abaloparatide and Osteoporosis

Osteoporosis poses a challenge to public health, causing fragility fractures, especially in postmenopausal women. Abaloparatide (ABL) is an effective anabolic agent to improve bone formation and resorption among postmenopausal women with osteoporosis. Our meta-analysis aims to assess the effectiveness and safety of ABL versus teriparatide (TPTD) in improving bone mineral density (BMD).. We searched Medline, Embase, Web of Science, Cochrane databases and Clinicaltrial.gov until September 2, 2022. We included data from randomized controlled trials (RCTs) and post hoc analyses of RCTs. Outcomes included BMD change from baseline and risks of adverse events. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of outcomes.. Four studies including 16 subgroups were included in this study. In particular, RCTs with head-to-head comparisons of ABL and TPTD were used in the meta-analysis, and all were from manufacturer-sponsored trials. All parameters in 24 weeks except lumbar spine (versus TPTD) showed significant advantages in the ABL group. Only the results of two subgroups in ABL versus TPTD demonstrated High GRADE quality (femoral neck: weighted mean difference (WMD) = 1.58 [0.52, 2.63]; Total hip: WMD = 1.46 [0.59, 2.32]). However, our fracture data were insufficient. Besides, we found no evident difference in serious adverse events or deaths in either group and the incidence of hypercalcemia in the ABL group lessened by 51% compared with the TPTD group. Nevertheless, compared with placebo, ABL demonstrated higher risks of nausea and palpitations.. ABL demonstrated a beneficial effect on BMD compared to both placebo and TPTD for postmenopausal women with osteoporosis. ABL also had insignificantly lowered adverse event risk than TPTD. ABL is an alternative for patients with postmenopausal osteoporosis.

Topics: Bone Density; Bone Density Conservation Agents; Female; Fractures, Bone; Humans; Lumbar Vertebrae; Osteoporosis; Osteoporosis, Postmenopausal; Teriparatide

Osteoporosis is a debilitating disease characterized by reduced bone mineral density and an increased risk of fractures. This review aims to provide a comprehensive overview of, and map current knowledge, obtained from preclinical and clinical studies of the osteoanabolic agent abaloparatide. PubMed and Embase were meticulously searched from inception to May 4, 2021.178 titles and abstracts were screened, and 57 full-text articles were assessed for inclusion. A total of 55 articles were included; 5 (9%) in vitro studies, 21 (38%) in vivo studies, and 29 (53%) clinical studies. Preclinical in vitro studies have demonstrated receptor conformation preferability, structural insights into the receptor-agonist complex, and proliferative effects of abaloparatide on osteoblasts. Preclinical studies have shown abaloparatide to be similarly effective to teriparatide using comparable doses in both ambulating mice and rats challenged by disuse. Other animal studies have reported that abaloparatide effectively mitigates or prevents bone loss from ovariectomy, orchiectomy, and glucocorticoids and improves fracture healing. The pivotal clinical study ACTIVE demonstrated 18 months of treatment with abaloparatide substantially increase bone mineral density and reduce fracture risk in post-menopausal women compared with placebo. The extension study ACTIVExtend highlighted that subsequent treatment with alendronate sustained the bone gained by abaloparatide treatment and the reduced fracture risk for up to two years. Post-hoc sub-group analyses have also supported the efficacy and safety of abaloparatide treatment independent of various baseline risk factors. In conclusion, mounting evidence from preclinical and clinical studies has uniformly reported that abaloparatide increases bone mineral density and reduces fracture risk.

Topics: Animals; Bone Density; Bone Density Conservation Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Treatment Outcome

Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.

Topics: Absorptiometry, Photon; Age Factors; Aged; Aged, 80 and over; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Denosumab; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Prognosis; Risk Assessment; Severity of Illness Index; Sex Factors; Treatment Outcome

Osteoporosis and fragility fractures are relevant health issues because of their impact in terms of morbidity, mortality, and socioeconomic burden. Despite this alarming scenario, both underdiagnosis and undertreatment are common features of osteoporotic patients, particularly those who have already sustained a fragility fracture. Pharmacotherapy of osteoporosis is the main treatment option for these patients because of strong evidence about the efficacy of available drugs targeting bone metabolism. However, several issues can interfere with the effectiveness of anti-osteoporotic drugs in clinical practice, such as lack of awareness of both healthcare providers and patients, poor adherence to therapy, and safety in long-term treatment. Therefore, new therapeutic strategies have been proposed to overcome these problems, such as sequential therapy or emerging molecules mainly targeting the stimulation of bone formation. In particular, abaloparatide has been demonstrated to reduce major nonvertebral fracture risk compared with both placebo and teriparatide, although the European Medicines Agency (EMA) refused the marketing authorization because the benefits of this drug did not outweigh its risks. On the other side, EMA has recently approved romosozumab, a monoclonal antibody directed against sclerostin and the only available therapeutic option targeting Wnt signaling, as both bone-forming and antiresorptive intervention to treat osteoporosis and fragility fractures.

