Parathyroid Hormone Analogs Research Articles

The Effect of Parathyroid Hormone Analogues When Added to Mineralized Bone Xenografts.

Implants can be a treatment option when there is sufficient quantity and quality of bone to provide support for long-term success. In the reconstruction of defects, autogenous bone remains the gold standard for its osteogenic and compatibility properties. However, the disadvantage of secondary surgery and the associated donor site morbidity prompts researchers to develop the ideal bone substitute for optimum bone reconstruction. Parathyroid hormone (PTH1-34) has provided a new option for improvement in bone regeneration. This study used a pig model to evaluate the effectiveness of parathyroid hormone when added to a xenograft, Bio-Oss, in reconstructing mandible defects. Six domestic pigs were used to create 3 posterior mandibular defects measuring 2 × 1-cm bilaterally with a total of 36 defects to simulate tooth extraction sites in humans. The defects were grafted in random order and divided into 3 groups as follows: control (no graft), Bio-Oss without PTH, and Bio-Oss with PTH. Defects were assessed with cone beam computerized tomography (CBCT), micro computerized tomography (microCT), nanoindentation, and histology. Results showed that adding PTH1-34 significantly enhanced the graft construct. CBCT showed a significant increase in the degree of bone mineralization. Nanoindentation showed increased hardness of regenerated bone and accelerated bone mineralization with PTH. MicroCT analysis revealed a trend toward higher bone regeneration and mineralization. The histological analysis showed a positive trend of the increase in cortical bone thickness and mineral apposition rate. In conclusion, the local addition of PTH1-34 to a xenograft has shown promising results to enhance bone regeneration in the reconstruction of mandibular defects.

Teriparatide relieves ovariectomy-induced hyperalgesia in rats, suggesting the involvement of functional regulation in primary sensory neurons by PTH-mediated signaling

Clinical studies have reported that teriparatide (TPTD), a human parathyroid hormone analog, reduces back pain in osteoporotic patients. However, the mechanistic insights of this pharmacological action remain elusive. This study investigated the antinociceptive effect of TPTD mainly on primary sensory neurons in ovariectomized (OVX) rats. The plantar test showed thermal hyperalgesia in the OVX rats, which was significantly, but not fully, recovered immediately after the initial TPTD administration. The von Frey test also demonstrated reduced withdrawal threshold in the OVX rats. This was partially recovered by TPTD. Consistently, the number and size of spinal microglial cells were significantly increased in the OVX rats, while TPTD treatment significantly reduced the number but not size of these cells. RNA sequencing-based bioinformatics of the dorsal root ganglia (DRG) demonstrated that changes in neuro-protective and inflammatory genes were involved in the pharmacological effect of TPTD. Most neurons in the DRG expressed substantial levels of parathyroid hormone 1 receptor. TPTD treatment of the cultured DRG-derived neuronal cells reduced the cAMP level and augmented the intracellular calcium level as the concentration increased. These findings suggest that TPTD targets neuronal cells as well as bone cells to exert its pharmacological action.

The microbiome adds to the complexity of parathyroid hormone action on bone.

Parathyroid hormone (PTH) has complex effects on bone, including stimulating bone formation and regulating the hematopoietic stem cell (HSC) niche. In the current issue of the JCI, Li et al. demonstrated that the microbiome, through the production of short-chain fatty acids and in particular, butyrate, is necessary for the ability of PTH to increase osteoblast numbers and stimulate bone formation. In addition to implications for the treatment of osteoporosis with PTH analogs, this pathway may be part of a broader mechanism through which the microbiome serves its key function of modulating the immune system.

