This study will test whether increasing the daily dose of PTH sustains its ability to improve bone formation, and optional sub-studies will test several potential reasons why PTH's effects on bone formation decline over time.
Detailed Description:. Drug Information available for: Parathyroid Hormone. FDA Resources. Arms and Interventions. Other Name: synthetic human parathyroid hormone Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. Layout table for investigator information Principal Investigator: Robert M. More Information. Time-dependent changes in skeletal response to teriparatide: escalating vs.
Epub Nov Osteoporosis Parathyroid hormone Teriparatide Bone formation Bone resorption. National Library of Medicine U. Bone 29 : — Hernandez C , Beaupre GS , Marcus R , Carter DR A theoretical analysis of the contributions of remodelling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment.
Bradbeer JN , Arlot ME , Meunier PJ , Reeve J Treatment of osteoporosis with parathyroid peptide hPTH and oestrogen: increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone. Clin Endocrinol Oxf 37 : — J Bone Miner Res 16 : — Hodsman AB , Steer BM Early histomorphometric changes in response to parathyroid hormone therapy in osteoporosis: evidence for novo bone formation on quiescent cancellous surfaces.
Bone 14 : — Pagitt AM Parathyroid hormone and periosteal expansion. J Bone Miner Res 17 : — J Bone Miner Res 18 : — Bone 28 : — J Clin Endocrinol Metab 87 : — J Bone Miner Res 18 : 9 — J Clin Endocrinol Metab 88 : — Burr DB , Hirano T , Turner CH , Hotchkiss C , Brommage R , Hock JM Intermittently administered human parathyroid hormone 1—34 treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys.
Calcif Tissue Int 66 : — J Bone Miner Res 14 : — Bone Miner Res 18 : — Hyldstrup L , Jorgensen JT , Gaich G Assessment of effects of LY [recombinant human parathyroid hormone 1—34 ] on cortical bone using digital x-ray radiogrammetry.
Bone 28 Suppl 1 : S97 Abstract. Osteoporos Int 11 Suppl 2 : S Abstract. Gam SM The earlier gain and later loss of cortical bone.
Springfield, IL : Charles C. J Bone Miner Res 6 : — Bone 30 : — VanRietbergen B , Majumdar S , Newitt D , MacDonald B High-resolution MRI and micro-FE for the evaluation of changes in bone mechanical properties during longitudinal clinical trials: application to calcaneal bone in postmenopausal women after one year of idoxifene treatment.
Clin Biomech 17 : 81 — Top Magn Reson Imaging 13 : — J Clin Invest 91 : — J Clin Endocrinol Metab 82 : — Results of a randomized controlled clinical trial. Marcus R , Wang O , Sattershite J , Mitlak B The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis.
J Bone Miner Res 18 : 18 — Osteoporos Int — Eli Lilly Product monograph: Forteo. Toronto, Ontario, Canada : Eli Lilly. J Cell Biol 83 : 93 — An evaluation of the evidence to date.
Can Med Assoc J : — National Institute for Clinical Excellence, Final Appraisal The clinical effectiveness and cost effectiveness of technologies for the secondary prevention of osteoporotic fractures in postmenopausal women.
Toxicol Pathol 30 : — Tashjian AH , Chabner BA Commentary on clinical safety of recombinant human parathyroid hormone 1—34 in the treatment of osteoporosis in men and postmenopausal women. Am J Clin Nutr 71 : — Osteoporos Int 7 : — Arch Intern Med : — Mosekilde L , Danielsen CC , Gasser J The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents estrogen and calcitonin , human parathyroid hormone 1—38 , and combination therapy, assessed in aged ovariectomized rats.
J Bone Miner Res 4 : — J Bone Miner Res 10 : — Bone 16 : — Osteoporos Int 1 : — J Bone Miner Res 19 : — J Bone Miner Res 13 : — Lindsay R. J Bone Miner Res 15 : — Oglesby AK , Minshall ME , Shen W , Xie S , Silverman SL The impact of incident vertebral and non-vertebral fragility fractures on Health-Related Quality of Life in established postmenopausal osteoporosis: results from the teriparatide randomized, placebo-controlled trial in postmenopausal women.
