Continuing Education Activity

Abaloparatide, a synthetic peptide analog of parathyroid hormone-related protein (PTHrP), is used to manage and treat osteoporosis. Osteoporosis is characterized by reduced bone mineral density due to changes in bone microstructure, resulting in an elevated risk of fractures. The US Food and Drug Administration (FDA) has approved abaloparatide use in postmenopausal women at high risk of fracture due to osteoporosis. In addition, abaloparatide is frequently prescribed for individuals who exhibit intolerance to or have not responded to conventional osteoporosis treatments.

In a double-blind, controlled, randomized phase II clinical trial, the safety and efficacy of abaloparatide demonstrated superiority in enhancing overall bone mineral density compared to teriparatide and placebo within these treatment groups. As osteoporosis primarily affects postmenopausal women, it is crucial to provide clinicians with essential knowledge about abaloparatide, which is vital to ensure optimal patient care and prevent disease progression. This activity reviews the indications, mechanism of action, administration, pharmacokinetics, and associated warnings related to abaloparatide. By enhancing the expertise of healthcare professionals with evidence-based strategies, this activity seeks to empower clinicians to incorporate abaloparatide into clinical practice seamlessly. This contribution aims to improve patient outcomes in the management of osteoporosis.

Objectives:

• Identify appropriate candidates for abaloparatide therapy, considering postmenopausal women at high risk of fractures and those intolerant or unresponsive to traditional osteoporosis treatments.

• Implement proper administration techniques, emphasizing subcutaneous injection and supplementing with calcium and vitamin D if dietary intake is inadequate.

• Select appropriate dosages and durations of abaloparatide based on individual patient characteristics and response to treatment.

• Collaborate with interprofessional healthcare teams, fostering a holistic approach to osteoporosis management, and seek specialist input when necessary.

Indications

Abaloparatide, a synthetic peptide analog of parathyroid hormone-related protein (PTHrP), is used to manage and treat osteoporosis. Osteoporosis is characterized by reduced bone mineral density (BMD) due to changes in bone microstructure, resulting in an elevated risk of fractures. BMD is commonly measured utilizing a dual-energy x-ray absorptiometry (DEXA or DXA) scan to assess BMD.[1]

A DEXA scan reports the t-score, measured in SDs, and reflects the difference between the patient's measured BMD and the mean value of BMD. The risk of fracture increases as bone density decreases.

• A t-score between −1 and +1 reflects healthy bone.
• A t-score between −1.0 and −2.5 reflects the diagnosis of osteopenia.
• A t-score below −2.5 reflects a diagnosis of osteoporosis.

The US Food and Drug Administration (FDA) has approved abaloparatide use in postmenopausal women at high risk of fracture due to osteoporosis.[2] In addition, abaloparatide is frequently prescribed for individuals who exhibit intolerance to or have not responded to conventional osteoporosis treatments.[3][4] In the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), subcutaneous abaloparatide significantly reduced the risk of new vertebral and nonvertebral fractures and clinical and major osteoporotic fractures compared to placebo. In the ACTIVE trial, 86% relative risk reduction (RRR) in new vertebral fractures and 43% RRR in nonvertebral fractures were observed.[5] The use of abaloparatide is not recommended for more than 2 years during a patient's lifetime.

Traditional therapy for osteoporosis includes bisphosphonates and teriparatide. Studies have compared the efficacy of conventional treatment to abaloparatide. In a double-blind, controlled, randomized phase II clinical trial, the safety and efficacy of abaloparatide were assessed compared to teriparatide and placebo. Among these treatment groups, abaloparatide demonstrated superiority in enhancing overall BMD. A comparative study comparing 2 sequential therapies (2 years of initial teriparatide followed by alendronate therapy and 2 years of abaloparatide followed by alendronate therapy) demonstrated that abaloparatide followed by alendronate has a greater treatment efficacy. 

