PTH/PTHrP analogues as osteoanabolic treatment in patients with osteoporosis

Abstract

Teriparatide (TPTD) and abaloparatide (ABL) are osteoanabolic drugs belonging to the group of parathyroid hormone analogues and parathyroid hormone-related protein analogues, respectively. Both drugs have been shown to be effective and safe in the treatment of postmenopausal osteoporosis (PMO), reducing the risk of vertebral and nonvertebral fractures and improving bone microarchitecture, especially in patients with severe osteoporosis. For this reason, guidelines recommend their use as first-line treatment for patients at very high risk of fracture. Although TPTD and ABL act on the same receptor, PTHR1, they trigger a different signalling response, which explains why their effects on bone remodelling are also different, with similar osteoanabolic action, but with less stimulation of resorption by ABL, which confers a greater benefit on cortical bone.

Resumen

Teriparatida (TPTD) y abaloparatida (ABL) son fármacos osteoanabólicos pertenecientes al grupo de los análogos de la parathormona y de la proteína relacionada con la parathormona, respectivamente. Ambos fármacos han demostrado ser eficaces y seguros en el tratamiento de la osteoporosis posmenopáusica (OPM), al reducir el riesgo de fractura vertebral y no vertebral, y mejorar la microarquitectura ósea, especialmente en pacientes con osteoporosis grave. Por este motivo, las guías recomiendan su utilización como primera línea de tratamiento para pacientes con muy alto riesgo de fractura. Aunque TPTD y ABL actúan sobre el mismo receptor, PTHR1, desencadenan una respuesta de señalización diferente, lo que explica que los efectos sobre el remodelado óseo también sean diferentes, con similar acción osteoanabólica, pero con menor estimulación de la resorción por parte de ABL, que le confiere un mayor beneficio sobre el hueso cortical.

Introduction

Osteoporosis is a systemic skeletal disease characterised by low bone mass and/or deterioration of skeletal microarchitecture, leading to increased bone fragility and a higher risk of fracture.¹ Given the high morbidity and mortality associated with fractures—particularly vertebral and hip fractures—and the negative impact on the quality of life of affected patients, osteoporosis is considered a major public health issue with significant socioeconomic implications.^2,3

Nevertheless, despite the availability of effective treatments to reduce fracture risk, a substantial treatment gap still persists.⁴

The most recent national^5–7 and international^8–11 clinical guidelines agree on recommending osteoanabolic treatment for patients classified as being at very high fracture risk, based on the superior efficacy and rapid action of osteoanabolic agents compared with antiresorptives, both in terms of gains in bone mineral density (BMD) and fracture risk reduction. There is also universal consensus that the benefits achieved with an osteoanabolic agent should be maintained through sequential treatment with an antiresorptive drug.^12–14

At present, three osteoanabolic agents are available in Spain, all administered subcutaneously: teriparatide (TPTD), a parathyroid hormone (PTH) analogue; romosozumab (ROMO), a sclerostin inhibitor; and the recently marketed abaloparatide (ABL), a PTH-related peptide (PTHrP) analogue.

The objective of this review is to examine the mechanism of action and the efficacy and safety data of the PTH/PTHrP analogues (ABL and TPTD), highlighting their main similarities and differences in order to define the most appropriate patient profile for each treatment.

Methodology

This narrative review was based on an exhaustive search of the scientific literature indexed in PubMed. The search terms used included “teriparatide” [MeSH Terms], “abaloparatide” [MeSH Terms], “PTH analogues” [MeSH Terms], “PTHrP analogues” [MeSH Terms], “osteoanabolics” [MeSH Terms], “bone forming agents” [MeSH Terms], “osteoporosis” [MeSH Terms], and “fracture” [MeSH Terms]. Filters were applied to include only articles in English or Spanish, and opinion articles and letters to the editor were excluded. The selected studies were critically reviewed by the authors to assess their methodological quality. Relevant information was extracted and synthesised to provide a comprehensive and up-to-date overview of the mechanism of action, efficacy, and safety of PTH/PTHrP analogues in the treatment of postmenopausal osteoporosis.