167. Assessment of the efficacy of teriparatide (Forteo) in patients undergoing posterolateral lumbar spinal fusion: a double-blinded randomized pilot study

BACKGROUND CONTEXT Lumbar spinal fusion is an increasingly common procedure for treating degenerative diseases of the lumbar spine. Non-solid fusion, or pseudarthrosis, at one year is a common complication associated with poor clinical outcomes and need for revision surgery. The risk of pseudarthrosis depends on the number of levels fused, the fusion material, and patient risk factors (osteoporosis, smoking, diabetes, etc.). Although there are multiple options for bone graft and osteoinductive materials, all have their benefits, side-effects and cost. Teriparatide is an injectable recombinant analog of parathyroid hormone that has been well-studied in its treatment of osteoporosis. However, no clinical studies of its effect on spinal fusion in humans have been published to date. PURPOSE To analyze the effect of teriparatide treatment on posterolateral spinal fusion in adults with degenerative diseases of the lumbar spine. STUDY DESIGN/SETTING Multicenter prospective double-blinded randomized study. PATIENT SAMPLE 60-90 year-olds with degenerative scoliosis, spondylolisthesis, or spondylosis at two medical centers undergoing instrumented posterolateral instrumented fusion >2levels. Use of BMP was excluded. OUTCOME MEASURES Pseudoarthrosis, screw loosening, PJK by CT. VAS, ODI, and Eq5D. METHODS Prospective randomized double-blind placebo-controlled pilot study performed at two large academic centers, UCSF and McGill University (Montreal). Included patients were aged 60-90 years with degenerative lumbar disease who were scheduled to undergo two-level or greater posterolateral lumbar spinal fusion. Patients were randomized in a 2:1 (Forteo:Placebo) manner. Patient were dosed 2 weeks pre-op and 10 weeks post-op. Patient derived outcomes were collected pre-op, 3, 6, 9, and 12 months. Fusions at 1 year were analyzed by helical CT. RESULTS A total of 36 patients completed the study. 58.3% (n=21) received teriparatide. 42.8% (n=9) reported an adverse event. Fusion rate of all patients was 47.2% (n=17); the remaining 52.8% (n=19) demonstrated pseudoarthrosis at 1 year. Fourty-seven percent of patients receiving teriparatide had a pseudoarthrosis, while 60% of placebo had a pseudoarthrosis. VAS, ODI, and Eq5D improved in all groups but no significant difference was found between groups. CONCLUSIONS Teriparatide appears to provide minimal benefit of avoiding pseudoarthroses in 60-90 year-olds undergoing thoracolumbar fusions. Teriparatide appears to have a fairly safe side effect profile. Further larger scale studies are warranted, possibly with the addition of BMP and/or bisphosphonates. FDA DEVICE/DRUG STATUS Unavailable from authors at time of publication.

The combined effect of Parathyroid hormone (1\u201334) and whole-body Vibration exercise in the treatment of postmenopausal OSteoporosis (PaVOS study): a randomized controlled trial

SummaryTreatment effects of combining teriparatide and whole-body vibration exercise (WBV) vs teriparatide alone in twelve months were compared using bone mineral density (BMD), bone microarchitecture, and bone turnover markers. We found an increased effect in lumbar spine BMD by adding WBV to teriparatide in postmenopausal osteoporotic women.IntroductionThe parathyroid hormone (PTH) analogue teriparatide is an effective but expensive anabolic treatment for osteoporosis. Whole-body vibration exercise (WBV) has been found to stimulate muscle and bone strength in some studies. Animal data demonstrate a beneficial effect on bone when combining PTH with mechanical loading. The aim of this study was to investigate if combining WBV exercise and teriparatide treatment gives additional beneficial effects on bone compared to teriparatide alone in postmenopausal women with osteoporosis.MethodsThe PaVOS study is a randomized controlled trial where postmenopausal osteoporotic women starting teriparatide 20 μg/day were randomized to WBV + teriparatide or teriparatide alone. WBV consisted of three sessions a week (12 min, including 1:1 ratio of exercise:rest). Bone mineral density (BMD) and bone microarchitecture, bone turnover markers, and sclerostin measurements were obtained. Data were analyzed using a linear mixed regression model with adjustment for baseline values or robust cluster regression in an intention-to-treat (ITT) analysis.ResultsThirty-five women were randomized (17 in teriparatide + WBV group and 18 in teriparatide group). At 12 months, both groups increased significantly in BMD at the lumbar spine. The teriparatide + WBV group increased by (mean ± SD) 8.90% ± 5.47 and the teriparatide group by 6.65% ± 5.51. The adjusted treatment effect of adding WBV to teriparatide was statistically significant at 2.95% [95% CI = 0.14–5.77; P = 0.040]. Markers of bone turnover increased significantly in both groups at three and six months with no significant difference between groups. No other treatment effects were observed in hip BMD, bone microarchitecture parameters, or sclerostin levels in either group.ConclusionTwelve months of WBV and teriparatide had a significant clinically relevant treatment effect in lumbar spine BMD compared to teriparatide alone in postmenopausal osteoporotic women.ClinicalTrials.gov:(NCT02563353).

