Learning objectives
- •
Evaluation of patients on long-term antiresorptive therapy.
- •
When and how to discontinue long-term bisphosphonate therapy.
The case study
Reasons for seeking medical help
- •
VP is a 74-year-old Caucasian woman, diagnosed with osteoporosis about 12 years ago after sustaining a fragility vertebral fracture while watching, at home, a movie with her daughter. The diagnosis of osteoporosis was confirmed by DXA scan: lowest T-score −3.0 and −2.9 for the left total hip and femoral neck, respectively. At that time, secondary causes of osteoporosis had been ruled out. She was prescribed alendronate, but could not tolerate the gastrointestinal adverse effects.
- •
She was switched to risedronate, tolerated it, and adhered well to this medication, but is now experiencing heart burn and abdominal discomfort after taking the medication. She would prefer not to continue taking that medication for her osteoporosis especially as she is essentially asymptomatic except for the abdominal pain and discomfort after taking risedronate.
- •
About 11 years ago, shortly after starting risedronate therapy, she was detailed as a missionary teacher to teach geography at schools in Africa where bone densitometry was not readily available. She nevertheless was able to get risedronate shipped and has been taking it regularly. She is now back in the USA and is on no other medication. She has no plans to return to Africa.
Past medical and surgical history
- •
Natural menopause at 45 years, no HRT.
- •
Menarche at age 12 years, regular menstrual periods.
Lifestyle
- •
Active physical lifestyle. She spends about an hour, three times a week, exercising in a gymnasium.
- •
Daily dietary calcium intake: about 1300 mg.
- •
No excessive sodium, caffeine, alcohol, and no cigarette smoking.
Medications
- •
Risedronate 35 mg once a week. VP is taking the medication exactly as directed.
- •
Multivitamin tablets once a day.
Family history
- •
Positive for osteoporosis: mother sustained bilateral fragility hip fractures.
Clinical examination
- •
Weight 142 pounds, steady, height 64″
- •
Get-Up-and-Go Test: completed in 9 s.
- •
No relevant clinical findings. No clinical evidence suggestive of atypical femoral shaft fracture or osteonecrosis of the jaw.
Laboratory results
- •
Comprehensive metabolic profile: no abnormal findings, eGFR >60 mL/min.
- •
Serum 25-hydroxy-vitamin D 46 ng/mL.
DXA and radiologic results
VP had only three DXA scans done: baseline, about 5 years later, and the last one a few weeks ago. Given that VP had her DXA scans done on different densitometers, by different densitometrists, in different centers, and also different countries, it is not possible to adequately evaluate the results and compare those of the present scan with the previous scans. Notwithstanding, the VFA shows evidence of T7 vertebral compression fracture. VP does not recall being subjected to any significant trauma on her back. The vertebral compression fracture is therefore a fragility fracture, and the final diagnosis is “established osteoporosis,” i.e., densitometric evidence of osteoporosis and the presence of a fragility fracture.
Multiple choice questions
- 1.
The following laboratory tests are recommended:
- A.
Serum CTX (Serum cross-linked C-telopeptide of type I collagen).
- B.
Serum P1NP (Procollagen Type I Intact N-terminal propeptide).
- C.
Serum vitamin D.
- D.
Comprehensive metabolic profile.
- E.
A and B.
Correct answer: E
Comment:
The comprehensive metabolic profile and serum vitamin D levels have been assayed about 3 weeks prior to this encounter and are within the normal range. There is no need to repeat these analyses. The serum CTX level is 54 pg/mL, well below the normal range of 100–1000 pg/mL. It is suggestive of a reduced rate of bone resorption in line with the intake of risedronate, an antiresorptive medication that VP has been taking for the past 10 years. Similarly, the serum P1NP is suggestive of a reduced rate of bone formation in line with the drug-induced low rate of bone turnover.
The serum vitamin D level is within normal limits. Parameters of renal functions are of particular interest as they will guide the choice of medication. Having this data available before seeing the patient helps determine the various options available without any delay.
- A.
- 2.
The data about VP suggest that:
- A.
She has not been adhering to the medication.
- B.
She has secondary osteoporosis.
- C.
She never had osteoporosis.
- D.
A and C.
- E.
None of the above.
Correct answer: E
Comment:
VP has been adhering to risedronate therapy as evidenced by the low serum CTX level. Osteoporosis is the diagnosis as evidenced by the fragility vertebral compression fracture she sustained some time ago. It is not possible to be more specific as to the occurrence of the vertebral compression fracture as it is “silent,” i.e., asymptomatic and occurs without the patient knowing that a vertebra is being crushed. This is not the case in patients sustaining clinical or symptomatic fractures that are usually associated with severe, often very severe, pain.
