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Published literature on physicians' preferences and sequential treatment patterns of osteoporosis therapy is scarce.A retrospective cohort study of patients who received bisphosphonates, denosumab, and/or raloxifene for at least 3 consecutive years or teriparatide for at least 18 months for osteoporosis. Data collection spanned 10 years, from October 2007 to September 2016, at a tertiary care center in the United States.In total, 12 885 patients were identified on the basis of receiving at least 1 treatment at any point in time; 1814 patients were randomly reviewed, and 274 patients met the inclusion criteria. The mean age was 68.8 ± 10.7 years, and women represented 90.9% of all the cases. Primary care physicians and rheumatologists constituted 65.7% and 22.6% of the prescribers, respectively. Before instituting a drug holiday, alendronate was the most common initial treatment (percentage, mean duration ± standard deviation in years: 69%, 5.4 ± 2.4 years) followed by ibandronate (9.5%, 4.9 ± 2.1 years) and raloxifene (9.1%, 5.2 ± 1.6 years). Denosumab was the most common second course of treatment, accounting for 29.3% of 82 patients who were subsequently prescribed another therapy, followed by alendronate (24.4%) and zoledronate (20.7%). Among patients who were placed on a drug holiday and eventually restarted on osteoporosis therapy, denosumab was the most common treatment instituted (n = 21), accounting for 40% of the total patients, followed by alendronate (32%) and zoledronate (16%). There was a progressive decline in osteoporosis therapy over the duration of the study.Alendronate was the most common initial therapy. Denosumab was the most common second course of treatment prescribed.

Background Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse side effect of antiresorptive agents. However, withdrawal of antiresorptive agents in patients with osteoporosis may increase the risk of fractures. The treatment of MRONJ is challenging and standard treatment guidelines have yet to be established. In this study, the aim was to examined whether adjunct daily or weekly teriparatide (TPTD) injections are beneficial for the bone exposure of MRONJ lesions compared to standard conservative management. We also studied the complications and patients’ responses to TPTD therapy. Methods We enrolled 27 patients, from January 2012 until December 2016, with chronic and refractory MRONJ. There were 4 men and 23 women, with 85% of the total number being females. Nine patients who did not select TPTD therapy for several reasons formed the non-TPTD group and the remaining 18 patients were randomly assigned to the daily (n=9) or weekly (n=9) groups. All subjects in both TPTD groups continued standard conservative therapy in addition to their daily or weekly subcutaneous injection of TPTD. The daily group received a daily injection of TPTD (20 μg) and the weekly group received a weekly injection of TPTD (56.5 μg). We evaluated the complications and benefits of TPTD therapy of MRONJ. Results Three patients in the daily group did not complete the study, resulting in six patients in the daily group, nine patients in the weekly group, and nine patients in the non-TPTD group for the final analysis. Each patient in TPTD group demonstrated complete coverage of the exposed bone with normal mucosa. The TPTD group showed a shorter healing period compared to the non-TPTD group. There were no complications of atypical fractures of the femoral head in any patient. Conclusions Daily and weekly TPTD treatment resulted in a shortened treatment period compared with standard conservative therapy with no increase in the rate of complications or worsening of osteoporosis.

The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50-70%, non-vertebral by 20-30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1-2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

The efficacy comparison of osteoporosis treatments can be hindered by the absence of head-to-head trials; instead, network meta-analyses (NMAs) have been used to determine comparative effectiveness. This study was the first to investigate the impact of time point-specific NMAs of osteoporosis treatments on variability in treatments' onset of action caused by their different mechanisms of actions and trial designs.A systematic literature review was conducted to identify randomized controlled trials (RCTs) of treatments for postmenopausal women with osteoporosis, including romosozumab (ROMO), teriparatide (TPTD), abaloparatide (ABL), alendronate (ALN), risedronate (RIS), ibandronate (IB), zoledronic acid/zoledronate (ZOL), denosumab (DEN), and raloxifene (RLX), on at least 1 fracture or bone mineral density (BMD) outcome. Of 100 RCTs identified in 5 databases, 27 RCTs were included for NMAs of new vertebral, nonvertebral, and hip fracture outcomes at 12, 24, and 36 months, and 47 RCTs were included for NMAs of BMD outcomes at lumbar spine, total hip, and femoral neck to compare the relative efficacy of osteoporosis treatments. Quality of included studies was assessed using the Cochrane Risk of Bias tool.For vertebral fractures, TPTD (83.63%), ABL (69.11%), and ROMO/ALN (78.70%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO/ALN had the highest probability (54.4%, 64.69%, and 90.29%, respectively) to be the most effective treatment for nonvertebral fractures at 12, 24, and 36 months. For hip fractures, ROMO/ALN (46.31%), ABL (61.1%), and DEN (55.21%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO had the highest probability (76.06%, 44.19%, and 51.78%, respectively) to be the most effective treatment for BMD outcomes at lumbar spine, total hip, and femoral neck.The importance of indirectly comparing available osteoporosis treatments using time point-specific NMAs was confirmed because indirect comparison results differed substantially across time points.

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group. In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.

The treatment of large segmental defects of long bones resulting from trauma, infection, or bone tumor resections is a major challenge for orthopedic surgeons. The reconstruction of bone defects with acellular allografts can be used as an osteoconductive approach. However, devitalized allografts are associated with high rates of clinical failure as a result of poor intrinsic osteoinduction properties and a lack of further remodeling. Nevertheless, evidence suggests that due to its anabolic properties, teriparatide (PTH1-34) could be effective as an adjuvant therapy for massive allograft healing. Therefore, our goal was to investigate in a murine critical-sized defect model whether the intermittent administration of PTH1-34 improves the incorporation and revitalization of acellular structural bone allografts. Thus, a 2.5-mm critical-sized defect was established in the right femur of C57BL/6 mice, followed by the reconstruction with a devitalized cortical structural allograft. A titanium micro locking plate was applied to the anterior femoral surface and secured in place with self-tapping locking screws. Subsequently, daily doses of PTH1–34 (30, and 40 µg/kg) or saline were administered to the mice for 14 days after surgery. The mice were maintained without PTH1–34 therapy for an additional 7 days before being euthanized at 3 weeks post-surgery. Bone graft consolidation was assessed on radiographic images and by histomorphometric analysis. Additionally, to determine the frequency of osteoprogenitor cells in the bone marrow and their in vitro osteogenic capacity, stromal cells were isolated from the bone marrow of animals treated with 30 or 40 µg/kg/day of PTH1-34 following the same protocol used for the experimental animals. Our results suggest that intermittent PTH1-34 treatment at 30 µg/kg/day after femoral allograft reconstruction surgery accelerated the healing process as evidenced by new bone formation induced on endosteal and periosteal surfaces, enhanced revitalization of allogeneic graft, and increased frequency and osteogenic capacity of bone marrow stromal cells (BMSC). These findings should encourage further studies aimed at investigating the potential therapeutic use of intermittent PTH1-34, specifically with regards to the optimal dosing regimen in clinically challenging orthopedic scenarios.

Medication-related osteonecrosis of the jaw (MRONJ) is a complex disease which can be associated with multiple morbidities and is challenging to treat. This review evaluates the literature on the role and efficacy of teriparatide (TPTD) as a treatment for MRONJ. The clinical, radiological, histopathological and serological parameters used to assess treatment response have been described. Electronic databases were searched to retrieve articles (April 2005 and April 2020) based on strict inclusion criteria. Seventeen articles were included in this review. Of the 91 patients treated; only six received TPTD as a standalone treatment. There were significant variations in defining treatment outcomes and measuring treatment response. The longest follow-up period was 26 months, and 12 studies failed to report follow-up. The overall quality of evidence is weak with potential for a high risk of bias, making it difficult to determine the efficacy of TPTD and its long-term effects. However, TPTD may play a role in the treatment of intractable MRONJ in osteoporotic patients or those unfit for surgery. Therefore, randomized clinical trials on larger patient cohorts with long-term follow-up is required to confirm efficacy, safety and inform treatment indications for TPTD in the treatment of MRONJ.

