. Tai Chi Rouli Ball, a traditional Chinese sport, is thought to have beneficial effects on physical health, but its impact on bone health in perimenopausal women is not well understood.Methods This study involved a randomized controlled trial with 52 perimenopausal women aged 45–55 years from community senior centers. Participants were divided into two groups: the Tai Chi Rouli Ball group and the control group. Baseline assessments of bone density, bone mineral content (BMC), and bone metabolism markers, including estrogen levels, were conducted. The Tai Chi Rouli Ball group underwent regular training for a specific period, while the control group did not receive any intervention. Post-experiment assessments were then compared to the baseline.Results Post-intervention, the Tai Chi Rouli Ball group showed a significant increase in spine bone density and BMC in various body parts, including the whole body, trunk/torso, and spine, compared to the control group. Bone metabolism indicators also improved, with increased levels of estrogen and a decrease in follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Calcium levels showed a significant increase, while other markers like alkaline phosphatase (ALP), phosphorus (P), and magnesium (Mg) had non-significant changes.Conclusions Tai Chi Rouli Ball exercise may positively influence bone health by improving bone density, BMC, and altering bone metabolism markers in perimenopausal women. These findings suggest that Tai Chi Rouli Ball could be a viable non-pharmacological approach to prevent osteoporosis in this demographic.

Premature ovarian insufficiency in patients with galactosemia

Background. Galactosemia is a congenital disorder of carbohydrate metabolism caused by a defect in any of the enzymes of galactose metabolism. One of the long-term complications is premature ovarian insufficiency (POI), which is more common in patients with the c.563A>G (Q188R) mutation in the homozygous state in the galactose-1-phosphate uridylyltransferase (GALT) gene. At the same time, fertility factors may be higher in patients with POI caused by classical galactosemia (CG) compared with other causes of POI, which makes it difficult to resolve the issue of the need to use fertility preservation methods for this group of patients in the prepubescent period. Case report. This article describes two clinical observations of patients with CG who were diagnosed with hypergonadotropic hypogonadism. Patient A. was initiated hormone replacement therapy (HRT) at the age of 11, and according to the results of osteodensitometry, there is currently no decrease in bone mineral density. In patient C. at the age of 14, before the start of HRT, ovaries without pronounced follicular apparatus, osteopenia and osteoporosis were detected. The issue of the necessity and timing of the use of fertility preservation methods is being considered. Conclusion. Patients with CG are recommended to monitor hormonal profile indicators for timely administration of HRT. Cryopreservation of ovarian tissue should be considered as one of the options for maintaining fertility in patients with CG, taking into account that some of them still have the possibility of spontaneous pregnancy, despite the POI.

Syndrome of imaginary excess of mineralocorticoids: a clinical case

The syndrome of apparent mineralocorticoid excess (AME) is a rare genetic disease characterized by juvenile hypertension, hypokalemia, suppression of renin and aldosterone. AME syndrome is caused by a mutation in the HSD11B2 gene, which encodes 11ß-hydroxysteroid dehydrogenase type 2, that converts cortisol into cortisone.The purpose of the article is to describe a clinical case of genetically confirmed (mutation C.911A>G of the HSD11B2 gene) AME syndrome. The disease manifested in the first years of life; the patient was prescribed mineralocorticoid receptor antagonists, potassium preparations, potassium-sparing diuretics, and other antihypertensive therapy. Due to the absence of normotonia and normokalemia, dexamethasone has been prescribed since the age of 12. Due to uncontrolled arterial hypertension and hypokalemia, complications developed (medullary nephrocalcinosis, myocardial remodeling), and prolonged dexamethasone intake led to a slowdown in puberty and a decrease in bone mineral density.

