Abaloparatide (brand name Tymlos) is a lab-made copy of a hormone-like protein your body already uses to manage bone and calcium. Doctors prescribe it as a once-daily shot under the skin for postmenopausal women whose osteoporosis puts them at high risk of breaking a bone. It was approved by the FDA in 2017 after a large trial showed it cut spine fracture risk far more than a placebo, and it's now backed by years of real-world use. It's meant to be used for a limited stretch of time and then followed by a different bone drug to lock in the gains.
How strong is the evidence?
This is one of the most solidly studied compounds in this guide. There's a large randomized, placebo-controlled trial in over 2,400 women (ACTIVE), a follow-up study tracking what happens after treatment stops (ACTIVExtend), several independent meta-analyses pooling dozens of osteoporosis trials, and large real-world insurance-claims studies following tens of thousands of patients for years. This isn't animal-only or lab-only science — it's an approved medicine with a real human track record.
Uses
What people use it for
Treating osteoporosis in postmenopausal women at high fracture risk
Human trialsThis is its one FDA-approved job. It's prescribed for women who've already had an osteoporosis-related fracture, have very low bone density, or have multiple risk factors that make a fracture likely soon.
Cutting the risk of a new spine (vertebral) fracture
Human trialsIn the main trial, women taking it for 18 months had far fewer new spine fractures show up on X-rays than women on placebo.
Cutting the risk of hip and other non-spine fractures
Human trialsIt also reduced fractures outside the spine, including hip fractures, both in the original trial and in later real-world tracking.
Bridge therapy after a rare bisphosphonate-related thigh fracture
Some human dataSome doctors use bone-building drugs like abaloparatide in patients who've had an atypical femoral fracture (a rare stress fracture linked to long-term bisphosphonate use) to protect against future fractures while the bone heals, though the effect on healing that specific fracture isn't fully worked out.
Potential benefits
What it may help with
Large drop in new spine fractures
Human trialsIn the pivotal 18-month trial, new spine fractures were cut by roughly 86% compared with placebo — one of the biggest effects seen for any osteoporosis drug.
Fewer hip and other non-spine fractures
Human trialsThe same trial showed about a 43% drop in non-spine fractures versus placebo, and a large real-world study of over 43,000 women found fewer hip and non-spine fractures with abaloparatide than with its main rival, teriparatide.
Bigger bone density gains at the hip than teriparatide
Human trialsAbaloparatide produced larger increases in bone density at the hip and femoral neck than teriparatide, the older drug in its class, while spine gains were similar between the two.
Less spike in blood calcium than teriparatide
Human trialsHypercalcemia (too much calcium in the blood) happened in about 3.4% of abaloparatide users versus 6.4% of teriparatide users in the same trial — a meaningfully lower rate.
Studies:27533157Fracture protection holds up when followed by a bisphosphonate
Human trialsWomen who took abaloparatide for 18 months and then switched to weekly alendronate for 2 more years kept most of their bone gains and had an 84% lower spine fracture rate than the placebo-then-alendronate group over the full 3.5 years.
Studies:29800372
What to watch for
Side effects & risks
- Mild
Temporary rise in blood calcium (hypercalcemia)
A mild, usually short-lived increase in blood calcium is the most distinctive side effect of this drug class, though it happens less often with abaloparatide than with teriparatide.
- Mild
Headache, nausea, and dizziness
These are the most commonly reported general side effects with abaloparatide and teriparatide, though most people tolerate the drug reasonably well.
- Moderate
More people stop treatment due to side effects than on placebo
Across pooled trial data, both abaloparatide and teriparatide had higher rates of people quitting the study because of adverse effects compared with placebo groups.
- Serious
Bone cancer (osteosarcoma) signal in rat studies, not confirmed in people
High, long-term doses in rat studies raised a bone cancer risk flag for this drug class. That risk hasn't shown up in extensive human use so far, but it's the reason the label caps treatment length and excludes people already at higher risk of bone cancer.
Dosing
Dosing — what studies used
In the pivotal trial and on the approved US label, abaloparatide is given as an 80 microgram shot just under the skin, once a day, self-injected with a pen device much like insulin. Treatment is typically used for up to 18 months in trials, with the label allowing up to 24 months total over a lifetime. After stopping, doctors follow up with a different bone drug — in the main extension study, weekly oral alendronate — to protect the gains. This dosing is well established because abaloparatide is an approved drug with a fixed label dose, not a case of unclear or self-experimented dosing.
Postmenopausal osteoporosis, main fracture-prevention trial (ACTIVE)
Human trial80 mcg
Once daily · 18 months · Subcutaneous injection
Compared against placebo and open-label teriparatide 20 mcg/day in the same trial.
FDA-approved label dose for postmenopausal osteoporosis at high fracture risk
Approved label80 mcg
Once daily · Up to 24 months lifetime maximum · Subcutaneous injection
Approved US labeling; only for postmenopausal women at high fracture risk.
Sequential follow-on therapy after stopping abaloparatide (ACTIVExtend)
Human trialAlendronate 70 mg
Once weekly · 24 months · Oral
Given after 18 months of abaloparatide or placebo to preserve bone density and fracture protection gains.
An investigational skin-patch (microneedle) version of abaloparatide has been tested but is not the approved product people currently get — the approved form is the daily injection.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Abaloparatide is a lab-made copy of a natural protein called PTHrP, which your body already uses to help manage calcium and bone growth. Given as a daily shot, it briefly switches on a receptor on bone-building cells called osteoblasts. Because the signal comes in short daily pulses rather than staying on all the time, it tips the balance toward building new bone faster than old bone is broken down. That's different from most osteoporosis drugs, like bisphosphonates, which mainly just slow down bone loss rather than actively building new bone.