Objectives To assess differences in efficacy of a 28.2-μg teriparatide formulation for twice-weekly use (2/W-TPTD) by patient characteristics. Methods A post hoc analysis was performed using data from a multicenter, randomized, double-blind, double-dummy, non-inferiority trial (TWICE study) conducted in Japan comparing the efficacies of once-weekly and twice-weekly injections of teriparatide (TPTD). Specifically, a stratified analysis of percentage changes from baseline was performed using the final data on lumbar spine bone mineral density (BMD) after a 48-week treatment period (n = 251, 2/W-TPTD; n = 239, a 56.5-μg teriparatide formulation for once-weekly use [1/W-TPTD]). Results Across all subgroups defined by patient characteristics that included 9 or more subjects, the lumbar spine BMD increased significantly in both groups. In the 2/W-TPTD group, the percentage change was significantly higher in subjects with no non-vertebral fractures without large external force occurring at or after age 50 years versus those with such fractures. The lower the stratification in baseline lumbar spine BMD, total hip BMD, or femoral neck BMD, the greater was the percentage change. Conclusions Whereas all subgroups can expect a significant improvement in lumbar spine BMD, there were some patient characteristics that affected the percentage increase in BMD.

International audience; Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it possible to better characterize them and to propose attractive therapeutic approaches based on the underlying pathophysiology. These diseases are often at the interface between nephrology and endocrinology. In this spirit of a multidisciplinary care, each specialty can bring its own critical point of view and its own specificities to improve patient care. The objective of this manuscript is to "read" with a nephrologist's point of view the main frameworks of diseases of phosphate/calcium metabolism, to illustrate the three crucial messages of nephro-protection sent to endocrinologists. First, calciuria must be interpreted both in absolute value (concentration hypercalciuria) and in ratio (flow hypercalciuria). Second, renal monitoring of therapies inducing hypercalciuria on kidneys with normal renal function (e.g. active vitamin D analogs or teriparatide) should be systematic. Last, hyperphosphatemia, often latent in hypoparathyroidism and pseudo-hypoparathyroidism, should be detected and at least benefit from dietary measures, in the context of Western diets rich in phosphate hidden in food additives.

Background This article presents evidence and recommendations regarding the efficacy and safety of the approved and available therapies in Mexico to treat severe or established osteoporosis (OP) with the aim of developing a position regarding therapeutics in this stage of the disease, according to the descriptive cards of the National Drug Formulary of the National General Health Council of Mexico (CBCMSS). Methods We performed a systematic and narrative review of the evidence of teriparatide and denosumab, from their pharmacological profile, effectiveness, and safety derived from clinical trials, as well as an analysis of the general recommendations of the national and international clinical practice guidelines. Results The evidence establishes that teriparatide and denosumab belong to different therapeutic classes, with biologically opposed mechanisms of action and indications of use, which are clearly differentiated in their respective national codes, therefore these drugs cannot be substitutable or interchangeable in severe OP therapy. Both represent the best options currently available for this stage of the disease; being similar in their efficacy in preventing new vertebral fragility fractures, with an RR of .35 (CI = 95%, .22−.55) for teriparatide, and .32 (CI = 95%, .26−.41) for denosumab. The absolute risk reduction (RRR) is higher with teriparatide 9.3% (21 months) compared with denosumab at 4.8% (36 months). Conclusions Our results agree with the recommendations available in national and international clinical practice guidelines, with both therapies proposed as a sequential, but not a substitute, treatment.

espanolAntecedentes El presente articulo muestra la evidencia y recomendaciones de la eficacia y seguridad de las terapias hasta hoy aprobadas y disponibles en Mexico para el tratamiento de la osteoporosis en su etapa severa o establecida, con la finalidad de establecer una postura terapeutica acerca de la eficacia y seguridad para esta etapa del padecimiento, de acuerdo con las cedulas descriptivas del Cuadro Basico y Catalogo de Medicamentos del Sector Salud en Mexico. Metodos Se realizo una revision sistematica y narrativa de la evidencia de teriparatida y denosumab, desde su perfil farmacologico, efectividad y seguridad derivado de ensayos clinicos, ademas de un analisis de las recomendaciones generales de las principales guias de practica clinica nacionales e internacionales. Resultados La evidencia establece que teriparatida y denosumab pertenecen a clases terapeuticas distintas, con mecanismos de accion biologicamente opuestos e indicaciones de uso claramente diferenciadas en sus respectivas cedulas, por lo cual no son sustituibles ni intercambiables en la terapia de osteoporosis severa. Ambas representan la mejor opcion disponible hasta el momento para esta etapa del padecimiento. Son similares en su eficacia de prevencion de nuevas fracturas vertebrales por fragilidad, con un RR de 0,35 (IC 95%: 0,22-0,55) para teriparatida, y de 0,32 (IC 95%: 0,26-0,41) para denosumab. La reduccion absoluta del riesgo es mayor con teriparatida 9,3% (21 meses) que con denosumab 4,8% (36 meses). Conclusiones Nuestros resultados concuerdan con las recomendaciones disponibles en las principales guias de practica clinica nacionales e internacionales, por lo que son propuestas ambas terapias como consecutivas y nunca como sustitutivas. EnglishBackground This article presents evidence and recommendations regarding the efficacy and safety of the approved and available therapies in Mexico to treat severe or established osteoporosis with the aim of developing a position regarding therapeutics in this stage of the disease, according to the descriptive cards of the National Drug Formulary of the National General Health Council of Mexico. Methods We performed a systematic and narrative review of the evidence of teriparatide and denosumab, from their pharmacological profile, effectiveness, and safety derived from clinical trials, as well as an analysis of the general recommendations of the national and international clinical practice guidelines. Results The evidence establishes that teriparatide and denosumab belong to different therapeutic classes, with biologically opposed mechanisms of action and indications of use, which are clearly differentiated in their respective national codes, therefore these drugs cannot be substitutable or interchangeable in severe osteoporosis therapy. Both represent the best options currently available for this stage of the disease; being similar in their efficacy in preventing new vertebral fragility fractures, with an RR of .35 (CI 95%; .22-.55) for teriparatide, and .32 (CI 95%: .26-.41) for denosumab. The absolute risk reduction is higher with teriparatide 9.3% (21 months) compared with denosumab at 4.8% (36 months). Conclusions Our results agree with the recommendations available in national and international clinical practice guidelines, with both therapies proposed as a sequential, but not a substitute, treatment.

Medications for osteoporosis have not been reported to reduce fracture rates in patients with spinal cord injury and disorders (SCI/D), yet these medications are still prescribed. Clinical decision-making underscoring the initiation and discontinuation of osteoporosis medications in SCI/D remains poorly understood.Veterans with a SCI/D with at least one prescription for an osteoporosis medication (bisphosphonate, calcitonin, denosumab, raloxifene, and teriparatide) who received healthcare within Veterans Affairs (VA) from 2005 to 2015 were identified using VA administrative databases. A 10% subsample of Veterans was selected for electronic health record review.Two hundred and sixty-seven Veterans with 330 prescriptions underwent electronic health record review. Bisphosphonates were the most frequently prescribed medication for osteoporosis (n = 223, 67.6%). Of the 187 Veterans with prescriptions for prevention or treatment of osteoporosis, the primary reason for initiation was Dual Energy X-ray Absorptiometry (DXA) scan with osteopenia or osteoporosis (n = 119, 63.6% of Veterans), primarily at the hip (81.0% of DXAs). The majority (79.0%) of DXAs were "screening tests," with SCI/D being the sole reason for the scan. Fractures (n = 51, 27.3%) and fall risk concerns (n = 29, 15.5%) were other major reasons for initiation. On average, oral bisphosphonates were filled for3 yr, with medication-related side effects (n = 23, 15.8% of bisphosphonates discontinued), predominately gastrointestinal (n = 17, 73.9% of reported side effects), the most common reason for discontinuation. Drug holidays occurred in 14.3% of 35 oral bisphosphonates used for ≥5 yr. No cases of osteonecrosis of the jaw were found. There was one case of an atypical femoral fracture which could not be confirmed.The decision to initiate pharmacological therapies in SCI/D is primarily based on osteopenia or osteoporosis at the hip by screening DXAs. Gastrointestinal side effects are the major reason for discontinuation of oral bisphosphonates. New therapies for osteoporosis in SCI/D are needed.

