Learning objectives
- •
Appreciate the mode of action of denosumab, its efficacy, and adverse effects.
- •
Develop a management strategy to follow up patients on denosumab.
The case study
Reason for seeking medical help
NB is a 58-year-old Caucasian woman diagnosed with osteoporosis about 3 months ago. She was prescribed alendronate but could not tolerate the upper gastrointestinal adverse effects she experienced, did not appreciate the “prolonged” routine involved in taking oral bisphosphonates, and did not wish to continue with these tablets, other oral bisphosphonates, or any medication for osteoporosis. She emphasizes that she is essentially asymptomatic; has not sustained any fractures, falls, or near-falls; and does not experience dizzy spells. She believes she therefore does not need any medication with adverse effects to treat a disease that is largely asymptomatic! It took quite some time to convince her of the natural history of osteoporosis and the importance of treating the disease before a fracture occurs.
Past medical and surgical history
- •
Osteoporosis, diagnosed about 3 months ago by bone densitometry. DXA scan results: T-scores left femoral neck −2.6, left total hip −2.2, L1–L4: −2.8.
- •
No evidence of fractures.
- •
Natural menopause at age 51 years, no HRT.
Lifestyle
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Daily dietary calcium intake about 1200 mg.
- •
No excessive caffeine, sodium, or alcohol intake.
- •
No cigarette smoking.
- •
Active physical lifestyle: jogs about 2 miles every weekday and cycles about 5 miles during most weekends.
Medication
- •
No medication.
Family history
- •
Older sister: fragility hip fracture, about 6 months ago.
Clinical examination
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Weight 151 pounds, height 62″.
- •
Get-Up-and-Go test completed in 7 s.
- •
No relevant clinical findings. No fractures, no orthostatic hypotension, no arrhythmias, no clinical evidence of sensitive carotid sinus, no arthropathies, no cervical spondylosis, and no localizing neurological lesions.
Laboratory results
- •
CBC, CMP, TSH within normal limits.
- •
Serum vitamin D: 42 ng/mL.
Multiple choice questions
- 1.
After reviewing treatment options, NB chose denosumab. The following is/are true about denosumab:
- A.
Antiresorptive agent.
- B.
Human antibody with high specificity.
- C.
Excreted by the kidneys.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
Denosumab is a highly specific, fully human, monoclonal antibody that specifically binds to Receptor Activator Nuclear Factor-Kappa-beta Ligand (RANK-L), thus preventing the activation of RANK which in turn prevents the recruitment of preosteoclasts to form osteoclasts, maturation of osteoclasts, and their subsequent activation. Denosumab is neither metabolized nor excreted by the kidneys. It therefore can be administered to patients with mild to moderately impaired renal functions. It is nevertheless important to monitor the serum calcium level to prevent hypocalcemia. Denosumab is well tolerated. When given a choice, more patients (92%) prefer denosumab to alendronate.
- A.
- 2.
In postmenopausal women with osteoporosis, compared to placebo, over a 3-year period, denosumab reduced the risk of:
- A.
Hip fractures by 40%.
- B.
Vertebral fractures by 68%.
- C.
Nonvertebral fractures by 20%.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
These are the results of the pivotal phase 3 study, a 3-year randomized double-blind, placebo-controlled study, which included 7868 postmenopausal women between the ages of 60 and 90 years and with a T-score of −2.5 or lower at lumbar vertebrae or total hip. Exclusion criteria included women who had a T-score of −4.0 or lower, one severe or more than two moderate vertebral compression fractures, and those with a serum vitamin D level lower than 12 ng/mL. Neutralizing antibodies did not develop in any of the subjects.
- A.
- 3.
In postmenopausal women with osteoporosis, compared to placebo, over a 3-year period, denosumab induced the following changes:
- A.
Lumbar vertebrae BMD increased by 9.2%.
- B.
CTX decreased by 72%.
- C.
P1NP decreased by 76%.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
In this study, at the end of the 3-year period, compared to placebo, patients on denosumab had an average 9.2% increase in lumbar vertebrae BMD (95% CI 8.2–10.1) and 6.0% total hip (95% CI 5.2–6.7). Serum CTX (C-telopeptide of type I collagen), a marker of bone resorption, decreased by 86%, 72%, and 72% at month 1, 6, and 36, respectively, and serum intact procollagen type I N-terminal propeptide (P1NP), a marker of bone formation, decreased by 18%, 50%, and 76% at month 1, 6, and 36, respectively.