Who should avoid it
- Anyone already at higher risk of bone cancer (osteosarcoma), including Paget's disease of bone, unexplained high alkaline phosphatase, prior radiation therapy involving the skeleton, or other bone cancers or bone metastases
- People with high blood calcium (hypercalcemia) or certain metabolic bone diseases
- Not approved for use in men — the current approval covers postmenopausal women only
- Pregnant or breastfeeding women
- People who are still growing (open growth plates), such as children and adolescents
Interactions to know
- Talk to your doctor before combining with calcium or vitamin D supplements, since it can raise blood calcium levels
- Not meant to be combined with other bone-building (anabolic) drugs like teriparatide or romosozumab at the same time
- Specific drug-drug interaction studies are limited in the literature reviewed here — any other medication changes should go through the prescribing doctor
The papers that matter most
Key studies
The pivotal trial: 80 mcg/day for 18 months cut new spine and non-spine fractures versus placebo, with less hypercalcemia than teriparatide.
Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial
Following abaloparatide with alendronate kept fracture protection going, cutting spine fracture risk 84% versus placebo/alendronate over 43 months total.
ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis
Pooling trial and real-world data, abaloparatide edged out teriparatide for preventing non-spine and hip fractures specifically.
PTH1 receptor agonists for fracture risk: a systematic review and network meta-analysis
In over 43,000 women, abaloparatide showed fewer hip and non-spine fractures than teriparatide, with similar heart-safety.
Comparative Effectiveness of Abaloparatide and Teriparatide in Women 50 Years of Age and Older
Confirmed strong fracture-reduction benefit but also flagged higher treatment-withdrawal rates due to side effects versus placebo.
Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis
Documents the FDA's 2017 approval for postmenopausal women with osteoporosis at high fracture risk, and the drug's development history.
Abaloparatide: First Global Approval
Bottom line
Abaloparatide is a real, FDA-approved bone-building shot for postmenopausal women with osteoporosis who are at high risk of a fracture — not a wellness or anti-aging peptide. The evidence is strong: a large trial plus years of real-world data show it meaningfully cuts spine and hip fracture risk and builds bone faster in some spots than older drugs. It's used for a capped stretch of time under a doctor's care, then handed off to another bone drug to protect the gains.
Research papers
Studies we have on file for Abaloparatide. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
38 papers
The clinician's guide to prevention and treatment of osteoporosis.
Osteoporosis is the most common metabolic bone disease in the USA and the world. It is a subclinical condition until complicated by fracture(s). These fractures place an enormous medical and personal burden on individuals who suffer from them and take a significant economic toll. Any new fracture in an adult aged 50 years or older signifies imminent elevated risk for subsequent fractures, particularly in the year following the initial fracture. What a patient perceives as an unfortunate accident may be seen as a sentinel event indicative of bone fragility and increased future fracture risk even when the result of considerable trauma. Clinical or subclinical vertebral fractures, the most common type of osteoporotic fractures, are associated with a 5-fold increased risk for additional vertebral fractures and a 2- to 3-fold increased risk for fractures at other sites. Untreated osteoporosis can lead to a vicious cycle of recurrent fracture(s), often resulting in disability and premature death. In appropriate patients, treatment with effective antifracture medication prevents fractures and improves outcomes. Primary care providers and medical specialists are critical gatekeepers who can identify fractures and initiate proven osteoporosis interventions. Osteoporosis detection, diagnosis, and treatment should be routine practice in all adult healthcare settings. The Bone Health and Osteoporosis Foundation (BHOF) - formerly the National Osteoporosis Foundation - first published the Clinician's Guide in 1999 to provide accurate information on osteoporosis prevention and treatment. Since that time, significant improvements have been made in diagnostic technologies and treatments for osteoporosis. Despite these advances, a disturbing gap persists in patient care. At-risk patients are often not screened to establish fracture probability and not educated about fracture prevention. Most concerning, the majority of highest risk women and men who have a fracture(s) are not diagnosed and do not receive effective, FDA-approved therapies. Even those prescribed appropriate therapy are unlikely to take the medication as prescribed. The Clinician's Guide offers concise recommendations regarding prevention, risk assessment, diagnosis, and treatment of osteoporosis in postmenopausal women and men aged 50 years and older. It includes indications for bone densitometry as well as fracture risk thresholds for pharmacologic intervention. Current medications build bone and/or decrease bone breakdown and dramatically reduce incident fractures. All antifracture therapeutics treat but do not cure the disease. Skeletal deterioration resumes sooner or later when a medication is discontinued-sooner for nonbisphosphonates and later for bisphosphonates. Even if normal BMD is achieved, osteoporosis and elevated risk for fracture are still present. The diagnosis of osteoporosis persists even if subsequent DXA T-scores are above - 2.5. Ongoing monitoring and strategic interventions will be necessary if fractures are to be avoided. In addition to pharmacotherapy, adequate intake of calcium and vitamin D, avoidance of smoking and excessive alcohol intake, weight-bearing and resistance-training exercise, and fall prevention are included in the fracture prevention armamentarium. Where possible, recommendations in this guide are based on evidence from RCTs; however, relevant published data and guidance from expert clinical experience provides the basis for recommendations in those areas where RCT evidence is currently deficient or not applicable to the many osteoporosis patients not considered for RCT participation due to age and morbidity.
