Combination anabolic and antiresorptive therapy for osteoporosis: Opening the anabolic window

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities in addition to increasing bone mass. The only anabolic agent currently approved for osteoporosis by the US Food and Drug Administration, teriparatide (recombinant human parathyroid hormone [1–34]), has emerged as a major approach to selected patients with osteoporosis. Recombinant human parathyroid hormone (1–84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture, and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect to stimulate processes associated with bone formation before it stimulates processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents have led to ways in which the anabolic window can be expanded.     

Recommendations for monitoring antiresorptive therapies in postmenopausal osteoporosis

Antiresorptive agents are effective in preventing and treating postmenopausal osteoporosis, provided they are taken as directed. Regular physical examinations including height measurements may fail to ensure optimal compliance. Bone mineral density (BMD) measurement is indispensable for determining whether treatment is warranted. The measurement can be repeated after 2 years at least, provided quality-control procedures are adequate. BMD changes over time should be compared to the least significant change calculated from the in vivo BMD reproducibility at the measurement center. However, BMD changes are not correlated with the fracture risk reduction induced by antiresorptive treatment. Biochemical markers for bone turnover can be monitored after only 3-6 months provided steps are taken to control for intraindividual variability. They are useful when patient compliance is poor or the treatment response inadequate.     

抗骨吸收和促骨形成药物在骨质疏松症治疗中的联合应用

骨质疏松症是一种以骨量减少、骨组织细微结构受损,导致脆性骨折为特征的一种常见疾病。随着人类寿命延长和老年人口的增加,骨质疏松症患病率持续增高,且所致的疼痛和骨折严重影响患者的生活质量,故骨质疏松症的治疗非常重要。目前抗骨质疏松症药物的疗效和安全性比较明确,是防治骨质疏松症的主要手段,但临床上发现单药治疗作用有限,基于不同的作用机制,有学者提出抗骨质疏松症药物的联合治疗。本文针对抗骨质疏松症药物中的两类即抗骨吸收和促骨形成药物之间的联合应用进展做一综述。     

Combination/sequential therapy in osteoporosis

Combination therapy includes the concomitant or sequential use of compounds sharing the same mode of action (eg, two or more inhibitors of bone resorption) or with distinct pathways of activity (eg, an inhibitor of resorption plus an anabolic agent). Combination use of antiresorptive agents may generate concerns, because of the risk of inducing oversuppression of bone turnover. However, if low doses of estrogen, used for the management of climacteric symptoms, are insufficient to normalize bone turnover, the addition of a bisphosphonate to hormone therapy may prove to be useful to achieve this objective. Patients pretreated with inhibitors of resorption, who have not achieved a full therapeutic response, are good candidates for treatment with anabolic agents. The increase in bone turnover that comes after the introduction of parathyroid hormone (PTH) in patients treated with an antiresorptive agent is similar to that observed in treatment-naíve patients and the pattern of bone mineral density (BMD) increase is also identical, with the exception of a 6 month delay in the spine and hip BMD changes observed in prior alendronate-treated subjects. Current data discourage the concomitant use of alendronate and PTH since the bisphosphonate appears to blunt (in men and women) the anabolic action of PTH. Whether this applies to other bisphosphonates or inhibitors of resorption, remains unknown. The use of an inhibitor of bone resorption after completion of PTH treatment seems an appropriate way to maintain the skeletal benefits gained during therapy. Long-term clinical studies, using fractures as an endpoint should be initiated to better understand the clinical and pharmaco-economic interest of combination therapies in the management of osteoporosis.     

