Drugs For Treatment Of Osteoporosis Research Articles

Age and drug therapy are key prognostic factors for first clinical fracture in patients with primary osteoporosis

We evaluated the characteristics of 1,142 women and men who attended Canadian osteoporosis clinics and had T-score < or = -2.0 and no prior fractures to determine the predictors of first clinical fracture. Greater age and failure to start osteoporosis drug treatment increased the risk of first clinical fracture. Although risk factors for osteoporotic fractures are well-known, it is unclear which factors predict poor prognosis in patients with primary osteoporosis. The purpose of this study was to determine prognostic factors for first clinical fracture in patients with T-score < or = -2.0 and no previous clinical fracture. We examined prospectively collected data from 1,142 patients aged 40 and over in the Canadian Database of Osteoporosis and Osteopenia. We used prognosis methodology and performed survival analysis to determine factors that increase the risk of first clinical fracture. Our inception cohort (mean age = 60.6 years, 91% females) had a cumulative fracture incidence of 5.1% (incidence rate: 2.53/100 person-years). Age and osteoporosis drug use predicted incident clinical fractures in multivariable regression analyses. The risk of first fracture increased by 3% per year. Failing to initiate osteoporosis treatment increased fracture risk by 2.4 times. In addition, low physical activity, high body mass index and low T-scores were found to predict fracture risk in certain patient subgroups using tree-structured survival analysis. These findings were robust and did not change with most sensitivity analyses. Age and osteoporosis drug treatment are the main prognostic predictors of first clinical fracture in patients with T-score < or = -2.0.

Compliance with osteoporosis drug therapy and risk of fracture

Patient compliance with osteoporosis drug therapy is often poor in clinical practice and may be associated with higher risk of fracture. A nested case-control study was undertaken using a US health insurance claims database. The source population included all women aged >or=45 years who began drug therapy for osteoporosis. Cases consisted of those who experienced an osteoporosis-related fracture; they were matched to controls without osteoporosis-related fracture. Compliance with osteoporosis drug treatment was assessed in terms of the number of therapy-days received and medication possession ratio (MPR). Conditional logistic regression was employed to examine the relationship between compliance and fracture risk. A total of 453 women with osteoporosis-related fracture were identified and matched to 2,160 controls. Fracture risk was significantly lower for patients with >180 days of therapy [181-360 days: odds ratio (OR) = 0.70, 95% CI = 0.49-0.99; >360 days: OR = 0.65, 95% CI = 0.43-0.99) versus those with <or=30 days. Risk was also lower for patients with MPR >or=90% (OR = 0.70, 95% CI = 0.52-0.93) versus those with MPR <30%. Fracture risk decreased as compliance increased (p(trend) < 0.05). Among women initiating drug therapy for osteoporosis, better compliance is associated with reduced risk of fracture.

Contribution of Three-Dimensional Trabecular Bone Microstructure of the Proximal Femur to its Mechanical Properties as Assessed by Micro-Finite Element Analysis

The purpose of this study was to investigate the contribution of the microstructural properties of trabecular bone in predicting its elastic modulus in the intertrochanteric region. A total of 15 trabecular bone core specimens were obtained from the proximal femurs of patients undergoing total hip arthroplasty. The micro-computed tomography (micro-CT) was used to scan each specimen to obtain micro-morphology. Microstructural parameters were directly calculated using software. Micro-CT images were converted to micro-finite element model using meshing technique, and then micro-finite element analysis (FEA) was performed to assess the mechanical property (Young’s modulus) of trabecular bone. The results showed that the ability to explain this variance of Young’s modulus is improved by combining the structural indices with each other. It suggested that assessment of bone microarchitecture should be added as regards detection of osteoporosis and evaluation of the efficacy of drug treatments for osteoporosis.

Is It Ethical to Use Placebos in Osteoporosis Trials?