Topics: Antibodies, Monoclonal; Bone Density Conservation Agents; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Teriparatide

Osteoporosis is a common and debilitating condition characterized by diminished bone mass and architecture leading to bone fragility. Antiresorptive medicines like bisphosphonates (and less commonly denosumab) are the typical first-line agents for the medical treatment of osteoporosis. However, newer anabolic agents have been shown to improve bone mass and architecture, as well as reduce fracture risk, to a greater degree than traditional antiresorptive therapies. Teriparatide (human recombinant parathyroid hormone (PTH) 1-34, Forteo, Ely Lilly, Indianapolis, IN), which was the first in class to be approved in the United States, is the most widely used anabolic osteoporosis medicine and has shown significant benefit over traditional antiresorptive therapies. However, abaloparatide (synthetic parathyroid-related peptide (PTHrP), Tymlos, Radius Health, Waltham, MA), the second drug in this family, has recently become available for use. In this narrative review, we review the mechanism, effects, and benefits of abaloparatide compared to alternative treatments as well as discuss the current literature in regard to its effect on osteoporosis-related complications in the spine.

Topics: Anabolic Agents; Bone Density; Bone Density Conservation Agents; Diphosphonates; Humans; Osteoporosis; Parathyroid Hormone-Related Protein; Spine; Teriparatide

Musculoskeletal disorders represent an elevated socioeconomic burden for developed aging societies. Osteoporosis (OP) has been treated with antiresorptive therapies or with teriparatide that was until recently the only anabolic therapy. However, approval of osteoporosis treatment in postmenopausal women with abaloparatide, which is an analog of parathyroid hormone-related peptide (PTHrP), has created a new alternative for OP management. The success of this new treatment is related to differential mechanisms of activation of PTH receptor type 1 (PTH1R) by abaloparatide and PTH. Here, we address the distinguishing mechanisms of PTH1R activation; the effects of PTH1R stimulation in osteoblast, osteocytes, and chondrocytes; the differences between PTH and abaloparatide actions on PTH1R; potential safety concerns; and future perspectives about abaloparatide use in other musculoskeletal disorders.

Topics: Chondrocytes; Female; Humans; Middle Aged; Osteoblasts; Osteocytes; Osteoporosis; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein; Receptor, Parathyroid Hormone, Type 1; Teriparatide

Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34-amino acid fragment that is identical in its primary sequence to the 34 amino acids of full-length human parathyroid hormone [hPTH(1-84)]. ABL is identical to parathyroid hormone-related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF-I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non-vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210 mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non-vertebral fractures.

Topics: Animals; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Drug Therapy, Combination; Humans; Osteoblasts; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Risk Factors; Signal Transduction; Spinal Fractures; Teriparatide; Treatment Outcome

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.

Topics: Antibodies, Monoclonal; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Resorption; Denosumab; Diphosphonates; Drug Therapy, Combination; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Teriparatide

The efficacy and safety of abaloparatide, a parathyroid hormone-related protein analog for the treatment of osteoporosis in postmenopausal women at high fracture risk, is reviewed.. A MEDLINE search was conducted for full text English-language articles, using the terms abaloparatide, parathyroid hormone, and osteoporosis. Published articles pertinent to the short- and long-term efficacy and safety of abaloparatide among postmenopausal women with osteoporosis were reviewed and summarized. Based on randomized, placebo-controlled and active-comparator studies, abaloparatide can reduce the risk of new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Abaloparatide can also significantly increase bone mineral density (BMD) at the total hip, femoral neck, and lumbar spine. Patients receiving abaloparatide experience faster and more robust changes in BMD compared to those receiving teriparatide. Overall, abaloparatide is well tolerated with a mild adverse effect profile, including dizziness, headache, nausea, and palpitations. Additionally, there is a lower incidence of hypercalcemia with abaloparatide than with teriparatide. At this time, the differences demonstrated between abaloparatide and teriparatide would not be considered clinically significant. Larger and more robust studies are needed to determine future clinical significance of abaloparatide compared with other agents for use in the postmenopausal osteoporotic population.. Abaloparatide is an effective anabolic agent to improve bone formation and resorption amongst postmenopausal women with osteoporosis. Based on its clinical evidence, abaloparatide can result in greater BMD increases and less hypercalcemia compared with the only current marketed anabolic agent, teriparatide. Adverse events associated with abaloparatide are generally mild in nature and include nausea, dizziness, headache, and palpitations.

Topics: Bone Density; Bone Density Conservation Agents; Female; Fractures, Bone; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein

Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.

Topics: Aged; Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Risk Factors; Teriparatide

In patients with osteoporosis and severely reduced bone mass and/or recurring fractures, antiresorptive therapy may not be the optimal first-line treatment. Two recent clinical trials comparing bone-forming treatment with antiresorptive therapy have demonstrated that bone-forming treatment is superior in reducing the fracture risk in patients with severe osteoporosis. All of the currently available bone-forming agents-teriparatide, abaloparatide, and romosozumab-increase bone mineral density (BMD) and reduce the fracture risk; however, the effect wears off with time and treatment is therefore only transient. Thus, a bone-forming therapy should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The BMD response to bone-forming treatment is reduced in patients previously treated with antiresorptive drugs; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with antiresorptives seems to be preserved. This review provides an overview of the existing bone-forming therapies for osteoporosis including considerations of sequential and combination therapy.

