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Lamy O, Everts-Graber J, Rodriguez EG. Denosumab for osteoporosis treatment: when, how, for whom, and for how long. A pragmatical approach. Aging Clin Exp Res 2025; 37:70. [PMID: 40055268 PMCID: PMC11889064 DOI: 10.1007/s40520-025-02991-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/21/2025] [Indexed: 03/12/2025]
Abstract
Denosumab produces a continuous increase in bone mineral density over ten years, associated with a low risk of vertebral and non-vertebral fractures. Denosumab is well tolerated and easy to manage in daily clinical practice. For all these reasons, this treatment has a huge success. On the other hand, discontinuation of treatment is associated with a severe rebound effect including a sharp increase in bone turnover markers, loss of the bone density gained and a risk of nearly 20% of multiple vertebral fractures in postmenopausal women. High doses of potent bisphosphonates are needed to maintain bone turnover markers in the low range of premenopausal women, to mitigate this rebound effect. Prolonged treatment with denosumab is associated with a greater rebound effect and increases the risk of an early rebound effect. The occurrence of rare side effects such as osteonecrosis of the jaw or atypical femoral fracture, as well as the onset of severe renal failure, leave clinicians at a therapeutic impasse. Continuing denosumab or switching to bisphosphonates remains suboptimal and, currently, no evidence clarifies the optimal treatment approach for these patients. The aim of this review is to give a very practical clinical approach to the use of denosumab (duration of treatment), and to the management of rebound effect and possible adverse effects.
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Affiliation(s)
- Olivier Lamy
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
- Interdisciplinary Center of Bone Diseases, Rheumatology Unit, Bone and Joint Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
- Service de médecine interne, CHUV, Rue du Bugnon 46, Lausanne, 1011, Switzerland.
| | - Judith Everts-Graber
- OsteoRheuma Bern, Bahnhofplatz 1, Bern, Switzerland
- Department of Rheumatology and Immunology, University Hospital, Bern, Switzerland
| | - Elena Gonzalez Rodriguez
- Interdisciplinary Center of Bone Diseases, Rheumatology Unit, Bone and Joint Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Lewiecki EM, Bilezikian JP, Clark A, Collins MT, Kado DM, Lane J, Langdahl B, McClung MR, Snyder PJ, Stein EM. Proceedings of the 2024 Santa Fe Bone Symposium: Update on the Management of Osteoporosis and Rare Bone Diseases. J Clin Densitom 2025; 28:101559. [PMID: 39826229 DOI: 10.1016/j.jocd.2024.101559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 01/22/2025]
Abstract
The 24th Annual Santa Fe Bone Symposium (SFBS) was held in Santa Fe, New Mexico, USA, on August 2-3, 2024. This was a "hybrid" meeting, with in-person and real-time remote participants representing a broad range of geographical locations and medical disciplines. The focus was on new developments in the care of patients with osteoporosis, other metabolic bone diseases, and inherited skeletal disorders. The most current medical evidence was presented and discussed with consideration of implications for patient management. Topics included an update on clinical uses of osteoanabolic agents, management of patients discontinuing denosumab, bone health optimization for orthopedic surgery, estrogen and testosterone in the management of osteoporosis, osteoporosis treatment in the very old, overview of rare bone diseases, treat-to-target for osteoporosis, and a progress report on global activities of Bone Health ECHO. There were two highly interactive faculty panel discussions - one with case presentations by attendees and another with open microphone for all topics of interest. Endocrinology fellows, selected from attendees of the Santa Fe Fellows Workshop on Metabolic Bone Diseases, held the two days preceding the SFBS, participated with presentations of oral abstracts. Ancillary events addressed modern approaches to menopause and bone health, case studies of management of patients at very high fracture risk, and management of patients with rare bone diseases, such as hypophosphatasia, fibrodysplasia ossificans progressiva, X-linked hypophosphatemia, and hypoparathyroidism. These proceedings of the SFBS present the clinical highlights of the plenary sessions and the discussions that followed.
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Affiliation(s)
- E Michael Lewiecki
- New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
| | - John P Bilezikian
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Amanda Clark
- Oregon Health & Science University, Portland, OR, USA
| | | | | | - Joseph Lane
- Hospital for Special Surgery, New York, NY, USA
| | - Bente Langdahl
- Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Peter J Snyder
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Zaimi M, Grapsa E. Current therapeutic approach of chronic kidney disease-mineral and bone disorder. Ther Apher Dial 2024; 28:671-689. [PMID: 38898685 DOI: 10.1111/1744-9987.14177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/14/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024]
Abstract
Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD-mineral and bone disorder (CKD-MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD-MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD-MBD, anti-osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD-MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD-MBD based on the current literature with special attention to recent advances.
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Affiliation(s)
- Maria Zaimi
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
| | - Eirini Grapsa
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
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Simonini M, Bologna A, Vezzoli G. Is denosumab an efficient and safe drug for osteoporosis in dialysis patients? Considerations and state of the art about its use in this setting. Int Urol Nephrol 2024; 56:3285-3293. [PMID: 38856936 DOI: 10.1007/s11255-024-04110-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/02/2024] [Indexed: 06/11/2024]
Abstract
PURPOSE In patients with chronic kidney disease (CKD), renal osteodystrophy may be associated with a progressive bone mass loss that increases fracture risk. Denosumab, a monoclonal antibody inhibiting osteoclast activity, is an antiresorptive medication used for the treatment osteoporosis. METHODS Its efficacy and safety were initially established in the FREEDOM study, showing a significant reduction in incident fractures in osteoporotic women treated with denosumab. Subsequent post hoc analyses showed its efficacy in patients stratified by kidney function, but these analyses did not include patients with advanced stages of CKD. The capability of denosumab in improving bone mineral density in uremic patients was evaluated in 12 studies including 461 dialysis patients with low bone mineral density. The improvement of bone mineral density was the final end point in these studies assessed during a follow-up of 6-60 months. Nine of these studies did not have hyperparathyroidism among criteria for patient inclusion and their participants may have low-turnover bone disease. Despite current recommendations, no patients underwent bone biopsy before denosumab therapy. RESULTS Overall, findings in these studies suggest that denosumab is a viable option for promoting bone mass recovery in patients with advanced stages of CKD having either high or low serum levels of PTH. However, the increase of bone mineral density was lower in patients with low serum markers of bone turnover at baseline. These studies also highlighted the need for calcium and vitamin D supplementation to prevent hypocalcemia that remains a serious concern. CONCLUSIONS Denosumab emerges as a potentially safe and effective option for enhancing bone health in CKD patients.
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Affiliation(s)
- Marco Simonini
- IRCCS San Raffaele Scientific Institute, Nephrology and Dialysis Unit, Milan, Italy
| | - Arianna Bologna
- IRCCS San Raffaele Scientific Institute, Nephrology and Dialysis Unit, Milan, Italy
- Università Vita Salute San Raffaele, Milan, Italy
| | - Giuseppe Vezzoli
- IRCCS San Raffaele Scientific Institute, Nephrology and Dialysis Unit, Milan, Italy.
- Università Vita Salute San Raffaele, Milan, Italy.
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Abu-Jwead A, Fisher DL, Goldabart A, Yoel U, Press Y, Tsur A, Fraenkel M, Baraf L. Safety of In-hospital Parenteral Antiosteoporosis Therapy Following a Hip Fracture: A Retrospective Cohort. J Endocr Soc 2024; 8:bvae172. [PMID: 39416429 PMCID: PMC11481011 DOI: 10.1210/jendso/bvae172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Indexed: 10/19/2024] Open
Abstract
Purpose To assess the safety of zoledronic acid (ZOL) and denosumab (Dmab) administered following hip fracture in a hospital setting. Methods Patients older than 65 years were treated by a fracture liaison service following hip fracture. Generally, patients who had a glomerular filtration rate (eGFR) > 35 mL/min were treated with ZOL, whereas patients who had previously received bisphosphonates or had a eGFR between 20 and 35 mL/min were treated with Dmab. Adverse events included hypocalcemia (calcium corrected for albumin less than 8.5 mg/day), renal functional impairment (0.5 mg/dL or more increase in serum creatinine) within 30 days of treatment, or a fever (>38 °C) within 48 hours of drug administration. Results Two hundred twenty-eight and 134 patients were treated with ZOL and Dmab, respectively. Mean body temperature was elevated following ZOL administration (0.18 °C P < .001) but remained below 38 °C. Hypocalcemia occurred in 18% and 29% of the ZOL and Dmab groups, respectively (P = .009). Renal functional impairment was observed in 9 and 6 patients (4% and 5%) in the ZOL and Dmab groups, respectively (P = .8). Pretreatment calcium above 9.3 mg/dL was associated with a lower risk of posttreatment hypocalcemia (odds ratio 0.30, 95% confidence interval 0.13-0.68, P = .004). While the absolute risk of hypocalcemia was higher in the Dmab group, multivariate analysis did not find that the choice of drug was predictive of hypocalcemia. Conclusion In-hospital parenteral osteoporosis treatment was rarely associated with fever or renal function impairment but was associated with hypocalcemia. Posttreatment hypocalcemia risk did not vary significantly between patients receiving ZOL or Dmab.
