Gprc5a is a novel parathyroid hormone-inducible gene and negatively regulates osteoblast proliferation and differentiation.

Teriparatide is a peptide derived from a parathyroid hormone (PTH) and an osteoporosis therapeutic drug with potent bone formation-promoting activity. To identify novel druggable genes that act downstream of PTH signaling and are potentially involved in bone formation, we screened PTH target genes in mouse osteoblast-like MC3T3-E1 cells. Here we show that Gprc5a, encoding an orphan G protein-coupled receptor, is a novel PTH-inducible gene and negatively regulates osteoblast proliferation and differentiation. PTH treatment induced Gprc5a expression in MC3T3-E1 cells, rat osteosarcoma ROS17/2.8 cells, and mouse femurs. Induction of Gprc5a expression by PTH occurred in the absence of protein synthesis and was mediated primarily via the cAMP pathway, suggesting that Gprc5a is a direct target of PTH signaling. Interestingly, Gprc5a expression was induced additively by co-treatment with PTH and 1α, 25-dihydroxyvitamin D3 (calcitriol), or retinoic acid in MC3T3-E1 cells. Reporter analysis of a 1 kb fragment of human GPRC5A promoter revealed that the promoter fragment showed responsiveness to PTH via the cAMP response element, suggesting that GPRC5A is also a PTH-inducible gene in humans. Gprc5a knockdown promoted cell viability and proliferation, as demonstrated by MTT and BrdU assays. Gprc5a knockdown also promoted osteoblast differentiation, as indicated by gene expression analysis and mineralization assay. Mechanistic studies showed that Gprc5a interacted with BMPR1A and suppressed BMP signaling induced by BMP-2 and constitutively active BMP receptors, ALK2 (ACVR1) Q207D and ALK3 (BMPR1A) Q233D. Thus, our results suggest that Gprc5a is a novel gene induced by PTH that acts in an inhibitory manner on both cell proliferation and osteoblast differentiation and is a candidate for drug targets for osteoporosis.

Treatment for Gorham-Stout syndrome with a combination of teriparatide and denosumab.

Gorham-Stout syndrome is an aggressive, non-hereditary, and rare disease affecting bone metabolism. Its etiology and pathogenesis remain elusive. The syndrome manifests with diverse clinical symptoms, often leading to frequent misdiagnoses and presenting challenges in treatment. In this study, we report a case of cranial and maxillary osteolysis in a 47-year-old female patient with somatic mutations in the VEGF-A, VEGF-B, and VEGF-C genes and the EPHB4 gene. After treatment with bisphosphonates, this patient still had persistent resorption of the mandible, but switching to a teriparatide and denosumab combination yielded substantial improvement. This study is the first report to show that teriparatide combined with denosumab can be used to treat Gorham-Stout syndrome.

Real-world efficacy of a teriparatide biosimilar (RGB-10) compared with reference teriparatide on bone mineral density, trabecular bone score, and bone parameters assessed using quantitative ultrasound, 3D-SHAPER® and high-resolution peripheral computer tomography in postmenopausal women with osteoporosis and very high fracture risk.

A retrospective analysis comparing a teriparatide biosimilar (RGB-10) with reference teriparatide for osteoporosis treatment in postmenopausal women at high fracture risk found them to be therapeutically equivalent. Both provided significant improvements in lumber spine BMD, TBS, and other parameters of bone health, assessed using multiple diagnostic methods. PURPOSE: To compare the therapeutic efficacy of a teriparatide biosimilar (RGB-10) with reference teriparatide for the treatment of osteoporosis in postmenopausal women at very high fracture risk. METHODS: A retrospective analysis of 25 postmenopausal female patients treated for osteoporosis with RGB-10 for 24 months and a matched cohort of 25 patients treated with reference teriparatide. The following outcomes were assessed at baseline, 12 and 24 months: bone mineral density (BMD) at the lumbar spine, femoral neck and total hip using dual-energy x-ray absorptiometry (DXA) and integral, trabecular and cortical volumetric and surface BMD using 3D-SHAPER® imaging, trabecular bone score (TBS), quantitative ultrasound (QUS) measurements, and high-resolution peripheral quantitative computed tomography (HRpQCT) imaging of the radius and tibia. RESULTS: No significant differences were observed between treatment groups in any of the measured parameters of BMD or bone health at baseline as well as in any timepoint when assessed using these various diagnostic methods. Both compounds provided equivalent significant improvements from baseline in measures of osteoporosis and fracture risk. CONCLUSION: The results of the analysis demonstrate the therapeutic equivalence of the teriparatide biosimilar (RGB-10) to reference teriparatide for the treatment of osteoporosis in postmenopausal women at very high risk of fracture.

