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Wimalawansa SJ. Enhancing the Design of Nutrient Clinical Trials for Disease Prevention-A Focus on Vitamin D: A Systematic Review. Nutr Rev 2025:nuae164. [PMID: 39928411 DOI: 10.1093/nutrit/nuae164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025] Open
Abstract
OBJECTIVES This systematic review (SR) highlights principles for nutrient clinical trials and explore the diverse physiological functions of vitamin D beyond its traditional role in the musculoskeletal system related to clinical study designs. BACKGROUND Thousands of published research articles have investigated the benefits of vitamin D (a nutrient example taken in this SR) beyond the musculoskeletal system, including the immune, pulmonary, and cardiovascular systems; pregnancy; autoimmune disorders; and cancer. They illustrated vitamin D's molecular mechanisms, interactions, and genomic and nongenomic actions. METHODS This SR was designed to identify shortcomings in clinical study designs, statistical methods, and data interpretation that led to inconsistent findings in vitamin D-related publications. SR also highlights examples and insights into avoiding study design errors in future clinical studies, including randomized controlled clinical trials (RCTs). The SR adheres to the latest PRISMA statement, guidelines, and the PICOS process. RESULTS Inappropriate or flawed study designs were frequent in clinical trials. Major failures discussed here include too short clinical study duration, inadequate or infrequent doses, insufficient statistical power, failure to measure baseline and achieved levels, and recruiting vitamin D-sufficient participants. These design errors have led to misleading interpretations. Thus, conclusions from such studies should not be generalized or used in guidelines, recommendations, or policymaking. CONCLUSION Adequately powered epidemiological studies and RCTs with sufficient vitamin D and duration in individuals with vitamin D deficiency reported favorable clinical outcomes, enriching the literature, enabling to understand its physiology and mechanisms. Proper study designs with rigorous methodologies and cautious interpretation of outcomes are crucial in advancing the nutrient field. The principles discussed apply not only to vitamin D, but also other micro-nutrients and nutraceutical research. Adhering to them enhances the credibility and reliability of clinical trials, SRs, and meta-analysis outcomes. The study emphasizes the importance of focused, hypothesis-driven, well-designed, statistically powered RCTs to explore the diverse benefits of nutrients, conducted in index nutrient deficient participants, and avoidance of study design errors. Findings from such studies should be incorporated into clinical practice, policymaking, and public health guidelines, improving the health of the nation and reducing healthcare costs.
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Affiliation(s)
- Sunil J Wimalawansa
- Department of Medicine, Endocrinology & Human Nutrition, North Brunswick, NJ, United States
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Castoldi NM, Pickering E, Sansalone V, Cooper D, Pivonka P. Bone turnover and mineralisation kinetics control trabecular BMDD and apparent bone density: insights from a discrete statistical bone remodelling model. Biomech Model Mechanobiol 2024; 23:893-909. [PMID: 38280951 PMCID: PMC11101591 DOI: 10.1007/s10237-023-01812-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/22/2023] [Indexed: 01/29/2024]
Abstract
The mechanical quality of trabecular bone is influenced by its mineral content and spatial distribution, which is controlled by bone remodelling and mineralisation. Mineralisation kinetics occur in two phases: a fast primary mineralisation and a secondary mineralisation that can last from several months to years. Variations in bone turnover and mineralisation kinetics can be observed in the bone mineral density distribution (BMDD). Here, we propose a statistical spatio-temporal bone remodelling model to study the effects of bone turnover (associated with the activation frequency Ac . f ) and mineralisation kinetics (associated with secondary mineralisation T sec ) on BMDD. In this model, individual basic multicellular units (BMUs) are activated discretely on trabecular surfaces that undergo typical bone remodelling periods. Our results highlight that trabecular BMDD is strongly regulated by Ac . f and T sec in a coupled way. Ca wt% increases with lower Ac . f and short T sec . For example, aAc . f = 4 BMU/year/mm3 and T sec = 8 years result in a mean Ca wt% of 25, which is in accordance with Ca wt% values reported in quantitative backscattered electron imaging (qBEI) experiments. However, for lower Ac . f and shorter T sec (from 0.5 to 4 years) one obtains a high Ca wt% and a very narrow skew BMDD to the right. This close link between Ac . f and T sec highlights the importance of considering both characteristics to draw meaningful conclusion about bone quality. Overall, this model represents a new approach to modelling healthy and diseased bone and can aid in developing deeper insights into disease states like osteoporosis.
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Affiliation(s)
- Natalia M Castoldi
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, Australia.
- UMR 8208, MSME, Univ Paris Est Creteil, Univ Gustave Eiffel, CNRS, Créteil, France.
| | - Edmund Pickering
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, Australia
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Australia
| | - Vittorio Sansalone
- UMR 8208, MSME, Univ Paris Est Creteil, Univ Gustave Eiffel, CNRS, Créteil, France
| | - David Cooper
- Department of Anatomy Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Peter Pivonka
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, Australia.
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Seeman E, Martin TJ. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol 2020; 15:225-236. [PMID: 30755735 DOI: 10.1038/s41584-019-0172-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.
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Affiliation(s)
- Ego Seeman
- Departments of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia. .,Mary MacKillop Institute of Health Research, Australian Catholic University, Melbourne, Victoria, Australia.
| | - T J Martin
- Department of Medicine and St Vincent's Institute, University of Melbourne, Melbourne, Victoria, Australia
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Gil IG, Ponte BM, Mateo ST, García JJ. Treatment of Bisphosphonate-Related Osteonecrosis of the Jaw With Plasma Rich in Growth Factors After Dental Implant Surgery: A Case Report. J ORAL IMPLANTOL 2019; 45:289-296. [DOI: 10.1563/aaid-joi-d-18-00254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Oral bisphosphonates are commonly used to improve bone density in patients who suffer from a variety of pathologies. However, they have also been known to cause bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this clinical case presentation is to (1) determine whether the currently recommended length of time that oral bisphosphonates should be discontinued, before performing dental implant surgery, is sufficient to prevent BRONJ and (2) to describe an alternative treatment for BRONJ. A 65-year-old female patient developed BRONJ after receiving mandibular dental implants 5 months after discontinuing alendronic acid (Fosamax). The BRONJ was treated by surgical osteotomy and plasma rich in growth factors (PRGF), and the patient was followed up with biweekly examinations, which included 0.2% chlorhexidine mouthwashes and removal of any remaining necrotic bone. The dental implants were loaded 41 weeks after surgery and followed up with periapical radiographs and implant stability quotient measurements at 3, 6, 12, and 24 months postloading. Although the Association of Oral and Maxillofacial Surgeons protocols for suspension of presurgical oral bisphosphonates were followed, this patient still developed BRONJ after implant surgery. While a multitude of treatments have been described in the literature, there is not enough scientific evidence to support any one treatment. Based on this clinical case, it can be concluded that the potential adverse effects of oral bisphosphonates on the jaws could be greater than expected and that treatment with PRGF produces promising results, although more long-term studies are necessary to confirm these findings.
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Affiliation(s)
| | | | | | - Jaime Jiménez García
- Private practice, Madrid, Spain
- Department of Implantology, European University of Madrid, Madrid, Spain
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Heaney RP. Alendronate plus Cholecalciferol for the Treatment of Osteoporosis. WOMENS HEALTH 2016; 2:23-7. [DOI: 10.2217/17455057.2.1.23] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Osteoporosis is a common medical condition in older individuals, responsible for approximately 1.5 million fragility fractures in the USA each year. Alendronate sodium with cholecalciferol (vitamin D3) is a newly developed combination formulation for the treatment of osteoporosis in women and for increasing bone mass in men with osteoporosis. It complements the existing once-weekly dosage formulation of alendronate sodium alone, providing, in addition to alendronate, a 2800 international unit (IU) dose of cholecalciferol (vitamin D3), equivalent to 400 IU daily. Its efficacy in reducing fracture risk is expected to be at least as good as that of once-weekly alendronate given for the same indications.
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Affiliation(s)
- Robert P Heaney
- Creighton University Medical Center, 601 North 30th St., Suite 4841, Omaha, NE 68131, USA, Tel.: +1 402 280 4029; Fax: +1 402 280 4751
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Bedimo R, Kang M, Tebas P, Overton ET, Hollabaugh K, McComsey G, Bhattacharya D, Evans C, Brown TT, Taiwo B. Effects of Pegylated Interferon/Ribavirin on Bone Turnover Markers in HIV/Hepatitis C Virus-Coinfected Patients. AIDS Res Hum Retroviruses 2016; 32:325-8. [PMID: 26499270 PMCID: PMC4817562 DOI: 10.1089/aid.2015.0204] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-α and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: ≥2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: −120 pg/ml and −8.48 μg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR (N = 91; vs. non-cEVR (N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG-IFN/RBV (p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone (p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions.
