Anti-osteoporosis Drugs Research Articles

Revisiting osteoporosis guidelines

The past 5 years have seen the completion of several major trials of novel anti-osteoporosis drugs. The findings from these trials have resulted in the registration of romosozumab in many countries, registration of abaloparatide in the USA, and the abandonment of odanacatib. No advanced trials of novel agents are currently underway, so now is a good time to review osteoporosis management to clarify where romosozumab and abaloparatide fit into current therapeutic strategies. As a result, several new sets of guidelines have been published,1 most recently from the North American Menopause Society (NAMS).

Correlation Analysis of Adverse Reactions of Antiosteoporosis Drugs by Different Mechanisms with Bone Turnover and Vitamin D.

Objective The risk factors for the most common adverse reactions of two types of antiosteoporosis drugs in the first treatment of postmenopausal osteoporosis were analyzed to investigate the relationship between the occurrence of adverse reactions and different bone transition states and vitamin D levels. Methods A total of 381 postmenopausal women who were diagnosed with osteoporosis in the Osteoporosis Clinic of Ningxia Medical University General Hospital from January 2017 to June 2020 were enrolled. A telephone follow-up survey was conducted on the mentioned subjects. According to the survey results, the mentioned subjects were selected according to their first use of antiosteoporosis drugs. They were divided into zoledronic acid and teriparatide acetate groups. The subjects in the two groups were divided into two groups according to the presence or absence of adverse reactions after medication and according to vitamin D level and P1NP level, and the correlation between the two factors and the occurrence of adverse reactions was analyzed. Results Among the 307 patients treated with zoledronic acid for antiosteoporosis, 99 patients developed acute phase adverse reactions (APR+), accounting for 32.2% of the total subjects. 56.7 percent of the subjects had vitamin D deficiency. The 25(OH)D level of the APR + subjects was 16.75 ± 9.20 ng/mL, significantly lower than that of the APR− patients (23.68 ± 10.67 ng/mL). Serological P1NP level in APR+ patients was 73.95 ± 34.50 ng/ml, significantly higher than that of APR− patients with 55.80 ± 36.91 ng/ml. Musculoskeletal symptoms were observed in 14 of the 74 subjects treated with teriparatide acetate, accounting for 18.9% of the total subjects. The 25(OH)D level was deficient in 59.5% of the subjects. The 25(OH)D level of the subjects with musculoskeletal symptoms was 15.96 ± 8.17 ng/ml, while that of the subjects without musculoskeletal symptoms was 20.86 ± 8.52 ng/ml, which showed no statistical significance. The reason was considered to be related to the small sample size included in the study. The P1NP level of subjects with musculoskeletal symptoms was 96.85 ± 58.52 ng/ml, significantly higher than the P1NP level of subjects without musculoskeletal symptoms (55.28 ± 27.87 ng/ml). Conclusions The 25(OH)D level in vivo was negatively correlated with the acute phase adverse reactions after the first infusion of zoledronic acid. When the rate of bone formation is increased and osteoblasts are active, the risk of acute phase adverse reactions is increased with the use of zoledronic acid as antiosteoporosis therapy. There was no significant correlation between 25(OH)D levels and musculoskeletal symptoms after teriparatide acetate treatment of osteoporosis. When the rate of bone formation is increased and osteoblasts are active, the risk of adverse reactions to musculoskeletal symptoms is increased with antiosteoporosis treatment with teriparatide acetate.

The Effect of Bisphosphonates on Fracture Healing Time and Changes in Bone Mass Density: A Meta-Analysis.

BackgroundOsteoporosis is a common complication of acute fracture, which can lead to fracture delayed union or other complications and resulting in poor fracture healing. Bisphosphate is a common anti-osteoporosis drug, but its application in fracture patients is still controversial because of its inhibitory effect on bone resorption.MethodStudies were acquired from literature databases in accordance with established inclusion criteria. Standard mean difference (SMD) and 95% confidence intervals (Cls) were calculated to evaluate the effectiveness of the bisphosphonates treatment in fracture patients. Data analysis was conducted with the Review Manager 5.4.1 software.ResultsA total of 16 studies involving 5022 patients obtained from selected databases were examined. As expected, bisphosphate had no significant effect on fracture healing time, but it could significantly increase BMD and prevent osteoporosis. Meanwhile, bisphosphate can inhibit both bone resorption and bone formation markers, resulting in low bone turnover state.ConclusionThis meta-analysis showed that bisphosphonate have no significant effect on fracture healing time but they do increase the changes in BMD and reduce bone synthesis and resorption markers. Early application of bisphosphonates after injury in the appropriate patient population should be considered.

