The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.     

Defining the role of raloxifene as a therapeutic agent for postmenopausal osteoporosis: focus on its pharmacological properties

In this semiar, I propose to describe the pharmacological properties of raloxifene that provide a basis for its role in the treatment of postmenopausal osteoporosis. These pharmacological properties can be described as providing therapeutic benefits in the following three areas: 1) reduction in bone turnover, 2) increases in bone mineral density, and 3) risk reduction in fractures. While reloxifene shares these effects with conventional bisphosphonates that are in common use for postmenopausal osteoporosis, it exerts its antiresorptive effects through a different mechanism of action from those of the bisphosphonates. Furthermore, raloxifene exerts its stimulatory or inhibitory effects on estrogen in a tissue-specific fashion as a selective estrogen-receptor-modulator (SERM), thereby providing a wide range of clinical benefits that result from its ability to exert estrogen-like beneficial effects in tissues other than bone while at the same time inhibiting estrogen-like deleterious effects in other tissues. I therefore propose to define the role of raloxifene as a viable therapeutic option in the treatment of postmenopausal osteoporosis in light of these unique pharmacological features. Current data suggests that raloxifene can be positioned somewhere in between hormone replacement therapy (HRT) and bisphosphonates, and is highly likely to be suitable for use in patients between the ages of 55 and 70, while other agents may be indicated in special populations, such as premenopausal patients, postmenopausal patients with hot flushes, or elderly patients who may be placed at accelerated risk of developing femoral neck fractures. Thus, as a novel therapeutic option with unique clinical benefits, a far greater role may be expected for raloxifene in the treatment of postmenopausal osteoporosis than for other conventional therapeutic agents.     

Osteocytes: Mechanosensors of Bone and Orchestrators of Mechanical Adaptation

Significant progress has been made in the field of mechanotransduction in bone cells. The knowledge about the role of osteocytes as the professional mechanosensor cells of bone as well as the lacuno-canalicular porosity as the structure that mediates mechanosensing is increasing. New insights might result in a paradigm for understanding the bone formation response to mechanical loading, and the bone resorption response to disuse. Under physiological loading conditions the strain-derived flow of interstitial fluid through the lacuno-canalicular porosity seems to mechanically activate the osteocytes, which subsequently alter the bone remodeling activity of osteoblasts and/or osteoclasts. Fatigue loading results in local microdamage, disruption of normal flow patterns, and osteocyte apoptosis. Apoptotic osteocytes likely attract osteoclasts to resorb the damaged bone. This concept allows explanation of local bone gain and loss, as well as remodeling in response to fatigue damage, as processes supervised by mechanosensitive osteocytes. Uncovering the cellular and mechanical basis of the osteocyte’s response to loading would greatly contribute to our understanding of the cellular basis for bone remodeling, and could contribute to the discovery of new treatment modalities for bone mass disorders, such as osteoporosis.     

骨质疏松症的联合治疗与序贯治疗

联合和序贯治疗骨质疏松症是为了追求更大疗效的一种选择,本文检索分析近45年来发表的此类临床研究结果。目前尚无证据表明两种抗骨吸收联合治疗有降低骨折发生率的叠加作用（如双膦酸盐加ERT或雷洛昔芬,雌激素加降钙素）,仅观察到联合治疗可以降低骨转换和增加骨密度的结果。联合甲状腺激素（PTH）同抗骨吸收药物,随着药物的不同对骨密度的效果各异。在停止使用促进骨形成剂PTH后序贯使用双膦酸盐、雷洛昔芬或锶盐,可以防止因停用PTH后的骨丢失,可能成为未来治疗严重的绝经后骨质疏松症的重要选择。     

Parathyroid hormone analogues in the treatment of osteoporosis

Osteoporosis is characterized by the occurrence of fragility fractures. Over the past years, various treatment options have become available, mostly antiresorptive agents such as bisphosphonates. However, antiresorptive therapy cannot restore bone mass and structure that has been lost due to increased remodeling. In this case, recombinant human parathyroid hormone (PTH) analogues-the full-length PTH(1-84) or the shortened molecule PTH(1-34), which is also known as teriparatide-present the possibility of increasing the formation of new bone substance by virtue of their anabolic effects. The bone formation induced by PTH analogues not only increases BMD or bone mass but also improves the microarchitecture of the skeleton, thereby leading to improved strength of bone and increased mechanical resistance. Controlled trials have shown that both analogues significantly reduce the incidence of vertebral fractures, and PTH(1-34) also reduces the risk of nonvertebral fractures. The need for daily self-injection and the higher cost compared with other forms of treatment limit the widespread use of PTH analogues. Nevertheless, treatment with PTH analogues should be considered in postmenopausal women and men with severe osteoporosis, as well as in patients on established glucocorticoid treatment with a high fracture risk. Concurrent therapy with antiresorptive agents should be avoided, but sequential therapy with these agents might consolidate the beneficial effects on the skeleton.     

Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis

INTRODUCTION: EUROFORS was a 2-yr prospective, randomized trial of postmenopausal women with established osteoporosis, designed to investigate various sequential treatments after teriparatide 20 microg/d for 1 yr. The present secondary analysis examined the effects of 2 yr of open-label teriparatide in women previously treated with antiresorptive drugs for at least 1 yr. METHODS: A subgroup of 245 women with osteoporosis who had 2 yr of teriparatide treatment were stratified by previous predominant antiresorptive treatment into four groups: alendronate (n=107), risedronate (n=59), etidronate (n=30), and non-bisphosphonate (n=49). Bone mineral density (BMD) at the lumbar spine and hip was determined after 6, 12, 18, and 24 months, and bone formation markers were measured after 1 and 6 months. RESULTS: Significant increases in bone formation markers occurred in all groups after 1 month of teriparatide treatment. Lumbar spine BMD increased at all visits, whereas a transient decrease in hip BMD, which was subsequently reversed, was observed in all groups. BMD responses were similar in all previous antiresorptive groups. Previous etidronate users showed a higher increase at the spine but not at the hip BMD. Duration of previous antiresorptive therapy and lag time between stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal site. Treatment-emergent adverse events were similar to those reported in treatment-naive postmenopausal women with osteoporosis treated with teriparatide. CONCLUSIONS: Teriparatide induces positive effects on BMD and markers of bone formation in postmenopausal women with established osteoporosis, regardless of previous long-term exposure to antiresorptive therapies.     

Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women

Postmenopausal osteoporosis is a common clinical entity; its complications represent a significant burden to society. In recent years the choice of therapies available for the treatment of postmenopausal osteoporosis has increased dramatically. There are a number of antiresorptive agents currently available including hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), bisphosphonates, and dual action bone agents. It is difficult to truly compare these therapies given the lack of direct head-to head studies. The efficacy of antiresorptive therapies can be assessed in a number of ways including measurement of bone mineral density (BMD), assessment of bone turnover markers, and fracture reduction. Other important factors include ease of administration and consequent patient compliance. This article reviews the currently available antiresorptive agents and their effects on the above outcome measures.     

Role of estrogens in the management of postmenopausal bone loss

It is well known that estrogen deficiency is the major determinant of bone loss in postmenopausal women. Estrogen is important to the bone remodeling process through direct and indirect actions on bone cells. The largest clinical experience exists with estrogen therapy, demonstrating its successful prevention of osteoporosis as well as its positive influence on oral bone health, vasomotor and urogenital symptoms, and cardiovascular risk factors, which may not occur with other nonestrogen-based treatments. Compliance with HRT, however, is typically poor because of the potential side effects and possible increased risk of breast or endometrial cancer. Nevertheless, there is now evidence that lower doses of estrogens in elderly women may prevent bone loss while minimizing the side effects seen with higher doses of estrogen. Additionally, when adequate calcium, vitamin D, and exercise are used in combination with estrogen-based treatments, more positive increases occur in bone density. The benefits and risks of HRT must be assessed on a case-by-case basis, and the decision to use HRT is a matter for each patient in consultation with her physician. Estrogen-based therapy remains the treatment of choice for the prevention of osteoporosis in most postmenopausal women, and there may be a role for estrogen to play in the prevention of corticosteroid osteoporosis. Combination therapies using estrogen should probably be reserved for patients who continue to fracture on single therapy or should be used in patients who present initially with severe osteoporosis.     

Antiresorptive therapy for osteoporosis and bone quality

In high turnover osteoporosis antiresorptive therapy is effective in increasing the stiffness and the toughness (bone strength) by increasing the mean degree of mineralization of bone tissue through the prolongation of secondary mineralization. But the long-term use of antiresorber would result in highly mineralized bone and disturbed repair of microcracks by inhibition of bone remodeling. Intermittent use of antiresorber could be recommended to avoid the deterioration of bone quality.     

应力负荷与骨骼结构及骨重建的关系

应力负荷是骨质量和骨骼几何形状的主要调节因子.骨细胞信号网络通过感知骨骼力学负荷而发挥作用,是应力负荷的主要传感器.骨细胞死亡后发生骨重建,骨骼力学负荷减小或丧失.骨折后所致长期卧床、局部制动导致骨细胞凋亡和骨吸收,引起严重的骨质疏松.通过分析骨骼适应应力负荷的机制,骨细胞感受机械刺激和骨骼的力学负荷,力学负荷对骨骼的作用和应力负荷与骨重塑过程的分子调控等,可以探讨应力负荷与骨骼结构及与骨重建的关系.     