Mechanism of action of PTH/PTHrP analogues

Parathyroid hormone (PTH) is an 84-amino-acid polypeptide synthesised and secreted by the parathyroid glands, playing a central role in calcium and phosphate metabolism. Although PTH was long thought to exert purely catabolic effects on bone, experimental and clinical evidence shows that elevated levels of PTH increase bone remodelling and lead to both anabolic and catabolic effects, depending on the pattern of exposure (continuous or intermittent). Preclinical studies have shown that exogenous administration of PTH once daily has a predominantly anabolic effect. Furthermore, it was found that the biological activity of intact PTH (hPTH₁₋₈₄) resides in its N-terminal sequence, particularly the first 34 amino acids. This discovery led to the synthesis and production of the first PTH analogue, TPTD, which corresponds to the 1–34 fragment of human PTH.^15,16

The primary target cell of PTH in bone, as well as of TPTD, is the osteoblast, although effects on osteocytes have also been described. Both PTH and TPTD bind to the type 1 PTH receptor (PTH1R), a G protein-coupled membrane receptor, and activate two parallel signalling pathways: the adenylate cyclase pathway and the protein kinase C (PKC) pathway. Adenylate cyclase catalyses the generation of the second messenger cyclic adenosine monophosphate (cAMP), which ultimately activates protein kinase A (PKA), responsible for stimulating osteoblast function, differentiation and proliferation.¹⁷

The anabolic effects of PTH and TPTD, when administered intermittently, are mediated by three main mechanisms: (1) upregulation of the transcription of pro-osteoblastogenic growth factors; (2) modulation of the osteoanabolic Wnt/β-catenin signalling pathway; and (3) increased expression and activity of Runx2. To exert its catabolic effects, PTH increases the expression of pro-osteoclastogenic cytokines such as receptor activator of nuclear factor kappa-B ligand (RANKL)^18,19 (Fig. 1).

Figure 1.

Differential activation of the PTH1R receptor by PTH and PTHrP analogues in osteoblasts. A) Mechanism of action of PTH and teriparatide (TPTD), resulting in high rates of formation and resorption. B) Mechanism of action of PTHrP and abaloparatide (ABL), resulting in high formation rates but lower resorption.

ABL: abaloparatide; cAMP: cyclic adenosine monophosphate; CREB: cAMP response element-binding protein; Gαs: G protein alpha subunit; PKA: protein kinase A; PTH: parathyroid hormone; PTHrP: parathyroid hormone-related peptide; PTHR1: parathyroid hormone receptor 1; RANK-L: receptor activator of nuclear factor κB ligand; TPTD: teriparatide.

Parathyroid hormone-related protein (PTHrP) is structurally similar to PTH at its amino-terminal end, which allows it to bind to the same receptor, PTH1R. Abaloparatide (ABL) is a synthetic analogue of PTHrP composed of 34 amino acids, 20 of which are identical to those of PTHrP.¹⁷ ABL binds to and interacts with the same receptor as TPTD, the PTH1R, also triggering a cAMP-dependent response.^17,18

PTH and TPTD, which have a higher affinity for the R0 conformation of the PTH1R, induce cAMP generation via both membrane Gαs activation and internalisation of the Gαs-bound receptor into endosomes. As a result, they produce high and sustained levels of cAMP, thereby enhancing the action of protein kinase A (PKA) and the expression of downstream effectors such as c-Fos, CREB and RANKL. Sclerostin is inhibited via a PKA-dependent mechanism that stimulates the Wnt/β-catenin signalling pathway. These signalling routes promote both bone formation and bone resorption^17,18 (Fig. 1).

In contrast, PTHrP and ABL preferentially bind to the RG conformation of PTH1R, inducing cAMP production solely via membrane Gαs activation. Consequently, they produce lower and shorter-lived cAMP levels, resulting in weaker PKA activity and less expression of downstream PKA effectors (c-Fos, CREB and RANKL). Sclerostin is also inhibited through PKA-dependent mechanisms, thereby stimulating the Wnt/β-catenin pathway similarly to PTH/TPTD. The result is a more favourable balance towards bone formation over resorption^17,18 (Fig. 1).

