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Potential effects of teriparatide (PTH (1–34)) on osteoarthritis: a systematic review

Potential effects of teriparatide (PTH (1–34)) on osteoarthritis: a systematic review Osteoarthritis (OA) is a common and prevalent degenerative joint disease characterized by degradation of the articu- lar cartilage. However, none of disease-modifying OA drugs is approved currently. Teriparatide (PTH (1–34)) might stimulate chondrocyte proliferation and cartilage regeneration via some uncertain mechanisms. Relevant therapies of PTH (1–34) on OA with such effects have recently gained increasing interest, but have not become widespread prac- tice. Thus, we launch this systematic review (SR) to update the latest evidence accordingly. A comprehensive literature search was conducted in PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase from their inception to February 2022. Studies investigating the effects of the PTH (1–34) on OA were obtained. The quality assessment and descriptive summary were made of all included studies. Overall, 307 records were identified, and 33 studies were included. In vivo studies (n = 22) concluded that PTH (1–34) slowed progression of OA by alleviating cartilage degeneration and aberrant remodeling of subchondral bone (SCB). Moreover, PTH (1–34) exhibited repair of cartilage and SCB, analgesic, and anti-inflammatory effects. In vitro studies (n = 11) concluded that PTH (1–34) was important for chondrocytes via increasing the proliferation and matrix synthesis but preventing apoptosis or hypertrophy. All included studies were assessed with low or unclear risk of bias in methodological quality. The SR demonstrated that PTH (1–34) could alleviate the progression of OA. Moreover, PTH (1–34) had beneficial effects on osteoporotic OA (OPOA) models, which might be a therapeutic option for OA and OPOA treatment. Keywords Teriparatide, Osteoarthritis, Systematic review, Treatment Background Guoqing Li, Su Liu, and Huihui Xu contributed equally to this work. Osteoarthritis (OA) is a common musculoskeletal dis- *Correspondence: order and prevalent degenerative disease worldwide [1, Liang Gao 2]. Both non-load bearing and load-bearing joints are lianggao@web.de Changhai Ding affected by multiple factors such as trauma, senility, gen - changhai.ding@utas.edu.au der, genetics, and obesity [3], which resulted in functional Hui Zeng disability or decreased quality of life. Articular cartilage zenghui_36@163.com Department of Bone & Joint Surgery, Peking University Shenzhen is an avascular tissue, while chondrocytes are unique cel- Hospital, Shenzhen 518036, People’s Republic of China lular components and responsible for the maintenance National & Local Joint Engineering Research Center of Orthopaedic of the extracellular matrix (ECM) via the balance of Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, People’s Republic of China catabolism and anabolism. Type II collagen (COL II) and Center for Clinical Medicine, Huatuo Institute of Medical Innovation aggrecan (AGC) are secreted proteins, which are essen- (HTIMI), Berlin, Germany tial for the integrity of cartilage. Break-down of chon- Sino Euro Orthopaedics Network (SEON), Berlin, Germany Clinical Research Centre, Zhujiang Hospital, Southern Medical University, drocytes is one of the molecular characteristics of OA, Guangzhou, People’s Republic of China which is characterized by progressive damage including © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. Arthritis Research & Therapy (2023) 25:3 Page 2 of 15 cartilage erosion, synovitis, and subchondral bone (SCB) Recommendation of OA treatment includes physi- disturbance. The normal metabolism of cartilage is dis - otherapy, pharmacological, and surgical interventions turbed by inflammatory cytokines such as tumor necro - [6, 7]. Physiotherapy should be advocated due to its sis factor-α (TNF-α) and interleukin-1β (IL-1β), shifting safety and effectiveness. However, limited choices and to catabolism and ECM degradation [4]. Oxidative stress less effectiveness of drugs were restricted to symptom and apoptosis generate the decrease of chondrocytes and relief and accompanied by adverse effects [8 ]. Currently, loss of cartilage [5]. The schematic diagram of normal no disease-modifying OA drugs (DMOADs) are avail- and osteoarthritic joint was illustrated in Fig. 1. able to alleviate the progression of OA. And therefore, Fig. 1 The schematic structures of normal (left part) and osteoarthritic (right part) joint. Multiple factors and pro-inflammatory cytokines resulting chondrocytes catabolism and ECM degradation in OA joints Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 3 of 15 strategies to protect the chondrocytes and the cartilage Study selection represent potential new therapeutic modalities. All records of five databases were imported into the ref - Teriparatide (PTH (1–34)) contains 34 amino acids of erence management software program Endnote X 9.3.3. parathyroid hormone, which was applied on the treat- After the removal of duplicates, two authors (GQL and ment of osteoporosis (OP) and bone fracture [9, 10] by SL) independently reviewed the titles and abstracts of the maintaining calcium homeostasis, increasing cortical remaining records for relevance to the topic. Studies that and trabecular thickness, and stimulating bone forma- potentially or completely met the inclusion criteria were tion [11]. In addition, quantitative studies documented kept and full texts were retrieved. The two authors (GQL PTH (1–34) could mediate anabolic effects among chon - and SL) independently assessed the full texts to decide drocytes [12] by enhancing chondral regeneration [13] whether to keep the records or not. A consensus meeting and increasing ECM synthesis [14]. Experimental stud- with a third reviewer (FY) was used to resolve discrep- ies investigated the benefits of PTH (1–34) on OA piti - ancies. The final included studies were reviewed by all ful without frequent practice or systematic review (SR). authors for agreement. For these reasons, we reviewed the accessible research to update the effect of PTH (1–34) on OA. Data extraction The information of in  vivo and in  vitro studies was Methods extracted in the standardized information forms: (1) first Protocol author’s surname, year of publication, and country; (2) We performed this SR in accordance with the Preferred subjects; (3) intervention; (4) dose and duration of treat- Reporting Items for Systematic Review and Meta- ment; (5) route; and (6) findings. Two investigators (GQL Analysis (PRISMA) statements [15]. We recorded the and SL) independently reviewed and extracted informa- study protocol on the international Prospective Reg- tion from included studies. Disagreements were dis- ister of Systematic Reviews (PROSPERO) with code cussed with a third author (JW) to reach a consensus. CRD42022315089. Quality assessment Literature search strategy The methodological quality of the in  vivo studies was A comprehensive literature search was conducted in assessed by SYRCLE’s risk of bias tool [16] while the 5 databases (PubMed, Web of Science, Medline, the in  vitro studies with Checklist for Reporting In-vitro Cochrane Library, and Embase) from their inception to Studies (CRIS) instruction [17]. Two authors (GQL and February 2022. The Medical Subject Headings (MeSH) SL) independently assessed the methodological quality of terms and keywords were combined with boolean opera- the articles included, and discrepancies were resolved by tors, “OR” or “AND”. The MeSH terms and keywords discussion with a third author (FY). were as follows: “Teriparatide,” “hPTH (1–34),” “Human Parathyroid Hormone (1–34),” “Parathar,” “Teriparatide Results Acetate,” “Forteo,” “Osteoarthritis,” “Osteoarthritides,” Identification of relevant studies “Osteoarthrosis,” “Osteoarthroses,” “Arthritis,” “Degener- The initial literature search resulted in 296 articles from ative,” “Arthritides,” “Degenerative,” “Degenerative Arth- PubMed (n = 35), Web of Science (n = 26), MEDLINE ritides,” “Degenerative Arthritis,” “Arthrosis,” “Arthroses,” (n = 90), the Cochrane Library (n = 101), and Embase “Osteoarthrosis Deformans.” In addition, the reference (n = 44) (Fig. 2). There are 152 duplicate records that were lists of all retrieved papers were further obtained manu- removed, and the remaining 144 records were screened ally. The search strategy of these five databases is pro - by title and 103 records were excluded. Next, 41 full- vided in Additional file 1. text articles were assessed for their eligibility. Nineteen were excluded for (1) review (n = 5); (2) research proto- Inclusion and exclusion criteria col (n = 3); (3) abstract only (n = 2); (4) commentaries or The eligible studies should meet the following criteria: editorials (n = 4); and (5) subjects treated without PTH (1) prospective and retrospective studies, randomized (1–34) (n = 5). In addition, 11 additional records were and controlled clinical trials; (2) patients or animal mod- added. Finally, 33 papers were considered and included. els with OA treated by PTH (1–34) directly or indirectly; and (3) studies published in the English language. Stud- In vivo studies showed potential effects of PTH (1–34) ies were excluded from this review if they were reviews, on OA models research protocols, abstracts only, commentaries, or According to the inclusion criteria, 22 in  vivo studies editorials. were included (Table  1). The studies were conducted in numerous countries including China (Shao et  al., Li et al. Arthritis Research & Therapy (2023) 25:3 Page 4 of 15 Fig. 2 PRISMA flowchart (Preferred Reporting Items for Systematic Reviews). A comprehensive literature search was conducted and from their inception to February, 2022 and of 33 studies were included ultimately 2020 [18]; Shao et  al., 2021 [19]; Chen et  al. 2021 [20]; and induce alterations in the microarchitecture of SCB Chen et  al. 2018 [21]; Rajalakshmanan et  al. 2012 [22]; to provoke early OA [31]. Moreover, PTH (1–34) would Ma et al. 2017 [23]; Zhang et al. 2022 [24]; Chang et al. stimulate articular cartilage and SCB repair [41]. Bellido 2009 [25]; Yan et al. 2014 [26]; Dai et al. 2016 [27]; Cui et  al. suggested that PTH (1–34) could improve micro- et  al. 2019 [28]; He et  al. 2021 [29];   Longo  et al. 2020 structural and remodeling parameters of SCB, which [30]), Germany (Orth et  al. 2014 [31]; Orth et  al. 2013 contributed to preventing cartilage damage and OA pro- [32]), and the USA (Dutra et  al. 2017 [33]; Sampson gression in OVX and ACLT rabbits [39]. et  al. 2011 [34]; Brien et  al. 2017 [35]; Bagi et  al. 2015 PTH (1–34) would reduce the predisposing factors [36]; Antunes et  al. 2013 [37]), Spain (Lugo et  al. 2012 for OA progression. At the dose of 40  μg/kg/day, Cui [38]; Bellido et al. 2011 [39]). et  al. believed that PTH (1–34) reduced the accumula- Studies implied that PTH (1–34) exhibited protec- tion of senescent cells in SCB by inhibiting p16 for age- tive effects on both cartilage and SCB. Shao et  al. con - related OA [28]. In addition, Sampson et  al. considered cluded similar findings among collagenase-induced OA that it might be useful to decelerate cartilage degenera- (CIOA) mouse models in a dose-dependent manner via tion among meniscal ligamentous injury (MLI) mice and the JAK2/STAT3 and WNT5A/ROR2 signaling path- induce ECM regeneration among OA patients [34]. Bagi way [18, 40]. At the dose of 10 μg/kg/day of PTH (1–34), et  al. concluded that PTH (1–34) would reduce joint Orth et  al. reported that PTH (1–34) could broaden the inflammation, curb excessive bone remodeling, improve calcified cartilage layer, result in cartilage degeneration, cartilage regeneration, and reduce pain in post-traumatic Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 5 of 15 Table 1 Characteristics of in vivo studies about the effect of teriparatide on OA Author (year, country) Subjects Intervention Dose (duration) Route Findings Shao et al. (2020, China) [18] CIOA mouse PTH (1–34) 10/40 μg/kg (6 weeks) SC PTH (1–34) exhibits protective effects on both cartilage and SCB in a dose-dependent manner via the JAK2/STAT3 signaling pathway Shao et al. (2021, China) [19] CIOA mouse PTH (1–34) 40 μg/kg (6 weeks) SC PTH (1–34) exhibits protective effects on both cartilage and SCB by down-regulating the expres- sion of JAK2/STAT3 and WNT5A/ ROR2 Chen et al. (2021, China) [20] Guinea pig PTH (1–34) 10 nM (12 weeks) IA PTH (1–34) improves spontane- ous OA by directly affecting the cartilage rather than the SCB or metaphyseal bone Chen et al. (2018, China) [21] ACLT Rats PTH (1–34) 10 nM (5 weeks) IA PTH (1–34) alleviates OA progres- sion after ACLT and histological molecular changes by reducing chondrocyte terminal differen- tiation and apoptosis and by increasing autophagy Eswaramoorthy et al. (2012, PIOA Rat PTH (1–34) 0.4 mg (5 weeks) IA PTH (1–34) has beneficial effects China) [22] on suppressing early OA progress PLGA microsphere-encapsulated PTH (1–34) with a controlled- release property represents a potent method to treat early OA Ma et al. (2017, China) [23] SD rats PTH (1–34) 15 μg/kg (2/6 weeks) SC PTH (1–34) up-regulates the Wnt/β-catenin signaling pathway and down-regulated RUNX2 through an alternative pathway Zhang et al. (2022, China) [24] Patellar ligament shortening PTH (1–34) 30 μg/kg (10 weeks) SC PTH (1–34) could improve carti- SD rats lage metabolism and SCB health in early PFJOA model Chang et al. (2009, China) [25] CIOA Rats PTH (1–34) 10 nM (10 days) SC PTH (1–34) treats early OA with- out affecting normal chondro - cytes, which might a potential effectiveness of the agent for OA treatment Yan et al. (2014, China) [26] Guinea pigs PTH (1–34) 15 μg/kg (3/6 months) SC PTH (1–34) prevents cartilage damage progression and retard the deterioration of SCB Dai et al. (2016, China) [27] Guinea pigs PTH (1–34) 24 μg/kg (12 weeks) SC Both celecoxib and PTH (1–34) exhibit protective effects on cartilage degeneration in menisc- ectomized guinea pigs PTH (1–34) exhibits superior per- formance to celecoxib not only in metabolism of cartilage tissue but also in maintenance of SCB micro-architecture Cui et al. (2019, China) [28] C57BL/6 J PTH (1–34) 40 μg/kg (4 weeks) SC PTH (1–34) reduces the accumu- lation of senescent cells in SCB by inhibiting p16 and improves bone marrow microenvironment to active bone remodeling process, indicating a potential preventa- tive and therapeutic treatment for age-related OA Li et al. Arthritis Research & Therapy (2023) 25:3 Page 6 of 15 Table 1 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings He et al. (2021, China) [29] DMM OA mice PTH (1–34) 80 μg/kg (4 weeks) SC PTH (1–34) has an obvious analgesic and anti-inflammatory effect, inhibits the matrix synthesis, and alleviates the OA progression PTH (1–34) inhibited TNF-α expression and antagonized TNF- α-induced MMP13 expression via the PKA pathway and the NF-κB signaling pathways Longo et al. (2020, China) [30] Meniscectomy Dogs PTH (1–34) 2.4 μg/kg (3 weeks) IA PTH (1–34) promotes the regen- erative and chondroprotective effects of the tissue-engineered meniscus total implantation in a canine model by inhibiting the terminal differentiation of BMSC chondrogenesis and degenera- tion of knee joint cartilage Orth et al. (2014, Germany) [31] Rabbits PTH (1–34) 10 mg/kg (6 weeks) SC PTH (1–34) causes broadening of the calcified cartilage layer and resulting in osteoarthritic cartilage degeneration PTH (1–34)-induced alterations of the normal SCB microarchitecture may provoke early OA Orth et al. (2013, Germany) [32] Rabbits osteochondral defects PTH (1–34) 10 μg/kg (6 weeks) SC PTH (1–34) stimulates articular cartilage and SCB repair, which emerges as a promising agent in the treatment of focal osteochon- dral defects Dutra et al. (2017, USA) [33] C57BL/6 J PTH (1–34) 80 μg/kg (21 days) SC PTH (1–34) results in early miner- alization of the MCC and cartilage degeneration PTH (1–34) induces alteration in the microarchitecture of the MCC and the SCB Sampson et al. (2011, USA) [34] MLI OA mice PTH (1–34) 40 μg/kg (8 weeks) SC PTH (1–34) may be useful for decelerating cartilage degenera- tion and inducing matrix regen- eration in OA model O’Brien et al. (2017, USA) [35] Transgenic mice PTH (1–34) 80 μg/kg (2 weeks) SC PTH (1–34) increases the number of Col1a1/Col2a1/Col10a1-posi- tive cells; bone volume fraction, tissue density and trabecular thickness of the SCB; proteogly- can distribution with a concomi- tant increase in MCC mineraliza- tion; chondrocytes differentiation and increases mineralization Bagi et al. (2015, USA) [36] Posttraumatic OA Rats PTH (1–34) 40 μg/kg (10 weeks) SC A single drug will have the capac- ity to reduce joint inflammation, curb excessive bone remodeling, improve cartilage regeneration, and reduce pain Both Zol and PTH does not pre- vent or correct the deterioration of the hyaline cartilage, thicken- ing of the SCB plate, osteophyte formation, and mechanical incapacity of the OA Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 7 of 15 Table 1 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings Antunes et al. (2013, USA) [37] Prg4 mutant mice PTH (1–34) 50 μg/kg (6 weeks) SC SCB contributes to the disruption of the articular cartilage in Prg4 mutant mice PTH (1–34) could not demon- strate a protective effect in the arthropathic joints because of Prg4 mutant Lugo et al. (2012, Spain) [38] OVX and ACLT rabbits PTH (1–34) 10 mg/kg (10 weeks) SC PTH (1–34) ameliorates OA by improving SCB integrity, inhibit- ing cartilage degradation, and exerting certain beneficial effects on synovial changes PTH (1–34) exhibits direct benefi- cial effects upon the synovium of this experimental model PTH (1–34) administration might hold a potential as therapeutic option for synoviopathy associ- ated with OA Bellido et al. (2011, Spain) [39] OVX and ACLT rabbits PTH (1–34) 10 μg/kg (10 weeks) SC PTH (1–34) prevents cartilage damage progression and micro- structural and remodeling of SCB in rabbits with early OPOA OA Osteoarthritis, CIOA Collagenase-induced osteoarthritis, PTH (1–34) Teriparatide, SC Subcutaneous injection, SCB Subchondral bone, IA Intra-articular, ACLT Anterior cruciate ligament transection, MCC Mandibular condylar cartilage, PLGA Poly lactic-co-glycolic acid, PIOA Induced osteoarthritis, OVX Ovariectomized, SD Sprague– Dawley, PFJOA Patellofemoral joint osteoarthritis, nM nmol/L, MLI Meniscal ligamentous injury, OPOA Osteoarthritis preceded by osteoporosis, DMM Destabilization of the medial meniscus OA rats [36]. At the dose of 80  μg/kg/day of PTH injection suppressed early stages of OA in papain- (1–34), Dutra et  al. found that it could result in miner- induced OA (PIOA) rats [22]. Chen et  al. suggested alization and alteration of the mandibular condylar car- that PTH (1–34) improved spontaneous OA by directly tilage (MCC), with cartilage degeneration and abnormal affecting the cartilage rather than the SCB or metaphy - remodeling of the SCB [33]. He et al. concluded that PTH seal bone [43], reduce chondrocyte terminal differentia - (1–34) had an obvious analgesic and anti-inflammatory tion and apoptosis, and increase autophagy on ACLT rats effect on DMM mice via the PKA and the NF-κB sign - via IA injection [44]. Longo et  al. concluded that PTH aling pathways [29]. Brien et  al. concluded that it would (1–34) promoted the regenerative and chondroprotective increase the differentiation and mineralization of chon - effects of the tissue-engineered meniscus by inhibiting drocytes as well as density of the SCB among the trans- the differentiation of mesenchymal stem cells (BMSC) genic mice [35]. chondrogenesis and cartilage degeneration among the PTH (1–34) prevents cartilage damage and retards the meniscectomy dogs [30], which represented a promis- deterioration of SCB. Yan et al. concluded that 15 μg/kg/ ing method to increase the chance of regeneration