Background Therapeutic strategies for patients with medication-related osteonecrosis of the jaw (MRONJ) remain controversial. The aim of the present study was to clarify the effectiveness and safety of teriparatide therapy in Japanese MRONJ patients based on a large number of case series with a multicenter retrospective analysis. Patients and methods Between January 2012 and December 2016, 29 patients who were diagnosed with MRONJ at 10 hospitals were treated with teriparatide. The medical records of these patients were retrospectively reviewed to assess the efficacy and safety of teriparatide therapy for MRONJ patients. Results Adverse events occurred in 17.2% of patients (5/29). One patient developed severe arthralgia and discontinued teriparatide therapy after 12 days, while others continued the treatment. Among 29 patients, the median period of administration of teriparatide was 14.0 months (range, 0.3-26 months), and treatment outcomes were evaluated as effective in 75.9% of patients with complete resolution in 65.5%. Among patients treated with oral bisphosphonates (BPs), 83.3% were effectively treated with teriparatide and 40% with intravenous BPs. The oral administration of BPs was associated with successful treatment outcomes with teriparatide (p = 0.062). Conclusions Teriparatide therapy has potential as an effective treatment option for MRONJ.

Objective: Provide an update regarding anabolic medications for osteoporosis, which are often considered to be the last resort for patients with osteoporosis, after multiple fractures have already occurred and other medications have already been administered. Methods: Literature review and discussion. Results: Recent pivotal trial data for anabolic agents and randomized trials comparing anabolic and antiresorptive medications suggest that three anabolic agents (teriparatide, abaloparatide, and romosozumab) reduce nonvertebral and vertebral fractures faster and to a greater extent than potent antiresorptive treatments. Furthermore, bone density accrual is maximized when patients are given anabolic agents first, followed by potent antiresorptive therapy. Since total hip bone density during or after osteoporosis treatment has emerged as an excellent surrogate for future fracture risk, attaining a greater hip bone mineral density is a treatment goal for high-risk osteoporosis patients. Conclusion: This review defines the highest-risk patients and summarizes the rationale for the evolving role of anabolic therapy in the management of postmenopausal women at high risk for fracture. Abbreviations: ACTIVE = Abaloparatide Comparator Trial in Vertebral Endpoints; ARCH = Active Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk; BMD = bone mineral density; FRAME = Fracture Study in Postmenopausal Women with Osteoporosis; FRAX = Fracture Risk Assessment Tool; PTH = parathyroid hormone; TBS = trabecular bone score

Introduction: Intermittent 1-34 parathyroid hormone (iPTH) administration, a bone-forming treatment, is widely used as a therapy for severe osteoporosis. It can only be used for a maximum of 24 mo and must be followed by an antiresorptive drug to retain the new formed tissue. Mechanical load, in the form of low-intensity and high-frequency vibration, has received considerable attention due to its ability to prevent bone loss. Aim: To investigate the ability of whole body mechanical vibration (MV) to potentiate the anabolic effects of iPTH and to inhibit bone resorption following discontinuation of iPTH treatment in estrogen-deficient rats. Methodology: Fifty-four 6-month-old female Wistar rats were ovariectomized (OVX) or sham-operated. After 5 mo, they were divided into 7 groups: Sham – non-OVX; Control – OVX, vehicle for 60 d; MV – OVX, submitted to MV for 60 d; PTH60d – OVX, injected with iPTH for 60 d; PTH+MV – OVX, injected with iPTH combined with MV for 60 d; PTH30d – OVX, injected with iPTH for 30 d, and untreated for 30 d; PTH30d/MV30d – OVX, injected with iPTH for 30 d, followed by MV for 30 d. Bone mineral density (BMD) and body composition (lean mass and fat) were evaluated at OVX (T0), the beginning (T1), and at the end (T2) of treatments by dual X-ray absorptiometry (DXA). Femurs were processed for histomorphometry (bone volume - BV/TV and cortical thickness - Ct.Th) and tibias for biomechanical test. Results: Body composition and BMD were similar among the groups at T0. In T2, MV presented higher fat than other groups (except PTH60d) and PTH30d/MV30d showed greater lean mass than Control. At T1, Sham presented the highest BMD, but between T1 vs T2 there was an increase in all iPTH-treated groups. At T2, BMD was higher in PTH60d and PTH+MV than in the Control and MV groups. The highest BV/TV was observed in the PTH+MV group, followed by PTH60d. Cortical thickness was increased in PTH60d and PTH+MV compared to Sham. Vibration applied post-iPTH (PTH30d/MV30d) improved the force at failure in tibias when compared to Sham and Control groups. Conclusion: MV potentiated iPTH anabolic effects in cancellous bone; however, MV was unable to maintain bone mass after stopping iPTH in ovariectomized rats.

Rituximab, an anti-CD20 monoclonal antibody, is an effective treatment for rheumatoid arthritis. Here we report the case of a patient with rheumatoid arthritis, having taken risedronate for 14 months to prevent corticosteroid-induced osteoporosis, more than 2 years ago, who presented osteonecrosis of jaw following herpetic gingivostomatitis two weeks after the beginning of a rituximab treatment associated with her usual anti-rheumatic drugs. Eight weeks later, no bone and/or gum healing was observed and a stage 2 medication-related osteonecrosis of the jaw (MRONJ) was diagnosed. A conservative approach was decided with antiseptic mouth washes, low-level laser treatment (LLLT) and systemic therapy with teriparatide. Complete mucosal coverage was obtained after more two years of follow-up. We suggest that rituximab as immunosuppressant might be a cause or a decompensating factor of MRONJ. Non-surgical periodontal treatment with LLLT and teriparatide are candidates for the treatment of MRONJ.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that can cause joint destruction and marked disability. Early treatment with disease-modifying drugs, including biological therapy, is the principal treatment to prevent the structural damage associated with this entity. Some studies have indicated that concomitant treatment with antiresorptives, such as bisphosphonates or denosumab, could prevent erosive lesions in this process, and it has even been suggested that treatment with a bone forming agent, such as teriparatide, could revert previously established erosive lesions. In this article we review the evidence available on the efficacy of treatment with antiresorptives and bone forming agents in the prevention and/or treatment of bone erosions associated with RA.

Osteogenesis imperfecta (OI) is an inherited connective tissue disease. The disease has been linked to mutations in one of the type I collagen genes. The diagnosis is based on clinical and radiologic findings. The management of OI in adults is not well-established and includes physical rehabilitation, surgical procedures, the use of antiresorptive therapy and anabolic agents. The aim of the present work was to analyze the clinical and analytical characteristics of these patients in adulthood, as well as to evaluate the different treatments administered. We reviewed the cases of OI diagnosed in our centre over the last 12 years (2005–2017). We describe 15 adult patients with OI.

Objective To systematically evaluate the effects of bone anabolic therapies (BATs) – specifically, drug therapy with teriparatide, abaloparatide or romosozumab – on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. Methods Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. Results Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. Conclusions Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.