Osteoporosis: A Review.
Osteoporosis is characterized by low bone mass, increased bone fragility, and increased susceptibility to fracture, which is associated with substantial morbidity, mortality, and economic costs. Worldwide, 1 in 3 women and 1 in 5 men older than 50 years of age experience osteoporotic fractures in their lifetime. Risk factors for osteoporosis include older age, female sex, prior fractures, prior falls, low body weight, history of hip fracture in a parent, glucocorticoid use, cigarette smoking, excess alcohol consumption, certain comorbidities (eg, inflammatory bowel disease, rheumatoid arthritis, and chronic liver and kidney disease), and low level of bone mineral density (BMD; measured by dual-energy x-ray absorptiometry). The fracture risk assessment algorithm combines these clinical risk factors and BMD measurement to estimate the 10-year absolute fracture risk for hip, spine, shoulder, and forearm fractures. For patients at high risk of fracture, such as those with a T score of -2.5 or less (equivalent to a bone mass that is ≥2.5 SDs below that of young adults) for BMD, history of vertebral or hip fracture, multiple fractures, or high 10-year absolute fracture risk (eg, ≥20%), antiresorptive agents (bisphosphonates or, if contraindicated, denosumab) are recommended to reduce vertebral fractures (risk difference, -52 [95% CI, -95 to -18 per 1000 person-years]) and hip fractures (risk difference, -6 [95% CI, -11 to -1 per 1000 person-years]). Anabolic medications (teriparatide, abaloparatide, and romosozumab) should be considered in very high-risk individuals (eg, recent vertebral fractures, hip fracture with a T score of ≤-2.5 for BMD), followed by an antiresorptive agent. The use of fracture liaison services (comprehensive inpatient or outpatient management program for patients after a fracture) was shown to increase medication initiation and adherence by 38% compared with 17% for patients who did not receive fracture liaison services (risk difference, 20% [95% CI, 16% to 25%]) and these benefits may reduce the rates of subsequent fracture. Patients are recommended to follow appropriate intake of calcium (1000 to 1200 mg) and vitamin D (600 to 800 IU) guidelines and to pursue a regimen of muscle resistance exercises (eg, squats, push-ups) and balance exercises (eg, heel raises, standing on 1 foot). Osteoporosis is a common condition among older adults that leads to increased susceptibility to fracture, which is associated with substantial morbidity and mortality. Antiresorptive agents such as bisphosphonates or denosumab are recommended for patients at high fracture risk. Anabolic treatment with parathyroid hormone analogs (such as teriparatide and abaloparatide) and sclerostin inhibitors (such as romosozumab) can be considered for very high-risk individuals.
Osteoporosis.
Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.
Osteoporosis in Older Adults.
Osteoporosis and osteoporosis-related fractures are common causes of morbidity and mortality in older adults. Healthy adults should be counseled about measures to prevent osteoporosis. Women should be screened for osteoporosis beginning at age 65. Screening for osteoporosis in men should be considered when risk factors are present. Appropriate screening intervals are controversial. Women and men with osteoporosis should be offered pharmacologic therapy. Choice of therapy should be based on safety, cost, convenience, and other patient-related factors. Bisphosphonates are a first-line therapy for many patients with osteoporosis. Other treatments for osteoporosis include denosumab, teriparatide, abaloparatide, romosozumab, and selective estrogen receptor modulators.
Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.
The prevalence of osteoporosis is increasing in the United States. To evaluate low bone mass and osteoporosis treatments to prevent fractures. Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms. Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. American College of Physicians. (PROSPERO: CRD42021236220).
Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial.
Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor. To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture. The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤-2.5 and >-5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤-2.0 and >-5.0 or without fracture criteria and a T score ≤-3.0 and >-5.0 could enroll. Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months. Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants. Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred less frequently in the active treatment groups vs placebo. The Kaplan-Meier estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo. BMD increases were greater with abaloparatide than placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) vs teriparatide (6.4%) (risk difference [RD], −2.96 [95%CI, −5.12 to −0.87]; P = .006). [table: see text]. Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. clinicaltrials.gov Identifier: NCT01343004.
Drug therapy for osteoporosis in older adults.
The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50-70%, non-vertebral by 20-30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1-2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.
Recent Advances in Osteoporosis Therapeutics.
Postmenopausal osteoporosis is a chronic progressive disease related to estrogen deficiency at menopause, aging, and superimposed genetic and environmental factors. Many patients with osteoporosis are not diagnosed, and the majority are not treated. Current therapies for osteoporosis include antiresorptive treatments, including bisphosphonates, denosumab, and raloxifene, and osteoanabolic treatments, including teriparatide, abaloparatide, and romosozumab, which is a dual-action agent. Sequential therapies aim to optimize fracture prevention and bone density outcomes for long-term management. Recent guidelines have suggested categorical risk stratification and a goal-directed individualized therapy strategy. New treatments under investigation also hold promise for further improving bone health in postmenopausal osteoporosis.
Update on Osteoporosis Screening and Management.
Osteoporosis is a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to an increased risk of fragility fractures. Central dual-energy X-ray absorptiometry measurements are the gold standard for determining bone mineral density. A well-balanced diet containing adequate amounts of calcium and vitamin D, exercise, smoking cessation, and limited alcohol intake are important to maintain bone health. Pharmacologic agents should be recommended in postmenopausal women who are at high risk for fractures. Newer anabolic therapies including teriparatide, abaloparatide, and romosozumab have emerged for use in severe osteoporosis.
