Learning objectives
- •
Evaluation of patients on long-term bisphosphonate therapy for drug resistance.
- •
Recognize lifestyle habits that can interfere with bisphosphonate efficacy.
The case study
Reasons for seeking medical help
Mrs. BF, a 54-year-old Asian woman, comes for a follow-up visit. She had been diagnosed with postmenopausal osteoporosis about 2 years ago: Her lowest T-score was −2.7 in the left total hip. The DXA scan done at that time also showed that she had sustained multiple fragility vertebral compression fractures. Clinical examination and laboratory investigations (CBC, blood chemistry profile, and serum vitamin D level) did not reveal a secondary cause for her osteoporosis. Alendronate 70 mg once a week was prescribed. Mrs. BF maintains that she takes the medication as directed and has not experienced any adverse effect.
Past medical and surgical history
- •
Postmenopausal osteoporosis diagnosed about 2 years ago. On alendronate therapy.
- •
Reached a natural menopause at the age of 51 years. She preferred not to take hormonal replacement therapy because she was afraid of breast cancer.
- •
Three children; all breast-fed. She could not remember whether or not she was taking calcium supplements on a regular basis during pregnancy and lactation.
Personal habits, lifestyle, and daily routine
- •
She dislikes milk and dairy products. The average daily calcium intake is about 500 mg.
- •
No cigarette smoking.
- •
No alcohol intake.
- •
Sedentary lifestyle.
Medications
- •
Alendronate 70 mg once a week started about 2 years ago. Mrs. BF maintains that she takes that medication exactly as directed by her physician.
- •
Over-the-counter calcium supplements amounting to 1200 mg daily.
- •
Ibuprofen for back pain, 400 mg as required. On average she takes about six tablets a week.
Family history
- •
Negative for osteoporosis.
Clinical examination
- •
Weight 140 pounds, height 5′2″, arm span 65″.
- •
No relevant significant clinical findings except for evidence of osteoarthritic changes in her hands and knees. She admits that she had these signs for a number of years.
DXA scan results
| Baseline | Baseline | 2 years later | 2 years later | |||
|---|---|---|---|---|---|---|
| Site | BMD | T-scores | BMD | T-scores | % BMD change | LSC % |
| Right total hip | 0.721 | −2.5 | 0.689 | −2.9 | −4.5 | 3.1 |
| Left total hip | 0.688 | −2.7 | 0.657 | −2.9 | −5.1 | 3.2 |
| Lumbar vertebrae | 0.991 | −1.1 | 0.975 | −1.3 | −1.6 | 3.0 |
| Left distal radius | 0.447 | −2.3 | 0.446 | −2.3 | −0.2 | 3.0 |
Multiple choice questions
- 1.
In Mrs. BF the observed changes in BMD:
- A.
Are significant in both hips only.
- B.
Are not significant in the lumbar vertebrae and the distal radius.
- C.
Are not significant in the distal radius.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comments:
When comparing the changes in DXA scans over a period of time, it is the percentage change in BMD that matters, not the changes in T-scores. If the change exceeds the Least Significant Change of the Center (LSC) in the center where the DXA scan is done then that change is significant.
Although the changes did not alter the diagnostic classification of the patient they are significant as they indicate that the bisphosphonate administered has not been able to increase the BMD or even maintain it at its original level.
This patient’s osteoporosis appears to be resistant to alendronate. True resistance to alendronate, however, is very rare. The three most common causes of apparent “resistance” to alendronate or other orally administered bisphosphonates are first the patient not taking the medication as directed, second the patient not getting enough calcium and/or vitamin D and is therefore not able to build up bone. Third, the patient has secondary osteoporosis.
- A.
- 2.
In Mrs. BF’s case the following inquiries should be made:
- A.
Exactly how is she taking alendronate?
- B.
What type of liquid is she using to take alendronate?
- C.
Is she taking any other medications with alendronate?
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comments:
Alendronate, like other orally administered bisphosphonates, has to be taken on its own, with no other medication. It should be taken with plain water. It may be even better if it were taken with distilled water which contains nothing but water as opposed to tap water, well water, and bottled water which may contain a number of additives or contaminants. Minerals and other additives or contaminants may interfere with the bioavailability of orally administered bisphosphonates. Even filtered water may contain some contaminants. Well water is usually rich in minerals which may interfere with the bioavailability of alendronate and other orally administered bisphosphonates.
It is important to ascertain that the patient is taking the medication exactly as directed. Often patients, not realizing the importance of taking the medication exactly as directed, may take it with coffee, orange juice, or some beverage other than plain water. Similarly, they may take it with mineral water or well water that may be rich in minerals. All these beverages may interfere with the absorption of bisphosphonates and reduce their bioavailability. Even if the patient states that she is taking the medication as prescribed, it behooves the clinician to ascertain that this indeed is how she should be taking it.