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Affiliation(s)
| | - Minhee Kang
- Harvard School of Public Health, Cambridge, Massachusetts
| | - Pablo Tebas
- University of Pennsylvania, Philadelphia, Pennsylvania
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van Schaick E, Zheng J, Perez Ruixo JJ, Gieschke R, Jacqmin P. A semi-mechanistic model of bone mineral density and bone turnover based on a circular model of bone remodeling. J Pharmacokinet Pharmacodyn 2015; 42:315-32. [PMID: 26123920 DOI: 10.1007/s10928-015-9423-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 06/09/2015] [Indexed: 11/24/2022]
Abstract
Development of novel therapies for bone diseases can benefit from mathematical models that predict drug effect on bone remodeling biomarkers. Therefore, a bone cycle model (BCM) was developed that takes into consideration the concept of the basic multicellular unit and the dynamic equilibrium of bone remodeling. The model is a closed form cyclical model with four compartments representing resorption, formation, primary mineralization, and secondary mineralization. Equations describing the time course of bone turnover biomarkers were developed using the flow rate of bone cycle units (BCU) between the compartments or the amount of BCU in each compartment. A disease progression model representing bone loss in osteoporosis, a vitamin D and calcium supplementation (placebo) model, and a drug model for antiresorptive treatments were added to the model. Initial model parameter values were derived from published bone turnover data. The BCM accurately described biomarker-time profiles in postmenopausal women receiving either placebo or bisphosphonate treatment. The slow continual increase in bone mineral density (BMD) observed after 1 year of treatment was accurately described when changes in bone turnover were combined with increases in mineralization. For this purpose, the secondary mineralization compartment was replaced by three catenary chain compartments representing increasing mineral content. The refined BCM satisfactorily predicted biomarker profiles after long-term (10-year) bisphosphonate treatment. Furthermore, the model successfully described individual bone turnover markers and BMD results following treatment with denosumab in postmenopausal women. Analyses with this model could be used to optimize dosing regimens and to predict effects of novel osteoporotic treatments.
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Affiliation(s)
- Erno van Schaick
- SGS Exprimo NV, Generaal de Wittelaan 19A b5, 2800, Mechelen, Belgium,
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Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 2015; 26:699-712. [PMID: 25432773 PMCID: PMC4312384 DOI: 10.1007/s00198-014-2944-6] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 10/02/2014] [Indexed: 01/13/2023]
Abstract
SUMMARY Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
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Affiliation(s)
- H G Bone
- Michigan Bone & Mineral Clinic, Detroit, MI, USA,
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Vanderoost J, Lenthe GHV. From histology to micro-CT: Measuring and modeling resorption cavities and their relation to bone competence. World J Radiol 2014; 6:643-56. [PMID: 25276308 PMCID: PMC4176782 DOI: 10.4329/wjr.v6.i9.643] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 04/22/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
The process of bone remodelling plays an essential role in the emergence and maintenance of bone geometry and its internal structure. Osteoclasts are one of the three main bone cell types that play a crucial role in the bone remodelling cycle. At the microstructural level, osteoclasts create bone deficits by eroding resorption cavities. Understanding how these cavities impair the mechanical quality of the bone is not only relevant in quantifying the impact of resorption cavities in healthy bone and normal aging, but maybe even more so in quantifying their role in metabolic bone diseases. Metabolic bone diseases and their treatment are both known to affect the bone remodelling cycle; hence, the bone mechanical competence can and will be affected. However, the current knowledge of the precise dimensions of these cavities and their effect on bone competence is rather limited. This is not surprising considering the difficulties in deriving three-dimensional (3D) properties from two-dimensional (2D) histological sections. The measurement difficulties are reflected in the evaluation of how resorption cavities affect bone competence. Although detailed 3D models are generally being used to quantify the mechanical impact of the cavities, the representation of the cavities themselves has basically been limited to simplified shapes and averaged cavity properties. Qualitatively, these models indicate that cavity size and location are important, and that the effect of cavities is larger than can be expected from simple bone loss. In summary, the dimensions of osteoclast resorption cavities were until recently estimated from 2D measures; hence, a careful interpretation of resorption cavity dimensions is necessary. More effort needs to go into correctly quantifying resorption cavities using modern 3D imaging techniques like micro-computed tomography (micro-CT) and synchrotron radiation CT. Osteoclast resorption cavities affect bone competence. The structure-function relationships have been analysed using computational models that, on one hand, provide rather detailed information on trabecular bone structure, but on the other incorporate rather crude assumptions on cavity dimensions. The use of high-resolution representations and parametric descriptions could be potential routes to improve the quantitative fidelity of these models.
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Liu HF, Yang L, He HC, Zhou J, Liu Y, Wang CY, Wu YC, He CQ. Pulsed electromagnetic fields on postmenopausal osteoporosis in southwest China: A randomized, active-controlled clinical trial. Bioelectromagnetics 2013; 34:323-32. [DOI: 10.1002/bem.21770] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 11/17/2012] [Indexed: 11/11/2022]
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Parathyroid hormone versus bisphosphonate treatment on bone mineral density in osteoporosis therapy: a meta-analysis of randomized controlled trials. PLoS One 2011; 6:e26267. [PMID: 22022584 PMCID: PMC3192168 DOI: 10.1371/journal.pone.0026267] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Accepted: 09/23/2011] [Indexed: 11/29/2022] Open
Abstract
Background Bisphosphonates and parathyroid hormone (PTH) represent the antiresorptive and anabolic classes of drugs for osteoporosis treatment. Bone mineral density (BMD) is an essential parameter for the evaluation of anti-osteoporotic drugs. The aim of this study was to evaluate the effects of PTH versus bisphosphonates on BMD for the treatment of osteoporosis. Methods/Principal Findings We performed a literature search to identify studies that investigated the effects of PTH versus bisphosphonates treatment on BMD. A total of 7 articles were included in this study, representing data on 944 subjects. The pooled data showed that the percent change of increased BMD in the spine is higher with PTH compared to bisphosphonates (WMD = 5.90, 95% CI: 3.69–8.10, p<0.01,). In the hip, high dose (40 µg) PTH (1–34) showed significantly higher increments of BMD compared to alendronate (femoral neck: WMD = 5.67, 95% CI: 3.47–7.87, p<0.01; total hip: WMD = 2.40, 95%CI: 0.49–4.31, p<0.05). PTH treatment has yielded significantly higher increments than bisphosphonates with a duration of over 12 months (femoral neck: WMD = 5.67, 95% CI: 3.47–7.86, p<0.01; total hip: WMD = 2.40, 95% CI: 0.49–4.31, P<0.05) and significantly lower increments at 12 months (femoral neck: WMD = −1.05, 95% CI: −2.26–0.16, p<0.01; total hip: WMD: −1.69, 95% CI: −3.05–0.34, p<0.05). In the distal radius, a reduction in BMD was significant between PTH and alendronate treatment. (WMD = −3.68, 95% CI: −5.57–1.79, p<0.01). Discussion Our results demonstrated that PTH significantly increased lumbar spine BMD as compared to treatment with bisphosphonates and PTH treatment induced duration- and dose-dependent increases in hip BMD as compared to bisphosphonates treatment. This study has also disclosed that for the distal radius, BMD was significantly lower from PTH treatment than alendronate treatment.
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Abstract
BACKGROUND Currently, antiresorptive therapy in the treatment and prevention of osteoporosis includes bisphosphonates, estrogen replacement, selective estrogen receptor modulators (raloxifene), and denosumab (a human antibody that inactivates RANKL). The original paradigm driving the development of antiresorptive therapy was that inhibition of bone resorption would allow bone formation to continue and correct the defect. However, it is now clear increases in bone density account for little of the antifracture effect of these treatments. QUESTIONS/PURPOSES We examined the antifracture benefit of antiresorptives deriving from bone quality changes. METHODS We searched the archive of nearly 30,000 articles accumulated over more than 40 years in our research center library using a software program (Refman™). Approximately 250 publications were identified in locating the 69 cited here. RESULTS The findings document antiresorptive agents are not primarily anabolic. All cause a modest increase in bone density due to a reduction in the bone remodeling space; however, the majority of their efficacy is due to suppression of the primary cause of osteoporosis, ie, excessive bone remodeling not driven by mechanical need. All of them improve some element(s) of bone quality. CONCLUSIONS Antiresorptive therapy reduces risk of fracture by improving bone quality through halting removal of bone tissue and the resultant destruction of microarchitecture of bone and, perhaps to some extent, by improving the intrinsic material properties of bone tissue. Information presented here may help clinicians to improve selection of patients for antiresorptive therapy by avoiding them in cases clearly not due to excessive bone remodeling.
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Affiliation(s)
- Robert R Recker
- Osteoporosis Research Center, Creighton University, 601 N 30th Street #5766, Omaha, NE 68131, USA.
