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Liu D, Qin H, Yang J, Yang L, He S, Chen S, Bao Q, Zhao Y, Zong Z. Different effects of Wnt/β-catenin activation and PTH activation in adult and aged male mice metaphyseal fracture healing. BMC Musculoskelet Disord 2020; 21:110. [PMID: 32075627 PMCID: PMC7031971 DOI: 10.1186/s12891-020-3138-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/12/2020] [Indexed: 12/25/2022] Open
Abstract
Background Fractures in older men are not uncommon and need to be healed as soon as possible to avoid related complications. Anti-osteoporotic drugs targeting Wnt/β-catenin and PTH (parathyroid hormone) to promote fracture healing have become an important direction in recent years. The study is to observe whether there is a difference in adult and aged situations by activating two signal paths. Methods A single cortical hole with a diameter of 0.6 mm was made in the femoral metaphysis of Catnblox(ex3) mice and wild-type mice. The fracture healing effects of CA (Wnt/β-catenin activation) and PTH (activated by PTH (1–34) injections) were assessed by X-ray and CT imaging on days 7, 14, and 21 after fracture. The mRNA levels of β-catenin, PTH1R(Parathyroid hormone 1 receptor), and RUNX2(Runt-related transcription factor 2) in the fracture defect area were detected using RT-PCR. Angiogenesis and osteoblasts were observed by immunohistochemistry and osteoclasts were observed by TRAP (Tartrate-resistant Acid Phosphatase). Result Adult CA mice and adult PTH mice showed slightly better fracture healing than adult wild-type (WT) mice, but there was no statistical difference. Aged CA mice showed better promotion of angiogenesis and osteoblasts and better fracture healing than aged PTH mice. Conclusion The application of Wnt/β-catenin signaling pathway drugs for fracture healing in elderly patients may bring better early effects than PTH signaling pathway drugs, but the long-term effects need to be observed.
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Affiliation(s)
- Daocheng Liu
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Hao Qin
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Jiazhi Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Lei Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Sihao He
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Sixu Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Quanwei Bao
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Yufeng Zhao
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China
| | - Zhaowen Zong
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, 400042, China.
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Liu D, He S, Chen S, Yang L, Yang J, Bao Q, Qin H, Zhao Y, Zong Z. Different effects of Wnt/β-catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice. Clin Exp Pharmacol Physiol 2019; 46:652-663. [PMID: 30908657 PMCID: PMC6593981 DOI: 10.1111/1440-1681.13088] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/01/2019] [Accepted: 03/18/2019] [Indexed: 11/27/2022]
Abstract
Parathyroid hormone (PTH) and agents related to the manipulation of Wnt/β-catenin signalling are two promising anabolic anti-osteoporotic therapies that have been shown to promote the healing of bone fractures. Now, it is widely accepted that cortical bone and trabecular bone are two different compartments, and should be treated as separate compartments in pathological processes, such as fracture healing. It is currently unknown whether PTH and the activation of β-catenin signalling would demonstrate different effects on cortical bone and trabecular bone healing. In the current study, single 0.6-mm cortex holes were made in the femur metaphysis and diaphysis of mice, and then, PTH application and β-catenin activation were used to observe the promoting effect on bone healing. The effects of β-catenin and PTH signalling on fracture healing were observed by X-ray and CT at 3, 6, and 14 days after fracture, and the levels of β-catenin were detected by RT-PCR assay, and the number of specific antigen-positive cells of BRDU, OCN, RUNX2 was counted by immunohistochemical staining. While β-catenin activation and PTH were found to demonstrate similar effects on accelerating metaphyseal bone healing, activation of β-catenin showed a more striking effect than PTH on promoting diaphyseal bone healing. These findings might be helpful for selecting proper medication to accelerate fracture healing of different bone compartments.
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Affiliation(s)
- Daocheng Liu
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Sihao He
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Sixu Chen
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Lei Yang
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Jiazhi Yang
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Quanwei Bao
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Hao Qin
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Yufeng Zhao
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Zhaowen Zong
- State Key Laboratory of Trauma, Burn and Combined injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
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Abstract
Metabolic bone diseases are a diverse group of conditions characterized by abnormalities in calcium metabolism and/or bone cell physiology. These unbalanced processes can eventually lead to bony deformities and altered joint biomechanics, resulting in degenerative joint disease. Not infrequently, patients with metabolic bone diseases have restricting hip joint pain that ultimately necessitates hip arthroplasty. To minimize complications, the surgeon must consider the particular characteristics of these patients. The surgical and medical management of patients with metabolic bone diseases undergoing hip arthroplasty requires appropriate preoperative diagnosis, careful attention to the technical challenges of surgery, and strategies to maximize the long-term results of the surgical intervention, such as the use of bone anabolic and anticatabolic agents.
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Rath B, Eschweiler J, Betsch M, Quack V, Lüring C, Tingart M. [Hip arthroplasty after corrective osteotomies : Pelvis and proximal femur]. DER ORTHOPADE 2017; 45:678-86. [PMID: 27385386 DOI: 10.1007/s00132-016-3294-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Pelvic and femoral osteotomies are frequently performed in patients with hip dysplasia. The aim of these surgeries are optimal biomechanical conditions of the hip joint thereby avoiding the occurrence of hip osteoarthritis or the delay of initial hip osteoarthritis progression. THERAPY Nevertheless even with good biomechanical conditions of the hip joint, progression of hip osteoarthritis can be recognized postoperatively. A total hip arthroplasty is indicated even more after a time period with conservative treatment. In preparation for the operation, a detailed documentation of the initial clinical situation, appropriate imaging, implant selection and preoperative planning are mandatory. In addition, a biomechanical model representing the desired pre- and postoperative situation can be included in the preoperative planning. According to the previous osteotomy, the size and shape of the acetabulum after the osteotomy and the current pivot centre of the hip joint should be considered. Depending on these observations the acetabular cup can be directly inserted into the bone stock of the acetabulum or an acetabular plasty is necessary before implantation of the acetabular cup. With respect to the previous osteotomy of the femur, it needs to be clarified wether hardware removal will be necessary before total hip replacement; moreover, the anatomy of the proximal femur is critical. In addition, if necessary, a re-osteotomy of the femur is required to enable a hip stem implantation. CONCLUSION Cementless total hip replacement should be preferred due to the younger patient age. The load of the hip replacement depends on the osseous anchoring and primary stability of the acetabular and femoral component.
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Affiliation(s)
- B Rath
- Klinik für Orthopädie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland.
| | - J Eschweiler
- Klinik für Orthopädie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland.,Lehrstuhl für Medizintechnik, Helmholtz Institut Aachen, Pauwelsstraße 20, 52074, Aachen, Deutschland
| | - M Betsch
- Klinik für Orthopädie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
| | - V Quack
- Klinik für Orthopädie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
| | - C Lüring
- Klinik für Orthopädie, Klinikum Dortmund, Beurhausstraße 40, 44137, Dortmund, Deutschland
| | - M Tingart
- Klinik für Orthopädie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
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Abstract
Background and purpose - Aseptic loosening is a main cause of late revision in total knee replacement (TKR). Teriparatide, a recombinant parathyroid hormone (PTH), stimulates osteoblasts and has been suggested to improve cancellous bone healing in humans. This might also be relevant for prosthesis fixation. We used radiostereometric analysis (RSA) to investigate whether teriparatide influences prosthesis fixation. Early migration as measured by RSA can predict future loosening. Patients and methods - In a randomized controlled trial with blind evaluation, 50 patients with osteoarthritis of the knee were allocated to a teriparatide treatment group (Forsteo, 20 μg daily for 2 months postoperatively) or to an untreated control group. RSA was performed postoperatively and at 6 months, 12 months, and 24 months. The primary effect variable was maximal total point motion (MTPM) from 12 to 24 months. Results - Median maximal total point motion from 12 to 24 months was similar in the 2 groups (teriparatide: 0.14 mm, 10% and 90% percentiles: 0.08 and 0.24; control: 0.13 mm, 10% and 90% percentiles: 0.09 and 0.21). [Authors: this is perhaps better than using "10th" and "90th", which looks ugly in print./language editor] The 95% confidence interval for the difference between group means was -0.03 to 0.04 mm, indicating that no difference occurred. Interpretation - We found no effect of teriparatide on migration in total knee replacement. Other trials using the same dosing have suggested a positive effect of teriparatide on human cancellous fracture healing. Thus, the lack of effect on migration may have been due to something other than the dose. In a similar study in this issue of Acta Orthopaedica, we found that migration could be reduced with denosumab (Ledin et al. 2017 ). The difference in response between the anabolic substance teriparatide and the antiresorptive denosumab suggests that resorption has a more important role during the postoperative course than any deficit in bone formation.
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Affiliation(s)
- Håkan Ledin
- Orthopedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Linköping;,Department of Orthopedics, Aleris Specialist Care Motala AB, Motala;,Correspondence:
| | - Lars Good
- Department of Orthopedics, Hospital of Oskarshamn, Oskarshamn
| | - Torsten Johansson
- Orthopedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Norrköping, Sweden
| | - Per Aspenberg
- Orthopedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Linköping
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Chesser TJS, Fox R, Harding K, Halliday R, Barnfield S, Willett K, Lamb S, Yau C, Javaid MK, Gray AC, Young J, Taylor H, Shah K, Greenwood R. The administration of intermittent parathyroid hormone affects functional recovery from trochanteric fractured neck of femur: a randomised prospective mixed method pilot study. Bone Joint J 2017; 98-B:840-5. [PMID: 27235530 PMCID: PMC4911544 DOI: 10.1302/0301-620x.98b6.36794] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 01/12/2016] [Indexed: 11/21/2022]
Abstract
Aims We wished to assess the feasibility of a future randomised controlled
trial of parathyroid hormone (PTH) supplements to aid healing of
trochanteric fractures of the hip, by an open label prospective
feasibility and pilot study with a nested qualitative sub study.
This aimed to inform the design of a future powered study comparing
the functional recovery after trochanteric hip fracture in patients
undergoing standard care, versus those who undergo administration
of subcutaneous injection of PTH for six weeks. Patients and Methods We undertook a pilot study comparing the functional recovery
after trochanteric hip fracture in patients 60 years or older, admitted
with a trochanteric hip fracture, and potentially eligible to be
randomised to either standard care or the administration of subcutaneous
PTH for six weeks. Our desired outcomes were functional testing
and measures to assess the feasibility and acceptability of the
study. Results A total of 724 patients were screened, of whom 143 (20%) were
eligible for recruitment. Of these, 123 were approached and 29 (4%)
elected to take part. However, seven patients did not complete the
study. Compliance with the injections was 11 out of 15 (73%) showing
the intervention to be acceptable and feasible in this patient population. Take home message: Only 4% of patients who met the inclusion
criteria were both eligible and willing to consent to a study involving
injections of PTH, so delivering this study on a large scale would
carry challenges in recruitment and retention. Methodological and
sample size planning would have to take this into account. PTH administration
to patients to enhance fracture healing should still be considered
experimental. Cite this article: Bone Joint J 2016;98-B:840–5.