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Affiliation(s)
- Alaa Abu-Jwead
- Goldman Medical School at the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - David L Fisher
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
| | - Adi Goldabart
- Clinical Research Center, Soroka University Medical Center, Beer Sheva 84101, Israel
| | - Uri Yoel
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Yan Press
- Geriatric Department, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Anat Tsur
- Department of Endocrinology and Metabolism, Clalit Health Services, Jerusalem 9310604, Israel
- The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9190500, Israel
| | - Merav Fraenkel
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Lior Baraf
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
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Pivonka P, Calvo-Gallego JL, Schmidt S, Martínez-Reina J. Advances in mechanobiological pharmacokinetic-pharmacodynamic models of osteoporosis treatment - Pathways to optimise and exploit existing therapies. Bone 2024; 186:117140. [PMID: 38838799 DOI: 10.1016/j.bone.2024.117140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/17/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
Osteoporosis (OP) is a chronic progressive bone disease which is characterised by reduction of bone matrix volume and changes in the bone matrix properties which can ultimately lead to bone fracture. The two major forms of OP are related to aging and/or menopause. With the worldwide increase of the elderly population, particularly age-related OP poses a serious health issue which puts large pressure on health care systems. A major challenge for development of new drug treatments for OP and comparison of drug efficacy with existing treatments is due to current regulatory requirements which demand testing of drugs based on bone mineral density (BMD) in phase 2 trials and fracture risk in phase 3 trials. This requires large clinical trials to be conducted and to be run for long time periods, which is very costly. This, together with the fact that there are already many drugs available for treatment of OP, makes the development of new drugs inhibitive. Furthermore, an increased trend of the use of different sequential drug therapies has been observed in OP management, such as sequential anabolic-anticatabolic drug treatment or switching from one anticatabolic drug to another. Running clinical trials for concurrent and sequential therapies is neither feasible nor practical due to large number of combinatorial possibilities. In silico mechanobiological pharmacokinetic-pharmacodynamic (PK-PD) models of OP treatments allow predictions beyond BMD, i.e. bone microdamage and degree of mineralisation can also be monitored. This will help to inform clinical drug usage and development by identifying the most promising scenarios to be tested clinically (confirmatory trials rather than exploratory only trials), optimise trial design and identify subgroups of the population that show benefit-risk profiles (both good and bad) that are different from the average patient. In this review, we provide examples of the predictive capabilities of mechanobiological PK-PD models. These include simulation results of PMO treatment with denosumab, implications of denosumab drug holidays and coupling of bone remodelling models with calcium and phosphate systems models that allows to investigate the effects of co-morbidities such as hyperparathyroidism and chronic kidney disease together with calcium and vitamin D status on drug efficacy.
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Affiliation(s)
- Peter Pivonka
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology, QLD 4000, Australia.
| | - José Luis Calvo-Gallego
- Departmento de Ingeniería Mecánica y Fabricación, Universidad de Sevilla, Seville 41092, Spain
| | - Stephan Schmidt
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
| | - Javier Martínez-Reina
- Departmento de Ingeniería Mecánica y Fabricación, Universidad de Sevilla, Seville 41092, Spain
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Ebina K, Nagayama Y, Kashii M, Tsuboi H, Okamura G, Miyama A, Etani Y, Noguchi T, Hirao M, Miura T, Fukuda Y, Kurihara T, Nakata K, Okada S. An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case-control study. Osteoporos Int 2024; 35:841-849. [PMID: 38296866 PMCID: PMC11031444 DOI: 10.1007/s00198-024-07019-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/06/2024] [Indexed: 02/02/2024]
Abstract
The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS The efficacy of ROMO may be attenuated by RA-related factors.
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Affiliation(s)
- Kosuke Ebina
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
| | - Yoshio Nagayama
- Nagayama Rheumatology and Orthopaedic Clinic, 4-3-25 Hiokisounishi-Machi, Higashi-Ku, Sakai, 599-8114, Japan
| | - Masafumi Kashii
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan
| | - Hideki Tsuboi
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-Cho, Kita-Ku, Sakai, 591-8025, Japan
| | - Gensuke Okamura
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan
| | - Akira Miyama
- Department of Orthopaedic Surgery, Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan
| | - Yuki Etani
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Takaaki Noguchi
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Makoto Hirao
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan
| | - Taihei Miura
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Yuji Fukuda
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Takuya Kurihara
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Ken Nakata
- Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Seiji Okada
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
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Sauhta R, Makkar D, Siwach PS. The Sequential Therapy in Osteoporosis. Indian J Orthop 2023; 57:150-162. [PMID: 38107815 PMCID: PMC10721775 DOI: 10.1007/s43465-023-01067-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023]
Abstract
Background Osteoporosis management often involves a sequential treatment approach to optimize patient outcomes and minimize fracture risks. This strategy is tailored to individual patient characteristics, treatment responses, and fracture risk profiles. Methods A thorough literature review was systematically executed using prominent databases, including PubMed and EMBASE. The primary aim was to identify original articles and clinical trials evaluating the effectiveness of sequential therapy with anti-osteoporosis drugs, focusing on the period from 1995 to 2023. The analysis encompassed an in-depth examination of osteoporosis drugs, delineating their mechanisms of action, side effects, and current trends as elucidated in the literature. Results and Discussion Our study yielded noteworthy insights into the optimal sequencing of pharmacologic agents for the long-term treatment of patients necessitating multiple drugs. Notably, the achievement of optimal improvements in bone mass is observed when commencing treatment with an anabolic medication, followed by the subsequent utilization of an antiresorptive drug. This stands in contrast to initiating therapy with a bisphosphonate, which may potentially diminish outcomes in the post-anabolic intervention period. Furthermore, it has been discerned that caution should be exercised against transitioning from denosumab to PTH homologs due to the adverse effects of heightened bone turnover and sustained weakening of bone structure. Despite the absence of fracture data substantiating the implementation of integrated anabolic/antiresorptive pharmacotherapy, the incorporation of denosumab and teriparatide presents a potential avenue worthy of consideration for individuals at a heightened vulnerability to fragility fractures. Conclusions A judiciously implemented sequential treatment strategy in osteoporosis offers a flexible and tailored approach to address diverse clinical scenarios, optimizing fracture prevention and patient outcomes.
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Affiliation(s)
- Ravi Sauhta
- Department Orthopedics and Joint
Replacement, Artemis Hospitals, Gurgaon, India
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Majdoub F, Ferjani HL, Nessib DB, Kaffel D, Maatallah K, Hamdi W. Denosumab use in osteogenesis imperfecta: an update on therapeutic approaches. Ann Pediatr Endocrinol Metab 2023; 28:98-106. [PMID: 37401056 DOI: 10.6065/apem.2346058.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 05/05/2023] [Indexed: 07/05/2023] Open
Abstract
Osteogenesis imperfecta (OI) is an inherited skeletal disorder that leads to bone fragility and multiple fractures. Given advances in the genetic understanding of existing phenotypes and newly discovered mutations, therapeutic management of OI has become challenging. Denosumab, a monoclonal antibody that inhibits the interaction between the receptor activator of nuclear factor kappa B ligand (RANKL) and its receptor RANK, has been approved to treat postmenopausal osteoporosis and emerged as an important therapy for malignancies and other skeletal disorders, including pediatric skeletal conditions such as OI. This review summarizes information about denosumab therapy in OI by exploring its mechanisms of action, main indications, and safety and efficacy. Several case reports and small series have been published about the short-term use of denosumab in children with OI. Denosumab was considered a strong drug candidate for OI patients with bone fragility and a high risk of fracture, particularly for patients with the bisphosphonate (BP)-unresponsive OI-VI subtype. The evidence for denosumab's effects in children with OI indicates that it effectively improves bone mineral density but not fracture rates. A decrease in bone resorption markers was observed after each treatment. Safety was assessed by tracking the effects on calcium homeostasis and reporting side effects. No severe adverse effects were reported. Hypercalciuria and moderate hypercalcemia were reported, suggesting that BPs be used to prevent the bone rebound effect. In other words, denosumab can be used as a targeted intervention in children with OI. The posology and administration protocol require more investigation to achieve secure efficiency.
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Affiliation(s)
- Fatma Majdoub
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
| | - Hanene Lassoued Ferjani
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
| | - Dorra Ben Nessib
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
| | - Dhia Kaffel
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
| | - Kaouther Maatallah
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
| | - Wafa Hamdi
- Rheumatology Department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia
- Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
- Research unit UR17SP04, 2010, Ksar Said 2010, Tunis, Tunisia
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Ferrari S, Langdahl B. Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone. Nat Rev Rheumatol 2023; 19:307-317. [PMID: 37024711 DOI: 10.1038/s41584-023-00935-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2023] [Indexed: 04/08/2023]
Abstract
Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings.
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Affiliation(s)
- Serge Ferrari
- Service of Bone Diseases, Department of Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
| | - Bente Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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11
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Kashii M, Kamatani T, Nagayama Y, Miyama A, Tsuboi H, Ebina K. Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis. Osteoporos Int 2023; 34:563-572. [PMID: 36585509 DOI: 10.1007/s00198-022-06642-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/12/2022] [Indexed: 01/01/2023]
Abstract
UNLABELLED Baseline serum PINP value was significantly and independently associated with the increased bone mineral density (≥ 3%) in both total hip and femoral necks by 12 months of romosozumab treatment in patients with treatment-naive postmenopausal osteoporosis. PURPOSE Some patients fail to obtain a sufficiently increased hip bone mineral density (BMD) by romosozumab (ROMO) treatment. This study aimed to investigate the prognostic factor for increased hip BMD with ROMO in patients with treatment-naive postmenopausal osteoporosis. METHODS This prospective, observational, and multicenter study included patients (n = 63: mean age, 72.6 years; T-scores of the lumbar spine [LS], - 3.3; total hip [TH], - 2.6; femoral neck [FN], - 3.3; serum type I procollagen N-terminal propeptide [PINP], 68.5 µg/L) treated by ROMO for 12 months. BMD and serum bone turnover markers were evaluated at each time point. A responder analysis was performed to assess the patient percentage, and both univariate and multivariate analyses were performed to investigate the factors associated with clinically significant increased BMD (≥ 3%) in both TH and FN. RESULTS Percentage changes of BMD from baseline in the LS, TH, and FN areas were 17.5%, 4.9%, and 4.3%, respectively. In LS, 96.8% of patients achieved ≥ 6% increased LS-BMD, although 57.1% could not achieve ≥ 3% increased BMD in either TH or FN. Multiple regression analysis revealed that only the baseline PINP value was significantly and independently associated with ≥ 3% increased BMD in both TH and FN (p = 0.019, 95% confidence interval = 1.006-1.054). The optimal cut-off PINP value was 53.7 µg/L with 54.3% sensitivity and 92.3% specificity (area under the curve = 0.752). CONCLUSIONS In a real-world setting, baseline PINP value was associated with the increased BMD of TH and FN by ROMO treatment in treatment-naive patients.