SUMMARY: BACKGROUND: In the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-induced bone formation, resulting in larger increases in hip and spine bone mineral density (BMD) than with either drug alone. We aimed to assess whether administration of denosumab with high dose teriparatide would stimulate larger increases in bone mass than those observed in the DATA study. METHODS: DATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts General Hospital. Eligible women were postmenopausal women (at least 36 months since last menses or since hysterectomy with a follicle-stimulating hormone concentration of ≥40 U/L) with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20 μg (standard dose) or 40 μg (high dose) daily via subcutaneous injection for 9 months. At 3 months, both groups were started on denosumab 60 mg every 6 months via subcutaneous injection for 12 months. Areal BMD (aBMD) was measured at 0, 3, 9, and 15 months. Treatment was given open label, but outcome assessors were masked. The primary endpoint was percentage change from baseline in spine areal BMD (aBMD) at 15 months. Women who completed at least one study visit after baseline were included in the modified intention-to-treat analysis. Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02176382. FINDINGS: Between Oct 15, 2014, and June 10, 2016, 269 women were assessed for eligibility. 76 participants were randomly assigned to 20 μg teriparatide (n=39) or 40 μg teriparatide (n=37), of whom 69 completed at least one post-baseline visit. At 15 months, mean spine aBMD had increased to a significantly greater extent in the 40 μg group (17·5% [SD 6·0] increase) than the 20 μg group (9·5% [3·2]; difference 8·1%, 95% CI 5·5 to 10·6, p

Objectives There is emerging evidence supporting sequential therapy with an osteoanabolic followed by an antiresorptive in patients at high-risk of fragility fractures. This study assessed the cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) [(ABL/ALN)] compared with teriparatide (TPTD) followed by ALN (TPTD/ALN). Methods A previously validated Markov microsimulation model was adapted to estimate the cost-effectiveness of sequential ABL/ALN compared with sequential TPTD/ALN and no treatment with a lifetime horizon from the US payer perspective. Patients were assumed to receive ABL or TPTD for 18 months followed by 5 years of ALN in line with clinical recommendations. The effects of ABL on fracture risk were derived from the ACTIVExtend trial. The effects of TPTD were assumed to be maintained during subsequent ALN treatment, consistent with ACTIVExtend findings for ABL. Evaluation was completed for patients, aged 50–80 years with a BMD T-score ≤ −3.5 or with a T-score between −2.5 and −3.5 and a history of ≥ one osteoporotic fracture. Results In all simulated populations, sequential ABL/ALN therapy was dominant (lower costs, higher QALYs) compared with sequential TPTD/ALN therapy, resulting from the improved efficacy and lower drug price of ABL. Probabilistic sensitivity analyses suggested that ABL/ALN was dominant in at least 99% of the simulations. Compared to no treatment, the cost per QALY gained of ABL/ALN was always below $130,000. Conclusions Sequential ABL/ALN therapy is a cost-effective (dominant) strategy compared with sequential TPTD/ALN therapy for the treatment of US women at increased risk of fractures.

Abaloparatide is an analog of human parathyroid hormone-related protein (PTHrP) that has recently been approved for the treatment of post-menopausal osteoporosis. Abaloparatide is a stimulator of bone formation similar to teriparatide (1-34 PTH/TPTD), the first-in-class osteoanabolic drug. Both PTH and PTHrP signal via the type 1 PTH receptor (PTH1R) however, the downstream signaling varies between the two ligands. Both ligands have a similar affinity for the RG (GTPγS-sensitive) state of PTH1R, but, TPTD has a four-fold higher affinity for R0 (GTPγS-insensitive) than PTHrP that results in a prolonged cAMP signaling. Consequently, a greater production from osteoblastic cells of a potent resorption inducer, receptor activator of nuclear factor κB ligand (RANKL) is caused by TPTD than PTHrP. TPTD causes an excess formation over resorption early on producing an anabolic "window" which is lost with time due to increased RANKL production causing resorption to catch up with the formation. Although highly labile, PTHrP has an osteogenic effect accompanied by lesser resorptive and hypercalcemic effects than TPTD because of faster PTHrP-PTH1R dissociation than PTH-PTH1R complex. Engineered from PTHrP (1-34), abaloparatide was made stable and overcame the loss of the anabolic window and hypercalcemia associated with TPTD. The receptor activating domain (1-21 amino acids) of both ligands is same but multiple substitutions between amino acids 22-34 of PTHrP were made to enhance the peptide's stability. In, women with osteoporosis, abaloparatide increased BMD faster than TPTD and decreased fracture risk at both vertebral and non-vertebral sites but unlike TPTD/PTH did not increase resorption or hypercalcemia.

Osteoporosis is a disease with a significant disease burden worldwide, affecting more than 75 million people in the US, Europe and Japan. With an ageing population the incidence of osteoporosis is growing. Osteoporotic fractures have significant individual morbidity but also strain Healthcare services. There is no screening service for osteoporotic fractures in the UK and physicians must actively identify patients who are at risk of osteoporotic fractures as well as managing appropriately patients who have sustained osteoporotic fractures. Diagnosis of osteoporosis is done with Dual energy X-ray Absorptiometry (DXA) scans to measure Bone Mineral Density (BMD). The World Health Organisation Fracture Risk Assessment (FRAX) score is used to identify patients who are at risk of fractures. Pharmacological treatment is recommended for those who obtain a risk score sufficient enough to warrant treatment. The treatment of osteoporosis includes calcium and vitamin D replacement, bisphosphonates , denosumab , teriparatide and hormone replacement therapy in women. Potential therapies that are currently undergoing clinical trials include Abaloparatide and Romosozumab .

There is currently an unmet clinical need for improved treatments for skeletal diseases such as osteoporosis and cancer-induced bone disease. This is due in part to a paucity of novel targets and an incomplete understanding of the mechanisms of action for established therapies. We defined the effects of anabolic treatments on bone and the bone marrow adipocyte (BMA). Sclerostin-neutralizing antibodies (Scl-Ab), romosozumab, human parathyroid hormone (hPTH, 1-34), and hPTH/hPTHrP analogues (e.g. teriparatide and abaloparatide) stimulate bone formation and have been studied in clinical trials for severe osteoporosis. In this study, eight-week-old male and female rats were administered vehicle, Scl-Ab (3 mg/kg or 50 mg/kg) weekly, or hPTH (1-34) (75 μg/kg) daily for 4 or 26 weeks. Histological analyses of distal femura were performed using a novel ImageJ method for trabecular bone and bone marrow adipose tissue (BMAT). Adipocyte number, circumference, and total adipose area were compared within the tissue area (T.Ar) or the marrow area (Ma.Ar), (defined as the T.Ar minus the trabecular bone area). After 26 weeks of treatment, a significant inverse correlation between bone and tissue adiposity (total adipocyte area divided by T.Ar) were observed in males and females (p 0.0001). However, there were no significant correlations between bone and marrow adiposity (total adipocyte area divided by Ma.Ar) for either sex after 26 weeks of treatments. Scl-Ab treatments also resulted in no effect on adipocytes based on marrow adiposity for either sex after 26 weeks. However, chronic hPTH treatments significantly reduced adipocyte number and adiposity within the T.Ar and within the Ma.Ar in males. Overall, our data suggest that with long-term treatment, Scl-Abs decrease total tissue adiposity mainly by increasing trabecular bone, resulting in an overall reduction in the space in which adipocytes can reside. These findings were determined by developing and comparing two different methods of assessment of the marrow cavity, defined to either include or exclude trabecular bone. Thus, researchers should consider which adiposity measurement is more informative and relevant for their studies. Overall, our findings should help design improved therapies or combination treatments to target a potential new contributor to bone diseases: the bone marrow adipocyte.