Salmon calcitonin nasal spray : An effective alternative to estrogen therapy in select postmenopausal women

The efficacy and safety of estrogen replacement therapy (ERT) and salmon calcitonin in the treatment of postmenopausal osteoporosis are reviewed with special consideration given to patients for whom ERT, the primary antiresorptive therapy for osteoporosis, is not indicated, tolerable, or is refused. The various formulations of estrogen and salmon calcitonin, for which the nasal spray formulation was recently approved for use in the United States, are reviewed in depth with reference to dose ranges, side effects, and convenience. Data regarding increases in bone mineral density (BMD) produced by each agent are presented. Specifically, the range of increases in BMD induced by ERT and salmon calcitonin are comparable. Given the substantial public health consequences of postmenopausal osteoporosis and osteoporotic fractures, the primary care physician is increasingly faced with the need to educated and recruit postmenopausal patients to appropriate therapy with the optimal agent for that particular patient. In the many patients who are unable or unwilling to accept, initiate, and comply with prescribed ERT, alternative therapeutic options are necessary Based on the established safety profile of salmon calcitonin, ease of administration, an uncomplicated dosing regimen, no reported drug interactions, and the lack of uterine bleeding associated with ERT or gastrointestinal adverse effects of other agents used to treat osteoporosis, salmon calcitonin nasal spray is an appropriate alternative approach for the treatment of postmenopausal bone loss.     

Raloxifene modulates interleukin-6 and tumor necrosis factor-alpha synthesis in vivo: results from a pilot clinical study

Raloxifene (RAL), a selective estrogen receptor modulator, is indicated for the prevention and treatment of postmenopausal osteoporosis. RAL, by decreasing bone turnover, prevents bone loss and microarchitecture damage, reducing the incidence of osteoporotic fractures. Our previous in vitro data demonstrated that RAL modulates osteoclast activity by, at least in part, an IL-6- and TNF-alpha-dependent mechanism. In this study we evaluated the effects of RAL treatment (60 mg/d) on circulating levels of these cytokines in 14 postmenopausal women with osteoporosis. Lumbar bone density (determined by dual energy x-ray absorptiometry) and IL-6 and TNF-alpha levels were measured before and after 6 and 24 months of therapy. After 24 months, RAL increased bone density. IL-6 and TNF-alpha expression, elevated before treatment, significantly decreased (50% and 30%, respectively) after 6 months. This effect was sustained up to the end of the treatment (75% and 35%, respectively). Thus, our data show that RAL can modulate circulating levels of cytokines involved in osteoclastogenesis and bone resorption, suggesting that modulation of soluble factors could play a pivotal role in the mechanisms of the osteoprotective effect of RAL.     

Estrogen modulates the recruitment of myelopoietic cell progenitors in rat through a stromal cell-independent mechanism involving apoptosis

Loss of ovarian function leads to a significant increase in the number of bone-resorbing osteoclasts. Estrogen replacement is known to manifest bone protective effects in the treatment of postmenopausal osteoporosis. In the present study, we used ovariectomized rats to examine the effects of estrogen loss at the osteoclast progenitor colony forming unit-granulocyte macrophage (CFU-GM) level. A significant increase in CFU-GM number was observed as early as 7 days following ovariectomy, and correlated directly with an increase in the number of osteoclast-like cells generated in marrow cultures. The increase in CFU-GM following ovariectomy was abrogated in animals that received estrogen treatment in vivo. A similar suppressive effect was observed on CFU-GM number when ovariectomized rat marrow was treated with estrogen in vitro. This effect was blocked in the presence of the estrogen antihormone ICI 164,384. Thus, the data suggest the possibility that estrogen exerts a direct effect on osteoclast progenitors, and does so through the estrogen receptor-mediated mechanism. Ovariectomy also led to an increase in the early hematopoietic stem/progenitor cell population (Thy 1.1+ cells) as determined by FLOW cytometry methods. Morphological changes as well as terminal deoxynucleotidyl transferase assays revealed that estrogen treatment negated growth factor-induced proliferation of these early progenitors by promoting apoptosis. The cellular effects of estrogen in vitro together with the immunocytochemical detection of the estrogen receptor in these cells, strongly support the contention that in addition to osteoclast progenitors such as CFU-GM, earlier hematopoietic progenitors are also unique cellular targets for estrogen action.     

