Learning objectives
- •
“Drug holidays” refer to the discontinuation—temporary or permanent—of bisphosphonate therapy following a 3- to 5-year period of continuous therapy whether oral or IV.
- •
Determine whether to continue or discontinue long-term antiresorptive therapy.
Analysis of data
The efficacy of drug holidays is questionable. Rebound increase in bone turnover is sometimes seen. Patients on drug holidays should be monitored.
Multiple choice questions
- 1.
The following is/are true about “drug holidays” in the management of osteoporosis:
- A.
They only apply to bisphosphonates.
- B.
They apply to any medication used to treat osteoporosis.
- C.
They do not apply to intravenously administered bisphosphonates.
- D.
Patients should be closely monitored: three monthly DXA scans and monthly bone markers.
- E.
A and D.
Correct answer: A
Comment:
Bisphosphonates are effective medications for the management of osteoporosis. They have been repeatedly shown to increase the bone density and significantly reduce the fracture risk, including the much-dreaded hip fractures, which can be reduced by as much as 50% after a three-year period of continuous bisphosphonate administration. With few exceptions, for the first 3–5 years of their administration, bisphosphonates are not associated with severe adverse effects apart from upper gastrointestinal adverse effects which, in most instances, can be easily managed. Furthermore, intravenously administered bisphosphonates such as zoledronic acid bypass the GI tract and eliminate the risk of upper GI adverse effects.
- A.
- 2.
The following is/are true about drug holidays programs:
- A.
The patient can take the orally administered medication with breakfast.
- B.
The patient can take the orally administered medication with any other medication.
- C.
The main purpose of the drug holidays program is to reduce the cost of treatment.
- D.
All of the above.
- E.
None of the above.
Correct answer: E
Comment:
“Drug holidays” refer to the discontinuation, temporary or permanent, of bisphosphonate therapy following a three- to five-year period of continuous daily, weekly, or annual iv infusion therapy. The rationale for this strategy is twofold: first, the assumption that benefits gained while the bisphosphonate was administered will persist after the medication has been stopped and second to reduce the risk of serious adverse effects of long-term bisphosphonate therapy such as atypical femoral fractures and osteonecrosis of the jaw.
“Drug holidays” should only apply to bisphosphonates and not denosumab because the discontinuation of denosumab may be associated with multiple vertebral compression and other fractures.
- A.
- 3.
The following is/are true about “Drug holidays”:
- A.
The BMD is maintained for at least the first 3 years of the “drug holiday.”
- B.
The fracture risk remains at the preholiday level for at least 3 years.
- C.
They are associated with a decrease in BMD.
- D.
The fracture risk increases when the “drug holiday” starts.
- E.
C and D.
Correct answer: E
Comment:
The long-term extension studies of alendronate (FIT/FLEX study) and zoledronic acid (HORIZON study) suggest that cessation of bisphosphonate administration (i.e., a “drug holiday”) after completing a three- to five-year course of orally administered bisphosphonate or three-year course of zoledronic acid is associated with a decrease in BMD and an increased fracture risk during the no treatment phase of the study: vertebral fractures were about 50% higher in those who discontinued the bisphosphonate compared to those who continued with the medication. There was, however, no increase in nonvertebral or hip fracture, probably due to the studies not being powered to assess changes in fractures. Similar results were observed after examining longitudinal data from the Kaiser Permanente and data from Medicare. It is also possible that had the duration of no bisphosphonate administration been shorter, i.e., about a year, the results would be different.
- A.
- 4.
The following is/are correct:
- A.
Bisphosphonates have a strong affinity to bone mineral hydroxyapatite in the bones.
- B.
They gradually dissociate themselves from hydroxyapatite and enter the activated osteoclasts.
- C.
In the osteoclasts they induce cellular apoptosis, mostly by inhibiting the farnesyl pyrophosphate enzyme and preventing essential protein synthesis.
- D.
All of the above.
- E.
None of the above.
Correct answer: D
Comment:
As the bisphosphonates slowly dissociate themselves from the hydroxyapatite crystals they continue to suppress bone turnover long after their intake is discontinued. In many instances, the fracture risk does not return to its original high level long after it has been discontinued. As such, therefore, bisphosphonates are ideal candidates for drug holidays, especially for patients with low to moderate risk of fracture. A popular regimen is 3–5 years of therapy followed by 2–3 years of “drug holiday,” i.e., no medication. Patients at high risk of fracture may benefit from switching to another medication for osteoporosis. Drug holidays are not recommended for patients on denosumab as its antifracture effect is short-lived and there may be a rebound increased fracture risk, especially vertebral fractures soon after discontinuing denosumab.
- A.
- 5.
The main adverse effects of long-term bisphosphonate use include:
- A.
Osteonecrosis of the jaw.
- B.
Atypical femoral fracture.
- C.
Oral mucosal ulceration.
- D.
Orbital inflammation.
- E.
All of the above.
Correct answer: E
Comment:
Ocular inflammation is a rare adverse effect in patients taking bisphosphonates. It usually presents with ocular and periocular pain, swelling, blurry vision, and photophobia. Whereas nonspecific conjunctivitis is usually benign, self-limited, and improves without specific therapy, uveitis and scleritis are serious complications, often preceded by chills, fever, fatigue, and malaise. It usually responds to high doses corticosteroid therapy. A case of severe oral mucosal ulceration associated with oral bisphosphonate use has been described: the patient stated that she was told she should keep the tablet in her mouth to be dissolved by saliva, then to sit upright for 45 min and then to drink water. After the first dose, she experienced sudden onset of gum pain associated with food intake and noticed a superficial ulcer about 1 cm on the hard palate. After the second dose the size of the ulcer had increased and she found it difficult to take any food. The ulcer extended to the upper gum. The ulceration progressed rapidly and involved the tongue and inside of the left lip. She responded well to prednisolone, antiseptic mouth rinse, and antiseptic gel. This case emphasizes the importance of giving clear instructions on how to take the oral bisphosphonate.
Osteonecrosis of the jaw and atypical femoral fractures are discussed in separate chapters in this book.
- A.
- 6.
The affinity of bisphosphonates for hydroxyapatite, in descending ranking:
- A.
Zoledronate, alendronate, ibandronate, risedronate, and etidronate.
- B.
Alendronate, zoledronate, risedronate, ibandronate, and etidronate.
- C.
Ibandronate, zoledronate, alendronate, risedronate, and etidronate.
- D.
Etidronate, zoledronate, alendronate, risedronate, ibandronate.
- E.
The affinity of a bisphosphonate to hydroxyapatite is essentially the same for all bisphosphonates.
Correct answer: A
Comment:
The potency and affinity of the various bisphosphonates determine the duration between cycles of bisphosphonates and no medication.
- A.
- 7.
The following is/are true about the “drug holidays” program:
- A.
The patient can take the orally administered medication with breakfast.
- B.
The patient can take the orally administered medication with any other medication.
- C.
The main purpose of the drug holidays program is to reduce the cost of treatment.
- D.
All of the above.
- E.
None of the above.
Correct answer: E
Comment:
Drug holidays refer to the discontinuation, temporary or permanent, of bisphosphonate therapy following a three- to five-year period of continuous daily, weekly, or annual iv infusion therapy. The rationale for this strategy is twofold: first, the assumption that benefits gained while the bisphosphonate was administered will persist after the medication has been stopped and second to reduce the risk of serious adverse effects of long-term bisphosphonate therapy such as atypical femoral fractures and osteonecrosis of the jaw.
Drug holidays should only apply to bisphosphonates and not denosumab because the discontinuation of denosumab may be associated with multiple vertebral compression fractures.
- A.
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