in the day of PTH (1–34) protected the cartilage among guinea tissue-engineered meniscus. pigs [26]. Dai et  al. found that 24  μg/kg/day of PTH (1–34) exhibited protective effects on cartilage degen - In vitro studies showed potential mechanism of PTH (1–34) eration among meniscectomy guinea pigs, which exhib- intracellularly ited superior performance to celecoxib in both cartilage Based on the inclusion criteria, 11 in  vitro investiga- metabolism and maintenance of SCB micro-architecture tions were included in the SR (Table  2). These studies [27]. Antunes et  al. argued that SCB contributed to the were conducted in numerous countries including China disruption of the cartilage, but PTH (1–34) protected the (Chang et al. 2009 [25], Shao et al. 2022 [45]; Chang et al. destruction of the SCB [37]. Zhang et  al. supposed that 2016 [46]), Canada (Mwale et  al. 2010 [47]), USA (Funk PTH (1–34) improved cartilage metabolism and SCB et al. 1998 [48]), Sweden (Petersson et al. 2006 [49]), Aus- health on patellar ligament shortening SD rats [42]. tralia (Music et al. 2020 [50]), Japan (Tsukazaki et al. 1996 Different routines would differ the effect of PTH [51]; Dogaki et al. 2016 [52]; Hosokawa et al. 2015 [53]), (1–34). Eswaramoorthy et  al. found that controlled- and Netherlands (Rutgers et al. 2019 [54]). release property of PTH (1–34) via intra-articular (IA) Li et al. Arthritis Research & Therapy (2023) 25:3 Page 8 of 15 Table 2 Characteristics of in vitro studies about the effect of teriparatide on OA Author (year, country) Subjects Intervention Dose (duration) Route Findings Chang et al. (2009, China) [25] Human articular PTH (1–34) 10 nM (10 days) Co-culture PTH (1–34) reverses the chondrocytes progression of terminal differ - entiation of human articular chondrocytes PTH (1–34) could be used to treat early OA without affect - ing normal chondrocytes Shao et al. (2022, China) [45] BMSCs PTH (1–34) 10 nM (48 h) Co-culture PTH (1–34) alleviates OA by increasing the migration, pro- liferation, and chondral matrix formation of OA chondrocytes by inhibiting proinflammatory cytokines −8 −7 Chang et al. (2016, China) [46] Human articular PTHrP 10 to 10 M (7 days) Co-culture PTH (1–34) is beneficial for chondrocyte preventing the chondro- degenerative changes initiated by dexamethasone treatment Mwale et al. (2010, Canada) [47] Human MSCs PTH (1–34) 100 nM (48 h) Co-culture p38 and AKT protein kinase signaling pathways may not be required to initiate the regulation of expression of COLII and COLX by PTH (1–34), which is necessary for preventing precocious MSC hypertrophy Funk et al. (1998, USA) [48] RA and OA synovial PTHrP (1–40)/ 0.3 pM (24 h) Co-culture Proinflammatory cytokine- tissue PTHrP (60–72)/ stimulated production of NH2 PTHrP (1–86) terminal PTHrP by synovial tis- sue directly invading cartilage and bone in RA, which might mediate joint destruction through direct effects on cartilage or indirectly via the induction of mediators of bone resorption Petersson et al. (2006, Sweden) [49] RA or OA Chondro- PTHrP (1–34) 0.1 to 100 nM (15 days) Co-culture PTHrP (1–34) increases pro- cytes liferation of human chondro- cytes PTHrP (1–34) increases the amount of YKL-40 from chondrocytes derived from RA patients Music et al. (2020, Australia) [50] BMSCs PTH (1–34) 0, 1, 10, or 100 nM (14 days) Co-culture PTH (1–34) suppresses BMSC hypertrophic gene expression in chondrogenic cultures PTH (1–34) has an anti- hypertrophic effect and a catabolic effect on BMSC as they become increasingly differentiated −13 −7 Tsukazaki et al. (1996, Japan) [51] Human chondrocytes PTH (l–34)/ 10 to 10 M (120 min) Co-culture PTHrP is thought to be an hPTHrP important autocrine/parac- (l–141)/hPTHrP rine factor for chondrocyte (100–114) metabolism No significant difference of exogenously PTHrP (1–141) regard to the action of these agents, cell growth, differen- tiation Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 9 of 15 Table 2 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings Dogaki et al. (2016, Japan) [52] Hematoma-derived PTH (1–34) 100 nM (14 days) Co-culture Pulsatile PTH (1–34) works on progenitor cells human cartilages in regarding to proliferation, osteogenic, and chondrogenic differen- tiation PTH (1–34) administration after fracture might positively act on other cells that contrib- ute to fracture healing −10 −9 −8 Hosokawa et al. (2015, Japan) [53] ATDC5 cells PTH (1–34) 10 /10 /10 M Co-culture PTH (1–34) regulates ATDC5 (21 days) cells in both chondrogenesis and the circadian clock as time-dependent properties of chondrocyte function and differentiation Rutgers et al. (2019, Netherlands) [54] Human chondrocytes PTH (1–34) 0.1 or 1.0 μM (4 weeks) Co-culture PTH (1–34) inhibits healthy human articular chondrocytes regeneration other than hypertrophic differentiation PTH (1–34) may be suitable for cartilage repair based on MSCs OA Osteoarthritis, BMSCs Bone marrow mesenchymal stem cells, PTH (1–34) Teriparatide, nM nmol/L, PTHrP Parathyroid hormone-related protein, M mol/L, MSC Mesenchymal stem cells, COL II Type II collagen, COLX Type X collagen, RA Rheumatoid arthritis, pM pmol/L, μM μmol/L As for the effects on human articular chondrocytes, PTH (1–34) protected MSC with various effects. Shao PTH (1–34) influenced its differentiation and regen - et  al. maintained that PTH (1–34) worked on MSC by eration. Tsukazaki et  al. concluded that PTHrP was an increasing the migration, proliferation, ECM formation, important autocrine and paracrine factor for chondro- and inhibiting proinflammatory cytokines [56]. Mwale cyte metabolism as for cell growth and differentiation et  al. argued that PTH (1–34) helped to prevent preco- [51]. Rutgers et  al. suggested that PTH (l–34) inhib- cious MSC hypertrophy [47]. Music et  al. believed that ited healthy human articular chondrocyte regeneration PTH (1–34) suppressed MSC hypertrophic [50]. Dogaki but did not influence hypertrophic differentiation [54]. et  al. implied that PTH (1–34) may not have a positive Chang et  al. concluded that PTH (l–34) could reverse effect at the fracture site because no positive effect was the terminal differentiation of chondrocytes without noticed when the fracture haematoma-derived progeni- affecting normal chondrocytes, while PTHrP prevented tor cells were treated with PTH (1–34) [52]. Hosokawa the chondrocyte degeneration initiated by dexametha- et al. indicated that PTH (1–34) could reset the circadian sone [25]. Moreover, Chang et al. held that PTH (1–34) rhythm of ATDC5 cells, which is expected to be useful treated early OA without affecting normal chondro - to assess the molecular mechanisms of PTH (1–34) on cytes [55]. When PTH (1–34) was applied for RA or OA chondrogenic differentiation [53]. PTH (1–34) played chondrocytes treatment, the survival and inflammatory a significant role in chondrocytes through affecting the cytokines would be affected. Petersson et al. found that proliferation and ECM synthesis. PTH (1–34) increased the proliferation of chondrocytes from human and RA patients [49]. However, Funk et al. Quality assessment of included studies revealed that the PTHrP could be examined in syn- Methodological quality was assessed for all 33 involved ovium and synoviocytes obtained from RA patients, studies (Fig. 3). An unclear risk of selection bias (because which help to clarify the pathogenesis of RA to a cer- of lacking data regarding randomization method: n = 16); tain extent and remain to be investigated further [48]. In detection bias (blinding of outcome assessment, n = 20); addition, Lugo et al. found that PTH (1–34) ameliorated performance bias (because of absent data about blinding OA by improving SCB integrity, inhibiting cartilage of subjects, n = 11), attrition bias (n = 17), reporting bias degradation, and exerting effects on synovial changes (n = 21), and other bias (n = 15) were found. [38]. PTH (1–34) held potential therapeutic option for synoviopathy associated with OA. Li et al. Arthritis Research & Therapy (2023) 25:3 Page 10 of 15 Fig. 3 Risk of bias assessment across the studies (n = 33). Methodological quality was assessed for all involved studies Discussion also enhanced COLII and AGC [26, 42]. Moreover, PTH To our knowledge, this is the first SR evaluating the (1–34) reversed terminal differentiation towards hyper - existing papers about the effect of PTH (1–34) on OA trophy and decreased apoptosis of chondrocytes [46, 47]. regarding in  vivo and in  vitro investigations. The chon - The anabolic effects of PTH (1–34) on both cartilage dro-protective and cartilage-regenerative effects were and SCB were explained by multiple mechanisms (Fig. 4). reviewed, indicating that PTH (1–34) might be a poten- The activation of NF-κB elevated inflammatory media - tial preventative and therapeutic treatment for OA. tors of IL-1β, TNF-α, cyclooxygenase-2 (COX2), and OA is the most prevalent degenerative joint disease inducible nitric oxide synthase (iNOS), which resulted in with complicated pathogenesis characterized with dam- the initiation of OA and regulated the levels of MMP13 age to cartilage, narrow synovial cavity, invasion of the [62]. It is well established that the parathyroid 1 recep- SCB, formation of osteophytes, and synovitis [57]. OP is tor (PTH1R) was a key regulator to induce differentiation a metabolic bone disease with decreased bone strength and endochondral ossification by inducing ECM syn - but increased fracture risk. OP and OA are common thesis, suppressing maturation, and inhibiting degenera- clinical conditions with high prevalence among older tion [20]. PTH (1–34) elevated the expression of PTH1R, adults. Antiresorptive agents exhibited effects on bone osteoprotegerin (OPG), and receptor activator of NF-κB mineralization and cartilage degradation for OA or ligand (RANKL) via the OPG/RANKL/RANK signaling OPOA [58]. However, treatments with polypharmacy pathway [26]. The Notch pathway was activated by PTH for OA are