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 Table of Contents  
SYSTEMATIC REVIEW
Year : 2021  |  Volume : 6  |  Issue : 2  |  Page : 84-90

Prevention of vertebral fractures in primary osteoporosis with once-weekly teriparatide: A systematic review and meta-analysis of randomized controlled trials


Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission30-Mar-2021
Date of Decision21-May-2021
Date of Acceptance24-May-2021
Date of Web Publication16-Jul-2021

Correspondence Address:
Prof. Sanjay Kumar Bhadada
Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jncd.jncd_11_21

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  Abstract 


Aims: The present meta-analysis was undertaken to summarize the data from hitherto available randomized controlled trials (RCTs) on the prevention of incident fractures in patients with primary osteoporosis following the use of once-weekly teriparatide.
Methods: PubMed/MEDLINE, Web of Science, and Google Scholar databases were systematically searched till May 21, 2021, to identify RCTs with duration ≥72 weeks, evaluating the efficacy of once-weekly teriparatide (at a dose of 56.5 &#s956;g/week or 28.2 μg/week) in the prevention of incident fractures as compared to placebo or active comparator.
Results: We identified 3 eligible RCTs, pooling data retrieved from 1643 participants with primary osteoporosis. Pooled data showed that the risk of incident morphometric vertebral fractures was significantly lower with once-weekly teriparatide compared to placebo/active comparator (RR 0.33, 95% confidence intervals [CI]: 0.12,0.90, P = 0.03; I2 = 86%). Sensitivity analysis after exclusion of the study where an active comparator had been used instead of placebo also showed a similar result (RR 0.20, 95% CI: 0.11,0.37, P < 0.00001; I2 = 0%). Data on clinical vertebral fractures or nonvertebral fractures were inadequately reported across the RCTs and hence could not be pooled together. Nevertheless, all the RCTs did not find any significant difference in the risk of incident nonvertebral fractures.
Conclusions: The present systematic review and meta-analysis show that once-weekly teriparatide leads to a 67% reduction in the risk of incident morphometric vertebral fractures. Considering the reasonable efficacy, once-weekly dose, and reduced cost, the formulation can be an important antiosteoporotic drug, especially in resource-constraint settings, like India.

Keywords: Daily teriparatide, meta-analysis, once-weekly teriparatide, vertebral fractures


How to cite this article:
Pal R, Bhadada SK, Dhiman V. Prevention of vertebral fractures in primary osteoporosis with once-weekly teriparatide: A systematic review and meta-analysis of randomized controlled trials. Int J Non-Commun Dis 2021;6:84-90

How to cite this URL:
Pal R, Bhadada SK, Dhiman V. Prevention of vertebral fractures in primary osteoporosis with once-weekly teriparatide: A systematic review and meta-analysis of randomized controlled trials. Int J Non-Commun Dis [serial online] 2021 [cited 2021 Aug 5];6:84-90. Available from: https://www.ijncd.org/text.asp?2021/6/2/84/321618




  Introduction Top


Osteoporosis is a major public health problem, affecting nearly 30% of postmenopausal women. Early diagnosis and timely management of osteoporosis reduce the risk of incident fragility fractures. Pharmacological antiosteoporotic treatment options include antiresorptive and osteoanabolic agents. Recombinant human parathyroid hormone (teriparatide) is the most commonly used osteoanabolic agent in clinical practice. The evidence of hip fracture reduction is limited and contradictory; nevertheless, treatment with teriparatide is associated with a 70% reduction in the risk of vertebral fractures.[1] However, teriparatide requires daily subcutaneous administrations that adversely affect patient compliance; nearly 40% of patients tend to stop teriparatide after 1 year of use.[2] In addition, the drug is expensive and unlikely to be afforded by all sections of the community. Considering these limitations, in a resource-constraint setting like India, where nearly 20% of the 230 million women over 50 years of age have osteoporosis,[3] prescribing teriparatide as an antiosteoporotic pharmacotherapy would not be a feasible option in the majority of the circumstances.

