Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis

Bisphosphonate inhibition of bone resorption was proposed to be due to osteoclast apoptosis. We tested this hypothesis for both the N-containing bisphosphonates alendronate and risedronate, which inhibit farnesyldiphosphate synthase and thus protein isoprenylation, and for clodronate and etidronate, which are metabolized to adenosine triphosphate (ATP) analogs. We found, in dose-response studies, that alendronate and risedronate inhibit bone resorption (in pit assays) at doses tenfold lower than those reducing osteoclast number. At an N-bisphosphonate dose that inhibited resorption and induced apoptosis, the antiapoptotic caspase inhibitor, Z-VAD-FMK, maintained osteoclast (Oc) number but did not prevent inhibition of resorption. Furthermore, when cells were treated with either alendronate alone or in combination with Z-VAD-FMK for 24 or 48 h, subsequent addition of geranylgeraniol, which restores geranylgeranylation, returned bone resorption to control levels. On the other hand, Z-VAD-FMK did block etidronate and clodronate inhibition of resorption. Moreover, in cells treated with etidronate, but not alendronate or risedronate, Z-VAD-FMK also prevented actin disruption, an early sign of osteoclast inhibition by bisphosphonates. These observations indicate that, whereas induction of apoptosis plays a major role in etidronate and clodronate inhibition of resorption, alendronate and risedronate suppression of bone resorption is independent of their effects on apoptosis.     

The effects of disodium ethane-1-hydroxy-1, 1-diphosphonate on adjuvant induced arthritis in rats

Freund's Adjuvant, consisting of deadMycobacterium butyricum suspended in mineral oil, produces an arthritic response in rats which resembles certain forms of arthritis in man. The arthritic response consists of soft tissue inflammation, pannus formation and two separate osteopathies; accelerated bone resorption and abnormal periarticular bone formation. Disodium etidronate administered at 4 mg/kg/day subcutaneously from the time of adjuvant injection markedly inhibited bone resorption, pannus formation, inflammatory erosion of cartilage, and the pathologic bone formation associated with the adjuvant model. When the disodium etidronate treatments were discontinued, the pathologic bone formation became radiologically visible within two weeks after cessation of treatment. The role of disodium etidronate in controlling bone resorption and surrounding tissue concentration of calcium and phosphate and the relation to arthritic processes in this rat model are discussed. The data suggest a potential use of disodium etidronate in some forms of human arthritis.Presented orally, in part, at the VIIIth European Symposium on Calcified Tissues, Jerusalem, Israel, April 1, 1971.     

Preclinical pharmacology of alendronate

This brief review summarizes some of the preclinical findings of studies aimed at assessing the efficacy and safety of the aminobisphosphonate alendronate (ALN) in preventing or restoring the bone loss caused by calcium or estrogen deficiency. Mode of action studies show that ALN localizes at sites of bone resorption and inhibits osteoclastic activity. In secondary hyperparathyroidism caused by calcium-deficient diets in the rat, ALN reduced the bone loss. For low doses, daily administration proved most efficient. In ovariectomized rats, ALN both prevented and reversed the bone changes produced by estrogen deficiency at oral doses equivalent to 0.1 mg/kg per day or higher, and also maintained the mechanical strength of vertebrae. In ovariectomized baboons, which show bone changes similar to those seen in ovariectomized women, ALN also prevented the increase in bone turnover and increased both bone volume and bone strength in vertebrae. In a comparative study between ALN and etidronate, we found that ALN was 1000-fold more potent in inhibiting bone resorption and had at least a 1000-fold higher safety margin with respect to inhibition of mineralization and osteomalacia.     

Remodeling and vascular spaces in bone.

In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed.     

