Osteoporosis Drug Research Articles

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice.

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124.

Mitochondrial toxicants in Xian-Ling-Gu-Bao induce liver injury by regulating the PI3K/mTOR signaling pathway: an in vitro study

BackgroundDrug-induced mitochondrial toxicity is thought to be a common mechanism of drug hepatotoxicity. Xian-Ling-Gu-Bao (XLGB) oral preparation is a commonly used drug for osteoporosis in China. Classical safety evaluation studies have shown that the entire preparation and six Chinese herbal medicines have high safety, but the incidence of drug-induced liver damage due to XLGB remains high, the mechanism and toxic substances causing liver injury are still unclear. The purpose of this study is to identify compounds with potential mitochondrial liabilities in XLGB, and to clarify their underlying mechanisms and related pathways.MethodsThe mitochondrial function analysis was performed using an extracellular flux assay, which simultaneously monitored both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Through network pharmacology and in vitro experimental verification, the potential protein targets, signaling pathways and molecular mechanism of mitochondrial toxicity have been studied.ResultsWe observed a significant decrease in mitochondrial respiration of Psoraleae Fructus and its five compounds in fundamental bioenergetics parameters such as basal respiration, ATP-linked production and maximal respiration, indicating mitochondrial dysfunction. The network pharmacology results showed that the influence of XLGB on mitochondrial dysfunction was closely related to PI3K-Akt signaling pathway, mTOR signaling pathway and Apoptosis. Western blot showed that the levels of mTOR, p-mTOR (Ser2448), Raptor, PI3K (p110α), Beclin 1, ATG5 and Caspase-9 were up-regulated after treatment with psoralidin, psoralen and bavachin, and the expression of Bcl-2 was down-regulated after bavachinin treatment.ConclusionsThe hepatotoxicity of XLGB is associated with mitochondrial dysfunction. Five compounds in Psoraleae Fructus showed mitochondrial damage, they are psoralidin, isobavachalcone, bavachinin, bavachin and psoralen, especially psoralidin showed significant reduction in reserve capacity and respiratory control ratios. The molecular mechanism is related to the activation of PI3K/mTOR signaling pathway to inhibit autophagy and induce mitochondrial apoptosis.

Release of drugs used in the treatment of osteoporosis from zeolites with divalent ions-Influence of the type of ion and drug on the release profile.

Bisphosphonates are drugs that are used to treat osteoporosis that causes the low mineral density of the bones. These drugs can be delivered in several ways, but each method has disadvantages. Materials with high potential as carriers of these drugs are zeolites with divalent ions. The aim of this study was to investigate the effect of divalent cations (calcium, magnesium, zinc) and drug type (risedronate, zoledronate) on sorption and release of the drug for osteoporosis. It was proved that drug sorption occurs on all zeolites presented in this work. Risedronate sorption was highest in zinc zeolite and lowest in calcium zeolite. In the case of zoledronate, sorption was most effective in magnesium zeolite and the least effective in zinc zeolite. Very large differences in drug release profiles were also observed. Risedronate was released several times longer than zoledronate. The diversity of the results indicates that the examined materials can be used in different types of drug delivery systems. They can be used, for example, intravenously or in the form of implants due to the different release profiles. Furthermore, the proposed carriers also release magnesium and calcium ions which are used in the prevention of osteoporosis, and zinc ions which have antibacterial properties.

Hypocalcemia Is a Common Risk Factor for Osteoporosis in Taiwanese Patients with Cushing's Syndrome.