Clinical effects of teriparatide, abaloparatide, and romosozumab in postmenopausal osteoporosis.
In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures.
Advances in Parathyroid Hormone-based medicines.
Parathyroid hormone (PTH), produced by the parathyroid glands, plays a critical role in the regulation of calcium and phosphate homeostasis, acting primarily on bone and kidney to maintain serum calcium levels within a narrow range. Parathyroid hormone also plays important roles in bone remodeling by directly stimulating osteoblasts and osteocytes, integrating its calcemic response with stimulation of bone formation. Through the RANK/RANK-ligand system, these cells activate osteoclasts, promoting a balanced process of bone formation and resorption that maintains bone density and strength. Dysregulation of PTH, as seen in disorders such as hyper- and hypoparathyroidism, can lead to significant clinical complications. In recent years, major advancements have been made in the development of PTH analogs, aimed at leveraging PTH's physiological effects on bone to treat conditions such as osteoporosis and hypoparathyroidism. While PTH promotes both bone formation and bone resorption, the net outcome may be a gain or loss of bone mass, depending largely on the administration pattern of PTH or its analogs. When PTH is given intermittently (eg, as once-daily subcutaneous injection), bone formation is favored. Continuous administration of PTH or chronic elevation of blood PTH levels as seen in primary hyperparathyroidism tend to promote bone resorption. Parathyroid hormone analogs, such as teriparatide (PTH(1-34)) and the PTHrP analog abaloparatide, administered once daily, have significant efficacy in stimulating bone formation, making them valuable options for the treatment of osteoporosis. Given this capacity to improve bone structure, these analogs hold broader therapeutic potential for other skeletal disorders, including fracture healing and oral bone repair, which expands the scope of PTH-based therapies beyond osteoporosis. Long-acting PTH analogs have applications in treating hypoparathyroidism, offering an alternative to conventional treatment with calcium and active vitamin D. This article reviews the molecular mechanisms of approved and emerging PTH-based medicines, their clinical applications, and recent advances in optimizing their therapeutic potential. We also discuss ongoing research aimed at developing next-generation PTH analogs with improved efficacy for skeletal and metabolic disorders.
Osteoporosis: Common Questions and Answers.
Osteoporosis affects 10.2% of adults older than 50 years and is expected to increase to 13.6% by 2030. Osteoporotic fractures, specifically hip fractures, significantly affect morbidity, mortality, and quality of life. Screening for osteoporosis with dual energy x-ray absorptiometry should be considered for all women 65 years and older or women who are postmenopausal with clinical risk factors. The Bone Health and Osteoporosis Foundation recommends screening men 70 years and older and men with clinical risk factors; however, the U.S. Preventive Services Task Force did not find sufficient evidence to support routine screening in men. Osteoporosis can be diagnosed by a T-score of -2.5 or less or the presence of a fragility fracture. All patients with osteoporosis should be counseled on weight-bearing exercise, smoking cessation, moderation of alcohol intake, and calcium and vita-min D supplementation. Treatment of osteoporosis is influenced by the patient's fracture risk, the effectiveness of fracture risk reduction, and medication safety. Patients at high risk of fracture should consider treatment with antiresorptive therapy, including bisphosphonates and denosumab. Anabolic agents such as teriparatide, abaloparatide, and romosozumab should be considered for patients at very high risk or with previous vertebral fractures.
Abaloparatide.
Abaloparatide is an investigational analog of human PTHrP (1-34) being developed for the treatment of osteoporosis. The amino-acid sequence of abaloparatide is identical to that of PTHrP in the first 20 amino-acids, while over half of the remaining amino-acids are different. Some studies in animals and in humans reported that abaloparatide presented a potent anabolic activity with reduced effects on bone resorption as compared to that observed with teriparatide. This may be due to a more transient signaling response of abaloparatide related to differing affinities of the two drugs to the specific conformations of the PTH1 receptor. In the ACTIVE study, a phase 3 fracture prevention trial, 2460 postmenopausal osteoporotic women at high risk for fracture were randomized to receive 18-months of either daily abaloparatide 80 μg s.c., placebo or teriparatide 20 μg s.c. The reduction in vertebral fracture rate with respect to placebo was 86% in the abaloparatide group and 80% in the teriparatide group. Abaloparatide also produced a significant 43% reduction in the rate of nonvertebral fractures (2.7 vs 4.0% with placebo, p=0.04) whereas teriparatide determined a 28% reduction (2.9 vs 4.0% with placebo, p=NS). Abaloparatide or teriparatide showed similar increases in BMD at lumbar spine, while the patients of the abaloparatide group showed significantly greater increases in BMD at both total hip (4.18 vs 3.26%) and femoral neck (3.60 vs 2.66%). Therefore, if the preliminary data of the ACTIVE study is confirmed, abaloparatide may become an important option for the anabolic treatment of postmenopausal osteoporosis.
Update on Atypical Femoral Fractures.