Update on hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder characterized by low or insufficient parathyroid hormone (PTH) concentrations leading to hypocalcemia, hyperphosphatemia, and markedly reduced bone turnover. Despite being a rare disease, hypoparathyroidism has a profound impact on affected patients. Recent epidemiologic surveys demonstrate a prevalence of between 5.3 and 40/100 000, confirming the orphan status of this disease. There is a female predominance, and anterior neck surgery is the most common etiology. Recent studies have better elucidated the chronic manifestations of the disease, impacting quality of life and multiple organ systems including the renal, cardiovascular, and skeletal systems. There are now data on longer term use of parathyroid hormone (PTH) and PTH analogs. This review focuses on recent contributions to the literature on the prevalence and epidemiology of the disease, risk of chronic manifestations, and treatment with PTH(1-34) and rhPTH(1-84). Further research is needed to determine the pathophysiology of complications in hypoparathyroidism and whether interventions can decrease future risk of these complications. In addition, further data are needed with regards to more physiologic dosing regimens and long-term treatment with PTH and PTH analogs.

Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review.

Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option.

OR30-3 Structural Basis of Activation and Sustained Signaling by the PTH Receptor

Parathyroid hormone (PTH) receptor (PTHR) is a medically important family B G Protein Coupled Receptor (GPCR) that primarily couples to Gs/cAMP and Gq/Ca2+ signaling pathways and has a central role in regulating Ca2+ homeostasis and bone turnover. PTHR is activated by two endogenous hormones, endocrine PTH and paracrine PTH related protein (PTHrP), but only PTH mediates prolonged activation of the receptor and sustained cAMP responses after receptor internalization to the endosomes. To investigate the structural basis of prolonged activation of PTHR, we employed cryo-EM and solved the high resolution (3Å) structure of PTHR coupled to Gs and activated by long-acting PTH (LA-PTH), an analog of PTH that remarkably sustains endosomal PTHR signaling and induces significantly prolonged elevation in blood calcium in mice and monkeys. LA-PTH binds the receptor as a single extended α-helix with its N-terminus inserted deep into the transmembrane domain (TMD) of the receptor, while positioning the extracellular domain (ECD) of PTHR perpendicular to the cell membrane. The receptor activating N-terminal half of LA-PTH forms a dense network of hydrophobic and polar interactions with receptor’s TMD resulting in a tight binding and giving structural basis for remarkably sustained activation of PTHR by LA-PTH. Binding of LA-PTH activates the receptor by inducing partial unwinding of the C-terminus of transmembrane helix 6 (TM6) and a sharp kink at the middle of this helix, a hallmark of family B GPCR activation. This results in a pronounced outward movement of TM6, opening the cytosolic cavity of the receptor, which allows subsequent G protein coupling. Additionally, our cryo-EM data revealed structural dynamics of PTHR demonstrated by the ability of receptor ECD to adopt multiple conformational states. Together, these results reveal the structural determinants of PTHR signaling and provide a molecular framework for structure-based design of novel therapeutics for osteoporosis and hypocalcaemia treatment.

Successful treatment of pathologic femoral shaft fracture associated with large arteriovenous malformations using a 3-dimensional external fixator and teriparatide: a case report