J Rheumatol 30 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation.
Volume Article Contents I. Biological Activity of PTH. Antiresorptive Therapy. Anabolic Therapy. PTH in Clinical Practice. Hodsman , Anthony B. Oxford Academic. Douglas C. David W. Larry Dian. David A. Steven T. David L. Michael R. Paul D. Wojciech P. Eric Orwoll , Eric Orwoll. Chui Kin Yuen. Cite Cite Anthony B. Select Format Select format. Permissions Icon Permissions. TABLE 1. A One or more randomized controlled trial s with adequate power, or metaanalysis a B Randomized controlled trial s not meeting all criteria for grade A a C Nonrandomized trial s or cohort studies, plus consensus D Any lower level of evidence supported by consensus including expert opinion.
Open in new tab. Open in new tab Download slide. TABLE 2. Controlled trials of PTH therapy. Design a. Age yr. Total enrolled no. Duration months. Primary outcome. Vertebral fractures. BMD T-score. TABLE 3. Teriparatide Neer et al. Alendronate Black et al. Risedronate Harris et al. Risedronate Reginster et al. Google Scholar Crossref. Search ADS. Google Scholar PubMed. Receptors for the carboxyl-terminal region of PTH 1—84 are highly expressed in osteocytic cells.
Carboxyl-terminal parathyroid hormone peptide 53—84 elevates alkaline phosphatase and osteocalcin mRNA levels in SaOS-2 cells. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis.
Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Effect of alendronate on risk fracture in women with low bone density but without vertebral fractures. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial.
Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Meta-analysis of therapies for postmenopausal osteoporosis. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. A pooled data analysis on the use of intermittent cyclical etidronate therapy for the prevention and treatment of corticosteroid induced bone loss.
Two year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy.
Risedronate reduces the risk of clinical vertebral fractures in just 6 months. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodelling in patients with osteoporosis. Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three-dimensional microcomputed tomography.
Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Reduction of vertebral fracture risk in post menopausal women with osteoporosis treated with raloxifene.
A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study.
Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women.
Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. The effect of low-dose estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. Effect of four monthly oral vitamin D3 cholecalciferol supplementation on fractures and mortality in men and women living in the community: a randomised double-blind controlled trial.
Alendronate increases the degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. A theoretical analysis of the contributions of remodelling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment.
Treatment of osteoporosis with parathyroid peptide hPTH and oestrogen: increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone. Histomorphometric evidence for increased bone turnover and cortical thickness without increased cortical porosity after 2 years of cyclical hPTH 1—34 therapy in women with severe osteoporosis.
Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. Early histomorphometric changes in response to parathyroid hormone therapy in osteoporosis: evidence for novo bone formation on quiescent cancellous surfaces. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis.
PTH treatment directly stimulates bone formation in cancellous and cortical bone in humans. Recombinant human parathyroid hormone 1—34 [teriparatide] improves both cortical and cancellous bone structure. Treatment with human parathyroid hormone 1—34 for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys Macaca fascicularis.
Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone 1—34 ] with alendronate in postmenopausal women with osteoporosis.
Effect of parathyroid hormone 1—34 on fractures and bone mineral density in postmenopausal women with osteoporosis. The effect of teriparatide [human parathyroid hormone 1—34 ] therapy on bone density in men with osteoporosis.
Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. Safety and efficacy of human parathyroid hormone 1—84 in increasing bone mineral density in postmenopausal osteoporosis. Effects of human parathyroid hormone 1—34 LY, on bone mass, remodelling, and mechanical properties of cortical bone during the first remodelling cycle in rabbits. Intermittently administered human parathyroid hormone 1—34 treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys.
Changes in geometry and cortical porosity in adult, ovary-intact rabbits after 5 months treatment with LY Anabolic effects of human biosynthetic parathyroid hormone fragment 1—34 , LY, on remodelling and mechanical properties of cortical bone in rabbits. Effects of teriparatide [recombinant human parathyroid hormone 1—34 ] on cortical bone in postmenopausal women with osteoporosis.