No association of anti-osteoporosis drugs with COVID-19-related outcomes in women: a nationwide cohort study.

SummaryThis study was performed to evaluate whether the use of drugs in the treatment of osteoporosis in women is associated with COVID-19 outcomes. The results showed that the risk of hospitalization, intensive care unit admission, and mortality was not altered in individuals taking anti-osteoporosis drugs, suggesting no safety issues during a COVID-19 infection.IntroductionWhether patients with COVID-19 receiving anti-osteoporosis drugs have lower risk of worse outcomes has not been reported yet. The aim of this study was to evaluate the association of anti-osteoporosis drug use with COVID-19 outcomes in women.MethodsData obtained from a nationwide, multicenter, retrospective cohort of patients diagnosed with COVID-19 from March 11th to May 30th, 2020 was retrieved from the Turkish Ministry of Health Database. Women 50 years or older with confirmed COVID-19 who were receiving anti-osteoporosis drugs were compared with a 1:1 propensity score-matched COVID-19 positive women who were not receiving these drugs. The primary outcomes were hospitalization, ICU (intensive care unit) admission, and mortality.ResultsA total of 1997 women on anti-osteoporosis drugs and 1997 control patients were analyzed. In the treatment group, 1787 (89.5%) women were receiving bisphosphonates, 197 (9.9%) denosumab, and 17 (0.9%) teriparatide for the last 12 months. Hospitalization and mortality rates were similar between the treatment and control groups. ICU admission rate was lower in the treatment group (23.0% vs 27.0%, p = 0.013). However, multivariate analysis showed that anti-osteoporosis drug use was not an independent associate of any outcome. Hospitalization, ICU admission, and mortality rates were similar among bisphosphonate, denosumab, or teriparatide users.ConclusionResults of this nationwide study showed that preexisting use of anti-osteoporosis drugs in women did not alter the COVID-19-related risk of hospitalization, ICU admission, and mortality. These results do not suggest discontinuation of these drugs during a COVID-19 infection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00198-021-06067-2.

Chicago sky blue 6B (CSB6B), an allosteric inhibitor of macrophage migration inhibitory factor (MIF), suppresses osteoclastogenesis and promotes osteogenesis through the inhibition of the NF-κB signaling pathway

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator involved in various pathophysiological and inflammatory states. Accumulating line of evidence suggests a role for MIF in regulating bone metabolism and therefore a prime candidate for therapeutic targeting. In this study, we showed that Chicago sky blue 6B (CSB6B) suppresses RANKL-induced osteoclast and bone resorption in vitro via the inhibition of NF-κB signaling activation and promoting proteasome-mediated degradation of MIF. Consequently, the induction of NFATc1 was impaired resulting in downregulation of NFATc1-responsive osteoclast genes. We also demonstrated that CSB6B treatment enhanced primary calvarial osteoblast differentiation and bone mineralization in vitro via the suppression of NF-κB activation and upregulation of Runx expression. Using two murine models of osteolytic bone disorders, we further showed that administration of CSB6B protected mice against pathological inflammatoryc calvarial bone destruction induced by titanium particles mice as well as estrogen-deficiency induced bone loss as a result of ovariectomy. Together, as an MIF inhibitor, CSB6B can inhibit osteoclast differentiation and bone resorption function and enhance the mineralization of osteoblasts through the inhibition of NF-κB pathway. MIF is a prime target for therapeutic targeting for the treatment of osteolytic bone disorders and the MIF inhibitor CSB6B could be potential anti-osteoporosis drug.

SCREENING FOR VIETNAMESE PLANT EXTRACTS WITH POTENTIAL BENEFIT FOR ANTI OSTEOCLASTOGENESISH

Bone's homeostasis is only achieved when there is a balance between bone formation and bone resorption. A metabolic disorder of bone-resorbing osteoclasts can lead to osteoporosis. Long-term use of anti-osteoporosis drugs can lead to undesirable side effects so traditional herbal can be a potential source of alternative medicine. In the present study, forty one Vietnamese plants (seventy methanol extracts) were screened for osteoclastogenesis inhibitory activities on RAW264.7 mouse macrophage cells. For the first time, 29 extracts from 24 species showed potential as effective inhibitors of osteoclastogenesis.