An alternative to conventional teriparatide is the once-weekly formulation. Once-weekly teriparatide is available for use in Japan and South Korea at a dose of 56.5 μg/injection.[4] A low-dose once-weekly formulation (28.2 μg/injection) has also been studied,[5] although not available for use in routine clinical practice. The advantages of once-weekly teriparatide over the conventional preparation include improved patient compliance, reduced cost of treatment, and opening of the “anabolic window.”[4] However, data on fracture prevention with once-weekly teriparatide therapy are limited and no meta-analysis exists in this regard.

Hence, the present meta-analysis was undertaken to collate and summarize the data from hitherto available randomized controlled trials (RCTs) on the prevention of incident fractures in patients with primary osteoporosis following the use of once-weekly teriparatide.


  Methods Top


This meta-analysis was reported according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) statement.[6]

Search strategy

Two investigators (RP and VD) independently performed a systematic search of the literature across the PubMed/MEDLINE, Web of Science, and Google Scholar databases from inception till May 21, 2021, using the following keywords interposed with appropriate Boolean operators: “weekly teriparatide” OR “once-weekly teriparatide” AND “fractures.” The language was restricted to English only. The references of relevant reviews and retrieved articles were also screened for potentially eligible articles. For missing data, the corresponding authors of the potentially eligible studies were contacted wherever possible.

Eligibility and exclusion criteria

Eligibility criteria were set as follows

  1. All studies had to be RCTs irrespective of the study design (parallel/cross-over), study blinding (single-blind, double-blind, or open-label), or sample size
  2. The RCTs should have included patients with primary osteoporosis, irrespective of the sex of the participants
  3. The intervention group should have been treated with once-weekly teriparatide either at a dose of 56.5 μg/week or 28.2 μg/week, administered subcutaneously
  4. The comparator group should have been treated with a placebo or any antiosteoporotic drug other than once-weekly teriparatide (active comparator)
  5. The minimum duration of the study should have been 72 weeks
  6. The RCTs should report the data comparing the rate of occurrence of incident fractures, vertebral (morphometric/clinical) or nonvertebral (as the number of “events”), in the intervention as compared to the placebo/active comparator group.


Exclusion criteria were set as follows

  1. RCTs that had included participants with secondary osteoporosis, like glucocorticoid-induced osteoporosis
  2. Post hoc analysis of RCTs
  3. Observational studies, postmarketing surveillance studies
  4. Reviews, abstracts, and animal studies
  5. Incompleteness in data.


Data extraction

Two investigators (RP and VD) independently scanned titles and/or abstracts to exclude duplicate studies and studies that failed to meet the aforementioned eligibility criteria. Potentially eligible studies were full-text assessed. Any discrepancies between the aforementioned investigators were solved by discussion, consensus, or arbitration by a third senior investigator (SKB). Studies hence selected were reviewed, and the following data were extracted from full-text reports for further assessment: study characteristics, baseline characteristics of the study participants, drug used as a comparator, and the rate of occurrence of incident fractures in the once-weekly teriparatide vs. the placebo/active comparator groups.

Assessment of study quality

Two investigators (RP and VD) independently assessed the risk of bias in the following domains using the corresponding Cochrane Collaboration's tool: random sequence generation, allocation concealment, blinding of participants and staff, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting.[7] Each domain was rated as “low,” “unclear,” or “high” risk of bias. A study was rated as being of low risk of bias in the presence of adequate procedures in all the domains; on the contrary, an inadequate procedure in at least one domain rated a study as being of a high risk of bias. In any other case, a study was labeled as being of unclear risk of bias. Any discrepancy was solved by a discussion, consensus, or arbitration by a third senior investigator (SKB).

Statistical analysis

The difference in the rate of occurrence of incident fractures (events) in the once-weekly teriparatide group vs. the placebo group was calculated using risk ratio (RR) with 95% confidence intervals (CI) after implementation of the Mantel-Haenszel fixed-effects model.