Topics: Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Bone Resorption; Clinical Trials, Phase III as Topic; Denosumab; Diphosphonates; Drug Therapy, Combination; Humans; Osteogenesis; Osteoporosis; Parathyroid Hormone-Related Protein; Randomized Controlled Trials as Topic; Teriparatide

Topics: Amino Acid Sequence; Anabolic Agents; Animals; Bone Density; Bone Density Conservation Agents; Humans; Osteoporosis; Parathyroid Hormone-Related Protein; Protein Binding; Teriparatide

Osteoporosis affects a segment of the population in which Chronic Kidney Disease is also greatly represented. Nephropathic patients may present peculiar biochemical abnormalities related to Chronic Kidney Disease, defining the Mineral and Bone Disorder. This kind of anomalies, in the worst scenarios, configure the typical histomorphology patterns of Renal Osteodystrophy. Scientific Societies of Endocrinology have established therapy guidelines for patients with osteoporosis only based on the glomerular filtration rate and recommend avoiding the use of some drugs for the more advanced classes of nephropathy. However, there is no clear therapeutic approach for patients with advanced nephropathy and bone abnormalities. In this paper we propose a systematic review of the literature and present our proposal for managing patients with advanced nephropathy, based on eGFR and on presence of Mineral and Bone Disorder.

Topics: Antibodies, Monoclonal; Bone Density Conservation Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Contraindications; Denosumab; Diphosphonates; Female; Fractures, Spontaneous; Glomerular Filtration Rate; Humans; Male; Osteoporosis; Parathyroid Hormone-Related Protein; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Risk Factors; Teriparatide

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1-34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1-34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Resorption; Genetic Markers; Humans; Insulin-Like Growth Factor I; Osteoblasts; Osteogenesis; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Spinal Fractures; Teriparatide; Wnt Signaling Pathway

Identification of patients at risk for fragility fractures is the first important step in the management of osteoporosis. Bisphosphonates have been the mainstay of treatment for decades, whereas denosumab and selective oestrogen receptor modulators are other available licensed antiresorptive drugs. Currently teriparatide is the only approved anabolic agent in Europe, while abaloparatide and romosozumab are awaiting approval and might be available in the near future. For bisphosphonates, current guidance suggests an initial treatment course of 3-5 years and more prolonged treatment should be pursued in patients with higher fracture risk. For patients with lower risk, a period off treatment might be considered after this initial course to minimize the risks associated with more prolonged treatment, but this only applies to bisphosphonates and not denosumab or teriparatide. This review discusses strategies for case finding of patients at risk, currently available treatment options, recent developments in pharmacological management and duration of treatment.

Topics: Antibodies, Monoclonal; Bone Density Conservation Agents; Diphosphonates; Humans; Immunologic Factors; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Practice Guidelines as Topic; Risk Assessment; Treatment Outcome

Osteoporosis is a common skeletal disease with serious consequences due to osteoporotic fractures and high costs to society for post-fracture care. Most patients at high risk for fracture are not receiving care to reduce fracture risk. The osteoporosis treatment gap has reached crisis proportions. Strategies to reduce the treatment gap include systematic methods for identifying and treating high risk patients, better education of patients and healthcare providers, better use of currently available drugs, and development of new drugs to treat osteoporosis. Areas covered: Two osteoanabolic agents with novel mechanisms of action have recently completed phase 3 clinical trials. The efficacy and safety findings of these studies are reviewed. Abaloparatide, a synthetic analog of parathyroid hormone-related protein, has received regulatory approval for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Romosozumab, a humanized monoclonal antibody to sclerostin, an endogenous inhibitor of bone formation, is under regulatory review. Expert opinion: Osteoanabolic therapy for osteoporosis can restore, at least in part, the degradation of bone microarchitecture that is a hallmark of this disease. The emergence of new osteoanabolic compounds expands the treatment options for patients at high risk for fracture.

Topics: Anabolic Agents; Animals; Antibodies, Monoclonal; Drug Design; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Patient Education as Topic

Osteoporosis is characterized by low bone mass and qualitative structural abnormalities of bone tissue, leading to increased bone fragility that results in fractures. Pharmacological therapy is aimed at decreasing the risk of fracture, mainly correcting the imbalance between bone resorption and formation at the level of bone remodeling units. Anabolic therapy has the capability to increase bone mass to a greater extent than traditional antiresorptive agents. The only currently available drug licensed is parathyroid hormone 1-34 (teriparatide); new drugs are on the horizon, targeting the stimulation of bone formation, and therefore improving bone mass, structure and ultimately skeletal strength. These are represented by abaloparatide (a 34-amino acid peptide which incorporates critical N-terminal residues, shared by parathyroid hormone and parathyroid hormone-related protein, followed by sequences unique to the latter protein) and romosozumab (an antibody to sclerostin). In the future, the availability of new anabolic treatment will allow a more extensive utilization of additive and sequential approach, with the goal of both prolonging the period of treatment and, more importantly, avoiding the side effects consequent to long-term use of traditional drugs.

Topics: Accidental Falls; Anabolic Agents; Antibodies, Monoclonal; Drug Combinations; Hip Fractures; Humans; Italy; Osteoporosis; Parathyroid Hormone-Related Protein; Teriparatide

Teriparatide, a PTH analogue, was the first anabolic agent to be approved for the treatment of osteoporosis in 2002. Abaloparatide was also recently approved by the FDA. The need for other anabolic agents is still unmet. Areas covered: In this review, we discuss target molecules and recent advances in the field of anabolic therapy for osteoporosis. PTH and PTHrP analogues binding to the PTH receptor and different routes of administration of teriparatide to avoid the burden of daily subcutaneous injections are discussed. We also review antibodies targeting suppressors of the Wnt pathway such as sclerostin and Dickopff-1. Expert opinion: The development of alternative ways of administering PTH receptor ligands is a promising field, especially via the transdermal route. Other more promising molecules are still at very early stages of development. FDA recently requested more data on Romosozumab.