Risks vs. benefits of switching therapy in patients with postmenopausal osteoporosis

ABSTRACT Introduction: Osteoporosis is characterized by the fragility of bones, leading to fractures and, consequently, the deterioration of functional capacity and quality of life. Postmenopausal women, in particular, are prone to osteoporosis and often require anti-osteoporosis treatment. In the last few decades, various anti-osteoporosis drugs have been approved for clinical use. In an aging society, osteoporosis cannot be treated using a single agent; therefore, switching therapy is an important treatment strategy. Areas covered: This review covers switching therapy in patients with postmenopausal osteoporosis. It’s extremely important to understand the characteristics of each drug including; limitations on the duration of use, side effects due to long-term use (such as atypical femur fracture and osteonecrosis of the jaw) or discontinuation (such as rebound phenomenon), compliance, and ability to prevent fractures. We review and summarize the risks and benefits of switching therapy. Expert opinion: When switching therapy, the order of drug administration is important. Routine monitoring should be continued after switching treatments. We recommend first using osteoanabolic agents in postmenopausal women with severe osteoporosis. In addition, identifying predictors of the efficacy and side effects of treatment may help prevent the inappropriate use of drugs for the treatment of osteoporosis.

Meta-Analysis of Clinical Fracture Risk Reduction of Antiosteoporosis Drugs: Direct and Indirect Comparisons and Meta-Regressions

ObjectiveAntiosteoporotic drug (AOD) trials have variabilities in duration and fracture risks. This study evaluated AOD’s versus controls regarding reduction in relative rates and rate differences in vertebral and hip fractures and comparative costs. MethodsPrimary randomized controlled trials of antiosteoporotic drugs in postmenopausal women with documentation of vertebral fracture rates or hip fracture rates were extracted from meta-analyses and PubMed through February 2021. Direct and indirect meta-analyses and meta-regressions analyzed the fracture reductions. ResultsThere were 24 randomized controlled trials of drug versus placebo (73 862 women) and 10 randomized controlled trials of drug versus drug. The reductions in the relative rates of vertebral fractures were significant for antiresorptive (alendronate, risedronate, zoledronate, denosumab, and raloxifene) and anabolic (teriparatide, abaloparatide, and romosozumab) drugs. Denosumab, teriparatide, and abaloparatide were more effective in reducing vertebral fracture rates than oral bisphosphates (all P < .05) but were not more effective in reducing vertebral fracture rates than zoledronate. The reductions in hip fracture rates were significant for alendronate, denosumab, and zoledronate (all P < .05), without significant differences among drugs. Anabolic drugs did not show significant hip fracture rate reduction. Meta-regression of rate differences enabled the calculation of costs per vertebral fracture prevented, which were estimated at >$100 000 for anabolic drugs and between $2289 and $28 947 for antiresorptive drugs. Many direct drug versus drug trials were underpowered to demonstrate benefits of one drug over another. ConclusionThis study suggests goal-directed, cost-effective therapies relative to patient risk for vertebral and hip fractures. Anabolic drugs are better at preventing vertebral fractures than oral bisphosphonates. Anabolic drugs are not superior to zoledronate or denosumab and are substantially more expensive. When comparing drugs that prevented hip fractures, there was no statistical benefit of any drug.

Evaluation of the Use of CT Attenuation for the Prediction of Subsequent Vertebral Fracture in Patients with Osteoporosis