Delayed and significant hypercalcaemia due to teriparatide therapy: a case report and review.

INTRODUCTION: Transient hypercalcaemia due to teriparatide occurs in up to 11% of patients though delayed hypercalcaemia (> 24 h post injection) is rare. We report the case of a female who developed significant delayed hypercalcaemia after teriparatide treatment for osteoporosis and review other cases in the literature to date. CASE REPORT: A 72-year-old female on teriparatide for the treatment of osteoporosis was found to have hypercalcaemia (3.30 mmol/l) on routine testing approximately 3 months after starting therapy. Serum calcium pretreatment was normal at 2.39 mmol/l. She was admitted to the hospital for investigations which identified a serum 25-hydroxyvitamin D of 94 nmol/l, a low parathyroid hormone of 6.0 pg/ml, and normal test results for 1,25 dihydroxyvitamin D (115 pmol/l), parathyroid hormone-related peptide (< 1.4 pmol/ml), serum electrophoresis and angiotensin-converting enzyme (39 IU/l). CT abdomen, pelvis, and thorax revealed no evidence of malignancy and an isotope bone scan ruled out skeletal metastases. Serum calcium normalised (2.34 mmol/l) several days after stopping teriparatide and calcium supplements and administering intravenous fluid. On restarting teriparatide, delayed hypercalcaemia reoccurred and treatment was switched to denosumab. DISCUSSION: Delayed moderate to severe hypercalcaemia (serum calcium > 3.0 mmol/l) due to teriparatide is rare but may lead to therapy withdrawal. The underlying predisposing risk factors remain unclear and highlight the importance of a routine serum calcium assessment on therapy.

Comparison of radiological and functional outcomes of conservative treatment with teriparatide and denosumab in thoracolumbar osteoporotic vertebral fracture.

Teriparatide and denosumab, anti-osteoporosis medications with different mechanisms, have been widely used in the patients with osteoporotic vertebral fracture (OVF) considered as advanced osteoporosis. Teriparatide has been shown to enhance bone formation and fracture healing in OVF, but there are still no sufficient evidences discussing about the role of denosumab in newly developed OVF. In this study, we found the similar radiological deformation and functional outcomes of conservative treatment with teriparatide and denosumab in thoracolumbar (TL) OVF, and teriparatide showed a more frequent incidence of fracture union with paravertebral bone bridge formation compared to denosumab. INTRODUCTION: Teriparatide and denosumab have been widely used to treat advanced osteoporosis and prevent subsequent fractures in patients with OVCF. Unlike teriparatide, which is considered to be effective in fracture healing, there is still no clear role and evidence for the effect of denosumab in acute OVCF. This study compared the radiological and functional outcomes of conservative treatment with teriparatide and denosumab in TL-OVF. METHODS: This retrospective study enrolled 78 women with mean age of 74.69 ± 7.66 (60-92) years diagnosed as a TL-OVF with no neurological deficits. All patients were treated conservatively with teriparatide (34 of group T, once-daily 20 µg) or denosumab (44 of group D, once-6 months 60 mg) for 6 months. We evaluated the radiological deformation (kyphotic angle, segmental vertebral kyphotic angle, and compression ratio) and the incidence of fracture union with paravertebral bone bridge formation (FUPB) and functional outcomes using the visual analog scale (VAS) and Oswestry Disability Index (ODI) at 0, 3, and 6 months. RESULTS: In the radiological deformation and functional outcomes, there were no significant differences at 0, 3, and 6 months between the two groups (P > 0.05). However, the incidence of FUPB at 6 months was higher in group T (20/34, 58.8%) compared to group D (11/44, 25.0%) (P = 0.004), and teriparatide was the most statistically significant factor for achieving FUPB (OR 4.486, P = 0.012) in multivariable logistic analysis. CONCLUSIONS: Teriparatide and denosumab, despite of their different pharmacological mechanisms, showed similar radiological deformation and functional outcomes in the conservative treatment of TL-OVF. However, teriparatide showed a significantly higher incidence of fracture union with paravertebral bone bridge formation.