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Affiliation(s)
- Masafumi Kashii
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka, 560-8565, Japan
| | - Takashi Kamatani
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka, 560-8565, Japan
| | - Yoshio Nagayama
- Nagayama Rheumatology and Orthopaedic Clinic, 4-3-25 Hiokisounishimachi, Higashi-Ku, Sakai, 599-8114, Japan
| | - Akira Miyama
- Department of Orthopaedic Surgery, Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan
| | - Hideki Tsuboi
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasonecho, Kita-Ku, Sakai, 591-8025, Japan
| | - Kosuke Ebina
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
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12
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Abstract
PURPOSE OF REVIEW To review the pathophysiology, the clinical consequences as well as way of mitigating the effects of denosumab discontinuation. RECENT FINDINGS Treatment with denosumab (DMAB) is reversible and upon discontinuation there is a rapid increase in bone turnover and a subsequent bone loss. During this phase of high bone turnover, an increased risk of fractures has been reported. Therefore, treatment with DMAB could be considered life-long. However, side-effects may prompt the need for discontinuation and moreover, treatment with DMAB may have increased BMD to levels where continuing treatment does not provide further fracture risk reduction. Patients stopping DMAB should be offered subsequent antiresorptive treatment with an intense monitoring regimen during the initial year as most of the bone loss occurs within these initial 12 months. In this review, we evaluated the literature published over the past 1 to 3 years investigating DMAB withdrawal with focus on bone turnover markers, bone mineral density, and fracture risk and the transition to other anti-osteoporosis therapies. Furthermore, we summarized the current recommendations of international guidelines. In this review, we evaluated the literature published over the past 1 to 3 years investigating denosumab (DMAB) discontinuation and the transition to other anti-osteoporosis therapies. Additionally, we summarized the current recommendations of international guidelines.
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Affiliation(s)
- Anne Sophie Sølling
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Internal Medicine, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Elena Tsourdi
- Department of Medicine III & Center for Healthy Aging, Universitätsklinikum Dresden, Dresden, Germany
| | - Torben Harsløf
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Bente L Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
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13
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Abstract
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
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Affiliation(s)
- Robert J Pignolo
- Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Endocrinology, and Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,The Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
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14
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Lim SY, Bolster MB. Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives. Int J Womens Health 2022; 14:1733-1747. [PMID: 36544862 PMCID: PMC9762257 DOI: 10.2147/ijwh.s315184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/05/2022] [Indexed: 12/23/2022] Open
Abstract
As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.
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Affiliation(s)
- Sian Yik Lim
- Hawaii Pacific Health Medical Group, Honolulu, HI, USA,Department of Family Medicine, John E Burns School of Medicine, University of Hawaii, Honolulu, HI, USA,Correspondence: Sian Yik Lim, Bone and Joint Center, Straub Clinic, 800 S. King Street, Honolulu, HI, 96813, USA, Tel +1 808-522-4232, Fax +1 808-522-4401, Email
| | - Marcy B Bolster
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA
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15
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Chandran M. The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:724-738. [PMID: 36382762 PMCID: PMC10118820 DOI: 10.20945/2359-3997000000564] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.
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16
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Everts-Graber J, Reichenbach S, Gahl B, Häuselmann H, Ziswiler HR, Studer U, Lehmann T. Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting. Bone 2022; 163:116498. [PMID: 35882310 DOI: 10.1016/j.bone.2022.116498] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/12/2022] [Accepted: 07/15/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. OBJECTIVE This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. METHODS We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6 months later. In patients with longer denosumab therapy (≥5 years), BTMs were measured every 3 months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2 years after the first zoledronate. RESULTS Bone loss after switching from denosumab to zoledronate was higher in patients with 10 ± 2 denosumab injections (n = 84) compared to 5 ± 2 injections (n = 144, p < 0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15 ± 2 injections (n = 54, p = 0.35 and p = 0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6 months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6 months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p = 0.37 for lumbar spine and p = 0.97 for femoral neck). CONCLUSIONS Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6 years, irrespective of the frequency of subsequent zoledronate therapy.
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Affiliation(s)
- Judith Everts-Graber
- OsteoRheuma Bern, Bahnhofplatz 1, Bern, Switzerland; Department of Rheumatology and Immunology, University Hospital, Bern, Switzerland.
| | - Stephan Reichenbach
- Department of Rheumatology and Immunology, University Hospital, Bern, Switzerland; Institute for Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Brigitta Gahl
- Clinical Trial Unit (CTU) Bern, University of Bern, Bern, Switzerland
| | - HansJörg Häuselmann
- Zentrum für Rheuma- und Knochenerkrankungen, Klinik Im Park, Hirslanden Zürich, Switzerland
| | | | - Ueli Studer
- OsteoRheuma Bern, Bahnhofplatz 1, Bern, Switzerland
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17
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Abstract
Bone science has over the last decades unraveled many important pathways in bone and mineral metabolism and the interplay between genetic factors and the environment. Some of these discoveries have led to the development of pharmacological treatments of osteoporosis and rare bone diseases. Other scientific avenues have uncovered a role for the gut microbiome in regulating bone mass, which have led to investigations on the possible therapeutic role of probiotics in the prevention of osteoporosis. Huge advances have been made in identifying the genes that cause rare bone diseases, which in some cases have led to therapeutic interventions. Advances have also been made in understanding the genetic basis of the more common polygenic bone diseases, including osteoporosis and Paget's disease of bone (PDB). Polygenic profiles are used for establishing genetic risk scores aiming at early diagnosis and intervention, but also in Mendelian randomization (MR) studies to investigate both desired and undesired effects of targets for drug design.
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Affiliation(s)
- Bente L Langdahl
- Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - André G Uitterlinden
- Laboratory for Population Genomics, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Stuart H Ralston
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
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18
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Lamarche BA, Thomsen JS, Andreasen CM, Lievers WB, Andersen TL. 2D size of trabecular bone structure units (BSU) correlate more strongly with 3D architectural parameters than age in human vertebrae. Bone 2022; 160:116399. [PMID: 35364343 DOI: 10.1016/j.bone.2022.116399] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 03/14/2022] [Accepted: 03/25/2022] [Indexed: 11/22/2022]
Abstract
Bone tissue is continuously remodeled. In trabecular bone, each remodeling transaction forms a microscopic bone structural unit (BSU), also known as a hemiosteon or a trabecular packet, which is bonded to existing tissue by osteopontin-rich cement lines. The size and shape of the BSUs are determined by the size and shape of the resorption cavity, and whether the cavity is potentially over- or under-filled by the subsequent bone formation. The present study focuses on the recently formed trabecular BSUs, and how their 2D size and shape changes with age and trabecular microstructure. The study was performed using osteopontin-immunostained frontal sections of L2 vertebrae from 8 young (aged 18.5-37.6 years) and 8 old (aged 69.1-96.4 years) control females, which underwent microcomputed tomography (μCT) imaging prior to sectioning. The contour of 4230 BSU profiles (181-385 per vertebra) within 1024 trabecular profiles were outlined, and their 2D width, length, area, and shape were assessed. Of these BSUs, 22 (0.5%) were generated by modeling-based bone formation (i.e. without prior resorption), while 99.5% were generated by remodeling-based bone formation (i.e. with prior resorption). The distributions of BSU profile width, length, and area were significantly smaller in the old versus young females (p < 0.005), and the median profile width, length, and area were negative correlated with age (p < 0.018). Importantly, these BSU profile size parameters were more strongly correlated with trabecular bone volume (BV/TV, p < 0.002) and structure model index (SMI, p < 0.008) assessed by μCT, than age. Moreover, the 2D BSU size parameters were positively correlated to the area of the individual trabecular profiles (p < 0.0001), which were significantly smaller in the old versus young females (p < 0.024). The BSU shape parameters (aspect ratio, circularity, and solidity) were not correlated with age, BV/TV, or SMI. Collectively, the study supports the notion that not only the BSU profile width, but also its length and area, are more influenced by the age-related bone loss and shift from plates to rods (SMI), than age itself. This implies that BSU profile size is mainly driven by changes in the trabecular microstructure, which affect the size of the resorption cavity that the BSU refills.
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Affiliation(s)
- Britney Alexi Lamarche
- Bharti School of Engineering and Computer Science, Laurentian University, Sudbury, Ontario, Canada
| | | | - Christina Møller Andreasen
- Clinical Cell Biology, Dept. of Pathology, Odense University Hospital, Odense, Denmark; Pathology Research Unit, Dept. of Molecular Medicine & Dept. of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - W Brent Lievers
- Bharti School of Engineering and Computer Science, Laurentian University, Sudbury, Ontario, Canada.
| | - Thomas Levin Andersen
- Clinical Cell Biology, Dept. of Pathology, Odense University Hospital, Odense, Denmark; Pathology Research Unit, Dept. of Molecular Medicine & Dept. of Clinical Research, University of Southern Denmark, Odense, Denmark; Dept. of Forensic Medicine, Aarhus University, Aarhus, Denmark.
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19
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Appelman-Dijkstra NM, Oei HLDW, Vlug AG, Winter EM. The effect of osteoporosis treatment on bone mass. Best Pract Res Clin Endocrinol Metab 2022; 36:101623. [PMID: 35219602 DOI: 10.1016/j.beem.2022.101623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Over the last two decades there have been significant developments in the pharmacotherapy of osteoporosis. The therapeutic arsenal has expanded with monoclonal antibodies which have been developed based on discoveries of the molecular mechanisms underlying bone resorption and bone formation. Denosumab, the antibody binding RANKL, inhibits bone resorption, and romosozumab, the antibody binding sclerostin, inhibits bone resorption and stimulates bone formation as well. Both antibodies have shown potent anti-fracture efficacy in randomized clinical trials and this review will discuss the preclinical and clinical studies focusing on the effects on bone mass. After discontinuation of these antibodies, bone mineral density quickly returns to baseline and in the case of denosumab, discontinuation can not only induce rebound bone loss, but also the occurrence of vertebral fractures. Therefore, sequential antiresorptive therapy to maintain bone mass gains and anti-fracture efficacy is of utmost importance and will also be discussed in this review.
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Affiliation(s)
- Natasha M Appelman-Dijkstra
- Department of Internal Medicine; Division Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, the Netherlands.
| | - H Ling D W Oei
- Department of Internal Medicine; Division Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Jan van Goyen Medical Center, Amsterdam, the Netherlands.
| | - Annegreet G Vlug
- Department of Internal Medicine; Division Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Jan van Goyen Medical Center, Amsterdam, the Netherlands.
| | - Elizabeth M Winter
- Department of Internal Medicine; Division Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, the Netherlands.