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Greenspan SL, Perera S, Recker R, Wagner JM, Greeley P, Gomberg BR, Seaman P, Kleerekoper M. Changes in trabecular microarchitecture in postmenopausal women on bisphosphonate therapy. Bone 2010; 46:1006-10. [PMID: 20051275 PMCID: PMC3889111 DOI: 10.1016/j.bone.2009.12.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Revised: 12/18/2009] [Accepted: 12/22/2009] [Indexed: 11/30/2022]
Abstract
PURPOSE In addition to bone mineral density (BMD), trabecular microstructure contributes to skeletal strength. Our goal was to examine changes in trabecular microstructure in women on therapy. MATERIALS AND METHODS We followed 10 postmenopausal women receiving a bisphosphonate, risedronate (35 mg once weekly), over 12 months and examined trabecular microarchitecture with high resolution wrist MR images (hr-MRI). MRI parameters included bone volume/total volume (BV/TV), surface density (representing plates), curve density (representing rods), surface-to-curve ratio and erosion index (depicting deterioration). We assessed BMD of the spine, hip and radius and markers of bone turnover. RESULTS Women had been receiving bisphosphonate therapy for 43+/-9 months (mean+/-SD) prior to the first MRI. Indices of hr-MRI demonstrated improvement in surface-to-curve ratio (13.0%) and a decrease in erosion index (12.1%) consistent with less deterioration (both p<0.05). BMD of the spine, hip and radius and markers of bone turnover remained stable. Parameters of hr-MRI were associated with 1/3 distal radius BMD (correlation coefficient 0.71 to 0.86, p<0.05). DISCUSSION We conclude that hr-MRI of the radius demonstrates improvements in trabecular microstructure not appreciated by conventional BMD and provides additional information on parameters that contribute to structural integrity in patients on antiresorptive therapy.
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Affiliation(s)
| | - Subashan Perera
- University of Pittsburgh, Department of Medicine, Pittsburgh, PA
| | | | - Julie M. Wagner
- University of Pittsburgh, Department of Medicine, Pittsburgh, PA
| | - Parmatma Greeley
- University of Pittsburgh, Department of Medicine, Pittsburgh, PA
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Wang CJ, Wang FS, Yang KD, Huang CC, Lee MSS, Chan YS, Wang JW, Ko JY. Treatment of osteonecrosis of the hip: comparison of extracorporeal shockwave with shockwave and alendronate. Arch Orthop Trauma Surg 2008; 128:901-8. [PMID: 18060419 DOI: 10.1007/s00402-007-0530-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2007] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Extracorporeal shockwave therapy (ESWT) and alendronate are reported effective in early osteonecrosis of the femoral head (ONFH). We hypothesized that joint effects of ESWT and alendronate may produce superior results. This prospective study compared the results of ESWT and alendronate with that of ESWT without alendronate in early ONFH. PATIENTS AND METHODS Forty-eight patients with 60 hips were randomly divided into tow groups. There were 25 patients with 30 hips in group A and 23 patients with 30 hips in group B. Both groups showed similar demographic characteristics. All patients were treated with 6,000 impulses of ESWT at 28 KV (equivalent to 0.62 mJ/mm(2)) to the affected hip as a single session. Patients in group B also received alendronate 70 mg per week for 1 year, whereas patients in group A did not. The evaluations included clinical assessment, radiograph and MR image of the affected hip. Both groups were compared statistically using paired t, Mann-Whitney and Chi square tests with statistical significance at P < 0.05. The primary end point is the need for total hip arthroplasty (THA). The secondary end point is the improvement in pain and function of the hip. The third end point is the progression or regression of the lesion on image study. RESULTS The overall clinical outcomes were improved in 83%, unchanged in 7% and worsened in 10% for group A; and improved in 77%, unchanged in 13% and worsened in 10% for group B. THA was performed in 10% of group A and 10% of group B (P = 1.000). Significant improvements in pain and function of the hip were noted in both groups (P < 0.001), however, the differences between the two groups were not significant (P = 0.400, 0.313). On MR images, the lesions showed progression in 10%, regression in 47% and unchanged in 43% in group A, and progression in 7%, regression in 53% and unchanged in 40% in group B (P = 0.830). CONCLUSION ESWT and alendronate produced comparable result as compared with ESWT without alendronate in early ONFH. It appears that ESWT is effective with or without the concurrent use of alendronate. The joint effects of alendronate over ESWT in early ONFH are not realized in short-term.
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Affiliation(s)
- Ching-Jen Wang
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University School of Medicine, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung, Taiwan.
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15
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Aloia JF, Arunabh-Talwar S, Pollack S, Yeh JK. The remodeling transient and the calcium economy. Osteoporos Int 2008; 19:1001-9. [PMID: 18224269 PMCID: PMC2777650 DOI: 10.1007/s00198-007-0542-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Accepted: 11/06/2007] [Indexed: 10/22/2022]
Abstract
UNLABELLED The remodeling transient describes a change in bone mass that lasts one remodeling cycle following an intervention that disturbs the calcium economy. We demonstrated the transient in a study of the response of bone density to calcium/vitamin D3 supplementation and show the hazards of misinterpretation if the transient is not considered. INTRODUCTION The remodeling transient describes a change in bone mass that lasts for one remodeling cycle following an intervention that disturbs the calcium economy. METHODS We report an intervention with calcium and vitamin D supplementation in 208 postmenopausal African-American women where the remodeling transient was considered a priori in the study design. Both groups (calcium alone vs. calcium + 20 microg (800 IU) vitamin D3) were ensured a calcium intake in excess of 1200 mg/day. RESULTS There were no differences between the two groups in changes in BMD over time. These BMD changes were therefore interpreted to reflect increased calcium intake in both groups but not any influence of vitamin D. A transient increase in bone mineral density was observed during the first year of study, followed by a decline. The remodeling period was estimated at about 9 months, which is similar to histomorphometric estimates. CONCLUSION It is problematic to draw conclusions concerning interventions that influence the calcium economy without considering the remodeling transient in study design. Studies of agents that effect bone remodeling must be carried out for at least two remodeling cycles and appropriate techniques must be used in data analysis.
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Affiliation(s)
- J. F. Aloia
- Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
| | - S. Arunabh-Talwar
- Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
| | - S. Pollack
- Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
| | - J. K. Yeh
- Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
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16
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Seeman E. Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy? Bone 2007; 41:308-17. [PMID: 17644058 DOI: 10.1016/j.bone.2007.06.010] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2006] [Revised: 05/31/2007] [Accepted: 06/04/2007] [Indexed: 10/23/2022]
Abstract
Anti-resorptive agents perturb steady state remodeling; they suppress, but do not abolish, the birth rate of new basic multicellular units (BMUs). In doing so, remodeling goes to completion with bone formation in the many BMUs created before treatment but now with fewer resorption cavities appearing concurrently. As a result, cortical porosity and trabecular stress concentrators decrease reducing bone fragility. From this improved bone strength, steady state is re-established at a slower remodeling rate that again produces bone fragility but more slowly as fewer new BMUs, each with a less negative BMU balance, produce cortical thinning and porosity, trabecular thinning and loss of connectivity while bone fragility progresses rapidly in controls. Thus, the fracture risk reduction--the incidence of fractures in patients treated with an anti-resorptive agent relative to the incidence in controls--is the net effect of the slowing or partial reversal of fragility and then reduced progression of structural abnormalities in treated patients and continued structural decay in controls. Although some morphological features in treated patients and controls may be captured in the bone mineral density (BMD) measurement, many are not. The early increase in BMD is largely determined by the pre-treatment remodeling rate whereas the later and more modest BMD increase is a function of the degree of suppression of remodeling and secondary mineralization. When pre-treatment remodeling rate is low, the increase in BMD is small but the fracture risk reduction (relative to controls with comparable baseline characteristics) is no different to that in patients with high baseline remodeling (relative to their controls) and a greater BMD increase. Therefore, a small increase in BMD does not mean treatment has failed and a large increase in BMD is not indicative of a greater fracture risk reduction.
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Affiliation(s)
- E Seeman
- Departments of Medicine and Endocrinology, Austin Health, University of Melbourne, Melbourne, Australia.