Following administration of TPTD and ABL, a rapid increase in bone formation markers is observed—although slightly lower in magnitude with ABL—followed by a later increase (after 2–3 months) in bone resorption markers. In the case of ABL, this resorptive response is lower and shorter in duration. Therefore, the so-called “anabolic window”—the period in which bone formation predominates over resorption—is probably wider with ABL than with TPTD, potentially resulting in a greater net anabolic effect²⁰ (Fig. 2).

Figure 2.

Anabolic window of teriparatide (A) and abaloparatide (B); these show the period of time during which the drugs exert their maximum osteoanabolic effect.

Source: figure adapted and with permission from Tabacco and Bilezikian.²⁰

Effects of PTH/PTHrP analogues on bone mineral density

Teriparatide

Teriparatide (TPTD) has consistently been shown to increase BMD in predominantly trabecular bone, such as the lumbar spine (LS), and to a lesser extent in cortical bone sites, such as the femoral neck (FN) and total hip (TH), where a slight BMD loss may even occur in the initial months of treatment. In the pivotal phase 3 Fracture Prevention Trial (FPT), in which women with postmenopausal osteoporosis (PMO) were treated for a median duration of 19 months, the mean increase in LS BMD in the group receiving 20 μg/day was 9.7%, compared with 1.1% in the placebo group.²¹ This gain in trabecular bone BMD with TPTD is highly consistent, as demonstrated in a post hoc analysis where 96% of patients experienced a significant LS BMD increase, with >5% gain in 72% of cases.²² However, changes in BMD at the hip and distal radius are less significant. In fact, a decrease in BMD has been reported, more notably at the radius, potentially due to increased endocortical remodelling and Haversian system activity in cortical bone, although this is offset by simultaneous periosteal apposition. In fact, biomechanical analysis techniques have confirmed that such structural changes result in stronger bone.²³

Abaloparatide

The effect of abaloparatide (ABL) on BMD in women with PMO was evaluated in a phase 2 dose-finding study²⁴ and in the pivotal phase 3 randomised, double-blind, 18-month trial (ACTIVE study), which compared ABL 80 μg, TPTD 20 μg, and placebo in 2463 postmenopausal women. In this study, BMD changes at 18 months (a secondary endpoint) were significantly greater with ABL than with placebo (+11.20% vs +0.63% at LS; +3.60% vs −0.43% at FN; +4.18% vs −0.10% at TH).²⁵

When comparing ABL with TPTD, no significant difference was observed in LS BMD gain after 18 months of treatment (+11.20% vs +10.49%). However, ABL resulted in significantly greater BMD increases at FN (+3.60% vs +2.66%) and TH (+4.18% vs +3.26%) compared to TPTD, suggesting a greater benefit of ABL on cortical bone.²⁵

Additionally, changes in bone turnover markers in the ACTIVE study were consistent with the observed BMD differences, showing that ABL induced less bone resorption, thus achieving a greater net anabolic effect compared to TPTD.²⁵

Effects of PTH/PTHrP analogues on bone microarchitecture

Teriparatide

Various animal and human studies have confirmed that TPTD 20 μg/day not only increases bone mass but also enhances trabecular number and connectivity, thereby improving bone microarchitecture and skeletal strength.²⁶ In cortical bone, TPTD increases cortical thickness due to new periosteal and endocortical bone formation, although it also results in increased cortical porosity.²⁷

In a substudy of the FPT, which assessed changes in bone microarchitecture using micro-computed tomography (μCT) of iliac crest biopsies, daily administration of TPTD for 19 months was associated with increased trabecular volume and connectivity, as well as increased cortical thickness. Despite the observed increase in intracortical porosity, bone strength was not compromised.^27,28

A separate analysis using quantitative computed tomography (QCT) in a subgroup of FPT patients showed positive changes in the cortical geometry of the distal radius, indicative of improved bone strength.²⁹

More recently, using DXA-3D software, an increase in trabecular volumetric BMD (vBMD) and a decrease in cortical vBMD have been observed at LS and FN³⁰ —findings consistent with previous QCT studies.²⁹

Abaloparatide

Preclinical studies have also demonstrated that ABL improves bone microarchitecture, leading to greater bone strength.^31–33 Unlike TPTD, however, ABL has been shown to increase histomorphometric indices of trabecular, endocortical, and periosteal bone formation without increasing osteoclast number or eroded surfaces.³³