limited to pain relief with less effective, which (1–34) with increased expression of JAGGED1 [63]. The should be individualized to reduce the risk of side effects expression of TNF-α was inhabited by PTH (1–34) via [59]. And therefore, DMOADs are highly demanded for the PKA signaling pathway [29]. PTH (1–34) inhibited OA or OPOA. chondrocyte differentiation towards hypertrophy via the Quantitative studies indicated that PTH (1–34) played p38 and the p-AKT signaling pathway [47]. PTH (1–34) a significant role in calcium metabolism with an anabolic downregulated JAK2/STAT3 and Wnt5A/ROR2 [19] but effect in the treatment of OP, fracture healing, non-union upregulated the Wnt/β-catenin through an alternative and stress fracture, augmentation of implant fixation, signaling pathway [64]. and chondro-protection in OA [14, 60]. In addition, In addition, the attenuation of signaling pathways PTH (1–34) could be a systemic pharmacology for OA including oxidative stress and apoptosis had an indispen- by influencing cartilage quality such as ECM and chon - sable role in OA. Autophagy was a protective mechanism drocyte contents [61]. The effects of PTH (1–34) were in normal cartilage. PTH (1–34) alleviated OA pro- involved in decreasing COLX or RUNX2 but increas- gression by reducing terminal differentiation, reducing ing AGC [34], which not only inhibited matrix metal- apoptosis, and increasing autophagy via the mechanis- lopeptidase 13 (MMP13) or ADAM metallopeptidase tic target of rapamycin (mTOR) and p62 [21]. Apoptosis with thrombospondin type 1 motif 4 (ADAMTS4), but was reversed, while both Bcl-2 and Bax were upregulated Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 11 of 15 Fig. 4 Relevant mechanisms of PTH (1–34) in the chondrocytes. The chondrocyte-protective and chondrocyte-regenerative effect of PTH (1–34) were explained by multiple mechanisms by PTH (1–34). Moreover, PTH (1–34) might reduce extraordinary lubrication, attributed to structures as well the accumulation of senescent cells by inhibiting p16 as the cellular constitutions. However, both synovitis [28]. Both the sustained and intermittent action of PTH and OP contributed to cartilage degradation [68] but all (1–34) suppressed OA effectively [22, 65]. IA application pathology above could be suppressed by PTH (1–34) [69]. would directly affect the cartilage rather than the SCB or Impairment of SCB aggravated cartilage damage in early metaphyseal bone [43]. PTH (1–34) inhibited the termi- OPOA rabbits [39] and is associated with weight-bearing nal differentiation of human chondrocytes in  vitro and pain [70]. Overall, PTH (1–34) exhibited protective effects inhibits OA progression in rats in  vivo [25]. PTHrP was on the change of synovitis as well as pain relief. up-regulated and mediated by calcium-sensing receptor Clinically, resorption played a significant role while in OA cartilage, which might promote both proliferation PTH (1–34) was a reasonable option for OP patients of chondrocyte and osteophyte formation [66]. Stimula- [71]. Successful osteoanabolic treatment with PTH tion of focal osteochondral defect, enhancement of allo- (1–34) benefited symptomatic stress concentration graft bone union, and differentiation of MSCs are various with completely stem tip pain-free [72]. The peripros - effects of PTH (1–34) in tissue engineering [32, 67]. thetic BMD was preserved after total hip arthroplasty An ideal DMOAD can not only repair and regenerate (THA) [73] while bone ingrowth was promoted after cartilage, but also alleviate inflammation of synovium and total knee arthroplasty (TKA) [74] enforced by PTH pain. Healthy synovial joints are capable of maintaining (1–34). In addition, nonunion of periprosthetic fracture Li et al. Arthritis Research & Therapy (2023) 25:3 Page 12 of 15 DMM Destabilization of the medial meniscus after TKA benefited from PTH (1–34) as well [75]. SD Sprague–Dawley However, early mineralization of the MCC caused by nM Nmol/L PTH (1–34) might shift modifications of the subar - PIOA Papain-induced osteoarthritis MSCs Mesenchymal stem cells ticular spongiosa. Overall, we had better use the PTH M mol/L (1–34) in proper situations and dosages. RA Rheumatoid arthritis There are some limitations in our current review. PTHrP Parathyroid hormone-related protein COLX Type X collagen Firstly, the present review cannot identify the mecha- MMP13 Matrix metallopeptidase 13 nisms accounting for the precious mechanism of PTH ADAMTS4 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 4 (1–34) on OA. Further research evidence is needed to PTH1R Parathyroid 1 receptor OPG Osteoprotegerin deepen our current review. Secondly, although a thor- RANKL Receptor activator of NF-κB ligand ough search was performed from five English databases, COX2 Cyclooxygenase-2 some pertinent studies may still have been missed. iNOS Inducible nitric oxide synthase MAPK Mitogen-activated protein kinase Thirdly, limited information in the current reviewed mTOR Target of rapamycin investigations is an urgent call for subsequent studies to THA Total hip arthroplasty confirm the findings based on additional information. TKA Total knee arthroplasty SC Subcutaneous injection Finally, there are only included studies published in Eng- IA Intra-articular lish; thereby, some studies in other languages would be PFJOA Patellofemoral joint osteoarthritis missed out. pM pmol/L μM μmol/L Supplementary Information Conclusion The online version contains supplementary material available at https:// doi. In conclusion, the SR, which included both in  vivo and org/ 10. 1186/ s13075- 022- 02981-w. in  vitro studies, described the beneficial effects of PTH (1–34) on OA via alleviating cartilage damage progres- Additional file 1. Search strategy sion, inhibiting the abnormal SCB remodeling, suppress- ing synovitis, reducing oxidative stress or apoptosis of Acknowledgements chondrocytes, and elevating autophagy. Some of the OA All persons who have made substantial contributions to the work reported in or OAOP patients might benefit from PTH (1–34) as the manuscript but do not meet the criteria for authorship are named in the Acknowledgements. We especially thank professor Yingqi Chen, Anjaneyulu well. The present SR is a description of existing studies Udduttula, Xiaoyan Huang, Jianchen, and Canhui Cao, who offered their kind regarding the effectiveness of PTH (1–34) administration assistance in writing, editing, reviewing, technical help, and general support in in OA together with mechanisms, which suggested the methodology. necessity for further clinical trials and animal investiga- Authors’ contributions tions to achieve concise conclusions about the effects of GL: investigation, methodology, data curation, formal analysis, writing—original PTH (1–34) on OA. draft, writing—review, editing. SL: investigation, methodology. HX: methodol- ogy, writing—review, editing. YC: investigation, methodology. JD: investigation, methodology. AX: methodology. DW: methodology. JW: investigation, review. FY: investigation, review. LG: investigation, review. CD: investigation, review. HZ: Abbreviations investigation, conceptualization, supervision, funding acquisition, resources, PTH (1–34) Teriparatide review, editing. The authors read and approved the final manuscript. OA Osteoarthritis SR Systematic review Authors’ information SCB Subchondral bone Not applicable. ECM Extracellular matrix COL II T ype II collagen Funding AGC Aggrecan This study was supported by grants from National Natural Science Foundation TNF-α Tumor necrosis factor-α of China (No. 82172432), Guangdong Basic and Applied Basic Research Foun- IL-1β Interleukin-1β dation (No. 2021A1515012586), Shenzhen Key Medical Subject (No. SZXK023), DMOADs Disease-modifying OA drugs Shenzhen “San-Ming” Project of Medicine (No. SZSM201612092), and the OP Osteoporosis Scientific Research Foundation of Peking University Shenzhen Hospital (No. PRISMA Preferred Reporting Items for Systematic Review and KYQD2021099). Meta-Analysis PROSPERO Prospective Register of Systematic Reviews Availability of data and materials MeSH M edical Subject Headings Data are available from the corresponding authors upon reasonable request CRIS Checklist for Reporting In-vitro Studies with the permission of Department of Bone and Joint Surgery in Peking CIOA Collagenase-induced osteoarthritis University Shenzhen Hospital. OPOA Osteoporotic osteoarthritis OVX Ovariectomized ACLT Ant erior cruciate ligament transection MLI Meniscal ligamentous injury MCC Mandibular condylar cartilage Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 13 of 15 17. Krithikadatta J, Gopikrishna V, Datta M. CRIS Guidelines (Checklist for Declarations Reporting In-vitro Studies): a concept note on the need for standard- ized guidelines for improving quality and transparency in reporting Ethics approval and consent to participate in-vitro studies in experimental dental research. Journal of conservative Not applicable. dentistry : JCD. 2014;17(4):301–4. 18. Shao LT, Gou Y, Fang JK, Hu YP, Lian QQ, Zhang YY, Wang YD, Tian FM, Consent for publication Zhang L. Parathyroid hormone (1–34) ameliorates cartilage degeneration Not applicable. and subchondral bone deterioration in collagenase-induced osteoarthri- tis model in mice. Bone Joint Res. 2020;9(10):675–88. Competing interests 19. Shao LT, Gou Y, Fang JK, Hu YP, Lian QQ, Yang Z, Zhang YY, Wang YD, Tian The authors declare that they have no competing interests. FM, Zhang L. The protective effects of parathyroid hormone (1–34) on cartilage and subchondral bone through down-regulating JAK2/STAT3 and WNT5A/ROR2 in a collagenase-induced osteoarthritis mouse model. Received: 9 September 2022 Accepted: 19 December 2022 Orthop Surg. 2021;13(5):1662–72. 20. Chen CH, Kang L, Chang LH, Cheng TL, Lin SY, Wu SC, Lin YS, Chuang SC, Lee TC, Chang JK, et al. 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Potential effects of teriparatide (PTH (1–34)) on osteoarthritis: a systematic review