Abaloparatide can be combined or administered before antiresorptive therapies such as bisphosphonates to maximize effects.[6][7] Abaloparatide is not recommended in pediatric patients with open epiphyses or genetic predispositions to bone malignancies. The effects of abaloparatide on pregnancy, breastfeeding mothers, breastfed infants, milk production, and the pediatric population are unknown. The clinical practice guidelines from the American College of Endocrinology support the use of abaloparatide for postmenopausal osteoporosis, endorsing the capacity to enhance BMD and decrease the likelihood of both vertebral and nonvertebral fractures in women with postmenopausal osteoporosis.[8] As osteoporosis primarily affects postmenopausal women, it is crucial to provide clinicians with essential knowledge about abaloparatide, which is vital to ensure optimal patient care and prevent disease progression. 

FDA-Approved Indications

• Osteoporosis in postmenopausal women at high risk for fracture.

• Increasing bone density in males with osteoporosis and an elevated risk of fractures or in patients who have demonstrated ineffectiveness or intolerance to other osteoporosis treatments.[9][10]

Off-Label Uses

• Abaloparatide is utilized off-label for symptomatic pseudarthrosis in patients with metabolic syndromes.[6] 

• Abaloparatide can also be used to treat epididymitis and orchitis.[11] 

• Abaloparatide prevents bone loss resulting from ovariectomy, orchiectomy, and prolonged use of glucocorticoids while also aiding in fracture healing.[12] 

• In cases of glucocorticoid-induced osteoporosis, the American College of Rheumatology conditionally suggests prioritizing the use of parathyroid hormone/PTHrP analogs such as abaloparatide over anti-resorptive medications for patients at an extremely high risk of fractures.[13]

Mechanism of Action

Abaloparatide, a PTHrP, is a selective parathyroid hormone receptor type 1 (PTH1R) agonist.[14] As an agonist, anabolic activity on PTH1R on osteoblasts stimulates the Gs-protein–mediated cyclic adenosine monophosphate (cAMP) pathway, which activates phospholipase C (PLC) and phosphokinase A (PKA) to increase osteoblast activity. Abaloparatide shifts the balance of bone remodeling to favor bone formation by osteoblasts with a minimal increase in osteoclast bone resorption. This leads to increases in the formation of bone at periosteal, trabecular, and endocortical surfaces.[15] 

Recent studies suggest that parathyroid hormone or PTHrP analogs can differentiate between R0 and RG conformations of PTH1R. Binding to the R0 conformation of PTH1R induces a longer-lasting signaling response that gradually increases cAMP.[16][17] This leads to an increased risk of hypercalcemia due to increased osteoclast activity, as seen with teriparatide.

The binding capacity of abaloparatide to the 2 high-affinity PTH1R conformations was evaluated using radioligand competition methods. Abaloparatide exhibited greater selectivity for the RG conformation, with weak binding to R0. The anabolic effects of abaloparatide can be explained by the greater affinity for RG, which leads to a rapid and swift increase in cAMP signaling while maintaining low osteoclast resorption.[18] 

This explains why patients prescribed abaloparatide are less likely to develop hypercalcemia than those prescribed teriparatide. A study was conducted to determine the efficacy and safety of abaloparatide in increasing BMD in Japanese patients with osteoporosis at high-risk fractures. The results showed that treatment with subcutaneous abaloparatide (80 µg once daily) led to significant increases in serum markers of bone formation (procollagen type 1 N-terminal propeptide or P1NP) and bone resorption (cross-linked C-terminal telopeptide of type 1 collagen or CTX) compared to placebo.[19]

Abaloparatide has off-label effects by activating Gq and β-arrestin-1 mechanisms in target cells such as the testis and epididymis to alleviate symptoms of epididymitis and orchitis.[11]

Pharmacokinetics

Absorption: The absolute bioavailability following the administration of 80 mcg of abaloparatide in healthy women is 36%.

Distribution: Abaloparatide exhibits an approximate volume of distribution of 50 L, with plasma protein binding estimated at around 70%.

Metabolism: Abaloparatide peptide fragments are primarily eliminated through renal excretion after nonspecific proteolytic degradation.

Elimination: The mean half-life of abaloparatide is approximately 1 hour.[16][20] Abaloparatide is predominantly eliminated from the body through the kidneys. Dosage adjustments are not necessary for women with mild, moderate, or severe renal impairment. However, close monitoring for adverse reactions is required for women with severe impairment.[21]

Administration

Available Dosage Forms and Strengths

Abaloparatide can be administered to patients through subcutaneous injection at a recommended dosage of 80 mcg/day into the periumbilical region of the abdomen. Transdermal patches can serve as a suitable alternative for patients who prefer to avoid injectables, potentially enhancing medication adherence. The patch utilizes a microneedle system to deliver variable doses of abaloparatide at 50 mcg, 100 mcg, and 150 mcg daily for up to 6 months.