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Affiliation(s)
- T J S Chesser
- Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK
| | - R Fox
- Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK
| | - K Harding
- Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK
| | - R Halliday
- Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK
| | - S Barnfield
- Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK
| | - K Willett
- Kadoorie Research Centre, John Radcliffe Hospital, Headley Way, Oxford OX9 3DU, UK
| | - S Lamb
- University of Oxford, Windmill Road, Oxford OX3 7LD, UK
| | - C Yau
- Stoke Mandeville Hospital, Aylesbury HP21 8AL, UK
| | - M K Javaid
- University of Oxford, Windmill Road, Oxford OX3 7LD, UK
| | - A C Gray
- Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
| | - J Young
- University Hospitals Coventry and Warwick, Coventry, UK
| | - H Taylor
- University of Bristol NHS Foundation Trust, Education Centre, Level 3, Maudlin Street, Bristol BS2 8AE, UK
| | - K Shah
- Kadoorie Research Centre, John Radcliffe Hospital, Headley Way, Oxford OX9 3DU, UK
| | - R Greenwood
- University of Bristol NHS Foundation Trust, Education Centre, Level 3, Maudlin Street, Bristol BS2 8AE, UK
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Apostu D, Lucaciu O, Lucaciu GDO, Crisan B, Crisan L, Baciut M, Onisor F, Baciut G, Câmpian RS, Bran S. Systemic drugs that influence titanium implant osseointegration. Drug Metab Rev 2017; 49:92-104. [PMID: 28030966 DOI: 10.1080/03602532.2016.1277737] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Titanium implants are widely used on an increasing number of patients in orthopedic and dental medicine. Despite the good survival rates of these implants, failures that lead to important socio-economic consequences still exist. Recently, research aimed at improving implant fixation, a process called osseointegration, has focused on a new, innovative field: systemic delivery of drugs. Following implant fixation, patients receive systemic drugs that could either impair or enhance osseointegration; these drugs include anabolic and anti-catabolic bone-acting agents in addition to new treatments. Anabolic bone-acting agents include parathyroid hormone (PTH) peptides, simvastatin, prostaglandin EP4 receptor antagonist, vitamin D and strontium ranelate; anti-catabolic bone-acting agents include compounds like calcitonin, biphosphonates, RANK/RANKL/OPG system and selective estrogen receptor modulators (SERM). Examples of the new therapies include DKK1- and anti-sclerostin antibodies. All classes of treatments have proven to possess positive impacts such as an increase in bone mineral density and on osseointegration. In order to prevent complications from occurring after surgery, some post-operative systemic drugs are administered; these can show an impairment in the osseointegration process. These include nonsteroidal anti-inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors. The effects of aspirin, acetaminophen, opioids, adjuvants, anticoagulants and antibiotics in implant fixations are not fully understood, but studies are being carried out to investigate potential ramifications. It is currently accepted that systemic pharmacological agents can either enhance or impair implant osseointegration; therefore, proper drug selection is essential. This review aims to discuss the varying effects of three different classes of treatments on improving this process.
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Affiliation(s)
- Dragos Apostu
- a Department of Orthopaedics and Traumatology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Ondine Lucaciu
- b Department of Oral Rehabilitation , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | | | - Bogdan Crisan
- d Department of Maxillofacial Surgery and Oral Implantology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Liana Crisan
- e Department of Oral and Maxillofacial Surgery , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Mihaela Baciut
- d Department of Maxillofacial Surgery and Oral Implantology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Florin Onisor
- e Department of Oral and Maxillofacial Surgery , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Grigore Baciut
- e Department of Oral and Maxillofacial Surgery , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Radu Septimiu Câmpian
- b Department of Oral Rehabilitation , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Simion Bran
- d Department of Maxillofacial Surgery and Oral Implantology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
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Tao ZS, Zhou WS, Tu KK, Huang ZL, Zhou Q, Sun T, Lv YX, Cui W, Yang L. Effect exerted by Teriparatide upon Repair Function of β-tricalcium phosphate to ovariectomised rat's femoral metaphysis defect caused by osteoporosis. Injury 2015; 46:2134-41. [PMID: 26306803 DOI: 10.1016/j.injury.2015.07.042] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 05/11/2015] [Accepted: 07/28/2015] [Indexed: 02/02/2023]
Abstract
In this study, we tested the effect of Teriparatide (PTH) in combination with β-tricalcium phosphate (β-TCP) as a bone void filler in an ovariectomised rat distal femoral metaphysis model.β-TCP is a completely resorbable synthetic calcium phosphate and the Teriparatide is a drug that can promote bone formation in the condition of osteoporosis. A critical size defect of 3mm in diameter, a through-hole bone defect, was drilled into each distal femur of the ovariectomised rats. The hole was filled with β-TCP and the rat was injected PTH Teriparatide (30μg/kg) in peritoneum 5 times per week. After 4and 8 weeks the animals were killed and the degree of bone healing analysed. In total, 60 animals were investigated. When the β-TCP and PTH were used, histological, biochemistry and histomor-phometric evaluations revealed significantly better bone healing in terms of quantity and quality of the newly formed bone. The Ovariectomised rats which suffer from femur metaphysis defect are cured by embedding β-tricalcuim phosphate and intermittently cured by parathyroid hormone (PTH).
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Affiliation(s)
- Zhou-Shan Tao
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
| | - Wan-Shu Zhou
- Endocrine & Metabolic Diseases Unit, Affiliated Hospital of Guizhou Medcial University, Guizhou 550001, China
| | - Kai-kai Tu
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
| | - Zheng-Liang Huang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
| | - Qiang Zhou
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
| | - Tao Sun
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
| | - Yang-Xun Lv
- Department of Orthopaedic Surgery, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
| | - Wei Cui
- Sichuan Provincial Orthopedics Hospital, No. 132 West First Section First Ring Road, Chengdu 610000, Sichuan, China
| | - Lei Yang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China.
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Tao ZS, Zhou WS, Tu KK, Huang ZL, Zhou Q, Sun T, Lv YX, Cui W, Yang L. Treatment study of distal femur for parathyroid hormone (1-34) and β-tricalcium phosphate on bone formation in critical-sized defects in osteopenic rats. J Craniomaxillofac Surg 2015; 43:2136-43. [PMID: 26507646 DOI: 10.1016/j.jcms.2015.09.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 08/12/2015] [Accepted: 09/17/2015] [Indexed: 12/11/2022] Open
Abstract
The objective of this study was to evaluate the effect of following combined treatment with parathyroid hormone (1-34) (PTH) and β-tricalcium phosphate (β-TCP) on local bone formation in a rat 3-mm critical-sized defect at the distal femur. Fourteen weeks were allowed to pass before defect surgery for the establishment of osteopenic animal models chronically fed a low-protein diet. All animals were randomly divided into four groups: group PTH; group β-TCP, group PTH + β-TCP, and a control group. All rats then underwent a surgical procedure to create bone defects in the bilateral distal femurs, and β-TCP was implanted into critical-sized defects for the groups designated as β-TCP and group PTH + β-TCP. After the defect operation, all animals from group PTH and group PTH + β-TCP received following subcutaneous injections with PTH (60 μg/kg, three times per week) until euthanasia at 4 and 8 weeks. The distal femurs and blood were collected for evaluation. The results of study showed the strongest effect on accelerating the local bone formation with treatment β-TCP and PTH at 4 weeks and 8 weeks. The results from our study demonstrate that a combination of PTH and β-TCP had an additive effect on local bone formation in osteopenic rats chronically fed a low-protein diet.
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Affiliation(s)
- Zhou-Shan Tao
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China
| | - Wan-Shu Zhou
- Endocrine & Metabolic Diseases Unit, Affiliated Hospital of Guizhou Medical University, Guizhou, 550001, China
| | - Kai-kai Tu
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China
| | - Zheng-Liang Huang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China
| | - Qiang Zhou
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China
| | - Tao Sun
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China
| | - Yang-Xun Lv
- Department of Orthopaedic Surgery, Wenzhou Central Hospital, Wenzhou, Zhejiang, 325000, China
| | - Wei Cui
- Sichuan Provincial Orthopedics Hospital, NO. 132 West First Section First Ring Road, Chengdu, Sichuan, 610000, China
| | - Lei Yang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China.
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Engraftment and bone mass are enhanced by PTHrP 1-34 in ectopically transplanted vertebrae (vossicle model) and can be non-invasively monitored with bioluminescence and fluorescence imaging. Transgenic Res 2015; 24:955-69. [PMID: 26271486 DOI: 10.1007/s11248-015-9901-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 08/04/2015] [Indexed: 10/23/2022]
Abstract
Evidence exists that parathyroid hormone-related protein (PTHrP) 1-34 may be more anabolic in bone than parathyroid hormone 1-34. While optical imaging is growing in popularity, scant information exists on the relationships between traditional bone imaging and histology and bioluminescence (BLI) and fluorescence (FLI) imaging. We aimed to evaluate the effects of PTHrP 1-34 on bone mass and determine if relationships existed between radiographic and histologic findings in bone and BLI and FLI indices. Vertebrae (vossicles) from mice coexpressing luciferase and green fluorescent protein were implanted subcutaneously into allogenic nude mice. Transplant recipients were treated daily with saline or PTHrP 1-34 for 4 weeks. BLI, FLI, radiography, histology, and µCT of the vossicles were performed over time. PTHrP 1-34 increased bioluminescence the most after 2 weeks, fluorescence at all time points, and decreased the time to peak bioluminescence at 4 weeks (P ≤ 0.027), the latter of which suggesting enhanced engraftment. PTHrP 1-34 maximized vertebral body volume at 4 weeks (P < 0.0001). The total amount of bone observed histologically increased in both groups at 2 and 4 weeks (P ≤ 0.002); however, PTHrP 1-34 exceeded time-matched controls (P ≤ 0.044). A positive linear relationship existed between the percentage of trabecular bone and (1) total bioluminescence (r = 0.595; P = 0.019); (2) total fluorescence (r = 0.474; P = 0.074); and (3) max fluorescence (r = 0.587; P = 0.021). In conclusion, PTHrP 1-34 enhances engraftment and bone mass, which can be monitored non-invasively by BLI and FLI.
