Teriparatide/abaloparatide—Part I: Differences and similarities
Learning objectives
- •
Pharmacologic profile: efficacy and adverse effects of teriparatide and abaloparatide.
- •
Teriparatide and abaloparatide: differences and similarities.
- •
Impact of recent label changes.
The case study
Reason for seeking medical help
VO, a 71-year-old Caucasian woman, sustained a fragility hip fracture after slipping in her granddaughter’s bedroom about a year ago. She underwent a successful hip replacement, responded well to physical therapy, and is now independent. Secondary causes of osteoporosis have been excluded; she is referred for the management of osteoporosis.
Past medical and surgical history
- •
Osteoporosis, diagnosed about a year ago, after she sustained a fragility hip fracture. She was prescribed oral bisphosphonates but developed severe upper gastrointestinal symptoms that she could not tolerate. After four doses, she decided to stop taking the bisphosphonate without notifying her treating physician. She also did not think she really needed any treatment: her hip fracture healed well; the range of lower limb movement is good. She is not in pain.
- •
Surgical menopause at age 37 years because of endometriosis. Good outcome. She has been on hormonal replacement therapy for about 3 years after the surgery. She then stopped taking it without notifying her primary care provider.
- •
No other relevant past medical history, no history of falls, no near-falls, no dizzy spells.
Lifestyle
- •
Physically independent, mentally good. She is a retired librarian.
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Sedentary lifestyle.
- •
Daily calcium intake about 1200 mg.
- •
No excessive sodium or caffeine intake, no cigarette smoking.
Medication
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Oral bisphosphonate, prescribed about a year ago, discontinued it after four doses because of gastrointestinal adverse effects.
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Multivitamin tablets, over the counter.
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Vitamin D, over the counter, 600 IU daily. She started taking these tablets after sustaining the fragility hip fracture, about a year ago. At that time her serum vitamin D level was within the normal range: 30 ng/mL.
Family history
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Mother sustained fragility hip fracture.
Clinical examination
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Weight 152 pounds, steady; height 62″, used to be 64″.
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Able to ambulate independently, steady. No orthostatic symptoms.
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Timed Get-up-and-Go test completed in 9.6 s.
Laboratory results
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CBC, comprehensive metabolic profile, serum 25-hydroxy-vitamin D all within normal limits.
DXA and radiologic results
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T-scores: L2–L4: −3.1; left femoral neck −2.8; left total hip −3.0.
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VFA: moderate biconcave compression fracture of T12 and L1, and severe wedge compression fracture of T7. VO denies any trauma to her back.
Multiple choice questions
- 1.
After considering various treatment options, VO opted for teriparatide:
- A.
Teriparatide is recombinant human parathyroid hormone 1–84.
- B.
Teriparatide is administered by daily subcutaneous injection.
- C.
Patients’ compliance with teriparatide is poor: adherence rate is less than 50%.
- D.
A and C.
- E.
B and C.
Correct answer: B
Comment:
Teriparatide is a recombinant parathyroid hormone (first 34 amino acids). It is administered subcutaneously through a fixed-dose prefilled delivery device that contains 28 doses. Most patients self-administer the medication. After overcoming the initial trepidation about the need for daily injections, most patients adhere well: compliance has been reported to be as high as 89% at 6 months and 82% at 18 months. It is nevertheless essential to motivate patients, and keep them motivated, to comply with the intake of the medication, especially if the patient is asymptomatic.
- A.
- 2.
In VO’s case, appropriate reasons for prescribing teriparatide include:
- A.
Diagnosis of established osteoporosis.
- B.
Fragility fractures (hip and vertebrae).
- C.
“Very high” fracture risk.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The diagnosis of “established osteoporosis” is made when, at least, two criteria are met. First, is the densitometric evidence of osteoporosis. Second, in addition, the patient sustained 3 fragility fractures at T7, T12, ad L1 (i.e., a fracture occurring in the absence of any trauma or after trauma that ordinarily one would not expect to lead to a fracture).
In VO’s case, the fracture risk satisfies the criteria of “Very High Risk” of sustaining a fracture, as defined by the American Association of Clinical Endocrinologists (AACE), the American College of Endocrinology (ACE), the Endocrine Society, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), and the International Osteoporosis Foundation (IOF). She has densitometric evidence of osteoporosis (lowest T-score −3.1 in the lumbar vertebrae), and in addition sustained a fragility hip fracture and three fragility vertebral compression fractures.
She also lost about 2″ in height, probably secondary to the vertebral compression fracture(s). Other risk factors for osteoporosis and fractures include Caucasian ethnicity; surgical menopause at age 37 years, with no HRT, except for about 3 years; and a positive family history of fragility hip fracture (her mother).
- A.
- 3.
In postmenopausal women with osteoporosis, teriparatide versus placebo has been shown to reduce the fracture risk of:
- A.