Statistical heterogeneity among studies was assessed using I2 statistics. Heterogeneity was quantified as low, moderate, and high with upper limits of 25%, 50%, and 75% for I2, respectively.[8] In the present meta-analysis, significant heterogeneity was considered when the I2 value was ≥50%, with a P < 0.05. Outcomes with significant heterogeneity were reanalyzed and reported using the random-effects model. A P < 0.05 was considered to be statistically significant.

Statistical analysis was performed using the Cochrane Collaboration Review Manager (RevMan) software version 5.4.


  Results Top


After a thorough literature search, we found three eligible RCTs pooling data retrieved from 1643 participants with primary osteoporosis.[5],[9],[10] The study selection process has been depicted in [Figure 1]. A recently published study evaluating the effect of once-weekly teriparatide in patients with glucocorticoid-induced osteoporosis was excluded.[11]
Figure 1: Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) flow diagram showing the study section process

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The details of the included studies are presented in [Table 1]. Notably, the landmark Randomized Teriparatide Once-Weekly Efficacy Research trial by Nakamura et al. had examined the effect of once-weekly teriparatide administered at a dose of 56.5 μg/week on the reduction of new vertebral fractures in subjects with primary osteoporosis and high fracture risk.[9] On the contrary, Fujita et al. had studied the effect of once-weekly injection of teriparatide administered at a lower dose of 28.2 μg/week.[5] The third RCT named the Japanese Osteoporosis Intervention Trial-05 (JOINT-05) examined the effect of once-weekly teriparatide compared to alendronate in Japanese women with primary osteoporosis who were at a high risk of fractures.[10] The risk of bias assessment of the three RCTs has been summarized in [Table 2]. The JOINT-05 had a high risk of bias while the other two RCTs had a low risk of bias.
Table 1: Overview of the randomized controlled trials included in the meta-analysis

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Table 2: The risk of bias assessment across various domains in the included randomized controlled trials

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The primary endpoint of the RCTs was incident morphometric vertebral fractures. Pooled data from all the three RCTs showed that the risk of incident morphometric vertebral fractures was significantly lower with once-weekly teriparatide compared to placebo or active comparator (RR 0.33, 95% CI: 0.12, 0.90, P = 0.03; I2 = 86%, random-effects model) [Figure 2]. Sensitivity analysis after exclusion of the study where an active comparator (alendronate) had been used instead of placebo also showed a similar result (RR 0.20, 95% CI: 0.11, 0.37, P < 0.00001; I2 = 0%, fixed-effects model) [Figure 3]. Data on clinical vertebral fractures or nonvertebral fractures were inadequately reported across both the RCTs and hence could not be pooled together in the present meta-analysis. Nevertheless, both the RCTs did not find any significant difference in the risk of incident nonvertebral fractures.
Figure 2: Forest plot showing the effect of once-weekly teriparatide on the risk of incident morphometric vertebral fractures as compared to placebo or active comparator in patients with primary osteoporosis

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Figure 3: Forest plot with sensitivity analysis showing the effect of once-weekly teriparatide on the risk of incident morphometric vertebral fractures as compared to placebo in patients with primary osteoporosis

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  Discussion Top


The present systematic review and meta-analysis show that the use of once-weekly teriparatide in patients with primary osteoporosis is associated with 67% reduction in the risk of incident morphometric vertebral fractures than placebo or alendronate. This makes once-weekly teriparatide a reasonably good option for the management of primary osteoporosis.