Topics: Anabolic Agents; Animals; Drug Design; Drugs, Investigational; Humans; Molecular Targeted Therapy; Osteoporosis; Parathyroid Hormone-Related Protein; Receptors, Parathyroid Hormone; Teriparatide

The treatment of osteoporosis is generally either by inhibition of bone resorption with antiresorptive agents or by stimulation of bone formation with anabolic agents. Currently, teriparatide (recombinant human parathyroid hormone 1-34 [rhPTH (1-34)]) is the only available approved anabolic agent in the U.S. Other anabolic agents are under investigation however. Abaloparatide is recombinant human parathyroid hormone-related peptide 1-34. This agent is an anabolic agent that appears more potent than teriparatide, and it may have more rapid onset of fracture reduction than teriparatide. It is currently undergoing FDA review, with approval expected in 2017.

Topics: Anabolic Agents; Bone Density Conservation Agents; Female; Humans; Osteogenesis; Osteoporosis; Parathyroid Hormone-Related Protein; Peptide Fragments; Teriparatide; Treatment Outcome

The purpose is to review the efficacy and optimal use of parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis treatment.. The parathyroid hormone analog teriparatide, a potent stimulator of bone remodeling, increases hip and spine bone mineral density and reduces the risk of vertebral and non-vertebral fractures in postmenopausal osteoporotic women. The parathyroid hormone-related protein analog, abaloparatide, also reduces fracture incidence but has pharmacological effects that differ from teriparatide, particularly in cortical bone. These analogs provide maximal benefit when their use is followed by a potent antiresorptive medication. Moreover, studies have shown that the combination of teriparatide and the RANK-ligand inhibitor, denosumab, increase bone density and estimated strength more than monotherapy and more than any currently available regimen. Parathyroid hormone and parathyroid hormone-related protein analogs, whether as monotherapy, in combination with antiresorptive agents or in sequence with antiresorptive agents, will likely play an expanding role in osteoporosis management.

Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Drug Therapy, Combination; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Spinal Fractures; Teriparatide

Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption, whereas osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces. In a phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, whereas procollagen type 1 N-terminal propeptide returned to normal. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase 2 clinical trial has reported areal bone mineral density gains at spine and hip that were greater with romosozumab compared with placebo, but also with teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a parathyroid hormone-related analogue with improved bone formation-resorption ratio.

Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Morphogenetic Proteins; Cathepsin K; Genetic Markers; Humans; Osteoporosis; Parathyroid Hormone-Related Protein

Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: -3.72% [95% confidence interval: -5.01%, -2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Bone Density; Bone Density Conservation Agents; Female; Humans; Lumbar Vertebrae; Minerals; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Postmenopause

This study aimed to determine the efficacy of abaloparatide in increasing bone mineral density (BMD) and its safety in postmenopausal Japanese women with osteoporosis.. Randomized, double-blind, placebo-controlled, dose-finding study of abaloparatide in postmenopausal Japanese women at high fracture risk. The primary endpoint was the change in lumbar spine (LS) BMD from baseline at the last visit after daily subcutaneous injections of placebo or 40 or 80 µg abaloparatide. Other endpoints included time-course changes in LS BMD at 12, 24, and 48 weeks, in total hip (TH) and femoral neck (FN) BMDs, and in bone turnover markers.. Increases in LS BMD with 40 and 80 µg abaloparatide were significantly higher than that with placebo (6.6% and 11.5%, respectively), with significant between-group differences for the abaloparatide groups (4.9%). TH BMD increased by 0.4%, 1.6%, and 2.9% and FN BMD increased by 0.6%, 1.5%, and 2.4% in the placebo and 40 and 80 µg abaloparatide groups, respectively. Serum PINP rapidly increased by 67.3% and 140.7% and serum CTX slowly increased by 16.4% and 34.5% in the 40 and 80 µg abaloparatide groups, respectively. Although more adverse events were observed in the abaloparatide groups, they were mild to moderate and not dose dependent.. In postmenopausal Japanese women with osteoporosis at high fracture risk, abaloparatide for 48 weeks dose-dependently increased LS, TH, and FN BMDs, supporting further investigation with 80 μg abaloparatide for the treatment of osteoporosis in this population.. JapicCTI-132381.

Topics: Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Humans; Lumbar Vertebrae; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause

Daily subcutaneous injection of 80 μg abaloparatide increased bone mineral density in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. Dual-energy X-ray absorptiometry-based hip structural analysis from ACTIVE-J data showed improved hip geometry and biomechanical properties with abaloparatide compared with placebo.. Abaloparatide (ABL) increased bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. To evaluate the effect of ABL on hip geometry and biomechanical properties, hip structural analysis (HSA) was performed using ACTIVE-J trial data.. Hip dual-energy X-ray absorptiometry scans from postmenopausal women and men (ABL, n = 128; placebo, n = 65) at baseline and up to week 78 were analyzed to extract bone geometric parameters at the narrow neck (NN), intertrochanteric region (IT), and proximal femoral shaft (FS). Computed tomography (CT)-based BMD and HSA indices were compared between baseline and week 78.. ABL treatment showed increased mean percent change from baseline to week 78 in cortical thickness at the NN (5.3%), IT (5.3%), and FS (2.9%); cross-sectional area at the NN (5.0%), IT (5.0%), and FS (2.6%); cross-sectional moment of inertia at the NN (7.6%), IT (5.1%), and FS (2.5%); section modulus at the NN (7.4%), IT (5.4%), and FS (2.4%); and decreased mean percent change in buckling ratio (BR) at the IT (- 5.0%). ABL treatment showed increased mean percent change in total volumetric BMD (vBMD; 2.7%) and trabecular vBMD (3.2%) at the total hip and decreased mean percent change in BR at femoral neck (- 4.1%) at week 78 vs baseline. All the changes noted here were significant vs placebo (P < 0.050 using t-test).. A 78-week treatment with ABL showed improvement in HSA parameters associated with hip geometry and biomechanical properties vs placebo.. JAPIC CTI-173575.