Vertebrae.
- B.
Hips.
- C.
Ribs.
- D.
All of the above.
- E.
A and B.
Correct answer: D
Comment:
Compared to placebo, teriparatide reduced the incidence of fragility and traumatic fractures of the vertebrae, hips, wrists, ankles, ribs, feet, and pelvis. This trial was prematurely terminated to evaluate the clinical implications of toxicology animal studies. As a result, the mean duration of treatment in this study was only about 18 months. Notwithstanding, compared to placebo, the mean percent increase in BMD was 9.7%, 2.8%, 3.5%, and 2.6% at the lumbar vertebrae, femoral neck, trochanter, and total hip, respectively.
- A.
- 4.
Teriparatide and abaloparatide:
- A.
Can be administered for more than 2 years.
- B.
Simultaneous administration of an antiresorptive, in addition to teriparatide, is advantageous.
- C.
It should not be prescribed if the glomerular filtration rate is less than 35 mL/min.
- D.
Once discontinued, an antiresorptive agent should be prescribed.
- E.
A and D.
Correct answer: E
Comment:
Teriparatide reduces the risk of vertebral and nonvertebral fractures in women with postmenopausal osteoporosis and glucocorticoid-induced osteoporosis.
Until recently the recommendation was to restrict the administration of teriparatide to 2 years because of the fear it might increase the risk of osteosarcoma. This was based on findings of an early study on experimental animals (Fischer 344 rats). A black box warning was issued by the US FDA (Food and Drug Administration). The 2-year limitation with teriparatide therapy was also justified by the observation that the initial robust increase in BMD tends to gradually taper off and that the readministration of teriparatide after a one-year hiatus does not replicate the robust initial increase in BMD.
In 2020 the results of a 15-year US postmarketing surveillance study became available and showed that teriparatide did not increase the risk of osteosarcoma. The FDA withdrew the 2-year lifetime teriparatide treatment limit and the black box warning about the potential risk of osteosarcoma. This was followed by the removal of the two-year treatment limit for abaloparatide. Now, for how long therapy with teriparatide should be continued in individual patients is a clinical issue. Therefore patients with a “high” or “very high” risk of fracture may continue with this medication, as long as clinically indicated, beyond the two-year limit.
When teriparatide is discontinued, BMD gains are lost unless an antiresorptive is prescribed. Starting bisphosphonate therapy immediately after discontinuing teriparatide induces further increases in BMD.
As teriparatide is neither metabolized nor excreted by the kidneys, it can be administered if the patient’s GFR is less than 35 mL/min. Good hydration is, nevertheless, recommended and caution should be exercised because many patients with renal impairment have secondary hyperparathyroidism. Teriparatide is contraindicated in patients who have received radiation therapy.
A meta-analysis of nine randomized controlled trials (RCTs) which included 2990 postmenopausal women with osteoporosis (1515 treated with teriparatide and 1475 treated with bisphosphonates) showed that teriparatide reduced the vertebral and nonvertebral fracture risk and increased BMD to a greater extent than bisphosphonates. Cyclic administration of teriparatide and denosumab was not superior to their sequential administration.
- A.
- 5.
Teriparatide increases bone formation by:
- A.
Increasing the number of preosteoblasts.
- B.
Downregulating RANLK-ligand.
- C.
Stimulating osteoprotegerin secretion.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Teriparatide administration increases the number of preosteoblasts, stimulates their differentiation into mature osteoblasts, and enhances their function. Teriparatide also improves bone microarchitecture by increasing trabecular connectivity and cortical thickness, thus increasing bending and buckling strength. In addition, teriparatide downregulates RANK-Ligand expression and stimulates osteoprotegerin secretion resulting in reduced osteoclast formation, maturation, and stimulation, and therefore reduced bone resorption.
- A.
- 6.
Teriparatide administration after a fracture:
- A.
Stimulates chondrogenesis in the callus.
- B.
Enhances chondrocyte maturation and mineralization.
- C.
Enhances fracture healing.
- D.
All of the above.
- E.
None of the above.
Correct answer: D
Comment:
Teriparatide is also useful to reduce back pain and improve quality of life in patients who have sustained a vertebral compression fracture. Studies on experimental animals document that teriparatide administration after a fracture enhances fracture healing by increasing the callus volume and enhancing endochondral bone formation through increased chondrogenesis, chondrocyte maturation and mineralization. There is still a relative paucity of large studies on the effect of teriparatide on fracture healing in humans.
- A.
- 7.
Main adverse events of teriparatide include:
- A.
Postural hypotension.
- B.
Nausea.
- C.