Teriparatide Does not Have Beneficial Effects on Bone Healing in Complete Atypical Femur Fractures.

Teriparatide is an anabolic drug sometimes administered to patients who have atypical femoral fracture (AFF). However, whether teriparatide has beneficial effects on bone healing remains uncertain. The present study aimed to analyze the association between teriparatide and bone healing in complete AFF. A total of 59 consecutive cases (58 patients) who underwent intramedullary nailing for complete AFF were categorized based on postoperative use of teriparatide into the non-teriparatide (non-TPTD, n = 34) and teriparatide groups (TPTD, n = 25). Time-to-bone union was evaluated and compared between the two groups. Additionally, multiple regression analysis was performed to evaluate factors affecting time-to-bone union. All participants were women, with a mean age of 77.6 years (range: 62-92). No significant difference in time-to-bone union was found between the non-TPTD and TPTD groups (5.5 months vs. 5.8 months, p = 0.359). Two patients in the non-TPTD group underwent reoperation (p = 0.503) due to failure caused by inadequate fixation, and both achieved bone healing after additional fixation with blocking screws. Multiple regression analysis revealed that the anterior gap of the fracture site postoperatively was a factor affecting time-to-bone union (p = 0.014). The beneficial effect of teriparatide on bone healing in complete AFF could not be confirmed. Additional randomized controlled trials are required. Nonetheless, appropriate techniques, including efforts to reduce the gap on the tensile side during the surgery, are important for reliable bone healing.

Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-ß antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.

Predictors of discontinuation of osteoporosis treatment: sub-analysis of the Japanese osteoporosis intervention trial-05 (JOINT-05).

INTRODUCTION: To identify predictors of discontinuing treatment with teriparatide (TPTD) and alendronate (ALN), data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high risk of fracture were re-analyzed. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks followed by ALN for 48 weeks (TPTD-ALN group) or monotherapy with ALN for 120 weeks (ALN group). Background data including comorbidities, fracture prevalence, cognitive function, quality of life, activities of daily living, bone metabolism parameters, and nutrient intake were collected. The endpoints were 3 types of discontinuations by the reason: a poor compliance, adverse events (AEs), or any reason including those unrelated to AEs or poor compliance. Odds ratios (ORs) of baseline predictors of discontinuation were evaluated by single or multiple regression analysis. RESULTS: A total of 234 (49.0%) patients in the TPTD-ALN group and 167 (34.2%) patients in the ALN group discontinued. In the TPTD-ALN group, a lower serum calcium level was a significant predictor of compliance-related discontinuation. Serum 25-hydroxyvitamin D levels were lower in patients with lower serum calcium levels than with higher serum calcium levels. In the ALN group, poor cognitive function was significantly associated with compliance-related discontinuation, and higher body mass index and alcohol intake were predictors of AE-related discontinuation. Predictors of discontinuation were drug-specific. Lower serum calcium levels and poor cognitive function were predictors of discontinuing once-weekly TPTD and ALN, respectively. CONCLUSION: When starting TPTD and ALN treatment, careful attention to patients with lower serum calcium levels and poor cognitive function, respectively, may be needed for better treatment continuity.

Clinical effects of teriparatide, abaloparatide, and romosozumab in postmenopausal osteoporosis.