Subsequent vertebral fracture (SVF) is one of the most common complications of percutaneous vertebral augmentation (PVA), which leads to lower back pain in patients. Low bone mineral density (BMD) is an independent risk factor for SVF. BMD measured using computed tomography (CT) trabecular attenuation correlates closely with BMD. This study aims to analyze the risk factors of SVF after PVA and to estimate the predictive role of CT trabecular attenuation. A retrospective review. Department of spinal surgery in an affiliated hospital of a medical university. A total of 515 patients were retrospectively enrolled between January 2015 and December 2019 into a 5-year follow-up investigation. Trabecular attenuation (Hounsfield units [HU]) was retrospectively measured at L1 on preoperative lumbar or thoracic CT scans, and the receiver operating characteristic (ROC) curve was used to evaluate its value for the prediction of SVF. Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify the risk factors for SVF. A total of 166 patients (32.2%) experienced SVF. ROC curve analysis demonstrated that an L1 trabecular attenuation of <= 95 HU has a sensitivity of 70.5% and a specificity of 79.9% for the prediction of SVF. Kaplan-Meier analysis showed that L1 trabecular attenuation <= 95 HU was significantly associated with lower SVF-free survival (P = 0.001; log-rank test). Multivariate analysis demonstrated that advanced age (hazard ratio [HR] = 1.03, P = 0.022), low body mass index (HR = 0.83, P = 0.001), diabetes status (HR = 1.50, P = 0.024), antiosteoporosis drugs use (HR = 0.65, P = 0.031), and decreased L1 trabecular attenuation (HR = 0.95, P = 0.001) were risk factors for SVF. A single-center retrospective study of a consecutive cohort of patients may include the inevitable bias. We periodically reviewed the full-length x-ray of the spine at every 3 months of follow-up visit, which we may miss some patients with SVF without low back pain. SVF is highly prevalent in patients with osteoporotic vertebral fracture who undergo single-level PVA. Low L1 trabecular attenuation is associated with a significant reduction in SVF-free survival, and when their L1 trabecular attenuation is <= 95 HU, patients may be at higher risk of SVF. Computed tomography, Hounsfield units, vertebral fracture, osteoporosis, percutaneous vertebral augmentation.

The Influence of Strontium on Bone Tissue Metabolism and Its Application in Osteoporosis Treatment.

Osteoporosis is a chronic disease characterized by low bone mass caused by increased bone turnover and impaired bone microarchitecture. In treatment, we use antiresorptive or anabolic drugs, which usually have a unidirectional effect, i.e., they inhibit the activity of osteoclasts or stimulate the effect of osteoblasts. Strontium ranelate is an anti-osteoporosis drug with a unique mechanism of action (used primarily in postmenopausal women). Unlike other medicines, it has a multidirectional effect on bone tissue, intensifying osteoblastogenesis while inhibiting osteoclastogenesis. It turns out that this effect is demonstrated by strontium ions, an element showing physical and chemical similarity to calcium, the basic element that builds the mineral fraction of bone. As a result, strontium acts through the calcium-sensing receptor (CaSR) receptor in bone tissue cells. In recent years, there has been a significant increase in interest in the introduction of strontium ions in place of calcium ions in ceramics used as bone replacement materials for the treatment of bone fractures and defects caused by osteoporosis. The aim of this study was to summarize current knowledge about the role of strontium in the treatment of osteoporosis, its effects (in various forms), and the ways in which it is administered.

Impact of osteogenic activity on degenerative aortic valve disease in patients with osteoporotic hip fracture

BackgroundPrevious studies have proposed that osteogenic and apoptotic processes of valve interstitial cells contribute to the mineralization and then calcification of the aortic valve. Osteoblast-like cells subsequently mediate calcification of the aortic valve as part of a highly regulated process analogous to skeletal bone formation. The objective of this study was to evaluate the pathogenesis of the sclerotic/calcific changes in the aortic valve from histological and biological findings, and investigate the role of osteoblasts in the calcified pathway of aortic stenosis. MethodsPreoperative echocardiography in 550 consecutive patients with osteoporotic hip fracture were retrospectively examined (475 females, mean 25th–75th, 89 [85–93] years). One hundred sixteen patients were under medical treatment with anti-osteoporosis drugs. We evaluated the prevalence and degree of degenerative changes in the aortic valve and examined the associations of bone turnover biomarkers N-terminal pro-peptide of type 1 collagen (P1NP) and serum tartrate-resistant acid phosphatase (TRACP-5b) with degenerative calcific changes in the aortic valve. ResultsOf 550 patients, 112 patients (20.9%) showed no leaflet calcification; 296 (53.8%), 1 leaflet calcification; and 142 (25.8%), 2 ≥ leaflets calcification. Significant (peak velocity ≥ 3.0m/s) Aortic stenosis was found in 43 patients (7.8%). In patients who were not taking anti-osteoporotic drugs, P1NP was higher in the 2 ≥ leaflets calcification group than in the other groups (p < 0.01). TRACP-5b was not significantly different among the three groups (p = 0.15). ConclusionsDegenerative changes in the aortic valve were related to bone biomarker activation in osteoporotic hip fracture patients.