Arthralgia.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Adverse events after teriparatide administration include arthralgia (10.1% teriparatide versus 8.4% placebo) and nausea (8.5% teriparatide, 6.7% placebo), but no vomiting. The latter is usually self-limited. In order to avoid it, many patients self-administer at night as they get ready for bed. As in most instances these symptoms occur late at night, when asleep, the patient may not notice them. Although symptomatic postural hypotension is rare (about 5%), it is nevertheless recommended that at least for the first few doses, teriparatide be administered under circumstances in which the patient can quickly sit or lie down should these symptoms arise.
- A.
- 8.
Teriparatide is contraindicated in patients with:
- A.
Hypercalcemia.
- B.
Hypocalcemia.
- C.
Nephrolithiasis.
- D.
A and C.
- E.
B and C.
Correct answer: D
Comment:
As teriparatide may increase the serum and urinary calcium it should not be administered to patients with hypercalcemia or a history of renal calculi. It is also contraindicated in patients with bone metastases, metabolic bone diseases other than osteoporosis or a history of skeletal malignancies.
- A.
- 9.
Osteosarcoma and teriparatide:
- A.
The risk of osteosarcoma is higher in patients on teriparatide.
- B.
Toxicology studies showed an increased incidence of osteosarcoma in experimental rats.
- C.
Teriparatide should not be administered to patients who have received radiation therapy.
- D.
A and B.
- E.
B and C.
Correct answer: E
Comment:
Toxicology studies document that when teriparatide is administered to Fischer 344 rats in doses up to 60 times higher than those used in humans, the incidence of osteosarcoma is increased in a dose- and duration-dependent manner. On the other hand, no bone tumors were detected after 18 months of teriparatide to mature oophorectomized monkeys, at doses 6 times higher than administered to humans. Similarly, the risk of osteosarcoma is not increased in patients with hyperparathyroidism.
Postmarketing surveillance showed that over a 15-year follow-up period the incidence of osteosarcoma in patients receiving teriparatide is not higher than in the general population. Teriparatide, nevertheless, is not recommended in children and young adults with open epiphyses and those in whom the risk of osteosarcoma is increased such as patients who have received radiation therapy and those with Paget’s disease of bone or unexplained increases in bony alkaline phosphatase levels.
- A.
- 10.
Teriparatide is used for the treatment of:
- A.
Women with postmenopausal osteoporosis at very high risk for fracture.
- B.
Men with primary or hypogonadal osteoporosis at very high risk for fracture.
- C.
Women and men with glucocorticoid-induced osteoporosis at very high risk for fracture.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Teriparatide is used for the treatment of all listed conditions. It is also used for treatment of patients who have failed or could not tolerate other medication for osteoporosis and for men and women with osteoporosis on daily doses of 5 mg or more prednisone. It is also used to help healing of insufficiency fractures.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
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Multiple fragility fractures: hip and three vertebrae.
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Previously diagnosed osteoporosis, no medication.
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Surgical menopause at 37 years, no HRT.
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Positive family history for osteoporosis.
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Sedentary lifestyle.
Factors protecting against bone demineralization/osteoporosis
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Good daily calcium intake.
- •
Vitamin D supplements.
- •
No excessive sodium or caffeine intake; no cigarette smoking.
Factors increasing risk of falls/fractures
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Fragility fractures sustained.
- •
Positive family history.
Factors reducing risk of falls/fractures
- •
Physically independent.
- •
Timed Get-up-and-Go test completed in less than 14 s.
Diagnosis
- •
Established osteoporosis and high fracture risk.
Management recommendations
Treatment recommendation(s)/follow-up
- •
Six to eight weeks after initial outpatient visit to ensure adherence with teriparatide daily subcutaneous injections, answer any question the patient may have, and allay any anxiety. During this visit, other lifestyle issues such as adequate nutrition, adopting a physically active lifestyle, and possibly joining an exercise program could be discussed, especially as VO admitted to leading a sedentary lifestyle.
- •
Further pharmacologic management will depend on the results of this DXA scan and range from discontinuing teriparatide, to continuing it for another 2-year period. This could be accomplished after 4 years of treatment with teriparatide and repeating the DXA scan at that time.
- •
Antiresorptive medication when teriparatide is discontinued, 2–4 years after initiating pharmacologic therapy.
Medication(s)
- •
Given the degree of osteoporosis and high fracture risk, an osteoanabolic medication such as teriparatide, abaloparatide, or romosozumab is a good choice. Alternative choices include an antiresorptive medication such as denosumab or zoledronic acid. Oral bisphosphonates are not recommended as they may induce upper gastrointestinal adverse events that the patient could not tolerate.
Diagnostic test(s)
- •
None recommended at this stage. The diagnosis of osteoporosis has been made and secondary causes excluded.
Lifestyle
- •
An active physical lifestyle should be recommended, and, if possible, enrolling in a supervised exercise program.
DXA and radiologic
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DXA scan every 2 years.
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