127 Utilizing predictive models for bone mineral content and bone mineral density as a tool to assess dietary phosphorous

Abstract Dietary phosphorous is a necessary nutrient for bone development in pigs at all stages of its growing. Deficiencies in phosphorous decrease bone mineral content (BMC) and bone mineral density (BMD) and may be a causative of lameness. However, the normal range expected in whole body (WB) and individual bones for BMC and BMD in commercial pigs has been poorly defined. Therefore, our objectives were to 1) model normal WB bone density at multiple timepoints in wean to finish pigs, and 2) determine the extent to which individual bone (femur and 3rd metatarsal) BMC and BMD could predict WB BMC and BMD. Mixed sex pigs [Camborough (1050) x 337, PIC] were utilized and included freshly weaned ~21 d (n = 8), ~44 d of age (n = 24), ~84 d of age (n = 24) and ~154 d of age (n = 24). Pigs were individually penned. Excluding weaning age, at each age group pigs were randomly assigned to diets adequate, marginally deficient, or deficient in available phosphorus (avP) and fed for 3, 4, and 6 wk (age group 44, 84, 154, respectively). Within each age group, diets were formulated to meet nutrient and energy requirements except for avP and pigs fed ad libitum. On-test and off-test body weight (BW) and feed intake and gain to feed ratio were assessed for each age group. At the end of each feeding period, all pigs were euthanized and WB, femur (F) and 3rd metatarsal (M) BMC and BMD determined by dual X-ray absorptiometry (DXA). Data were analyzed using linear and generalized additive models that predicted response variables (BMC or BMD) as a function of BW or age. Only pigs fed adequate avP diets were used in the model fit. Pigs fed adequate avP diets increased BMD with age (0.22, 0.42, 0.84 and 1.10 g/cm2, days of age 21, 44, 84 and 154 respectively, P < 0.001). Within day of age 84, marginally and deficient avP diets reduced BMC and BMD by 21 to 41% (P = 0.002) and 12 to 25% (P = 0.006), respectively. Within day of age 154, marginally and deficient avP diets reduced BMC and BMD by 9% (P = 0.05) and 6 to 8% (P = 0.06), respectively. Body weight record and individual bone (F and M) BMC and BMD from pigs fed deficient avP diets were used to predict WB BMC and BMD and the mean square error of prediction was selected as a criterion to evaluate the ability of the models to detect these inadequately fed pigs. Using the selected models, pigs fed nutritionally deficient diets were detected due to 2- to 7-fold increase in MSE of predicted WBMD or WBMC compared with pigs fed adequate diets. These models can be used to assess bone development and strength in growing pigs and to infer the adequacy of avP level supplied in their diets.

Abstract PO2-12-06: Comparative Study on Bone Mineral Density in Premenopausal Patients with Estrogen Receptor-Positive Breast cancer in ASTRRA study: a 5-year follow-up study