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17
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Frost ML, Cook GJR, Blake GM, Marsden PK, Fogelman I. The relationship between regional bone turnover measured using 18F-fluoride positron emission tomography and changes in BMD is equivalent to that seen for biochemical markers of bone turnover. J Clin Densitom 2007; 10:46-54. [PMID: 17289526 DOI: 10.1016/j.jocd.2006.10.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2006] [Revised: 10/26/2006] [Accepted: 10/26/2006] [Indexed: 11/18/2022]
Abstract
Bone turnover is an important determinant of fracture risk. (18)F-fluoride positron emission tomography ((18)F-PET) allows the direct assessment of bone turnover at the clinically important skeletal sites such as the lumbar spine. The aim of this study was to determine if the relationship between regional bone turnover measured using (18)F-PET and changes in bone mineral density (BMD) is equivalent to that seen for global skeletal measurements of biochemical markers of bone turnover. Forty-three women who had previously had an (18)F-PET scan at the lumbar spine, assessment of biochemical markers of bone turnover, and a dual-energy X-ray absorptiometry scan of BMD at the lumbar spine and hip (baseline assessments) were split into 1 of 2 groups: (1) 22 women who commenced treatment for osteoporosis within 2mo of having the baseline assessments (Treatment group); (2) 21 women who had not taken any treatments for osteoporosis since having the baseline assessments (Untreated group). Sixteen of the women in the Treatment group started risedronate therapy as part of a prospective study they were participating in, whereas the decision to treat the remaining 6 women was made by the subject's treating physician. Subjects had between 2 and 5 BMD scans over a median follow-up time of 4.1yr to estimate the annual percentage change in BMD since baseline. The relationship between the tertiles of (18)F-PET skeletal kinetic parameter K(i), reflecting regional bone turnover, and annual changes in lumbar spine and hip BMD were compared to that seen for bone formation (bone-specific alkaline phosphatase, BSALP) and bone resorption (urinary deoxypyridinoline) markers. Treated women in the highest tertile of both regional ((18)F-PET) and global (biochemical markers) bone turnover showed the greatest annual percentage increases in lumbar spine BMD. The annual increase in lumbar spine BMD was 1.8%, 2.2%, and 3.2% for women in the lowest, middle, and highest tertile of BSALP, respectively, which was similar to that obtained for the regional measurement of K(i) of 1.7%, 2.2%, and 2.7% respectively. Untreated women in the highest tertile of regional and global bone turnover had larger decreases in lumbar spine BMD compared to those women in the lowest tertile, with a 1.4- to 4.8-fold difference in the annual decrease in BMD between the two. Less consistent patterns were observed when assessing the relationship between regional and global bone turnover with changes in hip BMD. This study has demonstrated that the relationship between regional bone turnover measured directly at the lumbar spine with changes in BMD is similar to that seen for global skeletal bone turnover using biochemical markers.
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Affiliation(s)
- Michelle L Frost
- Osteoporosis Screening & Research Unit, King's College London School of Medicine, Guy's Hospital, London.
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18
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Abstract
Alendronate is one of the best and most extensively studied bisphosphonates in the treatment of osteoporosis. This review considers in detail the major pivotal study, the fracture intervention trial (FIT), upon which the use of alendronate is based and which was a landmark study in terms of design, size and clinical impact. The role of alendronate has subsequently been underscored by a range of studies extending the clinical indications for its use and consolidating the effect on reducing both vertebral and non-vertebral fracture risk. Although the emphasis of these studies has predominantly been on the management of postmenopausal osteoporosis, data is also available in primary prevention, men, and glucocorticoids-induced osteoporosis. Direct comparison between the different drugs used to treat osteoporosis with fracture end points are needed for patients and doctors to make informed choices, but the size of such studies are prohibitive. Clinical trials using surrogate markers such as bone mineral density and biochemical markers of bone turnover have been performed which provide some helpful information but the limitations of this approach need to be recognized.
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19
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Boonen S, Vanderschueren D, Haentjens P, Lips P. Calcium and vitamin D in the prevention and treatment of osteoporosis - a clinical update. J Intern Med 2006; 259:539-52. [PMID: 16704554 DOI: 10.1111/j.1365-2796.2006.01655.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Combined calcium and vitamin D supplementation is an essential component of the management of osteoporosis, supported by a strong scientific rationale. The types of individuals who should receive calcium and vitamin D supplements are those: (i) patients with documented osteoporosis receiving antiresorptive or anabolic treatment; (ii) patients receiving glucocorticoids; and (iii) individuals with or at high risk of calcium and/or vitamin D insufficiencies, in particular older women and men. This article describes the evidence base that supports targeting these groups. Benefits are most apparent when 800 IU day(-1) vitamin D is complemented with a dose of 1000-1200 mg day(-1) elemental calcium. Compliance is also key to optimizing clinical efficacy.
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Affiliation(s)
- S Boonen
- Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Belgium.
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20
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Abstract
It is now generally accepted that an adequate calcium intake is important for building and maintaining a skeleton that expresses quantitatively the full genetic program and reduces lifetime fracture risk. In this brief review we focus mainly on a new and growing body of evidence indicating a benefit of adequate calcium intake on qualitative features of the skeleton that, independent of the quantity of bone, themselves influence skeletal strength and fragility. Change in bone mass and size during growth are dependent on both calcium intake and exercise, with the largest differences being observed in prepubertal children who have both high exercise levels and high calcium intakes. Much of this benefit is expressed as increased bone diameter (and hence stiffness). Fracture risk peaks at about the time of puberty and is inversely related to bone mass. However, even prepubertally, children with low calcium intakes have been reported to have a fracture rate 2.7x that of their birth cohort. Bone remodeling triples from age 50 to 65 in typical women and is now recognized to have primarily a homeostatic basis. While remodeling improves bone strength by repairing acquired defects, homeostatic remodeling, while necessary to maintain blood calcium levels, contributes only structural weakness to bone. High calcium intakes in postmenopausal and older women reduce this homeostatic remodeling to approximately pre-menopausal values and improve bone strength immediately, well prior to any appreciable change in bone mass.
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Affiliation(s)
- Robert P Heaney
- Creighton University Medical Center, 601 N. 30th St., Suite 4841, Omaha, NE 68131, USA.
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21
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Abstract
Measurements of bone mineral density (BMD) and biochemical markers of bone turnover are useful in the diagnosis and management of osteoporosis, as well as in research relating to the pathogenesis and treatment of the disease. Recent challenges to the utility of these measures have resulted in some confusion among both researchers and clinicians. BMD accounts for the great majority of bone strength and is the current gold standard for the diagnosis of osteoporosis, as well as for prediction of fracture risk. Although bone turnover increases sharply after menopause, biochemical markers of bone turnover have limited usefulness in fracture risk prediction. Persistently elevated bone turnover throughout the menopause is associated with structural decrements, cannot be measured routinely and non-invasively. In research applications, both BMD and markers of bone turnover are used to identify candidate agents in preclinical and clinical studies. In addition, head-to-head comparisons of treatments utilize these measures, because fracture endpoint trials would need to be extraordinarily large and complex. Analyses that have suggested that change in BMD or bone turnover 'explains' little of change in fracture risk with treatment appear to be flawed. Although neither can perfectly predict fracture, they are our current best alternatives.
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Affiliation(s)
- Paul D Miller
- Colorado Center for Bone Research, Lakewood, CO, USA.
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22
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Wilkinson JM, Eagleton AC, Stockley I, Peel NFA, Hamer AJ, Eastell R. Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial. J Orthop Res 2005; 23:1-8. [PMID: 15607868 DOI: 10.1016/j.orthres.2004.06.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2004] [Accepted: 06/09/2004] [Indexed: 02/04/2023]
Abstract
In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar (P = 0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.
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Affiliation(s)
- J Mark Wilkinson
- Academic Unit of Bone Metabolism, Division of Clinical Sciences (North), Northern General Hospital, University of Sheffield, Sheffield S5 7AU, UK.
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23
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Nyman JS, Yeh OC, Hazelwood SJ, Martin RB. A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage. Bone 2004; 35:296-305. [PMID: 15207770 DOI: 10.1016/j.bone.2004.03.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2003] [Revised: 03/02/2004] [Accepted: 03/10/2004] [Indexed: 10/26/2022]
Abstract
Bisphosphonates increase bone mass and reduce fracture risk, but their anti-resorptive action may lead to increases in fatigue microdamage. To investigate how bisphosphonate effects influence changes in bone volume and microdamage in the long term, a strain-adaptive model of bone remodeling and microdamage balance was developed for a continuum-level volume of postmenopausal trabecular bone by invoking Frost's mechanostat hypothesis. Both disuse and fatigue microdamage were assumed to stimulate the activation frequency of basic multicellular units (BMUs) such that bone remodeling served to remove excess bone mass and microdamage. Bisphosphonate effects were simulated as follows: low, intermediate, high, or complete suppression of BMU activation frequency either without a change in resorption by the BMU or with an independent decrease in resorption while the bone formation process was unaffected (i.e., formation initially exceeded resorption). Of the bisphosphonate effects, a reduction in resorption relative to formation dictated the long-term gain in bone volume while the potency of activation frequency suppression controlled the rate of gain. A plateau in the bone mass gain that typically occurs in clinical studies of bisphosphonate treatment was predicted by the model because the resultant reduction in strain forced bone formation by the BMU to decrease over time until it matched the reduction in BMU resorption. A greater suppression of activation frequency proportionally increased microdamage, but the accumulation was limited over the long term as long as remodeling was incompletely suppressed. The results of the model suggest creating bisphosphonates that provide minimal suppression of remodeling and a large decrease in BMU resorption because this would minimize damage accumulation and increase bone mass, respectively.