Topics: Absorptiometry, Photon; Bone Density; East Asian People; Female; Femur Neck; Fractures, Bone; Humans; Male; Osteoporosis

Abaloparatide reduced fracture risk in postmenopausal women with osteoporosis in the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE). Its effect in Japanese patients remains unexamined.. This work aimed to determine the efficacy and safety of abaloparatide in increasing bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk.. This was a randomized, double-blind, placebo-controlled study conducted in Japan. Postmenopausal women and men with osteoporosis with high fracture risk were given daily subcutaneous 80 µg abaloparatide or placebo for 78 weeks (18 months). The primary end point was percentage change in lumbar spine (LS) BMD from baseline at the last visit. Secondary end points included time-course changes in LS, total hip (TH), and femoral neck (FN) BMDs and bone turnover markers, and cumulative number of fractures.. Abaloparatide increased LS, TH, and FN BMDs (mean [95% CI]) by 12.5% (10.3%-14.8%; P < .001), 4.3% (3.3%-5.3%), and 4.3% (2.9%-5.6%), respectively, vs placebo. Serum procollagen type I N-terminal propeptide increased rapidly to ~ 140% above baseline at 6 weeks and gradually decreased but was approximately 25% higher than baseline at 78 weeks. Serum carboxy-terminal cross-linking telopeptide of type I collagen gradually increased to 50% above baseline at 24 weeks and decreased gradually to the placebo-group level from 60 weeks. Four vertebrae of 3 participants in the placebo group, but none in the abaloparatide group, developed new vertebral fractures. The safety profile was similar to that in the ACTIVE study.. In Japanese patients with postmenopausal and male osteoporosis with high fracture risk, abaloparatide for 78 weeks robustly increased LS, TH, and FN BMDs, suggesting a similar efficacy in Japanese patients vs the ACTIVE study population.

Topics: Bone Density; Bone Density Conservation Agents; Collagen Type I; Double-Blind Method; Female; Humans; Japan; Lumbar Vertebrae; Male; Osteoporosis; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein

Abaloparatide significantly increased bone mineral density (BMD) in women with postmenopausal osteoporosis and decreased risk of vertebral, nonvertebral, and clinical fractures compared with placebo. The Abaloparatide for the Treatment of Men with Osteoporosis (ATOM; NCT03512262) study evaluated the efficacy and safety of abaloparatide compared with placebo in men. Eligible men aged 40 to 85 years with osteoporosis were randomized 2:1 to daily subcutaneous injections of abaloparatide 80 μg or placebo for 12 months. The primary endpoint was change from baseline in lumbar spine BMD. Key secondary endpoints included BMD change from baseline at the total hip and femoral neck. A total of 228 men were randomized (abaloparatide, n = 149; placebo, n = 79). Baseline characteristics were similar across treatment groups (mean age, 68.3 years; mean lumbar spine BMD T-score, -2.1). At 12 months, BMD gains were greater with abaloparatide compared with placebo at the lumbar spine (least squares mean percentage change [standard error]: 8.48 [0.54] versus 1.17 [0.72]), total hip (2.14 [0.27] versus 0.01 [0.35]), and femoral neck (2.98 [0.34] versus 0.15 [0.45]) (all p < 0.0001). The most common (≥5%) treatment-emergent adverse events were injection site reaction, dizziness, nasopharyngitis, arthralgia, bronchitis, hypertension, and headache. During 12 months of abaloparatide treatment, men with osteoporosis exhibited rapid and significant improvements in BMD with a safety profile consistent with previous studies. These results suggest abaloparatide can be considered as an effective anabolic treatment option for men with osteoporosis. © 2022 Radius Health Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Aged; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Femur Neck; Humans; Male; Osteoporosis; Parathyroid Hormone-Related Protein

Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture.. We assessed the cardiovascular safety profile of abaloparatide.. Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults.. Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACE + HF was longer with abaloparatide (P = 0.02 vs placebo) and teriparatide (P = 0.04 vs placebo).. Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.