➤ Atypical femoral fractures (AFFs) are stress fractures between the lesser trochanter and the metaphyseal flare that are most commonly related to prolonged (3 to 5 years) antiresorptive medication use.➤ An important finding is a visible transverse line in the lateral cortex, known as the "dreaded black line." Complete fractures are transverse and have minimal comminution.➤ Prodromal symptoms including hip, groin, thigh, and knee pain are present in more than one-half of cases and are usually misdiagnosed.➤ Nonoperative treatment for all patients with AFF includes withdrawal of bisphosphonates, assessment for secondary causes of osteoporosis, and optimization of vitamin D and calcium.➤ Incomplete fractures without a visible line can initially be treated nonoperatively with protected weight-bearing.➤ Intramedullary nailing is indicated for complete fractures and incomplete fractures with a visible fracture line. Delayed healing after fixation should be anticipated.➤ Treatment with parathyroid hormone (PTH) analogs (teriparatide and abaloparatide) after AFF prevents other fractures in high-risk patients, but the effect on healing of the fracture is unclear.
Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.
To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. PROSPERO CRD42019128391.
Recommendations for the optimal use of bone forming agents in osteoporosis.
Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.
Parathyroid hormone receptor agonists in the management of osteoporosis.
Parathyroid hormone (PTH) regulates bone homeostasis. Intermittent exposure to PTH results in bone formation being greater than bone resorption, and this effect has been harnessed through the development of agonists of the PTH and PTH-related protein type 1 receptor (PTH1R) to treat osteoporosis. Teriparatide, an analogue of the first 34 amino acids of PTH, and abaloparatide, which resembles PTH-related protein (PTHrP) in structure, are PTH1R agonists currently in clinical use. Both medications have been shown to increase bone mineral density at the lumbar spine, femoral neck and total hip. Randomized controlled trials with teriparatide or abaloparatide have also provided evidence of reduction in vertebral and non-vertebral fractures. The ACTIVE trial suggested slightly greater efficacy for major osteoporotic fractures (as an exploratory end point) for abaloparatide than for teriparatide. A similar potential superiority was suggested for hip fracture in a real-world, observational study. Side effects of these medications are usually transient, and although a risk of osteosarcoma was suggested by studies using murine models, no such risk has been observed in extensive human studies. Overall, both teriparatide and abaloparatide have demonstrated convincing clinical effectiveness and cost-effectiveness, with a reassuring safety profile. Potential differences in their effects on bone mineral density and their antifracture effects offer avenues for differentiation but require further validation in appropriately designed studies.
The 2024 UK clinical guideline for the prevention and treatment of osteoporosis.
The National Osteoporosis Guideline Group (NOGG) has updated the revised UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. This guideline is relevant for all healthcare professionals involved in osteoporosis management. The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013, 2017 and 2021. This paper presents a minor update of the 2021 guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men aged 50 years and older. Where available, systematic reviews, meta-analyses and randomised controlled trials have been used to provide the evidence base. Conclusions and recommendations have been systematically graded according to the strength of the available evidence. Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, as well as models of care for fracture prevention. Recommendations are made for training, service leads and commissioners of healthcare, and for review criteria for audit and quality improvement. Specific 2024 updates include guidance on fracture risk assessment by ethnicity, Parkinson's disease, Down's syndrome and lower-limb amputation; furthermore, the definition of very high fracture risk has been clarified. Hormone replacement therapy (HRT) is now recommended as a first-line treatment option in younger postmenopausal women with high fracture risk and low baseline risk for adverse events; recommendations regarding abaloparatide are included; additional training resources have been added. The guideline provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).
Diagnosis and Management of Osteoporosis in Advanced Kidney Disease: A Review.
Osteoporosis and fractures are common in persons with advanced chronic kidney disease (CKD) and on maintenance dialysis. Although the diagnosis of osteoporosis in this population can be difficult, imaging, especially with dual-energy x-ray absorptiometry (DXA), is helpful in identifying persons with CKD at the highest risk of fracture. Although blood biomarkers including parathyroid hormone and bone-specific alkaline phosphatase concentrations can aid in assessing bone turnover state, bone biopsy remains the gold standard in determining bone turnover in persons with advanced kidney disease and osteoporosis. With the increasing armamentarium of osteoporosis drugs, it now may be possible to prevent many fractures in advanced CKD. Unfortunately, data on these drugs are limited in persons with advanced CKD. Clinicians, aided by advances in imaging, biomarkers, and bone biopsy can now use these novel agents to target bone turnover abnormalities such as adynamic bone disease and high bone turnover disease. This review will discuss the most recent literature surrounding the diagnosis, management, and monitoring of osteoporosis and fractures in persons with advanced CKD or on maintenance dialysis.
Osteoporosis Therapeutics 2020.
Numerous safe and efficient drug therapies are currently available to decrease risk of low trauma fractures in patients with osteoporosis including postmenopausal, male, and secondary osteoporosis. In this chapter, we give first an overview of the most important outcomes regarding fracture risk reduction, change in bone mineral density (BMD by DXA) and/or bone markers of the phase III clinical studies of well-established therapies (such as Bisphosphonates, Denosumab or Teriparatide) and also novel therapies (such as Romosozumab or Abaloparatide) and highlight their mechanisms of action at bone tissue/material level. The latter understanding is not only essential for the choice of drug, duration and discontinuation of treatment but also for the interpretation of the clinical outcomes (in particular of eventual changes in BMD) after drug administration. In the second part of this chapter, we focus on the management of different forms of osteoporosis and give a review of the respective current guidelines for treatment. Adverse effects of treatment such as atypical femoral fractures, osteonecrosis of the jaw or influence of fracture healing are considered also in this context.
PTH1 receptor agonists for fracture risk: a systematic review and network meta-analysis.