The presence of a fragility fracture is diagnostic of osteoporosis and overrides the densitometric diagnosis. There is no indication that she has secondary osteoporosis. A DXA scan is nevertheless indicated as it can be used as a baseline against which the patient progress can be noted. Her T-scores are −3.0 in the upper four lumbar vertebrae, −2.9 and −2.8 in the left and right femoral neck, and −2.5 and −2.6 in the total right and left hip, respectively. The T-score of the nondominant distal 1/3 radius is −2.6.
- A.
- 3.
In VP case, at this stage, the following is recommended:
- A.
Discontinue risedronate.
- B.
Prescribe delayed release risedronate formulation.
- C.
Prescribe teriparatide.
- D.
All of the above.
- E.
None of the above.
Correct answer: A
Comment:
Given that her fasting serum CTX level is below the normal range indicating that her bone turnover rate is probably oversuppressed, the antiresorptive medication (risedronate) should be discontinued. An osteoanabolic agent such as teriparatide or abaloparatide may be considered to stimulate bone formation. Given the degree of osteoporosis, however, she also could be a good candidate for romosozumab which has a dual effect: stimulating bone formation and inhibiting bone resorption.
- A.
- 4.
Before comparing the present densitometric findings to previous ones, the following should be ascertained:
- A.
The least significant change of the center is known.
- B.
The same densitometer has been used for all the scans.
- C.
If there has been a change of densitometers, cross-calibration studies have been conducted.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
As deviations from optimum patient positioning on the densitometer may give rise to different results, precision studies are conducted to determine the technologist’s skills at repositioning patients in exactly the same position. Precision studies are done by scanning a patient, then asking her to get off the densitometer table, then repositioning her and scanning her again. This is repeated either twice in 30 patients or three times in 15 patients. This has been discussed in the chapter on bone densitometry. The data are then entered in a formula (available on the ISCD website) and the precision of the technologist performing the scans is calculated. From the precision study, the Least Significant Change (LSC) is calculated to determine the smallest change in BMD, for that particular technologist, using that particular densitometer, that is statistically significant, usually with a 95% level of confidence. LSC may be expressed as a percentage or an absolute value and should be known before interpreting any change in BMD. ISCD recommends that LSC be calculated separately for each technologist.
Precision studies and LSC calculation are not considered research but are quality assurance programs. It is nevertheless advisable to get clearance from the local Institutional Review Body where the scans are done. ISCD also recommends that changes not exceeding LSC be reported as “nonsignificant.”
- A.
- 5.
Cross-calibration studies:
- A.
Should be done when densitometers are changed.
- B.
Are not needed because formulae are available to convert results.
- C.
Are done by the manufacturers before delivering the new densitometer.
- D.
Can be done on the office staff or by using specially designed phantoms.
- E.
A and D.
Correct answer: A
Comment:
Cross-calibration studies should be done before changing densitometers and are necessary because results from different densitometers often cannot be compared as different manufacturers use different methods to produce the two waves of energy for densitometry, use different algorithms to separate soft from bone tissue, and sometimes use different anatomical sites, but use the same terminology. For instance, the “femoral neck” site is the area of the femoral neck adjacent to the greater trochanter for Hologic densitometers, whereas for GE/Lunar densitometers it is the area at the midpoint of the hip axis. These two areas may be anatomically distinct and therefore cannot be directly compared, hence the need for cross-calibration studies.
During cross-calibration studies a number of patients are scanned on both densitometers (the one about to be changed and the new model) and the results are plotted on a chart which can then be used to “convert” results obtained on one densitometer to the other. It is not recommended to use office staff to conduct cross-calibration studies as in most instances they do not represent patients being scanned. At the time of writing this manuscript, no phantoms are available for cross-calibration studies. Although formulae are available to convert data sets and are used for epidemiological studies, they are not sufficiently sensitive and specific to be used for clinical purposes.
- A.
- 6.
Match the following:
- (a)
Least significant change.
- (b)
Cross-calibration study.
- (c)
Accuracy study.
- (d)
Precision study.
- A.
Performed when the densitometer is about to be changed.
- B.
Phantoms can be used.
- C.
Reflects the technologist’s skills at positioning the patient on the densitometer table.
- D.
Needs to be known when evaluating changes in BMD
- E.
Reflects the sensitivity of the densitometer.
- A.
Correct answers: A (b); B (c); C (d); D (a); E (c)
Comment:
Sequential changes in BMD cannot be evaluated unless the LSC for the particular center where the scans are done is known. This is discussed further in the section on bone densitometry. Results of scans obtained from different densitometers cannot be compared unless cross-calibration studies have been done. It is therefore essential for these studies to be conducted prior to changing the densitometer. Although phantoms are available to check the accuracy and therefore sensitivity of the densitometer to accurately measure the bone mineral content and surface area of the bone scanned, no such phantoms are available to cross-calibrate densitometers.
- (a)
- 7.
VP should be offered a “drug holiday” because:
- A.
She has been on risedronate for about 12 years.
- B.
Her lowest T-score is −3.0 in the upper four lumbar vertebrae.
- C.
Her CTX is low.
- D.
A and C.
- E.
None of the above.