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Affiliation(s)
- Jeffry S Nyman
- Biomedical Engineering Graduate Group, College of Engineering, University of California at Davis, CA 95616, USA.
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24
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Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A, Manhart MD. Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone 2004; 34:736-46. [PMID: 15050906 DOI: 10.1016/j.bone.2003.12.013] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2003] [Revised: 12/12/2003] [Accepted: 12/17/2003] [Indexed: 10/26/2022]
Abstract
The deterioration of trabecular microarchitecture induced by elevated bone turnover is increasingly recognized as a factor in the pathogenesis of osteoporotic fractures. We investigated the effect of the reduction of turnover with risedronate on trabecular architecture in postmenopausal women with osteoporosis. Iliac crest bone biopsy specimens taken before and after 3 years of treatment from patients receiving risedronate 5 mg daily (n = 21) or placebo (n = 17) were analyzed using 3-D microcomputed tomography. We found a significant correlation between baseline bone turnover and bone loss in the placebo group, providing evidence that higher turnover induced higher bone loss leading to a greater degree of architectural degradation. When patients were classified into two groups based on baseline bone turnover (MS/BS less than or greater than the median value for the entire cohort), significant decreases in trabecular bone volume (BV/TV, P = 0.009) and trabecular thickness (Tb.Th*, P = 0.008) and an increase in marrow star volume (Ma.St.V, P = 0.008), a measure of trabecular porosity, were observed in the higher turnover (MS/BS> median) placebo-treated patients. The trabecular structure shifted from plates to rods as shown by an increase in structure model index (SMI, P = 0.028) and bone surface to bone volume ratio (BS/BV, P = 0.006). The changes from baseline in the lower turnover (MS/BS<median) placebo patients were variable and not statistically significant. In the risedronate group, the bone volume and the architectural parameters did not change significantly from baseline values in either the higher or the lower turnover groups. Comparing the pair-wise changes from baseline in the higher turnover group, the placebo group experienced decreases in BV/TV (P = 0.071) and Tb.Th* (P = 0.012), and increase in Ma.St.V (P = 0.043), compared to the risedronate-treated women. Also, in comparison to the risedronate group, the trabecular structures in the placebo group were more rod-like, indicated by higher SMI (P = 0.009) and BS/BV (P = 0.02). The results demonstrated that trabecular architecture deteriorated significantly in the placebo-treated women who had higher bone turnover at baseline, and this deterioration was prevented by 3 years of risedronate treatment, presumably because of the reduction in bone turnover. The preservation of architecture may be a contributory mechanism by which risedronate reduces the risk of vertebral fractures in osteoporotic women.
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Affiliation(s)
- Babul Borah
- Procter & Gamble Pharmaceuticals, Cincinnati, OH 45201, USA.
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25
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Wehren LE, Hosking D, Hochberg MC. Putting evidence-based medicine into clinical practice: comparing anti-resorptive agents for the treatment of osteoporosis. Curr Med Res Opin 2004; 20:525-31. [PMID: 15119990 DOI: 10.1185/030079904125003269] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To compare the effectiveness of antiresorptive agents in reducing the risk of vertebral and non-vertebral fractures using data from published meta-analyses and the technique of adjusted indirect comparisons. RESEARCH DESIGN AND METHODS Pairs of agents were compared by adjusted indirect comparison of 0.56 [0.40, 0.78], respectively) in reducing the their effects relative to a common comparator (placebo) using meta-analyses published by The Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. RESULTS Adjusted indirect comparisons identified only one pair of agents that had significantly different effects on vertebral fracture incidence: alendronate was 34% more effective than calcitonin (Relative Risk: 0.66, 95% Confidence Interval: 0.48-0.90). Alendronate was significantly more effective than risedronate, calcitonin, estrogen, etidronate, and raloxifene (Relative Risks: 0.70 [0.49, 0.99], 0.64 [0.42, 0.98], 0.59 [0.41, 0.84], 0.52 [0.32, 0.82], and incidence of non-vertebral fractures. No other significant pairwise differences were observed. CONCLUSIONS The results suggest that there are differences in anti-fracture efficacy among antiresorptive agents, particularly for non-vertebral fractures. Direct head-to-head comparisons would be needed to confirm these findings but are unlikely to be conducted.
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Affiliation(s)
- Lois E Wehren
- University of Maryland School of Medicine, Baltimore, MD, USA.
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26
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Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004; 350:1189-99. [PMID: 15028823 DOI: 10.1056/nejmoa030897] [Citation(s) in RCA: 874] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. METHODS The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. RESULTS Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.
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Affiliation(s)
- Henry G Bone
- Michigan Bone and Mineral Clinic, Detroit 48236, USA
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27
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Pioletti DP, Rakotomanana LR. Can the increase of bone mineral density following bisphosphonates treatments be explained by biomechanical considerations? Clin Biomech (Bristol, Avon) 2004; 19:170-4. [PMID: 14967580 DOI: 10.1016/j.clinbiomech.2003.10.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2002] [Accepted: 10/10/2003] [Indexed: 02/07/2023]
Abstract
OBJECTIVE We hypothesized that bone mineral density increase following bisphosphonates treatments may be explained by the influence of the drug on the mechanical bone remodeling parameters. BACKGROUND Patients treated with bisphosphonates continuously increase their bone mineral density. This increase is explained in the first 12-18 months following the treatment by the filling of the transient remodeling deficit. Recently, results of a clinical study of alendronate treatment over 7 years still show a continuous increase of bone mineral density. These results raised several questions regarding our understanding of bisphosphonates mode of action. METHODS Bone remodeling is influenced by different factors including mechanical forces. In the present study, we propose then to consider the effect of bisphosphonates also under biomechanical considerations. RESULTS Identification of the model with the clinical data showed that daily treatment of 10 and 20 mg alendronate decreased the bone turnover rate by 2% and 11%, respectively, in comparison with the 5 mg alendronate treatment. Moreover, the alendronate treatments decreases the resorption threshold stimulus by 19% (25%, 28%) for the 5 mg (10 and 20 mg, respectively) compared to placebo. CONCLUSIONS The increase of bone mineral density following bisphosphonates treatment may then be explained by biomechanical considerations. Based on this description, bisphosphonates treatment may indeed change the susceptibility of bone to its biomechanical environment decreasing the mechanical threshold where bone should undergo resorption.
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Affiliation(s)
- Dominique P Pioletti
- Bone Bioengineering Group, STI/BIO-E/CRO, Center for Orthopedic Research, Bat. AAB, EPFL, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
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28
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Abstract
Bone mineral consists of calcium phosphate, and phosphorus is as important as calcium in supporting bone augmentation and maintenance. Although typical adult diets contain abundant phosphorus, 10% to 15% of older women have intakes of less than 70% of the recommended daily allowance. When these women take high-dose calcium supplements that consist of the carbonate or citrate salts, all their food phosphorus may be bound and hence unavailable for absorption. Current-generation anabolic agents for treating osteoporosis require positive phosphorus balances of up to 90 mg/d. Attention to the nutritional adequacy of the diets of such patients is essential if they are to realize the full potential of such therapies. A calcium phosphate supplement may be preferable to the usual carbonate or citrate salts because its phosphate serves to spare food phosphorus.
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29
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van der Linden JC, Verhaar JAN, Pols HAP, Weinans H. A simulation model at trabecular level to predict effects of antiresorptive treatment after menopause. Calcif Tissue Int 2003; 73:537-44. [PMID: 14508627 DOI: 10.1007/s00223-002-2151-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2002] [Accepted: 04/18/2003] [Indexed: 01/19/2023]
Abstract
Antiresorptive drugs are widely used to prevent osteoporotic fractures in men and women. Large clinical trials have shown vertebral fracture risk reductions up to 50%, resulting from relatively small increases of 3-8% in bone mineral density (BMD). We developed a computer model that mimics bone turnover in human vertebral cancellous bone during menopause and antiresorptive treatment. This model links cell activity in trabeculae to changes in bone volume and mechanical properties. We asked whether treatment started shortly after menopause is better than treatment started late after menopause. In order to answer this question we used the model to simulate menopause and 5 years of anti-resorptive treatment with two different agents: one incorporated in the tissue, one not incorporated. We found that late treatment can result in almost the same bone mass as early treatment, but early treatment is much better in conserving the strength and stiffness of the cancellous bone. The effect of the incorporation of drugs in the tissue (giving the drugs a long half-life) was small. After discontinuation of treatment, bone was lost slower, but after 20 years the difference between the incorporated and the not incorporated drug in stiffness and bone volume was below 3%. This kind of simulation model may be used to preclinically test new pharmaceuticals and treatment protocols and to predict long-term effects of treatment before patient data become available.
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Affiliation(s)
- J C van der Linden
- Erasmus MC, Department of Orthopaedics, Ee1614, 3000 DR Rotterdam, The Netherlands.