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20
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John Martin T. Aspects of intercellular communication in bone and implications in therapy. Bone 2021; 153:116148. [PMID: 34389478 DOI: 10.1016/j.bone.2021.116148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/18/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
Communication processes among the cells of bone are essential for the structure and function of the organ. After it was proposed that communication from the osteoblast lineage to hemopoietic cells initiated osteoclastogenesis, the molecular controls were identified to be the tumour necrosis factor ligand and receptor families. This was followed by revelation of very many signalling processes among the cells of bone that regulate the three phases of bone remodelling, the resorption, reversal and formation phases. In many instances the ways in which these mechanisms operate can determine how drugs act on bone, whether they be inhibitors of resorption or promoters of formation.
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Affiliation(s)
- T John Martin
- St Vincent's Institute of Medical Research, The University of Melbourne Department of Medicine at St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
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21
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Robinson ST, Shyu PT, Guo XE. Mechanical loading and parathyroid hormone effects and synergism in bone vary by site and modeling/remodeling regime. Bone 2021; 153:116171. [PMID: 34492358 PMCID: PMC8499476 DOI: 10.1016/j.bone.2021.116171] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/01/2021] [Accepted: 08/31/2021] [Indexed: 01/22/2023]
Abstract
Intermittent injections of parathyroid hormone (PTH) and mechanical loading are both known to effect a net increase in bone mass. Fundamentally, bone metabolism can be divided into modeling (uncoupled formation or resorption) and remodeling (subsequent formation biologically coupled to resorption in space and time). Methods to delineate the bone response between these regimes are scant but have garnered recent attention and acceptance, and will be critical tools to properly assess short- and long-term efficacy of osteoporosis treatments. To this end, we employ a time-lapse micro-computed tomography strategy to quantify and localize modeling and remodeling volumes over 4 weeks of concurrent PTH treatment and mechanical loading. Modeled and remodeled volumes are probed for differences with respect to treatment, loading, and interactions thereof in trabecular and cortical bone compartments, which were further separated by plate/rod microarchitecture and periosteal/endosteal surfaces, respectively. Loading effects are further considered independently with regard to localized strain environments. Our findings indicate that in trabecular bone, PTH and loading stimulate anabolic modeling additively, and remodeling synergistically. PTH tends to lead to bone accumulation indiscriminate of trabecular microarchitecture, whereas loading tends to more strongly affect plates than rods. The cortical surfaces responded uniquely to PTH and loading, with synergistic effects on the periosteal surface for anabolic modeling, and on the endosteal surface for catabolic modeling. The increase in catabolic modeling due to loading, which is enhanced by PTH, is concentrated to areas of the endosteal surface under low strain and to our knowledge has not previously been reported. Taken together, the effects of PTH, loading, and their interactions, are shown to be dependent on the specific bone compartment and metabolic regime; this may explain some discrepancies in previously-reported findings.
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Affiliation(s)
- Samuel T Robinson
- Bone Bioengineering Laboratory, 351 Engineering Terrace, Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY 10027, USA.
| | - Peter T Shyu
- Bone Bioengineering Laboratory, 351 Engineering Terrace, Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY 10027, USA.
| | - X Edward Guo
- Bone Bioengineering Laboratory, 351 Engineering Terrace, Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY 10027, USA.
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22
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Smith MD, Haseman OJ, Velez Garza JA, Bruder JM. Bilateral atypical fractures of the femur: Ten years AFTER ten years of bisphosphonate therapy. Bone Rep 2021; 15:101112. [PMID: 34409133 PMCID: PMC8361289 DOI: 10.1016/j.bonr.2021.101112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 11/30/2022] Open
Abstract
Background Atypical femur fracture (AFF) is a clinically important complication of bisphosphonate (BP) use in the treatment of osteoporosis. The benefits of long-term BP therapy in preventing osteoporotic fractures have been shown to outweigh the risks of treatment. Discontinuation of BPs or "drug holidays" have been implemented as a strategy to reduce the risk of rare complications such as AFF. Case report We present the case of a 70-year-old postmenopausal woman who suffered bilateral AFF ten years after discontinuation of BP treatment. Management of this patient included fixation of the complete AFF with an intramedullary rod. A single dose of denosumab was administered prior to referral to endocrinology and seemed to contribute to callus formation. Denosumab was discontinued to prevent progression of the contralateral incomplete AFF. Teriparatide was indicated for the treatment of this patient's osteoporosis and also led to the resolution of the incomplete AFF. Conclusion Patients receiving long-term BP therapy should be periodically reevaluated in order to maximize the benefit and minimize the risk of treatment. Current research supports the implementation of drug holidays to decrease the risk of AFF; however, this case report confirms the need for continued monitoring after discontinuation of BP therapy. Additionally, our review of current literature highlights the need for more specific research regarding duration of BP treatment and drug holidays.
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Affiliation(s)
- Matthew D Smith
- Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Olen J Haseman
- Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Jorge A Velez Garza
- Texas Diabetes Institute, University Health System, 701 S. Zarzamora Street, San Antonio, TX 78207, USA
| | - Jan M Bruder
- UT Health Medical Arts & Research Center, Department of Endocrinology, 8300 Floyd Curl Drive, 3rd Floor - 3A, San Antonio, TX 78229, USA
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23
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Bonnet N, Douni E, Perréard Lopreno G, Besse M, Biver E, Ferrari S. RANKL-Induced Increase in Cathepsin K Levels Restricts Cortical Expansion in a Periostin-Dependent Fashion: A Potential New Mechanism of Bone Fragility. J Bone Miner Res 2021; 36:1636-1645. [PMID: 33856714 DOI: 10.1002/jbmr.4307] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 03/26/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
Receptor activator of nuclear factor-κΒ ligand (RANKL) is necessary and sufficient to promote osteoclastogenesis and a key pathogenic factor in osteoporosis. Failure of periosteal apposition to compensate for bone loss due to endosteal resorption further contributes to bone fragility. Whether these two processes are biologically related, however, remains unknown. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we first examined cortical bone parameters at distal radius and tibia in postmenopausal women (PMW) as well as in cadaveric human adult humeri. Increases in medullary area were negatively correlated with cortical bone volume but positively with total bone volume, and this relationship was stronger in the dominant arm, suggesting a mechanically driven process. To investigate the role of RANKL in this dual process, we used mice overexpressing huRANKL (huRANKLTg+ ). Trabecular and cortical bone volume (Ct.BV) are reduced in these mice, whereas cortical total volume (Ct.TV) is increased. In these bones, Sost mRNA levels are downregulated and periostin (Postn) mRNA levels upregulated, hence providing a positive message for periosteal bone formation. In turn, genetic deletion of Postn in huRANKLTg+ mice prevented the increase in Ct.TV and aggravated bone fragility. In contrast, cathepsin K (Ctsk) ablation improved Ct.TV in both huRANKLTg+ and wild-type (WT) mice and stimulated periosteal bone formation, while augmenting Postn protein levels. Therefore, bone strength in huRANKLTg+ /Ctsk-/- mice was restored to WT levels. These findings suggest that high levels of RANKL not only induce endosteal bone loss but may somewhat restrict periosteal bone formation by triggering periostin degradation through cathepsin K, hence providing a biological mechanism for the observed limited increase in cortical area in postmenopausal women. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Nicolas Bonnet
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
| | - Eleni Douni
- Department of Biotechnology, Agricultural University of Athens, Iera Odos, Athens, Greece.,Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece
| | - Geneviève Perréard Lopreno
- Laboratory of Prehistoric Archaeology and Anthropology, F.-A. Forel Department, Section of Earth and Environmental Sciences, University of Geneva, Uni Carl Vogt, Geneva, Switzerland
| | - Marie Besse
- Laboratory of Prehistoric Archaeology and Anthropology, F.-A. Forel Department, Section of Earth and Environmental Sciences, University of Geneva, Uni Carl Vogt, Geneva, Switzerland
| | - Emmanuel Biver
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
| | - Serge Ferrari
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
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Martin TJ, Sims NA, Seeman E. Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R. Endocr Rev 2021; 42:383-406. [PMID: 33564837 DOI: 10.1210/endrev/bnab005] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Indexed: 12/13/2022]
Abstract
Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis.
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Affiliation(s)
- T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Ego Seeman
- The University of Melbourne, Department of Medicine at Austin Health, Heidelberg, Victoria, Australia
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25
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Kobayakawa T, Miyazaki A, Saito M, Suzuki T, Takahashi J, Nakamura Y. Denosumab versus romosozumab for postmenopausal osteoporosis treatment. Sci Rep 2021; 11:11801. [PMID: 34083636 PMCID: PMC8175428 DOI: 10.1038/s41598-021-91248-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 05/17/2021] [Indexed: 01/22/2023] Open
Abstract
Denosumab and romosozumab, a recently approved new drug, are effective and widely known molecular-targeted drugs for postmenopausal osteoporosis treatment. However, no studies have directly compared their therapeutic effects or safety in postmenopausal osteoporosis. This retrospective observational registry study compared the efficacy of 12-month denosumab or romosozumab treatment in postmenopausal osteoporosis patients. The primary outcome was the change in bone mineral density (BMD) at the lumbar spine. Secondary outcomes included BMD changes at the total hip and femoral neck, changes in bone turnover markers, and adverse events. Propensity score matching was employed to assemble patient groups with similar baseline characteristics. Sixty-nine patients each received either denosumab or romosozumab for 12 months. The mean 12-month percentage change from baseline in lumbar spine BMD was 7.2% in the denosumab group and 12.5% in the romosozumab group, indicating a significant difference between the groups. The percentage changes in BMD at both the total hip and femoral neck were also significantly higher at 12 months in the romosozumab group than in the denosumab group. In denosumab patients, bone formation and bone resorption markers were significantly decreased at 6 and 12 months from baseline. In the romosozumab group, the bone formation marker was significantly increased at 6 months and then returned to baseline, while the bone resorption marker was significantly decreased at both time points. Adverse events were few and predominantly minor in both groups, with no remarkable difference in the incidence of new vertebral fractures. Romosozumab showed a higher potential for improving BMD than denosumab in this clinical study of postmenopausal osteoporosis patient treatment.