The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism

The 'calcitonin family' is a group of peptide hormones that share structural similarities with calcitonin, and includes calcitonin gene-related peptide (CGRP), amylin, adrenomedullin and adrenomedullin 2 (intermedin). These hormones are produced by different tissues, with calcitonin being produced in thyroid C cells, alphaCGRP predominantly in neural tissue, amylin in beta-islet cells of the pancreas and adrenomedullin in many tissues and cell types. Bone appears to be a common target for all the peptides of the calcitonin family, although the specific bone effects of the peptides vary. Administration of calcitonin produces rapid lowering of serum calcium levels, mainly through inhibition of bone resorption by osteoclasts. In vitro and in a number of animal experimental models, amylin and CGRP are also effective in inhibiting osteoclast activity and bone resorption. Amylin, adrenomedullin and CGRP can also affect cells of the osteoblast lineage, inducing osteoblast proliferation and promoting bone formation. Receptors for the peptides of the calcitonin family are formed by heterodimerization of the calcitonin receptor (CTR) or calcitonin receptor-like receptor (CLR) with receptor activity modifying proteins (RAMPs). Although the different combinations of these proteins create receptors with distinct ligand specificities, there is a degree of cross-reactivity and the receptors are able to bind other ligands from the family, usually with lower affinity. Analysis of the expression of the receptors for the calcitonin family in 16 samples of human osteoblasts showed high levels of CLR and RAMP1, low levels of RAMP2 and no expression of RAMP3 or CTR. Recent studies of the bone phenotype of knockout animals lacking the calcitonin, alphaCGRP or amylin gene indicated that in this experimental system the main physiological role of amylin in bone is the inhibition of bone resorption, that of CGRP is the activation of bone formation, while calcitonin, unexpectedly appears to be inhibiting bone formation without affecting bone resorption. Further investigations will be required to determine the mechanisms of action of calcitonin peptides in bone and their significance to human bone physiology.     

Calcium homeostasis

Precise maintenance of the physiologic levels of both extracellular and intracellular ionized calcium is essential to life. Calcium and phosphate homeostasis is complex, yet three important hormones are responsible for modulating most of the extracellular control of these minerals. Parathyroid hormone acts directly on bone and kidney and indirectly on the intestine to maintain or restore the serum calcium level. The signal for increased PTH synthesis and secretion is a decrease in the serum ionized calcium concentration and a decrease in serum levels of 1,25(OH)2-D. Calcitonin is produced in parafollicular cells of the thyroid and inhibits bone resorption in pharmacologic doses. These cells recognize the calcium signal in a different way. A diminution in serum calcium decreases calcitonin production and release. The role of calcitonin in normal human physiology, however, remains in dispute. Finally, the biologically potent metabolite of vitamin D, 1,25(OH)2-D, stimulates intestinal absorption of calcium and phosphate. It also probably plays a role in the orderly mineralization and resorption of bone and has some influence on renal resorption of filtered calcium and phosphorus. A major stimulus to its production by proximal renal tubule cells is elevated PTH and decreased serum levels of calcium and phosphate. The absence of PTH as well as high serum calcium and phosphate levels can reduce its synthesis and secretion. These three hormones along with other mediators and messengers work in concert to maintain the normal calcium homeostasis. A disturbance at any level in this intricate regulatory network will result in a host of compensatory changes that may lead to clinical disease. A complete understanding of these normal mechanisms is a prerequisite to investigating the etiology and treatment of the various pathologic responses seen with many of the metabolic bone disorders.     

Effects of Risedronate,Alendronate, and Etidronate on the Viability and Activity of Rat Bone Marrow Stromal Cells In Vitro

The effects of risedronate, alendronate, and etidronate were assessed in calcifying fibroblastic colony-forming unit (CFU-f) cultures of rat bone marrow cells in vitro. Biphasic effects on the formation of bone-like colonies were observed. Treatment with high concentrations (10(-5)-10(-4)M) of alendronate and risedronate caused a total inhibition of colony formation whereas etidronate had relatively little effect. It was also found that intermediate concentrations (10(-6)M) of alendronate and risedronate decreased the formation of colonies displaying osteoblastic characteristics such as alkaline phosphatase expression, collagen accumulation, and calcification. At lower concentrations (10(-9)-10(-7)M), risedronate and alendronate increased the formation of fibroblastic colonies, suggesting a mild anabolic effect, however, the formation of colonies with osteoblastic properties was not affected. Treating the cells with a combination of bisphosphonate and 1 mM geranylgeraniol could to some extent abrogate the cytotoxic effects of alendronate or risedronate, suggesting the involvement of the mevalonate pathway. The colony-stimulating activity of these bisphosphonates was, however, unaffected.     

Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study

Sodium etidronate is a diphosphonate compound that inhibits bone resorption and mineralization. The drug has been reported to be highly effective for the palliation of painful bone metastasis from prostatic cancer. Fifty-seven patients were entered into a randomized, prospective, double-blind, placebo-controlled study of sodium etidronate. All patients had hormone refractory metastatic prostatic cancer and bone pain requiring analgesics. No difference was seen in the symptomatic response rate or analgesic requirement between patients treated with sodium etidronate and placebo. With the dose scheme used in this study sodium etidronate was ineffective for palliation of bone pain from prostatic cancer.     

Mechanisms underlying the effects of phosphate and calcitonin on bone histology in postmenopausal osteoporosis

The aim of this study was to evaluate the mechanism underlying the beneficial effect of phosphate combined with calcitonin on trabecular bone mass in postmenopausal osteoporosis. Histomorphometric parameters of trabecular bone formation and resorption were assessed blindly on sections from tetracycline-labeled iliac crest bone biopsies from 44 women with postmenopausal osteoporosis obtained before and after 6 months of treatment with phosphate (n = 9), calcitonin (n = 13), combined therapy (n = 13), or double placebos (n = 9). Treatment with phosphate (1.5 g/day) increased the osteoblastic surface in correlation with the fractional trabecular surface with double tetracycline labeling. The mean wall thickness of the basic structural units increased significantly only in the two groups of patients treated with phosphate. Thus, oral phosphate therapy stimulated bone formation by increasing both the bone-forming surfaces and bone matrix production. The mean interstitial bone thickness, which is inversely related to the depth of resorbing cavities, was increased in the two groups treated with calcitonin (50 IU X 5 days every third week), indicating that calcitonin therapy partially inhibited the resorbing activity of osteoclasts. The combination of calcitonin and phosphate produced a reduction in bone resorption associated with a stimulation of bone matrix production. This effect resulted in a 22.1% increase in the thickness of the trabeculae and a 31.1% increase in trabecular bone volume. The data show that calcitonin combined with phosphate increased the trabecular bone volume in postmenopausal osteoporosis through reduction of bone resorption associated with stimulation of bone formation along the trabecular bone surface.     

Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro

Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20-100 microM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ss-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage.     

Association of serum calcitonin with coronary artery disease in individuals with and without chronic kidney disease

Background

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Recent data implicate disordered bone and mineral metabolism, including changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and fetuin A, as novel risk factors for arterial calcification. The potential role of calcitonin, another hormonal regulator of mineral and bone metabolism, has not been studied in detail.

Materials and methods

We investigated the link between serum calcitonin and the total burden of coronary artery disease (CAD) using the validated Gensini score, in a cross-sectional study of 88 patients with estimated GFR (eGFR) between 46 and 87?ml/min/1.73?m2 who underwent coronary angiography. We evaluated the associations between serum calcitonin, minerals (calcium, phosphate), calcium?×?phosphate product, and other factors that regulate mineral metabolism (intact PTH, 25-OH-vitamin D, FGF-23, and fetuin A) and the severity of CAD.

Results

The mean serum calcitonin was 11.5?±?7.8?pg/ml. In univariate analysis, the Gensini CAD severity score correlated significantly with male gender, eGFR, and serum levels of 25-OH-vitamin D, iPTH, FGF-23, fetuin A, and calcitonin (R?=?0.474, P?=?0.001 for the latter). In multivariate analysis adjusted for calcium, phosphate, 25-OH-vitamin D, iPTH, FGF 23, fetuin A, and calcitonin, only calcitonin (???=?0.20; P?=?0.03), FGF-23, fetuin A, and 25-OH-vitamin D emerged as independent predictors of Gensini score. In the second step, we adjusted for the presence of traditional risk factors, proteinuria, and GFR. After these adjustments, the FGF-23 and fetuin A remained statistically significant predictors of the Gensini score, while calcitonin did not.