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Silva EDP, Vasconcelos DFP, Marques MR, Silva MADD, Manzi FR, Barros SP. Intermittent administration of parathyroid hormone improves the repairing process of rat calvaria defects: A histomorphometric and radiodensitometric study. Med Oral Patol Oral Cir Bucal 2015; 20:e489-93. [PMID: 26034928 PMCID: PMC4523262 DOI: 10.4317/medoral.20412] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 03/08/2015] [Indexed: 01/30/2023] Open
Abstract
Background The aim of this study was to evaluate the effects of intermittent treatment of parathyroid hormone (PTH (1-34)) on the bone regeneration of critically-sized rat calvarial bone defects. Material and Methods Thirty-two male rats were trephined (4mm fullthickness diameter), in the central part of the parietal bones and divided into 2 groups of 16. The PTH group received subcutaneous injections of PTH (1-34) at 40µg/kg, 3 times a week and the control (CTL) group received the vehicle in the same regimen. The rats were sacrificed at 4 weeks post-treatment regimen, the parietal bones were extracted and samples were evaluated through histomorphometry and radiodensitometry. Results The histological observations showed that the PTH group presented more “island-like” new bone between the defect margins with fibrous tissues than did the CTL group. The PTH group significantly exhibited greater histologic bone formation than did the CTL group (1.5mm ±0.7; 1.9 mm ± 0.6, p<0.05/ for residual bone defect). The radiodensitometry analysis revealed significant differences among the PTH and CTL groups (2.1 Al eq. ±0.04; 1.8Al eq. ±0.06, p<0.05), demonstrating an increase in bone mineral density. The PTH treatment contributed to the bone formation with a higher amount of mineral and/or fibrous tissue when compared with the CTL group. Conclusions The results suggest that it was possible to increase the process of bone regeneration by accelerating the healing process in rat calvarial defects through intermittent administration of the PTH treatment. Key words:
Bone, skull, rats, bone regeneration, bone density.
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Affiliation(s)
- Eduardo-de-Paula Silva
- Universidade Federal do Piauí - UFPI, Campus Ministro Reis Veloso, Colegiado de Biomedicina, Av. São Sebastião, 2819, Reis Veloso, Parnaíba -PI -Brazil, 64204-035,
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Yang X, Ricciardi BF, Dvorzhinskiy A, Brial C, Lane Z, Bhimani S, Burket JC, Hu B, Sarkisian AM, Ross FP, van der Meulen MCH, Bostrom MPG. Intermittent Parathyroid Hormone Enhances Cancellous Osseointegration of a Novel Murine Tibial Implant. J Bone Joint Surg Am 2015; 97:1074-83. [PMID: 26135074 PMCID: PMC4574908 DOI: 10.2106/jbjs.n.01052] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Long-term fixation of uncemented joint implants requires early mechanical stability and implant osseointegration. To date, osseointegration has been unreliable and remains a major challenge in cementless total knee arthroplasty. We developed a murine model in which an intra-articular proximal tibial titanium implant with a roughened stem can be loaded through the knee joint. Using this model, we tested the hypothesis that intermittent injection of parathyroid hormone (iPTH) would increase proximal tibial cancellous osseointegration. METHODS Ten-week-old female C57BL/6 mice received a subcutaneous injection of PTH (40 μg/kg/day) or a vehicle (n = 45 per treatment group) five days per week for six weeks, at which time the baseline group was killed (n = 6 per treatment group) and an implant was inserted into the proximal part of the tibiae of the remaining mice. Injections were continued until the animals were killed at one week (n = 7 per treatment group), two weeks (n = 14 per treatment group), or four weeks (n = 17 per treatment group) after implantation. Outcomes included peri-implant bone morphology as analyzed with micro-computed tomography (microCT), osseointegration percentage and bone area fraction as shown with backscattered electron microscopy, cellular composition as demonstrated by immunohistochemical analysis, and pullout strength as measured with mechanical testing. RESULTS Preimplantation iPTH increased the epiphyseal bone volume fraction by 31.6%. When the data at post-implantation weeks 1, 2, and 4 were averaged for the iPTH-treated mice, the bone volume fraction was 74.5% higher in the peri-implant region and 168% higher distal to the implant compared with the bone volume fractions in the same regions in the vehicle-treated mice. Additionally, the trabecular number was 84.8% greater in the peri-implant region and 74.3% greater distal to the implant. Metaphyseal osseointegration and bone area fraction were 28.1% and 70.1% higher, respectively, in the iPTH-treated mice than in the vehicle-treated mice, and the maximum implant pullout strength was 30.9% greater. iPTH also increased osteoblast and osteoclast density by 65.2% and 47.0%, respectively, relative to the values in the vehicle group, when the data at post-implantation weeks 1 and 2 were averaged. CONCLUSIONS iPTH increased osseointegration, cancellous mass, and the strength of the bone-implant interface. CLINICAL RELEVANCE Our murine model is an excellent platform on which to study biological enhancement of cancellous osseointegration.
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Affiliation(s)
- Xu Yang
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Benjamin F Ricciardi
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Aleksey Dvorzhinskiy
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Caroline Brial
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Zachary Lane
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Samrath Bhimani
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Jayme C Burket
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - Bin Hu
- Department of Biomaterials and Biomimetics, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010
| | - Alexander M Sarkisian
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | - F Patrick Ross
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
| | | | - Mathias P G Bostrom
- Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:
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Tao ZS, Qiang Z, Tu KK, Huang ZL, Xu HM, Sun T, Lv YX, Cui W, Yang L. Treatment study of distal femur for parathyroid hormone (1-34) and β-tricalcium phosphate on bone formation in critical size defects in rats. J Biomater Appl 2015; 30:484-91. [PMID: 26116022 DOI: 10.1177/0885328215592854] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1-34), a surgically implanted synthetic β-tricalcium phosphate bone biomaterial serving as a matrix to support new bone formation. Twelve weeks after bilateral ovariectomy, all rats underwent bone defect in the distal femurs, and β-tricalcium phosphate was implanted into critical sized defects. After defect operation, all animals were randomly divided into four groups and received following subcutaneous injections until death at four and eight weeks: sham rats (group ST); sham rats + parathyroid hormone, 30 µg/kg, three times a week (group SPT); OVX rats (group OT); and OVX rats + parathyroid hormone (group OPT). The distal femurs of rats were harvested for evaluation. The treatment group demonstrating the highest levels of new bone formation was the defects treated with parathyroid hormone as assessed by micro-computed tomography, biomechanical strength, and histological analysis for sham rats. Furthermore, parathyroid hormone showed a stronger effect on accelerating the degradation of β-tricalcium phosphate. Osteoporosis can limit the function of parathyroid hormone and/or β-tricalcium phosphate. The results from our study demonstrate that combination of parathyroid hormone and β-tricalcium phosphate brings better effect to bone tissue repair in non-osteoporosis and/or osteoporosis status.
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Affiliation(s)
- Zhou-Shan Tao
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zhou Qiang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Kai-kai Tu
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zheng-liang Huang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Hong-ming Xu
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Tao Sun
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yang-Xun Lv
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Wei Cui
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Lei Yang
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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Xu Z, Zhao L, Wu Y, Wei X, Wang J, Tang N, Tang T, Zhao Z. Histomorphometric and biomechanical analyses of the osseointegration of loaded orthodontic microscrews inserted at different cortical bone thickness sites. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118:157-65. [DOI: 10.1016/j.oooo.2012.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Revised: 05/28/2012] [Accepted: 06/04/2012] [Indexed: 12/01/2022]
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Chesser T, Fox R, Harding K, Greenwood R, Javaid K, Barnfield S, Halliday R, Willett K, Lamb S. The administration of intermittent parathyroid hormone affects functional recovery from pertrochanteric fractured neck of femur: a protocol for a prospective mixed method pilot study with randomisation of treatment allocation and blinded assessment (FRACTT). BMJ Open 2014; 4:e004389. [PMID: 24477319 PMCID: PMC3913027 DOI: 10.1136/bmjopen-2013-004389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 11/27/2013] [Accepted: 11/28/2013] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Pertrochanteric hip fractures occur in an elderly population and cause considerable morbidity and loss of functional ability as the fracture heals. Recently, parathyroid hormone (PTH), which is licensed for the treatment of osteoporosis, has been shown to potentially accelerate bone healing in animal and human studies. If its administration could allow a faster functional recovery after pertrochanteric hip fracture, then a patient's hospital stay may be reduced and rehabilitation could be potentially accelerated. PTH can currently only be administered by subcutaneous injection. The acceptability of this intervention is unknown in this elderly population. The aim of this pilot study is to inform the design of a future powered study comparing the functional recovery after pertrochanteric hip fracture in patients undergoing standard care versus those who undergo administration of subcutaneous injection of PTH. METHODS AND ANALYSIS The study is an open label, prospective, randomised, comparative pilot study with blinded outcomes assessment to establish feasibility of the trial design. Patients will be randomised to receive a 6-week course of PTH or usual treatment. Functional outcomes will be assessed at 6 weeks and 12 weeks. Blinded assessment will be used to minimise the effect of bias of an open label study design. A nested qualitative study will investigate the patient experience of, and expectations following, hip fracture and the patient important aspects of recovery compared with the outcome measures proposed. RESULTS Results will be analysed to establish the potential recruitment, compliance and retention rates using 95% CIs, and trial outcomes quoted with SDs and 95% CIs for the effect size. ETHICS AND DISSEMINATION The study has been approved by the South West 2 Research Ethics committee (reference 10/H0206/34). The findings of this study will be disseminated to the medical community via presentations to orthopaedic, orthogeriatric and osteoporosis societies, and their relevant specialist journals. TRIAL REGISTRATION ISRCTN Register reference number: ISRCTN03362357. Eudract Number: 2010-020081-22.
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Affiliation(s)
- Tim Chesser
- Department of Orthopaedic Surgery, Frenchay Hospital, Bristol, UK
| | - Rebecca Fox
- Department of Orthopaedic Surgery, Frenchay Hospital, Bristol, UK
| | - Karen Harding
- Department of Orthopaedic Surgery, Frenchay Hospital, Bristol, UK
| | - Rosemary Greenwood
- University Hospitals Bristol NHS Foundation Trust, Level 3 Education Centre, Bristol, UK
| | - Kassim Javaid
- NIHR Botnar Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK
| | - Steven Barnfield
- Department of Orthopaedic Surgery, Frenchay Hospital, Bristol, UK
| | - Ruth Halliday
- Department of Orthopaedic Surgery, Frenchay Hospital, Bristol, UK
| | - Keith Willett
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kadoorie Critical Care Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Sallie Lamb
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kadoorie Critical Care Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK
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Fahlgren A, Yang X, Ciani C, Ryan JA, Kelly N, Ko FC, van der Meulen MCH, Bostrom MPG. The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit. Bone 2013; 52:718-24. [PMID: 22613252 PMCID: PMC4142202 DOI: 10.1016/j.bone.2012.05.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 05/07/2012] [Indexed: 11/19/2022]
Abstract
Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the peri-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on peri-implant bone volume fraction. In this model, PTH enhanced peri-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced peri-implant bone volume, and surgery and PTH treatment had a strong combined effect. This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.