Osteoporosis, defined by reduced bone mineral density and macro- and micro-architectural degradation, leads to increased fracture risk, particularly in aging populations. While randomized controlled trials (RCTs) demonstrate that PTH1 receptor agonists, teriparatide and abaloparatide, are effective at reducing fracture risk, real-world evidence (RWE) remains sparse. This study reviews and compares the anti-fracture efficacy of these agents, against each other and against other osteoporosis treatments using both RCTs and RWE. We systematically searched Medline, Embase, and Cochrane up to May 2024, focusing on RCTs and RWE studies reporting reduction in vertebral, non-vertebral, hip, or all fractures as primary endpoint. A network meta-analysis (NMA) was conducted, first through pairwise meta-analyses of teriparatide versus abaloparatide, then a Bayesian NMA comparing each to other treatments. Safety assessments included adverse events classified by MedDRA, with a particular attention to hypercalcemia and cardiac events. Seventeen studies (11 RCTs, 6 RWE) met inclusion criteria. Teriparatide and abaloparatide were effective in reducing vertebral and non-vertebral fractures in all pairwise meta-analyses versus placebo. Abaloparatide showed an advantage over teriparatide for non-vertebral fractures (OR: 0.87, 95% CI: 0.80-0.95) and hip fractures (OR: 0.81, 95% CI: 0.71-0.93). In the NMA model, teriparatide and abaloparatide were superior to placebo, raloxifene, and calcitonin in reducing vertebral fracture while teriparatide was further superior to denosumab and risedronate. For non-vertebral fracture, abaloparatide was better than any other treatment while teriparatide was only superior to alendronate or placebo. PTH1 analogs were better than placebo at reducing all fractures while no difference was observed for the risk of hip fracture. Both abaloparatide and teriparatide demonstrate comparable safety to other osteoporosis treatments, with no increased cardiovascular risk. This review highlights that PTH1 receptor agonists effectively reduce fracture risk, with abaloparatide offering enhanced benefits for non-vertebral and hip fractures compared to teriparatide. Both agents exhibit acceptable safety profiles, suggesting their valuable role in managing osteoporosis, particularly for high-risk patients.
Approach to the Patient: Pharmacological Therapies for Fracture Risk Reduction in Adults With Osteogenesis Imperfecta.
Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials. This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists. Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.
Probability of achieving bone mineral density treatment targets with abaloparatide and teriparatide.
The goal of treatment for women at high risk of fracture who have a T-score ≤-2.5 is to mitigate fracture risk by achieving T-scores at least above -2.5. In the ACTIVE trial, 2463 women with osteoporosis aged 49-86 yr were treated for 18 mo with abaloparatide (80 μg), teriparatide (20 μg), or placebo. In ACTIVExtend, eligible women from the abaloparatide and placebo groups received weekly treatment with 70 mg of alendronate for 2 additional years. This post hoc analysis of ACTIVE and ACTIVExtend included women with baseline TH or LS T-scores ≤-2.5. Logistic regression was used to predict the probability of achieving a T-score >-2.5 at the TH or LS during 18 mo of treatment with abaloparatide or teriparatide and during 3.5 yr with the sequence of abaloparatide/alendronate compared to placebo/alendronate. At baseline, 23% and 74% of women enrolled in ACTIVE had T-scores ≤-2.5 at the TH and LS, respectively. Over 18 mo of treatment, more than 50% of women were likely to achieve TH T-scores >-2.5, with baseline TH T-scores as low as -2.7 for both abaloparatide and teriparatide. More than 50% of women were predicted to achieve an LS T-score >-2.5 with a baseline LS T-score as low as -3.3 for abaloparatide or -3.2 on teriparatide. Over 3.5 yr of sequential treatment with abaloparatide/alendronate, >50% of women with baseline TH T-scores ≥-2.9 and LS T-scores ≥-3.5 were predicted to achieve T-scores >-2.5, respectively. A patient's BMD at baseline and the probability of achieving target T-scores with treatment should be considered when determining that treatment should be initiated in patients at high or very high risk of fracture.
Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis.
Abaloparatide (previously known as BA058) is a synthetic 34-amino acid peptide and novel selective activator of parathyroid hormone receptor 1 (PTHR1) currently under development as a new anabolic agent in the management of osteoporosis. This paper reviews the profile and potential of abaloparatide in the treatment of postmenopausal osteoporosis. This paper is based on clinical trials and a PubMed search. Search terms used were "abaloparatide", "BA058", and "PTHrP". This review outlines the effects of this anabolic PTHR1 activator, which increases bone mineral density in patients at high risk for osteoporosis. The potential adverse effects of abaloparatide are also summarized. Abaloparatide has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34). The molecule was meticulously selected to retain stability and potent bone anabolic activity, and it has a limited effect on bone resorption (hence, a low calcium-mobilizing potential). Abaloparatide has shown promising results in a reduction of new onset vertebral (approximately 86% reduction) and nonvertebral fractures (approximately 43% reduction). In clinical trials to date, abaloparatide appears to have a good safety and tolerability profile with a significantly lower degree of hypercalcemia compared to that of teriparatide. Based on the clinical trials, the optimum dose of abaloparatide is 80 mcg subcutaneous once daily.
ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis.
In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.
Abaloparatide: First Global Approval.