Adult Dosage

Abaloparatide is delivered through subcutaneous injection using a single-patient-use prefilled pen designed for 30 doses. If the patient's dietary intake of calcium and vitamin D is insufficient, supplementation should accompany subcutaneous administration of abaloparatide. For the initial few doses, the patient should be in an environment where they can sit or lie down, as orthostatic hypotension may occur within 4 hours of the injection.[22]

Transdermal patches are preferred by individuals who prefer to avoid injectables, potentially enhancing medication adherence. The transdermal patch is a novel mode of administration and is currently under evaluation in clinical trials. To administer abaloparatide intradermally, the medication is applied to the thigh for a duration of 5 minutes.[20] 

In a randomized, open-label, active-controlled study comprising 500 patients with postmenopausal osteoporosis with a high risk for fractures, the efficacy and safety of the transdermal patch were compared to the subcutaneous injection of abaloparatide. The subcutaneous abaloparatide injection resulted in 3.7% and 3.4% increases in total bone density in the hip and femoral neck, respectively.

The transdermal patch showed 2.0% and 1.9% increases in total hip and femoral neck bone density, respectively. Although transdermal patches prove to be safer and more tolerable, with fewer subjects withdrawing, interrupting, or discontinuing the patch compared to subcutaneous injection, it is unknown whether transdermal administration reduces vertebral fractures.[23]

The efficacy of the transdermal patch was compared to a placebo control group, with results indicating a reduction in nonvertebral fractures, increased BMD of the hip, spine, and femoral neck, and reduced incidence of hypercalcemia. Based on clinical studies, 80 mcg of abaloparatide is recommended for administration once daily via injection into the periumbilical region. Abaloparatide should not be used for more than 2 years in a patient's lifetime because of the unknown relevance of rodent osteosarcoma findings to humans.

Specific Patient Populations

Hepatic impairment: No dosage adjustment for abaloparatide is specified in the manufacturer's labeling.

Renal impairment: Patients with severe renal impairment should use abaloparatide cautiously, as the drug is eliminated through the kidneys. Dosage adjustments are unnecessary for patients with mild-to-moderate renal impairment.[15][24] 

Pregnancy considerations: Abaloparatide is not recommended for females of reproductive age due to a lack of data obtained from clinical studies regarding its use during pregnancy in healthy women.

Breastfeeding considerations: Information regarding the presence of abaloparatide in human milk, its impact on breastfed infants, or its effect on milk production is currently unavailable.

Pediatric patients: The safety and effectiveness of abaloparatide have not been demonstrated in pediatric patients.

Older patients: No discernible differences in the overall safety or effectiveness of abaloparatide have been observed between older and younger patient populations.

Adverse Effects

Adverse Effects

Abaloparatide is well tolerated and has mild adverse effects. Patients may experience nausea, dizziness, headache, palpitations, and hypercalciuria.[25] Abaloparatide has been associated with supraventricular extrasystoles and orthostatic hypotension.[19] The common (≥5%) treatment-emergent adverse drug reactions in men with osteoporosis are injection site reactions, nasopharyngitis, arthralgia, bronchitis, and hypertension.[10] 

The adverse effects reported from a randomized, double-blind, placebo-controlled trial among postmenopausal women with osteoporosis receiving 80 mcg of abaloparatide daily for 18 months [2] include hypercalcemia (11%), dizziness (10%), nausea (8%), headache (8%), palpitations (5%), fatigue (3%), upper abdominal pain (3%), and vertigo (2%).

Drug-Drug Interactions

Abaloparatide, at therapeutic concentrations, does not induce or inhibit cytochrome P450 enzymes. Currently, evidence does not exist to suggest any significant drug interactions.