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Affiliation(s)
- Anna Fahlgren
- Hospital for Special Surgery, New York, NY 10021, USA
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Abstract
This annotation describes some early rat studies which conclude that parathyroid hormone (PTH) has more dramatic stimulatory effects on bone repair than on untraumatized bone. It also suggests, based on the effects of PTH on osteoblasts, that it is more likely to accelerate normal fracture healing than to prevent non-union. The only 2 controlled clinical trials that have been published are critically discussed. Although both are encouraging and appear to show acceleration of normal fracture healing, they have methodological shortcomings that preclude definitive conclusions.
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Affiliation(s)
- Per Aspenberg
- Orthopedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Linköping, Sweden
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Abstract
INTRODUCTION Each fracture has a failing risk which can lead to a non-union. Among the non-invasive strategies proposed to improve bone healing, also in non-union, the use of teriparatide, a drug for the treatment of the osteoporosis, has increasing supporting data. EXPERIMENTAL DATA Many studies mainly on rats, but also on primates, demonstrate the positive effect on fracture healing of teriparatide, both in physiological and pathological conditions, with a more rapid evolution of the reparative callus. CLINICAL DATA A double blinded randomized controlled study on wrist fractures demonstrated a positive effect, in term of healing speed, of teriparatide at the dose of 20 μg/day, but not at the higher dose of 40 μg/day. A prospectic randomized study on pelvic fractures showed a faster healing in teriparatide treated patients. The use of teriparatide in non-unions is reported as effective in numerous case report. The effect of teriparatide seems very useful in the non-unions consequent to an atypical femoral fracture after long-term administration of bisphosphonates. CONCLUSIONS A conceivable positive effect of teriparatide on fracture healing is well-documented on animals, and very likely on humans, however further studies are needed to confirm these hopeful hypotheses.
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Virdi AS, Liu M, Sena K, Maletich J, McNulty M, Ke HZ, Sumner DR. Sclerostin antibody increases bone volume and enhances implant fixation in a rat model. J Bone Joint Surg Am 2012; 94:1670-80. [PMID: 22992878 PMCID: PMC3444952 DOI: 10.2106/jbjs.k.00344] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Previous studies have demonstrated that sclerostin blockade is anabolic for bone. This study examined whether systemic administration of sclerostin antibody would increase implant fixation and peri-implant bone volume in a rat model. METHODS Titanium cylinders were placed in the femoral medullary canal of ninety male Sprague-Dawley rats. One-half of the rats (n=45) received murine sclerostin antibody (Scl-Ab, 25 mg/kg, twice weekly) and the other one-half (n=45) received saline solution. Equal numbers of rats from both groups were sacrificed at two, four, or eight weeks after the implant surgery and the femora were examined by microcomputed tomography, mechanical pull-out testing, and histology. RESULTS Fixation strength in the two groups was similar at two weeks but was 1.9-fold greater at four weeks (p=0.024) and 2.2-fold greater at eight weeks (p<0.001) in the rats treated with sclerostin antibody. At two weeks, antibody treatment led to increased cortical area, with later increases in cortical thickness and total cross-sectional area. Significant differences in peri-implant trabecular bone were not evident until eight weeks but included increased bone volume per total volume, bone structure that was more plate-like, and increased trabecular thickness and number. Changes in bone architecture in the intact contralateral femur tended to precede the peri-implant changes. The peri-implant bone properties accounted for 61% of the variance in implant fixation strength, 32% of the variance in stiffness, and 63% of the variance in energy to failure. The implant fixation strength at four weeks was approximately equivalent to the strength in the control group at eight weeks. CONCLUSIONS Sclerostin antibody treatment accelerated and enhanced mechanical fixation of medullary implants in a rat model by increasing both cortical and trabecular bone volume.
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Affiliation(s)
- Amarjit S. Virdi
- Department of Anatomy and Cell Biology, Rush Medical College, Rush University Medical Center, 600 South Paulina Street, Room 507, AcFac, Chicago, IL 60612. E-mail address for D.R. Sumner:
| | - Min Liu
- Metabolic Disorders Research, Mail Stop 29-M-B, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320
| | - Kotaro Sena
- Department of Anatomy and Cell Biology, Rush Medical College, Rush University Medical Center, 600 South Paulina Street, Room 507, AcFac, Chicago, IL 60612. E-mail address for D.R. Sumner:
| | - James Maletich
- Department of Anatomy and Cell Biology, Rush Medical College, Rush University Medical Center, 600 South Paulina Street, Room 507, AcFac, Chicago, IL 60612. E-mail address for D.R. Sumner:
| | - Margaret McNulty
- Department of Anatomy and Cell Biology, Rush Medical College, Rush University Medical Center, 600 South Paulina Street, Room 507, AcFac, Chicago, IL 60612. E-mail address for D.R. Sumner:
| | - Hua Zhu Ke
- Metabolic Disorders Research, Mail Stop 29-M-B, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320
| | - Dale R. Sumner
- Department of Anatomy and Cell Biology, Rush Medical College, Rush University Medical Center, 600 South Paulina Street, Room 507, AcFac, Chicago, IL 60612. E-mail address for D.R. Sumner:
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Daugaard H, Elmengaard B, Andreassen TT, Lamberg A, Bechtold JE, Soballe K. Systemic intermittent parathyroid hormone treatment improves osseointegration of press-fit inserted implants in cancellous bone. Acta Orthop 2012; 83:411-9. [PMID: 22880714 PMCID: PMC3427634 DOI: 10.3109/17453674.2012.702388] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND AND PURPOSE Intermittent administration of parathyroid hormone (PTH) has an anabolic effect on bone, as confirmed in human osteoporosis studies, distraction osteogenesis, and fracture healing. PTH in rat models leads to improved fixation of implants in low-density bone or screw insertion transcortically. MATERIAL AND METHODS We examined the effect of human PTH (1-34) on the cancellous osseointegration of unloaded implants inserted press-fit in intact bone of higher animal species. 20 dogs were randomized to treatment with human PTH (1-34), 5 μg/kg/day subcutaneously, or placebo for 4 weeks starting on the day after insertion of a cylindrical porous coated plasma-sprayed titanium alloy implant in the proximal metaphyseal cancellous bone of tibia. Osseointegration was evaluated by histomorphometry and fixation by push-out test to failure. RESULTS Surface fraction of woven bone at the implant interface was statistically significantly higher in the PTH group by 1.4 fold with (median (interquartile range) 15% (13-18)) in the PTH group and 11% (7-13) in control. The fraction of lamellar bone was unaltered. No significant difference in bone or fibrous tissue was observed in the circumferential regions of 0-500, 500-1,000, and 1,000-2,000 μm around the implant. Mechanically, the implants treated with PTH showed no significant differences in total energy absorption, maximum shear stiffness, or maximum shear strength. INTERPRETATION Intermittent treatment with PTH (1-34) improved histological osseointegration of a prosthesis inserted press-fit at surgery in cancellous bone, with no additional improvement of the initial mechanical fixation at this time point.
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Affiliation(s)
- Henrik Daugaard
- Orthopaedic Research Laboratory, Department of Orthopedic Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Brian Elmengaard
- Orthopaedic Research Laboratory, Department of Orthopedic Surgery, Aarhus University Hospital, Aarhus, Denmark
| | | | - Anders Lamberg
- Orthopaedic Research Laboratory, Department of Orthopedic Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Joan Elisabeth Bechtold
- Orthopaedic Biomechanics Laboratory, Excelen Center for Bone and Joint Research and Minneapolis Medical Research Foundation, Minneapolis, MN, USA
| | - Kjeld Soballe
- Orthopaedic Research Laboratory, Department of Orthopedic Surgery, Aarhus University Hospital, Aarhus, Denmark
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Gamie Z, Korres N, Leonidou A, Gray AC, Tsiridis E. Sclerostin monoclonal antibodies on bone metabolism and fracture healing. Expert Opin Investig Drugs 2012; 21:1523-34. [DOI: 10.1517/13543784.2012.713936] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Lima LL, César Neto JB, Cayana EG, Nociti FH, Sallum EA, Casati MZ. Parathyroid hormone (1-34) compensates the negative effect of smoking around implants. Clin Oral Implants Res 2012; 24:1055-9. [PMID: 22712894 DOI: 10.1111/j.1600-0501.2012.02502.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2012] [Indexed: 11/30/2022]
Abstract
OBJECTIVES This study aimed to investigate the effect of Recombinant Human Parathyroid Hormone (PTH 1-34) on attenuating the influence of cigarette smoke on bone around titanium implants. MATERIAL AND METHODS Forty-eight female Wistar rats were used. At the beginning of the study, 15 animals were randomly assigned to Group 1 (control) and received subcutaneous injections of saline solution, three-times/week, after implant placement. The other animals received intermittent cigarette smoke inhalation (CSI), 60 days prior and 60 days after implant placement ( Al 2 O 3 -blasted titanium implants - 4.0 × 2.2 mm). After surgery, these animals were randomly assigned to: Group 2 - subcutaneous injections of saline solution, three-times/week (n = 16) and Group 3 - intermittent doses of PTH (1-34) (40 μg/Kg), three-times/week (n = 17). Animals were sacrificed 60 days after surgery, and degree of bone-to-implant contact (BIC), bone area (BA) within the limits of the threads and proportion of mineralized tissue (PMT) adjacent to the implants (500 μm wide zone) were separately obtained in cortical and cancellous bone. RESULTS Data analysis confirmed that CSI negatively affects bone around implants, as observed for BIC in cortical zone (Cohen's d (d) = -1.26) and for PMT in both zones (d = -6.09 and d = -4.46 for cortical and cancellous zones, respectively). In addition, in the presence of CSI, PTH (1-34) promoted the highest BIC in both regions and BA and PMT in cancellous bone (P < 0.05). The histometric parameter that was not influenced by both PTH and CSI (1-34) was BA in cortical bone (P > 0.05). CONCLUSION In the presence of cigarette smoke, a factor related to poor bone healing and low bone density, PTH (1-34) increased bone volume around implants.