Recombinant human parathyroid hormone, also known as teriparatide, is the most widely used osteoanabolic pharmacotherapy for managing osteoporosis. Teriparatide, administered subcutaneously at a dose of 20 μg/day, stimulates bone formation. The beneficial effects of teriparatide on bone qualities are seen predominantly in the cancellous skeleton. As a monotherapy, teriparatide has been shown to increase lumbar spine bone mineral density (BMD) by 9.7% and femoral neck BMD by 3% over a median treatment period of 19 months.[12] Accordingly, teriparatide reduces the risk of new vertebral fractures by nearly 70%.[1] Data on the prevention of nonvertebral fractures with teriparatide are less robust; a meta-analysis, however, showed that teriparatide also reduced the risk of nonvertebral fractures by 38%.[1]

Despite being a potent antiosteoporotic drug, teriparatide is usually reserved for use in patients with fragility fractures of the vertebrae (clinical or morphometric), those with very low BMD (T-score < −3.0) even in the absence of fractures, and individuals who have had a suboptimal response to antiresorptive pharmacotherapy. The widespread use of teriparatide as a primary antiosteoporotic therapy is partly limited by its mode of administration that requires daily subcutaneous administration and partly by its exorbitant cost. Nearly 40% of patients tend to stop once-daily teriparatide after only 1 year of use.[2] A Taiwan National Health Insurance Research Database-based study showed that only 33.9% of the individuals were adherent to teriparatide therapy for >12 months. Expectedly, patients adherent for >12 months had a lower incidence of hip and nonvertebral fracture than those adherent for ≤ 12 months.[13] On the contrary, adherence to therapy with once-yearly zoledronic acid is remarkably high, with few studies showing a compliance rate of 100% as well.[14]

To circumvent the problems, a once-weekly formulation of teriparatide has been developed and is available for routine clinical use in Japan and South Korea.[4] In the present systematic review and meta-analysis that had included 3 hitherto available RCTs, once-weekly teriparatide administered at a dose of 56.5 μg/week (or 28.2 μg/week) was shown to reduce the risk of incident morphometric vertebral fractures by 67% as compared to placebo or active comparator in patients with primary osteoporosis. In this regard, once-weekly teriparatide seems noninferior to its daily injection,[1],[12] even though the amount of weekly administered teriparatide is 56.5 μg for the once-weekly formulation which is much less than 140 μg a week for daily injection therapy. However, all the three RCTs did not significantly reduce the risk of incident nonvertebral fractures, although risk estimates could not be calculated due to inadequate data and a limited number of studies.

Apart from the once-weekly injection and a concomitant reduction in the cost of therapy, the underlying mechanisms for the anabolic effects of once-weekly teriparatide could be somewhat different from those of its daily injection. The most remarkable difference is their effects on bone metabolic markers. Serum levels of bone formation markers, especially N-terminal propeptide of type I procollagen (PINP), increase with daily administration of teriparatide followed by the increase in bone resorption markers, such as type I collagen cross-linked C-telopeptide. This profile of changes in bone metabolic markers, formation first followed by resorption, during daily injections of teriparatide provides an “anabolic window” that is temporally open for accumulation of a significant amount of new bone.[15]

In contrast, once-weekly teriparatide has no effects on urinary excretion of type I collagen cross-linked N-telopeptide as a bone resorption marker during the early treatment period, even followed by its decrease at 48 weeks of treatment and thereafter. It only transiently elevates serum PINP until 12 weeks of treatment.[9] Accordingly, at least theoretically, once-weekly teriparatide might also open the “anabolic window” with the temporal increase in bone formation without increased bone resorption.[4] However, clinical evidence suggests that at 72 weeks, once-weekly teriparatide administration increases BMD by 6.4%, 3.0%, and 2.3% at the lumbar spine, total hip, and femoral neck, respectively, compared with placebo.[9] A postmarketing observational study has also shown similar findings in BMD.[16] The gain in BMD with once-weekly teriparatide seems inferior to the daily formulation;[12] nonetheless, the expansion of the “anabolic window” would imply that the drug can be administered beyond the stipulated duration of 2 years, thereby, theoretically, resulting in a greater cumulative gain in BMD.