Systems pharmacology dissection of action mechanisms for herbs in osteoporosis treatment

ObjectiveOsteoporosis has become the biggest cause of non-fatal health issue. Currently, the limitations of traditional anti-osteoporosis drugs such as long-term ill-effects and drug resistance, have raised concerns toward complementary and alternative therapies, particularly herbal medicines and their natural active compounds. Thus, this study aimed to provide an integrative analysis of active chemicals, drug targets and interacting pathways of the herbs for osteoporosis treatment. MethodsHere, we introduced a systematic pharmacology model, combining the absorption, distribution, metabolism, and excretion (ADME) screening model, drug targeting and network pharmacology, to probe into the therapeutic mechanisms of herbs in osteoporosis. ResultsWe obtained 86 natural compounds with favorable pharmacokinetic profiles and their 58 targets from seven osteoporosis-related herbs. Network analysis revealed that they probably synergistically work through multiple mechanisms, such as suppressing inflammatory response, maintaining bone metabolism or improving organism immunity, to benefit patients with osteoporosis. Furthermore, experimental results showed that all the five compounds (calycosin, asperosaponin VI, hederagenin, betulinic acid and luteolin) enhanced osteoblast proliferation and differentiation in vitro, which corroborated the validity of this system pharmacology approach. Notably, gentisin and aureusidin among the identified compounds were first predicted to be associated with osteoporosis. ConclusionHerbs and their natural compounds, being characterized as the classical combination therapies, might be engaged in multiple mechanisms to coordinately improve the osteoporosis symptoms. This work may contribute to offer novel strategies and clues for the therapy and drug discovery of osteoporosis and other complex diseases.

The Effects of Trends in Osteoporosis Treatment on the Incidence of Fractures.

Objective This study focused on the trends in antiosteoporosis drug preferences and compared the incidence of fractures between patients treated orally and those who were exposed to an awareness campaign and assigned to intravenous/subcutaneous treatment. Methods Our hospital registry included 1,716 osteoporotic women who were over 65 years of age without preexisting vertebral and nonvertebral fractures over 1 year before this study, with bone mineral density (BMD) < −2.5 standard deviation (SD) and fracture assessment tool (FRAX) score > 20%, who were given 1,337 oral and 379 intravenous/subcutaneous prescriptions to treat their osteoporosis. Self-administered surveys (2012, 2013, 2014, 2015, and 2016) collected data on trends of preferences among nine drugs and fracture prevention using relative risk reduction (RRR). Results The number of patients taking oral prescriptions decreased gradually from 2012 to 2016, while the number of patients treated with intravenous and subcutaneous injections increased. The incidence of fracture was lower in patients receiving intravenous and subcutaneous injections than in patients taking oral medications. Conclusion These findings indicate a decrease in oral prescriptions for osteoporosis treatment and that treatment for osteoporosis using intravenous or subcutaneous injections of antiosteoporosis drugs is more effective for preventing fractures.

Strontium ranelate promotes chondrogenesis through inhibition of the Wnt/\u03b2-catenin pathway

BackgroundCartilage regeneration is a key step in functional reconstruction for temporomandibular joint osteoarthritis (TMJ-OA) but is a difficult issue to address. Strontium ranelate (SrR) is an antiosteoporosis drug that has been proven to affect OA in recent years, but its effect on chondrogenesis and the underlying mechanism are still unclear.MethodsBone mesenchymal stem cells (BMSCs) from Sprague–Dawley (SD) rats were induced in chondrogenic differentiation medium with or without SrR, XAV-939, and LiCl. CCK-8 assays were used to examine cell proliferation, and alcian blue staining, toluidine blue staining, immunofluorescence, and PCR analysis were performed. Western blot (WB) analyses were used to assess chondrogenic differentiation of the cells. For an in vivo study, 30 male SD rats with cartilage defects on both femoral condyles were used. The defect sites were not filled, filled with silica nanosphere plus gelatine-methacryloyl (GelMA), or filled with SrR-loaded silica nanosphere plus GelMA. After 3 months of healing, paraffin sections were made, and toluidine blue staining, safranin O/fast green staining, and immunofluorescent or immunohistochemical staining were performed for histological evaluation. The data were analyzed by SPSS 26.0 software.ResultsLow concentrations of SrR did not inhibit cell proliferation, and the cells treated with SrR (0.25 mmol/L) showed stronger chondrogenesis than the control. XAV-939, an inhibitor of β-catenin, significantly promoted chondrogenesis, and SrR did not suppress this effect, while LiCl, an agonist of β-catenin, strongly suppressed chondrogenesis, and SrR reversed this inhibitory effect. In vivo study showed a significantly better cartilage regeneration and a lower activation level of β-catenin by SrR-loaded GelMA than the other treatments.ConclusionSrR could promote BMSCs chondrogenic differentiation by inhibiting the Wnt/β-catenin signaling pathway and accelerate cartilage regeneration in rat femoral condyle defects.