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Affiliation(s)
- Liana Linhares Lima
- Dept. of Prosthodontics and Periodontics, Division of Periodontics, School of Dentistry at Piracicaba, University of Campinas, Piracicaba, Brazil
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Goldhahn J, Féron JM, Kanis J, Papapoulos S, Reginster JY, Rizzoli R, Dere W, Mitlak B, Tsouderos Y, Boonen S. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int 2012; 90:343-53. [PMID: 22451221 DOI: 10.1007/s00223-012-9587-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 02/15/2012] [Indexed: 12/27/2022]
Abstract
Osteoporotic fracture healing is critical to clinical outcome in terms of functional recovery, morbidity, and quality of life. Osteoporosis treatments may affect bone repair, so insights into their impact on fracture healing are important. We reviewed the current evidence for an impact of osteoporosis treatments on bone repair. Treatment with bisphosphonate in experimental models is associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. Experimental data for denosumab and raloxifene suggest no negative implications for bone repair. The extensive experimental results for teriparatide indicate increased callus formation, improved biomechanical strength, and greater external callus volume and total bone mineral content and density. Case reports and a randomized trial have produced mixed results but are consistent with a positive impact of teriparatide on clinical fracture healing. Studies with strontium ranelate in models of fracture healing indicate that it is associated with improved bone microstructure, callus volume, and biomechanical properties. Finally, there is experimental evidence for a beneficial effect of some of the agents currently being developed for osteoporosis, notably sclerostin antibody and DKK1 antibody. There is currently no evidence that osteoporosis treatments are detrimental for bone repair and some promising experimental evidence for positive effects on healing, notably for agents with a bone-forming mode of action, which may translate into therapeutic applications.
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Affiliation(s)
- J Goldhahn
- AO Clinical Priority Program "Fracture Fixation in Osteoporotic Bone", Institute for Biomechanics of ETH, Zurich, Switzerland.
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Papavasiliou KA, Nikopoulou A, Kenanidis EI, Potoupnis ME, Kyrkos MJ, Sayegh FE, Kapetanos GA. Serum intact-parathyroid hormone level following total knee arthroplasty. J Orthop Surg (Hong Kong) 2012; 20:27-31. [PMID: 22535807 DOI: 10.1177/230949901202000106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
PURPOSE To evaluate short-term parathyroid hormone (PTH) secretion following total knee arthroplasty (TKA). METHODS 119 Caucasian postmenopausal women aged 49 to 81 (mean, 69.8) years who underwent TKA for end-stage knee osteoarthritis were included. Serum levels of intact-PTH, calcium, phosphorus, and creatinine were evaluated pre- and post-operatively (on days -1 and 7). Creatinine clearance was also calculated. RESULTS In 67 of the patients, serum intact-PTH levels decreased after TKA; this sample proportion was not significant (p=0.82). In 16 of the patients, such levels elevated abnormally (above normal range). In the remaining 36 patients, such levels elevated within the normal range. Therefore, the mean serum intact- PTH level of all patients increased slightly after TKA (45.4 vs. 45.3, p=0.162). The serum intact-PTH level did not correlate to body weight (r=-0.045, p=0.624), patient age (r=-0.061, p=0.508), serum creatinine level (r=0.084, p=0.366), and clearance of creatinine (r=-0.037, p=0.692). CONCLUSION In most postmenopausal women, the serum intact-PTH level decreased moderately following TKA, but in some, the level was abnormally elevated. This may interfere the prosthesis incorporation process.
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Affiliation(s)
- Kyriakos A Papavasiliou
- 3rd Orthopaedic Department, Aristotle University of Thessaloniki-Medical School, Papageorgiou General Hospital, Thessaloniki, Greece.
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Datta NS. Osteoporotic fracture and parathyroid hormone. World J Orthop 2011; 2:67-74. [PMID: 22474638 PMCID: PMC3302045 DOI: 10.5312/wjo.v2.i8.67] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 04/19/2011] [Accepted: 06/01/2011] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH's clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.
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Agholme F, Isaksson H, Kuhstoss S, Aspenberg P. The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions. Bone 2011; 48:988-96. [PMID: 21329773 DOI: 10.1016/j.bone.2011.02.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 02/07/2011] [Accepted: 02/07/2011] [Indexed: 12/17/2022]
Abstract
The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, μCT and histology were used for evaluation. The animals were injected with either 10mg/kg Dkk1-ab or saline every 14days for 14, 28, or 42days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.
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Affiliation(s)
- Fredrik Agholme
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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27
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Daugaard H, Elmengaard B, Andreassen T, Bechtold J, Lamberg A, Soballe K. Parathyroid hormone treatment increases fixation of orthopedic implants with gap healing: a biomechanical and histomorphometric canine study of porous coated titanium alloy implants in cancellous bone. Calcif Tissue Int 2011; 88:294-303. [PMID: 21253714 PMCID: PMC3059756 DOI: 10.1007/s00223-010-9458-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Accepted: 11/18/2010] [Indexed: 11/17/2022]
Abstract
Parathyroid hormone (PTH) administered intermittently is a bone-building peptide. In joint replacements, implants are unavoidably surrounded by gaps despite meticulous surgical technique and osseointegration is challenging. We examined the effect of human PTH(1-34) on implant fixation in an experimental gap model. We inserted cylindrical (10 × 6 mm) porous coated titanium alloy implants in a concentric 1-mm gap in normal cancellous bone of proximal tibia in 20 canines. Animals were randomized to treatment with PTH(1-34) 5 μg/kg daily. After 4 weeks, fixation was evaluated by histomorphometry and push-out test. Bone volume was increased significantly in the gap. In the outer gap (500 μm), the bone volume fraction median (interquartile range) was 27% (20-37%) for PTH and 10% (6-14%) for control. In the inner gap, the bone volume fraction was 33% (26-36%) for PTH and 13% (11-18%) for control. At the implant interface, the bone fraction improved with 16% (11-20%) for PTH and 10% (7-12%) (P = 0.07) for control. Mechanical implant fixation was improved for implants exposed to PTH. For PTH, median (interquartile range) shear stiffness was significantly higher (PTH 17.4 [12.7-39.7] MPa/mm and control 8.8 [3.3-12.4] MPa/mm) (P < 0.05). Energy absorption was significantly enhanced for PTH (PTH 781 [595-1,198.5] J/m(2) and control 470 [189-596] J/m(2)). Increased shear strength was observed but was not significant (PTH 3.0 [2.6-4.9] and control 2.0 [0.9-3.0] MPa) (P = 0.08). Results show that PTH has a positive effect on implant fixation in regions where gaps exist in the surrounding bone. With further studies, PTH may potentially be used clinically to enhance tissue integration in these challenging environments.
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Affiliation(s)
- Henrik Daugaard
- Orthopaedic Department, Aarhus University Hospital, Aarhus, Denmark.
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28
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Daugaard H, Elmengaard B, Andreassen TT, Baas J, Bechtold JE, Soballe K. The combined effect of parathyroid hormone and bone graft on implant fixation. ACTA ACUST UNITED AC 2011; 93:131-9. [PMID: 21196558 DOI: 10.1302/0301-620x.93b1.24261] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Impaction allograft is an established method of securing initial stability of an implant in arthroplasty. Subsequent bone integration can be prolonged, and the volume of allograft may not be maintained. Intermittent administration of parathyroid hormone has an anabolic effect on bone and may therefore improve integration of an implant. Using a canine implant model we tested the hypothesis that administration of parathyroid hormone may improve osseointegration of implants surrounded by bone graft. In 20 dogs a cylindrical porous-coated titanium alloy implant was inserted into normal cancellous bone in the proximal humerus and surrounded by a circumferential gap of 2.5 mm. Morsellised allograft was impacted around the implant. Half of the animals were given daily injections of human parathyroid hormone (1-34) 5 μg/kg for four weeks and half received control injections. The two groups were compared by mechanical testing and histomorphometry. We observed a significant increase in new bone formation within the bone graft in the parathyroid hormone group. There were no significant differences in the volume of allograft, bone-implant contact or in the mechanical parameters. These findings suggest that parathyroid hormone improves new bone formation in impacted morsellised allograft around an implant and retains the graft volume without significant resorption. Fixation of the implant was neither improved nor compromised at the final follow-up of four weeks.
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Affiliation(s)
- H Daugaard
- Department of Orthopaedic Surgery, Orthopaedic Research Laboratory, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark.
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Kuchler U, Spilka T, Baron K, Tangl S, Watzek G, Gruber R. Intermittent parathyroid hormone fails to stimulate osseointegration in diabetic rats. Clin Oral Implants Res 2011; 22:518-23. [PMID: 21251075 DOI: 10.1111/j.1600-0501.2010.02047.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVES Diabetes is considered a risk factor in the osseointegration of dental implants, which suggests that these patients might benefit from anabolic therapies. Preclinical studies, including investigations by this research group, revealed that intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of titanium implants under physiological conditions. However, the anabolic effect of PTH on osseointegration under the hyperglycemic condition of diabetes is unknown. METHODS The ability of PTH to stimulate osseointegration was investigated in 40 female Wistar rats that were randomly divided into the following treatment groups: diabetes, diabetes plus PTH, control, and control plus PTH. Diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg) at 1 week before implantation. Rats received PTH at a dose of 60 μg/kg or a vehicle by subcutaneous injection starting at the day of implant insertion into the tibia. Histomorphometric analysis was performed after 4 weeks. RESULTS The medullary peri-implant bone area significantly increased in rats receiving PTH in comparison with the control group (41±12% to 20±12%; P<0.01). Moreover, there was an increased bone-to-implant contact (BIC) area in animals treated with PTH (47±18% to 27±16%; P<0.05). In contrast, diabetic rats failed to benefit from the anabolic treatment. A similar peri-implant bone area occurred in the diabetes group, independent of treatment with PTH (13±9% to 15±6%; P>0.05). Moreover, PTH did not affect the BIC area under hyperglycemic conditions (16±12% to 16±8%; P>0.05). No significant changes were observed in the cortical compartment of all groups. CONCLUSION These results demonstrate that the metabolic characteristics of the diabetic rats produced a condition that was unable to respond to PTH treatment. These findings led us to hypothesize that metabolic control of diabetes might be a critical determinant when diabetic patients are undergoing anabolic therapy to enhance osseointegration.
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Affiliation(s)
- Ulrike Kuchler
- Department of Oral Surgery, Medical University of Vienna, Austria
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Agholme F, Li X, Isaksson H, Ke HZ, Aspenberg P. Sclerostin antibody treatment enhances metaphyseal bone healing in rats. J Bone Miner Res 2010; 25:2412-8. [PMID: 20499342 DOI: 10.1002/jbmr.135] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Sclerostin is the product of the SOST gene. Loss-of-function mutations in the SOST gene result in a high-bone-mass phenotype, demonstrating that sclerostin is a negative regulator of bone mass. Primarily expressed by osteocytes in bone, sclerostin is reported to bind the LRP5/6 receptor, thereby antagonizing canonical Wnt signaling and negatively regulating bone formation. We therefore investigated whether systemic administration of a sclerostin-neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats. Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks. In four groups, the screws were tested for pull-out strength. At the time of euthanasia, a similar screw also was inserted in the contralateral tibia and pull-out tested immediately. Sclerostin antibody significantly increased the pull-out force by almost 50% compared with controls after 2 and 4 weeks. Also, the screws inserted at the time of euthanasia showed increased pull-out force. Micro-computed tomography (µCT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw. There also was a general increase in trabecular thickness in cancellous bone. Thus, as measured by the amount of bone and its mechanical resistance, the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone.