Objectives: The impact of patient background factors on changes in bone mineral density (BMD) and bone metabolic markers after treatment with once-weekly teriparatide (W-TPTD) has not been fully elucidated. To clarify the impact, I performed stratified analysis in addition to the efficacy and safety assessments to analyze treatment data with W-TPTD. Methods: The primary endpoint of the efficacy was the rate of change of the lumbar spine BMD at 18 months after treatment. In the exploratory analysis, bone metabolic markers at baseline were used to divide the patients into 3 groups, by the first tertile and the second tertile. The rate of change in the lumbar spine/femoral neck BMD and bone metabolic markers in each group were analyzed by stratification. Results: The rate of change in the lumbar spine BMD at 18 months was 9.0%, which represented a significant increase. The rate of change in the lumbar spine/femoral neck BMD in each group classified into tertiles by their baseline bone metabolic markers significantly increased, regardless of the type of bone metabolic markers and baseline value. For markers, all groups remained within the range of reference values at 18 months after treatment. Conclusions: I demonstrated that W-TPTD significantly increased the BMD of the lumbar spine and femur, regardless of baseline values of the bone metabolic markers. In addition, W-TPTD was able to normalize bone metabolic markers. I considered that W-TPTD would be useful, independent of bone metabolic markers in patients, as an agent to improve BMD, and be a useful option for the treatment of osteoporosis. Keywords: Teriparatide, Osteoporosis, Bone mineral density, Visual analogue scale, Bone metabolic markers

Osteoporosis is a skeletal condition characterized by low bone mineral density (BMD). Common in older patients undergoing spinal fusion, it is a significant risk factor for instrumentation failure and related complications. The objective of this review is to articulate clear suggestions for screening and medical/surgical management strategies in patients with osteoporosis. A thorough review of the literature was conducted using PubMed. Varied search terms were applied to yield published manuscripts on osteoporosis and spine surgery. Biomechanical studies and studies conducted in animal models were excluded. Screening should be considered in those that present with multiple risk factors for low BMD. Dual-energy x-ray absorptiometry (DEXA) remains the gold standard, but Hounsfield Units (HU) have emerged as a powerful complement to DEXA. While both bisphosphonates and teriparatide have been investigated in the perioperative setting and have a positive impact on outcomes, teriparatide maintains an advantage in comparative studies. Surgical treatment need not be postponed. Standard surgical modifications such as using multiple points of fixation, varied fixation equipment, anterior/posterior instrumentation, and modified screw design/trajectories should all be considered. However, recent clinical studies focus on cement augmentation and expandable pedicle screws. All have been shown to improve bone-screw interface strength, but extravasation remains a risk of cement augmentation, and hydroxyapatite cement (HAC), while an emerging alternative to polymethyl methacrylate (PMMA), is not as well investigated in the setting of osteoporosis. Furthermore, research on expandable pedicle screws is limited. To conclude, optimizing spine surgery outcomes in the osteoporotic patient is possible with a thorough preoperative workup, medical management, and a tailoring of the surgical technique. This is especially important when performing complex spinal instrumentation.

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.

Weekly teriparatide treatment is reported to reduce the incidence of osteoporotic vertebral fractures. However, the effect of weekly teriparatide on cortical bone has not been clarified. This study aimed to examine the effects of weekly teriparatide treatment on bone mass, intracortical structure, and remodeling of the lumbar vertebral cortical shell and its relation to mechanical properties in ovariectomized cynomolgus monkeys. Female monkeys, aged 9 to 15 years, were divided into four groups: (1) SHAM group, (2) ovariectomized group (OVX group), (3) OVX with 1.2 μg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 μg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein, and lumbar vertebrae were analyzed with histomorphometry and compressive mechanical tests. Following ovariectomy, we found reductions in the anterior cortical shell area of the vertebrae and reductions in nearly all of the tested vertebral mechanical properties. Weekly teriparatide significantly preserved the anterior cortical shell area and the energy absorption capacity of the lumbar vertebrae in a dose-dependent manner. Multiple regression analyses indicated that improved mechanical properties were more associated with the increased anterior cortical shell area rather than the cancellous bone volume. The intracortical structure of the Haversian canals was also preserved following teriparatide treatment after ovariectomy. These findings suggest the importance of the cortical shell as a therapeutic target in the treatment of osteoporosis. Weekly teriparatide treatment increases the compressive mechanical strength of the lumbar vertebrae by thickening the anterior cortical shell.

Purpose To assess the effect of teriparatide, a recombinant human parathyroid hormone, on rotator cuff healing after arthroscopic repair compared with patients who were not treated with teriparatide. Methods This was a prospective propensity-matched study. Thirty-one patients who underwent arthroscopic rotator cuff repair for tears >2 cm in size between January 2015 and June 2016 were recruited (group I). Daily subcutaneous injections of teriparatide 20 μg were administered for 3 months following surgery. In the same period, propensity score matching (1-to-4) was performed to generate an untreated control group undergoing rotator cuff repair alone (group II) with the same tear size. Magnetic resonance imaging evaluation of tendon healing was performed at least 1 year postoperatively, as well as the range of shoulder motion, American Shoulder and Elbow Surgeons score, Constant score, and simple shoulder test. Results There was no significant difference of the retraction size, the anterior to posterior dimension of torn rotator cuff, or the preoperative bone mineral density in groups I and II (P = .78, .87, and .96, respectively). The rate of retear was significantly lower in group I than in group II (16% vs 33.9%; P = .04). Range of motion and functional scores were not significantly different between the 2 groups (P > .05). Conclusions Teriparatide, a recombinant human parathyroid hormone, can be a systemic treatment option that significantly enhances the tendon-to-bone healing after arthroscopic rotator cuff repair for patients with rotator cuff tears >2 cm. Level of Evidence Level III, case-control study.

Cell surface protein B (CspB) from Corynebacterium glutamicum is used as a pH-responsive peptide tag to enable a simple solid–liquid separation method for isolating a CspB fusion protein. Here we demonstrate the first application of a CspB tag for the purification of Teriparatide, which is a biologic drug that is prescribed for osteoporosis. The Teriparatide was constructed as CspB50TEV-Teriparatide, comprising 50 amino acid residues of CspB, the cleavage site of TEV protease, and Teriparatide. CspB50TEV-Teriparatide was expressed in a culture supernatant by C. glutamicum secretion system at 3.0 g/L (equivalent to approximately 1.2 g/L Teriparatide). The CspB50TEV-Teriparatide was precipitated by reducing the pH of the culture supernatant, and the precipitate was then dissolved in a neutral buffer. A TEV protease treatment was applied to cleave the Teriparatide from the CspB50TEV-Teriparatide. Then, the remaining digested CspB50TEV, undigested CspB50TEV-Teriparatide, and TEV protease were precipitated in an acidic pH, whereas the soluble Teriparatide remained in the supernatant. The process had a yield of 96.5% and resulted in Teriparatide with a purity of 98.0% and productivity of 1.1 g/L of C. glutamicum culture. Thus, tag-free Teriparatide was successfully purified from the CspB fusion protein using only pH changes, centrifugation, and protease digestion without the need for chromatography. This versatile purification protocol is expected to be applicable to various proteins from laboratory to industrial scales.

We evaluated if equivalent doses of TPTD given cyclically over 4-years could increase BMD2-years of daily TPTD in 2 cohorts of women; previously untreated (Rx-Naïve) and women previously treated with ALN (ALN-Rx).In Rx-Naïve, women were randomized to daily TPTD for 24 months (Daily; n = 23) or cyclic TPTD for 48 months (3 months on, 3 months off; Cyclic; n = 25). In ALN-Rx, women were randomized to continued ALN plus daily TPTD for 24 months, followed by ALN alone for 24 months (Daily; n = 21) or TPTD for 48 months (3 months on, 3 months off) while ALN was continued (Cyclic; n = 20). BMD (DXA) was measured at spine (LS), total hip (TH) and femoral neck (FN). The primary analysis compared 4 years of cyclic therapy to 2 years of daily therapy in RX-naïve and ALN-RX cohorts.In Rx-Naïve, BMD changes at 24 months after Daily TPTD vs. 48 months after Cyclic TPTD were: LS 8.6% vs. 6.9%; TH 2.5% vs. 2.6%, and FN 1.6% vs. 2.2%. None of the BMD changes differed significantly between groups but all changes were significant over time within each group (p 0.01 except for FN where p = 0.17 Daily; p = 0.09 Cyclic). In ALN-Rx, BMD changes at 24 months after Daily TPTD vs. 48 months after Cyclic TPTD were: LS 7.5% vs. 7.2%; TH 3.8% vs. 4.1%, and FN 3.2% vs. 2.5%. There were no differences between groups but all changes were significant within each group (p 0.01).The same cumulative dose of TPTD given cyclically for 4-years, does not increase BMD more than standard daily TPTD over 2-years in either Rx-Naïve or ALN-Rx women.NCT00668941.