Bone microarchitecture, assessed indirectly by the Trabecular Bone Score (TBS) at the LS, was evaluated in a phase 2 controlled clinical trial comparing ABL 80 μg, TPTD 20 μg, and placebo. At study completion, TBS increases were significantly greater in both ABL and TPTD groups compared to placebo, and higher in the ABL group than in the TPTD group.³⁴ A subsequent analysis of patients in the ACTIVE study confirmed these findings after 18 months of subcutaneous ABL 80 μg treatment.³⁵ In the ACTIVExtend extension study, TBS gains were maintained in the group that continued with alendronate (ALN) following ABL treatment (ABL/ALN), with values superior to the placebo/ALN group (PBO/ALN).³⁵

A DXA-3D study in a random sample of ACTIVE participants showed that both ABL and TPTD increased trabecular vBMD similarly after 18 months. However, surface BMD (sBMD) and cortical vBMD increases were greater with ABL than with TPTD. These differences may reflect the greater intracortical porosity associated with TPTD compared to ABL.³⁶

Antifracture efficacy of PTH/PTHrP analogues

Teriparatide

The antifracture efficacy of TPTD was first evaluated in the FPT. A total of 1637 women with PMO and prevalent vertebral fractures were randomised to receive daily treatment with TPTD 20 µg, TPTD 40 µg or placebo (PBO). After 19 months, TPTD 20 µg, compared with PBO, significantly reduced the risk of new morphometric vertebral fractures by 65% and the risk of non-vertebral fractures by 53%.²¹ Although the incidence of hip fracture was lower in the TPTD-treated groups, the study was not sufficiently powered to assess differences between groups.²¹ Subsequent subgroup analyses from the FPT have shown that the antifracture efficacy of TPTD was independent of patient age, pre-treatment bone turnover values, baseline 25-hydroxyvitamin D levels, baseline BMD values and the number of prevalent vertebral fractures prior to study inclusion.³⁷

A controlled clinical trial specifically designed to evaluate the antifracture efficacy of TPTD versus a bisphosphonate (BP) was the VERO study. In this double-blind, double-dummy clinical trial, 1366 patients with severe PMO (at least two moderate vertebral fractures or one severe vertebral fracture, together with a T-score ≤ –1.5 at LS, FN or TH) were randomly assigned to receive either TPTD 20 µg/day or risedronate (RIS) 35 mg/week. After 24 months, women treated with TPTD, compared with those treated with RIS, showed a significant reduction in the risk of morphometric vertebral fracture and clinical fracture of 56% and 52%, respectively.³⁸ A subgroup analysis of the VERO study demonstrated that the antifracture efficacy of TPTD was maintained regardless of patient age, number and severity of vertebral fractures at inclusion, and prior BP treatment.³⁹

The fracture risk reduction in PMO patients treated with TPTD 20 µg observed in controlled clinical trials has been confirmed in real-world observational studies.^40,41

One area of controversy has been the alleged lack of efficacy of TPTD in reducing hip fracture risk in various clinical trials. However, a meta-analysis including 23 controlled clinical trials comparing TPTD with placebo or other anti-osteoporotic drugs showed that TPTD significantly reduced the risk of hip fracture by 56% after a median treatment duration of 18 months.⁴² Nonetheless, these results should be interpreted with caution due to the high heterogeneity of the included studies.

Abaloparatide

The antifracture efficacy of ABL was evaluated in the ACTIVE study. A total of 2463 women with PMO (defined by densitometric and/or fracture criteria) were randomised to receive daily treatment for 18 months with ABL 80 µg, TPTD 20 µg (open-label arm) or PBO. The primary endpoint was the incidence of new morphometric vertebral fractures. Additionally, the incidence of non-vertebral, clinical and major osteoporotic fractures (humerus, wrist, hip and clinical vertebral) was assessed. After 18 months, ABL, compared with PBO, significantly reduced the risk of new vertebral fractures (86%), non-vertebral fractures (43%), clinical fractures (43%) and major osteoporotic fractures (70%).²⁵ Although treatment with TPTD also significantly reduced the risk of new vertebral fractures (80%) versus PBO, no significant differences were observed between TPTD and PBO for the other fracture outcomes.²⁵ Notably, the reduction in major osteoporotic fracture risk (exploratory endpoint) was 55% greater with ABL than with TPTD. However, the study was not statistically powered to detect differences in fracture incidence between patients treated with ABL and those treated with TPTD.²⁵ The ACTIVE study was followed by a 24-month open-label extension, ACTIVExtend, in which patients previously treated with ABL were switched to alendronate (ALN).⁴³

