Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE

OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.     

Intravenous ibandronate: in the treatment of osteoporosis

Ibandronate (ibandronic acid) is a potent nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption in women with postmenopausal osteoporosis. Recently, an intravenous (IV) formulation of ibandronate for intermittent injection, which circumvents the fasting and posture requirements associated with administration of oral bisphosphonates, was approved for use in this patient population. In initial placebo-controlled studies of 1 year's duration, IV ibandronate (< or =2mg once every 3 months) increased lumbar spine bone mineral density (BMD) and reduced levels of biochemical markers of bone turnover in a dose-dependent manner. Dosages < or =1mg every 3 months were found to be suboptimal in terms of fracture prevention in a 3-year trial. Subsequently, the large randomised, double-blind, noninferiority DIVA trial showed that, in terms of increasing lumbar spine BMD (primary endpoint), IV ibandronate 3mg once every 3 months and 2mg once every 2 months for 1 year were noninferior and also superior to oral ibandronate 2.5mg once daily, a regimen with proven antifracture efficacy. Median reductions from baseline in biochemical markers of bone turnover were similar for the IV and oral regimens. IV ibandronate was generally well tolerated in clinical trials. Treatment-related adverse events included musculoskeletal events and transient influenza-like symptoms, the latter mainly associated with the first dose.     

Ibandronate produces significant,similar antifracture efficacy in North American and European women: new clinical findings from BONE

ABSTRACT

Objectives: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2?months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here.

Patients and methods: BONE was a randomized, double-blind, placebo-controlled, fracture-prevention study in 2946 postmenopausal women (age 55?years?80?years; ≥ 5?years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4?L4]). Participants received daily calcium (500?mg) and vitamin D (400?IU) plus either placebo, oral daily ibandronate (2.5?mg) or oral intermittent ibandronate (20?mg every other day for 12 doses every 3?months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations.

Results: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (?p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo.

Conclusions: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients’ geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.     

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.     

Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis

Ibandronate, a potent, nitrogen-containing bisphosphonate for the treatment of postmenopausal osteoporosis, is the subject of an ongoing clinical development program to explore novel oral and intravenous (i.v.) dosing regimens. As part of this program, an extensive modeling and simulation project was undertaken to develop and validate a pharmacologically realistic mathematical model for ibandronate in osteoporosis, the aim being to identify practical dosing regimens for clinical evaluation. A simplified kinetics of drug action or kinetic-pharmacodynamic (K-PD) model (developed from a 4-compartment pharmacokinetic-pharmacodynamic [PK-PD] model) accurately described the urinary excretion of the C-telopeptide of the alpha-chain of type I collagen (uCTX). The model was extended to consider the effects of supplemental calcium therapy and allow simultaneous fitting of i.v. and oral ibandronate data, and then externally validated. This model was used successfully in the selection of appropriate once-monthly doses for further clinical evaluation and recent clinical studies have confirmed the efficacy of the doses identified. Further development of the model may include investigating the effects of ibandronate on bone mineral density and fracture risk, which would further enhance its clinical utility and predictive value. Although modeling and simulation has been used to explore the efficacy of other bisphosphonates, the extensive program with ibandronate has produced a comprehensively validated model that is the first to be prospectively tested by evaluating novel dosing regimens.     

Ibandronate in profile: drug characteristics and clinical efficacy

BACKGROUND: Postmenopausal osteoporosis is a serious, chronic condition, for which nitrogen-containing bisphosphonates are now one of the treatments of choice. OBJECTIVE: To review the profile of ibandronate, a monthly oral (150 mg) or quarterly intravenous injection (3 mg) of bisphosphonate. METHODS: The literature search was limited to publications of ibandronate data. RESULTS/CONCLUSION: Ibandronate is rapidly absorbed and distributed in the bone; it is not metabolised and is excreted in urine. Clinical trial data have demonstrated the efficacy of ibandronate in reducing fracture risk, increasing bone mineral density and reducing bone turnover. These data are supported by recent meta-analyses and a large database study that have demonstrated antifracture efficacy with the ibandronate regimens used in clinical practice. Overall, ibandronate has generally been well tolerated. Therefore, ibandronate is a useful treatment for postmenopausal osteoporosis.     

Oral ibandronate: a less frequently administered therapeutic option for postmenopausal osteoporosis

Osteoporosis is a severe condition, associated with significant disability as a result of fragility fractures and increased mortality. Oral bisphosphonates effectively reduce the risk of osteoporotic fracture and are generally well tolerated. Unfortunately, patient outcomes are often compromised by suboptimal therapeutic adherence. In other disease areas, reduced dosing frequency has been shown to improve therapeutic adherence. A positive impact for adherence has been observed with a reduction in the bisphosphonate dosing frequency from daily to weekly. However, overall adherence remains suboptimal. Ibandronate is a potent nitrogen-containing bisphosphonate specifically designed for less frequent than weekly administration, without compromise for efficacy or tolerability. This article reviews the pharmacology, efficacy and tolerability of oral ibandronate when administered with extended dosing intervals in postmenopausal osteoporosis.     