Apart from the effect on the anabolic window, once-weekly teriparatide may have a differential effect on cortical bone compared to the daily formulation. Daily injections of teriparatide provide an enormous anabolic effect on the trabecular bone but much less on cortical bone, such as the shaft of the radius.[12] On the contrary, a significant increase in radial BMD has been observed following 12 months of once-weekly teriparatide use.[17]

Preclinical and clinical data have suggested that once-daily teriparatide injections increase cortical porosity in long bones.[18],[19] However, accumulating data from preclinical studies demonstrate that less frequent exogenous teriparatide administration could decrease cortical porosity.[18] Quantitative computed tomography data indicated that cortical thickness and cortical cross-sectional area of the femoral shaft was significantly increased with 72 weeks of treatment with once-weekly teriparatide compared with placebo, suggesting its favorable effects on cortical bone during the treatment period,[20] although effects of once-weekly teriparatide on cortical porosity in human are not yet available. Nevertheless, the available RCTs do not mention separately about hip fractures; hence, the effect of once-weekly teriparatide on hip fractures needs further exploration.

Considering the safety profile of once-weekly teriparatide, the drug has been found to be safe for the treatment of osteoporosis over 24 months.[21] In a postmarketing observational study of once-weekly teriparatide that had included 3575 Japanese osteoporosis patients, adverse drug reactions (ADRs) were reported in 898 patients (25.13%), and serious ADRs were reported in 26 patients (0.73%). The most frequent ADRs were nausea, vomiting, and headache.[16] No differences have been found between the placebo and teriparatide groups in the frequencies of any adverse events, deaths, or serious adverse events.[9]

The present systematic review and meta-analysis happen to be the first data summarizing the available clinical evidence on the effect of once-weekly teriparatide in preventing incident osteoporotic fractures. Nevertheless, we humbly acknowledge the limitations of the manuscript. First, we could pool data from only three eligible RCTs. Nevertheless, considering the stringent inclusion and exclusion criteria and the scarcity of data on once-weekly teriparatide, we could include only three RCTs in the present systematic review and meta-analysis. Incorporating only three studies would have compromised the power of the meta-analysis, nonetheless, considering the paucity of literature, only three studies are also sufficient to conduct a meta-analysis.[22],[23] Second, there was inadequate reporting of data on nonvertebral fractures, especially hip fractures, hence, could not be pooled together.


  Conclusions Top


The present systematic review and meta-analysis show that once-weekly teriparatide leads to a 67% reduction in the risk of incident morphometric vertebral fractures than placebo or active comparator in patients with primary osteoporosis and appears almost equivalent to daily teriparatide in this regard. Considering the reasonable efficacy, once-weekly dose, and reduced cost, the formulation can become an important antiosteoporotic drug, especially in resource-constraint settings, like India.

Ethical approval

Being a systematic review and meta-analysis, formal ethical approval was not required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Han SL, Wan SL. Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: Meta-analysis of randomised controlled trials. Int J Clin Pract 2012;66:199-209.  Back to cited text no. 1
    
2.
Tanaka I, Sato M, Sugihara T, Faries DE, Nojiri S, Graham-Clarke P, et al. Adherence and persistence with once-daily teriparatide in Japan: A retrospective, prescription database, cohort study. J Osteoporos 2013;2013:654218.  Back to cited text no. 2
    
3.
Khadilkar AV, Mandlik RM. Epidemiology and treatment of osteoporosis in women: An Indian perspective. Int J Womens Health 2015;7:841-50.  Back to cited text no. 3
    
4.
Takeuchi Y. How different is the once-weekly teriparatide from the daily one or the same? Osteoporos Sarcopenia 2019;5:27-8.  Back to cited text no. 4
    
5.
Fujita T, Fukunaga M, Itabashi A, Tsutani K, Nakamura T. Once-weekly injection of low-dose teriparatide (28.2 μg) reduced the risk of vertebral fracture in patients with primary osteoporosis. Calcif Tissue Int 2014;94:170-5.  Back to cited text no. 5
    