In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

Achieving osteoporosis treat-to-target goals with teriparatide or alendronate: sub-analysis of Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: The purpose of this study was to evaluate whether bone mineral density (BMD) ≥ -2.5 SD could be used as the treat-to-target (T2T) goal when treating osteoporosis with teriparatide (TPTD) and alendronate (ALN), and to investigate the relationship with incident vertebral fracture by re-analyzing data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high fracture risk. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks, followed by ALN for 48 weeks (TPTD-ALN group) or ALN monotherapy for 120 weeks (ALN group). BMDs were measured at the lumbar spine (L2-4), total hip, and femoral neck at 0, 24, 48, 72, and 120 weeks by dual-energy X-ray absorptiometry. The T2T goal was BMD ≥ -2.5 SD, and the endpoint was the proportion of participants with baseline BMD < -2.5 SD in three measurement sites achieving BMD ≥ -2.5 SD. RESULTS: A total of 559 participants were selected. BMD ≥ -2.5 SD at 120 weeks in the L2-4, total hip, and femoral neck sites was achieved in 20.5%, 23.1%, and 5.9%, respectively, in the TPTD-ALN group and 22.2%, 11.7%, and 7.3%, respectively, in the ALN group. Incident vertebral fractures occurred in areas of both lower and high BMD. CONCLUSION: During the 1.5-year treatment period, more than 20% of participants achieved BMD ≥ -2.5 SD as a T2T goal at L2-4. Since the achievement level differed depending on the BMD measurement site, the appropriate site should be selected according to the baseline BMD level.

Systematical mutational analysis of teriparatide on anti-osteoporosis activity by alanine scanning.

Osteoporosis is a progressive systemic skeletal disease that decreases bone density and bone quality, making them fragile and easy to break. In spite of effective anti-osteoporosis potency, teriparatide, the first anabolic medications approved for the treatment of osteoporosis, was proven to exhibit various side effects. And the relevant structure-activity relationship (SAR) of teriparatide was in need. In this work, we performed a systematical alanine scanning against teriparatide and synthesized 34 teriparatide derivatives. Their biological activities were evaluated and the importance of each residue for anti-osteoporosis activity was also revealed. A remarkable decrease in activity was observed for alanine replacement of the residue Gly12, His14, Ser17, Arg20 and Leu24, showcasing the important role of these residues in teriparatide on anti-osteoporosis activity. On contrary, when Gly13 and Gln30 were mutated to Ala, the peptide derivatives exhibited the significantly increased activities, demonstrating that these two residues could be readily replaced. Our research expanded the peptide library of teriparatide analogues and presented a potential opportunity for designing the more powerful anti-osteoporosis peptide agents.

Differential effects of teriparatide, denosumab and zoledronate on hip structural and mechanical parameters in osteoporosis; a real-life study.

PURPOSE: The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting. METHODS: We studied 249 patients with osteoporosis (OP) with mean [SD] age of 71.5 [11.1] years divided into 3 treatment groups; Group A received TPD; n = 55, Group B (Dmab); n = 116 and Group C (ZOL); n = 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 [1.3] years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS). RESULTS: Changes in parameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.56[1.6] % p = 0.01 and cross-sectional moment of inertia (CSMI): 4.1[1.8] % p = 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.3[0.67]% p < 0.001, cortical thickness (Co Th): 2.8[0.78]% p = 0.001, CSMI: 5.9[1.3]% p < 0.001, section modulus (Z):6.2[1.1]% p < 0.001 and buckling ratio (BR): - 3.0[0.86]% p = 0.001 with small changes at the FS: CSA: 1.2[0.4]% p = 0.005, Z:1.6 [0.76]%, p = 0.04. Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.5[0.77]% p = 0.017, Co Th: 2.4[0.84]% p = 0.012, CSMI: 3.9[1.3]% p = 0.017, Z:5.2[1.16]% p < 0.001 and BR: - 3.1[0.88]% p = 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.0[1.4]% p = 0.0005, endocortical diameter(ED): 4.3[1.67% p = 0.009, CSA:5.2[1.8]% p = 0.003, CSMI: 9.3[3.8]% p = 0.019. CONCLUSIONS: Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.