Abstract Background With the positive outcomes associated with Ovarian Function Suppression (OFS) treatment as reported in the ASTRRA study, which compare two therapeutic strategies, tamoxifen alone and ovarian function suppression (OFS) in premenopausal patients after chemotherapy, the role of OFS has getting important. However, considering the increased risk of bone density reduction associated with postmenopause in women, the understanding these effects is crucial in devising strategies that not only effectively combat the cancer but also concurrently safeguard the patients’ bone health. This study aimed to compare the impacts of two therapeutic strategies, tamoxifen alone and OFS on bone mineral density (BMD) in premenopausal patients after chemotherapy. Methods Of the 1483 premenopausal enrolled in ASTRRA study, we focused on a subset of 522 patients who had undergone BMD examinations at diagnosis, 3 years and 5 years after diagnosis. Patients were stratified into three categories: normal, osteopenia, osteoporosis, and we examined the changes in their classifications over the 3-year and 5-year periods from baseline to identify any deterioration in bone density. Also, Patients were examined ovarian function every 6 months for 2 years and have different randomization times. Further categorization was carried out according to the time of randomization, which means starting time of OFS after recovery of ovary function. Lastly, we conducted a subset analysis using data from the Asan Medical Center (AMC), specially focused on the absolute value of one density measured in g/cm3. Results The median age of 522 patients was 41.1 and at baseline, a higher incidence of osteopenia was observed in the OFS addition group (p=0.028). Both analysis of change in BMD categories of from baseline to 3-year and baseline to 5-year period showed no significant differences between TAM only and TAM+OFS group (3-year: p=0.567, 5-year: p=0.600). However, there was a significant increased risk of bone density deterioration in the OFS addition group, when randomization occurred at the first visit (HR= 2.970, p=0.008). Within the AMC subset, statistically significant decrease in BMD were observed in the OFS addition group at the spine (p=0.023) and femur (p=0.040) over a baseline to 3-year period. Although a decrease in BMD was also observed over a baseline to 5-year period at both the spine and femur, this change was not statistically significant. Conclusion This study revealed a deleterious impact on bone density associated with the addition of OFS, compared to tamoxifen-only treatment. Remarkably, our findings also indicated that early suppression of ovarian function exerts even more detrimental influence on bone health in premenopausal, estrogen receptor-positive breast cancer patients, who have recovered ovarian function. Change between baseline to 5 years according to randomization time interval The table shows the risk associated with bone health deterioration according to the duration of randomization, thus specifying the time interval between the recovery and suppression of ovarian function. Citation Format: Eunju Shin, Seung Il Kim, Min-ho Park, Hyun-Ah Kim, Yongsik Jung, Jai Min Ryu, Eun Hwa Park, Sung Yong Kim, Eun-Gyeong Lee, Min Hyuk Lee, Jung Ho Park, Seock-Ah Im, Soong June Bae, Su Hwan Kang, Woosung Lim, Hyun Jo Youn, Heung Kyu Park, Kyong Hwa Park, Tae-Hyun Kim, Shin-Young Park, Cheol wan Lim, Geum-Hee Kwak, Chanheun Park, Hyuk-Jae Shin, Young Bum Yoo, Sun Hee Kang, Bong Kyun Kim, Hee Jeong Kim. Comparative Study on Bone Mineral Density in Premenopausal Patients with Estrogen Receptor-Positive Breast cancer in ASTRRA study: a 5-year follow-up study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-06.

Possibilities of reproductive function realization in patients with premature ovarian insufficiency

Premature ovarian insufficiency (POI) directly affects the reproductive health of women all over the world. Currently, the study of this pathology is becoming an increasingly important issue due to the widespread prevalence of premature menopause in the female population. In addition to genetic predisposition, an important role in the development of premature menopause is played by the increasing number of ovarian surgeries due to the development of surgery, as well as radiation and chemotherapy for cancer, leading to premature depletion of the follicular reserve in the ovaries. An important component of treatment for women with POI is not only the management of undesirable symptoms of menopause, prevention of cardiovascular complications and fractures due to decreased bone mineral density, but also the possibility of realizing their reproductive function in the future. Therefore, other treatment options may be offered to women with POI in the absence of spontaneous pregnancy in the natural cycle. Oocyte donation may be recommended for such women, but this treatment option may not be suitable if the patient wishes to have genetically related children. In such a case, oogonal stem cell transplantation, ovarian cortex fragmentation or PRP therapy are possible. In women who will undergo chemotherapy and radiation therapy for cancer, reimplantation of ovarian cortical tissue is recommended to preserve fertility. If there is a risk of malignant cell transfer with this treatment modality, primordial follicles can be isolated from ovarian tissue, cultured and activated in vitro, fertilized, and transferred into the uterine cavity. IVF with surrogate embryo transfer may be an alternative choice for a woman with NPT, which allows her to realize her reproductive plans.

Exerkine FNDC5/irisin-enriched exosomes promote proliferation and inhibit ferroptosis of osteoblasts through interaction with Caveolin-1.

Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by a decrease in bone mineral density and deterioration of bone microstructure. Despite the high prevalence of this disease, no effective treatment for osteoporosis has been developed. Exercise has long been considered a potent anabolic factor that promotes bone mass via upregulation of myokines secreted by skeletal muscle, exerting long-term osteoprotective effects and few side effects. Irisin was recently identified as a novel myokine that is significantly upregulated by exercise and could increase bone mass. However, the mechanisms underlying exercise-induced muscle-bone crosstalk remain unclear. Here, we identified that polyunsaturated fatty acids (arachidonic acid and docosahexaenoic acid) are increased in skeletal muscles following a 10-week treadmill exercise programme, which then promotes the expression and release of FNDC5/irisin. In osteoblasts, irisin binds directly to Cav1, which recruits and interacts with AMP-activated protein kinase α (AMPKα) to activate the AMPK pathway. Nrf2 is the downstream target of the AMPK pathway and increases the transcription of HMOX1 and Fpn. HMOX1 is involved in regulating the cell cycle and promotes the proliferation of osteoblasts. Moreover, upregulation of Fpn in osteoblasts enhanced iron removal, thereby suppressing ferroptosis in osteoblasts. Additionally, we confirmed that myotube-derived exosomes are involved in the transportation of irisin and enter osteoblasts through caveolae-mediated endocytosis. In conclusion, our findings highlight the crucial role of irisin, present in myotube-derived exosomes, as a crucial regulator of exercise-induced protective effects on bone, which provides novel insights into the mechanisms underlying exercise-dependent treatment of osteoporosis.

Pan-immune inflammatory value a new diagnostic biomarker in postmenopausal osteoporosis

Aims: Postmenopausal osteoporosis (PMOP) is one of the most common bone diseases. We aimed to investigate the relationship between pan-immune inflammatory value and decreased bone mineral density in postmenopausal women. Methods: This prospective cross-sectional study was composed of 186 postmenopausal women. Osteoporosis was diagnosed with dual‐energy X‐ray absorptiometry (DEXA) results according to World Health Organization (WHO) recommendations and patients were separated into 3 groups; 1. control group with a T-score >-1; 2. group osteopenia with a T-score between -1,0 and -2,5; 3. group osteoporosis with a T-score ≤-2,5. After the physical examinations of all patients, venous blood samples were collected and the pan-immune inflammation value (PIV) was calculated. The parameters were evaluated statistically with the PIV value between the groups. Results: Groups are similar in terms of age, menopausal age, education, and occupation. PIV was significantly higher in postmenopausal women with osteoporosis than women with osteopenia and the control group (p

Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center

Background & AimsSteatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. MethodsIndividuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. ResultsA total of 1,410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34–0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00–1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97–1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. ConclusionThe present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

The Effect of Osteoporosis on Complications and Reoperation Rates After Surgical Management of Adult Thoracolumbar Spinal Deformity: A Systematic Review and Meta Analysis.

Systematic Review. While substantial research has explored the impact of osteoporosis on patients undergoing adult spinal deformity (ASD) correction, the literature remains inconclusive. As such, the purpose of this study is to synthesize and analyze existing studies pertaining to osteoporosis as a predictor of postoperative outcomes in ASD surgery. We performed a systematic review and meta-analysis to determine the effect that a diagnosis of osteoporosis, based on ICD-10 coding, dual-energy X-ray absorptiometry (DEXA) or computed tomography, has on the incidence of adverse outcomes following surgical correction of ASD. Statistical analysis was performed using Comprehensive Meta-Analysis (Version 2) using a random effects model to account for heterogeneity between studies. After application of inclusion and exclusion criteria, 36 and 28 articles were included in the systematic review and meta-analysis, respectively. The meta-analysis identified greater rates of screw loosening amongst osteoporotic patients (70.5% vs 31.9%, P = .009), and decreased bone mineral density in patients who developed proximal junctional kyphosis (PJK) (.69 vs .79g/cm2, P = .001). The systematic review demonstrated significantly increased risk of any complication, reoperation, and proximal junctional failure (PJF) associated with reduced bone density. No statistical difference was observed between groups regarding fusion rates, readmission rates, and patient-reported and/or functional outcome scores. This study demonstrates a higher incidence of screw loosening, PJK, and revision surgery amongst osteoporotic ASD patients. Future investigations should explore outcomes at various follow-up intervals in order to better characterize how risk changes with time and to tailor preoperative planning based on patient-specific characteristics.

Pharmacological prevention of bone loss and fractures following solid organ transplantations: Protocol for a systematic review and network meta-analysis.