The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. Teriparatide [rhPTH 1—34 ] treatment improves the structure of the proximal femur in women with osteoporosis. Assessment of effects of LY [recombinant human parathyroid hormone 1—34 ] on cortical bone using digital x-ray radiogrammetry.
Sexual dimorphism in vertebral fragility is more the result of gender differences in age-related bone gain than bone loss. Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment.
Effects of current and discontinued estrogen replacement therapy on hip structural geometry: the study of osteoporotic fractures. Radius bone strength in bending, compression and falling and its correlation with clinical densitometry at multiple sites. Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images.
High-resolution MRI and micro-FE for the evaluation of changes in bone mechanical properties during longitudinal clinical trials: application to calcaneal bone in postmenopausal women after one year of idoxifene treatment.
Quantitative magnetic resonance imaging in the calcaneus and femur of women with varying degrees of osteopenia and vertebral deformity status. Role of magnetic resonance for assessing structure and function of trabecular bone. An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis.
A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis. Prevention of estrogen deficiency-related bone loss with human parathyroid hormone 1—34 : a randomized controlled trial.
Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. Effect of an intermittent weekly dose of human parathyroid hormone 1—34 on osteoporosis: a randomized double-masked prospective study using three dose levels. Regulation of secretion of parathormone and secretory protein I from separate intracellular pools by calcium dibutyryl, cyclic AMP and 1 -isoproteronol.
Teriparatide reduces the incidence of new or worsening back pain in women with osteoporosis. Do bisphosphonates reduce the risk of osteoporotic fractures? The clinical effectiveness and cost effectiveness of technologies for the secondary prevention of osteoporotic fractures in postmenopausal women. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.
Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone 1—34 for two years and relevance to human safety. Commentary on clinical safety of recombinant human parathyroid hormone 1—34 in the treatment of osteoporosis in men and postmenopausal women. Osteosarcoma of bone in a patient with primary hyperparathyroidism: a case report. Vitamin D status: effects on parathyroid hormone and 1,dihydroxyvitamin D in postmenopausal women.
The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents estrogen and calcitonin , human parathyroid hormone 1—38 , and combination therapy, assessed in aged ovariectomized rats.
Resorption is not essential for the stimulation of bone growth by hPTH 1—34 in rats in vivo. Cyclical treatment of osteopenic ovariectomized adult rats with PTH 1—34 and pamidronate. The anabolic effect of human PTH 1—34 on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate—is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodelling system?
Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. The post-PTH experience in men with idiopathic osteoporosis: bisphosphonates versus non-pharmacologic therapy.
Differential effects of teriparatide after treatment with ralozifene or alendronate. Dosages of PTH ranged markedly across trials. They were variously reported in micrograms or units per day in the different articles.
Furthermore, because of different combinations across trials and different comparison groups, conclusions regarding dose effects are difficult. Three trials 28 , 30 , 31 directly compared different dosages of PTH with each other. Increases in lumbar bone mineral density BMD were dose-related range, 0. Although all dosages increased spine and femoral neck BMD compared with placebo, specific dose-effect analysis was not presented.
Increases in bone density ranged from 4. Although there was no change at the femoral neck with PTH compared with placebo, the group treated with PTH followed by alendronate had better femoral neck bone density than the group treated with placebo followed by alendronate. Both dosages increased spine and hip total hip, femoral neck, and trochanter BMD compared with placebo, but dose-effect analysis per se was not provided.
More dose-effect information is needed. The 2 trials described in 3 articles that did not involve hPTH— were small and involved postmenopausal osteoporosis 16 , 17 , 31 or idiopathic osteoporosis.
All trials except 2 involved administration by the SC route. The first exception was 1 trial 2 articles 18 , 19 testing intranasal PTH. The trial was designed with the goal of preventing bone loss induced by GnRH agonist therapy.
Therefore, the intranasal route of PTH has not been tested in the context of glucocorticoid-induced osteoporosis or postmenopausal osteoporosis, nor has it been tested in men. Therefore, although a few studies support the intranasal administration of PTH to prevent bone loss in women receiving specific endometriosis therapies, most data available refer to the SC route.