Subsequent post hoc analyses of the ACTIVE and ACTIVExtend studies confirmed that the antifracture efficacy of ABL is independent of baseline risk factors such as age, prior fracture, BMD and baseline fracture risk according to FRAX.^44–48

Although no studies have directly compared the antifracture efficacy of ABL versus a BP, a post hoc analysis comparing the ABL-treated group in ACTIVE with the ALN-only group (PBO/ALN) in ACTIVExtend concluded that the risk of new vertebral fracture was 71% lower with ABL than with ALN.⁴⁹

Finally, in a real-world study conducted in women with PMO, a significantly lower incidence of hip fractures was observed in patients treated with ABL compared to those treated with TPTD (22% relative risk reduction).⁵⁰ The study authors suggest that this result could be explained by histomorphometric and biomechanical differences in specific subregions of the hip observed in previously discussed studies.⁵⁰

Direct comparative clinical trials between ABL and TPTD are summarised in Table 1.

Table 1.

Comparative clinical studies between abaloparatide and teriparatide.

Type of study	Population	n	Drug, dose and route	Follow-up time	Bone mineral density (BMD)	Fractures	Safety	Ref.
Phase II, RCT (dose finding)	Women with OP (T-score BMD < –2.5 in LS, FN, or TH; or T-score < –2.0 with fragility fracture in the past 5 years; or T-score < –2.0 plus other OP risk factors), aged 55–85 years	222	ABL 20 μg sc	24 weeks	LS BMD: significant increase with ABL (40 and 80 μg) and TPTD vs Pbo.	NE	AEs reported in 71%–78%; mostly mild/moderate.	Leder BZ et al., 2015^24
			ABL 40 μg sc
			ABL 80 μg sc		FN BMD: significant increase with ABL 80 μg vs Pbo.		Headache and dizziness more common with ABL (40 and 80 μg).
			TPTD 20 μg sc		TH BMD: significant increase with ABL (40 and 80 μg) vs Pbo and vs TPTD.		Hypercalcaemia (Ca²^+ > 10.5 mg/dL at 4 h post-dose) more frequent with TPTD (40%) than ABL (7%–14%). Difference lost at 24 h.
			Pbo
Phase III, RCT	Women aged 49–86 years with PMO:	2,463	ABL 80 μg sc (n = 824)	18 months	Significant increases (p < 0.001) in BMD of the LS, FN and TH were observed with ABL compared to Pbo at 6, 12 and 18 months.	Significant reduction (p < 0.001) in the RR of new VFs compared to Pbo was observed with ABL (86%) and TPTD (80%).	The incidence of AEs, including serious ones, was similar across the three trial arms.	Miller PD et al., 2016^25
	– T-score < –2.5 and > –5.0 in LS or TH plus ≥2 mild or ≥1 moderate vertebral fractures (radiological), or fragility NVF in past 5 years		Pbo (n = 821)		Significant increases (p < 0.001) in BMD of the LS, FN and TH were observed with TPTD compared to Pbo at 6, 12 and 18 months.	Significant reduction in the RR of NVFs (43%; p < 0.05), clinical fractures (43%; p < 0.05), and major OP fractures (70%; p < 0.001) was observed with ABL compared to Pbo.	There were more withdrawals due to AEs in the ABL group (9.9%), with the most common causes of withdrawal with ABL being: nausea (1.6%), dizziness (1.2%), headache (1.0%), and palpitations (0.9%).
ACTIVE	– Aged >65 years, with fragility fracture and T-score < –2.0 and > –5.0, or without fracture and T-score < –3.0 and > –5.0		TPTD 20 μg sc (n = 818, open-label)		Significant increases (p < 0.001) in BMD of the FN and TH at 6, 12 and 18 months, and in BMD of the LS at 6 and 12 months, were observed with ABL compared to TPTD.	Significant reduction in the RR of major OP fractures was observed with ABL compared to TPTD (55%; p < 0.05)	The incidence of hypercalcaemia (serum calcium > 10.7 mg/dl) was significantly higher (p = 0.006) with TPTD (6.4%) than with ABL (3.4%) throughout the study.
Retrospective, observational study (health insurance company databases)	Women aged >50 years with ≥1 prescription for ABL or TPTD; Paget’s disease and cancer excluded	23,232	ABL 80 μg sc (n = 11,616)	Index date: May 2017 to July 2019.	NE	The RR for new NVF was comparable in the ABL (2.9%) and TPTD (3.2%) groups.	The estimated incidence of major adverse cardiovascular events (MACE), with or without heart failure, was similar in both groups: ABL (3.0%) and TPTD (3.1%)	Cosman et al.^50
			TPTD 20 μg sc (n = 11,616)
			Propensity-score matched populations	18-month follow-up after index date		A 22% reduction in the risk of hip fracture was observed with ABL compared to TPTD (p < 0.05)