Solid organ transplant (SOT) recipients can experience bone loss caused by underlying conditions and the use of immunosuppressants. As a result, SOT recipients are at risk for decreased bone mineral density (BMD) and increased fracture incidences. We propose a network meta-analysis (NMA) that incorporates all available randomized control trial (RCT) data to provide the most comprehensive ranking of anti-osteoporotic interventions according to their ability to decrease fracture incidences and increase BMD in SOT recipients. We will search MEDLINE, EMBASE, Web of Science, CINAHL, CENTRAL and CNKI for relevant RCTs that enrolled adult SOT recipients, assessed anti-osteoporotic therapies, and reported relevant outcomes. Title and full-text screening as well as data extraction will be performed in-duplicate. We will report changes in BMD as weighted or standardized mean differences, and fracture incidences as risk ratios. SUCRA scores will be used to provide rankings of interventions, and quality of evidence will be examined using RoB2 and CINeMA. To our knowledge, this systematic review and NMA will be the most comprehensive quantitative analysis regarding the management of bone loss and fractures in SOT recipients. Our analysis should be able to provide physicians and patients with an up-to-date recommendation for pharmacotherapies in reducing incidences of bone loss and fractures associated with SOT. The findings of the NMA will be disseminated in a peer-reviewed journal.

OA13 Alkaptonuria: a big mimic

Abstract Background/Aims Alkaptonuria is a rare metabolic disorder, often misdiagnosed as spondyloarthritis or degenerative musculoskeletal disease. The population most affected are young males in their 30s with characteristic arthritis involving the spine and large joints. The patient may notice their urine turning dark on standing and pigmentation over the skin and connective tissues (ochronosis); however, these subtle features may sometimes go unnoticed. Methods A 38-year-old-male with long standing back pain presented with right knee swelling. With a diagnosis of spondyloarthritis, he was previously treated with DMARDS but did not have any relief. There was a history of urine turning dark on standing. On examination, there was subtle hyperpigmentation over left ear concha and a spot on the sclera. An x-ray of the thoracic spine showed flattening and calcification of intervertebral disc spaces at multiple levels. Aspiration of synovial fluid showed suspended fragments of articular cartilage. His inflammatory markers were negative. We performed gas chromatography mass spectrometry which showed elevated excretion of homogentisic acid (HGA). A homozygous pathogenic variant in the homogentisate 1,2-dioxygenase gene associated with alkaptonuria was reported on whole genome sequencing. Results Ochronotic arthropathy is defined as progressive degenerative joint disease mainly affecting the spine and large joints. Most patients require at least one joint replacement by age 55. Small joints of hands and feet and sacroiliac joints are usually spared. Arthroscopy of the joint may reveal dark brown to black pigmented cartilage defects. The synovium may show fragments of pigmented cartilage suspended in the fluid (ground pepper sign). Plain spine radiographs may show flattening and calcifications of the intervertebral discs with a characteristic vacuum phenomenon (radiolucent gas collection). Periarticular structures like tendons and ligaments are also affected, leading to rupture in around 20-30% of patients. Alkaptonuria is also associated with decreased bone mineral density and subsequent risk for fragility fracture. Conclusion Alkaptonuria often mimics ankylosing spondylitis. A triad of ochronosis, dark urine and ochronotic arthropathy is the key to diagnosis. Definitive diagnosis is through biochemical or genetic testing. Nitisinone has proved to be effective but shows significant side effects. Management mainly involves physiotherapy and palliative care. Disclosure M. Shah: None. S. Upadhyaya: None.

P002 A comparison between radiologically reported osteopenia and the FRAX score as an indication for bone densitometry