Report of a collaborative study to establish the first Indian Pharmacopoeia reference standard for teriparatide.

A collaborative study was conducted to establish the first Indian Pharmacopoeia Reference Standard (IPRS) for teriparatide to be used in quality control testing of marketed products in compliance with the Indian Pharmacopoeia (IP) monograph. The study objective was to evaluate the candidate standard in terms of the WHO International Standard (IS) to assign its content in mg per vial terms. This study involved four laboratories from India and the candidate standard was calibrated against the WHO IS by each participant laboratory using high-performance liquid chromatography (HPLC) assay method per IP monograph. Direct calibration of the candidate standard resulted in an assigned content of 1.02 mg per vial. Based on the study results the candidate standard was judged suitable to serve as the first IPRS for teriparatide for identification and assay by HPLC.

Teriparatide alone versus vertebroplasty on pain control and radiographic outcomes after osteoporotic vertebral compression fracture.

PURPOSE: To investigate efficacy of 3-month teriparatide(TPD) and compare this treatment with vertebroplasty in terms of clinical and radiographic outcomes after osteoporotic vertebral compression fractures (OVCFs). METHODS: This is a retrospective matched cohort study. Patients who received conservative treatment with at least 3-month TPD treatment for acute OVCF with at least 6 months follow-up were included. Each enrolled TPD case was matched with 2 vertebroplasty cases using age and gender. 30 TPD cases and 60 vertebroplasty cases were enrolled. Patient-reported pain scores were obtained at diagnosis and 1, 3, 6 months after diagnosis. Radiographic parameters including middle body height, posterior body height, wedge angle and kyphotic angle were measured at diagnosis and 6 months after diagnosis. Fracture non-union and subsequent vertebral fracture were evaluated. RESULTS: TPD treatment showed inferior pain relief to vertebroplasty group at 1 month, but did not show difference at 3 and 6 months after diagnosis. In TPD cases, progression of vertebral body collapse was noted in terms of middle body height and wedge angle at final follow up. Instead, both middle body height and wedge angle increased significantly after operation in the vertebroplasty group. Fracture non-union was confirmed via MRI and 4 TPD patients were diagnosed with non-union (4/30, 13.3%). Subsequent compression fracture within 6 months was significant higher in vertebroplasty group (12/60, 20%) than in TPD group (1/30, 3.3%). CONCLUSION: In acute OVCFs, 3-month TPD treatment alone showed comparable pain improvement and less subsequent spine fracture than vertebroplasty.

Low-Intensity Pulsed Ultrasound Maintains Bone Mass After Withdrawal of Human Parathyroid Hormone in Ovariectomized Mice.

The intermittent injection of teriparatide, a recombinant fragment of human parathyroid hormone (PTH 1-34), activates anabolic activity on bone turnover. However, the PTH administration period is limited to 2 years. Thus, sequential therapy after discontinuation of PTH is required. Low-intensity pulsed ultrasound (LIPUS) has been widely used for bone fracture healing. In this study, we examined the effects of LIPUS on bone mass after PTH withdrawal in ovariectomized (OVX) model mice. The LIPUS-non-irradiated femoral trabecular bone mineral density (BMD) in the treated after PTH withdrawal was significantly decreased. Meanwhile, the femoral BMD in the OVX + PTH-LIPUS group was remarkably higher than that of the OVX group. Additionally, mRNA expression of Runx2, Osterix, Col1a1, and ALP increased significantly following LIPUS irradiation after PTH withdrawal. These results suggest that LIPUS protected against femoral trabecular BMD loss and up-regulated the osteogenic factors following PTH withdrawal in OVX mice.

Recommendations for the optimal use of bone forming agents in osteoporosis.

Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.

Analyzing the factors associated with efficacy among teriparatide treatment in postmenopausal women with osteoporosis.