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30
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Abstract
Reduction in bone mass has long dominated the thinking about and approach to the problem of osteoporosis. A now large body of evidence indicates that bone mass is not adequate to explain satisfactorily either the skeletal fragility of osteoporosis or the effects of bone active agents. By contrast, bone remodeling activity seems to provide a better explanation of both. It is suggested that current syntheses in the field are shifting to this conclusion. In attempting to make sense out of how a process designed by evolution to sustain bone strength could instead be contributing to weakness, I suggest: (1) prevailing bone remodeling levels are substantially higher than are optimal for maintenance of bone strength; (2) this high level has discernible environmental causes; and (3) such high remodeling is a major source-perhaps the major source-of osteoporotic bony fragility. Within this context, reduced bone mass, rather than the primary cause of fracture, is seen as a factor that predisposes individuals to the harmful effects of excessive remodeling.
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Affiliation(s)
- Robert P Heaney
- Creighton University, 601 N. 30th St., Suite 4841, Omaha, NE 68131, USA.
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Bagger YZ, Tankó LB, Alexandersen P, Ravn P, Christiansen C. Alendronate has a residual effect on bone mass in postmenopausal Danish women up to 7 years after treatment withdrawal. Bone 2003; 33:301-7. [PMID: 13678770 DOI: 10.1016/s8756-3282(03)00112-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Alendronate has been shown to reduce bone turnover and increase bone mass. However, little is known about the duration of the effect on bone after treatment withdrawal. The aim of this study was to investigate the long-term effects on bone mineral density (BMD) and bone turnover of various alendronate regimens after treatment withdrawal. In this study, we followed 203 postmenopausal women who previously participated in two alendronate randomized placebo-controlled trials. Daily oral treatment with various doses of alendronate (2.5-20 mg) were given for 2, 4, or 6 yr followed by no treatment for 7, 5, or 3 yr, respectively. Bone mineral density of the lumbar spine, hip, and forearm was measured by dual-energy x-ray absorptiometry. Biochemical markers of bone turnover were induced serum C-terminal telopeptides of type I collagen (CTX) and osteocalcin. Women who received alendronate (2.5-10 mg per day) for 2 yr had a 3.8% higher BMD compared to those receiving placebo when assessed 7 yr after withdrawal. The residual effect was proportionally larger in women who had received treatment for 4 (5.9%, P=0.02) or 6 yr (8.6%, P=0.002), respectively. However, the largest residual effect was found in women treated with alendronate 20 mg per day for 2 yr (9.7%, P=0.01 vs. placebo). The rate of bone loss after alendronate withdrawal was comparable to the bone loss observed in the placebo group. Bone markers tended to reverse back to normal levels, but were still affected even several years after withdrawal of treatment. This study has demonstrated that the efficacy of alendronate in preventing bone loss was proportional to the duration of treatment. The rate of bone loss after withdrawal of alendronate corresponded to the normal postmenopausal rate of bone loss. A residual effect on BMD was found up to 7 yr after treatment withdrawal.
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Affiliation(s)
- Yu Z Bagger
- Center for Clinical and Basic Research A/S, Ballerup Byvej 222, Ballerup, Denmark.
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32
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Pines A, Eckstein N, Kopernik G, Ayalon D, Comaneshter D, Frenkel Y. Month 3 and month 6 measurements of bone mineral density predict the annual outcome in postmenopausal women with osteoporosis in whom alendronate was added to long-term HRT. Maturitas 2003; 44:287-92. [PMID: 12697369 DOI: 10.1016/s0378-5122(03)00041-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To examine the predictive value of bone mineral density measurements done as early as months 3 and 6 after initiation of alendronate therapy (10 mg daily) in osteoporotic women already using long-term hormone replacement therapy. METHOD Lumbar spine and femoral neck bone density (DPX by Lunar) were performed at baseline, 3, 6, 12 months of combined therapy. The study group included 45 women at baseline, but 2 dropped-out at day 67 and at month 6 because of gastric complaints, leaving 43 women for analyses. RESULTS Group characteristics at baseline were as follows: mean age 61+/-5 years, mean duration of HRT use 7+/-3 years, lumbar spine bone density 0.863+/-0.089 g/cm(2), with a t-score of -2.75+/-0.8 S.D., and femoral neck density 0.706+/-0.085 g/cm(2) with a t-score of -2.28+/-0.7 S.D. Bone density increased during 1 year of combined therapy, totaling a 3.2% gain for the spine and a 2.4% gain for the femur. Most of the annual change was already observed at month 3: 2.1% for the spine and 1.4% for the femur. Moreover, the baseline to month 6 percentage difference showed a very good correlation with the yearly outcome (r=0.74, P<0.001 for both spine and femur). When different arbitrary cut-off definitions for a successful treatment (1%, 1.5% or 2% gain in density) were used in analyses, in the majority of cases the bone density at 1 year, whether elevated or not, could be predicted by months 3 and 6 results. Although urine deoxypyridinoline decreased throughout the study period, demonstrating a significant time trend (P=0.001), the baseline to month 3 changes did not correlate with baseline to annual bone density results. CONCLUSIONS In specific clinical settings when patients or physicians are looking for a good way to anticipate whether additional alendronate in hormone users would turn out to be beneficial, bone density measurements performed as early as 3-6 months after initiation of therapy might give the answer.
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Affiliation(s)
- Amos Pines
- Menopause Clinic, Ramat Marpe Hospital, Ramat Gan, Ichilov Hospital, Tel-Aviv, and Sheba Medical Center, Tel-Hashomer, Israel.
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Abstract
The current status of detection and treatment of osteoporosis is reviewed. Despite substantial advances in the past ten years, most patients with osteoporotic fractures are still not being treated for the underlying bony cause of the fracture, and most people at risk for fracture are not being offered known protective regimens. The foundation of any therapeutic program is adequate nutrition--specifically protein, calcium, phosphorus and vitamin D. Current anti-resorptive agents reduce vertebral fracture risk by 30% to 50% and teriparatide, a newly approved anabolic agent, reduces risk by up to 80+%. Effective treatments for chronic bony pain that occurs in some patients with spine fractures is affored by two minimally invasive procedures, kyphoplasty and vertebroplasty. Some of these chronically painful fractures represent instances of previously unrecognized non-union, and in them low-pressure vertebroplasty produces prompt and lasting relief. Fracture risk reductions with current anti-resorptive agents are at least twice as great as can be explained by drug effects on bone mass. Moreover, risk is reduced within a few months of starting therapy. These observations focus attention on bone remodeling and point to the need for improvement of biomarker technology, since it seems likely that reduction in remodeling activity underlies much of the fracture risk reduction and can therefore be used to monitor therapy.
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Affiliation(s)
- Robert P Heaney
- Osteoporosis Research Center, Creighton University, Omaha, Nebraska 68131, USA.
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Abstract
Calcium and vitamin D are essential for bone maintenance and for treatment-induced bone augmentation. Deficiencies of both nutrients are very common in the age group most afflicted by osteoporosis. Calcium enhancement of estrogen's effects now have been clearly demonstrated. Additionally, all currently approved bone active agents have been tested only in the presence of extra calcium, and newer anabolic agents create a skeletal need for mineral that will require even higher levels of calcium repletion. Prudent nutritional support for osteoporosis prevention and treatment consists of 30 to 40 mmol Ca/d together with sufficient vitamin D to maintain serum 25(OH)D levels above 80 nmol/L (i.e., approximately 25 microg vitamin D/d).
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Affiliation(s)
- Robert P Heaney
- Department of Medicine, Creighton University Medical Center, Omaha, NE 68131, USA.
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36
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Eriksen EF, Melsen F, Sod E, Barton I, Chines A. Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone 2002; 31:620-5. [PMID: 12477578 DOI: 10.1016/s8756-3282(02)00869-4] [Citation(s) in RCA: 144] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The effects of 3 years of oral risedronate treatment on bone quality and remodeling were assessed in women with postmenopausal osteoporosis. Transiliac bone biopsies were obtained at baseline and after treatment with placebo or risedronate 5 mg/day in 55 women (placebo, n = 27; risedronate 5 mg, n = 28); these pairs of samples allowed comparison of treatment effects vs. both baseline values and between treatment groups. A further 15 women (placebo, n = 6; risedronate 5 mg, n = 9) had measurements from a posttreatment biopsy, but not from a baseline biopsy. Samples were examined for qualitative changes (e.g., osteomalacia, peritrabecular fibrosis, and woven bone); no histological abnormalities were found to be associated with treatment. Among women with both baseline and posttreatment biopsies, risedronate-treated women experienced a moderate and expected reduction from baseline in bone turnover, which was reflected in mean decreases in mineralizing surface of 58% and in activation frequency of 47%. Histomorphometrical parameters indicated that bone formation rate decreased significantly from baseline with risedronate treatment, reflecting a decrease in bone turnover; bone mineralization was normal following treatment. Basic multicellular unit (BMU) balance tended to improve in the risedronate-treated women, whereas it tended to worsen in the placebo-treated women, although these changes were not statistically significant. There were no significant changes in structural parameters with treatment. The effects of 3 years of risedronate treatment on bone histology and histomorphometry reflect the antiresorptive mechanism of action, and are consistent with the antifracture efficacy and favorable bone safety profile demonstrated in large clinical trials.