- A.
- 3.
In Mrs. BF case the following inquiries should also be made:
- A.
How long does she wait before taking any other medication(s)?
- B.
How long does she wait before eating after taking the alendronate tablet?
- C.
When does she take her calcium supplements?
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comments:
All these questions are relevant. If another medication is taken within 30 min of ingesting the orally administered bisphosphonate, it may interfere with its bioavailability and hence efficacy. Similarly, if the patient ate within half an hour of taking the medication, food may interfere with the bioavailability of the bisphosphonate.
Mrs. BF stated that in order to remember taking her medications (alendronate, calcium, vitamin D, and mineral supplements), she takes them all at the same time. She thought it would be a good idea to take all her medications “for bone health” at the same time, even if one tablet, the bisphosphonate, is taken only once a week. It is therefore probable that the concomitant intake of calcium and other supplements interfered with the bioavailability of the bisphosphonate, reduced its absorption, and therefore effectiveness at reducing the rate of bone resorption which translated into a further loss of bone mass as evidenced by the BMD changes over the past 2 years. Finally, to be significant, the change in BMD should exceed the least significant changes of the center where the DXA scan is done.
- A.
- 4.
At this stage the following investigations are recommended:
- A.
Blood chemistry profile.
- B.
Serum estradiol level.
- C.
Serum FSH level.
- D.
Serum protein electrophoresis.
- E.
None of the above.
Correct answer: A
Comments:
The blood chemistry profile is indicated to assess renal functions to ensure her kidney functions have not deteriorated. This is an important finding affecting the treatment strategy as bisphosphonates are not recommended in patients with impaired renal functions. Assaying the serum vitamin D level will help ensuring she is not developing vitamin D deficiency. This also could be suspected if the serum alkaline phosphatase level has increased since the previous analysis, even though it may remain within the normal range.
Apart from these assessments, renal functions, and vitamin D status, at this stage, there is no need for any other blood test to be done. Mrs. BF has been fully investigated as far as her bone status is concerned about 2 years ago. The most probable reason for her nonresponse to alendronate is that she was taking it with dietary supplements which most probably interfered with its bioavailability and efficacy to increase bone density.
If vitamin D deficiency is suspected, the serum vitamin D metabolites could be assayed. The 25-hydroxy-cholecalciferol (or 25-hydroxy-vitamin D) represents the cumulative vitamin D obtained through diet and exposure to ultraviolet sunrays. In vitamin D deficiency, the level of 25-OH vitamin D is reduced. 1,25-di-hydroxy-cholecalciferol does not reflect the patient’s vitamin D status but rather the ability of the kidneys to hydroxylate 25-OH vitamin D at the 1-position, under the influence of circulating parathyroid hormone, to produce 1,25-di-hydroxy-vitamin D, the most active vitamin D metabolite. In vitamin D deficiency as the calcium levels tend to drop, the parathyroid hormone production is increased. This in turn increases the rate of hydroxylation of 25(OH) vitamin D to 1,25-di-hydroxy-vitamin D. The levels of the latter often remain within the normal range.
- A.
- 5.
Following the oral ingestion of bisphosphonates:
- A.
Most of the bisphosphonate is readily absorbed from the stomach.
- B.
Most of the absorption takes place within the first 30 min following the ingestion.
- C.
Less than 50% of the orally administered dose is absorbed.
- D.
A and B.
- E.
B and C.
Correct answer: E
Comments:
Most of the absorption of alendronate and risedronate takes place within the first 30 min after their ingestion. This period is 60 min for ibandronate. As a very small amount of the orally administered bisphosphonate is absorbed, any interference with its absorption may significantly reduce the amount absorbed, and hence efficacy of the bisphosphonate.
- A.
- 6.
The following statement(s) is/are true:
- A.
Patients taking oral bisphosphonates should be encouraged to have breakfast 30 min after taking alendronate or risedronate and 60 min after taking ibandronate.
- B.
The longer the patient can refrain from eating after taking the bisphosphonate the better will the results be.
- C.
The bisphosphonate should be taken with at least 6 oz of water, but the larger the quantity of water the better it will be.
- D.
A and C.
- E.
A, B, and C.
Correct answer: A
Comments:
It may be beneficial for the patient to have some food, preferably high-fiber food, after the period of abstinence, i.e. 30 min for alendronate and risedronate and 60 min after ibandronate. Eating food after the 30-min period has elapsed will allow the ingested food to coat the bisphosphonate particles that have not been absorbed and prevent them from irritating the gastrointestinal mucosa. High-fiber food is preferred to low-fiber food as the fiber is not digested and therefore will be evacuated while still coating the bisphosphonate particles, thus preventing them from irritating the gastrointestinal mucosa and avoiding the pain and heartburn the patient may experience.