Study duration varied substantially across trials, ranging from 6 weeks 27 to 3 years 29 ; the longest trial involving SC administration was 3 years Table 1. The more recent trials had access to more advanced bone density measurement technology, such as dual-energy x-ray absorptiometry, and measured a greater number of sites than did the older studies Table 2. Correspondingly, results are sometimes expressed in the context of different bone density measurement techniques.
First, the longer 1-year and 3-year trials will be described. A 1-year trial 24 reported a greater increase in spine However, changes were not significant with PTH plus estrogen or estrogen alone at the femoral neck, trochanter, or radius. The estrogen preparation and dosage were not specified. One month trial 32 revealed increases in lumbar The possible decrease in radius BMD emphasizes the importance of inclusion of control groups in trials of osteoporosis therapies.
In the other month trial, 31 lumbar BMD increased range, 4. Increases were less marked at the femoral neck Table 2. Differences between groups were less marked at the trochanter and radius. In contrast, the 1-year trial 24 already described did not specify exact hormone dosage and preparation. A briefer duration of therapy also results in increased BMD 30 Table 2.
Therefore, overall effects of 48 weeks to 3 years of therapy with PTH appear to be more marked at the spine than at other sites, may be detrimental at the radius, may be enhanced by combination with estrogen, and may be advantageous when combined sequentially with alendronate vs alendronate alone. The longest duration of therapy involved 3 years of PTH combined with HRT and showed benefit at the spine and total hip.
It may take 12 months after treatment cessation for the maximal anabolic effect of PTH to manifest at the hip. The largest studies involved 30 and patients. Therefore, results of larger trials were conflicting as to whether effects were limited to the spine and suggested detrimental effects on radius BMD.
In contrast, although smaller studies reported positive hip and lumbar effects, they generally suggested only minor bone loss at the radius Table 2. Only one study 30 was designed to formally compare bone density changes according to age and sex.
Parathyroid hormone benefits on bone density were similar with subjects 65 years and older vs younger than 65, at a weight of at least 50 kg vs less than 50 kg, whether baseline vertebral fracture was present or not, and regardless of time since menopause.
Most studies pertained to older men and women with established osteoporosis, with 2 exceptions. The second study 33 investigated bone marker changes in older men with advanced prostate cancer. All other studies included older men and women already affected by osteoporosis Table 1. Specifically, osteoporosis was postmenopausal osteoporosis, 16 , 17 , 20 , 21 , 27 - 31 , 34 , 35 idiopathic male osteoporosis, 16 , 17 , 32 or glucocorticoid-induced osteoporosis.
Postmenopausal osteoporosis is the setting of most studies. Effects were less consistently seen at the total hip, femoral neck, trochanter, and radius Table 2. Second, glucocorticoid-induced osteoporosis was studied in 1 trial.
Furthermore, the benefit of PTH at the lumbar spine was only apparent after 1 year, and the benefit at the total hip was only apparent 1 year after cessation of PTH. The benefit at the femoral neck or trochanter was not statistically significant. Effects of combination therapy on the radius showed an insignificant decrease compared with estrogen alone. Bone turnover effects of PTH in idiopathic male osteoporosis are discussed in the "Effects on Bone Formation Markers" subsection of the "Results" section.
In summary, increases in lumbar BMD are induced by PTH alone and possibly combined with other medications, as shown in the "PTH in Combination With Other Agents" subsection of the "Results" section in postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and idiopathic osteoporosis.
Effects at other sites are insignificant or conflicting. Parathyroid hormone may protect against GnRH agonist—related bone loss. Although BMD end points were beneficially affected by PTH in all studies, with some variability between sites, little data specifically analyzed the effects of PTH in older vs younger subjects or directly compared effects according to sex. Parathyroid hormone increased lumbar spine BMD in all studies, at several dosages, for any duration, in different clinical situations, and in combination with multiple agents Table 2.
However, results at the different hip subsites were conflicting. Femoral neck bone loss induced by nafarelin was only partly prevented by PTH. A single study 28 documented increases at all of the multiple sites ie, spine and all hip sites.
