The Effects of Parathyroid Hormone, Alendronate, or Both in Men with Osteoporosis

Finkelstein, Joel S.; Hayes, Ann-Marie; Hunzelman, Joy L.; Wyland, Jason J.; Lee, Hang; Neer, Robert M.

doi:10.1056/nejmoa035725

Cited by 771 publications

(455 citation statements)

References 31 publications

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“…(20) Similar results were reported in other clinical trials, which also showed little or no incidence of hypercalcemia within 24 hours after teriparatide injection. (26,28,29,79,80) In a post hoc analysis, Miller and colleagues (81) showed a significantly higher incidence of hypercalcemia in patients with moderate renal impairment (glomerular filtration rate [GFR] 30-49 mL/min).…”

Section: Hypercalcemia and Hypercalciuriamentioning

confidence: 99%

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

130

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IntroductionO steoporosis is a prevalent disease that affects more than 10 million Americans. The lifetime risk of an osteoporosisrelated fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture. (1) The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life.Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone and PTH(1-84)]. The fulllength PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1-84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval came with restrictions in duration of therapy (18-24 months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. The effects on rats was doseand duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose. (2) Similar toxicity was seen for PTH(1-84) (3) Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a ''black box warning'' and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget's disease of bone, prior skeletal radiation, and children with open epiphyses.Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1-84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term ¼ sclerostin þ anti-þ antibody). PTH mechanisms of actionTeriparatide is an amino-terminal fragment of PTH that is biologically identical to the amino-terminal fragment of human PTH. This fragment contains all the classical bio...

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Section: Hypercalcemia and Hypercalciuriamentioning

confidence: 99%

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

130

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“…(44) Other studies evaluating combination therapy with teriparatide and bisphosphonates enrolled patients in whom bisphosphonates were given prior to the introduction of teriparatide treatment. In one trial, (23) alendronate was given for only 6 months prior to the introduction of teriparatide. In that study, after 1 year of teriparatide treatment, results for the combination group and the teriparatide-alone group were quite similar to those seen in this study.…”

Section: Discussionmentioning

confidence: 99%

“…(3,13,23) Also, this study did not include other endpoints beyond DXA (e.g., QCT and finite-element modeling for bone strength or assessments of bone structure, such as bone biopsy or highresolution computed tomography). The zoledronic acid arm was not blinded, owing to the lack of teriparatide placebo; however, those who assessed endpoints in this study were blinded to the treatment assignment, and these were objective parameters.…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies evaluating combinations of PTH or teriparatide with antiresorptive agents have yielded inconsistent results, with differences related to which antiresorptive agent is used, (16)(17)(18)(19)(20)(21)(22) whether patients are treatment-naive or have been on antiresorptive therapy when combination treatment is started, (14,23) and, for patients on prior antiresorptives, whether the antiresorptive agent is continued or stopped when teriparatide is added. (24) In one study, (14) treatment-naive patients were randomized to alendronate or intact PTH(1-84) monotherapy versus combination therapy.…”

Section: Introductionmentioning

confidence: 99%

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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

303

172

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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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“…In the second, the effect of intermittent PTH treatment on cell proliferation within the ossicles was measured using luciferase tagged BMSCs in conjunction with in vivo bioluminescent imaging (BLI). Recent clinical studies conducted to evaluate the benefits of using combination therapy for postmenopausal osteoporosis treatment revealed the surprising findings that bisphosphonates blunted expected additive effects when used concurrently with PTH [12][13][14]. Hence, in the third strategy, PTH and bisphosphonate treatment were combined to gain new insight of how these two agents affect the pool of bone forming cells that facilitate new bone development.…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

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PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40μg/kg/d) or vehicle treatment initiated 1 day, 1, 2, or 3wks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and microCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggests that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

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The Effects of Parathyroid Hormone, Alendronate, or Both in Men with Osteoporosis

Abstract: 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.

Cited by 771 publications

References 31 publications

Safety of osteoanabolic therapy: A decade of experience

Safety of osteoanabolic therapy: A decade of experience

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

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

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