Oral ibandronate: a less frequently administered therapeutic option for postmenopausal osteoporosis

Osteoporosis is a severe condition, associated with significant disability as a result of fragility fractures and increased mortality. Oral bisphosphonates effectively reduce the risk of osteoporotic fracture and are generally well tolerated. Unfortunately, patient outcomes are often compromised by suboptimal therapeutic adherence. In other disease areas, reduced dosing frequency has been shown to improve therapeutic adherence. A positive impact for adherence has been observed with a reduction in the bisphosphonate dosing frequency from daily to weekly. However, overall adherence remains suboptimal. Ibandronate is a potent nitrogen-containing bisphosphonate specifically designed for less frequent than weekly administration, without compromise for efficacy or tolerability. This article reviews the pharmacology, efficacy and tolerability of oral ibandronate when administered with extended dosing intervals in postmenopausal osteoporosis.     

Treating osteoporosis with bisphosphonates and addressing adherence: a review of oral ibandronate

Osteoporosis is a common, chronic condition, affecting approximately half of all postmenopausal Caucasian women in the US. Vertebral fractures occur as a result of osteoporosis and lead to increased hospitalisation and mortality, and adversely affect patient quality of life. The burden of osteoporosis on healthcare systems is expected to rise as the elderly population continues to grow. Yet there are many medications for preventing and treating osteoporosis.Oral bisphosphonates are first-line treatment for osteoporosis, with demonstrated efficacy in increasing bone mineral density and reducing bone turnover, which reduces the incidence of fractures. However, adherence to medication is suboptimal, with approximately 40% of patients discontinuing treatment within 6 months. Recent reports have suggested simplifying the dosage regimen as a strategy to help address this issue.Ibandronate is a potent, nitrogen-containing bisphosphonate which is administered once-monthly. Preclinical studies initially revealed the feasibility of extending the between-dose interval. Subsequent clinical studies have provided further evidence of the positive effects of extended-interval ibandronate administration in reducing the risk of vertebral fractures through increasing bone mineral density and reducing bone turnover without compromising bone quality. These studies have also demonstrated that ibandronate has a safety profile similar to placebo. Ibandronate has recently been approved for use in the US to treat postmenopausal osteoporosis.This review summarises the efficacy and safety of once-monthly oral ibandronate and discusses the implications of such a treatment in primary care in the US.     

Intermittent bisphosphonate therapy in postmenopausal osteoporosis: progress to date

Bisphosphonates are the most widely prescribed drugs in osteoporosis today. They have unequivocally shown their ability to reduce fracture rate at the spine (alendronic acid, risedronic acid, ibandronic acid) and at the hip (alendronic acid and risedronic acid). However, their dosage and administration procedures and the adverse reactions induced by their oral intake are responsible for low adherence. Therefore, intermittent regimens have been developed. Weekly alendronic acid and risedronic acid provide similar benefits, in terms of bone mineral density (BMD) and changes in biochemical markers, as those seen with their daily formulations. Ibandronic acid has been shown to reduce vertebral fractures when given intermittently. Ibandronic acid given orally monthly and intravenously every 2 or 3 months provides increases in BMD similar to the daily formulation. Yearly intravenous infusions of zoledronic acid are currently being evaluated for their ability to reduce fractures. If the efficacy and safety of bisphosphonates given at administration intervals longer than weekly are confirmed, this might significantly improve patient adherence and long-term outcomes of bisphosphonate treatment in postmenopausal osteoporosis.     

The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data

Aim:

Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia.

Methods:

Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects'' bone mineral densities (BMDs), bone turnover markers (P1NP and β-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments.

Results:

All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group.

Conclusion:

The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow-up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability.     

Zoledronic acid: a review of its use in the treatment of osteoporosis

Zoledronic acid (Aclasta; Reclast), a third-generation nitrogen-containing bisphosphonate, is the first once-yearly treatment to have been approved for use in patients with postmenopausal osteoporosis or at high risk of fracture. Intravenous zoledronic acid 5 mg once yearly is effective in reducing the risk of several types of fracture in patients with postmenopausal osteoporosis or recent low-trauma hip fracture. Moreover, improvements in bone mineral density (BMD) and reductions in markers of bone turnover are also generally observed. Zoledronic acid is generally well tolerated. Additional comparative data are required to definitively position zoledronic acid with respect to other agents. In the meantime, intravenous zoledronic acid 5 mg once yearly is a convenient and effective treatment option that may have an advantage over some other agents, for which adherence to treatment regimens is a recognized problem.     