Abaloparatide (Tymlos™) is a synthetic peptide analogue of human parathyroid hormone-related protein that was developed by Radius Health as an osteoanabolic agent for the treatment of postmenopausal osteoporosis. Abaloparatide acts through selective activation of the parathyroid hormone type 1 receptor signalling pathway. In April 2017, subcutaneous abaloparatide received its first global approval, in the USA, for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. A Marketing Authorization Application for subcutaneous abaloparatide for the treatment of postmenopausal women with osteoporosis was accepted by the European Medicines Agency and is currently under review. Radius is also developing a transdermal formulation of abaloparatide, with administration via a microneedle patch. This article summarizes the milestones in the development of abaloparatide leading to this first approval for the treatment of women with postmenopausal osteoporosis.
Comparative Effectiveness of Abaloparatide and Teriparatide in Women 50 Years of Age and Older: Update of a Real-World Retrospective Analysis.
Abaloparatide and teriparatide are osteoanabolic treatments indicated for postmenopausal women and men with osteoporosis at high risk of fracture. In the Abaloparatide Comparator Trial In Vertebral Endpoints study, bone mineral density improvements were significantly greater with abaloparatide compared to teriparatide at the total hip and femoral neck. We conducted a retrospective claims study to examine the incidences of hip and nonvertebral fractures and cardiovascular events in women aged ≥50 years initiating abaloparatide or teriparatide therapy, expanding on a previous retrospective claims study. This retrospective observational study used anonymized claims data from ICON's Symphony Health, PatientSource for women aged ≥ 50 years with ≥ 1 prescription fill for abaloparatide or teriparatide. The index date was the date of the initial prescription dispensed. Times to first hip fracture, nonvertebral fracture, and serious cardiovascular event were compared between logistic regression-based propensity score-matched cohorts and in predefined subgroups by age, prior antiresorptive use, and prior fracture using Cox proportional hazards models. Patients (21 676 per cohort) were well matched on 73 baseline parameters. Forty-five percent of patients in the abaloparatide arm and 47% in the teriparatide arm were exposed to treatment for longer than 12 months. Over 18 months (+ 30 days follow-up), 245 (1.1%) and 296 (1.4%) women in the abaloparatide and teriparatide cohorts, respectively, had a hip fracture (HR [95% CI] 0.83 [0.70, 0.98]; P = .027); 947 (4.4%) and 1078 (5.0%) had a nonvertebral fracture (0.88 [0.80, 0.96]; P = .003). There were no significant treatment-subgroup interactions (P ≥ .2). Cardiovascular events were similar between groups. There were significantly lower rates of hip and nonvertebral fractures with abaloparatide compared to teriparatide, which were consistent across subgroups. No differences in cardiovascular safety were noted between cohorts.
Osteoporosis: A Review of Novel Agents.
Osteoporosis is a bone disease characterized by decreased new bone formation, increased bone resorption, or both processes occurring simultaneously. This disease affects more than 10 million individuals older than 50 years in the United States. If this disease is left untreated, it can result in fragility fractures, which are currently seen in more than 1 million people in the United States. New agents have been developed to add to the list of treatment options that can be used to treat this disease. This article summarizes two specific agents that were approved by the Food and Drug Administration within the last few years: abaloparatide (Tymlos) and romosozumab (Evenity). This article also highlights the crucial role that nursing staff may play in the management of osteoporosis.
The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence.
It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.
Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis.
Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.
The interplay of rheumatoid arthritis and osteoporosis: exploring the pathogenesis and pharmacological approaches.
Rheumatoid arthritis (RA) and osteoporosis are two chronic disorders that are often seen together. RA is an autoimmune disorder that causes pain and inflammation in the joints, while osteoporosis is a disorder in which the bones become weak and fragile. Risk factors for bone loss in RA include disease activity, longer disease duration, erosive disease, autoantibody positivity, and joint damage leading to impaired physical activity. Recent research has shown that there is a complex interplay between immune cells, cytokines, and bone remodeling processes in both RA and osteoporosis. The bone remodeling process is regulated by cytokines and immune system signaling pathways, with osteoclasts activated through the RANK/RANKL/OPG pathway and the Wnt/DKK1/sclerostin pathway. Understanding these mechanisms can aid in developing targeted therapies for treatment of osteoporosis in RA patients. Current pharmacological approaches include anti-osteoporotic drugs such as bisphosphonates, denosumab, teriparatide, abaloparatide, raloxifene, and romosozumab. Conventional disease-modifying antirheumatic drugs such as methotrexate and biologicals including TNF inhibitors, IL-6 inhibitors, rituximab, and abatacept lower disease activity in RA and can improve bone metabolism by reducing inflammation but have limited impact on bone mineral density. This review will shed light on the relationship between osteoporosis and rheumatoid arthritis as well as the various factors that influence the onset of osteoporosis in RA patients. We also explore several treatment approaches to effectively managing osteoporosis in RA patients.
Abaloparatide: Review of a Next-Generation Parathyroid Hormone Agonist.