BackgroundArteriovenous malformations (AVMs) are rare congenital vascular lesions associated with early quiescence, late expansion, and, ultimately, infiltration and destruction of local soft tissue and bone. The extremities are a common location. Incidence of bony involvement by AVM has been reported as high as 31%. However, there are few reports on management of pathologic fracture associated with AVM. Teriparatide is a recombinant parathyroid hormone (PTH) analogue consisting of the 1–34 fragment of PTH. Recently, some reports have shown the ability of teriparatide to improve fracture healing. Here, we present a case of pathologic femoral shaft fracture associated with large AVMs that was treated successfully by external fixation and teriparatide.Case presentationA 68-year-old Japanese woman, previously diagnosed as having large AVMs, sustained a right femoral shaft fracture due to a fall. At the time of admission, she presented with massive swelling and venous varicosities of the right thigh. Plain radiography of the right thigh revealed femoral shaft fracture with bony erosion and calcification of soft tissue. We planned closed reduction and intramedullary nailing with a unilateral external fixator following embolization of the feeding artery. However, closed reduction using the fracture table was difficult. When we attempted open reduction, massive bleeding (1000 mL) after incision of subcutaneous tissue occurred. Finally, we carefully applied a Taylor Spatial Frame. Fracture displacement was corrected successfully and bony union was obtained with administration of teriparatide 15 months after the initial surgery. The patient is able to walk using 1 cane.ConclusionWe present the first report of pathologic fracture associated with large AVMs that achieved bony union using a 3-dimensional external fixator and teriparatide.

Structural Basis of Activation and Sustained Signaling by the PTH Receptor

Parathyroid hormone (PTH) receptor (PTHR) is a medically important family B G Protein Coupled Receptor (GPCR) that primarily couples to Gs/cAMP and Gq/Ca2+ signaling pathways and has a central role in regulating Ca2+ homeostasis and bone turnover. PTHR is activated by two endogenous hormones, endocrine PTH and paracrine PTH related protein (PTHrP), but only PTH mediates prolonged activation of the receptor and sustained cAMP responses after receptor internalization to the endosomes. To investigate the structural basis of prolonged activation of PTHR, we employed cryo‐EM and solved the high resolution (3Å) structure of PTHR coupled to Gs and activated by long‐acting PTH (LA‐PTH), an analog of PTH that remarkably sustains endosomal PTHR signaling and induces significantly prolonged elevation in blood calcium in mice and monkeys. LA‐PTH binds the receptor as a single extended α‐helix with its N‐terminus inserted deep into the transmembrane domain (TMD) of the receptor, while positioning the extracellular domain (ECD) of PTHR perpendicular to the cell membrane. The receptor activating N‐terminal half of LA‐PTH forms a dense network of hydrophobic and polar interactions with receptor's TMD resulting in a tight binding and giving structural basis for remarkably sustained activation of PTHR by LA‐PTH. Binding of LA‐PTH activates the receptor by inducing partial unwinding of the C‐terminus of transmembrane helix 6 (TM6) and a sharp kink at the middle of this helix, a hallmark of family B GPCR activation. This results in a pronounced outward movement of TM6, opening the cytosolic cavity of the receptor, which allows subsequent G protein coupling. Additionally, our cryo‐EM data revealed structural dynamics of PTHR demonstrated by the ability of receptor ECD to adopt multiple conformational states. Together, these results reveal the structural determinants of PTHR signaling and provide a molecular framework for structure‐based design of novel therapeutics for osteoporosis and hypocalcaemia treatment.Support or Funding InformationNIH R01 DK116780, DK102495 and DK111427 awarded to JPV; the Jay and Betty Van Andel Foundation and NIH GM127710 grants awarded to EXThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Characterization and Expression Profiling of Recombinant Parathyroid Hormone (rhPTH) Analog 1–34 in Escherichia coli, Precise with Enhanced Biological Activity

Human truncated parathyroid hormone [hPTH (1–34)], a peptide hormone which accelerated the research interest towards the theraputical applications. This study outlines the effective expression of [hPTH (1–34)] in Escherichia coli and the recuperation of highly soluble truncated PTH from the fusion protein by proteolytic digestion. Successful expression of glutathione S-transferase (GST) fusion protein was achieved by incorporating truncated PTH with an enzymatic cleavage site into the “N” terminal GST of pGEX-4T-3 expression vector. Under the optimized condition, we achieved more than 120 mg of pure hPTH (1–34) per liter of bacterial culture, with an overall yield of 39%. Purification process was carried out through immobilized metal ion chromatography and membrane filter to produce maximum purity. Physical characterization using western blot analysis showed that the extracted truncated PTH is intact and reacts with anti-PTH antibodies. In vitro analysis of PTH stimulated adenylyl cyclase activation in UMR 106 cells confirmed biological activity for purified protein. We believe this vector and production methodology represents a generally applicable tool for the generation of recombinant peptides.