Functionalized anti-osteoporosis drug delivery system enhances osseointegration of an inorganic–organic bioactive interface in osteoporotic microenvironment

Osteoporosis leads to various complications, such as prosthesis loosening and periprosthetic fracture, after joint replacement. This is mainly due to the impaired osteogenesis and excessive osteoclastic activity in osteoporotic microenvironment, which leads to insufficient osseointegration between prostheses and host bone. In this study, a functional drug-releasing inorganic–organic bioactive interface was constructed, comprising inorganic three-dimensional (3D) printed porous titanium alloy interface and organic poloxamer 407 temperature-sensitive hydrogel loaded with a novel anti-osteoporosis drug (technetium methylenediphosphonate, 99Tc-MDP). The inorganic–organic bioactive interface showed good biocompatibility and exhibited a sustained release profile. This performance enhanced osteogenic differentiation, inhibited the expression of osteoclast-related genes and inhibited the osteoclastogenesis, as compared with traditional bisphosphonates (alendronate) in vitro. When implanted into the distal femoral defect using an osteoporotic rabbit model, the 99Tc-MDP-loaded bioactive interface exhibited the most stable osseointegration with native bone. Furthermore, the drug delivery system inhibited osteoclastic activity via regulation of the osteoprotegerin/receptor activator of NF-κB ligand (OPG/RANKL) signaling pathway, which significantly ameliorated the osteoporosis status to effectively prevent continuous bone destruction around the interface. This study has clinical significance, as it demonstrates that the 99Tc-MDP modified inorganic–organic interface serve as a novel artificial prosthetic interface for patients with poor osteogenesis.

Potential prescribing omissions of anti-osteoporosis drugs is associated with rehabilitation outcomes after fragility fracture: Retrospective cohort study.

We investigated the association between rehabilitation outcomes and polypharmacy, potentially inappropriate medications and potential prescribing omissions in older adults with fragility fractures. In total, we registered 217 older adults with fragility fractures (hip or vertebral) retrospectively and examined the association between rehabilitation outcome and polypharmacy, potentially inappropriate medications and potential prescribing omissions. Polypharmacy was defined as five or more drugs. Potentially inappropriate medications and potential prescribing omissions were defined by the Beers criteria (2015) and the screening tool to alert to treatment criteria version 2, respectively. The outcome was functional independence measure gain (functional independence measure at discharge - functional independence measure at admission). Multiple regression analyses revealed no association between functional independence measure gain and polypharmacy (crude: β = 0.058, P = 0.858; adjusted model: β = 0.013, P = 0.869) or potentially inappropriate medications (crude: β = 0.100, P = 0.144; adjusted model: β = 0.084, P = 0.260). However, there was a significant association between functional independence measure gain and potential prescribing omissions (crude: β = 0.167, P = 0.014; adjusted model: β = 0.180, P = 0.016). Participants without potential prescribing omissions (in other words, participants who were prescribed anti-osteoporosis drugs) had a greater functional independence measure gain than participants with potential prescribing omissions (in other words, those that were not prescribed anti-osteoporosis drugs). To the best of our knowledge, this study is the first to report that participants without potential prescribing omissions had significantly improved rehabilitation outcomes. Geriatr Gerontol Int 2021; 21: 386-391.

Clinical Characteristics of Primary Hyperparathyroidism: 15-Year Experience of 457 Patients in a Single Center in China.