Waiting for longer periods before eating will allow some of the unabsorbed bisphosphonate particles (i.e., most of the ingested tablet) to get in contact with the gastrointestinal mucosa and irritate it, thus causing abdominal discomfort and pain.
Six to eight ounces of water is the optimum amount to administer the bisphosphonate. Smaller amounts may not be sufficient to disperse the contents of the ingested tablet sufficiently to maximize its absorption. More than 8 oz is likely to distend the stomach and gastroesophageal area particularly in older patients and induce nausea.
- A.
- 7.
The most likely cause for Mrs. BF’s apparent resistance to alendronate is:
- A.
She is not taking alendronate as directed.
- B.
She stopped taking alendronate.
- C.
She’s not getting enough calcium.
- D.
She has secondary osteoporosis.
- E.
Any of the above
Correct answer: E
Comments:
Poor compliance is one of the main reasons for nonresponse to orally administered bisphosphonates. It is therefore important for the patient to fully understand how to take that medication and why it is so important to meticulously follow these directions. It may be appropriate to contact the patient 4–6 weeks after prescribing the orally administered bisphosphonate to ensure that the medication is taken exactly as directed and the patient has not experienced any adverse effect.
Follow-up:
Mrs. BF was told that, most probably, the reason for her nonresponse to the oral bisphosphonates is that she was not complying with the intake of this medication. The importance of taking that medication exactly as directed was further emphasized during her clinic visit. She appeared to understand the implications. Other treatment options were offered but she preferred to continue with oral alendronate once a week. A follow-up phone call to Mrs. BF about 6 weeks after the original encounter revealed that she is now taking the medication as directed and has not experienced any adverse effect. She stated she will make sure to take alendronate regularly and as directed.
- A.
- 8.
If the orally administered bisphosphonate is continued the following follow-up regimen is recommended to ascertain that the medication is taken as directed:
- A.
Compare baseline fasting C-telopeptide to that done 1 to 3 months later.
- B.
Repeat DXA scan in 6 months’ time.
- C.
Repeat DXA scan in 2 years’ time.
- D.
A and B.
- E.
A and C.
Correct answer: E
Comments:
Assaying the fasting C-telopeptide blood level at baseline and 2–3 months after the weekly self-administration of the oral bisphosphonate has resumed will indicate whether the patient is complying with the intake of that medication and whether it has been successful at reducing the rate of bone resorption.
If 2–3 months after reinitiating alendronate therapy there has been no significant reduction of the fasting serum C-telopeptide blood level, then either the patient is still not complying with the intake of alendronate or it is not absorbed in the gastrointestinal tract. In either instance there needs to be a change in the management strategy.
Follow-up:
The baseline fasting serum C-telopeptide level was 658 pg/mL, 8 weeks later it was 342 pg/mL, indicating that the rate of bone resorption has been significantly reduced. The patient was appraised of the results, encouraged to continue taking the bisphosphonate as directed, and to ensure an adequate daily calcium and vitamin D intake. She can now be reassured that, as long as she takes alendronate as directed, she should respond well and not experience gastrointestinal adverse effects. Her BMD is likely to increase and the risk of further fractures decreased.
A repeat DXA scan done 2 years later showed increases of 5.6%, 6.1%, and 7.3% in the right and left total hip scan and lumbar vertebrae, respectively. These increases are significant as they all, and each one, exceed the least significant change.
- A.
- 9.
If it is felt the patient will not comply with the intake of the orally administered bisphosphonate, the following is/are treatments options:
- A.
Zoledronic acid iv infusion once a year.
- B.
Denosumab 60 mg sc at 6-month intervals.
- C.
Teriparatide 20 mcg sc daily.
- D.
A or B.
- E.
Any of the above.
Correct answer: D
Comments:
Given that the patient is only 54 years old, and reached menopause when she was 51 years old, her rate of bone resorption is likely to be increased. She therefore would benefit most from an antiresorptive medication than from an osteoanabolic one. Therefore, although all three medications are effective at managing osteoporosis, in this patient’s case, antiresorptive medications should be the first ones to prescribe. The ease of their administration also increases the likelihood of good compliance.
- A.
- 10.
The time that should be allowed to elapse between the ingestion of the bisphosphonate and eating or taking any other medication is:
- A.
30 min with alendronate.
- B.
30 min with risedronate.
- C.
60 min with ibandronate.
- D.
30 min with all orally administered bisphosphonates.
- E.
A, B, and C.
Correct answer: E
Comments:
In order to maximize the absorption of bisphosphonates it is recommended that they be taken while the patient is fasting and that 30 min (for alendronate and risedronate) and 60 min (for ibandronate) elapse between the ingestion of the bisphosphonate and the consumption of food and drinks apart from plain water.
- A.
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