Correct answer: D
Comment:
VP should not be offered a “drug holiday” because she has “established osteoporosis” as evidenced by her densitometric data and also the fragility fractures she sustained. Her fracture risk is therefore high/very high and she should be prescribed medication to reduce the risk of fractures by increasing bone mass, i.e. osteoanabolic medications such as teriparatide or abaloparatide.
Risedronate should be stopped because of the risk of developing serious adverse effects such as osteonecrosis of the jaw (ONG) or atypical femoral fractures (AFF). For similar reasons other antiresorptive agents should not be prescribed as they may increase the risk of ONJ and AFF. Given that she has significant osteoporosis (T-score of −3.0 in the upper four lumbar vertebrae) and that the bone turnover is low as evidenced by the low serum bone marker levels, she no longer needs antiresorptive medication and may respond to an osteoanabolic medication that will stimulate bone growth. Romosozumab is unique as it is the only medication presently available that has a dual effect: increasing bone formation and reducing bone resorption.
- A.
- 8.
In VP’s case, follow-up should include:
- A.
Repeat DXA scan 1 year.
- B.
Repeat DXA scan 2 years.
- C.
Repeat CTX in 1 to 6 months.
- D.
A and C.
- E.
B and C.
Correct answer: E
Comment:
A repeat DXA scan in 2 years is recommended. Changes in BMD are not likely to be significant in DXA scans done earlier than 2 years. Assaying bone biomarkers will confirm that the rates of bone formation and bone resorption have changed after discontinuing risedronate and prescribing an osteoanabolic medication or romosozumab.
- A.
- 9.
The following is/are recommended:
- A.
Clinical examination of both upper femurs.
- B.
Plain X-ray of both upper femurs.
- C.
Technetium bone scan.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
An atypical femoral shaft fracture is one of the most serious adverse effects of long-term antiresorptive therapy. It usually first presents with tenderness along the upper shaft of the femur, and the patient may experience some pain when she stands on the affected leg. As the condition progresses the patient experiences pain aggravated by standing, walking, and especially running or jogging. An initial partial or incomplete fissure fracture can then be seen in the X-ray; eventually, the fissure fracture extends and becomes a full fracture.
Radiological features are characteristic: initially there appears to be a swelling of the bone and then a fissure fracture appears, cutting transversally across the shaft of the femur. Sometimes both sides are affected, albeit to different degrees. A technetium bone scan reveals an increased uptake on the site(s) of the fracture. Surgery is recommended while the fracture is still localized to one side of the femoral shaft. Atypical femoral shaft fractures are discussed in a separate chapter.
- A.
- 10.
The following also is recommended:
- A.
A full examination of the mouth, especially gums.
- B.
Ascertain the integrity of upper and lower gums.
- C.
Identify localized pain/tenderness in both gums.
- D.
None of the above.
- E.
All of the above.
Correct answer: E
Comment:
Osteonecrosis of the Jaw (ONJ) is a major adverse effect of long-term antiresorptive therapy for osteoporosis. Although it may occur spontaneously, it usually complicates tooth extraction. The initial presentation is an exposed area after a tooth extraction: similar to a “dry socket” which does not heal. Discomfort and pain are the initial presentations. At this stage the clinical examination reveals the presence of an exposed/ulcerated area that eventually becomes infected. Sinuses and fistulae eventually develop. ONJ and AFF are discussed in other case studies.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Status post natural menopause, no hormonal replacement therapy.
- •
The presence of a fragility vertebral fracture (T7).
- •
Positive family history: mother sustained bilateral fragility hip fractures.
Factors protecting against bone demineralization/osteoporosis
- •
Good daily calcium intake.
- •
Good well-balanced diet.
- •
Physically active lifestyle.
- •
No excessive sodium, no excessive caffeine, and no cigarette smoking.
- •
She has been taking risedronate, an orally administered bisphosphonate for approximately 12 years.
Factors increasing risk of falls/fractures
- •
None
Factors reducing risk of falls/fractures
- •
Physically active lifestyle.
- •
Good well-balanced diet.
- •
Completed the Get-Up-and-Go test in 9 s.
- •
Serum vitamin D level within normal range.
Diagnosis
- •
The complete diagnosis is: established osteoporosis as manifested by:
- 1.
Fragility fracture of T7.
- 2.
Densitometric evidence of osteoporosis: lowest T-score of −3.0 in the upper four lumbar vertebrae.
- 3.
Status post long-term bisphosphonate therapy, i.e. increased risk of osteonecrosis of the jaw (ONF) and Atypical Femoral Fractures (AFF). These are discussed at the end of this section.
- 1.
Management recommendations
Treatment recommendation(s)
- •
Discontinue risedronate.
- •
Panoramic X-ray of the jaws, because of possible ONJ.
- •
Prescribe an osteoanabolic medication or romosozumab.
- •
Review and reassess bone health in 2 years’ time.
Lifestyle changes
- •
None, maintain level of physical activity.
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