The use of placebo control groups (e.g., subjects using calcium and vitamin D) in osteoporosis trials with subjects at high risk for fracture has been systematically questioned by institutional review boards (IRBs). Regulatory agencies, on the other hand, continue to not only recommend but also require that placebo-controlled trials be presented for the registration of new drugs for osteoporosis treatment. The Declaration of Helsinki and its updates have upheld the principle that protection of research subjects' rights is of primary concern. Nevertheless, even the Declaration keeps clearly opening the possibility of using placebo-control designs if it is justified for "compelling and scientifically sound methodological reasons." The use of intermediary endpoints or surrogates to establish the efficacy or safety of new medications in the management of osteoporosis is currently considered scientifically insufficient. This concept has led regulatory agencies, such as the Food and Drug Administration in the United States and the European Medicines Agency in the European Union, to require "fragility fracture reduction" as the primary endpoint in clinical trials for the registration of new drugs. Superiority or noninferiority trials are alternatives to placebo-controlled designs. However, factors such as sample size, cost, and statistical limitations render these models impractical for the registration of new medications for osteoporosis. We recommend collaboration among regulatory agencies, IRBs, scientists, and ethicists on the design of clinical trials for the registration of new medications for reduction of fracture risk. Delay in developing mutually acceptable models may impair scientific development in the field and possibly deprive patients of potentially beneficial treatments.

Newer drug treatments: Their effects on fracture prevention

Drug treatment of osteoporosis is based on the knowledge of mechanisms of bone turnover and the manipulation of the cellular components of bone turnover in terms of recruitment, activation and apoptosis of the cells involved. Based on their mechanisms of action, drugs used in the treatment of osteoporosis can be divided into those that inhibit bone turnover (bisphosphonates, SERMs, calcitonin), those that stimulate bone turnover (parathyroid hormone), and those with mixed effects (strontium ranelate). In this chapter we discuss the anti-fracture effects of some newer drugs together with innovative aspects of intake (monthly oral intake for ibandronate) or mechanisms of action (parathyroid hormone and strontium ranelate). Some new drugs that are being studied for their potential anti-fracture effects are listed.

Organization of the biosynthetic gene cluster for the macrolide concanamycin A in Streptomyces neyagawaensis ATCC 27449

The macrolide antibiotic concanamycin A has been identified as an exceptionally potent inhibitor of the vacuolar (V-type) ATPase. Such compounds have been mooted as the basis of a potential drug treatment for osteoporosis, since the V-ATPase is involved in the osteoclast-mediated bone resorption that underlies this common condition. To enable combinatorial engineering of altered concanamycins, the biosynthetic gene cluster governing the biosynthesis of concanamycin A has been cloned from Streptomyces neyagawaensis and shown to span a region of over 100 kbp of contiguous DNA. An efficient transformation system has been developed for S. neyagawaensis and used to demonstrate the role of the cloned locus in the formation of concanamycin A. Sequence analysis of the 28 ORFs in the region has revealed key features of the biosynthetic pathway, in particular the biosynthetic origin of portions of the backbone, which arise from the unusual polyketide building blocks ethylmalonyl-CoA and methoxymalonyl-ACP, and the origin of the pendant deoxysugar moiety 4'-O-carbamoyl-2'-deoxyrhamnose, as well as the presence of a modular polyketide synthase (PKS) encoded by six giant ORFs. Examination of the methoxymalonyl-specific acyltransferase (AT) domains has led to recognition of an amino acid sequence motif which can be used to distinguish methylmalonyl-CoA- from methoxymalonyl-ACP-specific AT domains in natural PKSs.

Possible roles of gene deficient mice as a model of osteoporosis

Recent technical advance for making of gene modified mice includes gene targeting and transgenic mice are clarify the biological function of its targeted molecules. The evidence from gene modified mice on sex-steroid hormones may contribute to develop clinical drugs for osteoporosis treatment especially. Gene deficient mice of the sole enzyme for estrogen synthesis (aromatase), estrogen receptor and androgen receptor deficient mice have great potential to elucidate further mechanisms of pathogenesis of osteoporosis.

Genetics of osteoporosis

Genetic factors play an important role in regulating bone mineral density and other phenotypes relevant to the pathogenesis of osteoporosis such as ultrasound properties of bone, skeletal geometry, and bone turnover. Progress has been made in identifying quantitative traits for regulation of bone mineral density by linkage studies in man and mouse, but relatively few causal genes have been identified. Dramatic progress has been made in identifying the genes responsible for monogenic bone diseases and it appears that polymorphisms in many of these genes also play a role in regulating bone mineral density in the general population. Advances in knowledge about the genetic basis of osteoporosis and other bone diseases offer the prospect of developing new markers for assessment of fracture risk and the identification of novel molecular targets for the design of new drug treatments for osteoporosis.