Bone turnover and bone collagen maturation in osteoporosis: effects of antiresorptive therapies

Summary Bone collagen maturation may be important for anti-fracture efficacy as the reduction in risk is only partly explained by a concomitant increase in BMD during anti-resorptive therapy. Different treatments caused diverse profiles in bone collagen degradation products, which may have implications for bone quality. Introduction The aim of the present study was to evaluate the effect of different anti-resorptive treatments on bone collagen maturation measured as the ratio between the degradation products of newly synthesized and mature isomerized C-telopeptides of type I collagen. Methods Participants were from cohorts of healthy postmenopausal women participating in double blind, placebo-controlled 2-year studies of alendronate, ibandronate, intranasal hormone replacement therapy (HRT), oral HRT, transdermal HRT, or raloxifene (n = 427). The non-isomerized ααCTX and isomerized ββCTX were measured in urine samples obtained at baseline, and after 6, 12, and 24 months of therapy. Results Bone collagen maturation measured as the ratio between ααCTX and ββCTX showed that bisphosphonate treatment induced a collagen profile consistent with an older matrix with a 52% (alendronate) and 38% (ibandronate) reduction in the ratio between the two CTX isoforms vs. 3% and 15% with HRT or raloxifene, respectively. Conclusions Anti-resorptive treatments had different effects on the endogenous profile of bone collagen maturation. Whether that effect on bone collagen has an impact on bone strength independent on the treatment-dependent effect on BMD should be investigated.     

Different effects of antiresorptive therapies on vertebral and nonvertebral fractures in postmenopausal osteoporosis.

In postmenopausal osteoporosis, controlled clinical trials with antiresorptive therapies have shown consistent effects on vertebral fracture incidence while their effects on nonvertebral fractures, especially at the hip, have been reported with some agents, but not others. These discrepancies stress the differences in the pathogenesis of vertebral and nonvertebral fractures as discussed below, and the need to further investigate the mechanisms of action of various antiresorptive agents.     

Validation of urinary calcium isotope excretion from bone for screening anabolic therapies for osteoporosis

Summary

Urinary excretion of calcium tracers in labeled individuals decreases in response to antiresorptive therapy, providing a tool to rapidly screen potential therapies. Using teriparatide, we demonstrate in this study that anabolic therapy also decreases tracer excretion, confirming that this method can also be used to screen potential anabolic therapies.

Introduction

Changes in urinary excretion of calcium tracers from a labeled skeleton may be a rapid and sensitive method to screen potential therapies for osteoporosis. This method has been used to screen antiresorptive therapies, but the effect of anabolic therapies on tracer excretion is unknown.

Methods

Eight-month-old female Sprague Dawley rats (n?=?11) were given 50 μCi ⁴⁵Ca iv. After a 1-month equilibration period, baseline urinary ⁴⁵Ca excretion and total bone mineral content (BMC) were measured. Rats were then treated with 30 μg/kg teriparatide sc per day, a bone anabolic agent, for 80 days. Urine was collected throughout the study and analyzed for ⁴⁵Ca and total Ca, and BMC was measured at the beginning and end of the study.

Results

Teriparatide decreased urinary ⁴⁵Ca excretion by 52.1 % and increased BMC by 21.7 %. The change in bone calcium retention as determined by the ratio of ⁴⁵Ca to total Ca excretion in urine from day 6 through 15 of teriparatide treatment was significantly correlated (p?=?0.036) with the change in BMC after 80 days of teriparatide treatment.

Conclusion

Urinary excretion of calcium tracers from labeled bone is an effective method to rapidly screen potential anabolic therapies for osteoporosis.     

Prevention and treatment of osteoporosis: efficacy of combination of hormone replacement therapy with other antiresorptive agents.

