Learning objectives
- •
Monitor patients on long-term antiresorptive therapy.
- •
Determine whether to continue or discontinue long-term antiresorptive therapy.
- •
Determine whether a “Drug holiday” is appropriate in the management of osteoporosis.
The case study
Reasons for seeking medical help
- •
MR, 62-year-old Caucasian woman, has been diagnosed with osteoporosis about 10 years ago. At that time her T-scores were −3.1 in the lumbar vertebrae, −2.8 in the right femoral neck, and −2.6 in the right total hip. The original DXA scan is not available. Secondary causes of osteoporosis had been ruled out. She was prescribed alendronate. She adheres well with this medication, has incorporated its intake in her daily routine, and is happy to continue taking it. She is essentially asymptomatic.
- •
Her primary care provider wonders whether the continued administration of a bisphosphonate (for more than 10 years) is appropriate.
Past medical and surgical history
- •
Natural menopause at age 41 years, no hormonal replacement therapy.
- •
Menarche at age 13 years.
- •
No history of fractures.
Lifestyle
- •
Daily dietary calcium intake estimated to be about 1200 mg.
- •
Active physical lifestyle, plays tennis at least once a week and jogs about 2 miles twice a week.
- •
She has not experienced any dizzy spell, falls, or near-falls.
- •
No excessive sodium, caffeine, or alcohol intake. No cigarette smoking.
Medication(s)
- •
Alendronate 70 mg once a week.
- •
Multivitamin tablets once a day.
Family history
- •
Positive for osteoporosis: mother and both grandmothers sustained fragility hip fractures.
Clinical examination
- •
Weight 124 pounds, steady, height 62″
- •
No relevant clinical findings.
Laboratory result(s)
- •
Comprehensive metabolic panel (CMP): no abnormal findings, eGFR >60 mL/min.
- •
Serum 25-hydroxy-vitamin D 42 ng/mL.
DXA and radiological result(s)
- •
T-scores: −2.1 upper 4 lumbar vertebrae, −1.6 right femoral neck, and −1.8 right total hip.
- •
A comparison of the BMD changes is not possible because the scans were done on different densitometers, in different health care offices, and by different technician. DXA scan illustrations and information about the least significant changes are not available. It transpired that the original scan was done about 10 years ago at a visiting “Health Care Exhibition” that is no longer in business. No other DXA scans during this 10-year period are available.
- •
Vertebral fracture assessment: no evidence of vertebral compression fractures.
- •
FRAX scores and 10-year risks of sustaining a hip or major fracture, as per the National Osteoporosis Foundation guidelines: 1.4% and 8% for the risk of a hip or major fracture, respectively. Neither reaches the threshold level recommended by the NOF to initiate pharmacologic treatment: 3% and 20% for the 10-year risk of fractures in the hip or major bones, respectively.
Multiple choice questions
- 1.
The following is/are correct:
- A.
There has been a significant improvement in the DXA scans.
- B.
Continuing alendronate is expected to further improve bone health.
- C.
Discontinuing alendronate may induce a rebound increased bone resorption phase.
- D.
None of the above.
- E.
A and C
Correct answer: C
Comment:
T-scores are used to make a densitometric diagnosis: osteoporosis, osteopenia, or normal bone density. Changes in BMD can be used to determine whether there has been a significant change in the patient’s BMD at the various sites examined.
However, as many factors modulate the calculation of the BMD, including make of densitometer, precision, accuracy, least significant change, and possibly, different reference populations used, it is not possible to ensure that the observed “changes” in BMD reflect an actual change and are not due to some artifact and extraneous factor. It is just not possible to compare BMDs if the scans were done on different densitometers, in different centers, and by different technicians, especially as the report sometimes only includes the patient’s T-scores, not the BMD, and frequently does not indicate the center’s precision, Least Significant Change (LSC), and even reference population. Furthermore, often, especially in older people, increases in lumbar vertebrae BMD are due to degenerative changes and not a genuine increase in BMD.
Changes in BMD, and not T-scores, therefore should be used to monitor the patient’s response, or lack of response, to treatment. In this respect, therefore, the validity of available results of the scan done 10 years ago cannot be established because the only parameters reported were the T-scores. There is no mention of the BMD, and the quality of the scan is not addressed. It is therefore possible that the original DXA scan, done about 10 years ago, was of poor quality and unreliable, and therefore cannot be used for clinical purposes. In this case, therefore, it may be more appropriate to disregard altogether the results of the DXA scan done about 10 years ago and to consider the scan done recently as the new baseline.
- A.
- 2.
At this stage, the most appropriate management strategy includes:
- A.
Continue the administration of alendronate.
- B.
Discontinue alendronate.
- C.
Prescribe an osteoanabolic medication such as teriparatide or abaloparatide.
- D.
A and C.
- E.
B and C.
