1. Teriparatide in individuals with a prior history of radiation therapy-a case series
Ole-Petter Riksfjord Hamnvik,Yee-Ming Melody Cheung Arch Osteoporos . 2021 Oct 4;16(1):149. doi: 10.1007/s11657-021-01007-3.
Purpose:Teriparatide is a highly effective anabolic therapy for use in patients with osteoporosis at elevated fracture risk but carries a warning about an increased risk of osteosarcoma based on findings from pre-approval animal studies. Since approval, follow-up of individuals treated with teriparatide has not shown an increased risk of osteosarcoma, but it is still recommended to avoid teriparatide in patients with risk factors for osteosarcoma. One such risk factor is radiotherapy; deciding whether to use teriparatide therapy in patients at high risk of fracture but with a history of radiotherapy is therefore a frequent clinical problem.Methods:We sought to identify whether clinicians are using teriparatide in patients with a history of radiotherapy despite the warning and to explore the rationale for this choice. Herein, we describe six cases where the likelihood of fracture, osteosarcoma, and the benefits of teriparatide treatment are assessed to determine the appropriateness of prescribing teriparatide in the setting of prior or concurrent radiotherapy.Results:All six patients had severe osteoporosis with limited treatment options. For those who completed 2 years of teriparatide, no further fractures during the follow-up period have occurred, and improvements in bone density (as measured by dual-energy X-ray absorptiometry) were observed.Conclusion:Despite radiotherapy being a relative contraindication to teriparatide use, there may be a role for teriparatide in select cases where osteoporosis is complex and severe and where other treatment options are not suitable or have been exhausted. The risks vs. benefits of prescribing teriparatide in this population should always be carefully considered, and both the patient and treating oncologist should be educated on the potential risk of osteosarcoma development when teriparatide is continued during radiotherapy.
2. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis
H K Genant,B H Mitlak,J R Zanchetta,E F Eriksen,C D Arnaud,J Y Reginster,A B Hodsman,O Wang,S Ish-Shalom,R Prince,G A Gaich,R M Neer N Engl J Med . 2001 May 10;344(19):1434-41. doi: 10.1056/NEJM200105103441904.
Background:Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown.Methods:We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry.Results:New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache).Conclusions:Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.
3. Chronic hypoparathyroidism and treatment with teriparatide
Gemma Marcucci,Laura Masi,Caterina Fossi,Simone Parri,Maria Luisa Brandi,Giorgio Gronchi,Francesca Giusti,Luisella Cianferotti Endocrine . 2021 Apr;72(1):249-259. doi: 10.1007/s12020-020-02577-x.
Purpose:Chronic hypoparathyroidism is usually treated with calcium and active vitamin D metabolites or analogs, despite the fact that their chronic use can lead to long-term complications. The use of hormone replacement therapy with PTH peptides [teriparatide and rhPTH (1-84)] has therefore been proposed. The main purpose of this study was to investigate the efficacy of teriparatide dose at 20 µg once or twice daily, in order to maintain normocalcemia reducing standard treatment, in adult patients with chronic hypoparathyroidism not well controlled with conventional treatment.Methods:The study was a Phase III, open-label, non-comparative, clinical investigation (study period: 3 months), at a tertiary care clinical research center. Thirty patients with chronic hypoparathyroidism were screened, and 12 started teriparatide. After the optimization phase (0-4 weeks), calcium and calcitriol supplements were progressively reduced, while teriparatide 20 µg once daily was administered (5-7 weeks), and then could be titrated up to 20 µg twice daily (7-17 weeks). The main outcome measures included serum and urinary biochemical exams and Rand 36-Item Short Form Health Survey.Results:This study showed that teriparatide 20 µg once daily was insufficient to discontinue calcium and calcitriol supplements to maintain normal serum calcium concentrations. Conversely, for more than half of patients treated with teriparatide 20 µg twice daily, calcium and calcitriol administration was avoidable, but in some cases at the expense of serum calcium and phosphate oscillations.Conclusions:Since intervention trials evaluating the efficacy and safety of teriparatide in hypoparathyroid patients are not yet available, the routine use of this molecule poses some doubts.
4. Combination and sequential treatment in women with postmenopausal osteoporosis
Stergios A Polyzos,Maria P Yavropoulou,Athanasios D Anastasilakis,Polyzois Makras Expert Opin Pharmacother . 2020 Mar;21(4):477-490. doi: 10.1080/14656566.2020.1717468.