To review the efficacy, safety, and economics of abaloparatide in the treatment of postmenopausal osteoporosis. PubMed (1966 to October 2017), Clinicaltrials.gov (October 2017), and Scopus (1970 to October 2017) were searched using abaloparatide, Tymlos, BA058, PTHrP 1-34 analog, and parathyroid hormone-related peptide 1-34 analog. Human studies published in peer-reviewed publications in English were the primary sources for efficacy, safety, and economic data. In the 2 randomized, published clinical studies of 24 weeks and 18 months duration, bone mineral density changes were higher for abaloparatide (lumbar spine, 6.7%-11.2%; femoral head, 3.1%-3.2%; total hip, 2.6%-4.2%) compared with placebo (lumbar spine, 0.6%-1.6%; femoral head, -0.4% to 0.8%; total hip, -0.1% to 0.4%; P < 0.05) and compared with teriparatide in the 24-week study (total hip 2.6% vs +0.5%, P < 0.05). New vertebral and nonvertebral fractures occurred in 0.6% and 2.7% of patients on abaloparatide compared with 4.2% and 4.7% on placebo in the 18-month study ( P < 0.05). Abaloparatide appears to have a somewhat higher risk for adverse effects, discontinuation as a result of adverse effects, and serious or severe adverse effects than teriparatide, but teriparatide has a higher risk for hypercalcemia. Pharmacoeconomic modeling appears to favor abaloparatide if differences in efficacy and cost are maintained. Abaloparatide, which has less effect on osteoclasts, is an alternative to teriparatide in patients with postmenopausal osteoporosis who are at high risk for fractures or who have failed antiresorptive therapy based on initial clinical studies and economic modeling.
Abaloparatide and the Spine: A Narrative Review.
Osteoporosis is a common and debilitating condition characterized by diminished bone mass and architecture leading to bone fragility. Antiresorptive medicines like bisphosphonates (and less commonly denosumab) are the typical first-line agents for the medical treatment of osteoporosis. However, newer anabolic agents have been shown to improve bone mass and architecture, as well as reduce fracture risk, to a greater degree than traditional antiresorptive therapies. Teriparatide (human recombinant parathyroid hormone (PTH) 1-34, Forteo, Ely Lilly, Indianapolis, IN), which was the first in class to be approved in the United States, is the most widely used anabolic osteoporosis medicine and has shown significant benefit over traditional antiresorptive therapies. However, abaloparatide (synthetic parathyroid-related peptide (PTHrP), Tymlos, Radius Health, Waltham, MA), the second drug in this family, has recently become available for use. In this narrative review, we review the mechanism, effects, and benefits of abaloparatide compared to alternative treatments as well as discuss the current literature in regard to its effect on osteoporosis-related complications in the spine.
[Osteoporosis].
After one year of treatment with denosumab, the incidence of fracture is lower in patients previously treated one year with romosozumab as compared with placebo. Cessation of denosumab injections is followed by a rebound of bone resorption, a decrease of bone mineral density and increased risk of multiple vertebral fractures. For safety reasons, odanacatib, an inhibitor of cathepsine K and consecutively of bone resorption will not be available. Abaloparatide, a PTHrp(Parathormon related protein) analog, decreases the incidence of vertebral and non vertebral fractures. In patients with diabetes, the incidence of fractures is increased mainly due to alterations quality of bone.
[Osteo-anabolic treatment strategies].
Teriparatide and abaloparatide are osteoanabolic agents that promote the formation of new bone by activating the PTH1 receptor, significantly reducing the risk of fractures, particularly vertebral fractures. Romosozumab works by inhibiting sclerostin. To maintain the therapeutic benefit after osteoanabolic therapy, subsequent anti-resorptive therapy is obligatory for all of these agents. Teriparatide is approved for use in men and postmenopausal women at high risk of fracture, as well as for the treatment of glucocorticoid-induced osteoporosis. However, the approval of romosozumab and abaloparatide is currently limited to the treatment of postmenopausal women. The choice of drug should be made on a patient-specific basis, taking into account risk factors, fracture history, and comorbidities. Osteoanabolic drugs are an effective therapeutic strategy for reducing individual fracture risk and treating osteoporosis.
Daclizumab.
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The December 2016 monograph topics are ozenoxacin cream, ocrelizumab, naldemedine, eteplirsen, and abaloparatide. The Safety MUE is on buprenorphine buccal.
Osteoanabolic Agents for Osteoporosis.
Medications for osteoporosis are classified as either antiresorptive or anabolic. Whereas antiresorptive agents prevent bone resorption, anabolic agents promote new bone formation. Anabolics should be considered in individuals with severe osteoporosis, failure of alternative osteoporosis agents, intolerability or contraindications to other osteoporosis agents, and glucocorticoid-induced osteoporosis. There are currently two approved anabolic therapies, teriparatide and abaloparatide, and a third anabolic agent, romozosumab, is under review by the US Food and Drug Administration. Teriparatide and abaloparatide are administered as daily subcutaneous injections and have been shown to reduce vertebral and nonvertebral fractures significantly. The most common side effects are headache and nausea, but teriparatide and abaloparatide are generally well tolerated. The sequence of administration of anabolic therapy is important. Benefits of anabolics are attenuated in individuals with prior antiresorptive exposure; however, antiresorptive agents administered after anabolics consolidate bone mineral density gains.
Latest on Anabolic Agents for Osteoporosis Treatment.
In the last decades, novel therapeutics with anabolic bone properties have been developed and are currently used in the management of osteoporosis particularly in patients with high-risk of fragility fractures. These drugs include PTH-Related Analogues, teriparatide and abaloparatide, and the anti-sclerostin agent romosozumab, this latter drug currently approved only in female patients. Their efficacies in preventing fragility fractures are widely demonstrated and their potential serious side effects were progressively downgraded, including risk of malignancies in teriparatide- and cardiovascular events in romosozumab-users, respectively. Further data are warranted about their efficacy in glucocorticoids-induces osteoporosis and fracture healings.
Quick links (PubMed)
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- PMID 38499817 — 2024 · The interplay of rheumatoid arthritis and osteoporosis: exploring the pa…
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- PMID 39448133 — 2024 · Latest on Anabolic Agents for Osteoporosis Treatment.