Correct answer: B
Comment:
Alendronate, like most bisphosphonates, has a very long half-life and therefore can be safely discontinued after it has been administered for a few years. On the other hand, the continued administration of bisphosphonates and other antiresorptive medication increases the risk of rare, but serious adverse effects, such as osteonecrosis of the jaw and atypical femoral shaft fractures. The longer the administration of antiresorptives, the greater the risk. Similarly, discontinuing alendronate therapy decreases the risk of the patient developing osteonecrosis of the jaw and atypical femoral shaft fractures and in many cases, but not all cases, does not lead to a rebound increased bone resorption. The recommendation therefore would be to discontinue alendronate for 2 to 3 years and reevaluate the patient.
- A.
- 3.
Discontinuing alendronate after 5 years of continuous therapy leads to:
- A.
Declines in BMD, but mean BMD higher than pretreatment BMD.
- B.
Declines in BMD, but mean BMD lower than pretreatment BMD.
- C.
Increases in markers of bone resorption levels.
- D.
Decreases in markers of bone formation levels.
- E.
A and C.
Correct answer : E
Comment:
A 5-year study was conducted on 1099 postmenopausal women who had completed the 5-year Fracture Intervention Trial (FIT) and were enrolled in the alendronate group. They were then randomly allocated to either alendronate or placebo. Compared to placebo, those on alendronate showed the following mean % changes in BMD :
- •
Lumbar vertebrae: +5.26% alendronate versus +1.52% placebo.
- •
Total hip: −1.02% alendronate versus −3.38% placebo.
- •
Femoral neck: +0.46% alendronate versus −1.48% placebo.
- •
Trochanter: −0.08% alendronate versus −3.25% placebo.
- •
Total body: +1.01% alendronate versus −0.27% placebo.
- •
Forearm: −1.19% alendronate versus −3.21% placebo.
Similarly, when compared to the baseline BMD values 10 years previously, the BMD increases were significantly higher in those patients who had been on alendronate for 10 years versus those who were on alendronate for only 5 years, followed by 5 years of placebo.
- •
Lumbar vertebrae: +14.80% alendronate versus +10.99% placebo.
- •
Total hip: +2.41% alendronate versus −0.16% placebo.
- •
Femoral neck: +4.75% alendronate versus +2.50% placebo.
- •
Trochanter: +5.95% alendronate versus +2.62% placebo.
- •
Total body: +3.60% alendronate versus +2.48% placebo.
- A.
- 4.
In patients who have completed 5 years of alendronate therapy, continuing alendronate versus discontinuing alendronate for another 5 years leads to:
- A.
Lower risk of nonvertebral fractures.
- B.
Lower risk of clinical vertebral fractures.
- C.
Lower risk of hip fractures.
- D.
A and B.
- E.
A, B, and C.
Correct answer: B
Comment:
Apart from the decrease in clinical vertebral fractures, there were no differences in the fracture risk among patients who continued with alendronate for 5 years and those who were allocated to the placebo group after completing 5 years of alendronate therapy.
Another retrospective study on postmenopausal women with osteoporosis shows that when bisphosphonates are discontinued after 3 to 5 years of treatment, those who continued to receive the bisphosphonate had a 40% lower risk of sustaining fractures than those who stopped taking bisphosphonates.
- A.
- 5.
Sequential BMD changes in patients on treatment:
- A.
The greatest increases are seen in the first few years and then tend to become less pronounced.
- B.
Larger increases in BMD are associated with greater reductions in fracture risk.
- C.
Increases in BMD explain most of the fracture risk reduction.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
The greatest increases induced by various medications for osteoporosis occur within the first 3 to 4 years and then tend to slow down. Larger increases in BMD, however, are associated with greater reductions in the fracture risk. Other factors, apart from changes in BMD, modulate the fracture risk. BMD changes explain less than half of the medication-induced fracture risk reduction. Most medications for osteoporosis affect bone microarchitecture as well as BMD. Changes in bone microarchitecture and strength are not always captured by bone densitometry.
- A.
- 6.
While considering therapeutic decisions, the following should be noted:
- A.
The rate and direction of change in BMD.
- B.
The T-score.
- C.
The patient’s Z -score.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
The absolute BMD value, per se, is of little use unless compared to that of previous scans, preferably done on the same densitometer and considering the Least Significant Change (LSC) of the center where the DXA scans are done. The rate and direction of BMD change as well as the T-scores and the serum levels of bone biomarkers are all useful parameters to monitor the patient’s response to therapy and determine whether the continued long-term administration of antiresorptives is indicated.
Changes in the levels of bone biomarkers help determine whether bone resorption and bone formation are increased, decreased, or unchanged. Based on these results, a management strategy individualized for individual patients is developed: patients with a low rate of bone formation are more likely to benefit from an osteoanabolic agent whereas patients with a high rate of bone resorption rate are more likely to benefit from an antiresorptive medication.
In MR’s case, unfortunately there are only two points in time: the first scan done about 10 years ago, and the second scan done at the time of the visit. As the reliability of the first scan is questionable, it is probably better ignored altogether, especially as there is no information about the patient’s adherence with the intake of alendronate.
Bone turnover markers offer a different perspective: if markers of bone formation are suppressed, an osteoanabolic medication is likely to be of benefit. On the other hand, if the markers of bone resorption are elevated, antiresorption medication is recommended. Combining antiresorptive and osteoanabolic medication is not recommended.