It was also the only trial comparing the effect of different dosages of PTH vs placebo at multiple sites for treatment of postmenopausal osteoporosis. This study was the largest, most recent, well-designed trial and was the only trial comparing different dosages of PTH with placebo, as opposed to use in sequential or combination regimens. This trial confirmed the detrimental effect of PTH on radius BMD suggested in other studies 17 , 32 of postmenopausal osteoporosis.
Because of the paucity of data, there is as yet no proof that the decrement in radius BMD translates into increased radius fractures. In summary, when used for postmenopausal osteoporosis treatment, PTH compared with placebo increases BMD at the spine and at multiple sites of the hip.
Effects are less clear at nonspine sites when PTH is used as part of combination or sequential therapy or for treatment of glucocorticoid-induced osteoporosis. Bone quality must be assessed by histomorphometry to prevent unintentional augmentation in fracture risk, even if BMD increases occur. As an example, fluoride increased fracture risk, despite inducing impressive increases in BMD. Histomorphometric consequences of PTH use were investigated in 1 trial 21 Table 5.
In women with postmenopausal osteoporosis, cyclical PTH increased trabecular bone turnover and induced positive remodeling balance, without detrimentally affecting cortical bone. In a sex-comparative analysis after 3 years of combined PTH and HRT, cancellous bone area was maintained in women and increased in men 26 Table 5. Wall width of trabecular packets was maintained in women and significantly increased in men.
Cortical width increases slightly in women and significantly in men. Most patients had increased trabecular connectivity by three-dimensional scan. Bone turnover markers are sometimes used as surrogates to assess therapeutic effects of osteoporosis medications, although whether such application is clinically relevant is a matter of active controversy.
Bone markers can give useful insights into medication mechanisms. Markers of bone formation include serum alkaline phosphatase, serum osteocalcin, and C-terminal propeptide of type I procollagen.
Parathyroid hormone would be expected to increase alkaline phosphatase on the basis of its mechanism as an inducer of bone formation. Correspondingly, in some trials, 18 - 20 , 22 , 25 , 30 , 31 PTH increased serum alkaline phosphatase, although 1 brief trial 27 reported no increase during 6 weeks. Some investigators found an increase with PTH administered alone, but not when followed by antiresorptive treatment with calcitonin.
Two studies 27 , 32 reported an increase in serum C-terminal propeptide of type I procollagen with PTH plus alendronate vs alendronate alone, or with PTH vs placebo.
Markers of bone resorption that increase during PTH therapy include urinary pyridinoline, 18 , 30 , 32 deoxypyridinoline, 19 , 22 , 30 and N -telopeptide 20 , 29 , 31 , 32 excretion. Induction of hypogonadism in older men may cause changes in skeletal sensitivity to PTH. Data regarding urinary hydroxyproline are conflicting. A decrease was reported in 1 trial. Some data suggest that the increase in bone formation and resorption is disproportionate, suggesting that PTH could be uncoupling bone formation and resorption.
Results of combination therapy trials confirm what would be predicted according to medication mechanism. Neither alendronate nor HRT increased formation markers when administered alone. Parathyroid hormone—induced increased bone resorption and formation peaked at 6 months. Subsequently, when patients were maintained on HRT alone for another year, no significant changes in turnover markers occurred.
It may be possible to make use of serial bone marker measurements to identify skeletal responders to anabolic therapy in estrogen-replete women with glucocorticoid-induced osteoporosis. In summary, PTH increases bone formation markers. The increase in bone formation is probably larger in magnitude and may have a different time of onset compared with the increase in resorption. Antifracture efficacy is the single most critical efficacy outcome for osteoporosis treatment.
As it is difficult to include adequate numbers of subjects to yield substantial numbers of fracture events, fracture outcome data for PTH are sparse. Although not a satisfactory state of affairs, this has historically been the case with other osteoporosis therapies as well. Often, fractures are only monitored as part of adverse outcome assessment, as opposed to constituting a primary outcome.
Table 4 summarizes fracture outcome data for PTH. Rates of radiographically detected fractures were generally low.
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