New anti-osteoporotic agents have been developed, potentially enriching the therapeutic armamentarium. Currently available osteoanabolic therapies are the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) synthetic analogues, teriparatide and abaloparatide. Daily administration at doses of 20 and 80 μg, respectively, in contrast to continuous PTH secretion, leads to increased bone formation and reduces vertebral and non-vertebral fracture risk. Teriparatide is more effective than bisphosphonates (alendronate, risedronate) in increasing bone mineral density (BMD), improving bone architecture and reducing fracture risk. Abaloparatide leads to greater BMD gain, has greater anti-fracture efficacy regarding major osteoporotic fractures (upper arm, wrist, hip or clinical spine) compared with teriparatide (without a difference in morphometric vertebral and non-vertebral fractures), and has a lower risk of hypercalcaemia. Romosozumab, a sclerostin inhibitor, both induces bone formation and suppresses bone resorption. Administered at monthly subcutaneous doses of 210 mg, it reduces vertebral, non-vertebral and hip fracture risk compared with either placebo or alendronate. However, concerns have arisen about increased cardiovascular risk, which has suspended its approval by the FDA. Anabolic therapy should always be followed by administration of an anti-resorptive agent, such as bisphosphonates or denosumab, which preserves and may further increase BMD gain. Denosumab provides the greatest benefit for BMD when administered sequentially after its combination with teriparatide for 24 months and constitutes a reasonable option for patients at high risk of fracture. However, longitudinal data are needed to confirm the efficacy and safety of these therapeutic interventions.

Intermittent PTH-like drugs are the only approved so-called anabolic agent that increases bone mass in both mice and humans. It is well documented that PTH targets mature cells of the osteoblast lineage, with only indirect evidence of its actions on early cells of the osteoblast lineage. Using a triple transgenic mouse model that allowed labeling of very early cells of the osteoblast lineage, we traced the progeny of these into osteoblast lineage in adult mice. These early cells expressed PTH1R and multiplied when PTH (1-34) was administered daily. We also showed that the early mesenchymal cells showed accelerated differentiation into mature osteocalcin-positive osteoblasts and osteocytes. Rather surprisingly, when teriparatide administration was stopped, these early mesenchymal precursors differentiated into adipocytes. We showed that the adipogenic differentiation is accompanied by a decrease in wnt signaling in osteoblast precursors. In this review, we discuss the possible clinical relevance of this finding and the possible molecular mechanisms that contribute to this phenotype in vivo.

Glucocorticoid-induced osteoporosis remains the most common type of secondary osteoporosis, mostly due to use of oral glucocorticoids rather than due to endogenous overproduction of cortisol. Partly because glucocorticoids are prescribed by a wide variety of clinicians for many different inflammatory disorders, only a minority of older individuals have adequate and timely assessment of their enhanced fracture risk, and fewer are offered treatment. Assessment should include bone density, the FRAX calculation, and, in many cases, images of the spine. Glucocorticoids decrease osteoblast function and increase apoptosis of osteoblasts and osteocytes, leading to increased fracture risk soon after starting glucocorticoids. Guidelines provide evidence-based recommendations for evaluation and treatment, but there are differences in extant guidelines, and methods to improve adherence to the guidelines have mostly failed. A strong case can be made to use anabolic drugs first in high-risk patients based on pathophysiology and head-to-head clinical trials.

Cell surface protein B (CspB) from Corynebacterium glutamicum has been developed as a reversible pH-responsive tag for protein purification. CspB fusion proteins precipitate at acidic pH, after that they completely dissolve at neutral pH. This property has been used in a non-chromatographic protein purification method named pH-responsive Precipitation-Redissolution of CspB tag Purification (pPRCP). However, it is difficult to apply pPRCP to proteins that are unstable under acidic conditions. In an effort to shift the precipitation pH to a milder range, we investigated the solution conditions of CspB-fused Teriparatide (CspB50TEV-Teriparatide) during the process of pH-responsive precipitation using pPRCP. The purified CspB50TEV-Teriparatide in buffer without additives precipitated at pH 5.3. By contrast, CspB50TEV-Teriparatide in buffer with 0.5 M Na

Teriparatide, a recombinant human parathyroid hormone analogue, is associated with increased bone mineral density and a decreased risk of fractures. A dose-dependent increase in the incidence of osteosarcoma was observed in toxicology studies conducted in rats. The primary objective of this study was to estimate the incidence of osteosarcoma over a 10-year period among teriparatide-treated patients versus patients unexposed to teriparatide with osteoporosis and patients in the general population using national pharmacy dispensing data linked with data from participating state cancer registries (SCRs) in the US.Patients aged 18 years or older with a dispensed teriparatide prescription formed two different cohorts: Teriparatide-Osteoporosis (Teriparatide-OP) was formed by matching teriparatide patients to unexposed patients with osteoporosis and Teriparatide-General Population (Teriparatide-GP) was formed by matching teriparatide patients to general population patients with a dispensed prescription for a medication other than teriparatide. Matching was performed using select demographics and other variables. Study cohorts were linked to SCR data to ascertain osteosarcoma status. To account for missing outcome data from non-participating SCRs, two analytic approaches were used: the first adjusted the person-time at-risk using a coverage fraction and the second restricted the analyses to patients from states with participating SCRs.There were 18 osteosarcoma cases across four study cohorts: the same three cases in the Teriparatide-OP and Teriparatide-GP cohorts, six cases in the Osteoporosis cohort, and nine cases in the General Population cohort. For the analysis using the coverage fraction the incidence rate ratio (IRR) comparing the Teriparatide-OP and Teriparatide-GP cohorts to the Osteoporosis and General Population cohorts was 1.0 (95% CI: 0.2, 4.5) and 1.3 (95% CI: 0.2, 5.1), respectively. When restricting the analysis to patients from states with participating SCRs, the IRR was 0.6 (95% CI: 0.1, 3.6) and 0.8 (95% CI 0.1, 4.0), respectively.The estimates of association between teriparatide and osteosarcoma were imprecise due to the small number of observed osteosarcoma cases. However, the incidence of osteosarcoma observed in each study cohort was within the expected range given background rates for the US general population. The evidence generated by this study, in conjunction with other real-world studies evaluating the risk of osteosarcoma, was used to support changes to the US teriparatide label (including removal of the black box warning regarding potential risk of osteosarcoma) and expand treatment options for patients with osteoporosis.

The PTH1-34 peptide, teriparatide (TPTD), acts through the PTH1 receptor to rapidly stimulate bone formation and then bone remodeling. Abaloparatide (ABL), a synthetic analogue of PTH related peptide (PTHrP), also acts through the PTH1 receptor, with preferential affinity for the receptor conformation associated with bone formation. Both TPTD and ABL provide rapid protection against vertebral and nonvertebral fractures within 18–19 months as well as improving BMD rapidly in both spine and hip regions. These agents are thus well suited to patients at high risk of fracture, particularly those at high imminent risk. TPTD and ABL are contraindicated in individuals at elevated risk for osteosarcoma (skeletal radiation and Paget's disease) and those with primary or metastatic bone cancer, myeloma, hyperparathyroidism or hypercalcemia. TPTD and ABL treatment should be followed by potent antiresorptive therapy, usually either Denosumab or a potent bisphosphonate to enhance and/or maintain BMD and gains in bone strength. This review highlights the most important recent clinical studies with TPTD and ABL, including the ABL extension study and a direct head to head fracture outcome study comparing TPTD and risedronate. This paper provides a rationale for early proactive use of anabolic treatment of osteoporosis in patients at high risk of fracture.