If antiresorptives are prescribed, rare long-term complications such as atypical femoral shaft fractures and osteonecrosis of the jaws should be anticipated and avoided while still in the early phase. Patients on long-term antiresorptive therapy should be educated about the early symptoms and signs of atypical femoral shaft fractures and osteonecrosis of the jaw. Both conditions are discussed in separate chapters.
- A.
- 7.
At this stage the following is recommended:
- A.
Check gums to ensure she is not likely to have or develop Osteonecrosis of the Jaw (ONJ).
- B.
Perform radiologic studies: plain X-rays or technetium bone scan to ensure she does not have fragility fractures that may lead to atypical femoral shaft fractures.
- C.
Assess the glomerular filtration rate.
- D.
A and B.
- E.
All of the above.
Correct answer: E
Comment:
MR has been on alendronate for about 10 years; continuing with this medication or other antiresorptive medication further increases the risk of sustaining rare complications, especially atypical femoral shaft fractures or osteonecrosis of the jaw. It is therefore appropriate to assess these patients for both adverse effects and discontinue the bisphosphonate. Discontinuing the bisphosphonate is associated with a reduced risk of rare adverse effects.
- A.
- 8.
Alternatively, alendronate may be discontinued and replaced by:
- A.
Raloxifene.
- B.
Denosumab.
- C.
Zoledronic acid.
- D.
A, B, or C.
- E.
None of the above.
Correct answer: E
Comment:
At this stage, there is no need for either continuing with alendronate or switching to another antiresorptive or osteoanabolic medication.
- A.
- 9.
“Drug holidays”
- A.
Should be considered in many patients on antiosteoporosis treatment for more than 5 years.
- B.
Reduce the risk of adverse events, especially rare adverse effects such as osteonecrosis of the jaw and atypical femoral shaft fracture.
- C.
Promote patient adherence with medication.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The concept of “Drug holidays” is gaining popularity especially as adherence to the “drug” often entails changes in lifestyle and the “drug” is prescribed for an essentially asymptomatic condition. Also, patients may be more motivated if they knew the medication is prescribed for a finite period of time.
Bisphosphonate drug holidays are based on the fact that bisphosphonates are incorporated and kept in the bone matrix until they are released during bone resorption. As such, therefore, their biological half-life could extend for a number of years and their antiresorptive activity and fracture risk reduction continue for a long time: one or more years after the administration of the bisphosphonate has stopped. Discontinuing the medication reduces the risk of rare adverse effects, such as osteonecrosis of the jaw and atypical femoral shaft fractures.
- A.
- 10.
A “bisphosphonate drug holiday” should be considered in patients:
- A.
Treated with bisphosphonates for 3–5 years.
- B.
No longer at high fracture risk.
- C.
The patient is keen to discontinue the medication.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
There is ample evidence that the risk/benefit ratio of bisphosphonates is in favor of benefit in the first 3–5 years of their administration. After this period, the balance may move slightly in the opposite direction. Three to 5 years is therefore a good landmark to reevaluate the patient’s osteoporosis and determine whether on balance, continuing the medication is likely to offset potential adverse effects. Factors that need to be considered include the changes in BMD, the T-scores, biomarkers, and the patient’s attitude toward taking the medication: patients who dislike taking the medication are more likely to adhere to it if they knew the intake was for a finite period.
The underlying principle of drug holidays does not apply to nonbisphosphonate therapy for osteoporosis, even other antiresorptives such as denosumab, because their biological effects are often quickly reversed once the medication is stopped.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Age: 62 years old.
- •
Early natural menopause: at age 41 years. No hormonal replacement therapy.
Case summary
Factors protecting against bone demineralization/osteoporosis
- •
Alendronate therapy, prescribed about 10 years ago. MR is taking the medication as directed, has not experienced adverse effects, and, if recommended is happy to continue taking that medication.
- •
Good daily calcium intake from food.
- •
Active physical lifestyle.
- •
No excessive sodium, caffeine, and alcohol intake.
- •
No evidence of hypovitaminosis D.
- •
No cigarette smoking.
Factors increasing risk of falls/fractures
- •
Positive family history of fragility fractures: patient’s mother and both grandmothers sustained fragility fractures.
Factors reducing risk of falls/fractures
- •
Physically active lifestyle.
- •
Good adherence to alendronate tablets.
Diagnosis
Osteopenia as per densitometric evidence: T-scores between −2.5 and −1.0.
Results of the DXA scan done about 10 years ago will be rejected.
Management recommendations
Treatment(s)
- •
Stop alendronate therapy: she has been taking it for about 10 years.
- •
After the initial assays of bone markers, reevaluate BMD, bone turnover, and vitamin D status.
Diagnostic test(s)
- •
No diagnostic tests are recommended at this stage. However, in order to evaluate future changes in bone turnover, bone markers such as C-Tx, P1NP, and bone-specific alkaline phosphatase will establish a baseline against which future assessments will be made. For similar reasons a baseline serum vitamin D level is also recommended.
Lifestyle
- •
Maintain a physical active lifestyle.
- •
Ensure a well-balanced diet with good calcium and vitamin D intake.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