Hormone replacement therapy and fractures in older adults

Estrogen deficiency in women is associated with accelerated bone loss, and estrogen replacement therapy has been proven to be effective in preventing osteoporosis and fractures in postmenopausal women. The introduction of selective estrogen receptor modulators that have an estrogen-like effect on the skeleton but have a different pattern of effects on other tissues may have an important role in the management of osteoporosis in women in the near future. In men, androgen deficiency has been shown to be associated with osteoporosis. Although androgen replacement in hypogonadal men may decrease bone resorption and increase bone mass, long-term placebo-controlled trials are needed to better define the benefits and risks of such therapy before it can be recommended. Sex hormone deficiency is linked to the development of osteoporosis in both women and men. In women, hormonal replacement by estrogen or the newly developed selective estrogen receptor modulators may prevent the development of osteoporosis and its related fractures. In men, there is early evidence that testosterone replacement therapy may enhance bone mass in hypogonadal men.     

骨质疏松症治疗新进展

骨转换失衡是骨质疏松症发病的重要病理机制,骨质疏松症的治疗靶点主要集中在抑制破骨细胞活性及增强成骨细胞活性。新型骨吸收抑制剂包括核因子-κB受体活化因子配体（RANKL）的单克隆抗体、组织蛋白酶K抑制剂、新型选择性雌激素受体调节剂、口服降钙素等;新型骨形成促进剂有骨硬化素单克隆抗体、Dickkopf-1单克隆抗体、甲状旁腺激素（PTH）制剂及钙敏感受体拈抗剂等。此外,含有维生素D的复方制剂也是很有应用前景的骨质疏松治疗新药。     

骨质疏松症治疗新进展

骨转换失衡是骨质疏松症发病的重要病理机制,骨质疏松症的治疗靶点主要集中在抑制破骨细胞活性及增强成骨细胞活性.新型骨吸收抑制剂包括核因子-kB受体活化因子配体(RANKL)的单克隆抗体、组织蛋白酶K抑制剂、新型选择性雌激素受体调节剂、口服降钙素等;新型骨形成促进剂有骨硬化素单克隆抗体、Dickkopf-1单克隆抗体、甲状旁腺激素(PTH)制剂及钙敏感受体拮抗剂等.此外,含有维生素D的复方制剂也是很有应用前景的骨质疏松治疗新药.     

Combination therapy for postmenopausal osteoporosis

A number of agents have been shown to reduce the risk of fractures in patients with postmenopausal osteoporosis. However, the additional benefits of combination therapy as opposed to monotherapy are uncertain. We performed a MEDLINE search and reviewed the published randomized trials of agents used in combination. Combination therapy results in greater gains in bone mineral density than monotherapy and possibly greater effects on bone turnover. However, none of these studies are large enough or of sufficient duration to determine whether a greater reduction in fracture is achieved. Combination therapy has important cost implications and is likely to be associated with an increased prevalence of adverse events, reduced tolerability and a reduction in adherence. Furthermore, over-suppression of bone turnover as a result of combination antiresorptive therapy might have adverse effects on bone strength, particularly with long-term treatment. Thus, the use of combination therapy for treatment of osteoporosis cannot be recommended on the basis of currently available evidence.     

Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint

Antiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.     

The Osteocyte as an Orchestrator of Bone Remodeling: An Engineer’s Perspective

Bone is adapted to mechanical loading. The trabeculae in cancellous bone and the osteons in cortical bone are aligned to the mechanical loading direction. Our bones are constantly remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts, cooperating in so-called basic multicellular units or BMUs. In cortical bone, osteoclasts dig tunnels through solid bone, while in cancellous bone, they dig trenches across the trabecular surface. Osteoblasts fill these tunnels and trenches, creating osteons and hemi-osteons, respectively. How mechanical forces guide these cells is still uncertain, but mechanosensitive osteocytes are believed to orchestrate bone remodeling by sending signals to the cells at the bone surface. Computer simulations have demonstrated that local remodeling regulated by mechanosensitive osteocytes indeed produces load-aligned trabeculae and osteons. The strains around a BMU resorption cavity are concentrated at the lateral sides, away from the loading axis. Strain-induced osteocyte signals from these regions likely repel osteoclasts, forcing them to resorb bone in the loading direction, and at the same time, such signals could recruit osteoblasts to start bone formation. Thus, mechanosensitive osteocytes likely regulate the steering of and coupling within BMUs. A region of osteocyte death (therefore, lacking osteoclast-repelling signals) near the path of the BMU redirects its course to resorb this region. This may provide a mechanism for damage removal, because osteocyte death is associated with microdamage. BMUs may also function with disuse-induced osteocyte signals that recruit osteoclasts to the relatively unloaded region in front of the BMU and inhibit osteoblastic bone formation by osteoblast-inhibiting signals such as sclerostin when the tunnel or trench is sufficiently filled.