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Affiliation(s)
- Tomonori Kobayakawa
- Kobayakawa Orthopedic and Rheumatologic Clinic, 1969 Kunou, Fukuroi, Shizuoka, 437-0061, Japan
| | - Akiko Miyazaki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Makoto Saito
- Department of Clinical Support Office, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkagome, Bunkyou-ku, Tokyo, 113-8677, Japan
| | - Takako Suzuki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.,Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, 22 Sanban-cho, Chiyoda-ku, Tokyo, 102-8341, Japan
| | - Jun Takahashi
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
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26
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Tourolle DC, Dempster DW, Ledoux C, Boaretti D, Aguilera M, Saleem N, Müller R. Ten-Year Simulation of the Effects of Denosumab on Bone Remodeling in Human Biopsies. JBMR Plus 2021; 5:e10494. [PMID: 34189383 PMCID: PMC8216138 DOI: 10.1002/jbm4.10494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/17/2021] [Indexed: 01/22/2023] Open
Abstract
Postmenopausal osteoporosis is a disease manifesting in degradation of bone mass and microarchitecture, leading to weakening and increased risk of fracture. Clinical trials are an essential tool for evaluating new treatments and may provide further mechanistic understanding of their effects in vivo. However, the histomorphometry from clinical trials is limited to 2D images and reflects single time points. Biochemical markers of bone turnover give global insight into a drug's action, but not the local dynamics of the bone remodeling process and the cells involved. Additionally, comparative trials necessitate separate treatment groups, meaning only aggregated measures can be compared. In this study, in silico modeling based on histomorphometry and pharmacokinetic data was used to assess the effects of treatment versus control on μCT scans of the same biopsy samples over time, matching the changes in bone volume fraction observed in biopsies from denosumab and placebo groups through year 10 of the FREEDOM Extension trial. In the simulation, treatment decreased osteoclast number, which led to a modest increase in trabecular thickness and osteocyte stress shielding. Long-term bone turnover suppression led to increased RANKL production, followed by a small increase in osteoclast number at the end of the 6-month-dosing interval, especially at the end of the Extension study. Lack of treatment led to a significant loss of bone mass and structure. The study's results show how in silico models can generate predictions of denosumab cellular action over a 10-year period, matching static and dynamic morphometric measures assessed in clinical biopsies. The use of in silico models with clinical trial data can be a method to gain further insight into fundamental bone biology and how treatments can perturb this. With rigorous validation, such models could be used for informing the design of clinical trials, such that the number of participants could be reduced to a minimum to show efficacy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
| | - David W Dempster
- Department of Pathology and Cell BiologyCollege of Physicians and Surgeons of Columbia UniversityNew YorkNYUSA
| | | | | | | | | | - Ralph Müller
- Institute for BiomechanicsETH ZurichZurichSwitzerland
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27
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Fujii N, Tsukamoto M, Okimoto N, Mori M, Ikejiri Y, Yoshioka T, Kawasaki M, Kito N, Ozawa J, Nakamura R, Takano S, Fujiwara S. Differences in the effects of BMI on bone microstructure between loaded and unloaded bones assessed by HR-pQCT in Japanese postmenopausal women. Osteoporos Sarcopenia 2021; 7:54-62. [PMID: 34278000 PMCID: PMC8261728 DOI: 10.1016/j.afos.2021.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 01/22/2023] Open
Abstract
Objectives The relationship between weight-related load and bone mineral density (BMD)/bone microstructure under normal load conditions using high-resolution peripheral quantitative computed tomography (HR-pQCT) remains unconfirmed. The study aims to investigate the differences in effect of body mass index (BMI) on BMD/bone microstructure of loaded and unloaded bones, respectively, in Japanese postmenopausal women. Methods Fifty-seven postmenopausal women underwent HR-pQCT on the tibia and radius. Correlation analysis, principal component (PC) analysis, and hierarchical multiple regression were performed to examine the relationship between BMI and HR-pQCT parameters. Results Several microstructural parameters of the tibia and radius correlated with BMI through a simple correlation analysis, and these relationships remained unchanged even with an age-adjusted partial correlation analysis. PC analysis was conducted using seven bone microstructure parameters. The first PC (PC1) reflected all parameters of trabecular and cortical bone microstructures, except for cortical porosity, whereas the second PC (PC2) reflected only cortical bone microstructure. Hierarchical multiple regression analysis indicated that BMI was more strongly related to BMD/bone microstructure in the tibia than in the radius. Furthermore, BMI was associated with trabecular/cortical BMD, and PC1 (not PC2) of the tibia and radius. Thus, BMI was strongly related to the trabecular bone microstructure rather than the cortical bone microstructure. Conclusions Our data confirmed that BMI is associated with volumetric BMD and trabecular bone microstructure parameters in the tibia and radius. However, although BMI may be more related to HR-pQCT parameters in the tibia than in the radius, the magnitude of association is modest.
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Affiliation(s)
- Norifumi Fujii
- Department of Rehabilitation, Shimura Hospital, Hiroshima, Japan.,Hiroshima International University Major in Medical Engineering and Technology Graduate School of Medical Technology and Health Welfare Sciences, Hiroshima, Japan
| | - Manabu Tsukamoto
- Department of Orthopedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Nobukazu Okimoto
- Okimoto Clinic, Hiroshima, Japan.,Department of Orthopedic Surgery, Shimura Hospital, Hiroshima, Japan
| | - Miyuki Mori
- Department of Radiology, Shimura Hospital, Hiroshima, Japan
| | - Yoshiaki Ikejiri
- Department of Orthopedic Surgery, Shimura Hospital, Hiroshima, Japan
| | - Toru Yoshioka
- Department of Orthopedic Surgery, Shimura Hospital, Hiroshima, Japan
| | - Makoto Kawasaki
- Department of Orthopedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Nobuhiro Kito
- Department of Rehabilitation, Hiroshima International University, Hiroshima, Japan
| | - Junya Ozawa
- Department of Rehabilitation, Hiroshima International University, Hiroshima, Japan
| | - Ryoichi Nakamura
- Department of Rehabilitation, Shimura Hospital, Hiroshima, Japan
| | - Shogo Takano
- Department of Rehabilitation, Shimura Hospital, Hiroshima, Japan
| | - Saeko Fujiwara
- Department of Pharmacy, Yasuda Women's University, Hiroshima, Japan
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28
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Evenepoel P, Cunningham J, Ferrari S, Haarhaus M, Javaid MK, Lafage-Proust MH, Prieto-Alhambra D, Torres PU, Cannata-Andia J. European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4-G5D. Nephrol Dial Transplant 2021; 36:42-59. [PMID: 33098421 DOI: 10.1093/ndt/gfaa192] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Indexed: 12/16/2022] Open
Abstract
Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4-G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of bone fragility in patients with CKD G4-G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4-G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4-G5D to replace current variations in care and treatment nihilism.
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Affiliation(s)
- Pieter Evenepoel
- Department of Nephrology, KU Leuven University Hospitals Leuven, Leuven, Belgium
| | - John Cunningham
- Centre for Nephrology, UCL Medical School, Royal Free Campus, London, UK
| | - Serge Ferrari
- Service of Bone Diseases, Geneva University Hospital, Switzerland
| | - Mathias Haarhaus
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Diaverum Sweden, Stockholm, Sweden
| | | | | | | | - Pablo Ureña Torres
- Department of Dialysis, AURA Nord Saint Ouen, Saint Ouen, France.,Department of Renal Physiology, Necker Hospital, University of Paris Descartes, Paris, France
| | - Jorge Cannata-Andia
- Bone and Mineral Research Unit (ISPA) (REDinREN), Hospital Universitario Central Asturias, Oviedo University, Spain
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29
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Langdahl B. Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: Combined and sequential approaches. Bone 2020; 139:115516. [PMID: 32622871 DOI: 10.1016/j.bone.2020.115516] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 06/08/2020] [Accepted: 06/29/2020] [Indexed: 12/26/2022]
Abstract
Efficient therapies are available for the treatment of osteoporosis. Bisphosphonates and denosumab are the most commonly used antiresorptive therapies. Despite differences in the increase in bone mineral density seen with these drugs, the reductions in fracture risk are similar; 50-70%, 20%, and 40% for vertebral, non-vertebral and hip fractures, respectively. The bone-forming treatments; teriparatide and abaloparatide increase bone mineral density more than the antiresorptives and the reductions in fracture risk are 85% and 40-50% for vertebral and non-vertebral fractures, respectively, compared to placebo. The VERO study demonstrated a >50% reduction in vertebral and clinical fractures in women treated with teriparatide compared to risedronate. The dual-action treatment; romosozumab leads to more pronounced increases in BMD than other treatment modalities and reduces the risk of vertebral and clinical fractures by 73% and 36% compared to placebo after 12 months and the sequential treatment regime; romosozumab for 12 months followed by alendronate reduced the risk of vertebral, non-vertebral and hip fractures by 48%, 20% and 38%, respectively compared to alendronate after 2-3 years. The evidence for combination therapy targeting both resorption and formation is limited as only short-term studies with BMD as the endpoint have been performed. All bone-forming and dual-action treatments increase BMD and reduce the fracture risk, however, the effect wears off with time and treatment is therefore only temporary and should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The sequence of treatment matters as the BMD response to teriparatide is reduced in patients previously treated with bisphosphonates; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with risedronate seems to be preserved after bisphosphonate therapy. The DATA study suggested that transitioning from denosumab to teriparatide is problematic due to the increase in bone resorption occurring after stopping denosumab. Studies have shown further improvements in BMD when transitioning from oral bisphosphonates to zoledronic acid or denosumab. Management of osteoporosis will in many patients include a long-term treatment plan. This will often include sequential therapy which in severe cases preferably should start with bone-forming followed by antiresorptive treatment. The severity of osteoporosis, reaching a treatment goal, and responding to treatment failure are important factors determining the treatment sequence in the individual patient.
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Affiliation(s)
- Bente Langdahl
- Aarhus University Hospital, Endocrinology and Internal Medicine, Palle Juul Jensen Boulevard 115, DK8200 Aarhus N, Denmark.
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30
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Wang L, Huang B, Chen X, Su J. New insight into unexpected bone formation by denosumab. Drug Discov Today 2020; 25:S1359-6446(20)30340-8. [PMID: 32916270 DOI: 10.1016/j.drudis.2020.09.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/26/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
Denosumab (Dmab) was the first monoclonal antibody (mAb) approved for the treatment of osteoporosis. It blocks the receptor activator for nuclear factor κB ligand (RANKL) and acts as a potent antiresorptive agent. In contrast to classic antiresorptive agents, Dmab treatment leads to a progressive increase in bone mass, but the mechanisms remain controversial. Recently, RANKL signaling in osteoblastogenesis and bone formation and RANKL reverse signaling in coupling bone resorption and formation were demonstrated. Thus, here we discuss the roles of RANKL signaling and RANKL reverse signaling in the bone-forming effects of Dmab.