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Affiliation(s)
- E F Eriksen
- University Department of Endocrinology, Aarhus Amtssygehus, Denmark
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37
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Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A, Dore RK, Correa-Rotter R, Papaioannou A, Cumming DC, Hodsman AB. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002; 87:4528-35. [PMID: 12364430 DOI: 10.1210/jc.2002-020334] [Citation(s) in RCA: 231] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.
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Affiliation(s)
- Jean-Jacques Body
- Department of Medicine, Institut J. Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
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Ravn P, Neugebauer G, Christiansen C. Association between pharmacokinetics of oral ibandronate and clinical response in bone mass and bone turnover in women with postmenopausal osteoporosis. Bone 2002; 30:320-4. [PMID: 11792604 DOI: 10.1016/s8756-3282(01)00665-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Data from the 1-year, phase II trial of oral ibandronate for treatment of postmenopausal osteoporosis are presented (n = 180). Participants were at least 10 years past menopause and had osteopenia defined as a forearm bone mineral density at least 1.5 SD below the premenopausal mean value. Doses were 0.25, 0.50, 1.0, 2.5, or 5.0 mg daily oral ibandronate or placebo. A total of 116 women treated with ibandronate completed the study. Blood samples for pharmacokinetic analyses were drawn 20 min, 40 min, 60 min, 2 h, 4 h, and 6 h after the first and last administration of the study drug. An enzyme-linked immunosorbent assay was used to determine the concentration of ibandronic acid (BM 21.0955) in serum (Enzymun-Test System ES 600). The assay is based on streptavidine technology to fix the capture antibody to the wall of the tube. Standards were prepared for each participant using individual drug-free serum. The serum concentration-time curves of ibandronate, expressed as the area under the curve over the sampling period (AUC(0-6h)), revealed a highly significant dose-response relationship, p < 0.0001, and linear pharmacokinetic behavior. An initial half-life (T(1/2lambda1)) in serum representing distribution and early elimination was 1.3 hours. Steady-state AUC (AUC(0-6h ss)) increased by a factor of 2.5, which is consistent with an apparent elimination half-life of 32.6 h and a dosing interval of 24 h. There was an exponential association between AUC(0-6h) (ss) and the change from baseline at month 12 in the bone markers (n = 116): r = -0.37 (serum total osteocalcin), r = -0.65 (urine C-telopeptides of type I collagen), and r = -0.65 (serum C-telopeptides of type I collagen), all p < 0.0001. All bone markers were maximally depressed at values of AUC(0-6h ss) of about 3 ng h/mL. AUC(0-6h ss) furthermore revealed a logarithmic association with change from baseline at month 12 in spine BMD, r = 0.39, p < 0.0001. In conclusion, the serum concentration of ibandronate was determined validly by the enzyme-linked immunosorbent assay. The data are the first to show highly significant associations between pharmacokinetic parameters of a bisphosphonate and the clinical response in bone mass and bone turnover.
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Affiliation(s)
- P Ravn
- Center for Clinical and Basic Research, Ballerup, Denmark.
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39
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Hernandez CJ, Beaupré GS, Marcus R, Carter DR. A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment. Bone 2001; 29:511-6. [PMID: 11728920 DOI: 10.1016/s8756-3282(01)00613-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.
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Affiliation(s)
- C J Hernandez
- Rehabilitation Research and Development Center, VA Palo Alto Health Care System, CA, Palo Alto, USA.
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40
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Abstract
The bone remodeling transient is a temporary alteration in the balance between bone formation and bone resorption, brought about by any agency that affects bone remodeling. Ascertaining the steady state effect of an intervention requires factoring the component of the change due to the transient out of the total bony response. Since parathyroid hormone (PTH) is the principal regulator of the quantity of remodeling activity, and since calcium intake influences PTH secretion, it follows that altering calcium intake will always induce a remodeling transient. Worked examples from three published calcium intervention studies are presented, and the errors that can be made by ignoring the transient and simply measuring change in bone mass across treatment are described.
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Affiliation(s)
- R P Heaney
- Creighton University, Omaha, Nebraska 68178, USA
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41
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Lucasey B. CORTICOSTEROID-INDUCED OSTEOPOROSIS. Nurs Clin North Am 2001. [DOI: 10.1016/s0029-6465(22)02568-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Shapses SA, Von Thun NL, Heymsfield SB, Ricci TA, Ospina M, Pierson RN, Stahl T. Bone turnover and density in obese premenopausal women during moderate weight loss and calcium supplementation. J Bone Miner Res 2001; 16:1329-36. [PMID: 11450709 DOI: 10.1359/jbmr.2001.16.7.1329] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Bone turnover is increased during weight loss in postmenopausal women and can be suppressed with calcium supplementation. In this study, we assessed the influence of energy restriction with and without calcium supplementation (1 g/day) in premenopausal women. Thirty-eight obese premenopausal women (body mass index [BMI] of 35.0 +/- 3.9 kg/m2) completed a 6-month study of either moderate weight loss or weight maintenance. During weight loss, women were randomly assigned to either a calcium supplementation (n = 14) or placebo group (n = 14) and lost 7.5 +/- 2.5% of their body weight. The control group of women (n = 10) maintained their body weight. Total body and lumbar bone mineral density (LBMD) and content were measured by dual-energy X-ray absorptiometry (DXA) at baseline and after weight loss. Throughout the study, blood and urine samples were collected to measure bone turnover markers and hormones. During moderate energy restriction, dietary calcium intake decreased (p < 0.05) and the bone resorption marker deoxypyridinoline (DPD) increased slightly (p < or = 0.05) without evidence of bone loss. Calcium supplementation during weight loss tended to increase lumbar BMD by 1.7% (p = 0.05) compared with the placebo or weight maintenance groups. In contrast to our previous findings in postmenopausal women, premenopausal obese women who consume a low calcium diet do not lose bone over a 6-month period, whether their weight is stable or decreasing moderately.
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Affiliation(s)
- S A Shapses
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey 08901-8525, USA
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43
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Grotz W, Nagel C, Poeschel D, Cybulla M, Petersen KG, Uhl M, Strey C, Kirste G, Olschewski M, Reichelt A, Rump LC. Effect of ibandronate on bone loss and renal function after kidney transplantation. J Am Soc Nephrol 2001; 12:1530-1537. [PMID: 11423583 DOI: 10.1681/asn.v1271530] [Citation(s) in RCA: 115] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Severe osteoporosis frequently is observed after organ transplantation. In kidney transplantation, it adds to pre-existing renal bone disease and strategies to prevent osteoporosis are not established. Eighty kidney recipients were included in a randomized controlled prospective intervention trial. Treated patients (n = 40) received an injection of ibandronate, a bisphosphonate, immediately before and at 3, 6, and 9 mo after transplantation. The primary outcome measured was the change in bone mineral density. Secondary measures included graft outcome, spinal deformities, fracture rate, body height, and hormonal and metabolic data. Loss of spongy and cortical bone after transplantation was prevented by ibandronate. Changes of bone mineral density (ibandronate versus controls) were as follows: lumbar spine, -0.9 +/- 6.1% versus -6.5 +/- 5.4% (P < 0.0001); femoral neck, +0.5 +/- 5.2% versus -7.7 +/- 6.5% (P < 0.0001); and midfemoral shaft, +2.7 +/- 12.2% versus -4.0 +/- 10.9% (P = 0.024). Fewer spinal deformities developed with ibandronate (7 patients with 7 deformities versus 12 patients with 23 deformities; P = 0.047). Loss of body height was 0.5 +/- 1.0 cm versus 1.1 +/- 1.0 cm in control subjects (P = 0.040). Two bone fractures occurred in each group. There were fewer acute rejection episodes with ibandronate (11 versus 22; P = 0.009). Graft function after 1 yr was comparable. Bone loss, spinal deformation, and loss of body height during the first year after kidney transplantation are prevented by injection of ibandronate at intervals of 3 mo. The smaller number of rejection episodes of the ibandronate-treated group should be confirmed and its mechanism should be explored in additional studies.