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Abstract

Osteoarthritis (OA) is a common and prevalent degenerative joint disease characterized by degradation of the articu- lar cartilage. However, none of disease-modifying OA drugs is approved currently. Teriparatide (PTH (1–34)) might stimulate chondrocyte proliferation and cartilage regeneration via some uncertain mechanisms. Relevant therapies of PTH (1–34) on OA with such effects have recently gained increasing interest, but have not become widespread prac- tice. Thus, we launch this systematic review (SR) to update the latest evidence accordingly. A comprehensive literature search was conducted in PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase from their inception to February 2022. Studies investigating the effects of the PTH (1–34) on OA were obtained. The quality assessment and descriptive summary were made of all included studies. Overall, 307 records were identified, and 33 studies were included. In vivo studies (n = 22) concluded that PTH (1–34) slowed progression of OA by alleviating cartilage degeneration and aberrant remodeling of subchondral bone (SCB). Moreover, PTH (1–34) exhibited repair of cartilage and SCB, analgesic, and anti-inflammatory effects. In vitro studies (n = 11) concluded that PTH (1–34) was important for chondrocytes via increasing the proliferation and matrix synthesis but preventing apoptosis or hypertrophy. All included studies were assessed with low or unclear risk of bias in methodological quality. The SR demonstrated that PTH (1–34) could alleviate the progression of OA. Moreover, PTH (1–34) had beneficial effects on osteoporotic OA (OPOA) models, which might be a therapeutic option for OA and OPOA treatment. Keywords Teriparatide, Osteoarthritis, Systematic review, Treatment Background Guoqing Li, Su Liu, and Huihui Xu contributed equally to this work. Osteoarthritis (OA) is a common musculoskeletal dis- *Correspondence: order and prevalent degenerative disease worldwide [1, Liang Gao 2]. Both non-load bearing and load-bearing joints are lianggao@web.de Changhai Ding affected by multiple factors such as trauma, senility, gen - changhai.ding@utas.edu.au der, genetics, and obesity [3], which resulted in functional Hui Zeng disability or decreased quality of life. Articular cartilage zenghui_36@163.com Department of Bone & Joint Surgery, Peking University Shenzhen is an avascular tissue, while chondrocytes are unique cel- Hospital, Shenzhen 518036, People’s Republic of China lular components and responsible for the maintenance National & Local Joint Engineering Research Center of Orthopaedic of the extracellular matrix (ECM) via the balance of Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, People’s Republic of China catabolism and anabolism. Type II collagen (COL II) and Center for Clinical Medicine, Huatuo Institute of Medical Innovation aggrecan (AGC) are secreted proteins, which are essen- (HTIMI), Berlin, Germany tial for the integrity of cartilage. Break-down of chon- Sino Euro Orthopaedics Network (SEON), Berlin, Germany Clinical Research Centre, Zhujiang Hospital, Southern Medical University, drocytes is one of the molecular characteristics of OA, Guangzhou, People’s Republic of China which is characterized by progressive damage including © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. Arthritis Research & Therapy (2023) 25:3 Page 2 of 15 cartilage erosion, synovitis, and subchondral bone (SCB) Recommendation of OA treatment includes physi- disturbance. The normal metabolism of cartilage is dis - otherapy, pharmacological, and surgical interventions turbed by inflammatory cytokines such as tumor necro - [6, 7]. Physiotherapy should be advocated due to its sis factor-α (TNF-α) and interleukin-1β (IL-1β), shifting safety and effectiveness. However, limited choices and to catabolism and ECM degradation [4]. Oxidative stress less effectiveness of drugs were restricted to symptom and apoptosis generate the decrease of chondrocytes and relief and accompanied by adverse effects [8 ]. Currently, loss of cartilage [5]. The schematic diagram of normal no disease-modifying OA drugs (DMOADs) are avail- and osteoarthritic joint was illustrated in Fig. 1. able to alleviate the progression of OA. And therefore, Fig. 1 The schematic structures of normal (left part) and osteoarthritic (right part) joint. Multiple factors and pro-inflammatory cytokines resulting chondrocytes catabolism and ECM degradation in OA joints Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 3 of 15 strategies to protect the chondrocytes and the cartilage Study selection represent potential new therapeutic modalities. All records of five databases were imported into the ref - Teriparatide (PTH (1–34)) contains 34 amino acids of erence management software program Endnote X 9.3.3. parathyroid hormone, which was applied on the treat- After the removal of duplicates, two authors (GQL and ment of osteoporosis (OP) and bone fracture [9, 10] by SL) independently reviewed the titles and abstracts of the maintaining calcium homeostasis, increasing cortical remaining records for relevance to the topic. Studies that and trabecular thickness, and stimulating bone forma- potentially or completely met the inclusion criteria were tion [11]. In addition, quantitative studies documented kept and full texts were retrieved. The two authors (GQL PTH (1–34) could mediate anabolic effects among chon - and SL) independently assessed the full texts to decide drocytes [12] by enhancing chondral regeneration [13] whether to keep the records or not. A consensus meeting and increasing ECM synthesis [14]. Experimental stud- with a third reviewer (FY) was used to resolve discrep- ies investigated the benefits of PTH (1–34) on OA piti - ancies. The final included studies were reviewed by all ful without frequent practice or systematic review (SR). authors for agreement. For these reasons, we reviewed the accessible research to update the effect of PTH (1–34) on OA. Data extraction The information of in  vivo and in  vitro studies was Methods extracted in the standardized information forms: (1) first Protocol author’s surname, year of publication, and country; (2) We performed this SR in accordance with the Preferred subjects; (3) intervention; (4) dose and duration of treat- Reporting Items for Systematic Review and Meta- ment; (5) route; and (6) findings. Two investigators (GQL Analysis (PRISMA) statements [15]. We recorded the and SL) independently reviewed and extracted informa- study protocol on the international Prospective Reg- tion from included studies. Disagreements were dis- ister of Systematic Reviews (PROSPERO) with code cussed with a third author (JW) to reach a consensus. CRD42022315089. Quality assessment Literature search strategy The methodological quality of the in  vivo studies was A comprehensive literature search was conducted in assessed by SYRCLE’s risk of bias tool [16] while the 5 databases (PubMed, Web of Science, Medline, the in  vitro studies with Checklist for Reporting In-vitro Cochrane Library, and Embase) from their inception to Studies (CRIS) instruction [17]. Two authors (GQL and February 2022. The Medical Subject Headings (MeSH) SL) independently assessed the methodological quality of terms and keywords were combined with boolean opera- the articles included, and discrepancies were resolved by tors, “OR” or “AND”. The MeSH terms and keywords discussion with a third author (FY). were as follows: “Teriparatide,” “hPTH (1–34),” “Human Parathyroid Hormone (1–34),” “Parathar,” “Teriparatide Results Acetate,” “Forteo,” “Osteoarthritis,” “Osteoarthritides,” Identification of relevant studies “Osteoarthrosis,” “Osteoarthroses,” “Arthritis,” “Degener- The initial literature search resulted in 296 articles from ative,” “Arthritides,” “Degenerative,” “Degenerative Arth- PubMed (n = 35), Web of Science (n = 26), MEDLINE ritides,” “Degenerative Arthritis,” “Arthrosis,” “Arthroses,” (n = 90), the Cochrane Library (n = 101), and Embase “Osteoarthrosis Deformans.” In addition, the reference (n = 44) (Fig. 2). There are 152 duplicate records that were lists of all retrieved papers were further obtained manu- removed, and the remaining 144 records were screened ally. The search strategy of these five databases is pro - by title and 103 records were excluded. Next, 41 full- vided in Additional file 1. text articles were assessed for their eligibility. Nineteen were excluded for (1) review (n = 5); (2) research proto- Inclusion and exclusion criteria col (n = 3); (3) abstract only (n = 2); (4) commentaries or The eligible studies should meet the following criteria: editorials (n = 4); and (5) subjects treated without PTH (1) prospective and retrospective studies, randomized (1–34) (n = 5). In addition, 11 additional records were and controlled clinical trials; (2) patients or animal mod- added. Finally, 33 papers were considered and included. els with OA treated by PTH (1–34) directly or indirectly; and (3) studies published in the English language. Stud- In vivo studies showed potential effects of PTH (1–34) ies were excluded from this review if they were reviews, on OA models research protocols, abstracts only, commentaries, or According to the inclusion criteria, 22 in  vivo studies editorials. were included (Table  1). The studies were conducted in numerous countries including China (Shao et  al., Li et al. Arthritis Research & Therapy (2023) 25:3 Page 4 of 15 Fig. 2 PRISMA flowchart (Preferred Reporting Items for Systematic Reviews). A comprehensive literature search was conducted and from their inception to February, 2022 and of 33 studies were included ultimately 2020 [18]; Shao et  al., 2021 [19]; Chen et  al. 2021 [20]; and induce alterations in the microarchitecture of SCB Chen et  al. 2018 [21]; Rajalakshmanan et  al. 2012 [22]; to provoke early OA [31]. Moreover, PTH (1–34) would Ma et al. 2017 [23]; Zhang et al. 2022 [24]; Chang et al. stimulate articular