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Affiliation(s)
- Lipeng Wang
- Graduate Management Unit, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Biaotong Huang
- Institute of Translational Medicine, Shanghai University, 99 Shangda Road, Shanghai 201900, China
| | - Xiao Chen
- Department of Orthopedics Trauma, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
| | - Jiacan Su
- Department of Orthopedics Trauma, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
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31
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Saeki C, Saito M, Oikawa T, Nakano M, Torisu Y, Saruta M, Tsubota A. Effects of denosumab treatment in chronic liver disease patients with osteoporosis. World J Gastroenterol 2020; 26:4960-4971. [PMID: 32952342 PMCID: PMC7476181 DOI: 10.3748/wjg.v26.i33.4960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.
AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.
METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).
RESULTS Among the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.
CONCLUSION Denosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo 1058461, Japan
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32
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Miyaoka D, Imanishi Y, Kato E, Toi N, Nagata Y, Kurajoh M, Yamada S, Inaba M, Emoto M. Effects of denosumab as compared with parathyroidectomy regarding calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism. Endocrine 2020; 69:642-649. [PMID: 32621048 DOI: 10.1007/s12020-020-02401-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/24/2020] [Indexed: 01/22/2023]
Abstract
PURPOSE To evaluate the effects of denosumab (Dmb) on calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism (PHPT) and compare with those who underwent a parathyroidectomy (PTX) procedure. METHODS This retrospective, longitudinal study included patients treated with Dmb (60 mg) once every 6 months (n = 19) and those who successfully underwent a PTX procedure (n = 19) corrected calcium (cCa), eGFR, bone mineral density (BMD) in the lumbar spine (LS), total hip (TH), and femoral neck (FN) and LS-trabecular bone score (TBS) changes at 1 year after beginning Dmb or undergoing PTX were measured. RESULTS Dmb group had older age, and showed milder disease activity and lower eGFR as compared with PTX group. In PTX group, cCa and eGFR were significantly decreased following surgery, while those were stable in Dmb group. There were significant increases in LS, TH, and FN-BMD in both Dmb (LS: 6.0 ± 0.8%, TH: 3.7 ± 1.0%, FN: 4.3 ± 1.5%) and PTX (LS: 11.2 ± 1.5%, TH: 7.5 ± 1.5%, FN: 7.9 ± 2.1%) groups. In Dmb group, LS-TBS was significantly improved by 3.0 ± 1.0%, while TBS change in PTX group approached significance (2.8 ± 1.5%). Percent change in TH-BMD was significantly correlated with baseline tartrate-resistant acid phosphatase-5b (TRACP-5b) in both groups. CONCLUSIONS Dmb treatment not only increased BMD, dependent on bone turnover status, the same as PTX, but also improved LS-TBS. In addition, it did not decrease the level of eGFR, whereas PTX did. These results suggest that Dmb treatment help in the clinical management of osteoporotic patients with PHPT who do not undergo surgery as alternative to PTX.
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Affiliation(s)
- Daichi Miyaoka
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Yasuo Imanishi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Eiko Kato
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norikazu Toi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuki Nagata
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masafumi Kurajoh
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shinsuke Yamada
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masanori Emoto
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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Dempster DW, Chines A, Bostrom MP, Nieves JW, Zhou H, Chen L, Pannacciulli N, Wagman RB, Cosman F. Modeling-Based Bone Formation in the Human Femoral Neck in Subjects Treated With Denosumab. J Bone Miner Res 2020; 35:1282-1288. [PMID: 32163613 PMCID: PMC9328280 DOI: 10.1002/jbmr.4006] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 02/25/2020] [Accepted: 03/04/2020] [Indexed: 12/13/2022]
Abstract
Denosumab is associated with continued gains in hip and spine BMD with up to 10 years of treatment in postmenopausal women with osteoporosis. Despite potent inhibition of bone remodeling, findings in nonhuman primates suggest modeling-based bone formation (MBBF) may persist during denosumab treatment. This study assessed whether MBBF in the femoral neck (FN) is preserved in the context of inhibited remodeling in subjects receiving denosumab. This open-label study enrolled postmenopausal women with osteoporosis who had received two or more doses of denosumab (60 mg subcutaneously every 6 months [Q6M]) per standard of care and were planning elective total hip replacement (THR) owing to osteoarthritis of the hip. Transverse sections of the FN were obtained after THR and analyzed histomorphometrically. MBBF, based on fluorochrome labeling and presence of smooth cement lines, was evaluated in cancellous, endocortical, and periosteal envelopes of the FN. Histomorphometric parameters were used to assess MBBF and remodeling-based bone formation (RBBF) in denosumab-treated subjects (n = 4; mean age = 73.5 years; range, 70 to 78 years) and historical female controls (n = 11; mean age = 67.8 years; range, 62 to 80 years) obtained from the placebo group of a prior study and not treated with denosumab. All analyses were descriptive. All subjects in both groups exhibited MBBF in the periosteal envelope; in cancellous and endocortical envelopes, all denosumab-treated subjects and 81.8% of controls showed evidence of MBBF. Compared with controls, denosumab-treated subjects showed 9.4-fold and 2.0-fold higher mean values of MBBF in cancellous and endocortical envelopes, respectively, whereas RBBF mean values were 5.0-fold and 5.3-fold lower. In the periosteal envelope, MBBF and RBBF rates were similar between subjects and controls. These results demonstrate the occurrence of MBBF in the human FN and suggest that denosumab preserves MBBF while inhibiting remodeling, which may contribute to the observed continued gains in BMD over time after remodeling is maximally inhibited. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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Affiliation(s)
- David W Dempster
- Columbia UniversityNew YorkNYUSA
- Helen Hayes HospitalWest HaverstrawNYUSA
| | | | | | - Jeri W Nieves
- Columbia UniversityNew YorkNYUSA
- Helen Hayes HospitalWest HaverstrawNYUSA
| | - Hua Zhou
- Helen Hayes HospitalWest HaverstrawNYUSA
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Omiya T, Hirose J, Omata Y, Tominari T, Inada M, Watanabe H, Miyamoto T, Tanaka S. Sustained anti-osteoporotic action of risedronate compared to anti-RANKL antibody following discontinuation in ovariectomized mice. Bone Rep 2020; 13:100289. [PMID: 32577437 PMCID: PMC7305378 DOI: 10.1016/j.bonr.2020.100289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/19/2020] [Accepted: 06/02/2020] [Indexed: 01/22/2023] Open
Abstract
Bisphosphonates and the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab are effective anti-resorptive drugs commonly prescribed for osteoporosis. Both drugs may, however, have intolerable side effects; so, it is critical to examine their residual efficacy such as maintenance of bone mass following cessation. Therefore, we compared the changes in bone histology following discontinuation of the aminobisphosphonate risedronate and anti-RANKL antibody in ovariectomized (OVX) mice. Twelve-week-old female C57BL/6 N mice were OVX or sham operated. Four weeks after surgery, mice were treated with vehicle, a single injection of anti-RANKL antibody (5 mg/kg), or risedronate (5 μg/kg/day, s.c.) for 4 weeks (the treatment period), followed by vehicle treatment for an additional 4 weeks (discontinuation period). The lumbar spine and proximal tibia were evaluated by micro-computed tomography. In addition, the lumbar spine, proximal tibia, and the femoral shaft were examined by bone histomorphometry. After 4 weeks of discontinuation, OVX mice initially treated with the anti-RANKL antibody exhibited a trend of bone loss associated with increased turnover in both trabecular and cortical bones, although the difference was not significant. By contrast, OVX mice treated with risedronate exhibited maintained or even increased bone mass and suppressed bone turnover. Patients discontinuing denosumab should be carefully monitored for recurrent osteoporosis symptoms, and a replacement drug should be considered.
Bone mass and suppression of turnover were maintained after stopping bisphophonates. Bone turnover was rapidly increased after discontinuation of anti-RANKL antibody. Periosteal bone formation was maintained after administration of antiresorptive drugs.
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Affiliation(s)
- Toshinobu Omiya
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Jun Hirose
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yasunori Omata
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.,Bone and Cartilage Regenerative Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tsukasa Tominari
- Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei-shi, Tokyo 184-8588, Japan
| | - Masaki Inada
- Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei-shi, Tokyo 184-8588, Japan
| | - Hisato Watanabe
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Takeshi Miyamoto
- Department of Orthopedic Surgery, Keio University, School of Medicine, 35 Shinano-machi, Shinjuku, Tokyo 160-8582, Japan
| | - Sakae Tanaka
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
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35
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Frost M, Rahbek ET, Ejersted C, Høilund-Carlsen PF, Bygum A, Thomsen JS, Andreasen CM, Andersen TL, Frederiksen AL. Modeling-based bone formation transforms trabeculae to cortical bone in the sclerotic areas in Buschke-Ollendorff syndrome. A case study of two females with LEMD3 variants. Bone 2020; 135:115313. [PMID: 32151766 DOI: 10.1016/j.bone.2020.115313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
Buschke-Ollendorff syndrome is a rare autosomal dominant condition caused by pathogenic variants in LEMD3 and characterized by connective tissue nevi and sclerotic bone abnormalities known as osteopoikilosis. The bone phenotype in Buschke-Ollendorff syndrome including osteopoikilosis remains unclear. We investigated bone turnover markers, pelvis and crura X-rays; lumbar spine and femoral neck DXA; bone activity by NaF-PET/CT, bone structure by μCT and dynamic histomorphometry in adults with Buschke-Ollendorff syndrome. Two women aged 25 and 47 years with a BMI of 30 and 32 kg/m2, respectively, were included in the investigation. Bone turnover markers were within normal range. aBMD Z-scores were comparable to that of controls in the lumbar spine and increased at the hip. Radiographies exposed spotted areas in crura and pelvis, and NaF-PET/CT exposed abnormal pattern of irregular shaped NaF uptake in the entire skeleton. In both biopsies, μCT showed trabecular structure comparable to that of controls with stellate shaped sclerotic noduli within the cavity and on the endocortex. Histomorphometric analyses of the sclerotic lesions revealed compact lamellar bone with a normal bone remodeling rate, but partly replaced by modeling-based bone formation. Woven bone was not observed in the nodules. Therefore, while bone turnover and BMD were largely within normal reference range in patients with the Buschke-Ollendorff syndrome, osteosclerotic lesions appear to emerge due to modeling-based bone formation with secondary bone remodeling. These observations indicate that LEMD3 may be important for the activation of bone lining cells leading to modeling-based bone formation.