The BMD increases were further enhanced in the Extension study: compared to baseline, patients who had been for 5 years on denosumab had mean increases of 13.7% at the lumbar vertebrae, 7.0% total hip, 6.1% femoral neck, and 2.3% at 1/3 radius (all P < 0.001). Patients who had been on denosumab for 10 years had a 21.7% increase in BMD of the lumbar vertebrae and 9.2% in the total hip.
- A.
- 4.
In the initial 3 years of the FREEDOM trial, the main adverse effects of denosumab included:
- A.
Increased risk of cellulitis/skin infections.
- B.
Systemic infections.
- C.
Cutaneous/mucosal lichenoid drug eruptions.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
In this study, eczema, cellulitis, and serious infections occurred more frequently in patients on denosumab than those on placebo. These trends, however, were not maintained in the extension study.
- A.
- 5.
Possible long-term adverse effects include:
- A.
Osteonecrosis of the jaw.
- B.
Atypical femoral shaft fracture.
- C.
Increased risk of bone loss and fractures after stopping denosumab.
- D.
All of the above.
- E.
A and B.
Correct answer: D
Comment:
Like most other antiresorptive medications, the risk of osteonecrosis of the jaw and atypical femoral shaft fractures is increased in patients on long-term denosumab therapy. The fracture risk is also increased in patients who discontinue denosumab and are not prescribed another antiresorptive medication.
The increased risk of vertebral fractures has been observed in patients who discontinue denosumab injections and may occur as early as missing just one single dose by about a month, i.e., 7 months from the previous subcutaneous dose.
- A.
- 6.
Contraindications to the ad min istration of denosumab include:
- A.
Patients 80 years of age and older.
- B.
Hypercalcemia.
- C.
Creatinine clearance less than 35 mL/min.
- D.
Hyperparathyroidism.
- E.
None of the above.
Correct answer: E
Comment:
Old age is not a contraindication to the administration of denosumab. A retrospective study on 60 female patients, mean age 83.9± years, treated with denosumab every 6 months for 12 months showed significant increases in the BMD of the lumbar vertebrae: 3.02 ± 2.74% ( P = .000), femoral neck 3.10 ± 6.90% ( P = .005), and total hip 2.89 ± 5.80 ( P = .002). Similarly, the serum bone marker levels of the C-terminal telopeptide type I collagen and osteocalcin declined significantly after 12 months of treatment: −34.8 ± 45.9% ( P = .002) and −35.5 ± 38.9% ( P = .004), respectively.
By reducing the rate of bone resorption and therefore the mobilization of calcium from bones to circulation, denosumab may induce or worsen an existing hypocalcemia. It is therefore contraindicated in patients who have hypocalcemia. Checking the serum calcium level prior to the administration of denosumab is recommended.
As denosumab is not excreted by the kidneys, it can be safely administered to patients with impaired renal functions. Care should nevertheless be exercised as these patients’ calcium homeostasis is precarious. Denosumab is not contraindicated in patients with hyperparathyroidism.
In patients with normal serum calcium and vitamin D levels, normal renal functions, and administered 1-g calcium carbonate and 800 IU cholecalciferol daily, the administration of denosumab was followed by significant increases in serum parathyroid hormone level at 1-month, returning to baseline at 6 months: baseline serum PTH: 34.8 ± 2.8; 1 month: 62.4 ± 13.3 and 6 months 40.7 ± 4.0 pg/mL.
- A.
- 7.
Discontinuation of denosumab therapy is associated with:
- A.
Increased fracture risk.
- B.
Decreases in BMD.
- C.
Increases in markers of bone turnover.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Discontinuation of denosumab is associated with increases in bone turnover, decreases in BMD, and an increased vertebral fracture risk, especially multiple vertebral compression fractures, often more than the pretreatment fracture risk.
“Drug holidays” when denosumab is discontinued are therefore not recommended in patients who have been on denosumab unless some other antiresorptive medication is prescribed when the administration of donepezil is stopped.
The increased fracture risk after discontinuing denosumab can be as early as 7 months after the last injection, i.e., postponing the intake of denosumab by as short a period as 1 month can be sufficient to trigger an increased rate of bone resorption and an increased risk of fractures sustaining fractures. Most fractures nevertheless occur between 9 and 19 months of discontinuance of denosumab. This “rebound phenomenon” may lead to multiple vertebral compression fractures. It can be, at least partly, avoided if the cessation of denosumab is followed by the administration of a bisphosphonate. Unfortunately, in some instances, the denosumab rebound-associated vertebral fractures continue despite reinstitution of denosumab.