New Targets and Emergent Therapies for Osteoporosis.

The 11 existing FDA-approved osteoporosis drug treatments include hormone replacement therapy, 2 SERMs (raloxifene and bazedoxifene), 5 inhibitors of bone-resorbing osteoclasts (4 bisphosphonates and anti-RANKL denosumab), 2 parathyroid hormone analogues (teriparatide and abaloparatide), and 1 WNT signaling enhancer (romosozumab). These therapies are effective and provide multiple options for patients and physicians. As the genomic revolution continues, potential novel targets for future drug development are identified. This review takes a wide perspective to describe potentially rewarding topics to explore, including knowledge of genes and pathways involved in bone cell metabolism, the utility of animal models, targeting drugs to bone, and ongoing advances in drug design and delivery.

Combination therapy with parathyroid hormone analogs and antiresorptive agents for osteoporosis: a systematic review and meta-analysis of randomized controlled trials.

Combination therapy with parathyroid hormone (PTH) analogs and antiresorptive agents may be more effective than monotherapy for the treatment of osteoporosis. This study aimed to estimate the effectiveness and safety of this combination therapy for osteoporosis. MEDLINE, EMBASE, and Cochrane Library were searched from inception to May 1, 2018, including randomized controlled trials (RCTs) with a duration of at least 6months on adults with osteoporosis treated with combination therapy versus monotherapy. Outcomes included fractures, bone mineral density (BMD) changes, and adverse events. A meta-analysis was performed using a random-effect model, to estimate risk ratios (RRs) for fractures, and mean differences (MDs) for BMD changes. A total of 19 RCTs and 2177 patients were included. Compared with monotherapy, combination therapy had an advantage of 36% (RR, 0.64; 95% confidence interval (CI), 0.42-0.98) regarding fracture risk reduction. It also appears to improve lumbar spine BMD by 4.06% (95%CI = 2.60-5.53) and total hip BMD by 1.89% (95%CI = 1.25-2.53). No RCT reported an increased risk of serious adverse events. Among patients with osteoporosis, combination therapy was superior to monotherapy regarding improvement of the lumbar spine and total hip BMD, without risk of serious adverse events. Combination therapy also had an advantage over monotherapy on fracture risk reduction. However, owing to the limited sample size, additional larger studies are required to confirm this benefit.

EXPERIENCE OF LONG-TERM TERIPARATIDE USE FOR THE TREATMENT OF POSTOPERATIVE HYPOPARATHYROIDISM ASSOCIATED WITH OSTEOPOROSIS IN ELDERLY PATIENT

The aim of studyis to reflect the possibilities and effectiveness of teriparatide for the treatment of postoperative hypoparathyroidism associated with severe systemic osteoporosis, based on the data of the clinical case.Materials and methods.Patient N., aged 69, having a history of resection of 2/3 of the stomach according by Bilrot-2, urolithiasis, hypertension; since 2011 has been repeatedly hospitalized in National Medical Research Centre of Endocrinology, Ministry of Health of Russia, for secondary hyperparathyroidism and severe systemic osteoporosis. In 2016 thyroidectomy was performed in connection with papillary thyroid cancer and removal of left parathyroid gland adenoma, after which the patient developed postoperative hypoparathyroidism with severe uncontrolled hypocalcemia. As a replacement therapy, a synthetic analogue of parathyroid hormone, teriparatide, was used. For this work we used epicrisis of 2011–2016, as well as the results of the patient’s examination performed during the inpatient treatment in the Endocrinology Department of City Clinical Hospital № 4 (Ivanovo) from 2016 to 2018.Results.As a result of treatment with teriparatide in this patient, according to the results of a three-year follow-up, there is a positive clinical effect in the form of absence of convulsive syndrome, normalization of total and ionized calcium levels, absence of new compression fractures of vertebral bodies. Since the recovery of parathyroid gland function after surgery has not occurred, the use of this drug to the patient is recommended for the life term.Conclusion.The study describes a clinical case involving teriparatide as a therapy for postoperative hypoparathyroidism in combination with severe systemic osteoporosis and impaired calcium absorption in an elderly patient. The clinical effect of this type of treatment over a period of 3 years was proved in the form of normalization of phosphorus-calcium metabolism and the processes of bone remodeling in the absence of any side effects.

