The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.
ABSTRACT Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density.
We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine.
The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons).
Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.
SourceAvailable from: sciencedirect.com[Show abstract] [Hide abstract]
ABSTRACT: We examined the individual and combined effects of teriparatide and anti-RANKL (receptor activator of nuclear factor κB ligand) monoclonal antibody in ovariectomized mice. Three-month-old female C57BL/6 mice were ovariectomized (OVX) or sham operated. Four weeks after OVX, they were assigned to 3 different groups to receive anti-RANKL monoclonal antibody (Ab) alone (5 mg/kg single injection at 4 weeks after OVX, Ab group), teriparatide alone (80 μg/kg daily injection for 4 weeks from 4 weeks after OVX, PTH group), or mAb plus teriparatide (Ab + PTH group). Mice were sacrificed 8 weeks after OVX. Bone mineral density (BMD) was measured at the femur and lumbar spine. Hind limbs were subjected to histological and histomorphometric analysis. Serum osteocalcin and CTX-I levels were measured to investigate the bone turnover. Compared with Ab group, Ab + PTH group showed a significant increase in BMD at distal femur and femoral shaft. Cortical bone volume was significantly increased in PTH and Ab + PTH groups compared with Ab group. Bone turnover in Ab + PTH group was suppressed to the same degree as in Ab group. The number of TRAP-positive multinucleated cells was markedly reduced in Ab and Ab + PTH groups. These results suggest that combined treatment of teriparatide with anti-RANKL antibody has additive effects on BMD in OVX mice compared with individual treatment.
[Show abstract] [Hide abstract]
ABSTRACT: Co-administration of antiresorptive and anabolic therapies has appeal because these treatments target the two main abnormalities in bone remodeling responsible for bone loss and microstructural deterioration. Anti-resorptives reduce the number of basic multicellular units (BMUs) remodeling bone and reduce the volume of bone each BMU resorbs. Intermittent parathyroid hormone (PTH) increases the volume of bone formed by existing BMUs and those generated by PTH administration. PTH also increases bone formation by stimulating the differentiation, maturation and longevity of osteoblast lineage cells residing upon quiescent bone surfaces. Despite these rationally targeted actions, enthusiasm for this approach waned when combined therapy blunted the increase in areal bone mineral density (aBMD) relative to that produced by PTH. Although many studies have since reported additive effects of combined therapy, whatever the aBMD result - blunting, additive or null, these outcomes give little, if any, insight into changes in bone's material composition or microstructure, and give misleading information concerning the net effects on bone strength. Combined therapy remains a potentially valuable approach to therapy. As studies of anti-fracture efficacy comparing combined with single therapy are unlikely to be done in humans, efforts should be directed towards improving methods of quantifying the net effects of combined therapy on bone's material composition, microarchitecture and strength. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2015; DOI:10.1002/jbmr.2496 · 6.59 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The Wnt signaling pathway is long known to play fundamental roles in various aspects of embryonic development, but also in several homeostatic processes controlling tissue functions in adults. The complexity of this system is best underscored by the fact that the mammalian genome encodes for 19 different Wnt ligands, most but not all of them acting through an intracellular stabilization of β-catenin, representing the key molecule within the so-called canonical Wnt signaling pathway. Wnt ligands primarily bind to 10 different serpentine receptors of the Fzd family, and this binding can be positively or negatively regulated by additional molecules present at the surface of the respective target cells. One of these molecules is the transmembrane protein Lrp5, which has been shown to act as a Wnt co-receptor. In 2001, Lrp5, and thereby Wnt signaling, entered center stage in the research area of bone remodeling, a homeostatic process controlling bone mass, whose disturbance causes osteoporosis, one of the most prevalent disorders worldwide. More specifically, it was found that inactivating mutations of the human LRP5 gene cause osteoporosis-pseudoglioma syndrome, a rare genetic disorder characterized by impaired bone formation and persistence of hyaloid vessels in the eyeballs. In addition, activating LRP5 mutations were identified in individuals with osteosclerosis, a high bone mass condition characterized by excessive bone formation. Especially explained by the lack of cost-effective osteoanabolic treatment options, these findings had an immediate impact on the research regarding the bone-forming cell type, i.e. the osteoblast, whose differentiation and function is apparently controlled by Wnt signaling. This review summarizes the most important results obtained in a large number of studies, involving tissue culture experiments, mouse models and human patients. While there are still many open questions regarding the precise molecular interactions controlling Wnt signaling in osteoblasts, it is obvious that understanding this pathway is a key to optimize the therapeutic strategies for treating various skeletal disorders, including osteoporosis.07/2014; 2(22). DOI:10.1186/2052-8426-2-22