ABL: abaloparatide; AE: adverse event; BMD: bone mineral density; Ca²⁺: serum calcium; FN: femoral neck; HF: heart failure; LS: lumbar spine; MACE: major adverse cardiovascular events; NVF: non-vertebral fracture; OP: osteoporosis; Pbo: placebo; PMO: postmenopausal osteoporosis; RCT: randomised clinical trial; RR: relative risk; sc: subcutaneous; TH: total hip; TPTD: teriparatide; VF: vertebral fracture; μg: microgram.

Safety profile of PTH/PTHrP analogues

PTH/PTHrP analogues are generally well tolerated. In controlled clinical trials of TPTD^21,38 and ABL,²⁵ as well as in real-world studies,^40,41,50 the most commonly reported adverse events (AEs) with both treatments were nausea, dizziness, headache, orthostatic hypotension, cramps, back pain, arthralgia, and pain in the extremities. Some patients treated with TPTD or ABL may experience hypercalcaemia, hypercalciuria, hyperuricaemia or hypomagnesaemia. Hypercalcaemia is typically mild, asymptomatic and transient. In the ACTIVE study, the incidence of hypercalcaemia (a prespecified safety endpoint) was lower in the ABL group than in the TPTD group, consistent with the lower bone resorption induced by ABL compared to TPTD.²⁵ In the same study, discontinuation due to vascular AEs (palpitations, dizziness, nausea and headache) was more frequent with ABL than with TPTD, although these events were of mild to moderate intensity.²⁵ The study authors did not rule out the possibility of reporting bias due to the open-label TPTD arm.²⁵

Cardiovascular safety

The cardiovascular (CV) safety of TPTD and ABL has been assessed in pivotal trials and in a real-world observational study. After 18 months of treatment, TPTD and ABL were associated with similarly low risks of major adverse CV events (MACE), including myocardial infarction, stroke and in-hospital CV death (3.1% with TPTD vs 3% with ABL).⁵⁰

Skeletal safety (no proven risk of osteosarcoma)

The pivotal FPT trial of TPTD, designed for 3 years, was prematurely terminated after a median of 19 months of treatment²¹ when a concurrent toxicological study in Fischer 344 rats showed a potential increased incidence of osteosarcoma.⁵¹ The US Food and Drug Administration (FDA) approved TPTD (Forteo®) for use but limited to a maximum of 24 months and with a boxed warning regarding the potential risk of osteosarcoma in the product information.⁵²

In 2020, the FDA, considering the absence of osteosarcoma cases in humans since the marketing of TPTD, decided to remove the warning about potential osteosarcoma risk, while maintaining the recommendation to avoid treatment in populations at higher risk for this tumour (e.g. patients with Paget’s disease or a history of skeletal radiation therapy).⁵²

During the clinical development of ABL, similar bone toxicity studies to those of TPTD were conducted.⁵³ As it had previously done with Forteo®, the FDA approved ABL (Tymlos^®) with a 24-month use restriction (including any prior use of a PTH analogue such as TPTD) and with a boxed warning on the risk of osteosarcoma. In 2021, as with TPTD, the FDA also removed the osteosarcoma warning for ABL.⁵⁴