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Affiliation(s)
- Fredrik Agholme
- Orthopedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Linköping, Sweden.
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31
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Jacobson JA, Yanoso-Scholl L, Reynolds DG, Dadali T, Bradica G, Bukata S, Puzas EJ, Zuscik MJ, Rosier R, O'Keefe RJ, Schwarz EM, Awad HA. Teriparatide therapy and beta-tricalcium phosphate enhance scaffold reconstruction of mouse femoral defects. Tissue Eng Part A 2010; 17:389-98. [PMID: 20807012 DOI: 10.1089/ten.tea.2010.0115] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
To investigate the efficacy of endocrine parathyroid hormone treatment on tissue-engineered bone regeneration, massive femoral defects in C57Bl/6 mice were reconstructed with either 100:0 or 85:15 poly-lactic acid (PLA)/beta-tricalcium phosphate (β-TCP) scaffolds (hereafter PLA or PLA/βTCP, respectively), which were fabricated with low porosity (<30%) to improve their structural rigidity. Experimental mice were treated starting at 1 week postop with daily subcutaneous injections of 40 μg/kg teriparatide until sacrifice at 9 weeks, whereas control mice underwent the same procedure but were injected with sterile saline. Bone regeneration was assessed longitudinally using planar X-ray and quantitative microcomputed tomography, and the reconstructed femurs were evaluated at 9 weeks either histologically or biomechanically to determine their torsional strength and rigidity. Teriparatide treatment increased bone volume and bone mineral content significantly at 6 weeks and led to enhanced trabeculated bone callus formation that appeared to surround and integrate with the scaffold, thereby establishing union by bridging bone regeneration across the segmental defect in 30% of the reconstructed femurs, regardless of the scaffold type. However, the bone volume and mineral content in the PLA reconstructed femurs treated with teriparatide was reduced at 9 weeks to control levels, but remained significantly increased in the PLA/βTCP scaffolds. Further, bridged teriparatide-treated femurs demonstrated a prototypical brittle bone torsion behavior, and were significantly stronger and stiffer than control specimens or treated specimens that failed to form bridging bone union. Taken together, these observations suggest that intermittent, systemic parathyroid hormone treatment can enhance bone regeneration in scaffold-reconstructed femoral defects, which can be further enhanced by mineralized (βTCP) particles within the scaffold.
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Affiliation(s)
- Justin A Jacobson
- The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
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Ellegaard M, Jørgensen NR, Schwarz P. Parathyroid hormone and bone healing. Calcif Tissue Int 2010; 87:1-13. [PMID: 20428858 DOI: 10.1007/s00223-010-9360-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Accepted: 03/22/2010] [Indexed: 12/13/2022]
Abstract
Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.
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Affiliation(s)
- M Ellegaard
- Research Center of Aging and Osteoporosis, Department of Medicine, Copenhagen University Hospital Glostrup, Nordre Ringvej, 2600, Glostrup, Denmark.
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Goldhahn J, Little D, Mitchell P, Fazzalari NL, Reid IR, Aspenberg P, Marsh D. Evidence for anti-osteoporosis therapy in acute fracture situations--recommendations of a multidisciplinary workshop of the International Society for Fracture Repair. Bone 2010; 46:267-71. [PMID: 19833244 DOI: 10.1016/j.bone.2009.10.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Revised: 10/04/2009] [Accepted: 10/05/2009] [Indexed: 11/15/2022]
Abstract
The International Society for Fracture Repair convened a multidisciplinary workshop to assess the current evidence around the interaction between anti-osteoporosis drugs and the healing of incident fractures, with a view to making recommendations for clinical practice. The consensus was that there is no evidence-based reason to withhold anti-resorptive therapy while a fracture heals, whether or not the patient was taking such therapy when the fracture occurred. The workshop also considered existing models of service provision for secondary prevention and concluded that the essential ingredient for reliable delivery is the inclusion of a dedicated coordinator role. Several unresolved issues were defined as subjects for further research, including the question of whether continuous long-term administration of anti-resorptives may impair bone quality. The rapidly changing area requires re-assessment of drugs and their interaction with fracture healing in the near future.
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Affiliation(s)
- J Goldhahn
- AO Clinical Priority Program Fracture Fixation in Osteoporotic Bone, Schulthess Klinik Zurich, Switzerland.
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Aleksyniene R, Thomsen JS, Eckardt H, Bundgaard KG, Lind M, Hvid I. Parathyroid hormone PTH(1-34) increases the volume, mineral content, and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits. Acta Orthop 2009; 80:716-23. [PMID: 19995322 PMCID: PMC2823317 DOI: 10.3109/17453670903350032] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND AND PURPOSE Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans. METHODS 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 microg/kg/day for 30 days, saline for 10 days and PTH 25 microg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test. RESULTS In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group. INTERPRETATION We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans.
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Affiliation(s)
- Ramune Aleksyniene
- Orthopaedic Division of Northern Denmark, Aalborg University Hospital, University of Aarhus, Aalborg, Denmark
| | - Jesper Skovhus Thomsen
- Department of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, Århus, Denmark
| | | | - Kristian G Bundgaard
- Sector for Limb Reconstruction and Paediatric Orthopaedics, Aalborg University Hospital, University of Aarhus, Aalborg, Denmark
| | - Martin Lind
- Department of Orthopaedics, Sector for Sports Medicine, Aarhus University Hospital, Århus, Denmark
| | - Ivan Hvid
- Sector for Paediatric Orthopaedics, Department of Orthopaedics, Aarhus University Hospital, Århus, Denmark
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Papavasiliou KA, Kenanidis EI, Potoupnis ME, Sarris IK, Kirkos JM, Kapetanos GA. Incidence of secondary hyperparathyroidism among postmenopausal women with end-stage knee osteoarthritis. J Orthop Surg (Hong Kong) 2009; 17:310-2. [PMID: 20065370 DOI: 10.1177/230949900901700313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
PURPOSE To evaluate the incidence of secondary hyperparathyroidism (SH) among postmenopausal women with end-stage knee osteoarthritis scheduled for total knee replacement (TKR). METHODS 283 Caucasian postmenopausal women aged 49 to 81 (mean, 70) years with end-stage idiopathic knee osteoarthritis were scheduled to undergo primary TKR. They had been menopausal for 7 to 31 (mean, 19) years. Their preoperative serum levels of intact parathyroid hormone (I-PTH), calcium, phosphorus, creatinine, and the clearance of creatinine were evaluated. RESULTS 100 patients had abnormally elevated serum I-PTH. The overall incidence of SH was 35%. Serum levels of calcium and phosphorus were elevated in 33 and 12 patients, respectively. The serum level of I-PTH correlated positively with patient age (r=0.158, p=0.008) and serum creatinine level (r=0.138, p=0.021) and negatively with clearance of creatinine (r= -0.169, p=0.004). CONCLUSION SH is common among elderly postmenopausal women and may affect bone healing and implant fixation. Preoperative screening/evaluation of the serum PTH level in postmenopausal women scheduled for TKR is recommended.
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Affiliation(s)
- Kyriakos A Papavasiliou
- 3rd Orthopaedic Department, Medical School of the Aristotle University of Thessaloniki, Greece.
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Skripitz R, Johansson HR, Ulrich SD, Werner A, Aspenberg P. Effect of alendronate and intermittent parathyroid hormone on implant fixation in ovariectomized rats. J Orthop Sci 2009; 14:138-43. [PMID: 19337803 DOI: 10.1007/s00776-008-1311-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 12/11/2008] [Indexed: 01/13/2023]
Abstract
BACKGROUND Intermittent administration of parathyroid hormone (PTH) leads to bone formation by increasing osteoblast numbers and activity levels. Animal studies have shown that intermittent PTH administration increases implant fixation in normal rats. The purpose of this study was to analyze the osseous incorporation of an implant in osteoporotic rats while treating them with intermittent PTH (1-34) or alendronate. METHODS A total of 36 ovariectomized (OVX) Wistar rats were randomized into three groups. Polymethylmethacrylate cement rods were implanted in one tibia in each rat. The three groups received daily PTH (60 mug/kg body weight [BW]), alendronate (200 mug/kg BW), or saline (0.5 ml/kg BW). A sham-ovariectomized group (n = 12) was treated with saline. After 2 weeks, the area around the implants was analyzed by histomorphometry for bone volume density (BVD) and implant bone contact. Bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS The BVD was higher in the specimens treated with PTH than in the other groups. PTH improved the BVD, BMD, and implant bone contact. Alendronate doubled the implant bone contact compared to the OVX and sham groups but did not improve BVD or BMD. CONCLUSIONS These findings confirm that intermittent PTH enhances implant fixation in osteoporotic bone. The clinical significance of these findings is that application of intermittent PTH may be beneficial for early implant fixation in fractures, nonunions, and prosthetic replacements when bone density is decreased.
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Affiliation(s)
- R Skripitz
- Department of Orthopedic Surgery, University Hospital Rostock, 142 Doberaner Strasse, Rostock, D-18057, Germany
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Sebastian EM, Suva LJ, Friedman PA. Differential effects of intermittent PTH(1-34) and PTH(7-34) on bone microarchitecture and aortic calcification in experimental renal failure. Bone 2008; 43:1022-30. [PMID: 18761112 PMCID: PMC2644420 DOI: 10.1016/j.bone.2008.07.250] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Revised: 07/18/2008] [Accepted: 07/24/2008] [Indexed: 01/01/2023]
Abstract
PTH(1-84) and PTH(7-84) are elevated in chronic kidney disease (CKD). These peptides, as their shorter analogs PTH(1-34) and PTH(7-34) both promote PTH receptor (PTH1R) internalization but only PTH(1-34) and PTH(1-84) activate the receptor. Here, we examined the effects of intermittent administration of PTH(1-34) and PTH(7-34) on mineral ion metabolism, bone architecture, and vascular calcification in rats with experimental CKD. CKD with or without parathyroidectomy (PTX) was established by 5/6 nephrectomy (NPX) in rats. Animals were divided into 4 groups: Sham PTX+ sham NPX (Sham); PTX+ sham NPX (PTX); Sham PTX+NPX (NPX); PTX+NPX (PTX/NPX). Rats were treated with single daily doses of 40 microg/kg PTH(1-34), PTH(7-34), or vehicle. Creatinine was higher in NPX and Ca lower in PTX and PTX/NPX groups than in Sham or NPX rats. Plasma phosphate was higher in PTX, NPX and PTX/NPX than in Sham rats. PTH(1-34) was more hypercalcemic than PTH(7-34) in PTX rats. Fractional bone volume in rats treated with PTH(1-34) increased significantly in all groups compared to that of vehicle treatment. In addition, trabecular number, thickness and volumetric bone density increased in rats treated with PTH(1-34). In contrast, PTH(1-34) diminished vascular calcification. Bone and renal PTH1R mRNA expression was reduced as much or more in PTX/NPX rats as in NPX alone, whereas PTH(7-34) had no effect on PTH1R expression. Renal but not bone PTH1R mRNA increased in response to PTH(1-34). These findings suggest that PTH(1-34) exerts greater hypercalcemic and anabolic effects in parathyroidectomized and/or nephrectomized rats than does PTH(7-34). There was no evidence for significant bone or vascular actions of PTH(7-34). We conclude that PTH(1-34) protects against vascular calcification and bone demineralization in experimental renal failure.
