Learning objectives
- •
Understand bone turnover, its various components, and how they can be manipulated.
- •
Recognize the role of sclerostin and romosozumab in bone turnover.
- •
Identify patients who are suitable candidates for romosozumab.
The case study
Reasons for seeking medical help
- •
RE is a 74-year-old Caucasian woman who, about 2 weeks ago, sustained a fragility fracture of her left hip after tripping on a toy her great grandchild had left on the carpet. The fracture was surgically reduced and healed well. She is now physically independent.
- •
About 15 years ago she sustained a Colles’ fracture of the right radius and was diagnosed with osteoporosis. The fragility fracture of the right radius healed well. She was prescribed alendronate but could not tolerate it. It was then changed to risedronate, but she also could not tolerate it. She is on no medication for osteoporosis.
- •
Given her impaired renal functions: creatinine clearance 20 mL/min, she was not considered for either orally administered bisphosphonates or zoledronic acid intravenous infusions. RE preferred not to be prescribed medication that has to be self-administered daily such as teriparatide or abaloparatide. She also was concerned that because of her osteoarthritic changes she may not be able to self-administer subcutaneous injections.
- •
She seems amenable to denosumab, 6-monthly subcutaneous injections administered by a health care provider but is concerned that as she travels extensively visiting children, grandchildren, and great-grandchildren and is very often away from home, she may not be able to ensure regular 6-monthly subcutaneous injections.
Past medical and surgical history
Apart from one vertebral fragility fracture of T7, and a Colley sustained, RE has been enjoying good health. Her two fractures healed well. She is physically independent and mentally good. She lives on her own in a retirement community and travels extensively.
Lifestyle
- •
Physically active lifestyle. When not traveling she enjoys going for walks, playing golf, and swimming at least three times a week.
- •
Body weight: steady at about 120 pounds
- •
She enjoys three cups of hot tea a day. No alcoholic drinks, no cigarette smoking, no excessive salt intake.
- •
Good nutritional intake, daily calcium intake estimated to be about 1500 mg; oral vitamin D intake about 800 units.
Medications
- •
She is not taking any medication, except for the occasional analgesic.
Family history
- •
All family members are in good health.
Clinical examination
- •
Osteoarthritic changes affecting hands and knees, but not interfering with her daily activities.
- •
Clinical examination essentially within normal limits. She just had her annual physical examination. No significant signs detected. BP 152/82 sitting, 154/85 standing, no orthostasis. No arrhythmias, no clinical evidence of sensitive carotid sinus, carotid stenosis, and no vertebrobasilar insufficiency. No clinical evidence of cervical spondylosis. Heart sounds clearly audible, no added sounds, no ectopic beats, no JVD, no clinical signs of heart failure. No edema of the lower limbs. Chest clear. Examination of the chest and abdomen does not reveal any significant signs.
- •
Timed Get-Up-and-Go test, completed within 8.2 s
Laboratory results
- •
CBC, CMP, GFR, and TSH, all essentially within normal range.
DXA and radiologic results
- •
T-scores:
Left total hip: −2.7.
Left femoral neck: −2.5.
Right total hip: −2.5.
Left femoral neck: −2.4.
Distal 1/3 left radius: −2.6.
- •
Vertebral fracture assessment: evidence of moderate vertebral compression fracture at T7.
Multiple choice questions
- 1.
Romosozumab:
- A.
Is a monoclonal antibody against sclerostin.
- B.
Suppresses bone resorption.
- C.
Stimulates bone formation.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Bone is a dynamic tissue which constantly undergoes remodeling to accommodate for the mechanical demands of the body: a solid, mechanical stress-sustaining skeleton, and the metabolic needs of the body: a readily accessible, well-stocked calcium and mineral reservoir. Osteoblasts are the bone-forming cells and osteoclasts are the bone-resorbing cells. These two mechanisms of bone formation and bone resorption are responsible for changes in bone mass, density, and mechanical strength throughout life and are referred to as bone turnover.
The bone remodeling cycle is initiated by osteocytes in response to changes of the body’s need for calcium or by the physical mechanical stress on individualized foci in the skeleton. The phase of increased bone resorption by the activated osteoclasts is dynamic and ready to change according to skeletal activities and demands for calcium and other minerals. This period is followed by a reversible phase when the osteoclasts, having met the demands imposed on them, withdraw from the cavities they have created while resorbing bone tissue and make room for the osteoblasts to refill the resorbed areas. The osteoblasts then either become osteocytes, buried in the skeleton, ready to become active again, or become bone-lining cells, also ready to respond to appropriate stimuli. The main goal is to maintain a healthy skeleton and a well-stocked calcium and mineral reservoir.
