The Effects of Parathyroid Hormone and Alendronate Alone or in Combination in Postmenopausal Osteoporosis

Black, Dennis M.; Greenspan, Susan L.; Ensrud, Kristine E.; Palermo, Lisa; McGowan, Joan A.; Lang, Thomas; Garnero, Patrick; Bouxsein, Mary L.; Bilezikian, John P.; Rosen, Clifford J.

doi:10.1056/nejmoa031975

Cited by 1,076 publications

(594 citation statements)

References 21 publications

Supporting

Mentioning

537

Contrasting

Unclassified

Order By: Relevance

“…Over the long term, the overall BMD response to PTH in DMAbtreated subjects might be determined primarily by the capacity of PTH to promote trabecular modeling-based bone formation, and hence remain quite modest. At cortical sites, antiresorptive co-therapy with Aln does not appear to significantly blunt PTH-mediated BMD increases (9,10). This outcome might reflect the potential for Aln to reduce cortical porosity and remodeling-based cortical bone formation, which could have offsetting effects on cortical BMD in that population.…”

Section: Discussionmentioning

confidence: 95%

“…Consistent with this notion, PTH was able to increase BMD much If remodeling is indeed important for PTH anabolism, it is important to understand why, under certain conditions, PTH is capable of robustly increasing BMD in mice or rats co-treated with potent antiresorptives such as Aln (28,29,30) or OPG (28,30). This is a particularly important question because the additive effects of PTH and Aln on vertebral BMD in rodents stands in contrast to the blunted vertebral BMD response to PTH plus Aln versus PTH alone in human studies (9,10). One hypothesis is that mice and rats have a greater capacity than humans for PTH stimulation of modeling-based bone formation, which occurs in the absence of prior osteoclast activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Pierroz

Bonnet

Baldock

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover, -i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK ؊/؊ mice. PTH increased osteocalcin similarly in RANK ؊/؊ and WT mice. It also increased BMD in RANK ؊/؊ mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.Parathyroid hormone (PTH), 2 when administered intermittently, increases bone mineral density (BMD) and improves bone microarchitecture and strength (1). PTH induces a rapid increase in markers of bone formation before it also increases bone resorption, which has been described as an "anabolic window" (2). In this window, PTH has been suggested to directly activate bone formation via bone lining cells on quiescent bone surfaces (i.e. modeling surfaces), as indicated by an increase in double tetracycline-labeled surfaces and a smooth cement line (3). PTH subsequently stimulates bone remodeling, first through activation of osteoclastic bone resorption in the basic multicellullar units (BMU), followed by new bone formation by osteoblasts. These remodeling-based BMUs are associated with scalloped cement lines by microscopy. Data from untreated adult rodents indicate that the ratio of bone modeling:remodeling surfaces is less than 1:5 and further decreases with age (4). Although PTH has been shown to increase bone modeling in rodents, the vast majority of bone formation in humans appears to be remodeling-based (5). Data from humans treated with PTH indicate that bone formation on modeling surfaces accounts for only 5-30% of PTH anabolic effects (6). While intermittent PTH can partially restore bone microarchitecture by increasing bone formation in mo...

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Pierroz

Bonnet

Baldock

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It will also be important to investigate whether concurrent or sequential administration of an anti-resorptive treatment in combination with Y2 receptor deletion can allow a more effective anabolic response. Interestingly, recent studies of co-administration of the only available anabolic therapy, parathyroid hormone-(1-34) with anti-resorptive bisphosphonate, indicated that the anti-resorptive treatment may reduce the anabolic potential of parathyroid hormone (24,25).…”

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Allison

Baldock

Sainsbury

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormonedeficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.With age, changes in endocrine function can significantly affect physiological processes often with detrimental effects on health. One of the most substantial changes occurs with menopause in women, with cessation of estrogen production by the ovaries. This abrupt and dramatic decrease in estrogen production results in a number of acute and long term physiological effects, among the most notable of these being the loss of bone leading to the development of osteoporosis and increased deposition of white adipose tissue, contributing to an increased risk of heart disease and associated complications.In the adult skeleton, bone mass and strength are determined by the multicellular process of bone remodeling, in which osteoclastic bone resorption is followed by osteoblastic bone formation. This turnover process is normally tightly coupled, such that the amount of bone resorbed equals the amount of bone formed, maintaining a constant bone mass. Multiple endocrine factors regulate turnover, in particular the sex hormones estrogen and testosterone, which protect bone by exerting anti-apoptotic effects on osteoblasts and pro-apoptotic effects on osteoclasts, in addition to suppressing osteoclast activity through both direct and indirect mechanisms (1, 2). Loss of sex hormones following menopause in women or in hypogonadal males results in increased osteoclast activity and loss of bone mass. Most current osteoporosis treatments inhibit bone resorption; however, although thes...

show abstract

“…In a published study, there was no evidence of synergy between teriparatide and alendronate, and the changes in the density and cortical volume suggested that the concurrent use of alendronate may reduce the anabolic effects of teriparatide 106. The apparent absence of synergistic effect of teriparatide and alendronate should not obscure the potential benefit of using an inhibitor of resorption after treatment with teriparatide.…”

Section: Combination and Sequential Treatmentsmentioning

confidence: 98%

Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective

Raef

Al-Bugami

Balharith

et al. 2011

Annals of Saudi Medicine

View full text Add to dashboard Cite

Postmenopausal osteoporosis and osteoporosis in elderly men are major health problems, with a significant medical and economic burden. Although osteopenia and osteoporosis are more common locally than in the West, fracture rates are generally less than in Western countries. Vitamin D deficiency is common in the region and contributes adversely to bone health. Vitamin D deficiency should be suspected and treated in all subjects with ostopenia or osteoporosis. The use of risk factors to determine fracture risk has been adopted by the World Health Organization and many international societies. Absolute fracture risk methodology improves the use of resources by targeting subjects at higher risk of fractures for screening and management. The King Faisal Specialist Hospital Osteoporosis Working Group recommends screening for women 65 years and older and for men 70 years and older. Younger subjects with clinical risk factors and persons with clinical evidence of osteoporosis or diseases leading to osteoporosis should also be screened. These guidelines provide recommendations for treatment for postmenopausal women and men older than 50 years presenting with osteoporotic fractures for persons having osteoporosis—after excluding secondary causes—or for persons having low bone mass and a high risk for fracture. The Working Group has suggested an algorithm to use at King Faisal Specialist Hospital that is based on the availability, cost, and level of evidence of various therapeutic modalities. Adequate calcium and vitamin D supplement are recommended for all. Weekly alendronate (in the absence of contraindications) is recommended as first-line therapy. Alternatives to alendronate are raloxifene or strontium ranelate. Second-line therapies are zoledronic acid intravenously once yearly, when oral therapy is not feasible or complicated by side effects, or teriparatide in established osteoporosis with fractures.

show abstract

The Effects of Parathyroid Hormone and Alendronate Alone or in Combination in Postmenopausal Osteoporosis

Cited by 1,076 publications

References 21 publications

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective

Contact Info

Product

Resources

About