Conclusions

Our study suggests that, in addition to other well-known components of mineral metabolism, increased calcitonin levels are associated with greater severity of CAD. However, this relation was not independent of traditional and nontraditional cardiovascular risk factors. Longitudinal studies in larger populations including patients with more advanced CKD are needed.     

Alendronate inhibits urinary calcium microlith formation in a three-dimensional culture model

Osteoporosis is associated with the pathogenesis of urinary stone formation. Urinary stones are similar to bone diseases such as osteoporosis and bone metabolism in terms of pathogenesis. Bisphosphonates are potent inhibitors of bone resorption, and are used in the management of bone disease. Furthermore, bisphosphonates have a strong affinity for calcium, and a reported inhibitory effect on calcium oxalate crystallization in vitro. Thus, bisphosphonates might also inhibit urinary stone formation. Madin-Darby canine kidney (MDCK) cells form calcium phosphate microliths at the basolateral side in vitro. We investigated the inhibitory effects of new generation bisphosphonates (alendronate and incadronate) on calcium phosphate microlith formation and on the expression of osteopontin, which is an important urinary stone matrix. MDCK cells formed two types of colonies in three-dimensional soft agar culture; dark colonies containing calcium phosphate microliths and clear colonies free from microliths. We applied purified alendronate and incadronate at concentrations of 10^–11, 10^–9, 10^–7 and 10^–5 M to MDCK cells cultured in three-dimensional soft agar and investigated the efficiency of colony formation and the dark colony ratio (number of dark colonies relative to the total number of colonies). The administration of 10^–9 and 10^–7 M alendronate decreased the dark colony ratio compared with controls, whereas incadronate did not significantly alter this colony ratio compared with controls. The expression of osteopontin in cultured cells was inhibited by the 10^–7 M alendronate administration. The present findings show that alendronate inhibits calcium stone formation, suggesting that it is effective in the prevention of urolithiasis.     

Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD)

The effects of 1.5-2 years oral administration of disodium (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) on bone metabolism were studied in male and female rats. APD was mixed in the food at levels of 500, 2,000 and 10,000 ppm. A dose-dependent increase in metaphyseal bone was found, indicative of continued inhibition of bone and cartilage resorption. APD did not affect mineralization of bone and cartilage, primary bone formation, or periosteal apposition. A short-term metabolic balance study was performed to compare the effects of oral with subcutaneous APD. Absorption of APD was in the order of 0.2%. Oral APD increased absorption of phosphate, probably by complexation of calcium with APD. The excess absorbed phosphate increased phosphaturia and decreased urinary calcium.     

Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates

Bisphosphonates (BPS) inhibit bone resorption and are divided into two classes according to their chemical structure and mechanism of action: nonnitrogen containing BPS such as etidronate and clodronate that are of low potency and inhibit osteoclast function via metabolism into toxic ATP-metabolites and nitrogen-containing BPS (NBPS), such as alendronate and risedronate that inhibit the enzyme of the mevalonate biosynthetic pathway farnesyl pyrophosphate synthase (FPPS), resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton. Previously, studies in various cell types suggested, however, that pamidronate functions by mechanism(s) additional or independent of the mevalonate pathway. To examine if such mechanism(s) are also involved in the action of NBPS on osteoclastic bone resorption, we examined the action of alkyl and heterocyclic NBPS with close structural homology on FPPS/isopentenyl pyrophosphate isomerase (IPPI) activity, on osteoclastic resorption, and on reversibility of this effect with GGOH. As expected, both pamidronate and alendronate suppressed bone resorption and FPPS/IPPI activity, the latter with greater potency than the first. Surprisingly, however, unlike alendronate, the antiresorptive effect of pamidronate was only partially reversible with GGOH, indicating the involvement of mechanism(s) of action additional to that of suppression of FPPS. Comparable results were obtained with the heterocyclic NBP NE-21650, a structural analog of risedronate. Thus, despite an effect on FPPS, the actions on bone resorption of some NBPS may involve mechanisms additional to suppression of FPPS. These findings may lead to identification of additional pathways that are important for bone resorption and may help to differentiate among members of the NBP class which are currently distinguished only according to their potency to inhibit bone resorption.     