- A.
- 8.
When denosumab is combined with teriparatide, over a 12-month period, compared to either medication on its own, changes in the following parameters are significant:
- A.
Increases in BMD.
- B.
Decreases in fracture risk.
- C.
Decreases in markers of bone resorption.
- D.
A and C.
- E.
A, B, and C.
Correct answer: D
Comment:
At the end of a 12-month period, the combination of denosumab and teriparatide induced larger increases in the BMD and more pronounced changes in bone turnover markers than either medication alone. The mean increases in BMD at the lumbar vertebrae were 6.2%, 5.5%, and 9.1% for the teriparatide, denosumab, and combination group, respectively. Changes in femoral neck BMD were 0.8%, 2.1%, and 4.2% and in the total hip were 0.7%, 2.5%, and 4.9%, respectively. Markers of bone resorption (CTX) were decreased more in the denosumab and combination group than in the teriparatide group. Markers of bone formation (osteocalcin and P1NP) increased more with teriparatide than either denosumab alone or denosumab combined with teriparatide. Fracture risk reduction was not assessed given the short duration of the study: 12 months.
- A.
- 9.
Match the following:
- (a)
Denosumab.
- (b)
Bisphosphonates.
- (c)
Both.
- (d)
Neither.
- A.
Embedded in bone matrix.
- B.
Stimulate osteoblast receptors.
- C.
Cleared by reticuloendothelial system.
- D.
Recycling occurs after medication is discontinued.
- E.
Inhibit osteoclast intracellular enzymes.
- A.
Correct answers: A (b); B (d); C (a); D (b); E (b)
Comment:
The antiresorptive effect of bisphosphonates and denosumab is mediated differently. Bisphosphonates become embedded in the bone matrix calcified hydroxyapatite crystals until released by the acidic environment created by the osteoclasts during bone resorption. Once engulfed by osteoclasts they inhibit intracellular enzymes, interfere with bone-resorbing activity, and induce apoptosis. Denosumab prevents the activation, differentiation, maturation, and activation of osteoclasts by binding with RANK-L which stimulates RANK surface receptors.
Denosumab is cleared by the reticuloendothelial system and is not excreted by the kidneys. It therefore can be administered safely to patients with impaired renal functions. Bisphosphonates are cleared through renal excretion. Neither bisphosphonates nor denosumab is metabolized by the liver. “Recycling” occurs as bisphosphonates are released from the bone matrix to the circulation. No recycling occurs with denosumab.
- (a)
- 10.
In patients on hormonal ablation therapy, denosumab:
- A.
In men with prostate cancer, increases BMD, reduces bone turnover and fracture risk.
- B.
In women with breast cancer, increases BMD, reduces bone turnover and fracture risk.
- C.
In men and women, adverse effects were similar to placebo.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
In men with prostate cancer on hormonal ablation therapy, over a 3-year period, compared to placebo, denosumab reduced the risk of new vertebral fractures at 12 months: 0.3% denosumab, 1.9% placebo; 24 months: 1.0% versus 3.3%; and 36 months: 1.5% versus 3.9%. Denosumab also induced increases in BMD and decreases in bone turnover markers. Similarly, in women with nonmetastatic breast cancer on aromatase inhibitors, over a 2-year period, compared to placebo, denosumab reduced the risk of nonvertebral fractures, increased BMD, and decreased bone turnover.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Status postmenopause, no HRT.
- •
Caucasian race.
- •
Positive family history for osteoporosis and fragility fractures: older sister sustained fragility hip fracture.
Factors protecting against bone demineralization/osteoporosis
- •
Good daily dietary calcium intake.
- •
Active physical lifestyle.
- •
No alcohol abuse, no cigarette smoking, no excess sodium or caffeine.
Factors increasing risk of falls/fractures
- •
None.
Factors reducing risk of falls/fractures
- •
Active physical lifestyle.
Diagnosis
Osteoporosis, as diagnosed by bone densitometry: a T-score of −2.5 or lower in one of the hips, lumbar vertebrae, or distal one-third radius. No fractures.
Management recommendations
Further tests
- •
None at this stage.
Medications
- •
Denosumab 60 mg sc at 6-month intervals.
Lifestyle
- •
Maintain present healthy lifestyle.
Follow-up
- •
6, 12, and 18 months visits, before the administration of denosumab, to ensure the serum calcium level is within the normal range and renal functions are normal prior to next denosumab sc injection.
- •
2 years: DXA scan, serum calcium level, and serum vitamin D level prior to fourth denosumab injection.
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