Background: Osteoporosis is a cardinal manifestation of Cushing’s syndrome. There is a lack of relevant research on risk factors for osteoporosis among patients with Cushing’s syndrome (CS) in Taiwan. Thus, this study was designed to explore the possible risk factors of osteoporosis. Methods: We gathered patients with a diagnosis of CS between 2001 and 2017 in the Chang Gung Research Database (CGRD). We extracted data including diagnoses and biochemistry from hospital records. The diagnosis of CS was based on ICD-9-CM codes (255.0). Osteoporosis was defined by a T value equal to or less than −2.5 in BMD examination and hypocalcemia was defined as serum calcium concentrations < 8.0 mg/dL. Results: A total of 356 patients with CS who made regular visits to the outpatient department were enrolled in this study. The mean age was 68.6 years, and 74.9% of the patients were female. Of them, 207 patients (58.1%) were diagnosed with osteoporosis. Multivariable logistic regression models indicated that serum calcium level was negatively associated with osteoporosis (OR 0.70, CI 0.54−0.91, p < 0.001) after adjustment for age, sex, and other confounding risk factors. In addition, hypocalcemia was associated with heart failure (HF) (OR 2.14, CI 1.02−4.47, p < 0.05), stroke (OR 2.58, CI 1.21−5.46, p < 0.05) and osteoporosis (OR 3.04, CI 1.24−7.41, p < 0.05) in multivariate analysis. Conclusions: Our study found that lower serum calcium levels were common among patients with CS and osteoporosis. Furthermore, CS patients with HF or stroke had high proportion of hypocalcemia. Therefore, these patients must pay more attention to adequate calcium supplementation and undergo the appropriate osteoporosis drug treatment to reduce the risk of subsequent fracture and disability.

Commentary: Zebrafish as a Model for Osteoporosis—An Approach to Accelerating Progress in Drug and Exercise-Based Treatment

Osteoporosis (OP) is a degenerative disease characterized by reduced bone strength and increased fracture risk. As the global population continues to age, the prevalence and economic burden of osteoporosis can be expected to rise substantially, but there remain various gaps in the field of OP care. For instance, there is a lack of anti-fracture drugs with proven long-term efficacy. Likewise, though exercise remains widely recommended in OP prevention and management, data regarding the safety and efficacy for patients after vertebral fracture remain limited. This lack of evidence may be due to the cost and inherent difficulties associated with exercise-based OP research. Thus, the current research landscape highlights the need for novel research strategies that accelerate OP drug discovery and allow for the low-cost study of exercise interventions. Here, we outline an example of one strategy, the use of zebrafish, which has emerged as a potential model for the discovery of anti-osteoporosis therapeutics and study of exercise interventions. The strengths, limitations, and potential applications of zebrafish in OP research will be outlined.

Altered signaling at the PTH receptor via modified agonist contacts with the extracellular domain provides a path to prolonged agonism in vivo

The parathyroid hormone type 1 receptor (PTHR1), a Class B GPCR, is activated by long polypeptides, including drugs for osteoporosis and hypoparathyroidism. The PTHR1 engages peptide agonists via a two-step mechanism. Initial contact involves the extracellular domain (ECD), which has been thought to contribute primarily to receptor-peptide binding, and then the N terminus of the peptide engages the receptor transmembrane domain (TMD), which is thought to control the message conveyed to intracellular partners. This mechanism has been suggested to apply to other Class B GPCRs as well. Here, we show that modification of a PTHR1 agonist at ECD-contact sites can alter the signaling profile, an outcome that is not accommodated by the current two-step binding model. Our data support a modified two-step binding model in which agonist orientation on the ECD surface can influence the geometry of agonist-TMD engagement. This expanded binding model offers a mechanism by which altering ECD-contact residues can affect signaling profile. Our discoveries provide a rationale for exploring agonist modifications distal from the TMD-contact region in future efforts to optimize therapeutic performance of peptide hormone analogs.

Delivery of the reduced form of vitamin K2(20) to NIH/3T3 cells partially protects against rotenone induced cell death

Mitochondria generate energy through the action of the electron transport chain (ETC) and ATP synthase. Mitochondrial malfunction can lead to various disorders, including neurodegenerative diseases. Several reports have shown that menaquinone-4 (MK-4, vitamin K2(20)), a safe drug for osteoporosis, may improve mitochondrial function. Here, we hypothesized that the efficient delivery of menahydroquinone-4 (MKH), an active form of MK-4, could exert a supporting effect. We verified the effects of MKH delivery on mitochondrial dysfunction by using MK-4 and MKH ester derivatives in NIH/3T3 mouse fibroblast cells treated with mitochondrial inhibitors. MK-4 and MKH derivatives suppressed cell death, the decline in mitochondrial membrane potential (MMP), excessive reactive oxygen species (ROS) production, and a decrease in intrinsic coenzyme Q9 (CoQ9) induced by rotenone (ROT, complex I inhibitor). MK-4 and MKH derivatives delivered MKH to NIH/3T3 cells, acting as an effective MKH prodrug, proving that the delivered MKH may reflect the mitigation effects on ROT-induced mitochondrial dysfunction. MKH prodrugs are also effective against 3-nitropropionic acid (3-NP, complex II inhibitor) and carbonyl cyanide-m-chlorophenylhydrazone (CCCP, uncoupler)-induced cell death. In conclusion, MKH delivery may mitigate mitochondrial dysfunction by maintaining MMP, ROS, and CoQ9, indicating that MKH prodrugs may be good candidates for treating mitochondrial disorders.