Alendronate and Etidronate do not Regulate Interleukin 6 and 11 Synthesis in Normal Human Osteoblasts in Culture

Bisphosphonates exert a potent inhibitory effect on bone resorption. Several studies have been performed, with contradictory results, to ascertain whether the effect of bisphosphonates on osteoclasts could be produced, at least in part, by modulation of the synthesis of resorption-promoting factors by osteoblasts. The aim of this study was to evaluate the effect of etidronate (10-4-10-9 M) and alendronate (10-7-10-12 M) on the production of IL-6 and IL-11 using human osteoblast cultures. Cytokines were quantified by ELISA, and mRNA expression was tested. Treatment with alendronate and etidronate had no effect on the synthesis of IL-6 or IL-11, and IL-6 and IL-11 mRNA levels. These results were obtained both in nonstimulated cultures and in cultures stimulated by means of TNF-a, IL-1b, and TNF-a+IL-1b, with or without FCS. In conclusion, a possible indirect osteoclast-mediated effect of alendronate and etidronate on bone resorption would not be exerted through reduction in osteoblastic synthesis of IL-6 and IL-11.     

Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers.

We describe a sinus, referred to as a bone remodeling compartment (BRC), which is intimately associated with cancellous bone remodeling. The compartment is lined on its marrow side by flattened cells and on its osseous side by the remodeling bone surface, resembling a roof of flattened cells covering the bone surface. The flat marrow lining cells are in continuity with the bone lining cells at the margins of the BRC. We examined a large number of diagnostic bone biopsy specimens received during recent years in the department. Furthermore, 10 patients (8 women and 2 men, median age 56 [40-69] years) with the high turnover disease of primary hyperparathyroidism who were treated with parathyroidectomy and followed for 3 years were included in the histomorphometric study. Bone samples for the immuno-enzyme staining were obtained from an amputated extremity of child. The total cancellous bone surface covered by BRC decreases by 50% (p < 0.05) following normalization of turnover and is paralleled by a similar 50% decrease in remodeling surface (p < 0.05). The entire eroded surface and two-thirds of the osteoid surface are covered by a BRC. BRC-covered uncompleted walls are 30% (p < 0.05) thinner than those without a BRC. This indicates that the BRC is invariably associated with the early phases of bone remodeling, that is, bone resorption, whereas it closes during the late part of bone formation. Immuno-enzyme staining shows that the flat marrow lining cells are positive for alkaline phosphatase, osteocalcin, and osteonectin, suggesting that they are bone cells. The first step in cancellous bone remodeling is thought to be the lining cells digesting the unmineralized matrix membrane followed by their disappearance and the arrival of the bone multicellular unit (BMU). We suggest that the lining cell barrier persists during bone remodeling; that the old lining cells become the marrow lining cells, allowing bone resorption and bone formation to proceed under a common roof of lining cells; that, at the end of bone formation, new bone lining cells derived from the flattened osteoblasts replace the marrow lining cells thereby closing the BRC; and that the two layers of lining cells eventually becomes a single layer. The integrity of the osteocyte-lining cell system is reestablished by the new generation of lining cells. The BRC most likely serves multiple purposes, including efficient exchange of matrix constituents and minerals, routing, monitoring, or modulating bone cell recruitment, and possibly the anatomical basis for the coupling of bone remodeling.     

Effects of calcitonin on bone quality and osteoblastic function

Conclusion In conclusion, there is considerable support for the thesis that, in addition to its inhibitory effects on bone resorption, calcitonin enhances osteoblastic bone formation both in vitro and in vivo. These data are compatible with the presence of calcitonin receptors in a variety of osteoblast-like cell lines [37]. The chronic effects of calcitonin to increase BMD may be related in part to anabolic osteoblastic actions of calcitonin. Agents that exclusively inhibit bone resorption can cause a secondary decrease in bone formation due to the coupling of resorption and formation. The putative anabolic osteoblastic effect of calcitonin may be of clinical importance in sustaining the bone formation rate despite inhibition of bone resorption.     