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Affiliation(s)
- M Frost
- Dept. of Endocrinology, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark; Steno Diabetes Center Odense, J.B. Winsløws Vej 4, DK-5000 Odense C, Denmark; Dept. of Clinical Research, Faculty of Health, University of Southern Denmark, J.B. Winsloews vej 19, DK-5000 Odense C, Denmark.
| | - E T Rahbek
- Dept. of Clinical Genetics, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark.
| | - C Ejersted
- Dept. of Endocrinology, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark.
| | - P F Høilund-Carlsen
- Dept. of Clinical Research, Faculty of Health, University of Southern Denmark, J.B. Winsloews vej 19, DK-5000 Odense C, Denmark; Dept. of Nuclear Medicine, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark.
| | - A Bygum
- Dept. of Clinical Research, Faculty of Health, University of Southern Denmark, J.B. Winsloews vej 19, DK-5000 Odense C, Denmark; Dept. of Dermatology and Allergy Centre, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark.
| | - J S Thomsen
- Dept. of Biomedicine, Aarhus University, Wilhelm Meyers Allé, DK-8000 Aarhus C, Denmark..
| | - C M Andreasen
- Clinical Cell Biology, Pathology Research Unit, Odense University Hospital, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark; Dept. of Molecular Medicine, University of Southern Denmark, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark; Dept. of Clinical Research, University of Southern Denmark, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark.
| | - T L Andersen
- Clinical Cell Biology, Pathology Research Unit, Odense University Hospital, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark; Dept. of Molecular Medicine, University of Southern Denmark, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark; Dept. of Forensic Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark; Dept. of Clinical Research, University of Southern Denmark, J. B Winsloews Vej 25, DK-5000 Odense C, Denmark.
| | - A L Frederiksen
- Dept. of Clinical Research, Faculty of Health, University of Southern Denmark, J.B. Winsloews vej 19, DK-5000 Odense C, Denmark; Dept. of Clinical Genetics, Odense University Hospital, J.B. Winsloews Vej 4, DK-5000 Odense C, Denmark.
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36
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Iolascon G, Moretti A, Toro G, Gimigliano F, Liguori S, Paoletta M. Pharmacological Therapy of Osteoporosis: What's New? Clin Interv Aging 2020; 15:485-491. [PMID: 32273690 PMCID: PMC7105363 DOI: 10.2147/cia.s242038] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/07/2020] [Indexed: 02/05/2023] Open
Abstract
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.
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Affiliation(s)
- Giovanni Iolascon
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Antimo Moretti
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giuseppe Toro
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Francesca Gimigliano
- Department of Physical and Mental Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Sara Liguori
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marco Paoletta
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy
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37
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Langdahl BL. Overview of treatment approaches to osteoporosis. Br J Pharmacol 2020; 178:1891-1906. [PMID: 32060897 DOI: 10.1111/bph.15024] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 01/16/2020] [Accepted: 01/31/2020] [Indexed: 12/28/2022] Open
Abstract
Efficient therapies are available for the treatment of osteoporosis. Anti-resorptive therapies, including bisphosphonates and denosumab, increase bone mineral density (BMD) and reduce the risk of fractures by 20-70%. Bone-forming or dual-action treatments stimulate bone formation and increase BMD more than the anti-resorptive therapies. Two studies have demonstrated that these treatments are superior to anti-resorptives in preventing fractures in patients with severe osteoporosis. Bone-forming or dual-action treatments should be followed by anti-resorptive treatment to maintain the fracture risk reduction. The BMD gains seen with bone-forming and dual-action treatments are greater in treatment-naïve patients compared to patients pretreated with anti-resorptive treatments. However, the antifracture efficacy seems to be preserved. Treatment failure will often lead to switch of treatment from orally to parentally administrated anti-resorptives treatment or from anti-resorptive to bone-forming or dual-action treatment. Osteoporosis is a chronic condition and therefore needs a long-term management plan with a personalized approach to treatment. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
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Affiliation(s)
- Bente L Langdahl
- Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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38
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Seeman E, Martin TJ. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol 2020; 15:225-236. [PMID: 30755735 DOI: 10.1038/s41584-019-0172-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.
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Affiliation(s)
- Ego Seeman
- Departments of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia. .,Mary MacKillop Institute of Health Research, Australian Catholic University, Melbourne, Victoria, Australia.
| | - T J Martin
- Department of Medicine and St Vincent's Institute, University of Melbourne, Melbourne, Victoria, Australia
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Ramchand SK, Seeman E. Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy. Handb Exp Pharmacol 2020; 262:423-450. [PMID: 32232792 DOI: 10.1007/164_2020_354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume.Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling - fewer BMUs remodel, "turn over," the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50-60% but only reduce nonvertebral fractures by 20-30%.Restoring bone volume, microstructure, and material composition, "curing" bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested.
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Affiliation(s)
- Sabashini K Ramchand
- Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA.
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia.
| | - Ego Seeman
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia
- Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC, Australia
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40
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Palmisano B, Spica E, Remoli C, Labella R, Di Filippo A, Donsante S, Bini F, Raimondo D, Marinozzi F, Boyde A, Robey P, Corsi A, Riminucci M. RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease. J Bone Miner Res 2019; 34:2171-2182. [PMID: 31295366 PMCID: PMC8408916 DOI: 10.1002/jbmr.3828] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/13/2019] [Accepted: 06/30/2019] [Indexed: 12/19/2022]
Abstract
Fibrous dysplasia of bone/McCune-Albright syndrome (Polyostotic FD/MAS; OMIM#174800) is a crippling skeletal disease caused by gain-of-function mutations of Gs α. Enhanced bone resorption is a recurrent histological feature of FD and a major cause of fragility of affected bones. Previous work suggests that increased bone resorption in FD is driven by RANKL and some studies have shown that the anti-RANKL monoclonal antibody, denosumab, reduces bone turnover and bone pain in FD patients. However, the effect of RANKL inhibition on the histopathology of FD and its impact on the natural history of the disease remain to be assessed. In this study, we treated the EF1α-Gs αR201C mice, which develop an FD-like phenotype, with an anti-mouse RANKL monoclonal antibody. We found that the treatment induced marked radiographic and microscopic changes at affected skeletal sites in 2-month-old mice. The involved skeletal segments became sclerotic due to the deposition of new, highly mineralized bone within developing FD lesions and showed a higher mechanical resistance compared to affected segments from untreated transgenic mice. Similar changes were also detected in older mice with a full-blown skeletal phenotype. The administration of anti-mouse RANKL antibody arrested the growth of established lesions and, in young mice, prevented the appearance of new ones. However, after drug withdrawal, the newly formed bone was remodelled into FD tissue and the disease progression resumed in young mice. Taken together, our results show that the anti-RANKL antibody significantly affected the bone pathology and natural history of FD in the mouse. Pending further work on the prevention and management of relapse after treatment discontinuation, our preclinical study suggests that RANKL inhibition may be an effective therapeutic option for FD patients. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Biagio Palmisano
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Emanuela Spica
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Cristina Remoli
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Rossella Labella
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | | | | | - Fabiano Bini
- Department of Mechanical and Aerospace Engineering, Sapienza University, Rome, Italy
| | | | - Franco Marinozzi
- Department of Mechanical and Aerospace Engineering, Sapienza University, Rome, Italy
| | - Alan Boyde
- Dental Physical Sciences, Barts' and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, UK
| | - Pamela Robey
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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41
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Ferrari S. Response to Letter to the Editor: "Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment". J Clin Endocrinol Metab 2019; 104:5806. [PMID: 31290968 DOI: 10.1210/jc.2019-01388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 07/03/2019] [Indexed: 11/19/2022]
Affiliation(s)
- Serge Ferrari
- Division of Bone Diseases, Geneva University Hospitals, Geneva, Switzerland
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42
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Abstract
PURPOSE OF REVIEW The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder. RECENT FINDINGS The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition. SUMMARY Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.
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Affiliation(s)
- Vittoria Rossi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA
- Texas Children’s Hospital, Houston TX, USA
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA
- Texas Children’s Hospital, Houston TX, USA
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Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab 2019; 104:3450-3461. [PMID: 31125092 DOI: 10.1210/jc.2019-00271] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/20/2019] [Indexed: 01/22/2023]
Abstract
CONTEXT Evidence for further nonvertebral fracture (NVF) reductions with long-term antiresorptive therapy in osteoporosis is lacking. OBJECTIVE To evaluate NVF risk reduction in subjects receiving ≤10 years of denosumab treatment. DESIGN Phase 3, randomized, placebo-controlled, 3-year Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (NCT00089791) and its open-label 7-year extension (NCT00523341). SETTING One hundred seventy-two study centers worldwide. PATIENTS Women 60 to 90 years, lumbar spine or total hip bone mineral density T-scores <-2.5 (≥-4.0 at both). INTERVENTIONS Subjects randomly assigned 1:1 denosumab 60 mg SC Q6M (long-term) or placebo (crossover) in FREEDOM; eligible subjects could enroll in the extension to receive denosumab 60 mg SC Q6M. MAIN OUTCOME MEASURES NVF Exposure-adjusted subject incidence (per 100 subject-years) during denosumab treatment years 1 to 3 and 4 to 7 (all subjects) and years 4 to 10 (long-term only), and rate ratios (RRs) for years 4 to 7 or 4 to 10 vs 1 to 3. RESULTS Among 4074 subjects (2343 long-term, 1731 crossover), NVF rates (95% CI) in all subjects were 2.15 (1.90 to 2.43) during years 1 to 3 and 1.53 (1.34 to 1.75) during years 4 to 7 of denosumab treatment [RR (95% CI) = 0.72 (0.61 to 0.86); P < 0.001]; in long-term only were 1.98 (1.67 to 2.34) during years 1 to 3 and 1.44 (1.24 to 1.66) during years 4 to 10 [RR = 0.74 (0.60 to 0.93); P = 0.008]. combined osteonecrosis of the jaw and atypical femoral fracture rate was 0.06. CONCLUSIONS Long-term denosumab treatment, >3 and ≤10 years, was associated with further reductions in NVF rates compared with the first 3 years.