Sequential Treatment with Eldecalcitol After PTH Improves Bone Mechanical Properties of Lumbar Spine and Femur in Aged Ovariectomized Rats

Parathyroid hormone (PTH) analogs have a powerful anabolic effect on bone and are used in the treatment of patients with severe osteoporosis. However, there are limitations to how long they can be safely administered. Withdrawal of PTH results in the cancelation of its effects, necessitating subsequent treatment to maintain the bone quantity and quality. This study assessed the effects of Eldecalcitol (ELD), an active vitamin D3 derivative, after PTH in estrogen-deficient osteoporotic rats. Six-month-old female rats were ovariectomized, and PTH administration was started 7 weeks later. After 4 weeks of PTH treatment, the animals were divided into three groups and either continued to receive PTH (PTH–PTH), or were switched to ELD (PTH–ELD) or vehicle (PTH–Veh) for an additional 4 weeks. In the femur, increased BMD by 4 weeks treatment of PTH was significantly reduced in PTH–Veh but not in PTH–PTH and PTH–ELD. The same tendency was observed in the lumbar vertebrae. MicroCT imaging and histomorphometry analysis revealed that the favorable bone structure changes by PTH administration were also maintained in the femurs and tibias of the PTH–PTH and PTH–ELD groups. Increased bone strength by 4-week treatment of PTH in lumber also maintained in PTH–ELD. Furthermore, minimodeling was observed in the PTH–ELD group. These results demonstrate that treatment with ELD sequentially following PTH prevented the bone quantity and strength reduction that accompanies PTH withdrawal in estrogen-deficient rats.

Russian federal clinical guidelines on the diagnostics, treatment, and prevention of osteoporosis

Screening using the Fracture Risk Assessment Tool (FRAX) is recommended in all postmenopausal woman and mеn over 50 (A1) in order to identify individuals with high probability of fractures. It is recommended to diagnose osteoporosis and start treatment in patients with fragility fracture of large bones of the skeleton and/or high individual probability of major fragility fractures (FRAX) and/or detected decrease in bone mineral density (BMD) up to –2.5 T-score as assessed by DXA in the femoral neck and/or lumbar vertebrae (A1). Patients with back pain, lifetime height loss of 4 cm or height loss of 2 cm since a previous medical examination, those who receive glucocorticoids, patients with long lasting decompensated type 2 diabetes mellitus, or those receiving insulin therapy, as well as patients who were previously diagnosed with fragility fractures at the other sites are advised to underwent standard lateral X-ray imaging of the spine (Th4—L5) in order to verify the presence of compression vertebral fractures (B1).
 Dual-energy X-ray absorptiometry (DXA) is recommended for individuals whose 10-year probability of major osteoporotic fracture (FRAX) falls within the medium risk group (B1). It is recommended to include the trabecular bone score (TBS) the FRAX algorithm in order to improve the sensitivity of this method (B1).
 Laboratory testing is recommended for the differential diagnosis with other causes of increased skeletal fragility in all patients with newly diagnosed osteoporosis and when previously prescribed antiosteoporostic treatment was ineffective (B1).
 Bisphosphonates (BPs), antibodies to receptor activator of nuclear factor kappa-beta ligand (RANKL) (denosumab), or parathyroid hormone analogue (teriparatide) are equally recommended to prevent fragility fractures and increase BMD in patients with osteoporosis (A1). Denosumab is also recommended to prevent BMD loss and fractures in females receiving aromatase inhibitors therapy for breast cancer and males with prostate cancer receiving hormone-deprivation therapy and having no bone metastases (A1). Since teriparatide has the anabolic effect, it is recommended as the first line treatment in patients with severe osteoporosis having history of vertebral fractures, in the individuals with very high risk of fragility fractures, or in the cases when antiresorptive treatment was ineffective (B1). All medications for treatment of osteoporosis are recommended in combination with calcium and vitamin D supplements (A1).