cartilage and SCB repair [41]. Bellido 2009 [25]; Yan et al. 2014 [26]; Dai et al. 2016 [27]; Cui et  al. suggested that PTH (1–34) could improve micro- et  al. 2019 [28]; He et  al. 2021 [29];   Longo  et al. 2020 structural and remodeling parameters of SCB, which [30]), Germany (Orth et  al. 2014 [31]; Orth et  al. 2013 contributed to preventing cartilage damage and OA pro- [32]), and the USA (Dutra et  al. 2017 [33]; Sampson gression in OVX and ACLT rabbits [39]. et  al. 2011 [34]; Brien et  al. 2017 [35]; Bagi et  al. 2015 PTH (1–34) would reduce the predisposing factors [36]; Antunes et  al. 2013 [37]), Spain (Lugo et  al. 2012 for OA progression. At the dose of 40  μg/kg/day, Cui [38]; Bellido et al. 2011 [39]). et  al. believed that PTH (1–34) reduced the accumula- Studies implied that PTH (1–34) exhibited protec- tion of senescent cells in SCB by inhibiting p16 for age- tive effects on both cartilage and SCB. Shao et  al. con - related OA [28]. In addition, Sampson et  al. considered cluded similar findings among collagenase-induced OA that it might be useful to decelerate cartilage degenera- (CIOA) mouse models in a dose-dependent manner via tion among meniscal ligamentous injury (MLI) mice and the JAK2/STAT3 and WNT5A/ROR2 signaling path- induce ECM regeneration among OA patients [34]. Bagi way [18, 40]. At the dose of 10 μg/kg/day of PTH (1–34), et  al. concluded that PTH (1–34) would reduce joint Orth et  al. reported that PTH (1–34) could broaden the inflammation, curb excessive bone remodeling, improve calcified cartilage layer, result in cartilage degeneration, cartilage regeneration, and reduce pain in post-traumatic Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 5 of 15 Table 1 Characteristics of in vivo studies about the effect of teriparatide on OA Author (year, country) Subjects Intervention Dose (duration) Route Findings Shao et al. (2020, China) [18] CIOA mouse PTH (1–34) 10/40 μg/kg (6 weeks) SC PTH (1–34) exhibits protective effects on both cartilage and SCB in a dose-dependent manner via the JAK2/STAT3 signaling pathway Shao et al. (2021, China) [19] CIOA mouse PTH (1–34) 40 μg/kg (6 weeks) SC PTH (1–34) exhibits protective effects on both cartilage and SCB by down-regulating the expres- sion of JAK2/STAT3 and WNT5A/ ROR2 Chen et al. (2021, China) [20] Guinea pig PTH (1–34) 10 nM (12 weeks) IA PTH (1–34) improves spontane- ous OA by directly affecting the cartilage rather than the SCB or metaphyseal bone Chen et al. (2018, China) [21] ACLT Rats PTH (1–34) 10 nM (5 weeks) IA PTH (1–34) alleviates OA progres- sion after ACLT and histological molecular changes by reducing chondrocyte terminal differen- tiation and apoptosis and by increasing autophagy Eswaramoorthy et al. (2012, PIOA Rat PTH (1–34) 0.4 mg (5 weeks) IA PTH (1–34) has beneficial effects China) [22] on suppressing early OA progress PLGA microsphere-encapsulated PTH (1–34) with a controlled- release property represents a potent method to treat early OA Ma et al. (2017, China) [23] SD rats PTH (1–34) 15 μg/kg (2/6 weeks) SC PTH (1–34) up-regulates the Wnt/β-catenin signaling pathway and down-regulated RUNX2 through an alternative pathway Zhang et al. (2022, China) [24] Patellar ligament shortening PTH (1–34) 30 μg/kg (10 weeks) SC PTH (1–34) could improve carti- SD rats lage metabolism and SCB health in early PFJOA model Chang et al. (2009, China) [25] CIOA Rats PTH (1–34) 10 nM (10 days) SC PTH (1–34) treats early OA with- out affecting normal chondro - cytes, which might a potential effectiveness of the agent for OA treatment Yan et al. (2014, China) [26] Guinea pigs PTH (1–34) 15 μg/kg (3/6 months) SC PTH (1–34) prevents cartilage damage progression and retard the deterioration of SCB Dai et al. (2016, China) [27] Guinea pigs PTH (1–34) 24 μg/kg (12 weeks) SC Both celecoxib and PTH (1–34) exhibit protective effects on cartilage degeneration in menisc- ectomized guinea pigs PTH (1–34) exhibits superior per- formance to celecoxib not only in metabolism of cartilage tissue but also in maintenance of SCB micro-architecture Cui et al. (2019, China) [28] C57BL/6 J PTH (1–34) 40 μg/kg (4 weeks) SC PTH (1–34) reduces the accumu- lation of senescent cells in SCB by inhibiting p16 and improves bone marrow microenvironment to active bone remodeling process, indicating a potential preventa- tive and therapeutic treatment for age-related OA Li et al. Arthritis Research & Therapy (2023) 25:3 Page 6 of 15 Table 1 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings He et al. (2021, China) [29] DMM OA mice PTH (1–34) 80 μg/kg (4 weeks) SC PTH (1–34) has an obvious analgesic and anti-inflammatory effect, inhibits the matrix synthesis, and alleviates the OA progression PTH (1–34) inhibited TNF-α expression and antagonized TNF- α-induced MMP13 expression via the PKA pathway and the NF-κB signaling pathways Longo et al. (2020, China) [30] Meniscectomy Dogs PTH (1–34) 2.4 μg/kg (3 weeks) IA PTH (1–34) promotes the regen- erative and chondroprotective effects of the tissue-engineered meniscus total implantation in a canine model by inhibiting the terminal differentiation of BMSC chondrogenesis and degenera- tion of knee joint cartilage Orth et al. (2014, Germany) [31] Rabbits PTH (1–34) 10 mg/kg (6 weeks) SC PTH (1–34) causes broadening of the calcified cartilage layer and resulting in osteoarthritic cartilage degeneration PTH (1–34)-induced alterations of the normal SCB microarchitecture may provoke early OA Orth et al. (2013, Germany) [32] Rabbits osteochondral defects PTH (1–34) 10 μg/kg (6 weeks) SC PTH (1–34) stimulates articular cartilage and SCB repair, which emerges as a promising agent in the treatment of focal osteochon- dral defects Dutra et al. (2017, USA) [33] C57BL/6 J PTH (1–34) 80 μg/kg (21 days) SC PTH (1–34) results in early miner- alization of the MCC and cartilage degeneration PTH (1–34) induces alteration in the microarchitecture of the MCC and the SCB Sampson et al. (2011, USA) [34] MLI OA mice PTH (1–34) 40 μg/kg (8 weeks) SC PTH (1–34) may be useful for decelerating cartilage degenera- tion and inducing matrix regen- eration in OA model O’Brien et al. (2017, USA) [35] Transgenic mice PTH (1–34) 80 μg/kg (2 weeks) SC PTH (1–34) increases the number of Col1a1/Col2a1/Col10a1-posi- tive cells; bone volume fraction, tissue density and trabecular thickness of the SCB; proteogly- can distribution with a concomi- tant increase in MCC mineraliza- tion; chondrocytes differentiation and increases mineralization Bagi et al. (2015, USA) [36] Posttraumatic OA Rats PTH (1–34) 40 μg/kg (10 weeks) SC A single drug will have the capac- ity to reduce joint inflammation, curb excessive bone remodeling, improve cartilage regeneration, and reduce pain Both Zol and PTH does not pre- vent or correct the deterioration of the hyaline cartilage, thicken- ing of the SCB plate, osteophyte formation, and mechanical incapacity of the OA Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 7 of 15 Table 1 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings Antunes et al. (2013, USA) [37] Prg4 mutant mice PTH (1–34) 50 μg/kg (6 weeks) SC SCB contributes to the disruption of the articular cartilage in Prg4 mutant mice PTH (1–34) could not demon- strate a protective effect in the arthropathic joints because of Prg4 mutant Lugo et al. (2012, Spain) [38] OVX and ACLT rabbits PTH (1–34) 10 mg/kg (10 weeks) SC PTH (1–34) ameliorates OA by improving SCB integrity, inhibit- ing cartilage degradation, and exerting certain beneficial effects on synovial changes PTH (1–34) exhibits direct benefi- cial effects upon the synovium of this experimental model PTH (1–34) administration might hold a potential as therapeutic option for synoviopathy associ- ated with OA Bellido et al. (2011, Spain) [39] OVX and ACLT rabbits PTH (1–34) 10 μg/kg (10 weeks) SC PTH (1–34) prevents cartilage damage progression and micro- structural and remodeling of SCB in rabbits with early OPOA OA Osteoarthritis, CIOA Collagenase-induced osteoarthritis, PTH (1–34) Teriparatide, SC Subcutaneous injection, SCB Subchondral bone, IA Intra-articular, ACLT Anterior cruciate ligament transection, MCC Mandibular condylar cartilage, PLGA Poly lactic-co-glycolic acid, PIOA Induced osteoarthritis, OVX Ovariectomized, SD Sprague– Dawley, PFJOA Patellofemoral joint osteoarthritis, nM nmol/L, MLI Meniscal ligamentous injury, OPOA Osteoarthritis preceded by osteoporosis, DMM Destabilization of the medial meniscus OA rats [36]. At the dose of 80  μg/kg/day of PTH injection suppressed early stages of OA in papain- (1–34), Dutra et  al. found that it could result in miner- induced OA (PIOA) rats [22]. Chen et  al. suggested alization and alteration of the mandibular condylar car- that PTH (1–34) improved spontaneous OA by directly tilage (MCC), with cartilage degeneration and abnormal affecting the cartilage rather than the SCB or metaphy - remodeling of the SCB [33]. He et al. concluded that PTH seal bone [43], reduce chondrocyte terminal differentia - (1–34) had an obvious analgesic and anti-inflammatory tion and apoptosis, and increase autophagy on ACLT rats effect on DMM mice via the PKA and the NF-κB sign - via IA injection [44]. Longo et  al. concluded that PTH aling pathways [29]. Brien et  al. concluded that it would (1–34) promoted the regenerative and chondroprotective increase the differentiation and mineralization of chon - effects of the tissue-engineered meniscus by inhibiting drocytes as well as density of the SCB among the trans- the differentiation of mesenchymal stem cells (BMSC) genic mice [35]. chondrogenesis and cartilage degeneration among the PTH (1–34) prevents cartilage damage and retards the meniscectomy dogs [30], which represented a promis- deterioration of SCB. Yan et al. concluded that 15 μg/kg/ ing method to increase the chance of regeneration in the day of PTH (1–34) protected the cartilage among guinea tissue-engineered meniscus. pigs [26]. Dai et  al. found that 24  μg/kg/day of PTH (1–34) exhibited protective effects on cartilage degen - In vitro studies showed potential mechanism of PTH (1–34) eration among meniscectomy guinea pigs, which exhib- intracellularly ited superior performance to celecoxib in both cartilage Based on the inclusion criteria, 11 in  vitro investiga- metabolism and maintenance of SCB micro-architecture tions were included in the SR (Table  2). These studies [27]. Antunes et  al. argued that SCB contributed to the were conducted in numerous countries including China disruption of the cartilage, but PTH (1–34) protected the (Chang et al. 2009 [25], Shao et al. 2022 [45]; Chang et al. destruction of the SCB [37]. Zhang et  al. supposed that 2016 [46]), Canada (Mwale et  al. 2010 [47]), USA (Funk PTH (1–34) improved cartilage metabolism and SCB et al. 1998 [48]), Sweden (Petersson et al. 2006 [49]), Aus- health on patellar ligament shortening SD rats [42]. tralia (Music et al. 2020 [50]), Japan (Tsukazaki et al. 1996 Different routines would differ the effect of PTH [51]; Dogaki et al. 2016 [52]; Hosokawa et al. 2015 [53]), (1–34). Eswaramoorthy et  al. found that controlled- and Netherlands (Rutgers et al. 2019 [54]). release property of PTH (1–34) via intra-articular (IA) Li et al. Arthritis Research & Therapy (2023) 25:3 Page 8 of 15 Table 2 Characteristics of in vitro studies about the effect of teriparatide on OA Author (year, country) Subjects Intervention Dose (duration) Route Findings Chang et al. (2009, China) [25] Human articular PTH (1–34) 10 nM (10 days) Co-culture PTH (1–34) reverses the chondrocytes progression of terminal differ - entiation of human articular chondrocytes PTH (1–34) could be used to treat early OA without affect - ing normal chondrocytes Shao et al. (2022, China) [45] BMSCs PTH (1–34) 10 nM (48 h) Co-culture PTH (1–34) alleviates OA by increasing the migration, pro- liferation, and chondral matrix formation of OA chondrocytes by inhibiting proinflammatory cytokines −8 −7 Chang et al. (2016, China) [46] Human articular PTHrP 10 to 10 M (7 days) Co-culture PTH (1–34) is beneficial for chondrocyte preventing the chondro- degenerative changes initiated by dexamethasone treatment Mwale et al. (2010, Canada) [47] Human MSCs PTH (1–34) 100 nM (48 h) Co-culture p38 and AKT protein kinase signaling pathways may not be required to initiate the regulation of expression of COLII and COLX by PTH (1–34), which is necessary for preventing precocious MSC hypertrophy Funk et al. (1998, USA) [48] RA and OA synovial PTHrP (1–40)/ 0.3 pM (24 h) Co-culture Proinflammatory cytokine- tissue PTHrP (60–72)/ stimulated production of NH2 PTHrP (1–86) terminal PTHrP by synovial tis- sue directly invading cartilage and bone in RA, which might mediate joint destruction through direct effects on cartilage or indirectly via the induction of mediators of bone resorption Petersson et al. (2006, Sweden) [49] RA or OA Chondro- PTHrP (1–34) 0.1 to 100 nM (15 days) Co-culture PTHrP (1–34) increases pro- cytes liferation of human chondro- cytes PTHrP (1–34) increases the amount of YKL-40 from chondrocytes derived from RA patients Music et al. (2020, Australia) [50] BMSCs PTH (1–34) 0, 1, 10, or 100 nM (14 days) Co-culture PTH (1–34) suppresses BMSC hypertrophic gene expression in chondrogenic cultures PTH (1–34) has an anti- hypertrophic effect and a catabolic effect on BMSC as they become increasingly differentiated −13 −7 Tsukazaki et al. (1996, Japan) [51] Human chondrocytes PTH (l–34)/ 10 to 10 M (120 min) Co-culture PTHrP is thought to be an hPTHrP important autocrine/parac- (l–141)/hPTHrP rine factor for chondrocyte (100–114) metabolism No significant difference of exogenously PTHrP (1–141) regard to the action of these agents, cell growth, differen- tiation Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 9 of 15 Table 2 (continued) Author (year, country) Subjects Intervention Dose (duration) Route Findings Dogaki et al. (2016, Japan) [52] Hematoma-derived PTH (1–34) 100 nM (14 days) Co-culture Pulsatile PTH (1–34) works on progenitor cells human cartilages in regarding to proliferation, osteogenic, and chondrogenic differen- tiation PTH (1–34) administration after fracture might positively act on other cells that contrib- ute to fracture healing −10 −9 −8 Hosokawa et al. (2015, Japan) [53] ATDC5 cells PTH (1–34) 10 /10 /10 M Co-culture PTH (1–34) regulates ATDC5 (21 days) cells in both chondrogenesis and the circadian clock as time-dependent properties of chondrocyte function and differentiation Rutgers et al. (2019, Netherlands) [54] Human chondrocytes PTH (1–34) 0.1 or 1.0 μM (4 weeks) Co-culture PTH (1–34) inhibits healthy human articular chondrocytes regeneration other than hypertrophic differentiation PTH (1–34) may be suitable for cartilage repair based on MSCs OA Osteoarthritis, BMSCs Bone marrow mesenchymal stem cells, PTH (1–34) Teriparatide, nM nmol/L, PTHrP Parathyroid hormone-related protein, M mol/L, MSC Mesenchymal stem cells, COL II Type II collagen, COLX Type X collagen, RA Rheumatoid arthritis, pM pmol/L, μM μmol/L As for the effects on human articular chondrocytes, PTH (1–34) protected MSC with various effects. Shao PTH (1–34) influenced its differentiation and regen - et  al. maintained that PTH (1–34) worked on MSC by eration. Tsukazaki et  al. concluded that PTHrP was an increasing the migration, proliferation, ECM formation, important autocrine and paracrine factor for chondro- and inhibiting proinflammatory cytokines [56]. Mwale cyte metabolism as for cell growth and differentiation et  al. argued that PTH (1–34) helped to prevent preco- [51]. Rutgers et  al. suggested that PTH (l–34) inhib- cious MSC hypertrophy [47]. Music et  al. believed that ited healthy human articular chondrocyte regeneration PTH (1–34) suppressed MSC hypertrophic [50]. Dogaki but did not influence hypertrophic differentiation [54]. et  al. implied that PTH (1–34) may not have a positive Chang et  al. concluded that PTH (l–34) could reverse effect at the fracture site because no positive effect was the terminal differentiation of chondrocytes without noticed when the fracture haematoma-derived progeni- affecting normal chondrocytes, while PTHrP prevented tor cells were treated with PTH (1–34) [52]. Hosokawa the chondrocyte degeneration initiated by dexametha- et al. indicated that PTH (1–34) could reset the circadian sone [25]. Moreover, Chang et al. held that PTH (1–34) rhythm of ATDC5 cells, which is expected to be useful treated early OA without affecting normal chondro - to assess the molecular mechanisms of PTH (1–34) on cytes [55]. When PTH (1–34) was applied for RA or OA chondrogenic differentiation [53]. PTH (1–34) played chondrocytes treatment, the survival and inflammatory a significant role in chondrocytes through affecting the cytokines would be affected. Petersson et al. found that proliferation and ECM synthesis. PTH (1–34) increased the proliferation of chondrocytes from human and RA patients [49]. However, Funk et al. Quality assessment of included studies revealed that the PTHrP could be examined in syn- Methodological quality was assessed for all 33 involved ovium and synoviocytes obtained from RA patients, studies (Fig. 3). An unclear risk of selection bias (because which help to clarify the pathogenesis of RA to a cer- of lacking data regarding randomization method: n = 16); tain extent and remain to be investigated further [48]. In detection bias (blinding of outcome assessment, n = 20); addition, Lugo et al. found that PTH (1–34) ameliorated performance bias (because of absent data about blinding OA by improving SCB integrity, inhibiting cartilage of subjects, n = 11), attrition bias (n = 17), reporting bias degradation, and exerting effects on synovial changes (n = 21), and other bias (n = 15) were found. [38]. PTH (1–34) held potential therapeutic option for synoviopathy associated with OA. Li et al. Arthritis Research & Therapy (2023) 25:3 Page 10 of 15 Fig. 3 Risk of bias assessment across the studies (n = 33). Methodological quality was assessed for all involved studies Discussion also enhanced COLII and AGC [26, 42]. Moreover, PTH To our knowledge, this is the first SR evaluating the (1–34) reversed terminal differentiation towards hyper - existing papers about the effect of PTH (1–34) on OA trophy and decreased apoptosis of chondrocytes [46, 47]. regarding in  vivo and in  vitro investigations. The chon - The anabolic effects of PTH (1–34) on both cartilage dro-protective and cartilage-regenerative effects were and SCB were explained by multiple mechanisms (Fig. 4). reviewed, indicating that PTH (1–34) might be a poten- The activation of NF-κB elevated inflammatory media - tial preventative and therapeutic treatment for OA. tors of IL-1β, TNF-α, cyclooxygenase-2 (COX2), and OA is the most prevalent degenerative joint disease inducible nitric oxide synthase (iNOS), which resulted in with complicated pathogenesis characterized with dam- the initiation of OA and regulated the levels of MMP13 age to cartilage, narrow synovial cavity, invasion of the [62]. It is well established that the parathyroid 1 recep- SCB, formation of osteophytes, and synovitis [57]. OP is tor (PTH1R) was a key regulator to induce differentiation a metabolic bone disease with decreased bone strength and endochondral ossification by inducing ECM syn - but increased fracture risk. OP and OA are common thesis, suppressing maturation, and inhibiting degenera- clinical conditions with high prevalence among older tion [20]. PTH (1–34) elevated the expression of PTH1R, adults. Antiresorptive agents exhibited effects on bone osteoprotegerin (OPG), and receptor activator of NF-κB mineralization and cartilage degradation for OA or ligand (RANKL) via the OPG/RANKL/RANK signaling OPOA [58]. However, treatments with polypharmacy pathway [26]. The Notch pathway was activated by PTH for OA are limited to pain relief with less effective, which (1–34) with increased expression of JAGGED1 [63]. The should be individualized