Introduction: Titanium dioxide has been classified by the International Agency for Research on Cancer (IARC) as a Group 2B carcinogen. As indispensable material for dental implant fixture, dental patients are exposed to its toxicological reactions. Objectives: The primary aim of this research is to prevent making nanoparticle titanium dioxide from the corrosion of dental implant fixture and gain possible osseointegration. Methods: The authors introduce two-layer coating system for controlling corrosional toxicity of TiO2 from the surface of two dental implant fixtures by medronic acid and teriparatide acetate. Results: The first layer coated with medronic acid will generate phosphate bridges, functioning as a corrosion-resistant sheath layer, and will be the only connector to Forteo (Teriparatide Acetate). The second layer encloses the essential elements of teriparatide like C, N, O and H with saving the functional radicals like CNO-, C2H3O-, CHO2-, C3H3O- and C2H3O2-, for and it will stimulate the coated implant fixture with PTH receptors, osteoblasts, and osteogenesis. The first layer covers Ti-O-P, acting as a titanium grade 4 antioxidant. Conclusion: The top surface radicals in the second layer of the fixture have pharmaceutically functioning parts of the chemical structure of Teriparatide (C181H291N55O51S2) activating osteoblasts more than osteoclasts, which leads to an overall increase in bone. Though the recommended duration of use for grade 4 implant fixtures is 3 years, but these new coated fixtures are expected to use longer than 3 years by containing the stimulating effect of new alveolar bone formation by increasing the mineral density of the alveolar bone around the fixture besides preventing corrosional toxicity from the surface of preexisting titanium fixtures. Cheaper producing cost of a coated implant fixture are also suggested.

Previous studies of ovariectomized (OVX) monkeys, treated with recombinant human parathyroid hormone (PTH) (1-34) at 1 or 5 μg/kg/day for 18 months or for 12 months followed by 6 months withdrawal from treatment, displayed significant changes in geometry, histomorphometry, and bone quality, but without strict tissue age criteria, of the midshaft humerus. Since bone quality significantly depends on tissue age among other factors, the aim of the present study was to establish the bone-turnover independent effects of two doses of PTH, as well as the effects of treatment withdrawal on bone quality by measuring bone material composition at precisely known tissue ages ranging from osteoid, to mineralized tissue older than 373 days. Raman microspectroscopic analysis of bone tissue from the mid-shaft humerus of OVX monkeys demonstrated that the clinically relevant dose of PTH administered for 18 months reverses the effects of ovariectomy on bone quality when compared against SHAM. Both doses investigated in this study restore the mineralization regulation mechanisms to SHAM levels. The study also showed that the beneficial effects induced by 12 months of clinically relevant PTH therapy were sustained after six months of therapy withdrawal.

PURPOSE: We have previously shown that a brief course of teriparatide (TPTD) stimulates bone formation in the cancellous and endocortical envelopes of the human femoral neck, and the regions of tension and compression respond differently. The purpose of the present study was to determine how much of the new bone was formed by modeling-based formation (MBF) or remodeling-based formation (RBF). METHODS: We performed a double-blind trial of TPTD vs Placebo (PBO) in patients about to undergo a total hip replacement (THR) for osteoarthritis. Participants were randomized to receive daily TPTD 20 mcg or PBO for an average of 6.1 weeks (range 4.1–11.8 weeks) prior to THR. After an average of 3 weeks of study drug, double tetracycline labels were administered per standard protocol. During the THR an intact sample of the mid-femoral neck (FN) was procured; this was fixed, embedded, and sectioned transversely. Histomorphometric analysis was performed in the cancellous, endocortical, and periosteal envelopes. Additionally, separate analyses were performed in the tensile and compressive regions of the endocortical and periosteal envelopes. Sites of new bone formation were identified by the presence of tetracycline labels and designated as MBF if the underlying cement line was smooth and as RBF if it was scalloped. New bone formation on smooth cement lines adjacent to scalloped reversal lines was designated as overflow RBF (oRBF). The referent for all indices was bone surface (BS). RESULTS: In the cancellous and endocortical envelopes, the proportion of mineralizing surface engaged in RBF and oRBF was higher in the TPTD-treated than the PBO-treated subjects. There was also a trend towards higher MBF in TPTD vs PBO in both envelopes. In linear mixed-effects models, TPTD was predicted to increase formation differently on the tensile and compressive surfaces depending on patient-specific anatomy, including body weight, FN angle, offset, and cortical width and porosity. Eroded surface was not different between groups in either envelope and no significant differences were observed in any parameter in the periosteal envelope. CONCLUSION: We conclude that the predominant early effect of TPTD in the human femoral neck is to stimulate RBF and oRBF with a trend towards an increase in MBF in the endocortical and cancellous envelopes.

The protease present in a host may reduce the yield and biological activity of heterologous proteins. In this study, we used protease overexpression and deletion strategies to examine the effect of the Clp protease system in Corynebacterium glutamicum on the recombinant protein and to produce a highly efficient heterologous protein expression host. In this study, we identified seven genes in the Clp protease family in Corynebacterium glutamicum ATCC 13032 through bioinformatics analysis, and studied their effects on the enhanced green fluorescent protein (EGFP) reporter protein. The fluorescence intensity of the knockout strain was significantly higher, and the effect of the clpS deletion strain was the most obvious. To verify the universal effect of the lack of clpS, the excellent industrial strain C. glutamicum 1.15647 was transformed to form recombinant 15647-ΔclpS. Based on the results, 15647-ΔclpS had a more significant effect on improving protein expression. Furthermore, recombinant human teriparatide (rhPTH) and variable domain of heavy chain of heavy-chain antibody (VHH) were selected to verify the universal applicability of the knockout strain for expressing heterologous proteins. Accordingly, we found that protease deficiency could increase the production of heterologous proteins. Finally, through a large-scale fermentation, the 15647-ΔclpS strain was used to produce VHH. Its yield was approximately 530 mg/L, which was 65% higher than that of WT-15647. In this study, a host that could effectively increase heterologous protein expression was successfully obtained.

Although no effective therapies have been established for osteonecrosis of the jaw caused by bisphosphonate (BP) preparations, a good therapeutic response has been recently reported after treatment with teriparatide (PTH) and teriparatide acetate (PTH-A), both formulations of the thyroid hormone teriparatide. We report a case of Stage 2 medication-related osteonecrosis of the jaw (MRONJ) that responded to treatment with teriparatide. The patient was a 78-year-old woman. She was examined for the chief complaint of stomatitis in the torus palatinus. Intraoral examination revealed bone exposure in the palate and swelling, redness and pus discharge in the surrounding mucosa. CT revealed a sequestrum measuring 14 × 4 mm in the superficial layer of the torus palatinus. The patient had taken oral sodium risedronate for seven years and six months. There was continuous bone exposure for three months and she had not undergone radiotherapy in the jaw region. Based on this history, Stage 2 MRONJ was diagnosed. Subcutaneous injections of PTH-A was started in March 2013. In week 17 of treatment the exposed bone was completely covered by mucosal epithelium and in week 42 of treatment the sequestrum had disappeared.

Osteoporosis in men remains under-diagnosed and under-appreciated. After a low trauma fracture, a man is less likely to have evaluation and treatment. The lifetime risk for osteoporotic fracture in older men may range from 13 to 25%, and as men live longer, there will be more fractures. Newer strategies for determining which men should have bone density testing are emerging. Information from observational studies are providing insights that allow targeted testing and treatment of those men at the highest risk for fracture. Treatment with most of the same medications used in women is efficacious and generally safe. Nonetheless, the fear of side effects of treatments for an asymptomatic disorder (before a fracture) and other barriers have made management challenging in men at risk for fracture. This review provides updates on epidemiology, pathophysiology, evaluation and treatment of male osteoporosis.