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Affiliation(s)
- Ely M. Sebastian
- Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Larry J. Suva
- Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Peter A. Friedman
- Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- correspondence: Peter A. Friedman, Department of Pharmacology, University of Pittsburgh School of Medicine, W-1340 Biomedical Science Tower, Pittsburgh, PA 15261, USA., Tel: 412-383-7783, FAX: 412-648-1945, e-mail:
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Ohkawa Y, Tokunaga K, Endo N. Intermittent administration of human parathyroid hormone (1-34) increases new bone formation on the interface of hydroxyapatitecoated titanium rods implanted into ovariectomized rat femora. J Orthop Sci 2008; 13:533-42. [PMID: 19089541 DOI: 10.1007/s00776-008-1275-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Accepted: 07/29/2008] [Indexed: 01/29/2023]
Abstract
BACKGROUND As hydroxyapatite (HA) has good osteoconductive properties, HA is used as coating material for the implants in cementless arthroplasty. However, its effect is not sufficient for osteoporotic bone. Parathyroid hormone (PTH) is known to have anabolic effects on bone formation. Intermittent administration of PTH increases both cancellous and cortical bone mass. The aim of this study was to confirm the effect of the fixation strength of HA-coated implants in the osteoporotic condition with a mechanical test and a bone histomorphometric method. METHODS Female Sprague-Dawley rats were used for this study. Four weeks after ovariectomy (OVX) or sham surgery, HA-coated titanium rods were inserted into the distal femoral canal (Sham+HA group and OVX+HA group). PTH was administered immediately after the implantation of the HAcoated rods (OVX+HA+P group). We measured the shear strength at the bone-implant interface by a push-out test and the newly formed bone volume on the implant (BV.Im) by bone histomorphometry at 2 and 4 weeks after implantation. RESULTS The bone-implant shear strength in the OVX+HA group was significantly lower than that in the Sham+HA group at 2 weeks after implantation of the rods. In the OVX+HA+P group, the strength was significantly higher than that in the other groups. Similarly, at 4 weeks, statistically significant differences were confirmed in the bone-implant shear strength among the Sham+HA group, the OVX+HA group, and the OVX+HA+P group. BV.Im in the OVX+HA group was significantly lower than that in the Sham+HA group at 2 weeks after implantation. BV.Im was significantly higher in the OVX+HA+P group than that in the OVX+HA group. However, there was no difference in BV.Im between the Sham+HA group and the OVX+HA+P group. At 4 weeks after implantation, BV.Im was significantly lower in the OVX+HA group than that in the other groups, but no difference was found between the Sham+HA group and the OVX+HA+P group. CONCLUSIONS Intermittent administration of PTH has an effect to increase new bone formation on the surface of HA-coated implants in the osteoporotic condition. This finding suggests that PTH administration is useful to improve the initial fixation of HA-coated implants even in osteoporotic patients.
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Affiliation(s)
- Yutaka Ohkawa
- Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
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Wermelin K, Aspenberg P, Linderbäck P, Tengvall P. Bisphosphonate coating on titanium screws increases mechanical fixation in rat tibia after two weeks. J Biomed Mater Res A 2008; 86:220-7. [PMID: 17975821 DOI: 10.1002/jbm.a.31583] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Recently published data indicate that immobilized N-bisphosphonate enhances the pullout force and energy uptake of implanted stainless steel screws at 2 weeks in rat tibia. This study compares titanium screws with and without a bisphosphonate coating in the same animal model. The screws were first coated with an approximately 100-nm thick crosslinked fibrinogen film. Pamidronate was subsequently immobilized into this film via EDC/NHS-activated carboxyl groups within the fibrinogen matrix, and finally another N-bisphosphonate, ibandronate, was physically adsorbed. The release kinetics of immobilized (14)C-alendronate was measured in buffer up to 724 h and showed a 60% release within 8 h. Mechanical tests demonstrated a 32% (p = 0.04) and 48% (p = 0.02) larger pullout force and energy until failure after 2 weeks of implantation, compared to uncoated titanium screws. A control study with physically adsorbed pamidronate showed no effect on mechanical fixation, probably due to a too small adsorbed amount. We conclude that the fixation of titanium implants in bone can be improved by fibrinogen matrix-bound bisphosphonates.
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Affiliation(s)
- Karin Wermelin
- Division of Orthopaedics, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
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Aspenberg P, Wermelin K, Tengwall P, Fahlgren A. Additive effects of PTH and bisphosphonates on the bone healing response to metaphyseal implants in rats. Acta Orthop 2008; 79:111-5. [PMID: 18283582 DOI: 10.1080/17453670710014851] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND When PTH is used to increase the amount of bone in osteoporotic patients, combination with bisphosphonates is known to attenuate the response. This might be explained by the reduced number of remodeling sites after bisphosphonate treatment, which reduces the number of cells able to respond to PTH. However, in a repair situation after trauma, a large number of osteoblasts reside in the wound site. If their activity is no longer coupled to osteoclasts, decreased resorption by bisphosphonates and stimulation of osteoblastic activity by PTH should both (independently) increase bone formation. Thus, we hypothesized that in contrast to the case in osteoporosis treatment, PTH and bisphosphonates have an additive effect in situations involving bone regeneration. MATERIAL AND METHODS Stainless steel screws, either coated with biphosphonates or uncoated, were inserted in 46 rat tibias. This normally elicits a bone repair response, leading to a gradual increase in the strength of screw fixation. Half of the rats also received daily injections of teriparatide (PTH). Thus, there were 4 groups: control, bisphosphonate, PTH, and bisphosphonate plus PTH. Pull-out force and energy were measured after 2 weeks. RESULTS The combined treatment had the strongest effect. It doubled the pull-out force and tripled the pull-out energy, compared to untreated controls. Also, bisphosphonate or PTH alone increased the pull-out force and energy, although less. No treatment cross-dependency was observed. INTERPRETATION Because bisphosphonates mainly influence osteoclasts, and intermittent administration of PTH mainly influences osteoblasts, our findings indicate that to a large extent these cells work without coupling in this model. It appears that bisphosphonates are unlikely to attenuate the response to PTH during the formation of new bone.
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Affiliation(s)
- Per Aspenberg
- Section of Orthopedics, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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Wermelin K, Suska F, Tengvall P, Thomsen P, Aspenberg P. Stainless steel screws coated with bisphosphonates gave stronger fixation and more surrounding bone. Histomorphometry in rats. Bone 2008; 42:365-71. [PMID: 18055289 DOI: 10.1016/j.bone.2007.10.013] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2007] [Revised: 10/05/2007] [Accepted: 10/10/2007] [Indexed: 10/22/2022]
Abstract
Coating of stainless steel screws with bisphosphonate in a fibrinogen matrix leads to an enhancement of the pullout strength 2 weeks after insertion in rat tibiae. This effect then increases over time until at least 8 weeks. The pullout force reflects the mechanical properties of the bone within the threads, which acts as a screw nut. The aim of the present study was to find descriptive and morphometric histological correlates to the increased pullout strength. Because the bisphosphonates are applied via the implant surface, we also measured bone to implant contact and how far away from the surface any effects could be seen. Stainless steel screws underwent one of three treatments: uncoated control, controls coated with a layer of cross-linked fibrinogen, or screws further modified with bisphosphonates covalently linked and physically adsorbed to the fibrinogen layer. At 1 (n=33) and 8 (n=27) weeks, bone to implant contact and bone area density in the threads were measured, as well as bone area density at 250 and 500 microm from the outer edge of the threads. Additionally, removal torque for each screw treatment was measured at 2 weeks (n=28). At 8 weeks, the part of the bisphosphonate screw that was located in the marrow cavity had become surrounded with bone, whereas there was almost no bone surrounding the controls. The bone area density in the threads along the entire bisphosphonate screw was increased by 40% compared with uncoated controls, and at 250 microm distance it was more than doubled. At 1 week, coated screws had less implant-bone contact, but at 8 weeks there was no difference between uncoated and bisphosphonate-coated screws. The bisphosphonate screws had 50% increased removal torque at 2 weeks compared to uncoated screws. Howship's lacunae and osteoclasts were found near the screws with bisphosphonates at 8 weeks, suggesting that some bone remodeling took place near the implant, in spite of the presence of bisphosphonates.
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Affiliation(s)
- K Wermelin
- Section for Orthopaedics, Inst. of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
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Abstract
Bone regeneration and repair is a goal of many skeletal therapies and numerous agents positively or negatively impact these processes. New therapeutic agents and effective model systems are continually sought to identify agents and characterize their mechanisms of action are in constant demand. In addition, investigations of tumor cell-bone interaction in the skeletal metastatic microenvironment require well-defined and readily orchestrated models. This chapter describes a novel ectopic ossicle model and a vossicle modification that can be used to provide focused and rapid feedback of bone growth and bone-cellular interactions. The ossicle model is a bone marrow stromal cell (BMSC)-based model and the vossicle model is a neonatal vertebral bone transplant model. These models offer opportunities to mix and compare mesenchymal (donor derived) and hematopoietic elements (host derived). Multiple implants can be placed in one mouse to facilitate various outcome analyses, such as histomorphometry, micro-CT, gene expression studies, and cell tracking using markers such as luciferase, in response to pharma cological or genetic manipulation. Implants can also be combined with other cell types, such as cancer cells to evaluate the bone-tumor microenvironment.