Abstract Background/Aims Osteopenia is defined as a bone mineral density score between -1 and -2.5 standard deviations compared to a young adult reference mean (T-score) based on dual energy x-ray absorptiometry (DXA). Radiologists continue to use the term in a generic and qualitative manner to mean decreased bone mineral density, but they cannot distinguish between osteopenia and osteoporosis which means patients then go on to have a DXA. We would like to see if a FRAX (fracture risk assessment tool) can safely replace osteopenia as an indication for a DXA. Methods We retrospectively identified 2276 patients to have had a DXA scan from October 2022 to March 2023 according to the departmental database. Their referral forms were obtained from the Electronic Medical Record (EMR). Out of these, 150 patients were referred with a sole indication being radiologically reported osteopenia. Out of 150 patients, 22 were excluded as they were found to have other indications not reported on their referral from and seven more were excluded as three had bilateral hip replacement, three were below 40 and one was undergoing gender reassignment and was on oestrogen. The remaining 121 patients were included in the study and their post BMD ( bone mineral density) FRAX score was obtained from patient EMR. Pre BMD FRAX was also calculated using clinical information available on patient’s EMR retrospectively. NOGG ( National Osteoporosis Guideline Group) recommendation of treatment based on the fracture risk as per the FRAX were then compared between pre and post BMD retrospectively to see if there would be any change in treatment plan. Results Of total 121 patients included, 94 were female. Mean age was 68 years. Retrospective review of the case notes revealed that using a FRAX with BMD, total 34 (28.1%) patients needed treatment for osteoporosis while 87 (71.9%) did not. Of 87 patients not requiring treatment, 55 would not have received DXA scan if FRAX assessment was done without BMD. Of the 34 who did need treatment, 32 would still be recommended for a DXA while only two patients wouldn’t. However, these two patients had other clinical indications for osteoporosis assessment and would still have required a specialist referral such that a decision can be made about DXA. Conclusion If radiologically reported osteopenia as an indication for a DXA is replaced by FRAX, DXA would not be needed in nearly half of the patients. This will have potential to save scarce DXA resource without compromising patient safety, treatment plan, and will reduce waiting times. Disclosure S. Srinivas: None. K. Hood: None. H. Sapkota: None.

Osteogenic Effects of the Diospyros lotus L. Leaf Extract on MC3T3-E1 Pre-Osteoblasts and Ovariectomized Mice via BMP2/4 and TGF β Pathways.

Osteoporosis, a disease defined by the primary bone strength due to a low bone mineral density, is a bone disorder associated with increased mortality in the older adult population. Osteoporosis is mainly treated via hormone replacement therapy, bisphosphates, and anti-bone resorption agents. However, these agents exert severe side effects, necessitating the development of novel therapeutic agents. Many studies are focusing on osteogenic agents as they increase the bone density, which is essential for osteoporosis treatment. Here, we aimed to investigate the effects of Diospyros lotus L. leaf extract (DLE) and its components on osteoporosis in MC3T3-E1 pre-osteoblasts and ovariectomized mice and to elucidate the underlying related pathways. DLE enhanced the differentiation of MC3T3-E1 pre-osteoblasts, with a 1.5-fold elevation in ALP activity, and increased the levels of osteogenic molecules, RUNX family transcription factor 2, and osterix. This alteration resulted from the activation of bone morphogenic protein 2/4 (BMP2/4) and transformation of growth factor β (TGF β) pathways. In ovariectomized mice, DLE suppressed the decrease in bone mineral density by 50% and improved the expression of other bone markers, which was confirmed by the 3~40-fold increase in osteogenic proteins and mRNA expression levels in bone marrow cells. The three major compounds identified in DLE exhibited osteogenic and estrogenic activities with their aglycones, as previously reported. Among the major compounds, myricitrin alone was not as strong as whole DLE with all its constituents. The osteogenic activity of DLE was partially suppressed by the inhibitor of estrogen signaling, indicating that the estrogenic activity of DLE participated in its osteogenic activity. Overall, DLE suppresses osteoporosis by inducing osteoblast differentiation.

Extra-Skeletal Manifestations in Osteogenesis Imperfecta Mouse Models.

Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.

Zoledronate After Denosumab Discontinuation: Is Repeated Administrations More Effective Than Single Infusion?

After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, P = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P = .009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P = .014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX.