Central quantitative computed tomography (QCT) is increasingly used in clinical trials and practice to assess bone mass or strength and to evaluate longitudinal changes in response to drug treatment. Current studies utilize single-energy (SE) QCT scans, which may be confounded both by the amount of bone marrow fat at baseline and changes in marrow fat over time. However, the extent to which marrow fat changes either underestimate volumetric BMD (vBMD) measurements at baseline or under-/overestimate longitudinal changes in vivo in humans remains unclear. To address this issue, 197 early postmenopausal women [median age (IQR) 56.7 (54.4–58.7) years] underwent spine and hip QCT scans at baseline and 3 years using a 128-slice dual-source dual-energy (DE) scanner. The scans were analyzed as either SE scans (100 kVp) or DE scans (100 kVp and 140 kVp), with the latter accounting for bone marrow fat. At baseline, vertebral trabecular vBMD was (median) 17.6% lower (P < 0.001) while femur neck (FN) cortical vBMD was only 3.2% lower (P < 0.001) when assessed by SE vs DE scanning. SE scanning overestimated the 3 year rate of bone loss for trabecular bone at the spine by 24.2% (P < 0.001 vs DE rates of loss) but only by 8.8% for changes in FN cortical vBMD (P < 0.001 vs DE rates of loss). The deviation between SE and DE rates of bone loss in trabecular vBMD became progressively greater as the rate of bone loss increased. These findings demonstrate that SE QCT scans underestimate trabecular vBMD and substantially overestimate rates of age-related bone loss due to ongoing conversion of red to yellow marrow. Further, the greater the rate of bone loss, the greater the overestimation of bone loss by SE scans. Although our findings are based on normal aging, recent evidence from animal studies demonstrates that the skeletal anabolic drugs teriparatide and romozosumab may markedly reduce marrow fat, perhaps accounting for the disproportionate increases in trabecular vBMD by SE QCT as compared to dual-energy x-ray absorptiometry with these agents. As such, future studies using recently available DE scanning technology that has satisfactory precision and radiation exposure are needed to evaluate changes in trabecular vBMD independent of changes in marrow fat with aging and drugs that may alter marrow fat composition.

Treatment of osteoporosis should be directed primarily towards secondary prevention of fractures. The occurrence of drug-related adverse effects for the treatment of osteoporosis has led to a reevaluation of the indications, the duration of treatment and even withdrawal of some drugs from the market. This review has been made from different patient profiles that practitioners will find in usual practice; from patients with hip fracture with cognitive impairment, limitation of their day-to-day living activities and comorbidities, to active patients without any limitations; patients with vertebral fractures and non-vertebral fractures where secondary prevention is highly important. In general, antiresorptive drugs (alendronate and risedronate) will be the first choice. Zoledronate or denosumab will be indicated in cases of digestive intolerance, poor adherence or an increased risk of hip fracture. Teriparatide will be indicated to patients with 2or more previous vertebral fractures or very low bone density.

Promising news in the treatment of osteoporosis is that sequestering sclerostin from circulation with antibodies stimulates robust bone formation. Pre-clinical studies on rodents and monkeys have confirmed that treatment with anti-sclerostin monoclonal antibody (Scl-Ab) increases bone mass, improves bone strength and enhances fracture repair. Clinical trials show that bone gain (anabolic effect) is transient and are primarily at central (spine and hips) than peripheral (wrist) sites. Interestingly Scl-Ab also inhibited bone resorption. Thus Scl-Ab is being regarded as the pharmacologic agent with dual properties - stimulating bone formation and decreasing bone resorption. Sclerostin neutralization transiently increases bone formation markers in post-menopausal women and like parathyroid hormone (PTH) activates osteoblasts and lining cells resulting in bone anabolic effect. However, unlike PTH, sclerostin antibody also decreases bone resorption (anti-catabolic). Although, the U.S. Food and Drug Administration have accepted the Biologics License Application for one of the monoclonal antibodies against sclerostin (romosozumab) for review, many questions remain before romosozumab can be introduced as a skeletal anabolic agent to clinical practice. For example, neutralizing sclerostin alters calcium homeostasis and increases PTH. In addition, sclerostin depletion in preclinical studies has been reported to severely compromises B cell depletion in bone marrow. We have reviewed the currently available evidences that support the use of sclerostin antibody in treating osteoporosis and compare its efficacy and mechanism of action with the currently available anabolic drug, human PTH.

Genetic ablation of cyclooxygenase-2 (COX-2) in mice is known to impair fracture healing. To determine if teriparatide (human PTH1-34) can promote healing of Cox-2-deficient fractures, we performed detailed in vivo analyses using a murine stabilized tibia fracture model. Periosteal progenitor cell proliferation as well as bony callus formation was markedly reduced in Cox-2-/- mice at day 10 post-fracture. Remarkably, intermittent PTH1-34 administration increased proliferation of periosteal progenitor cells, restored callus formation on day 7, and enhanced bone formation on days 10, 14 and 21 in Cox-2-deficient mice. PTH1-34 also increased biomechanical torsional properties at days 10 or 14 in all genotypes, consistent with enhanced bony callus formation by radiologic examinations. To determine the effects of intermittent PTH1-34 for callus remodeling, TRAP staining was performed. Intermittent PTH1-34 treatment increased the number of TRAP positive cells per total callus area on day 21 in Cox-2-/- fractures. Taken together, the present findings indicate that intermittent PTH1-34 treatment could compensate for COX-2 deficiency and improve impaired fracture healing in Cox-2-deficient mice.

Objective To evaluate the effects of different doses and durations of teriparatide therapy on MRONJ resolution in rats. Subjects and methods A total of 120 rats that had been affected with MRONJ (after six weekly zoledronate injections and tooth extraction) were randomly divided into eight subgroups: 2, 10, and 20 μg/kg/day teriparatide were administered to L4, M4, and H4 for 4 weeks, and to L8, M8, and H8 for 8 weeks, respectively. C4 and C8 received saline for 4 and 8 weeks, respectively. One week after the final injection, rats were sacrificed and assessed clinically (bone exposure/fistula) and histologically (number of osteocytes in extraction socket and empty lacunae in alveolar bone). Results MRONJ was clinically improved in 72.2%, 61.5%, and 40% of stage I, II, and III experimental rats, respectively. In the control rats, the results were 20.8% for stage I and no improvement for stages II and III. Aside from L4 and L8, the experimental subgroups had a significantly higher rate of clinical and histological improvement compared with their corresponding controls. There was a significantly higher number of osteocytes and lower number of empty lacunae in M4 and H4 compared with C4, in H4 compared with L4, in M8 and H8 compared with C8, and in H8 compared with L8. Conclusion Teriparatide therapy improved clinical and histological features of MRONJ in a dose-dependent manner, but clinically relevant doses of teriparatide might not be sufficient for MRONJ resolution in rats. Extending the duration of teriparatide therapy from 4 to 8 weeks did not affect treatment outcomes.

Osteopenia and osteoporosis have become increasingly common in the elderly population, as has the concern from treating spinal surgeons. Many adverse surgical outcomes have been associated with poor bone quality, including decreased fusion rates, hardware complications, and osteoporotic fractures. Teriparatide, a recombinant form of parathyroid hormone, has been used as a major pharmaceutical intervention in osteoporosis treatment. This article provides an overview of the mechanism of teriparatide followed by a detailed review of the literature concerning outcomes of medical management with teriparatide in both animal models and humans with osteoporosis/osteopenia. Improved fusion rates and duration, as well as reduced osteoporosis-related complications are evident upon reviewing clinical and radiographic outcomes of teriparatide therapy in spinal surgery patients.