Teriparatide Increases Bone Formation in Modeling and Remodeling Osteons and Enhances IGF-II Immunoreactivity in Postmenopausal Women With Osteoporosis

Li, Yanfei; Zeng, Qing‐Yin; Donley, David W.; Ste-Marie, Line; Gallagher, J. Christopher; Dalsky, G. P.; Marcus, Robert; Eriksen, Erik Fink

doi:10.1359/jbmr.060314

Cited by 209 publications

(174 citation statements)

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“…Histomorphometric analyses in humans have demonstrated that the increases in bone-forming surfaces with PTH treatment were primarily through remodeling-based mechanisms in short- (19) and longer-term studies. (20) Examination of the impact of sclerostin inhibition on bone resorption and bone modeling warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength

Ominsky

Vlasseros²,

Jolette³

et al. 2010

Journal of Bone and Mineral Research

395

265

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The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. ß

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Section: Discussionmentioning

confidence: 99%

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength

Ominsky

Vlasseros²,

Jolette³

et al. 2010

Journal of Bone and Mineral Research

395

265

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“…(34,35) During the second half of the study, the anabolic effect in the combination group occurred with increased bone remodeling, with formation and resorption marker levels above baseline. (6) One of the potential limitations of PTH treatment is that its stimulatory effect on intracortical bone remodeling can increase cortical porosity. This may not translate into decreased mechanical strength, however, because the porosity is concentrated at the endocortical surface (close to the neutral axis of bone) and may be offset by increased periosteal apposition and increased cortical thickness.…”

Section: Discussionmentioning

confidence: 99%

“…(1)(2)(3)(4) Unlike the bisphosphonates, which reduce bone remodeling, teriparatide is an anabolic agent that stimulates bone formation and increases bone remodeling. (4) While both classes of agents improve bone mineral density (BMD) and reduce fracture risk, teriparatide also improves the microarchitecture of cancellous and cortical bone in the iliac crest, (5)(6)(7) providing even greater improvements in bone strength (as measured by finite-element analysis) than those observed with antiresorptive agents alone. (4,8,9) In one head-to-head comparison of alendronate and teriparatide in patients with glucocorticoid-induced osteoporosis, vertebral fracture (but not nonvertebral fracture) incidence was lower with teriparatide than with alendronate.…”

Section: Introductionmentioning

confidence: 99%

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Cosman

Eriksen

Recknor

et al. 2010

Journal of Bone and Mineral Research

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303

173

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Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 mg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 AE 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 mg (n ¼ 137), zoledronic acid alone (n ¼ 137), or teriparatide alone (n ¼ 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively ( p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone ( p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks ( p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum b-C-telopeptide of type I collagen [b-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone ( p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. ß

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“…Increased bone formation is manifested as early as 28 days as evidenced by a rise in the level of circulating markers of osteoblast function, and an increase in tetracycline-labeled surface in transileal biopsies [7][8][9]. By 6 months, indices of bone resorption have also increased [1,9].…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

608

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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Teriparatide Increases Bone Formation in Modeling and Remodeling Osteons and Enhances IGF-II Immunoreactivity in Postmenopausal Women With Osteoporosis

Cited by 209 publications

References 50 publications

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

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