Topics: Aged; Blood Pressure; Bone Density; Bone Density Conservation Agents; Female; Heart Failure; Heart Rate; Humans; Middle Aged; Osteoporosis; Parathyroid Hormone-Related Protein; Postmenopause; Teriparatide; Treatment Outcome

Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p < 0.001) and nonvertebral fractures by 43% (p = 0.049) in postmenopausal women with osteoporosis. Abaloparatide-SC increased bone mineral density (BMD) 3.4% at the total hip, 2.9% at the femoral neck, and 9.2% at the lumbar spine at 18 months (all p < 0.001 versus placebo). The analysis reported here was designed to evaluate whether fracture risk reductions and BMD accrual were consistent across different levels of baseline risk. Risk factor subgroups were predefined categorically for BMD T-score of the lumbar spine, total hip, and femoral neck (≤-2.5 versus >-2.5 and ≤-3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (<65 versus 65 to <75 versus ≥75 years) at baseline. Forest plots show that there were no clinically meaningful interactions between any of the baseline risk factors and the treatment effect of abaloparatide-SC on new morphometric vertebral fractures, nonvertebral fractures, or BMD increases. Abaloparatide provides protection against fractures consistently across a wide variety of ages and baseline risks, including those with and without prior fractures, and it has potential utility for a broad group of postmenopausal women with osteoporosis. © 2016 American Society for Bone and Mineral Research.

Topics: Aged; Aged, 80 and over; Bone Density; Female; Humans; Middle Aged; Odds Ratio; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Postmenopause; Risk Factors

Topics: Anabolic Agents; Animals; Bone Remodeling; Denosumab; Osteoporosis; Rats; Rotator Cuff; Rotator Cuff Injuries

Parathyroid hormone (PTH) plays an important role in maintaining mineral homeostasis by regulating calcium and phosphate levels. Clinical trials have shown that peptides of PTH (1-34), PTH-related protein (PTHrP 1-36), and the new peptide modeled on PTHrP, abaloparatide, can have different anabolic effects on osteoporotic subjects, but the underlying mechanisms are still unclear. The prevalence of moderate and major gingival recession has been shown to be higher in postmenopausal women with osteoporosis. In addition, there is a significant association between osteoporosis and tooth loss.. We investigated the actions of these peptides on the cementoblasts and teeth of mice. The murine cementoblast line, OCCM-30, known to express collagen I (Col1a1), was treated with intermittent PTH (1-34), PTHrP (1-36), or abaloparatide for 6 h/d for 3 days. Microcomputed tomography was performed on the teeth of mice receiving daily injections of phosphate-buffered saline, PTH (1-34), or abaloparatide. Statistical differences were analyzed by a 2-way or 1-way analysis of variance followed by a Tukey's post-hoc test. Results are expressed as mean ± standard deviation, and P <0.05 was considered significant.. Gene expression showed regulation of Bsp, Col1a1, Opg, Rankl, and Mmp13 by the 3 peptides in these cells. Western blots revealed that after intermittent treatment for 3 days, PTH (1-34) caused an increase in COL1A1 protein immediately after treatment. In contrast, abaloparatide showed a latent effect in increasing COL1A1 protein 18 hours after treatment. PTHrP had no effect on COL1A1 expression. Immunofluorescence confirmed the same result as the Western blots. Microcomputed tomography of teeth showed PTH (1-34) injections increased molar root mineral density in mice, whereas abaloparatide increased density in roots of incisors and molars.. This study reveals the differential anabolic effects of intermittent PTH (1-34), PTHrP (1-36), and abaloparatide on cementoblasts, as revealed by COL1A1 expression and root mineral density. Abaloparatide may be a potential therapeutic approach for achieving improved cementogenesis.

Topics: Anabolic Agents; Animals; Collagen Type I; Collagen Type I, alpha 1 Chain; Dental Cementum; Female; Mice; Minerals; Osteoporosis; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Phosphates; Tooth Root; X-Ray Microtomography

Topics: Anabolic Agents; Animals; Bone Remodeling; Denosumab; Osteoporosis; Rats; Rotator Cuff; Rotator Cuff Injuries

Bone anabolic agents can benefit orthopaedic patients perioperatively and improve outcomes after fragility fractures. However, preliminary animal data raised concern for the potential development of primary bony malignancies after treatment with these medications.. This investigation examined 44,728 patients older than 50 years who were prescribed teriparatide or abaloparatide and compared them with a matched control group to evaluate risk of primary bone cancer development. Patients younger than 50 years with a history of cancer or other risk factors of bony malignancy were excluded. A separate cohort of 1,241 patients prescribed an anabolic agent with risk factors of primary bone malignancy, along with 6,199 matched control subjects, was created to evaluate the effect of anabolic agents. Cumulative incidence and incidence rate per 100,000 person-years were calculated as were risk ratios and incidence rate ratios.. The overall risk of primary bone malignancy development for risk factor-excluded patients in the anabolic agent-exposed group was 0.02%, compared with 0.05% in the nonexposed group. The incidence rate per 100,000 person-years was calculated at 3.61 for the anabolic-exposed patients and 6.46 for control subjects. A risk ratio of 0.47 ( P = 0.03) and incidence rate ratio of 0.56 ( P = 0.052) were observed for the development of primary bone malignancies in patients undergoing treatment with bone anabolic agents. Among high-risk patients, 5.96% of the anabolic-exposed cohort developed primary bone malignancies and 8.13% of nonexposed patients developed primary bone malignancy. The risk ratio was 0.73 ( P = 0.01), and the incidence rate ratio was 0.95 ( P = 0.67).. Teriparatide and abaloparatide can safely be used for osteoporosis and orthopaedic perioperative management without increased risk of development of primary bone malignancy.