BACKGROUND: Teriparatide (TPTD) is a widely used anabolic agent for the treatment of osteoporosis. Several factors have been identified to be related to bone mineral density (BMD) increase in anti-osteoporosis treatment with other agents; however, there has been no systematic analysis to summarize the associated determinants of BMD reaction to daily teriparatide treatment. METHODS: In this retrospective study, we performed a comprehensive investigation involving not only clinical data but also several relevant lifestyle factors to be examined for their potential contribution to BMD response. This post-hoc analysis included 258 post-menopaused patients with osteoporosis who received TPTD at 20 µg/day for 12 months. Univariate and multivariate analyses were conducted to distinguish the response variables of lumbar spine (LS) BMD transformation, the principal outcome measure of efficacy, from the baseline at 12 months. RESULTS: Twelve months of TPTD treatment resulted in an absolute 0.39 ± 0.37 increase in T-score of LS BMD. Gastrointestinal disease, prior bisphosphonate or glucocorticoid treatment, no vitamin K2 supplementation, low levels of serum 25(OH)D and PINP, weak increment of PINP and ß-CTX at 3 months, unhealthy lifestyle (excessive smoking, tea, coffee, and drinking), vegetarian diet pattern, low ALT level, and high BMD at baseline were determined by univariate analyses to be related to the weak reaction of TPTD treatment (P < 0.10). In the multiple regression model, postmenopausal women with vitamin K2 supplementation, higher baseline serum 25(OH)D level, and higher PINP concentration at 3 months indicated a good reaction of LS BMD at 12 months (P < 0.05). Patients with gastrointestinal disease, prior bisphosphonate and glucocorticoid treatment, vegetarian diet pattern, and higher baseline BMD were significantly more likely to have a lower absolute LS BMD response compared to patients without these characteristics (P < 0.05). Further analysis confirmed the negative effect of unhealthy lifestyle on TPTD treatment. CONCLUSION: Our results emphasize the significance of a comprehensive assessment of clinical or lifestyle-related characteristics of postmenopausal women with osteoporosis in the management of TPTD therapy in routine care.

Therapeutic advantage of teriparatide in very elderly patients with proximal femoral fractures: a functional and BMD analysis.

BACKGROUND: Teriparatide, a recombinant parathyroid hormone, is pivotal in osteoporosis treatment, particularly in post-surgical recovery for hip fractures. This study investigates its efficacy in functional recovery post-hip fracture surgery in elderly patients, a demographic particularly susceptible to osteoporotic fractures. METHODS: In this retrospective cohort study, 150 elderly patients with proximal femoral fractures undergoing open reduction and internal fixation were enrolled. They were categorized into two groups: receiving 20 µg of daily teriparatide injections for 18 months and receiving standard antiresorptive medications during a 24-month follow-up. Detailed records of patient demographics, Fracture Risk Assessment Tool scores, and comorbidities were kept. Key outcomes, including bone mineral density (BMD) and functional scores (Barthel Index and Visual Analog Scale for hip pain), were evaluated at 3 and 24 months post-surgery. RESULTS: Out of the original cohort, 126 patients (20 men and 106 women with an average age of 85.5 ± 9.3 years) completed the study. The teriparatide group exhibited significant enhancements in both functional scores and BMD when compared to the control group. Notably, functional improvements were less pronounced in male patients compared to female patients. Additionally, the incidence of new fractures was markedly lower in the teriparatide group. CONCLUSION: Administering teriparatide daily for 18 months post-surgery for proximal femoral fractures significantly benefits very elderly patients by improving functionality and bone density, with observed differences in recovery between genders. These results reinforce the efficacy of teriparatide as a potent option for treating osteoporosis-related fractures in the elderly and highlight the importance of considering gender-specific treatment and rehabilitation strategies.

Gli1+ Progenitors Mediate Glucocorticoid-Induced Osteoporosis In Vivo.

For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1+ metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1+ MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1+ MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1+ MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1+ MMPs. Thus, Gli1+ MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.