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Affiliation(s)
- Wolfgang Grotz
- Department of Internal Medicine, Division of Nephrology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Christian Nagel
- Department of Internal Medicine, Division of Nephrology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Daria Poeschel
- Department of Internal Medicine, Division of Nephrology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Markus Cybulla
- Department of Internal Medicine, Division of Nephrology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Karl-Georg Petersen
- Department of Internal Medicine, Division of Endocrinology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Markus Uhl
- Department of Diagnostic Radiology, Division of Transplantation, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Christoph Strey
- Department of Surgery, Division of Transplantation, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Günter Kirste
- Department of Surgery, Division of Transplantation, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Manfred Olschewski
- Department of Medical Biometrics, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Achim Reichelt
- Department of Orthopedics, Division of Transplantation, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
| | - Lars Christian Rump
- Department of Internal Medicine, Division of Nephrology, University Hospital, Albert-Ludwigs-University, Freiburg, Germany
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Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 2000; 85:231-6. [PMID: 10634392 DOI: 10.1210/jcem.85.1.6267] [Citation(s) in RCA: 213] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There is a current debate about the extent to which antifracture efficacy of antiresorptive drugs are related to changes in bone mineral density (BMD). In vitro studies show that most of the variability in bone strength is related to BMD, and prospective studies have shown that low BMD is an important predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a reduction in activation frequency or resorption depth would lead to fewer (and/or shallower) resorption sites and refilling of existing sites initially. There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and this may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural elements would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term antifracture efficacy of antiresorptive drugs will depend on the extent to which treatment can increase and maintain BMD. To examine this issue, we compiled data from clinical trials of antiresorptive agents and plotted the relative risk of vertebral fractures against the average change in BMD for each trial. The confidence intervals are large for individual trials, and there was substantial variability in antifracture efficacy at any given level of change in BMD. Overall, however, trials that reported larger increases in BMD tended to observe greater reductions in vertebral fracture risk. Poisson regression was used to quantify this relationship. The model predicts that treatments that increase spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings are consistent with the short-term predictions of the conceptual model and with reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD technology.
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Affiliation(s)
- R D Wasnich
- Hawaii Osteoporosis Center, Honolulu 96814, USA.
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45
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Ravn P, Bidstrup M, Wasnich RD, Davis JW, McClung MR, Balske A, Coupland C, Sahota O, Kaur A, Daley M, Cizza G. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med 1999; 131:935-42. [PMID: 10610644 DOI: 10.7326/0003-4819-131-12-199912210-00005] [Citation(s) in RCA: 111] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Up to 3 years of treatment with alendronate, 5 mg/d, prevents postmenopausal bone loss. OBJECTIVE To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued. DESIGN Randomized, controlled trial. SETTING United States and Europe. PARTICIPANTS 1609 postmenopausal women 45 to 59 years of age. INTERVENTION Participants were randomly assigned to receive oral alendronate, 5 mg/d or 2.5 mg/d; placebo; or open-label estrogen-progestin. Women in the alendronate groups received alendronate for the first 2 years of the study. Treatment was then continued without change or replaced with placebo for the last 2 years of the study. MEASUREMENTS Annual measurement of bone mineral density. RESULTS By year 4, the bone mineral density of participants in the placebo group had decreased by 1% to 6% (P < 0.001). Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine (mean change [+/-SE], 3.8%+/-0.3%), hip (mean, 2.9%+/-0.2%), and total body (mean, 0.9%+/-0.2%) (P < 0.001 overall). By year 4, bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo. In years 3 and 4, bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo. Compared with 5 mg of alendronate per day, estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater. CONCLUSIONS Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss. A residual effect was seen 2 years after alendronate therapy was stopped; however, continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo.
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Affiliation(s)
- P Ravn
- Center for Clinical and Basic Research, Ballerup, Denmark
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46
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Abstract
Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. Bisphosphonates have been extensively used in the elderly with primary and secondary osteoporosis, Paget's disease, and hypercalcemia of malignancy. In recent years, bisphosphonates have been used to treat children acutely for resistant hypercalcemia and chronically for various metabolic bone diseases. The theoretical concerns of possible adverse effects of these drugs on the growing skeleton have not been proven to be true. In the present review, we have critically analyzed the available literature on bisphosphonate therapy in both adult and pediatric clinical trials. Although not yet approved by the FDA for use in children, bisphosphonates, from published experience, demonstrate benefit to the child with no serious adverse effects. Based on the literature analysis the review furnishes detailed recommendations and practical guidelines regarding the use of oral and intravenous bisphosphonates in children. Bisphosphonates might be the first agents to provide the pediatrician with an opportunity to treat mineral and bone disorders of childhood, which until recently did not have satisfactory therapy.
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Affiliation(s)
- T Srivastava
- Section of Nephrology, Children's Mercy Hospital, Kansas City, MO 64108, USA
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47
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48
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Kaplan NM, Palmer BF, Rubin CD. Treatment Considerations in the Management of Age-Related Osteoporosis. Am J Med Sci 1999. [DOI: 10.1016/s0002-9629(15)40608-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hochberg MC, Ross PD, Black D, Cummings SR, Genant HK, Nevitt MC, Barrett-Connor E, Musliner T, Thompson D. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. ARTHRITIS AND RHEUMATISM 1999; 42:1246-54. [PMID: 10366118 DOI: 10.1002/1529-0131(199906)42:6<1246::aid-anr22>3.0.co;2-u] [Citation(s) in RCA: 185] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To investigate whether the incidence of vertebral fractures is related to the magnitude of change in bone mineral density (BMD) during alendronate treatment. METHODS Women in this study were age 55-81 years (n = 2,984). While participating in the Fracture Intervention Trial, they received 5 mg/day of alendronate for 2 years followed by 10 mg/day for the remaining 12-30 months of the study. Their BMD was measured at baseline and at 12 and 24 months, and spine radiographs were obtained at baseline and again at 36 or 48 months to identify new vertebral fractures. RESULTS After 12 months of alendronate treatment, 35% of participants had increases of > or =3% in total hip BMD, and 21% had either decreased total hip BMD or no change. Women who had larger increases in total hip BMD during the first 12 months had a lower incidence of new vertebral fractures during the entire followup period. Only 3.2% of women with increases of > or =3% in total hip BMD experienced new vertebral fractures, whereas twice as many women (6.3%) whose BMD declined or stayed the same experienced new fractures (adjusted odds ratio 0.45, 95% confidence interval 0.27-0.72). Similar patterns were observed for spine BMD at 12 months, and for both sites using change in BMD at 24 months. CONCLUSION Women with increases of > or =3% in BMD during the first 1 or 2 years of alendronate treatment had the lowest incidence of new vertebral fractures. These findings suggest that, among women taking antiresorptive agents, greater increases in BMD are associated with lower risk of new vertebral fractures.
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Affiliation(s)
- M C Hochberg
- University of Maryland School of Medicine, Baltimore, USA
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Ravn P, Clemmesen B, Christiansen C. Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group. Bone 1999; 24:237-44. [PMID: 10071916 DOI: 10.1016/s8756-3282(98)00183-5] [Citation(s) in RCA: 98] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Data from the Danish cohort (n = 67) of a multicenter trial of oral alendronate in the prevention of postmenopausal osteoporosis were used to evaluate the capacity of the biochemical markers to predict changes in bone mineral density (BMD). A panel of markers were measured: serum N-terminal midfragment osteocalcin (N-MID OC); serum total osteocalcin (total OC); bone-specific alkaline phosphatase (BSAP); serum and urine C-telopeptides of type I collagen (sCL and uCL); urine N-telopeptide crosslinks of type I collagen (NTX); and deoxypyridinoline (dPyr). The correlation between change from baseline at months 3-12 in total OC, N-MID OC, sCL, uCL, and NTX and 2 year response in spine BMD ranged from r = -0.45 to r = -0.78 (p < 0.001), and from r = -0.38 to r = 0.10 (n.s. to p < 0.002) for BSAP and dPyr. Sensitivity and specificity were used to assess the accuracy of change from baseline at month 6 in the biochemical markers for predicting prevention of bone loss in the spine over 2 years. The cutpoints used were a 30% (N-MID OC) or 50% (all other markers) decrease from baseline. Sensitivity levels were 82% (N-MID OC), 98% (total OC), 78% (sCL and NTX), and 89% (uCL). Specificities were 91% (N-MID OC), 59% (total OC), 100% (sCL), 71% (uCL), and 84% (NTX). Positive predictive values were 95% (N-MID OC), 82% (total OC), 100% (sCL), 87% (uCL), and 90% (NTX). In comparison, the predictive capacities of change from baseline at year 2 in hip BMD in predicting prevention of bone loss at the spine were similar: sensitivity, 82%; specificity, 55%; and positive predictive value, 79%. In conclusion, short-term changes in biochemical markers were valid predictors of long-term changes in BMD. Short-term changes in the sensitive biochemical markers revealed a predictive capacity similar to bone densitometry at the hip measured over 2 years. The sensitive biochemical markers offered a fast and valid alternative to bone densitometry for monitoring of alendronate treatment.
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Affiliation(s)
- P Ravn
- Center for Clinical and Basic Research, Ballerup, Denmark
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