Sclerostin inhibits the differentiation of precursor cells into mature bone-forming osteoblasts and decreases bone formation. Conversely, inhibiting sclerostin binding to osteoblasts allows an increase of osteoblastic activity and bone mass.
Sclerostin was originally discovered in patients with sclerosteosis and van Buchem disease, two rare inherited diseases characterized by an increased bone mass, deformities, characteristic facial features, and nerve compression due to the expanding skeleton.
Romosozumab is a humanized monoclonal antibody developed to inhibit the effects of sclerostin and increase the bone mass. It is used in the management of osteoporosis. The elimination half-life of romosozumab is estimated to be 12.6 days after the administration of three doses. Whereas the inhibited rate of bone resorption is maintained throughout the course of therapy, the increased rate of bone formation returns to the original pretreatment levels after the 9th month of regular monthly administration. After cessation of therapy markers of bone formation, bone resorption and BMD gradually return to baseline levels.
- A.
- 2.
Romosozumab is administered:
- A.
Daily
- B.
Once a week
- C.
Once a month
- D.
Once every 3 months
- E.
Once every year
Correct answer: C
Comment:
Romosozumab is administered subcutaneously, once a month, for 12 months. It is recommended that on completion of the 12-month period, the patient be prescribed an antiresorptive medication.
- A.
- 3.
A comparison of the effects of denosumab and romosozumab shows that after a 12-month period:
- A.
The increase in BMD of the lumbar vertebrae is about the same in both groups.
- B.
Patients on denosumab have significant increases in the serum P1NP.
- C.
Significantly more patients who sustained fragility fractures were in the denosumab group.
- D.
All of the above.
- E.
None of the above.
Correct answer: E
Comment:
A retrospective, observational cohort study was conducted on women with postmenopausal osteoporosis to compare the efficacy of denosumab to that of romosozumab. In this study one of the two medications was administered to 69 matched patients. At the end of a 6-month period, patients in the romosozumab group had mean increases in the lumbar vertebrae, total hip, and femoral neck BMD of 7.4%, 3.4%, and 3.0%, respectively. Those on denosumab had increases of 6.0%, 2.4%, and 2.0% in the lumbar vertebrae, total hip, and femoral neck, respectively. Similarly, in patients on romosozumab the increases at the end of the 12-month period were 12.5%, 6.0%, and 5.5% for the lumbar vertebrae, total hip, and femoral neck, respectively. Patients on denosumab had a decrease in the P1NP of 63.1% at 6 months and 68.2% at 12 months in the serum P1NP level, an index of bone formation. Patients on romosozumab had decreases of P1NP of 5.9% and 5.6% at 6 and 12 months, respectively. These results have been replicated in other similar studies and suggest that the magnitude of changes in BMD and bone markers is more pronounced in previously untreated patients.
- A.
- 4.
The use of oral antiresorptive medications is limited by:
- A.
Frequency of adverse effects.
- B.
Poor adherence rates.
- C.
Severity of adverse effects.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
The intake of oral bisphosphonates is cumbersome: the tablet has to be taken in the morning, while the patient is fasting and has to be taken with 6 oz of water and then the patient has to fast for about half an hour. Other issues related to the intake of oral bisphosphonate are discussed in another case study. Adherence to the intake of oral bisphosphonates is problematic.
- A.
- 5.
The anabolic response to the administration of romosozumab as determined by changes of P1NP, a marker of bone formation, is approximately:
- A.
A 5% increase.
- B.
A 50% increase.
- C.
A 150% increase.
- D.
1-month duration.
- E.
Lasts about 1 week.
Correct answer: C
Comment:
The increase in bone formation induced by romosozumab, as measured by changes in P1NP, a marker of bone formation, is quite robust: reaching approximately 150% of baseline value. It is, however, short lived and normalizes back to baseline in about 9 months. A second course of romosozumab after one year of no treatment (i.e., romosozumab then placebo, then romosozumab again) induced further increases in the BMD of the lumbar vertebrae (12.4%) and total hip (5.5%). If, however, the second course of romosozumab is administered after completion of the first course, followed by a course of denosumab (i.e., romosozumab, denosumab, then romosozumab), then the increases of BMD are smaller: 2.3% in the lumbar vertebrae and unchanged in the total hip.