to reduce the risk of side effects expression of TNF-α was inhabited by PTH (1–34) via [59]. And therefore, DMOADs are highly demanded for the PKA signaling pathway [29]. PTH (1–34) inhibited OA or OPOA. chondrocyte differentiation towards hypertrophy via the Quantitative studies indicated that PTH (1–34) played p38 and the p-AKT signaling pathway [47]. PTH (1–34) a significant role in calcium metabolism with an anabolic downregulated JAK2/STAT3 and Wnt5A/ROR2 [19] but effect in the treatment of OP, fracture healing, non-union upregulated the Wnt/β-catenin through an alternative and stress fracture, augmentation of implant fixation, signaling pathway [64]. and chondro-protection in OA [14, 60]. In addition, In addition, the attenuation of signaling pathways PTH (1–34) could be a systemic pharmacology for OA including oxidative stress and apoptosis had an indispen- by influencing cartilage quality such as ECM and chon - sable role in OA. Autophagy was a protective mechanism drocyte contents [61]. The effects of PTH (1–34) were in normal cartilage. PTH (1–34) alleviated OA pro- involved in decreasing COLX or RUNX2 but increas- gression by reducing terminal differentiation, reducing ing AGC [34], which not only inhibited matrix metal- apoptosis, and increasing autophagy via the mechanis- lopeptidase 13 (MMP13) or ADAM metallopeptidase tic target of rapamycin (mTOR) and p62 [21]. Apoptosis with thrombospondin type 1 motif 4 (ADAMTS4), but was reversed, while both Bcl-2 and Bax were upregulated Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 11 of 15 Fig. 4 Relevant mechanisms of PTH (1–34) in the chondrocytes. The chondrocyte-protective and chondrocyte-regenerative effect of PTH (1–34) were explained by multiple mechanisms by PTH (1–34). Moreover, PTH (1–34) might reduce extraordinary lubrication, attributed to structures as well the accumulation of senescent cells by inhibiting p16 as the cellular constitutions. However, both synovitis [28]. Both the sustained and intermittent action of PTH and OP contributed to cartilage degradation [68] but all (1–34) suppressed OA effectively [22, 65]. IA application pathology above could be suppressed by PTH (1–34) [69]. would directly affect the cartilage rather than the SCB or Impairment of SCB aggravated cartilage damage in early metaphyseal bone [43]. PTH (1–34) inhibited the termi- OPOA rabbits [39] and is associated with weight-bearing nal differentiation of human chondrocytes in  vitro and pain [70]. Overall, PTH (1–34) exhibited protective effects inhibits OA progression in rats in  vivo [25]. PTHrP was on the change of synovitis as well as pain relief. up-regulated and mediated by calcium-sensing receptor Clinically, resorption played a significant role while in OA cartilage, which might promote both proliferation PTH (1–34) was a reasonable option for OP patients of chondrocyte and osteophyte formation [66]. Stimula- [71]. Successful osteoanabolic treatment with PTH tion of focal osteochondral defect, enhancement of allo- (1–34) benefited symptomatic stress concentration graft bone union, and differentiation of MSCs are various with completely stem tip pain-free [72]. The peripros - effects of PTH (1–34) in tissue engineering [32, 67]. thetic BMD was preserved after total hip arthroplasty An ideal DMOAD can not only repair and regenerate (THA) [73] while bone ingrowth was promoted after cartilage, but also alleviate inflammation of synovium and total knee arthroplasty (TKA) [74] enforced by PTH pain. Healthy synovial joints are capable of maintaining (1–34). In addition, nonunion of periprosthetic fracture Li et al. Arthritis Research & Therapy (2023) 25:3 Page 12 of 15 DMM Destabilization of the medial meniscus after TKA benefited from PTH (1–34) as well [75]. SD Sprague–Dawley However, early mineralization of the MCC caused by nM Nmol/L PTH (1–34) might shift modifications of the subar - PIOA Papain-induced osteoarthritis MSCs Mesenchymal stem cells ticular spongiosa. Overall, we had better use the PTH M mol/L (1–34) in proper situations and dosages. RA Rheumatoid arthritis There are some limitations in our current review. PTHrP Parathyroid hormone-related protein COLX Type X collagen Firstly, the present review cannot identify the mecha- MMP13 Matrix metallopeptidase 13 nisms accounting for the precious mechanism of PTH ADAMTS4 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 4 (1–34) on OA. Further research evidence is needed to PTH1R Parathyroid 1 receptor OPG Osteoprotegerin deepen our current review. Secondly, although a thor- RANKL Receptor activator of NF-κB ligand ough search was performed from five English databases, COX2 Cyclooxygenase-2 some pertinent studies may still have been missed. iNOS Inducible nitric oxide synthase MAPK Mitogen-activated protein kinase Thirdly, limited information in the current reviewed mTOR Target of rapamycin investigations is an urgent call for subsequent studies to THA Total hip arthroplasty confirm the findings based on additional information. TKA Total knee arthroplasty SC Subcutaneous injection Finally, there are only included studies published in Eng- IA Intra-articular lish; thereby, some studies in other languages would be PFJOA Patellofemoral joint osteoarthritis missed out. pM pmol/L μM μmol/L Supplementary Information Conclusion The online version contains supplementary material available at https:// doi. In conclusion, the SR, which included both in  vivo and org/ 10. 1186/ s13075- 022- 02981-w. in  vitro studies, described the beneficial effects of PTH (1–34) on OA via alleviating cartilage damage progres- Additional file 1. Search strategy sion, inhibiting the abnormal SCB remodeling, suppress- ing synovitis, reducing oxidative stress or apoptosis of Acknowledgements chondrocytes, and elevating autophagy. Some of the OA All persons who have made substantial contributions to the work reported in or OAOP patients might benefit from PTH (1–34) as the manuscript but do not meet the criteria for authorship are named in the Acknowledgements. We especially thank professor Yingqi Chen, Anjaneyulu well. The present SR is a description of existing studies Udduttula, Xiaoyan Huang, Jianchen, and Canhui Cao, who offered their kind regarding the effectiveness of PTH (1–34) administration assistance in writing, editing, reviewing, technical help, and general support in in OA together with mechanisms, which suggested the methodology. necessity for further clinical trials and animal investiga- Authors’ contributions tions to achieve concise conclusions about the effects of GL: investigation, methodology, data curation, formal analysis, writing—original PTH (1–34) on OA. draft, writing—review, editing. SL: investigation, methodology. HX: methodol- ogy, writing—review, editing. YC: investigation, methodology. JD: investigation, methodology. AX: methodology. DW: methodology. JW: investigation, review. FY: investigation, review. LG: investigation, review. CD: investigation, review. HZ: Abbreviations investigation, conceptualization, supervision, funding acquisition, resources, PTH (1–34) Teriparatide review, editing. The authors read and approved the final manuscript. OA Osteoarthritis SR Systematic review Authors’ information SCB Subchondral bone Not applicable. ECM Extracellular matrix COL II T ype II collagen Funding AGC Aggrecan This study was supported by grants from National Natural Science Foundation TNF-α Tumor necrosis factor-α of China (No. 82172432), Guangdong Basic and Applied Basic Research Foun- IL-1β Interleukin-1β dation (No. 2021A1515012586), Shenzhen Key Medical Subject (No. SZXK023), DMOADs Disease-modifying OA drugs Shenzhen “San-Ming” Project of Medicine (No. SZSM201612092), and the OP Osteoporosis Scientific Research Foundation of Peking University Shenzhen Hospital (No. PRISMA Preferred Reporting Items for Systematic Review and KYQD2021099). Meta-Analysis PROSPERO Prospective Register of Systematic Reviews Availability of data and materials MeSH M edical Subject Headings Data are available from the corresponding authors upon reasonable request CRIS Checklist for Reporting In-vitro Studies with the permission of Department of Bone and Joint Surgery in Peking CIOA Collagenase-induced osteoarthritis University Shenzhen Hospital. OPOA Osteoporotic osteoarthritis OVX Ovariectomized ACLT Ant erior cruciate ligament transection MLI Meniscal ligamentous injury MCC Mandibular condylar cartilage Li  et al. Arthritis Research & Therapy (2023) 25:3 Page 13 of 15 17. Krithikadatta J, Gopikrishna V, Datta M. CRIS Guidelines (Checklist for Declarations Reporting In-vitro Studies): a concept note on the need for standard- ized guidelines for improving quality and transparency in reporting Ethics approval and consent to participate in-vitro studies in experimental dental research. Journal of conservative Not applicable. dentistry : JCD. 2014;17(4):301–4. 18. Shao LT, Gou Y, Fang JK, Hu YP, Lian QQ, Zhang YY, Wang YD, Tian FM, Consent for publication Zhang L. Parathyroid hormone (1–34) ameliorates cartilage degeneration Not applicable. and subchondral bone deterioration in collagenase-induced osteoarthri- tis model in mice. Bone Joint Res. 2020;9(10):675–88. Competing interests 19. Shao LT, Gou Y, Fang JK, Hu YP, Lian QQ, Yang Z, Zhang YY, Wang YD, Tian The authors declare that they have no competing interests. FM, Zhang L. The protective effects of parathyroid hormone (1–34) on cartilage and subchondral bone through down-regulating JAK2/STAT3 and WNT5A/ROR2 in a collagenase-induced osteoarthritis mouse model. Received: 9 September 2022 Accepted: 19 December 2022 Orthop Surg. 2021;13(5):1662–72. 20. Chen CH, Kang L, Chang LH, Cheng TL, Lin SY, Wu SC, Lin YS, Chuang SC, Lee TC, Chang JK, et al. 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Journal

Arthritis Research & Therapy – Springer Journals

Published: Jan 6, 2023

Keywords: Teriparatide; Osteoarthritis; Systematic review; Treatment

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