Clinic effect of alendronate sodium treatment in osteoporosis patients with hip fracture

To assess efficacy and safety of alendronate sodium treatment in osteoporosis patients with hip fracture. One year randomized, double-blind clinical trial was carried out in 77 osteoporosis patients with hip fracture. The bone mineral density (BMD) in lumbar spine (L(2 - 4)), femoral neck (Neck), Wards triangle (Wards) and great trochanter (Troch) was measured by dual energy x-ray absorptiometer (DEXA). In our study, alendronate sodium induced marked increases in BMD of the L(2 - 4) (7.0% +/- 13.0%), Neck (7.3% +/- 11.1%), Wards (4.6% +/- 5.9%), Troch (4.5% +/- 3.2%) (mean +/- s) versus decreases of 2.0% +/- 4.5%, -0.9% +/- 6.9%, 3.6% +/- 4.9% and 1.14% +/- 6.0% with placebo (P < 0.05). Blood Ca, P, ALP, BGP and Urine Pyd/C were no significant difference between before and after therapy. There were usually mild and transient side-effect, such as gastrointestinal symptoms. Alendronate is an efficacy and safety drug in treatment of osteoporosis.

Mortality and morbidity associated with osteoporosis drug treatment following hip fracture

This study examined post-fracture osteoporosis drug treatment in hip fracture patients and the association of treatment with mortality and morbidity. Pre- and post-fracture demographic/health information was collected on a cohort of hip fracture patients aged 65+ years. Post-fracture administrative data on prescription drug use and health care utilization was linked to the cohort data. Five classes of osteoporosis drugs were available during the study period: hormone replacement therapy (HRT), bisphosphonates (BSP), calcitonin, selective estrogen receptor modulators (SERMs) and vitamin D(3) (Rocaltrol). Pre-fracture, 38 of 449 patients (8%) were on osteoporosis medications. Post-fracture, 81 of 356 patients (23%) were treated; 63 of these patients were untreated prior to fracture. Both treated and untreated patients had similar rates of subsequent hip fracture (6% and 4%, respectively) and Colles fracture (2%). Regardless of treatment status, patients were also equally likely to be hospitalized, both in the short-term (28% in treated, 27% in untreated) and in the long-term (43% versus 37%). However, mortality was significantly lower in the treated group. The lower mortality in the treated group, combined with the knowledge that antiresorptive drugs reduce fractures and increase bone density, merit undertaking a randomized trial to confirm our findings that antiresorptive therapy should be considered in all patients post-hip fracture.

Women’s Willingness to Pay Out-of-Pocket for Drug Treatment for Osteoporosis Before and After the Enactment of Regulations Providing Public Funding: Evidence from a Natural Experiment in Israel

This study examines women's willingness to pay (WTP) for drug treatment for osteoporosis before and after the enactment of regulations approving public funding for the drugs and for a hypothetical more effective but not funded drug. One hundred and nine postmenopausal women recruited sequentially from a large bone metabolism outpatient clinic in central Israel were asked by telephone interview to report their maximum WTP out-of-pocket for a drug that would reduce the risk of hip fracture by 50% in four hypothetical cases varying by the level of risk described. Additionally, after the regulations, responses were elicited also for a hypothetical more effective drug. Information regarding participants' sociodemographic and health characteristics, as well as their knowledge of osteoporosis, was also collected. Women would pay considerable sums of money (between 85% to 124% of the price of the drugs) for osteoporosis treatment and these sums increase significantly as the risk of suffering a hip fracture increases. After the enactment of the regulations, women were still willing to pay 54% to 100% of the price of the drugs out-of-pocket. Increased WTP after the regulations was associated with increased ability to pay and to lower levels of knowledge of the disease. After the enactment, participants' WTP for a more effective drug was no different from their WTP for a less effective drug. WTP measures show relative stability over time. The dissemination of information regarding policy or regulatory changes should be encouraged in order to ensure rational decision-making processes.

Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates.

Alendronate has been approved as a first antiresorptive drug for treatment of osteoporosis in men. Except for fluoride, in some countries so far there has been no approved anabolic substance for the treatment of male osteoporosis. From small studies in men and male patients included in studies on postmenopausal osteoporosis there is sufficient evidence that fluoride has the same osteoblast-stimulating potency in men and women. In our own study on 64 men with idiopathic osteoporosis without prevalent fractures, a low-dose intermittent fluoride regimen (15 mg fluoride ions 3 months on, 1 month off) resulted in an average gain of lumbar spine BMD of 3% per year and a lower rate of incident fractures as compared with patients treated with calcium only. A combination of fluoride with an antiresorptive drug may improve the therapeutic results in terms of pattern of biochemical marker response and gain in BMD. This was shown for postemopausal osteoporosis in several studies using fluoride and hormone replacement therapy (HRT). Encouraged by a Dutch study using etidronate/fluoride in corticoid-induced osteoporosis, we performed a pilot study in 33 men with severe established primary osteoporosis giving cyclically etidronate for 14 days followed by fluoride plus calcium/vitamin D for 76 days. This combined regimen resulted in significantly higher increases of BMD than fluoride or etidronate alone. In an ongoing trial we are studying a continuous, combined treatment of alendronate and fluoride plus calcium/vitamin D in established idiopathic osteoporosis in men. The results of a preliminary evaluation look very promising. A large study with a bisphosphonate plus fluoride, taking fractures as the primary endpoint and bone biopsies to assess safety, would be very valuable.

Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines.

Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis.

Current and potential future drug treatments for osteoporosis.

There has been a major interest in the drug treatment of osteoporosis and an increase in the number of drugs available in most countries. The ideal drug (one which increases or restores bone density and trabecular connectivity) is still not available. However, in patients with relatively preserved trabecular connectivity and moderately reduced bone density, several agents have shown substantial clinical benefit. Oestrogens are still the mainstay of drug treatment, but the risks of breast cancer versus the cardiovascular and skeletal benefits with long term use have to be assessed in the individual. Newer tissue specific oestrogens show some promise in this respect. The bisphosphonates and possibly fluoride are likely to be the major alternatives to oestrogens in the medium term. The newer bisphosphonates, alendronate and in the future risedronate, are likely to supersede etidronate. Calcitriol probably has a limited role, confined to those patients in whom HRT or bisphosphonates are not appropriate. Calcium supplementation, or an increase in dietary intake if deficient, irrespective of which agent is used, is also of benefit. In older patients there is considerable support for using a combination of calcium and vitamin D. Whether combination treatment, for example oestrogens, bisphosphonates, and calcium together, will result in greater efficacy remains to be conclusively shown, but may be an attractive option in younger patients with higher bone turnover. Apart from fluoride, bone formation stimulators are unlikely to have a major role until the next century, although it may be possible to use growth factors as part of an ADFR regimen (A = activate remodelling, D = depress resorption, F = free formation, and R = repeat). This is still an important theoretical approach and needs further work with newer agents to see if increased efficacy can be found. In addition sequential treatment may be necessary in view of the limited time periods over which particular agents, such as intermittent fluoride (four years), have been examined, and this will have to be individually tailored. Other approaches include trying to increase peak bone mineral density, although influencing the young to prevent a disease that may not manifest itself for half a century is daunting.

骨粗しょう症治療薬の臨床薬理学 骨吸収抑制剤 ビスホスフォネートとカルシトニンの作用機序

骨粗しょう症治療薬の臨床薬理学 骨吸収抑制剤 ビスホスフォネートとカルシトニンの作用機序

骨粗しょう症治療薬の臨床薬理学 治療薬の効果判定と新薬開発のガイドライン

骨粗しょう症治療薬の臨床薬理学 治療薬の効果判定と新薬開発のガイドライン

骨粗しょう症治療薬の臨床薬理学 骨形成促進剤

骨粗しょう症治療薬の臨床薬理学 骨形成促進剤

骨粗しょう症治療薬の臨床薬理学 骨のリモデリングとその調節因子

骨粗しょう症治療薬の臨床薬理学 骨のリモデリングとその調節因子