Chitosan - zeolite scaffold as a potential biomaterial in the controlled release of drugs for osteoporosis

Chitosan scaffolds are a potential material in many biomedical applications. A particularly interesting application is their use in bone tissue engineering. Because of their biocompatibility and nontoxicity, they are an ideal material for this application. What is missing from chitosan scaffolds is controlled drug release. They can obtain this property by adding drug carriers. In this work, chitosan‑calcium zeolite scaffolds were prepared and used in the controlled release of the drug for osteoporosis - risedronate. Their properties have been compared with those of the popular chitosan-hydroxyapatite scaffold. The zeolite was evenly distributed throughout the scaffold. More drug was retained on the scaffold with the addition of zeolite compared to that with the hydroxyapatite. The new scaffolds have proven to be able to retain the drug and slowly release it in small doses. The results obtained are promising and show great potential for this material in bone tissue engineering.

Evaluation of sodium alendronate drug released from TiO2 nanoparticle doped with hydroxyapatite and silver–strontium for enhancing antibacterial effect and osteoinductivity

Hydroxyapatite (HA) nanocrystalline coatings on implants increase bone/implant joint fusion, but bacteria grow on hydroxyapatite-coated implants and cause infections. To solve this problem, silver (Ag), strontium (Sr), and chitosan were used to modify the surface of the titanium dioxide nanoparticles (TNPs) coated with hydroxyapatite. Ag was used for antimicrobial properties, and Sr was used to control drug release and increase the ossification of titanium implants. Chitosan (Chit) is a natural polymer with good biocompatibility, low toxicity, and strong antibacterial properties. The results show that HA + Sr + Ag + Chit coating causes controlled and long-term release (more than 16 days) of the alendronate sodium drug, an osteoporosis drug, from the implant. Electrochemical corrosion studies reveal that the Sr + Ag + HA + Drug + Chit coating on titanium dioxide nanoparticles has reduced the corrosion penetration rate compared to pure titanium dioxide nanoparticle (TNP). The cytotoxicity analysis results show that the TNP + Sr + Ag + HA + Drug sample has the highest cell viability, equal to 99.3%. Microbial study shows that coated TNPs have more inhibition of Staphylococcus aureus growth than uncoated TNPs. Among the coated TNP samples, TNP samples with HA + Sr + Ag coating had the highest inhibition of bacterial growth.

PSAT156 Abaloparatide Implementation and Follow-Up: Real-World Results of a Pharmacist-Run Anabolic Osteoporosis Clinic