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Affiliation(s)
| | | | - David L Kendler
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Paul D Miller
- Colorado Center for Bone Research, Lakewood, Colorado
| | | | | | | | | | - E Michael Lewiecki
- New Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico
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Yamada H, Ochi Y, Mori H, Nishikawa S, Hashimoto Y, Tanaka M, Deacon S, Kawabata K. Cortical bone mineral density is increased by the cathepsin K inhibitor ONO-5334, which leads to a robust increase in bone strength: results from a 16-month study in ovariectomised cynomolgus monkeys. J Bone Miner Metab 2019; 37:636-647. [PMID: 30357565 DOI: 10.1007/s00774-018-0968-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 10/01/2018] [Indexed: 02/07/2023]
Abstract
This study evaluated the long-term effects of the cathepsin K inhibitor ONO-5334 on bone mass and strength in ovariectomised (OVX) cynomolgus monkeys. Animals were assigned to one of the following six groups: Sham (non-OVX), OVX control treated with vehicle, ONO-5334 1.2, 6 or 30 mg/kg/day, p.o., or alendronate (ALN) 0.05 mg/kg/2 weeks, i.v. for 16 months. Peripheral quantitative computed tomography (pQCT) analysis revealed that ONO-5334 increased not only trabecular bone mineral density (BMD) but also cortical BMD in the distal radius and the lumbar vertebra. ONO-5334 and ALN suppressed the deterioration of trabecular architecture by micro-CT analysis in the distal radius. Assessments of bone strength showed that ONO-5334 increased maximum load at the distal and midshaft radius. The linear regression lines between bone mass and strength in the lumbar vertebra were tended to be shifted towards increasing bone strength in the ONO-5334 6 and 30 mg/kg groups compared with the ALN groups. This indicated that bone strength was higher in the ONO-5334 groups than the ALN group, even though bone mineral content (BMC) and BMD were comparable. Subpopulation analysis revealed that, at similar integral BMC or BMD level, cortical bone mass for ONO-5334 was higher than for ALN; the opposite effects were observed for trabecular bone. In conclusion, ONO-5334 preferentially increased cortical bone, which may provide a greater contribution to bone strength. Since these results support a different mode of action for ONO-5334 compared with that of ALN, ONO-5334 may offer new therapeutic options to patients with osteoporosis.
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Affiliation(s)
- Hiroyuki Yamada
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan.
| | - Yasuo Ochi
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
| | - Hiroshi Mori
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
| | - Satoshi Nishikawa
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
| | - Yasuaki Hashimoto
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
| | - Makoto Tanaka
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
| | - Steve Deacon
- Drug Development, ONO Pharma UK LTD, MidCity Place, 71 High Holborn, London, WC1V 6EA, UK
| | - Kazuhito Kawabata
- Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan
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Abstract
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.
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Affiliation(s)
| | - Michael R McClung
- Department of Medicine, Oregon Health and Science University, Portland, OR, USA; Mary MacKillop Institute for Health, Australian Catholic University, Melbourne, VIC, Australia
| | - William D Leslie
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
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Ramchand SK, Seeman E. Advances and Unmet Needs in the Therapeutics of Bone Fragility. Front Endocrinol (Lausanne) 2018; 9:505. [PMID: 30237785 PMCID: PMC6135909 DOI: 10.3389/fendo.2018.00505] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/10/2018] [Indexed: 01/22/2023] Open
Abstract
The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < -2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20-30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.
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Affiliation(s)
- Sabashini K. Ramchand
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology, Austin Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Ego Seeman
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology, Austin Health, The University of Melbourne, Melbourne, VIC, Australia
- Mary Mackillop Institute of Health Research, Australian Catholic University, Melbourne, VIC, Australia
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Ebina K, Hirao M, Hashimoto J, Hagihara K, Kashii M, Kitaguchi K, Matsuoka H, Iwahashi T, Chijimatsu R, Yoshikawa H. Assessment of the effects of switching oral bisphosphonates to denosumab or daily teriparatide in patients with rheumatoid arthritis. J Bone Miner Metab 2018; 36:478-487. [PMID: 28766140 DOI: 10.1007/s00774-017-0861-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/12/2017] [Indexed: 01/12/2023]
Abstract
The aim of this observational, non-randomized study was to clarify the unknown effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) in patients with rheumatoid arthritis (RA). The characteristics of the 194 female patients included in the study were 183 postmenopausal, age 65.9 years, lumbar spine (LS) T score -1.8, femoral neck (FN) T score -2.3, dose and rate of taking oral prednisolone (3.6 mg/day) 75.8%, and prior BP treatment duration 40.0 months. The patients were allocated to (1) the BP-continue group (n = 80), (2) the switch-to-DMAb group (n = 74), or (3) the switch-to-TPTD group (n = 40). After 18 months, the increase in bone mineral density (BMD) was significantly greater in the switch-to-DMAb group than in the BP-continue group (LS 5.2 vs 2.3%, P < 0.01; FN 3.8 vs 0.0%, P < 0.01) and in the switch-to-TPTD group than in the BP-continue group (LS 9.0 vs 2.3%, P < 0.001; FN 4.9 vs 0.0%, P < 0.01). Moreover, the switch-to-TPTD group showed a higher LS BMD (P < 0.05) and trabecular bone score (TBS) (2.1 vs -0.7%; P < 0.05) increase than the switch-to-DMAb group. Clinical fracture incidence during this period was 8.8% in the BP-continue group, 4.1% in the switch-to-DMAb group, and 2.5% in the switch-to-TPTD group. Both the switch-to-DMAb group and the switch-to-TPTD group showed significant increases in LS and FN BMD, and the switch-to-TPTD group showed a higher increase in TBS compared to the BP-continue group at 18 months. Switching BPs to DMAb or TPTD in female RA may provide some useful osteoporosis treatment options.
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Affiliation(s)
- Kosuke Ebina
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Makoto Hirao
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Jun Hashimoto
- Department of Rheumatology, National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka, 586-8521, Japan
| | - Keisuke Hagihara
- Department of Kampo Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masafumi Kashii
- Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Kazuma Kitaguchi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hozo Matsuoka
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Toru Iwahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryota Chijimatsu
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hideki Yoshikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab 2018; 103:2498-2509. [PMID: 29672714 PMCID: PMC6037073 DOI: 10.1210/jc.2017-02669] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 04/11/2018] [Indexed: 12/13/2022]
Abstract
CONTEXT Denosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis. OBJECTIVE Determine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics. DESIGN AND SETTING International, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension. PATIENTS Postmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points. INTERVENTIONS FREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years. OUTCOMES Bone histology, histomorphometry, matrix mineralization. RESULTS Ten-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter. CONCLUSIONS Denosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.
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Affiliation(s)
- David W Dempster
- Department of Pathology and Cell Biology, Columbia University, New York, New York
- Helen Hayes Hospital, West Haverstraw, New York
- Correspondence and Reprint Requests: David W. Dempster, BSc (Hons), PhD, FRMS, Regional Bone Center, Helen Hayes Hospital, Route 9W, West Haverstraw, New York 10993. E-mail:
| | - Jacques P Brown
- Division of Rheumatology, Faculty of Medicine, Laval University and CHU de Quebec Research Centre, Quebec City, Quebec, Canada
| | | | - David Kendler
- Department of Medicine (Endocrinology), University of British Columbia, Vancouver, British Columbia, Canada
| | - Sebastien Rizzo
- Bone and Chronic Diseases, INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Ivo Valter
- Center for Clinical and Basic Research, Tallinn, Estonia
| | | | - Xiang Yin
- Clinical Development, Amgen Inc., Thousand Oaks, California
| | - Susan V Yue
- Clinical Development, Amgen Inc., Thousand Oaks, California
| | - Georges Boivin
- Bone and Chronic Diseases, INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France
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Dempster DW, Zhou H, Ruff VA, Melby TE, Alam J, Taylor KA. Longitudinal Effects of Teriparatide or Zoledronic Acid on Bone Modeling- and Remodeling-Based Formation in the SHOTZ Study. J Bone Miner Res 2018; 33:627-633. [PMID: 29194749 DOI: 10.1002/jbmr.3350] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 10/31/2017] [Accepted: 11/22/2017] [Indexed: 01/22/2023]
Abstract
Previously, we reported on bone histomorphometry, biochemical markers, and bone mineral density distribution after 6 and 24 months of treatment with teriparatide (TPTD) or zoledronic acid (ZOL) in the SHOTZ study. The study included a 12-month primary study period, with treatment (TPTD 20 μg/d by subcutaneous injection or ZOL 5 mg/yr by intravenous infusion) randomized and double-blind until the month 6 biopsy (TPTD, n = 28; ZOL, n = 30 evaluable), then open-label, with an optional 12-month extension receiving the original treatment. A second biopsy (TPTD, n = 10; ZOL, n = 9) was collected from the contralateral side at month 24. Here we present data on remodeling-based bone formation (RBF), modeling-based bone formation (MBF), and overflow modeling-based bone formation (oMBF, modeling overflow adjacent to RBF sites) in the cancellous, endocortical, and periosteal envelopes. RBF was significantly greater after TPTD versus ZOL in all envelopes at 6 and 24 months, except the periosteal envelope at 24 months. MBF was significantly greater with TPTD in all envelopes at 6 months but not at 24 months. oMBF was significantly greater at 6 months in the cancellous and endocortical envelopes with TPTD, with no significant differences at 24 months. At 6 months, total bone formation surface was also significantly greater in each envelope with TPTD treatment (all p < 0.001). For within-group comparisons from 6 to 24 months, no statistically significant changes were observed in RBF, MBF, or oMBF in any envelope for either the TPTD or ZOL treatment groups. Overall, TPTD treatment was associated with greater bone formation than ZOL. Taken together the data support the view that ZOL is a traditional antiremodeling agent, wheareas TPTD is a proremodeling anabolic agent that increases bone formation, especially that associated with bone remodeling, including related overflow modeling, with substantial modeling-based bone formation early in the course of treatment. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- David W Dempster
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA.,Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA
| | | | | | - Jahangir Alam
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
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50
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Variability of Denosumab densitometric response in postmenopausal osteoporosis. Rheumatol Int 2018; 38:461-466. [DOI: 10.1007/s00296-018-3929-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 01/04/2018] [Indexed: 10/18/2022]
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