Osteoporosis is a debilitating disease characterized by decreased bone mineral density (BMD) leading to fractures. It primarily affects postmenopausal women and elderly men. Prevention of osteoporosis is very important because present therapies do not have the potential to mend damage to the bone microarchitecture caused by osteoporosis. The first line of prevention and treatment of osteoporosis is hormone replacement therapy (HRT). All of the approved drugs for the prevention and treatment of osteoporosis act as inhibitors of bone resorption; these drugs include HRT, selective estrogen receptor modulators, calcitonin, and bisphosphonates. The latter two drugs have also been shown to prevent fractures. This article discusses data from nine controlled prospective clinical studies. Study 1 was designed to assess the efficacy of combined HRT and bisphosphonate in preventing osteoporosis during the early stages of menopause. This combined therapy increased the lumbar spine BMD by 10.9% and femoral BMD by 7.3% over 4 yr, compared with 6.8 and 4.0% with HRT alone, and 6.8 and 1.2% with bisphosphonate alone. Study 2 was conducted on postmenopausal women with established osteoporosis. These results showed a 10.4 and 7.0% increase in BMD in vertebrae and femora, respectively, compared with 7.3 and 4.8% increases in the HRT group, and 6.8 and 0.9% in the bisphosphonate group. Data from study 3 demonstrated similar findings in that the combination of alendronate and HRT also enhanced BMD values. Studies 4 and 5 assessed the efficacy of the combined therapy of HRT and calcitonin in the prevention of early postmenopausal bone loss. Both studies demonstrated a significant increase in BMD over and above that observed with either HRT or calcitonin alone. Studies 6, 7, and 8 demonstrated that the addition of testosterone to estrogen therapy further increased BMD when compared to estrogen therapy alone, and also prevented the expected decreases in markers of bone formation in early postmenopausal women. Study 9 demonstrated a synergistic effect on BMD in postmenopausal women, when HRT was coadministered with monofluorophosphate. Other combination therapies may also enhance BMD (e.g., the combination of alendronate and parathyroid hormone [PTH]). However, some agents either lose their efficacy or have no added effects on BMD when they are coadministered (e.g., tiludronate and PTH, calcitonin and PTH, calcitonin and anabolic steroids). These studies illustrate that in a subgroup of patients (i.e., patients with high bone turnover and/or severe osteoporosis), specific combination treatments such as HRT with bis-phosphonates, calcitonin, or androgens (and perhaps also with PTH, fluoride, nitric oxide donors) provide additional beneficial effects over a single-drug therapy. Whether these combination therapies are more effective than individual drugs in reducing fractures still needs to be determined.     

Advantages of concurrent use of anabolic and antiresorptive agents over single use of these agents in increasing trabecular bone volume, connectivity, and biomechanical competence of rat vertebrae

The purpose of this study was to evaluate the usefulness of a combination regimen of anabolic and antiresorptive agents in increasing skeletal quantity and quality in comparison to a single-drug regimen with these agents. We examined histomorphometrically and biomechanically the effects of separate and combined administration of intermittent parathyroid hormone (PTH) and estrogen or bisphosphonate on both axial and appendicular skeletons of male Wistar rats, which were 4 months old and weighed approximately 300 g at the beginning of the treatment. The animals were untreated or injected with vehicle, recombinant human PTH(1-84) (PTH; 100 μg/kg daily), 17β-estradiol (E₂, 500 μg/kg every other day), incadronate disodium (YM175, 80 μg/kg every other day), combined PTH and E₂ (PTH + E₂), or a combination of PTH and YM175 (PTH + YM175). After 1 month of treatment, the three groups in which PTH was administered (PTH, PTH + E₂, and PTH + YM175) had significantly higher trabecular bone volume and connectivity in the proximal tibial metaphyses (PTMs) compared with the untreated and vehicle-treated groups, whereas only combination groups (PTH + E₂ and PTH + YM175) showed significant increases in these indices in the lumbar vertebrae. This site-related discrepancy was attributed to the fact that PTH significantly elevated bone resorption not in the PTMs but in the vertebrae. This increased bone resorption in the vertebrae was suppressed by the addition of an antiresorptive agent. As a result, trabecular bone mass, connectivity, and mechanical strength of the vertebrae were significantly increased from control levels only in the concurrent treatment groups (PTH + E₂ and PTH + YM175). The superior skeletal effects of PTH cotherapy over PTH monotherapy were not seen with regard to bone mass, but with increased connectivity and mechanical strength. The concurrent use of PTH and an antiresorptive agent has been shown to be superior to the single use of PTH for enhancing these properties of rat vertebrae, which encourages future research, especially in larger animals.     