Fluorides and bisphosphonates in the treatment of osteoporosis

The therapeutic aim in osteoporosis to maintain or increase bone mass can be achieved by inhibition of osteoclastic resorption (antiresorptive treatment), stimulation of osteoblastic formation (anabolic treatment), or a combination of both strategies. Antiresorptive therapy of osteoporosis with the nitrogen-containing bisphosphonates alendronate and risedronate is regarded today as evidence-based medicine. A significant reduction in the number of patients with new vertebral fractures has been documented already after 1 year. Anabolic therapy with fluoride was studied less extensively. The low price of fluoride salts and the lack of a patent protection may have contributed to this deficit in large studies. However, several recent medium-sized trials with a low-dose fluoride regimen consistently show a continuous increase in bone density and also a decrease in the rate of new fracture events. In our own pilot study with intermittent etidronate/fluoride therapy, we found significantly additive effects on bone mineral density. A larger trial with this therapeutic strategy using fractures as the primary endpoint would be of great interest.     

DASRR程序治疗131例绝经后骨质疏松症妇女的5年临床研究

目的：观察DASRR程序治疗方案长期治疗绝经后骨质疏松症的疗效。方法：131例绝经后骨质疏松症患，用DASRR方案按程序先用二膦酸盐2周（羟乙膦酸钠）或4周（阿仑膦酸钠），以抑制骨吸收活动；接着用氟化物1个月，以刺激骨形成；再用活性维生素D3及钙剂1个月以加强成骨，停药1个月自发诱导下一个骨代谢周期，再按上述程序重复周期，结果：通过2－12个重复程序的治疗，骨密度（BMD）多呈明显上升趋势，其中腰椎增加13．41％（P＜0．05），双髋部平均BMD增加9．36％（P＜0．05）；骨折率逐年降低，结论：DASRR程序长期治疗绝经后骨质疏公症能更显增加腰椎和髋部BMD，降低新骨折率。     

Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice.

We examined the effects of 60 days of co-treatment of PTH with either OPG or alendronate in oophorectomized mice. Compared with PTH alone, co-treatment of PTH with either of these two mechanistically distinct anti-catabolics improved bone volume, mechanical strength, and appendicular and axial mineralization and prolonged the beneficial effect of PTH on BMD. INTRODUCTION: Conflicting evidence exists as to whether the anabolic effect of PTH is inhibited by the action of anti-catabolics. To examine this issue, we assessed the effects of alendronate and osteoprotegerin (OPG), two anti-catabolics with different modes of action, on the anabolic activity of PTH(1-34) in the skeleton of 4-month-old oophorectomized mice. MATERIALS AND METHODS: Mice treated with vehicle alone (PBS), alendronate alone (100 microg/kg/week), OPG alone (10 mg/kg twice a week), or PTH alone (80 microg/kg/day) were compared with each other and with animals administered PTH plus alendronate or PTH plus OPG. We assessed lumbar spine and femoral BMD at 0, 30, and 60 days. Contact radiography, histology, and histomorphometry, three-point bending assay of the femur, and serum osteocalcin and TRACP5b assays were performed at 2 months. RESULTS: Although alendronate and OPG each suppressed bone turnover, at the doses used, this was more profound with OPG. Increases in lumbar spine and femoral BMD and in trabecular bone volume were at least as great with OPG as with alendronate, and mechanical indices of femoral bone strength improved only with OPG. Both produced a plateau in spine and femoral BMD increases by 30 days. Co-treatment of PTH with each anti-catabolic produced additive increases in BMD in the femur and supra-additive increases in the lumbar spine with no plateau effects. Neither anti-catabolic impeded the PTH-induced increase in bone volume or the increase in mechanical strength of the femur. CONCLUSIONS: These studies show that the highly potent anti-catabolic OPG can produce dramatic increases in BMD and bone strength; that the temporal pattern of activity of bone formation and resorption modulators may have major influence on net skeletal accrual; and that, depending on timing, inhibition of osteoclastic activity may markedly augment the anabolic action of PTH.