Contraindications

Box Warnings

Abaloparatide is contraindicated in individuals with a history of systemic hypersensitivity to either abaloparatide or its excipients. Cases of eczema and urticaria have been reported.[19]

Warning and Precautions

Abaloparatide previously carried a boxed warning for an increased risk of osteosarcoma, but the FDA has removed this warning when retaining information about osteosarcoma as a caution. In a 2-year animal study, abaloparatide administration showed increased events of osteosarcoma and osteoblastoma. A comprehensive pathology study of rats undergoing prolonged parathyroid hormone analog treatment exhibited increased rates of osteosarcoma, osteosarcoma-related mortality, and metastatic potential.[26] This is not advisable in patients who have open epiphyses or those who have a genetic predisposition to osteosarcoma.

Abaloparatide use is also not recommended in patients with Paget disease, idiopathic increased alkaline phosphatase levels, open epiphyseal plates, or bone malignancies. Abaloparatide should not be given to patients who have previously undergone implant radiation therapy or external beam radiotherapy that involved their skeleton.[27] There is an increased risk of hypercalciuria, urolithiasis, and postural hypotension.[28][29]

Monitoring

Abaloparatide use increases the risk of osteosarcoma and osteosarcoma-related mortality.[26] Compared to teriparatide, another parathyroid hormone analog, abaloparatide, has a reduced incidence of hypercalcemia. Patients with preexisting conditions of severe renal impairment, hypercalcemia, or primary hyperparathyroidism should be closely monitored for hypercalciuria or active urolithiasis while taking abaloparatide. 

The injection site should be monitored for reactions, and administration should be stopped if a reaction does occur. Blood pressure should be monitored after injection to evaluate the patient for orthostatic hypotension.[30][19] The Endocrine Society guideline recommends monitoring bone turnover markers, such as serum C-terminal cross-linking telopeptide for antiresorptive treatment or procollagen type 1 N-terminal propeptide for bone anabolic therapy, as an approach to identify insufficient response or non-adherence to therapy.[3] For abaloparatide, procollagen type 1 N-terminal propeptide can be obtained to monitor response to therapy.[10]

Toxicity

Signs and Symptoms of Overdose

Symptoms of abaloparatide toxicity include headache, nausea, asthenia, and vertigo.

Management of Overdose

No specific antidote for abaloparatide toxicity currently exists. If an overdose is suspected, abaloparatide should be discontinued by closely monitoring calcium and phosphorus levels. Supportive measures should be implemented.

Enhancing Healthcare Team Outcomes

Osteoporosis is a chronic disease that decreases BMD and increases the risk of fractures. Managing osteoporosis requires an empathetic interdisciplinary team of rheumatologists, endocrinologists, orthopedic surgeons, nutritionists, nurses, nuclear medicine technicians, and physical therapists to diagnose, treat, and rehabilitate patients.

Abaloparatide is a human PTHrP analog that is FDA-approved in postmenopausal women with osteoporosis at a high fracture risk to reduce vertebral and nonvertebral fractures. Patients should be educated on postmenopausal osteoporosis, self-treatment with abaloparatide, and possible adverse effects. In addition, dietician intervention is beneficial in ensuring the patient's adequate calcium and vitamin D intake.

Individuals who experience fractures or bone breakage should be treated by orthopedic surgeons and physical therapists for rehabilitation, leading to improved quality of life. Rheumatologists and endocrinologists should maintain follow-ups to monitor calcium and phosphorus levels and assess for hypercalcemia or other adverse effects. Abaloparatide is associated with an increased risk of osteosarcoma. Thus, individuals taking abaloparatide may require a nuclear medicine technician to monitor them for the development of malignancies or possible metastasis. The interprofessional team should be continuously updated on the patient's status and osteoporosis management guidelines.

Abaloparatide treatment is self-administered in an environment where the patient can sit or stand if orthostatic hypotension occurs. Patients without adequate calcium or vitamin D should be advised to take supplements.

Abaloparatide use is indicated in postmenopausal women and not in females of reproductive potential. The effects of abaloparatide on pregnancy, breastfeeding mothers, breastfed infants, milk production, and the pediatric population are unknown. Abaloparatide is not recommended in pediatric patients with open epiphyses or genetic predispositions to bone malignancies.[31]

Patient education, improved clinician-patient communication, and ease of medication administration all play a significant role in successful treatment initiation, management, and improvement of patient outcomes. An interprofessional team approach and open communication between clinicians optimize the treatment response to abaloparatide.