Abstract Introduction Osteoporosis, the most common bone disorder worldwide, is associated with increased morbidity and mortality. Available treatments include antiresorptive agents and anabolic therapies. Anabolic therapies are indicated in patients at high risk of osteoporotic fracture. There are challenges to utilizing anabolic therapies, however, including providing training on injection technique, addressing patient concerns about medication safety, and completion of medication prior authorizations. Pharmacist involvement could help ensure the safe and effective use of anabolic therapy. Objective To describe the 4-year, real-world results of a pharmacist-run abaloparatide osteoporosis clinic. Methods The primary study endpoint was the comparison of DXA T-scores and BMD values of the total hip, femoral neck, spine, and 1/3 radius (wrist) at baseline, after abaloparatide therapy, and following 1 year of follow-up antiresorptive therapy. The secondary end point was the number of documented fractures. Each patient served as his/her own control. Paired T-tests were performed to compare mean differences in pre- and post- T-scores and BMD values. Results Between April 2017 and October 2021, 146 patients were referred for abaloparatide therapy, with 91 patients (62.3%) initiating therapy. Eighteen patients refused to begin therapy because of concerns of adverse drug reactions, lack of interest in treating their osteoporosis, or because of the route of drug administration. Other consenting patients did not initiate therapy due to high monthly co-pay costs (15), insurance preferring teriparatide (1), insurance refusing coverage of any anabolic therapy (1), and contraindication to abaloparatide therapy (10). The average age at initiation of therapy was 66.7 (+ 7.7) years, 97.8% were women, 98.9% were Caucasian, mean BMI was 25.2 (+ 6.0), 56% had a history of osteoporotic fracture, baseline T-Scores of the femoral neck and spine were -2.5 (+ 0.7), and -2.4 (+ 1.3), respectively, and 49.5% of patients were osteoporosis drug naïve. There were significant improvements in T-scores and BMD at the spine, total hip and femoral neck during an average of 12 + 2 months (range 9–18 months) of abaloparatide therapy, and a significant decrease in T-score at the 1/3 radius. All patients received follow-up antiresorptive therapy, with 84.1% of patients receiving denosumab. After 1 year of antiresorptive therapy, significant increases in T-scores and BMD were seen at the total hip and lumbar spine, with nonsignificant changes in the femoral neck and 1/3 radius. There was one reported fracture during the evaluation period. Eighteen patients (19.8%) discontinued therapy due to an ADR. Conclusion Abaloparatide is effective in increasing BMD and T-scores and in preventing osteoporosis-related fractures. The fact that 37.7% of referred patients did not initiate therapy, indicates that significant barriers to anabolic osteoporosis treatment remain. Noteworthy, however, is the achieved 72.5% persistence rate of the patients initiating abaloparatide at this pharmacist-run anabolic osteoporosis clinic. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT158 Dimeric [Cys25]PTH(1-34) and Monomeric PTH(1-34) Differentially Regulate the Expression of Genes Related to Calcium Homeostasis in Bone and Kidney

Abstract Osteoporosis and its resulting fractures threaten health and life of many patients worldwide; therefore, the development of effective and safe drugs for osteoporosis is an urgent need. In our previous report, dimeric [Cys25]PTH(1-34) peptide with arginine-to-cysteine mutation at position 25 (Dimer) showed a substantial osteo-anabolic effect similar or superior to that of PTH(1-34) in several mouse models. Surprisingly, cAMP was not elevated in serum or urine the Dimer-treated group unlike in the PTH(1-34)-treated group. From this, we hypothesized that the Dimer stimulates anabolic responses through a signaling pathway different from the cAMP-PKA pathway. To test this hypothesis, we assessed responses down-stream of the activated signal cascade from PTHR1 using GPCR Phospho Antibody Array in cells, as well as the expression levels of mRNAs and proteins related to calcium metabolism in bones and kidneys of mice. Cell lysates obtained from GP2.3 cells (treated with PTH(1-34) and Dimer with PBS as a control) were applied to the GPCR-MAPK Pathway Phosphorylation Antibody Array (Full Moon BioSystems, USA), containing 193 antibodies. Each of the antibodies has 6 replicates that are printed on standard-size coated glass microscope slides. The results of the Phospho-antibody array were further confirmed by Western Blot assay. Eighteen CD1 mice of 9 WO were divided into three groups: control, PTH(1-34)-treated, and Dimer-treated groups. 40 µg/kg of PTH(1-34) and 80 µg/kg of the Dimer were subcutaneously injected for each of the experimental groups, respectively. Then, two hours after the injection, the animals were sacrificed, and their kidneys and tibiae were harvested. Total mRNA samples from kidneys and tibiae were extracted using trizol reagent. Protein samples were extracted via protein extraction buffer. We estimated mRNA and protein levels of biomarkers related to calcium regulation via RT-PCR and ELISA with harvested bone and kidney tissues. Several changes of phosphorylation of signaling proteins in GP2.3 cells were detected between Dimer-treated group and PTH(1-34)-treated group. Expression of mRNA and protein levels of RANKL was lower in the Dimer-treated group compared to the PTH(1-34)-treated group. In contrast, expression of mRNA level of OPG in tibia samples was lower in the Dimer-treated group. In kidney, the mRNA and protein levels of 1α(OH)ase in the Dimer-treated group were lower than in the PTH(1-34)-treated group. However, mRNA level of 24(OH)ase was higher in the Dimer-treated group than in the PTH(1-34)-treated group. Other parameters were not significantly different between the Dimer-treated and PTH(1-34)-treated groups. We speculate that the osteoanabolic effect of Dimer uses a signaling pathway different from the cAMP-PKA pathway, regulating different expression parameters related to calcium metabolism in both the bone and kidney. Further studies are required to define exact signaling pathway that Dimer acts on. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

What is the Risk of Developing Osteonecrosis Following Dental Extractions for Patients on Denosumab for Osteoporosis?