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Affiliation(s)
- Glenda J Pettway
- Departments of Periodontics & Oral Medicine and Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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43
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Skoglund B. Linköping University Medical Dissertation No. 1033. Following the mevalonate pathway to bone heal alley. ACTA ORTHOPAEDICA. SUPPLEMENTUM 2007; 78:3-22. [PMID: 18283564 DOI: 10.1080/17453670710046549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Björn Skoglund
- Department of Clinical and Experimental Medicine, Materials in Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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44
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Wermelin K, Tengvall P, Aspenberg P. Surface-bound bisphosphonates enhance screw fixation in rats--increasing effect up to 8 weeks after insertion. Acta Orthop 2007; 78:385-92. [PMID: 17611854 DOI: 10.1080/17453670710013979] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A bisphosphonate coating improves screw fixation 2 weeks after implantation in cancellous bone. This study on rats examined further development of fixation over time for screws inserted in cancellous and cortical bone. METHODS SS screws were coated with a multiple layer of fibrinogen. Half of the screws were coated further with bisphosphonates, which were linked to the fibrinogen. The screws were inserted in cancellous and cortical bone in rats. The rats were killed after 5 h, 4 days, 1, 2, 4, 8, and 24 weeks, and fixation was evaluated by pullout test. RESULTS There was a gradual increase in pull-out force over time in both cancellous and cortical bone. The bisphosphonate coating improved fixation. Moreover, the difference between the bisphosphonate and control groups increased with time. The pull-out force was almost twice that of the controls for screws inserted in cancellous bone at 8 weeks. Energy uptake was increased more than 3-fold. DISCUSSION The energy uptake and pull-out force of a screw depends on the bone engaged with the threads. Thus, the presence of bisphosphonates increased the amount or quality of this bone by affecting the resorption/formation in a positive way. The increased effect of the bisphosphonates with time thus suggests that bisphosphonate is retained within the remodeling bone, with a positive effect on its gradual adaptation to the implant.
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Affiliation(s)
- Karin Wermelin
- Orthopedics Section, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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45
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Chalidis B, Tzioupis C, Tsiridis E, Giannoudis PV. Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications. Expert Opin Investig Drugs 2007; 16:441-9. [PMID: 17371193 DOI: 10.1517/13543784.16.4.441] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Parathyroid hormone (PTH) has become the most widely studied hormone with regard to its administration to various species and their respective skeletal responses. Beyond its affirmative effect in osteoporosis treatment, systemic PTH administration seems to stimulate bone formation in the fracture healing process. According to preclinical experimental studies, once-daily administration of PTH enhances the morphometric and mechanical properties of fracture calluses and accelerates the normal fracture healing. Its anabolic effect is obvious even in low doses, as well as in cases of implant fixation and distraction osteogenesis. There is little evidence of toxic effects and there are only a few reports of adverse events related to its use. The incidence of bone neoplasms in animal studies depends on the dose and duration of treatment. However, it is not prognostic of an equivalent risk potential of carcinogenesis in humans. In summary, the clinical promise of parathyroid hormone is very high and a positive effect in fracture healing should be anticipated.
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Affiliation(s)
- Byron Chalidis
- University of Leeds, Academic Unit, Clarendon Wing, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds, UK
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46
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Abstract
STUDY DESIGN Review article of preoperative evaluation of surgical patients as relates to adult spine patients. OBJECTIVE To determine which patients should undergo preoperative evaluation and review options for improved preoperative preparation for these patients. SUMMARY OF BACKGROUND DATA There is increasing attention paid to preoperative preparation for surgical patients to decrease perioperative morbidity. Better preoperative evaluation may lead to decreased complication rates and may improve outcomes. METHODS The literature to date, including surgical, hospitalist, and critical care, was reviewed and combined with the authors' experience. RESULTS Suggestions for preoperative screening questions are summarized. CONCLUSION Better recognition of preoperative risk factors may help spine surgeons improve preoperative preparation in their patients, leading to decreased complication rates.
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Affiliation(s)
- Serena S Hu
- Department of Orthopedic Surgery, University of California-San Francisco, San Francisco, CA 94143-0728, USA.
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47
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Gabet Y, Müller R, Levy J, Dimarchi R, Chorev M, Bab I, Kohavi D. Parathyroid hormone 1-34 enhances titanium implant anchorage in low-density trabecular bone: a correlative micro-computed tomographic and biomechanical analysis. Bone 2006; 39:276-82. [PMID: 16617039 DOI: 10.1016/j.bone.2006.02.004] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Revised: 01/18/2006] [Accepted: 02/04/2006] [Indexed: 11/17/2022]
Abstract
The use of endosseous titanium implants is the standard of care in dentistry and orthopaedic surgery. Nevertheless, implantation in low-density bone has a poor prognosis and experimental studies show delayed implant anchorage following gonadectomy-induced bone loss. Intermittently administered human parathyroid hormone 1-34 [iahPTH(1-34)] is the leading bone anabolic therapy. Hence, this study assessed whether iahPTH(1-34) enhances titanium implant integration in low-density bone. Threaded titanium implants, 0.9 mm in diameter, were inserted horizontally into the proximal tibial metaphysis of 5-month-old rats, 7 weeks postorchiectomy (ORX). Subcutaneous administration of iahPTH(1-34), at 5, 25 and 75 microg/kg/day commenced immediately thereafter and lasted for 8 weeks. Quantitative micro-computed tomography (muCT) at the implantation site was carried out at 15 microm resolution using high energy and long integration time to minimize artifacts resulting from the high implant radiopacity. Osseointegration (OI) was calculated as percent implant surface in contact with bone (%OI) quantified as the ratio of "bone"-to-total voxels in contact with the implant. Additionally, the trabecular bone volume density (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and connectivity density (Conn.D) were measured in the peri-implant bone. All microCT parameters were stimulated by iahPTH(1-34) dose-dependently; the percent maximal enhancement was %OI = 143, BV/TV = 257, Tb.Th = 150, Tb.N = 140 and Conn.D = 193. The maximal values of %OI, BV/TV and Tb.Th in iahPTH(1-34)-treated ORX rats exceeded significantly those measured in the implantation site of untreated sham-ORX controls. The same specimens were then subjected to pullout biomechanical testing. The biomechanical parameters were also enhanced by iahPTH(1-34) dose-dependently, exceeding the values recorded in the sham-ORX controls. The percent iahPTH(1-34)-induced maximal enhancement was: ultimate force = 315, stiffness = 270 and toughness = 395. Except for the BV/TV and Tb.Th, there was no significant difference between the effect of the 25 and 75 microg/kg/day doses. There was a highly significant correlation between the morphometric and biomechanical parameters suggesting the use of quantitative CT as predictive of the implant mechanical properties. These findings demonstrate that iahPTH(1-34) effectively stimulates implant anchorage in low-density trabecular bone and thus the feasibility of administering iahPTH(1-34) to improve the clinical prognosis in low-density trabecular bone sites.
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Affiliation(s)
- Yankel Gabet
- Bone Laboratory, The Hebrew University of Jerusalem, PO Box 12272, Jerusalem 91120, Israel
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48
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Whitfield JF. Parathyroid hormone and leptin--new peptides, expanding clinical prospects. Expert Opin Investig Drugs 2006; 14:251-64. [PMID: 15833057 DOI: 10.1517/13543784.14.3.251] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
There are three injectable and one oral bone-building (i.e., bone anabolic) parathyroid hormone (PTH) peptides. One of the four, Lilly's injectable teriparatide (Forteo), is currently being used, and the other three are in clinical trials. They are being used or assessed only for treating postmenopausal osteoporosis. However, their potential clinical targets now extend far beyond osteoporosis. They can accelerate the mending of even severe non-union fractures; they will probably be used to strengthen the anchorage of pros-theses to bone; they have been shown to treat psoriasis that has resisted other treatments; they can increase the size of haematopoietic stem cell proliferation and accelerate the endogenous repopulation or repopulation by donor transplants of bone marrow depleted by chemotherapeutic drugs; and they may prevent vascular ossification. Leptin, a member of the cytokine superfamily has a PTH-like osteogenic activity and may even partly mediate PTH action. But leptin has two drawbacks that cloud its therapeutic future. First, apart from directly stimulating osteoblastic cells, it targets cells in the hypothalamic ventromedial nuclei and through them it reduces oestrogenic activity by promoting osteoblast-suppressing adrenergic activity. Second, it stimulates vascular and heart valve ossification, which leads to such events as heart failure and diabetic limb amputations.
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Affiliation(s)
- James F Whitfield
- Institute for Biological Sciences, The National Research Council of Canada, Building M-54, Montreal Road Campus, Ottawa, ON, K1A0R6, Canada.
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Bianchi ML, Romano G, Saraifoger S, Costantini D, Limonta C, Colombo C. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 2006; 21:388-96. [PMID: 16491286 DOI: 10.1359/jbmr.051023] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2005] [Revised: 11/02/2005] [Accepted: 11/18/2005] [Indexed: 11/18/2022]
Abstract
UNLABELLED Longer survival in cystic fibrosis has led to more bone complications. One hundred thirty-six young patients were studied for 12-24 months. Low BMD was found in 66%. Fat mass and lean mass were also reduced. Impaired pulmonary function and total steroid dose had the greatest negative influence on bone. INTRODUCTION Low BMD is reported as a frequent complication in adult patients affected by cystic fibrosis (CF), but the available data are less consistent for younger patients. MATERIALS AND METHODS This study was designed to evaluate BMD longitudinally over 12-24 months in a sample of 136 young patients (3-24 years of age) and to investigate its major determinants. BMC and body composition were also evaluated. RESULTS BMD (expressed as Z score) of spine and of total body was reduced in 66% of patients. The prevalence of low BMD was the same in children, adolescents, and young adults. The main determinants of BMD were forced expiratory volume in 1 s (FEV1; as an index of pulmonary function), puberty, platelet count (as an index of portal hypertension), and cumulative steroid dose. Changes of FEV1 over time influenced BMD changes. Bone mass, fat mass (FM) and fat-free (lean) mass (FFM) were reduced in CF patients at both total body and subregions (trunk, limbs). Lean mass influenced BMD of total body and lower limbs, whereas fat mass (and BMI) influenced spine BMD. FEV1 also influenced FFM. CONCLUSIONS Low BMD was present in a significant proportion of CF patients, independent of sex and age. BMD depended on pulmonary function, steroid dose, and presence of advanced liver disease. Pulmonary function and puberty were the main stimuli for the increase of BMD over time. CF also altered body composition, and FFM was influenced by pulmonary function.
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Affiliation(s)
- Maria Luisa Bianchi
- Centro Malattie Metaboliche Ossee, Istituto Auxologico Italiano IRCCS, Milano, Italy.
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50
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Affiliation(s)
- Per Aspenberg
- Department of Neuroscience and Locomotion, Faculty of Health Science, Orthopaedics and Sports Medicine, Linköping, SE-581 85, Sweden.
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