Topics: Anabolic Agents; Animals; Bone Density; Bone Density Conservation Agents; Neoplasms; Osteoporosis; Teriparatide

Abaloparatide (ABL) significantly increases bone mineral density in men with osteoporosis similar to what was reported in postmenopausal women with osteoporosis. The cost effectiveness of sequential treatment with ABL followed by alendronate (ALN) in men at high fracture risk was compared to relevant alternative treatments.. A Markov-based microsimulation model based on a lifetime US healthcare decision maker perspective was developed to evaluate the cost (expressed in US$2021) per quality-adjusted life-years (QALYs) gained of sequential ABL/ALN. Comparators were sequential treatment unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Discount rates of 3% were used. Consistent with practice guidelines, patients received 18 months of ABL or TPTD followed by ALN for 5 years, or 5 years of ALN monotherapy. Analyses were conducted in high-risk men aged over 50 years defined as having a bone mineral density T-score ≤-2.5 and a recent fracture. Time-specific risk of subsequent fracture after a recent fracture, incremental costs up to 5 years following fractures, real-world medication adherence, and mostly US men-specific data were included in the model. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of results.. Over the full age range, sequential ABL/ALN led to more QALYs for lower costs than sequential unbranded TPTD/ALN, while no treatment was dominated (more QALYs, lower costs) by ALN monotherapy. The costs per QALY gained of sequential ABL/ALN were lower than the US threshold of US$150,000 versus generic ALN monotherapy. The probabilities that sequential ABL/ALN was cost effective compared to ALN monotherapy were estimated at 51% in men aged 50 years and between 88 and 90% in those aged ≥ 60 years.. Sequential therapy using ABL/ALN may be cost effective compared with generic ALN monotherapy in US men aged ≥ 50 years at high fracture risk, especially in those aged ≥ 60 years. Unbranded TPTD/ALN and no treatment were dominated interventions (less QALY, more costs) compared with ABL/ALN or ALN monotherapy.

Topics: Alendronate; Bone Density Conservation Agents; Cost-Benefit Analysis; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Quality-Adjusted Life Years; Teriparatide; United States

The PTH-related peptide(1-34) analog, abaloparatide (ABL), is the second anabolic drug available for the treatment of osteoporosis. Previous research demonstrated that ABL had a potent anabolic effect but caused hypercalcemia at a significantly lower rate. However, the mechanism by which ABL maintains the stability of blood calcium levels remains poorly understood. Our in vivo data showed that ABL treatment (40 µg/kg/day for 7 days) significantly increased rat blood level of 1,25-dihydroxyvitamin D [1,25-(OH)2D] without raising the blood calcium value. ABL also significantly augmented the carboxylated osteocalcin (Gla-Ocn) in the blood and bone that is synthesized by osteoblasts, and increased noncarboxylated Ocn, which is released from the bone matrix to the circulation because of osteoclast activation. The in vitro data showed that ABL (10 nM for 24 hours) had little direct effects on 1,25-(OH)2D synthesis and Gla-Ocn formation in nonrenal cells (rat osteoblast-like cells). However, ABL significantly promoted both 1,25-(OH)2D and Gla-Ocn formation when 25-hydroxyvitamin D, the substrate of 1α-hydroxylase, was added to the cells. Thus, the increased 1,25-(OH)2D levels in rats treated by ABL result in high levels of Gla-Ocn and transient calcium increase in the circulation. Gla-Ocn then mediates calcium ions in the extracellular fluid at bone sites to bind to hydroxyapatite at bone surfaces. This regulation by Gla-Ocn at least, in part, maintains the stability of blood calcium levels during ABL treatment. We conclude that the signaling pathway of ABL/1,25-(OH)2D/Gla-Ocn contributes to calcium homeostasis and may help understand the mechanism of ABL for osteoporosis therapy.

Topics: Animals; Calcium; Osteocalcin; Osteoporosis; Parathyroid Hormone-Related Protein; Rats; Signal Transduction

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Aged; Bone Density; Female; Humans; Middle Aged; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein; Postmenopause

Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12-13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 μg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess.

Topics: Adipocytes; Animals; Biomarkers; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Femur; Glucocorticoids; Immunohistochemistry; Mechanical Phenomena; Mice; Osteocytes; Osteogenesis; Osteoporosis; Parathyroid Hormone-Related Protein; X-Ray Microtomography

Topics: Anabolic Agents; Antibodies, Monoclonal; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Humans; Osteoporosis; Parathyroid Hormone-Related Protein; Teriparatide

Topics: Alendronate; Female; Humans; Osteoporosis; Parathyroid Hormone-Related Protein; Postmenopause; Risk Reduction Behavior

Topics: Alendronate; Anorexia Nervosa; Bone and Bones; Bone Density Conservation Agents; Contraceptives, Oral; Disease Management; Humans; Osteoporosis; Parathyroid Hormone-Related Protein