Osteonecrosis of the jaws (ONJ) occurs in patients on antiresorptive drugs for osteoporosis with the risk with oral bisphosphonates being known to be of the order of 0.1 to 0.3% while the risk for patients on denosumab for osteoporosis is not known. The aim of this study was to determine the risk of developing ONJ in a consecutive series of patients on denosumab for osteoporosis having dental extractions. A prospective cohort study of patients on denosumab for osteoporosis having dental extractions in the period January 1, 2017 and June 30, 2021 were compared to a control group not on antiresorptives. Detailed demographic records including length of time on antiresorptives and CTX values were obtained. Comparison to further define risk factors was made between those patients developing ONJ to those who didn't. The treatment group included 427 patients who were on denosumab for osteoporosis; they collectively underwent 561 episodes of dental treatment involving extractions for a total of 1081 extractions, with 10 developing ONJ (risk 2.3%). The control group consisted of 299 patients who were not taking denosumab; they collectively underwent 315 episodes of dental treatment for a total of 669 extractions, and none of them developed ONJ. There were significant differences in age and sex, but not medical comorbidities between the treatment and control groups. Within the treatment group, there were no significant differences in any of these characteristics between those who did, and those who didn't, develop ONJ. Within the treatment group, the number of extractions modified the risk of developing ONJ (odds ratio, 1.35; confidence interval, 1.1-1.7). Of the 76 patients who had extractions between 6 and 7months after the last denosumab injection, none developed ONJ. The risk of ONJ in patients on denosumab for osteoporosis is a magnitude greater than for patients on the oral bisphosphonates 2.3% v 0 - 0.3%, which is 7.7 times more likely. Number of extractions and early resumption of the next dose of denosumab increases the risk of ONJ.

Osteoclast and Sclerostin Expression in Osteocytes in the Femoral Head with Risedronate Therapy in Patients with Hip Fractures: A Retrospective Comparative Study.

Background and Objectives: The majority of research on the effects of osteoporosis drugs has measured the bone mineral density (BMD) of the spine and femur through dual-energy X-ray absorptiometry (DEXA) and compared and analyzed the effects of the drugs through changes in the BMD values. This study aims to compare osteoclast and sclerostin expression in osteocytes after risedronate therapy by obtaining femoral heads from patients with hip fractures. Materials and Methods: We obtained the femoral heads of 10 female patients (age: ≥65 years) who received risedronate therapy for at least 1 year through hip arthroplasty during 2019-2021 (risedronate group). Meanwhile, 10 patients who had never received osteoporosis treatment were selected as controls using propensity scores with age, body mass index, and bone density as covariates (control group). While the osteoclast count was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, the sclerostin expression in osteocytes was assessed using immunohistochemistry. Moreover, Western blotting and polymerase chain reaction (PCR) were performed for receptor activation of nuclear factor kappa-Β ligand (RANKL), RANK, osteoprotegerin (OPG), sclerostin, and bone morphogenetic protein-2 (BMP2). Results: TRAP staining revealed significantly more TRAP-positive cells in the control group (131.75 ± 27.16/mm2) than in the risedronate group (28.00 ± 8.12/mm2). Moreover, sclerostin-positive osteocytes were expressed more in the control group (364.12 ± 28.12/mm2) than in the risedronate group (106.93 ± 12.85/mm2). Western blotting revealed that the expressions of RANKL, RANK, sclerostin, and BMP2 were higher in the control group than in the risedronate group (p &lt; 0.05). Furthermore, RANK, sclerostin, and OPG protein levels were higher in the control group than in the risedronate group. Conclusions: In this study, the risedronate group demonstrated lower osteoclast activity and sclerostin expression in osteocytes in the femoral head than the control group.