Introduction: Since postmenopausal osteoporosis is a chronic, potentially disabling condition requiring long-term treatment, the physician is expected to decide the optimal treatment strategy, e.g. how to use the available osteoanabolic and antiresorptive agents, sequentially or in combination, in the most effective and safe way, based on personalized patient care.Areas covered: Herein, the authors outline clinical data regarding the efficacy and safety of various sequential treatment strategies. More specifically, they compare the efficacy of osteoanabolic agents when they precede or follow antiresorptive treatment, as well as the efficacy of antiresorptives following other antiresorptives. Finally, the authors quote and discuss available evidence regarding the efficacy and safety of the co-administration of osteoanabolics and antiresorptives in comparison with monotherapies.Expert opinion: Initiation with an osteoanabolic agent followed by an antiresorptive seems to be the optimal treatment sequence, at least in patients with severe osteoporosis. Osteoanabolic treatment following antiresorptives seems to lead in more modest responses in bone mineral density (BMD) and bone turnover markers. Combination therapy with teriparatide and denosumab or zoledronate has achieved higher BMD gains compared to each agent alone; however, due to the high cost, combination therapy is rarely compensated. On the contrary, the combination of teriparatide with alendronate results in smaller BMD increases than TPTD monotherapy.
5. Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial
Benjamin Z Leder,Yuli Zhu,Katelyn Foley,Sherri-Ann M Burnett-Bowie,Alexander V Uihlein,Joy N Tsai,Robert M Neer,Hang Lee J Clin Endocrinol Metab . 2014 May;99(5):1694-700. doi: 10.1210/jc.2013-4440.
Context:Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone.Objective:The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent.Design:Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months.Participants:Participants were 94 postmenopausal women with osteoporosis.Outcome measures:Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.Results:At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.Conclusions:Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
6. Osteoporosis Therapeutics 2020
Klaus Klaushofer,Roland Kocijan,Barbara M Misof Handb Exp Pharmacol . 2020;262:397-422. doi: 10.1007/164_2020_373.
Numerous safe and efficient drug therapies are currently available to decrease risk of low trauma fractures in patients with osteoporosis including postmenopausal, male, and secondary osteoporosis. In this chapter, we give first an overview of the most important outcomes regarding fracture risk reduction, change in bone mineral density (BMD by DXA) and/or bone markers of the phase III clinical studies of well-established therapies (such as Bisphosphonates, Denosumab or Teriparatide) and also novel therapies (such as Romosozumab or Abaloparatide) and highlight their mechanisms of action at bone tissue/material level. The latter understanding is not only essential for the choice of drug, duration and discontinuation of treatment but also for the interpretation of the clinical outcomes (in particular of eventual changes in BMD) after drug administration. In the second part of this chapter, we focus on the management of different forms of osteoporosis and give a review of the respective current guidelines for treatment. Adverse effects of treatment such as atypical femoral fractures, osteonecrosis of the jaw or influence of fracture healing are considered also in this context.
7. Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur
I Tarkin,G Gruen,K Vujevich,P Siska,B Hamlin,S Perera,A Herradura,S L Greenspan,C Britton Osteoporos Int . 2018 Feb;29(2):501-506. doi: 10.1007/s00198-017-4286-7.
The Fracture Improvement with Teriparatide (Fix-IT) study randomized 13 women with an atypical femur fracture to immediate vs delayed teriparatide therapy; all were followed for 12 months. Results suggested a trend for superior healing and lesser bone mineral density declines in the immediate vs delayed group with no differences in adverse events.Purpose:Little clinical data are available on the use of teriparatide for the treatment of bisphosphonate-associated atypical femur fractures (AFF). The goal of the Fix-IT study was to determine if immediate therapy with teriparatide was superior for fracture healing after an AFF compared to a 6-month delay in teriparatide therapy.Methods:This randomized pilot clinical trial included 13 women with an AFF who were randomized to immediate teriparatide vs a delay of 6 months. All were followed for 12 months on teriparatide. The primary outcomes included individual and composite measures of radiologic bone healing (scored 1 point [no healing] to 4 points [complete healing]) at 6 and 12 months. Secondary outcomes included bone mineral density of the unfractured contralateral hip, spine, 1/3 distal radius, and adverse events.Results:We found there was a trend for superior healing with the composite score (12.6 vs 11.2 at 6 months and 15.4 vs 13.2 at 12 months), and lesser bone mineral density declines at the 1/3 distal radius (12-month change - 1.9 vs - 6.1%) in the immediate vs the delayed group. There were no differences in adverse events. There was one implant failure in the delayed group.Conclusions:There is a preliminary signal for greater improvements with immediate teriparatide therapy vs delayed therapy. However, because an AFF is a rare event, and only a small number of patients were included, the results must be interpreted with caution.
8. Teriparatide for osteoporosis: importance of the full course
J H Krege,R Lindsay,J J Stepan,F Marin,L Jin Osteoporos Int . 2016 Aug;27(8):2395-410. doi: 10.1007/s00198-016-3534-6.
Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton. The use of teriparatide clinically is limited to 24 months. We review clinical findings during daily teriparatide treatment over time. Teriparatide appears to increase bone formation more than bone resorption as determined biochemically and histologically. Teriparatide exerts its positive effects on bone formation in two distinct fashions. The first is direct stimulation of bone formation that occurs within active remodeling sites (remodeling-based bone formation) and on surfaces of bone previously inactive (modeling-based bone formation). The second is an increase in the initiation of new remodeling sites. Both processes contribute to the final increase in bone density observed by non-invasive tools such as DXA. Remodeling is the repair process by which skeletal tissue is maintained in a young healthy state, and when stimulated by TPTD is associated with a positive bone balance within each remodeling cavity. It seems likely therefore that this component will contribute to the anti-fracture efficacy of TPTD. Teriparatide reduces the risk of fracture, and this effect appears to increase with longer duration of therapy. The use of novel treatment regimens, including shorter courses, should be held in abeyance until controlled clinical trials are completed to define the relative fracture benefits of such approaches in comparison to the 24-month daily use of the agent. Summary In patients with osteoporosis at high risk for fracture, the full continuous 24-month course with teriparatide results in improved skeletal health and outcomes than shorter time periods.
9. Teriparatide or alendronate in glucocorticoid-induced osteoporosis
Steven Boonen,Kathleen A Taylor,Fernando Marín,David W Donley,Elizabeth Shane,Kenneth G Saag,Gail P Dalsky,Robert Marcus N Engl J Med . 2007 Nov 15;357(20):2028-39. doi: 10.1056/NEJMoa071408.
Background:Bisphosphonate therapy is the current standard of care for the prevention and treatment of glucocorticoid-induced osteoporosis. Studies of anabolic therapy in patients who are receiving long-term glucocorticoids and are at high risk for fracture are lacking.Methods:In an 18-month randomized, double-blind, controlled trial, we compared teriparatide with alendronate in 428 women and men with osteoporosis (ages, 22 to 89 years) who had received glucocorticoids for at least 3 months (prednisone equivalent, 5 mg daily or more). A total of 214 patients received 20 microg of teriparatide once daily, and 214 received 10 mg of alendronate once daily. The primary outcome was the change in bone mineral density at the lumbar spine. Secondary outcomes included changes in bone mineral density at the total hip and in markers of bone turnover, the time to changes in bone mineral density, the incidence of fractures, and safety.Results:At the last measurement, the mean (+/-SE) bone mineral density at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2+/-0.7% vs. 3.4+/-0.7%, P<0.001). A significant difference between the groups was reached by 6 months (P<0.001). At 12 months, bone mineral density at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6% vs. 6.1%, P=0.004); the incidence of nonvertebral fractures was similar in the two groups (5.6% vs. 3.7%, P=0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium.Conclusions:Among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate. (ClinicalTrials.gov number,NCT00051558[ClinicalTrials.gov].).
10. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial
Benjamin Z Leder,Sherri-Ann M Burnett-Bowie,Paul M Wallace,Joy N Tsai,Alexander V Uihlein,Hang Lee,Robert M Neer Lancet . 2015 Sep 19;386(9999):1147-55. doi: 10.1016/S0140-6736(15)61120-5.
Background:Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments.Methods:This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to teriparatide received denosumab (teriparatide to denosumab group), those originally assigned to denosumab received teriparatide (denosumab to teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, numberNCT00926380.Findings:Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9-21·8) in 27 women in the teriparatide to denosumab group, 14·0% (10·9-17·2) in 27 women the denosumab to teriparatide group, and 16·0% (14·0-18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the teriparatide to denosumab group vs the denosumab to teriparatide group, p=0·30 for the teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the teriparatide to denosumab group (6·6% [95% CI 5·3-7·9]) than in the denosumab to teriparatide group (2·8% [1·3-4·2], p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% [7·1-10·0]; p=0·0446 vs the teriparatide to denosumab group, p<0·0001 vs the denosumab to teriparatide group). Similarly, femoral neck bone mineral density increased more in the teriparatide to denosumab group (8·3% [95% CI 6·1-10·5]) and the combination to denosumab group (9·1% [6·1-12·0]) than in the denosumab to teriparatide group (4·9% [2·2-7·5]; p=0·0447 for teriparatide to denosumab vs denosumab to teriparatide, p=0·0336 for combination to denosumab vs denosumab to teriparatide). Differences between the combination to denosumab group and the teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the teriparatide to denosumab group (0·0% [95% CI -1·3 to 1·4]), whereas it decreased by -1·8% (-5·0 to 1·3) in the denosumab to teriparatide group, and increased by 2·8% (1·2-4·4) in the combination to denosumab group (p=0·0075 for the teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to teriparatide group vs the combination to denosumab group). One participant in the denosumab to teriparatide group had nephrolithiasis, classified as being possibly related to treatment.Interpretation:In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients.Funding:Amgen, Eli Lilly, and National Institutes of Health.