PTH/PTHrP analogues in sequential therapy

Clinical guidelines recommend the use of PTH/PTHrP analogues, within the group of osteoanabolic drugs, as first-line treatment in patients with osteoporosis (OP) at very high fracture risk.^5–11 However, the limited treatment duration of PTH and PTHrP analogues—up to a maximum of 24 and 18 months, respectively—and the risk of loss of BMD and bone quality gains after treatment discontinuation, necessitate the planning of sequential therapy with antiresorptive agents. Current evidence appears to support the sequence of an anabolic agent followed by an antiresorptive, both in terms of BMD gains and antifracture efficacy.^12–14

Antiresorptives followed by PTH/PTHrP analogues

A blunted and delayed anabolic response to TPTD has been observed when administered after BPs, particularly the more potent ones. Nevertheless, the early attenuating effect on BMD from prior BP treatment does not appear to negatively impact bone strength or the antifracture efficacy of TPTD, as demonstrated in a subgroup analysis from the VERO study.³⁹

The DATA-Switch study found that switching treatment from denosumab (DMAB), a potent antiresorptive agent, to TPTD was associated with increased bone remodelling and significant but transient losses of BMD at the hip and LS, and even greater losses at the distal radius⁵⁵. For this reason, some experts recommend that in patients with treatment failure on DMAB, TPTD should be initiated in combination with continued DMAB therapy. The DATA-Switch study did not assess the impact of this treatment on fracture incidence, so it remains unknown whether these changes in BMD translate into an increased risk of fracture.⁵⁵

PTH/PTHrP analogues followed by antiresorptives

This is the most widely recommended therapeutic sequence for patients with severe OP or very high fracture risk and is reflected in current OP management guidelines based on available evidence.

In ACTIVExtend—the only clinical trial to evaluate fracture risk following transition from a PTH/PTHrP analogue to an antiresorptive—after a total of 42 months (18 + 24), the ABL/ALN group, compared to the PBO/ALN group, maintained the reduction in risk for vertebral fracture (84%), non-vertebral fracture (39%), clinical fracture (34%) and major osteoporotic fracture (50%).⁴³

Patient profile eligible for teriparatide or abaloparatide

The most recent national^5–7 and international^8–11 clinical guidelines for the management of OP position osteoanabolic drugs (PTH analogues and ROMO) as first-line treatment for patients with OP and a very high risk of fracture, for the duration specified in the respective product information leaflets, followed by potent antiresorptive treatment, preferably zoledronic acid or DMAB.

The definition of “very high fracture risk” varies among the guidelines of different medical societies. In Spain, the 2022 guidelines of SEIOMM⁷ and SECOT⁵ use a risk stratification approach based on prior fractures and/or BMD values measured by T-score. The 2019 SER recommendations for the treatment of osteoporosis include the category of “high fracture risk” based on FRAX values or the presence of two or more high-risk fracture factors.⁶

When choosing between TPTD and ABL, it is important to note that both have similar safety profiles and no significant differences in the reduction of vertebral fracture risk. The main differences lie in their effect on cortical bone, with ABL achieving greater BMD gains in the proximal femur.^25,46

Therefore, ABL could be indicated in the same way as TPTD for patients at very high fracture risk, with or without prior vertebral fracture, although it may be more beneficial than TPTD in patients with very low hip BMD or a history of non-vertebral or hip fractures.

It is worth noting that at the time of writing this review article, ABL is only approved in Europe for use in postmenopausal women, whereas TPTD is also indicated for men at high risk of fracture.

Conclusions

PTH/PTHrP analogues, included within the group of osteoanabolic or bone-forming drugs, have proven to be effective and safe in the treatment of PMO, particularly in patients with severe osteoporosis and very high fracture risk.

TPTD and ABL share certain similarities but also present differences. Both drugs bind to the same receptor, PTH1R, and trigger similar intracellular signalling responses, resulting in comparable anabolic effects. However, TPTD is associated with a greater resorptive effect, especially on cortical bone.^17–19 For this reason, the anabolic window is likely wider with ABL²⁰, leading to greater BMD gains, particularly at the hip.^25,46 Nevertheless, comparative clinical studies between the two treatments are needed to confirm these differences.

Ethical considerations: obtaining informed consent

Not applicable.

Funding

No funding was received for conducting the study or writing the manuscript.