Ibandronate: new options in the treatment of osteoporosis

Bisphosphonates are currently considered the treatment of choice for corticosteroid-induced male osteoporosis and represent one of the options for the prevention and treatment of postmenopausal osteoporosis. The treatment of osteoporosis with antiresorbing agents requires long-lasting or even lifelong therapies. Oral bisphosphonates are reasonably well tolerated, but a sizable proportion of patients report esophageal symptoms which are occasionally severe. In addition, their intestinal absorption is only 0.5-1% and the presence of any residual food in the stomach completely blocks absorption. Intravenous bisphosphonate administration, which avoids the upper gastrointestinal tolerability concerns associated with oral regimens, may be of considerable value for many patients such as elderly and institutionalized patients because it ensures full treatment compliance, but the intravenous route has to be used with caution since acute renal failure has been observed following the intravenous administration of several bisphosphonates and prolonged intravenous infusions can also be potentially associated with thrombotic complications and infections. Bisphosphonate dosing by intravenous injection could provide a convenient alternative to intravenous infusion that would be suitable for use in the primary care setting and would avoid many of the complications associated with prolonged infusions. This option is viable with the highly potent, nitrogen-containing bisphosphonates such as ibandronate, which, unlike other lower potency bisphosphonates, can be administered as an intravenous injection of only a few milligrams in regimens with extended between-dose intervals. In this review, the data obtained with ibandronate, using both oral administration and intravenous injection, for the treatment and prevention of postmenopausal osteoporosis are summarized.     

Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women

This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N-telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C-telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. The BMD was characterized by a turnover model with stimulation of bone formation and degradation by AOB (active osteoblasts) and AOC pools. The estimated basal sNTX, uNTX and uCTX concentrations were 7.24 nm, 14.4 nmol/mmolCr and 31μg/mmolCr. The BMD degradation rate was 0.00161 day(-1) with stimulation constants associated with AOB and AOC of 1214 and 790 pm(-1) . The plasma ibandronate concentration producing 50% of maximum inhibition of osteoclast differentiation was 522 ng/l. The integrated model, which incorporates multiple pathways of therapeutic intervention, quantitatively describes changes in clinical biomarkers of bone turnover and BMD after denosumab and ibandronate exposures in postmenopausal women.     

Denosumab: a review of its use in the treatment of postmenopausal osteoporosis

Denosumab (Prolia?) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

ZT-031, a cyclized analog of parathyroid hormone(1-31) for the potential treatment of osteoporosis

ZT-031 is a cyclic 31-amino acid analog of parathyroid hormone (PTH) that is in development by Zelos Therapeutics Inc for the treatment of osteoporosis and other bone-related disorders. ZT-031 activates the PTH type 1 receptor - the molecular target of the currently marketed osteogenic peptides PTH and PTH(1-34). Daily subcutaneous injections of ZT-031 prevented bone loss and replaced bone that had already been lost in an ovariectomized rat model of osteoporosis. Daily subcutaneous injections of ZT-031 in gonad-intact monkeys increased bone mineral density (BMD) at cortical and cancellous bone sites and increased serum levels of bone formation markers. The daily subcutaneous administration of ZT-031 to postmenopausal women with osteoporosis elicited a dose-dependent increase in BMD of the lumbar spine, proximal femur and total hip area. Plasma levels of bone formation markers were significantly increased above baseline after 1 month of dosing, and prior to increases in bone resorption markers. ZT-031 was demonstrated to be safe and well tolerated; episodes of hypercalcemia were infrequent and observed with a frequency greater than with placebo only at the highest doses tested for the drug. Although available data are limited, the results obtained following treatment with ZT-031 have generally been at least as favorable as those obtained with other osteogenic PTH peptides. A novel dosing paradigm has been planned for the drug.     

Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis

OBJECTIVE: The efficacy and tolerability of risedronate once-a-week dosing (35 and 50mg) were compared with risedronate daily dosing (5mg) in a 2-year study in women with osteoporosis. DESIGN AND METHODS: This was a randomized, double-blind, active-control study with lumbar spine bone mineral density (BMD) as the primary efficacy endpoint at 1 year. Subjects were women aged 50 years or older, postmenopausal for at least 5 years, and had either a BMD T-score of -2.5 or lower (lumbar spine or total proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. In addition to risedronate treatment, the subjects received 1000 mg daily of elemental calcium supplementation and received vitamin D if the baseline serum 25-hydroxyvitamin D(3) level was low. RESULTS: The results after 1 year of treatment were previously published. Of the 1456 women who were randomized and received study medication, 1127 (77%) completed the 2-year study. Over the 2 years of treatment, the incidence of both new vertebral fractures (2.9, 1.5, and 1.7% for the 5, 35, and 50 mg groups, respectively; for women with postmenopausal osteoporosis who p = 0.298) and osteoporosis-related non-vertebral fractures reported as adverse events (5.0, 4.9, and 4.5% for the 5, 35, and 50 mg groups, respectively; p = 0.918) was similar for all 3 treatment groups. The reduction from baseline at Month 24 in bone turnover markers was similar based on an analysis of variance for the 5 mg daily and the 35 mg once-a-week groups. The mean percentage change in lumbar spine BMD after 24 months was 5.17, 4.74, and 5.47% for the 5, 35, and 50 mg groups, respectively. Both the 35 and 50 mg once-a-week treatment groups met the pre-specified criterion of non-inferiority to the 5 mg daily treatment group. No apparent difference in the pattern or distribution of serious and upper gastrointestinal adverse events was observed. CONCLUSIONS: The 2-year data agree with the 1-year results demonstrating that the risedronate once-a-week doses are comparable in efficacy and safety to the 5 mg daily dose. Risedronate 35 mg once a week is considered the optimal dose want a once-a-week dosing regimen.     

重组人甲状旁腺素(1-34)对绝经后骨质疏松患者血基质金属蛋白酶1及其组织抑制因子的影响

目的观察重组人甲状旁腺素(1-34)[rhPTH(1-34)]对绝经后骨质疏松患者血清基质金属蛋白酶1(MMP-1)及其组织抑制因子(TIMP-1)水平的影响,探讨其调节骨代谢的机制。方法绝经后女性90名分为骨质疏松组和正常组,骨质疏松组每日皮下注射rhPTH(1-34)20μg+钙剂600 mg+维生素D_3 200 IU,正常组不给予任何药物干预。检测腰椎骨密度(BMD),血钙、磷、MMP-1、TIMP-1、内源性全段甲状旁腺素(iPTH)、骨特异性碱性磷酸酶(BSAP)以及尿Ⅰ型胶原交联氨基末端肽(NTX)水平,并分析参数之间的相关关系。结果正常组BMD、血钙高于骨质疏松组(p<0.01),而iPTH、BSAP、MMP-1和尿NTX低于骨质疏松组(P<0.05)。rhPTH(1-34)治疗后,骨质疏松组患者腰椎BMD,血钙、磷、MMP-1、BSAP和尿NTX增高,而iPTH下降,与治疗前相比差异显著(P<0.05)。血TIMP-1与腰椎BMD成负相关(r=-0.376,P=0.014),校正年龄、体重指数后关系仍然存在;MMP-1与其他指标没有相关性。结论小剂量rhPTH(1-34)可促进绝经后骨质疏松患者血MMP-1水平增高,从而使成骨活性增强,这可能是其促进骨形成的机制之一。     

Review of ibandronate in the treatment of osteoporosis

Several antiresorptive treatments that reduce the risk of osteoporotic fracture are now available, including bisphosphonates. Ibandronate is a new potent bisphosphonate, currently under development, with unique features. In several animal models of human osteoporosis, it has been shown to inhibit bone resorption and improve bone mechanical properties. Ibandronate is more potent than most current bisphosphonates. Several dosages and schedules have been tested in humans. With the oral daily dose of 2.5 mg, a reduction of 62% in the incidence of vertebral fracture has been demonstrated in a randomised, placebo-controlled trial. In the same trial, a reduction of 50% has been observed - for the first time using a bisphosphonate - with an intermittent regimen (20 mg every other day for the first 24 days, followed by 9 weeks without the treatment). In contrast, another randomised, placebo-controlled trial failed to find a significant reduction in vertebral fracture risk using an dose of 1 mg i.v. every 3 months. Thus, ibandronate can be considered as a promising new option for the treatment of postmenopausal osteoporotic women.     

Bisphosphonates in osteoporosis: recent clinical experience

Bisphosphonates are potent inhibitors of bone resorption that have come to play a prominent role in the prevention and treatment of various forms of osteoporosis and other metabolic bone disorders. Therapy in women with osteoporosis and at high fracture risk substantially reduces the incidence of vertebral and non-vertebral fractures. In younger postmenopausal women, bisphosphonates are attractive alternatives to oestrogen to prevent bone loss and the subsequent development of osteoporosis. Bisphosphonates have recently become the treatment of choice to prevent and treat the skeletal consequences of chronic corticosteroid therapy. When administered appropriately, these drugs are very well tolerated and have an excellent safety profile. The challenges now to clinicians are to identify the patients for whom bisphosphonate therapy is indicated and to devise dosing and monitoring strategies to enhance the long-term adherence to therapy required to realise the full benefits of these treatments.