ObjectivePrimary hyperparathyroidism (PHPT) is a common endocrine disorder of calcium metabolism. However, data concerning a large cohort of PHPT patients in the Chinese population are scarce. Thus, the objective of this study was to determine the general clinical signatures of 457 Chinese PHPT patients and explore the clinical characteristic differences between benign and malignant PHPT.MethodsA single-center retrospective study was designed. Medical records between preoperation and postoperative follow-up, were assessed and statistical analysis of the clinical data was performed.ResultsPatients with PHPT aged 12–87 years, with a mean onset age of 56.16 ± 14.60 years, were included. Most patients (68.7%) in our center had symptomatic patterns described as bone pain (74.8%), urolithiasis (25.5%), fatigue (17.5%), and pathological fracture (13.1%), but an increasing tendency has been established in the proportion of patients with asymptomatic forms. Correlation analysis revealed that patients with higher serum levels of parathyroid hormone (PTH) and calcium presented higher serum levels of bone turnover markers (BTMs) and lower 25-hydroxy-vitamin D (25OHD) values (P<0.001). Gains in bone mineral density (BMD) at L1–4, the femoral neck and the total hip were observed 1–2 years after parathyroidectomy (9.6, 5.9, and 6.8%). Parathyroid carcinoma patients presented prominently higher serum PTH and calcium levels and BTMs and lower BMD at femoral neck and total hip than benign PHPT patients (P<0.05), while no significant differences in age, sex, and serum 25OHD concentration were observed between benign and malignant PHPT patients.ConclusionsPHPT should be paid attention to in the patients with bone pain. While, BMD and BTMs can differentiate parathyroid carcinoma from parathyroid adenoma and hyperplasia to some extent. In addition, anti-osteoporosis drugs could be used when necessary to avoid hip fractures in patients with parathyroid carcinoma.

Anti-Osteoporosis Drugs for Overall Mortality in the Old (Ages ≥ 50 Years) and Oldest-Old (Ages ≥ 75): A Systematic Review and Meta-Analysis

Background: Findings from recent meta-analyses of anti-osteoporosis drugs have shown that there is no association of anti-osteoporosis drugs with overall mortality, possibly because of population limitations such as age, sex, the presence or absence of fractures, and other parameters, which are associated with increased mortality in the elderly. There is no report about possible associations between anti-osteoporosis drugs and overall mortality in the old (ages ≥ 50 years) or oldest (ages ≥ 75 years) population. The purpose of using anti-osteoporosis drugs is not only to improve bone mineral density and reduce fractures, but also to prolong life expectancy, especially in the old or oldest population. We determined the association between anti-osteoporosis drugs and overall mortality in the old and oldest populations, and determined the effects of different demographic parameters. Methods: We searched Web of Science, Embase, the Cochrane Database, and PubMed from inception to January 10, 2021, for trials reporting the effects of anti-osteoporosis drugs on overall mortality. The effects of calcium and vitamin D were excluded. We included all randomized trials comparing interventions with different anti-osteoporosis drugs, and we included elderly (ages ≥ 50 years) without other metabolic bone diseases. We pooled data using a fixed effects meta-analysis with weighted mean differences and reported 95% confidence intervals (CIs). We also used the I² statistic to assess heterogeneity in the results of individual studies. The primary endpoint was the total number of people in the drug treatment and placebo groups, and the number of deaths during the follow-up periods. Findings: Of 23,242 citations identified by the search strategy, 25 studies (mean duration: 3.0 years, comprising 93,782 participants; 91.4% women; average age: 73.2 years) met the inclusion criteria. A total of 21 studies were mainly comprised of Caucasians. In 25 studies, anti-osteoporosis drugs included bisphosphonate, selective estrogen receptor modulators (SERMs), parathyroid hormone analogues, receptor-activated nuclear factor-κB ligand inhibitor, anti-sclerostin antibodies. and strontium ranelate. One of the studies used two anti-osteoporosis drugs compared with placebos, while all the other studies used one anti-osteoporosis drug.In the elderly population, anti-osteoporosis drugs did not reduce individual mortalities (weight RR: 0.96; 95% CI: 0.90–1.02), with heterogeneity among trials (I² = 2%, p = 0.43); however, none of the anti-osteoporosis drugs was significantly associated with overall mortality. Stratified analyses were performed according to age and sex, with osteoporosis, and with or without fractures. In different age groups (> 65 years of age, > 75 years of age, and > 80 years of age), the associations between anti-osteoporosis drugs and overall mortalities were not significant. In the female and male groups, none of the associations between anti-osteoporosis drugs and overall mortality were significant. In the with or without osteoporosis groups, these drugs did not reduce overall mortalities. However, these drugs did show reduced mortality (RR: 0.83; 95% CI: 0.70–0.99), but only in the group with fractures. Interpretation: None of the anti-osteoporosis drugs reduced overall mortality, but in the old population with recent fractures, these drugs showed a reduced overall mortality. The association between anti-osteoporosis drugs and overall mortality did not influence by age and sex. The use of these drugs in the old and oldest populations was safe, and was effective in patients with fractures. Funding Statement: This work was supported by grants from the Chongqing Health and Family Planning Commission (No. 2015MSXM016), Chongqing Development and Reform Commission (No. [2013] 1420), and National Key Clinical Specialties Construction Program of China (No. [2013] 544). Declaration of Interests: None.