Fracture risk increases with age, but few studies focus on persons ≥80 years. In the ACTIVE trial, treatment with abaloparatide for 18 months reduced osteoporotic fracture risk and increased bone mineral density. These effects were maintained with 24 months alendronate treatment in ACTIVExtend. We postulated that similar improvements in bone mineral density and safety would be demonstrated in women ≥80 years.. Post hoc analyses of bone mineral density and fracture incidence in women with osteoporosis at high risk of fracture ≥80 years from ACTIVExtend.. In total, 56 women aged ≥80 years at ACTIVE baseline entered the ACTIVExtend study; 46 of these completed the study. Mean age was 83.3 years; other baseline characteristics were similar. At the end of ACTIVE, bone mineral density increased at all sites for abaloparatide versus placebo. Bone mineral density increased in parallel in both groups during alendronate therapy (19 to 43 months) in ACTIVExtend. At month 43, mean percent change in bone mineral density from baseline was 17.2% abaloparatide/alendronate versus 8.6% placebo/alendronate (P < 0.0001) at the lumbar spine, 5.3% abaloparatide/alendronate versus 3.0% placebo/alendronate (P = 0.024) at the total hip, and 4.6% abaloparatide/alendronate versus 3.1% placebo/alendronate (P = 0.044) at the femoral neck. Fracture incidence was low and did not differ significantly between groups. Sequential treatment with abaloparatide followed by alendronate was well tolerated; the proportion of participants reporting adverse events was similar between groups.. Sequential treatment with abaloparatide followed by alendronate (43 months follow-up) in this small subgroup of ACTIVExtend participants suggests abaloparatide is well tolerated and effective in women aged ≥80 years. : Video Summary:http://links.lww.com/MENO/A618.. Video Summary:http://links.lww.com/MENO/A618.

Topics: Aged, 80 and over; Alendronate; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein

Androgen deficiency is a leading cause of male osteoporosis, with bone loss driven by an inadequate level of bone formation relative to the extent of bone resorption. Abaloparatide, an osteoanabolic PTH receptor agonist used to treat women with postmenopausal osteoporosis at high risk for fracture, increases bone formation and bone strength in estrogen-deficient animals without increasing bone resorption. This study examined the effects of abaloparatide on bone formation, bone mass, and bone strength in androgen-deficient orchiectomized (ORX) rats, a male osteoporosis model. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery. Eight weeks later, sham-operated rats received vehicle (saline; n = 10) while ORX rats (n = 10/group) received vehicle (Veh) or abaloparatide at 5 or 25 μg/kg (ABL5 or ABL25) by daily s.c. injection for 8 weeks, followed by sacrifice. Dynamic bone histomorphometry indicated that the tibial diaphysis of one or both abaloparatide groups had higher periosteal mineralizing surface, intracortical bone formation rate (BFR), endocortical BFR, and cortical thickness vs Veh controls. Vertebral trabecular BFR was also higher in both abaloparatide groups vs Veh, and the ABL25 group had higher trabecular osteoblast surface without increased osteoclast surface. By micro-CT, the vertebra and distal femur of both abaloparatide-groups had improved trabecular bone volume and micro-architecture, and the femur diaphysis of the ABL25 group had greater cortical thickness with no increase in porosity vs Veh. Biomechanical testing indicated that both abaloparatide-groups had stronger vertebrae and femoral necks vs Veh controls. These findings provide preclinical support for evaluating abaloparatide as an investigational treatment for male osteoporosis.

Topics: Animals; Biomechanical Phenomena; Cancellous Bone; Cortical Bone; Disease Models, Animal; Femur Neck; Male; Organ Size; Osteoporosis; Parathyroid Hormone-Related Protein; Rats, Sprague-Dawley; Spine; X-Ray Microtomography

Side-effects from allograft, limited bone stock, and site morbidity from autograft are the major challenges to traditional bone defect treatments. With the advance of tissue engineering, hydrogel injection therapy is introduced as an alternative treatment. Therapeutic drugs and growth factors can be carried by hydrogels and delivered to patients. Abaloparatide, as an analog of human recombinant parathyroid hormone protein (PTHrp) and an alternative to teriparatide, has been considered as a drug for treating postmenopausal osteoporosis since 2017. Since only limited cases of receiving abaloparatide with polymeric scaffolds have been reported, the effects of abaloparatide on pre-osteoblast MC3T3-E1 are investigated in this study. It is found that in vitro abaloparatide treatment can promote pre-osteoblast MC3T3-E1 cells' viability, differentiation, and mineralization significantly. For the drug delivery system, 3D porous structure of the methacrylated gelatin (GelMA) hydrogel is found effective for prolonging the release of abaloparatide (more than 10 days). Therefore, injectable photo-crosslinked GelMA hydrogel is used in this study to prolong the release of abaloparatide and to promote healing of defected bones in rats. Overall, data collected in this study show no contradiction and imply that Abaloparatide-loaded GelMA hydrogel is effective in stimulating bone regeneration.

Topics: Animals; Bone Diseases; Bone Regeneration; Cell Differentiation; Cell Line; Cell Survival; Drug Delivery Systems; Gelatin; Humans; Hydrogels; Methacrylates; Mice; Osteoblasts; Osteoporosis; Parathyroid Hormone-Related Protein; Teriparatide

The recently published Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) assessed the efficacy and safety of abaloparatide (80 µg daily subcutaneous) (ABL) vs placebo during 18 months, in postmenopausal osteoporosis. Teriparatide (20 µg daily subcutaneous) (TPD) was used as an open label active comparator. The results of the study suggest that ABL increases bone mineral density more than TPD and reduces major osteoporotic fractures to a greater extent than TPD with a more rapid onset of action. These outcomes combined with a positive safety profile make ABL an interesting addition to the armamentarium against postmenopausal osteoporosis.

Topics: Aged; Bone Density Conservation Agents; Female; Humans; Osteoporosis; Parathyroid Hormone-Related Protein

Topics: Female; Humans; Osteoporosis; Parathyroid Hormone-Related Protein; Postmenopause; Spinal Fractures