- A.
- 6.
Inclusion criteria for the “Fracture Study in Postmenopausal Women” (FRAME study) include:
- A.
Postmenopausal women between the ages of 55 and 90 years.
- B.
Lumbar vertebrae T-score ≤2.0.
- C.
Serum vitamin D level <20 ng/mL.
- D.
None of the above.
- E.
All of the above.
Correct answer: A
Comments:
The FRAME study included postmenopausal women between the ages of 55 and 90 years, who had osteoporosis as evidenced by a T-score of −2.5 or lower at the total hip or femoral neck. Patients who had sustained a hip fracture or had evidence of a severe or more than two moderate vertebral compression fractures were excluded from the study.
- A.
- 7.
After 12 months, compared to placebo, the following is/are true about the results of the FRAME study (Fracture Study in Postmenopausal Women):
- A.
BMD of the lumbar vertebrae increased by 13.3%.
- B.
BMD of the total hip increased by 6.9%.
- C.
BMD of the femoral neck increased by 5.9%.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
The first part of the FRAME study included 7180 postmenopausal women aged 55–90 years, with a T-score of ≤2.5 at the total hip or femoral neck, randomly allocated to romosozumab (3589 patients) or placebo (3591 patients). The first part of the study lasted 12 months. At the end of this period, all participants were prescribed denosumab 60 mg every 6 months, administered subcutaneously. This part of the study lasted 24 months. All patients enrolled in this study were also prescribed calcium (500–1000 mg) and vitamin D (600–800 IU) daily. Main endpoints were fractures at 12 and 24 months.
- A.
- 8.
Concerning the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis (ARCH study):
- A.
Recruited postmenopausal women aged between 55 and 90 years.
- B.
T-score ≤−2.5 at the total hip or femoral neck.
- C.
One moderate/severe OR two mild vertebral compression fractures.
- D.
During the first year of the study, participants were allocated to either romosozumab one subcutaneous injection monthly or alendronate orally, 70 mg once a week.
- E.
All of the above.
Correct answer: E
Comments:
For the ARCH study, 4903 postmenopausal women with evidence of osteoporosis were recruited. They were randomly allocated to either romosozumab or alendronate. At the end of the first year they were all switched to alendronate 70 mg once a week for the remaining 2 years of the study.
- A.
- 9.
Results of the ARCH study include:
- A.
The number of vertebral compression fractures sustained during the study was about the same in both groups (romosozumab /alendronate: 2046 patients, alendronate/alendronate: 2047 patients).
- B.
More patients in the alendronate/alendronate cohort sustained hip fractures than the romosozumab/alendronate group.
- C.
Patients included in the ARCH study were much younger and healthier than the general population with osteoporosis.
- D.
A and B.
- E.
B and C.
Correct answer: B
Comments:
Whereas 11.9% of the patients allocated to the alendronate group sustained a new vertebral compression fracture, only 6.2% of the patients in the romosozumab to alendronate group sustained a new vertebral compression fracture. Similarly, hip fractures occurred more frequently in the alendronate to alendronate group (13.0%) than in the romosozumab to alendronate group (9.7%). Finally, changes in BMD were larger in the romosozumab to alendronate group than on the alendronate to alendronate group: 13.7%, 15.2%, and 14.9% for increases at month 12, 24, and 36, respectively.
- A.
- 10.
The following is/are correct:
- A.
The efficacy of romosozumab is higher in patients at high risk of sustaining fractures.
- B.
A second 12-month course of romosozumab leads to no further increases in BMD.
- C.
Romosozumab should not be administered to patients with impaired renal functions.
- D.
A and C.
- E.
B and C.
Correct answer: A
Comment:
The efficacy of romosozumab at reducing the fracture risk is higher in patients who are at an increased risk of sustaining fractures. In this study, fracture risk was determined by the FRAX score.
A second course of romosozumab after a 12-month period on placebo (i.e., romosozumab then placebo then romosozumab) leads to increases in BMD of the lumbar vertebrae similar to those achieved after the first 12-month series: 12.4% and 12.0% increases in the first and second series, respectively. Less pronounced increases were achieved in the total hip BMD: 6.0% and 5.5%, respectively.
A second course after a month of denosumab (i.e. romosozumab then denosumab then romosozumab) leads to smaller increases in BMD than the first course: 2.3% in the lumbar vertebrae and no change at the total hip. This study was conducted on 167 participants.
- A.
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