Regulation of Bone Remodeling by Parathyroid Hormone.

Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone anabolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone matrix. Here, we will provide an overview of the multiple cellular and molecular mechanisms through which PTH influences bone homeostasis. Notably, net skeletal effects of continuous versus intermittent can differ significantly. Where possible, we will highlight mechanisms through which continuous hyperparathyroidism leads to bone loss, and through which intermittent hyperparathyroidism boosts bone mass. Given the therapeutic usage of intermittent PTH (iPTH) treatment for osteoporosis, particular attention will be paid toward mechanisms underlying the bone anabolic effects of once daily PTH administration.

Parathyroid hormone analogues for fracture healing: protocol for a systematic review and meta-analysis of randomised controlled trials

IntroductionFracture healing is a complex physiological process. Impaired healing will increase the need for care and cause serious complications. Thus, identifying strategies to accelerate the rate of healing, preventing delayed...

Therapeutic Approaches to Secondary Fracture Prevention in High Risk Populations: Current Recommendations and Advances

Background: Osteoporotic fragility fracture is a burgeoning health epidemic that is associated with high rates of disability, morbidity, and mortality. Based on NHANES data, approximately 10 million Americans are affected by this disease. Areas of Uncertainty: Successful secondary fracture prevention measures are often limited by the under-diagnosis of osteoporosis after fragility fractures because of lack of patient and physician awareness of the disease, lack of follow-up, and medical nonadherence. Therapeutic Advances: Current guidelines recommend the use of Bisphosphonate as the first-line therapy for secondary fracture prevention. Compared with placebo, randomized controlled trials have demonstrated a significant reduction in vertebral and nonvertebral fractures using Alendronate, Risedronate, Ibandronate, and Zoledronic acid. All but Ibandronate showed a significant reduction in hip fractures as well (all trials with P < 0.05). Denosumab is an option in patients with impaired renal function or who are unresponsive to other therapies. It significantly decreases the risk of new vertebral fracture [hazard ratio (HR) = 0.32, 95% confidence interval (CI), 0.26–0.41], hip fracture (HR = 0.60, 95% CI, 0.37–0.97) and nonvertebral fracture (HR = 0.80; 95% CI, 0.67–0.95) without an increased in adverse events. Hormonal therapy has been shown to be effective but should be used in the lowest effective dose to minimize the risk of coronary heart disease, stroke, and venous thromboembolism. Selective estrogen replacement modulators, calcitonin, and parathyroid hormone analog are other alternatives described in this article. In addition to current therapies, emerging therapies under investigation such as Abaloparatide, a parathyroid receptor ligand, and Romosozumab, a monoclonal anti-sclerotin antibody both showed a reduction in new morphometric vertebral fractures compared with placebo (0.58% vs. 4.22%, relative risk = 0.14, 95% CI, 0.05–0.39 and 0.5 vs. 1.8%, relative risk = 0.27, 95% CI, 0.16–0.47, respectively). In this article, we summarize advances in current therapeutic agents used for secondary fracture prevention and provide insight into potential therapies that hold promise in the future of osteoporosis. Conclusion: Secondary prevention of fragility fractures through care coordination and initiation of various pharmacologic agents is crucial in the elderly population. Careful risk assessment and stratification should be performed before the initiation of pharmacologic treatment to optimize disease management.

Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism.

Human parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. The novel compound was then repurposed as an improved therapy for hypoparathyroidism. A longer-acting form of PTH was synthesised by altering the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a compound, which was tested in an animal model of osteoporosis before entering human trials. This compound was subsequently tested in two independent animal models of hypoparathyroidism. The peptide identified, LY627-2K, exhibited delayed internalization kinetics. In an ovariectomy-induced bone loss rat model, LY627-2K demonstrated improved vertebral bone mineral density and biomechanical properties at skeletal sites and a modest increase in serum calcium. In a Phase I clinical study, dose-dependent increases in serum calcium were reproduced. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favourably to treatment with wild-type PTH. We summarize the repositioning of a therapeutic candidate with substantial preclinical and clinical data. Our results support its repurposing and continued development, from a common indication (osteoporosis) to a rare disease (hypoparathyroidism) by exploiting a shared molecular target. This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.