6.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009;339:b2700.  Back to cited text no. 6
    
7.
Higgins J, Sterne J, Savovic J, Page M, Hróbjartsson A, Boutron I, et al. A revised tool for assessing risk of bias in randomized trials. Cochrane Database Syst Rev 2016;10:29-31.  Back to cited text no. 7
    
8.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 8
    
9.
Nakamura T, Sugimoto T, Nakano T, Kishimoto H, Ito M, Fukunaga M, et al. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 2012;97:3097-106.  Back to cited text no. 9
    
10.
Hagino H, Sugimoto T, Tanaka S, Sone T, Nakamura T, Soen S, et al. A randomized, controlled trial of once-weekly teriparatide injection versus alendronate in patients at high risk of osteoporotic fracture: Primary results of the Japanese Osteoporosis Intervention Trial-05. Osteoporos Int 2021.  Back to cited text no. 10
    
11.
Tanaka I, Tanaka Y, Soen S, Oshima H. Efficacy of once-weekly teriparatide in patients with glucocorticoid-induced osteoporosis: The TOWER-GO study. J Bone Miner Metab 2021;39:446-55.  Back to cited text no. 11
    
12.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.  Back to cited text no. 12
    
13.
Chan DC, Chang CH, Lim LC, Brnabic AJ, Tsauo JY, Burge R, et al. Association between teriparatide treatment persistence and adherence, and fracture incidence in Taiwan: Analysis using the National Health Insurance Research Database. Osteoporos Int 2016;27:2855-65.  Back to cited text no. 13
    
14.
Fobelo Lozano MJ, Sánchez-Fidalgo S. Adherence and preference of intravenous zoledronic acid for osteoporosis versus other bisphosphonates. Eur J Hosp Pharm 2019;26:4-9.  Back to cited text no. 14
    
15.
Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 2007;357:905-16.  Back to cited text no. 15
    
16.
Ifuku E, Yoshimura T, Uzawa T, Hokonohara T. Safety and efficacy in actual clinical practice of once-weekly subcutaneous teriparatide for osteoporosis patients with a high fracture risk. Osteoporos Sarcopenia 2019;5:44-50.  Back to cited text no. 16
    
17.
Nakayama H, Toho H, Sone T. Utility of radius bone densitometry for the treatment of osteoporosis with once-weekly teriparatide therapy. Osteoporos Sarcopenia 2018;4:29-32.  Back to cited text no. 17
    
18.
Zebaze R, Takao-Kawabata R, Peng Y, Zadeh AG, Hirano K, Yamane H, et al. Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide. Bone 2017;99:80-4.  Back to cited text no. 18
    
19.
Tsai JN, Uihlein AV, Burnett-Bowie SA, Neer RM, Zhu Y, Derrico N, et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: The DATA-HRpQCT Study. J Bone Miner Res 2015;30:39-45.  Back to cited text no. 19
    
20.
Ito M, Oishi R, Fukunaga M, Sone T, Sugimoto T, Shiraki M, et al. The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT. Osteoporos Int 2014;25:1163-72.  Back to cited text no. 20
    
21.
Sugimoto T, Shiraki M, Fukunaga M, Hagino H, Sone T, Nakano T, et al. 24-month open-label teriparatide once-weekly efficacy research trial examining bone mineral density in subjects with primary osteoporosis and high fracture risk. Adv Ther 2017;34:1727-40.  Back to cited text no. 21
    
22.
Valentine JC, Pigott TD, Rothstein HR. How many studies do you need? A primer on statistical power for meta-analysis. J Educ Behav Stat 2010;35:215-47.  Back to cited text no. 22
    
23.
Pal R, Gautam A, Bhadada SK. Role of bisphosphonates in the prevention of postoperative hungry bone syndrome in primary hyperparathyroidism: A meta-analysis and need for randomized controlled trials. Drug Res (Stuttg) 2021;71:108-9.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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