Interplay between mineral crystallinity and mineral accumulation in health and postmenopausal osteoporosis

Osteoporosis is characterized by an imbalance between bone formation and resorption rates, resulting in bone loss. For ethical reasons, effects of antiosteoporosis drugs are compared against patients receiving vitamin D and calcium supplementation which is a mild antiresorptive regimen. Bone formation may be resolved into two phases: the initial formation of mineral crystals (primary nucleation) and the subsequent mineral accumulation (secondary nucleation and mineral growth) on them. In this study, we used Raman microspectroscopic analysis of iliac crest biopsies from healthy females (N = 108), postmenopausal osteoporosis patients receiving vitamin D and calcium supplementation (PMOP-S; N = 66), and treatment-naïve postmenopausal osteoporosis patients (PMOP-TN; N = 12) to test the hypothesis that at forming trabecular surfaces, mineral maturity / crystallinity of the youngest crystallites associates with the amount of subsequent mineral accumulation. The surfaces of analysis were chosen based on the presence of fluorescent double labels, defining three distinct tissue ages. The results indicated that when adjusted for age and tissue age, there were no differences in amount of mineral formed between healthy females and either PMOP-S or PMOP-TN, while both PMOP-S and PMOP-TN had larger crystallites compared to healthy females. Moreover, significant differences existed between PMOP-S and PMOP-TN in size of initial crystals formed as well as rate of mineral accumulation and maturation. These findings suggest an additional mechanism that may contribute to the decreased mineral content evident in PMOP, and provide a potential target for the development of new interventions. Statement of SignificanceWe used Raman microspectroscopic analysis of iliac crest biopsies from healthy females and postmenopausal osteoporosis patients (PMOP) receiving placebo to test the hypothesis that at forming trabecular surfaces, mineral maturity / crystallinity (MMC) of the youngest crystallites associates with the amount of subsequent mineral accumulation. This can affect bone mechanical properties as larger crystallites have been shown to result in compromised mechanical attributes; and larger crystallites grow slower compared to smaller ones. The results of the present analysis indicate that increased MMC of the youngest formed mineral may contribute to the bone mineral loss evident in PMOP and the accompanying increased fracture risk independently of bone turnover rate.

An UHPLC-MS/MS method for simultaneous determination of ten sex steroid hormones in ovariectomy-induced osteoporosis rat and its application in discovery of sex steroid hormones regulatory components of Xian-Ling-Gu-Bao capsule

Sex steroid hormones could directly affect the bone metabolism by regulating cell physiological functions. In female, it inevitably causes the abnormal levels of sex steroid hormones at post-menopause in vivo. Ovariectomized rats and mice are classic animal models of osteoporosis to better understand the action mechanism of anti-osteoporosis drugs. However, it is not clear whether Xian-Ling-Gu-Bao capsule (XLGB), a kidney-tonifying traditional Chinese medicine prescription, treat osteoporosis via regulating multiple sex steroid hormones. In the present study, a reliable method involving ultra high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC/TQ-XS-MS) was developed for simultaneous quantitative analysis of ten sex steroid hormones (three estrogens, five androgens and two progestogens) in rat and mouse serum. The results of methodology were acceptable. The validated method was then successfully applied in the determination of the levels of sex steroid hormones in ovariectomy-induced osteoporosis rats, as well as drug (17β-estradiol and XLGB) intervened rats. As a result, XLGB could not only significantly increase the level of 17β-estradiol, but also improve the levels of progesterone, 17α-hydroxyprogesterone and androstenedione. Combined with molecular docking results and pharmacokinetic parameters, psoralen, isopsoralen and sweroside were considered as the key effective components of XLGB to activate adenylyl cyclase on promoting the biosynthesis of multiple sex steroid hormones. It is the first time to evaluate the regulatory effect of kidney-tonifying traditional Chinese medicine prescription on the levels of steroids in ovariectomy-induced osteoporosis rat, as well as the potential substance basis and mechanism of steroid hormone regulation.