Topical application of the plant extract SDTL-E in ovariectomized rats: A potential new approach for treating osteoporosis.

Current osteoporosis medications have drawbacks of causing side effects and having slow onset, therefore developing osteoporosis drugs with faster onset and less side effects is essential. This study investigated the effects of the natural plant extract, SDTL-E, in ovariectomized (OVX)-induced osteoporosis rats. Rats were randomly assigned to sham operation control group (Control Group); OVX rat model group (Model Group) or OVX rat SDTL-E treatment group (SDTL-E Group). All groups underwent ovariectomy, but the Control Group did not have the ovaries removed. SDTL-E Group was treated with SDTL-E, Model and Control Groups were treated with vegetable oil, treatments were topically applied twice daily for 20 days. Results showed when compared with Model Group, SDTL-E Group significantly restored serum estradiol back to near Control Group level, serum ALP activity, serum and urinary calcium were significantly decreased, bone mechanics indicators increased and trabecular bone numbers slightly increased. These results demonstrated 20 days of SDTL-E topical treatment improved bone strength and trabecular bone structure in OVX-induced osteoporosis rats. The underlying mechanisms include restoring estradiol level, reducing bone turnover, net bone resorption, bone calcium loss, and calcium excretion through kidney. These findings suggest topical application of plant extract is a potential new approach with quick efficacy for treating osteoporosis.

The role of melatonin in the development of postmenopausal osteoporosis.

Melatonin is an important endogenous hormone that modulates homeostasis in the microenvironment. Recent studies have indicated that serum melatonin levels are closely associated with the occurrence and development of osteoporosis in postmenopausal women. Exogenous melatonin could also improve bone mass and increase skeletal strength. To determine the underlying mechanisms of melatonin in the prevention and treatment of postmenopausal osteoporosis, we performed this review to analyze the role of melatonin in bone metabolism according to its physiological functions. Serum melatonin is related to bone mass, the measurement of which is a potential method for the diagnosis of osteoporosis. Melatonin has a direct effect on bone remodeling by promoting osteogenesis and suppressing osteoclastogenesis. Melatonin also regulates the biological rhythm of bone tissue, which benefits its osteogenic effect. Additionally, melatonin participates in the modulation of the bone microenvironment. Melatonin attenuates the damage induced by oxidative stress and inflammation on osteoblasts and prevents osteolysis from reactive oxygen species and inflammatory factors. As an alternative drug for osteoporosis, melatonin can improve the gut ecology, remodel microbiota composition, regulate substance absorption and maintain metabolic balance, all of which are beneficial to the health of bone structure. In conclusion, our review systematically demonstrates the effects of melatonin on bone metabolism. Based on the evidence in this review, melatonin will play a more important role in the diagnosis, prevention and treatment of postmenopausal osteoporosis.

Drug-Inclusive Inorganic-Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate.

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr2+ and Ba2+) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr2+ or Ba2 and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.

Osteoporosis Treatment After Osteoporotic Fractures: Data From a Single Medical Center

ObjectiveMost patients do not receive osteoporosis treatment after osteoporotic fracture. This study reviewed osteoporosis treatment after osteoporotic fractures in a center without a Fracture Liaison Service. MethodsWe identified all patients with hip, vertebral, humeral or radial fractures, evaluated in Meir Medical Center, in 2017. The exclusion criteria were not a Clalit Health Services member, high-energy fracture or 30-day postoperative mortality. The primary endpoint was osteoporosis drugs issued within 12 months of fracture. Secondary endpoints included bone densitometry and 1-year mortality. ResultsFive-hundred-eighty-two patients (average age 78.6 ± 11.1 years, 75.8% women) were included. There were 321 (55.5%) hip, 84 (14.1%) humeral, 33 (5.6%) vertebral, and 144 (24.7%) radial fractures. Osteoporosis drugs were issued to 26.5% of the patients; those with humeral fractures received the least (21.4%) and vertebral, the most (30.3%; P = .51). Bone densitometry was performed in 23.2% of patients. One-year mortality after hip fracture was 12.1%, followed by humeral (3.6%; P < .05). Logistic regression showed that previous treatment (odds ratio [OR] = 7.4; 95% confidence interval [CI] 3.6–15.2), bone densitometry (OR = 4.4; 95% CI 2.6–7.4) and endocrinology visit (OR = 2.6; 95% CI, 1.4–4.6) were the most important factors associated with treatment. ConclusionFewer than one third of patients received pharmacotherapy within 1 year after fracture. Because pharmacotherapy reduces future fractures and mortality, we recommend that medical staff who care for patients with fracture adopt practical and effective strategies to increase treatment rates among patients with osteoporotic fractures.