2MD, a new anabolic agent for osteoporosis treatment

Introduction 2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) is a new analog of 1α,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) that has unique properties (distinct from 1α,25-dihydroxyvitamin D₃) in stimulating osteoblasts to form bone in culture. This analog has now been extensively tested in aged ovariectomized female rats maintained on a diet adequate in calcium and phosphorus. Methods Retired female rats obtained from Sprague–Dawley were ovariectomized, and were either dosed with vehicle or 2MD at 5–7 ng/kg body weight each day. Results A marked increase in total bone mass resulted during the 28-week study. This increase in bone mass resulted from an increase in both cortical and trabecular bone, with increases to the order of 25% in the cancellous bone. Histomorphometry revealed that 2MD increased bone mass primarily by increasing bone formation. It also revealed little or no effect on bone resorption. The resulting bone is of high quality revealed by histology and biomechanical testing. Conclusion Throughout the study, serum calcium remained within the normal range and thus 2MD shows great promise for the treatment of bone diseases characterized by bone loss, including osteoporosis.     

Combination therapies for deep venous thrombosis

Nearly 1 million patients are treated for deep venous thrombosis annually in the United States, typically with anticoagulant therapy alone. While anticoagulation reduces risk for pulmonary embolism, up to two-thirds of patients experience some degree of postthrombotic syndrome. This review details the recent introduction of a variety of novel mechanical thrombectomy devices that, in combination with local delivery of thrombolytic agents, offers a new approach for rapid and effective removal of venous thrombus, while minimizing attendant risks of bleeding complications.     

Nutrition and anabolic agents in burned patients

PURPOSE OF REVIEW: Much of the morbidity and mortality of severely burned patients is connected with hypermetabolism and catabolism with its accompanying impairment of wound healing and increased infection risks. In order to prevent the erosion of body mass, nutritional support and other strategies to prevent catabolism have become a major focus in the care of severely burned patients. RECENT FINDINGS: Major themes discussed in recent literature are dealing with enteral versus parenteral nutrition and gastric versus duodenal feeding. The possibility of overfeeding is another important aspect of high calorie nutrition as commonly used in burned patients. Specific formulas for enteral nutrition for specific metabolic abnormalities are under evaluation as well as the role of anabolic and anticatabolic agents. SUMMARY: From the clinical literature, total enteral nutrition starting as early as possible without any supplemental parenteral nutrition is the preferred feeding method for burned patients. Using a duodenal approach, especially in the early postburn phase, seems to be superior to gastric feeding. Administration of high calorie total enteral nutrition in any later septic phase should be critically reviewed due to possible impairment of splanchnic oxygen balance. Therefore, measurement of CO(2)-gap should be considered as a monitoring method during small bowel nutrition. The impact on the course of disease of supplements such as arginine, glutamine and vitamins as well as the impact of the use of anabolic and anticatabolic agents is not yet evident. Furthermore, the effect of insulin administration and low blood sugar regimes on wound healing and outcome in burned patients should be evaluated in future studies.     

抗骨质疏松症药物序贯治疗研究现状

骨质疏松症是一种常见的全身性骨骼疾病,其造成的骨折等一系列临床终末事件正严重影响着我国国民健康水平。目前抗骨质疏松药物长程用药的风险、疗效尚不明确,骨质疏松症的慢病管理面临挑战。近年来许多临床研究表明不同类型药物的序贯治疗可以有效改善患者的骨密度、降低骨折风险,序贯治疗已经成为治疗骨质疏松症的重要手段,但是具体的序贯方案还有待进一步研究、探讨。笔者旨在对近年来抗骨质疏松药物序贯治疗的重要研究成果进行归纳总结,为临床工作提供参考和借鉴。     

Combination therapy for osteoporosis: Considerations and controversy

Combination therapy, the simultaneous use of two pharmaceutical agents with the goal being reduction of fracture risk, is an area of substantial clinical interest. This paper summarizes the rationale, existing clinical trials data, and other considerations relevant to combination therapy for osteoporosis. Combinations of antiresorbers (eg, estrogen plus bisphosphonates) produce greater increases in bone mass than either treatment alone. Conversely, combining anabolic agents (parathyroid hormone) with bisphosphonates does not produce additive effects. None of the existing studies are large enough to determine whether combination treatment reduces fracture risk to a greater extent than use of a single agent. However, it is certain that combination treatment will increase cost and likely that it will increase side effects and reduce therapy adherence. Given the absence of demonstrated fracture reduction benefit, increased cost and likely increase in adverse events, combination therapy is not currently recommended.