Zinc finger protein 36 like 2-histone deacetylase 1 axis is involved in the bone responses to mechanical stress

The molecular mechanism underlying the promotion of fracture healing by mechanical stimuli remains unclear. The present study aimed to investigate the role of zinc finger protein 36 like 2 (ZFP36L2)-histone deacetylase 1 (HDAC1) axis on the osteogenic responses to moderate mechanical stimulation. Appropriate stimulation of fluid shear stress (FSS) was performed on MC3T3-E1 cells transduced with ZFP36L2 and HDAC1 recombinant adenoviruses, aiming to validate the influence of mechanical stress on the expression of ZFP36L2-HDAC1 and the osteogenic differentiation and mineralization. The results showed that moderate FSS stimulation significantly upregulated the expression of ZFP36L2 in MC3T3-E1 cells (p < 0.01). The overexpression of ZFP36L1 markedly enhanced the levels of osteogenic differentiation markers, including bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), Osterix, and collagen type I alpha 1 (COL1A1) (p < 0.01). ZFP36L2 accelerated the degradation of HDAC1 by specifically binding to its 3’ UTR region, thereby fulfilling its function at the post-transcriptional regulatory gene level and promoting the osteogenic differentiation and mineralization fate of cells. Mechanical unloading notably diminished/elevated the expression of ZFP36L2/HDAC1, decreased bone mineral density and bone volume fraction, hindered the release of osteogenic-related factors and vascular endothelial growth factor in callus tissue (p < 0.01), and was detrimental to fracture healing. Collectively, proper stress stimulation plays a crucial role in facilitating osteogenesis through the promotion of ZFP36L2 and subsequent degradation of HDAC1. Targeting ZFP36L2-HDAC1 axis may provide promising insights to enhance bone defect healing.

Assessing Change in Spine Bone Density from Different Numbers and Combinations of Lumbar Vertebrae: The Manitoba BMD Registry

Introduction: Change in bone mineral density (BMD) is considered significant when it exceeds the 95 % least significant change (LSC) derived from that facility's precision study. The lumbar spine is often affected by structural artifact such that not all four lumbar vertebrae are evaluable. Guidelines suggest using a site-matched LSC when omitting vertebrae from the BMD measurement. The current study describes significant BMD change related to intervening anti-osteoporosis treatment for different numbers and combinations of lumbar vertebrae using site-matched LSC values.Methodology: We identified 10,526 untreated adult women mean age 59.6 years with baseline and repeat spine BMD testing (mean interval 4.7 years) where all 4 lumbar vertebrae were evaluable. Change in spine BMD for different combinations of lumbar vertebrae was assessed in relation to intervening anti-resorptive treatment, contrasting women with high treatment exposure (medication possession ratio, MPR ≥ 0.8) versus women who remained untreated. Site-matched LSC values were derived from 879 test-retest precision measurements.Results: There was consistent linear trend between increasing MPR and BMD change exceeding the LSC for all lumbar vertebral combinations, positive with BMD increase and negative with BMD decrease (all p-trend <0.001). In the high treatment exposure group, mean percent increases in spine BMD were similar for all vertebral combinations, from L1-4 to a single vertebra. In untreated women, mean percent decreases in spine BMD were also similar for all vertebral combinations. The net treatment response (proportion of women with treatment-concordant changes minus proportion with treatment-discordant changes exceeding the LSC) was 29.7 % for 4 vertebrae, 27.5-30.0 % for 3 vertebrae, 22.4-28.5 % for 2 vertebrae, and 18.1-21.9 % for a single vertebra.Conclusions: All numbers and combinations of lumbar vertebrae, when used in conjunction with site-matched LSC values, can provide clinically meaningful follow-up in treated and untreated patients, even when spine BMD is based on a single vertebral body.

Assessment and management of low bone mineral density in children with cerebral palsy

Cerebral palsy (CP) is an impairment in motor function and coordination due to a nonprogressive brain injury that occurs pre-, peri-, or postnatally until 2 years of age with a prevalence of one to four per 1,000 live births. Along with impaired motor function, decreased bone mineral density (BMD) in children with CP is of concern for providers. An algorithm has been created to help identify patients at risk for decreased BMD who are seen by providers. Factors included in the algorithm are medication history, fracture history, ketogenic diet, ambulation status, history of an endocrinopathy, and pubertal stage.BMD levels are measured using dual-energy x-ray absorptiometry (DXA) scans. Once a patient is identified as having decreased BMD several treatment options are available. BMD can be increased through stander use, diet, and bisphosphonate treatment. This paper serves as a summary of the current ways in which children with CP are assessed at each visit, as well as how to treat low BMD once it has been identified.