Study quantifies risk of depression, anxiety with osteoporosis drugs

Study quantifies risk of depression, anxiety with osteoporosis drugs

Evaluation of intravenous zoledronic acid-induced acute-phase response in the emergency department

Background/Aim: A temporary influenza-like condition, called acute-phase reaction (APR), is commonly observed with intravenous (IV) administration of nitrogen-containing amino bisphosphonates, such as zoledronic acid (ZOL). This single-center study aimed to evaluate the incidence of APR symptoms after intravenous (IV) ZOL administration in patients with postmenopausal osteoporosis who were admitted to emergency department (ED).&#x0D; Methods: In this cross-sectional study, 107 osteoporotic patients who were diagnosed with post-menopausal osteoporosis (bone mineral density T-score equal to or below −2.5 with/without prevalent fractures) and who had an ED admission in the first 72 h after intravenous injection of ZOL were included in the study. The patient’s pre-treatment blood sample measurements, presenting symptoms (such as fever, fatigue, hyperpyrexia, headache), family history, previous medical treatment, and adverse effects caused by osteoporosis drugs, in addition to information on co-morbidities and comedications were obtained from clinical records.&#x0D; Results: One-hundred seven osteoporotic patients (19.56%) patients experienced APR and were admitted to the ED after IV-ZOL administration. The mean age was 64.58 (11.15) years (n = 107). The three most commonly reported symptoms were diffuse musculoskeletal symptoms, influenza-like illness, and gastrointestinal symptoms (34.5%, 21.5%, and 18.5%, respectively). Seventy percent of the patients who presented to the ED with APR symptoms were prescribed drugs only, and 30% of the patients received treatment specific for their symptoms in the ED. Most of the diffuse musculoskeletal symptoms consisted of myalgia (22.4%). A positive correlation between the onset time of APR symptoms and the number of IV bisphosphonate (BP) doses was found (r = 0.597; P = 0.032).&#x0D; Conclusion: Our study indicates that as the number of IV-ZOL administrations increase yearly in patients with osteoporosis, symptom onset time occurs later. A linear relationship was found between the number of drug applications and the duration of symptoms. Also, the incidence of APR following IV-ZOL administration was 19% in the osteoporotic patient population who presented to the ED or to other clinics according to the symptoms.

Mechanistic PK-PD model of alendronate treatment of postmenopausal osteoporosis predicts bone site-specific response.

Alendronate is the most widely used drug for postmenopausal osteoporosis (PMO). It inhibits bone resorption, affecting osteoclasts. Pharmacokinetics (PK) and pharmacodynamics (PD) of alendronate have been widely studied, but few mathematical models exist to simulate its effect. In this work, we have developed a PK model for alendronate, valid for short- and long-term treatments, and a mechanistic PK-PD model for the treatment of PMO to predict bone density gain (BDG) at the hip and lumbar spine. According to our results, at least three compartments are required in the PK model to predict the effect of alendronate in both the short and long terms. Clinical data of a 2-year treatment of alendronate, reproduced by our PK-PD model, demonstrate that bone response is site specific (hip: 7% BDG, lumbar spine: 4% BDG). We identified that this BDG is mainly due to an increase in tissue mineralization and a decrease in porosity. The difference in BDG between sites is linked to the different loading and dependence of the released alendronate on the bone-specific surface and porosity. Osteoclast population diminishes quickly within the first month of alendronate treatment. Osteoblast population lags behind but also falls due to coupling of resorption and formation. Two dosing regimens were studied (70 mg weekly and 10 mg daily), and both showed very similar BDG evolution, indicating that alendronate accumulates quickly in bone and saturates. The proposed PK-PD model could provide a valuable tool to analyze the effect of alendronate and to design patient-specific treatments, including drug combinations.