Learning objectives
- •
The pharmacology profile of orally administered bisphosphonates.
- •
Initiating and maintaining pharmacologic treatment with oral bisphosphonates.
The case study
Reason for seeking medical help
- •
BJ, a retired schoolteacher, is referred for the management of osteoporosis recently diagnosed by bone densitometry performed because her sister fractured her distal right radius and two ribs after tripping on a small rug in her granddaughter’s bedroom. BJ also has a strong family history of osteoporosis: her mother, both grandmothers, older sister, and cousin sustained fragility fractures. BJ is, however, asymptomatic and did not sustain any fracture. She also has not experienced any dizzy spells.
Past medical and surgical history
- •
Natural menopause at age 48 years, no hormonal replacement therapy.
- •
Menarche at age 13, regular menstrual periods.
- •
Always enjoyed good health.
Lifestyle
- •
For the past 14 years she adopted a physically active lifestyle: jogging and gardening daily, weather permitting. Prior to this she led a largely sedentary lifestyle.
- •
Estimated daily dietary calcium intake: average 1000 mg.
- •
No cigarette smoking.
- •
No alcohol abuse.
- •
No excessive sodium or caffeine intake.
- •
She experienced neither falls nor near-falls.
Medication(s)
- •
Multivitamin tablets once a day.
- •
Cholecalciferol tablets 400 units daily.
Family history
- •
Positive for osteoporosis, as outlined before.
- •
Two healthy children aged 20 and 16 years.
Clinical examination
- •
Weight 141 pounds, steady, height 62″, used to be 63″, arm span 62″.
- •
Mild kyphosis, largely postural.
- •
No significant clinical findings. BP: 155/81 sitting, 162/82 standing. No evidence of orthostasis, sensitive carotid sinus, vertebrobasilar insufficiency, carotid stenosis, heart failure, arthropathy, and no localizing neurological lesions. Trachea central, no adventitious sounds. Thyroid gland not palpable. No evidence of peripheral vascular insufficiency.
- •
Get-up-and-Go test completed in 8 s.
Laboratory result(s)
- •
Comprehensive metabolic panel (CMP): no abnormal finding.
- •
Serum 25-hydroxy-vitamin D: normal at 42 ng/mL.
DXA and radiological result(s)
- •
T-scores: right femoral neck −2.7, right total hip −2.3, left femoral neck −2.6, left total hip −2.1, lumbar vertebrae −2.8.
- •
Vertebral fracture assessment: no evidence of vertebral compression fractures.
Multiple choice questions
- 1.
In BJ’s case, the following is/are correct:
- A.
The diagnosis is osteoporosis, as per bone densitometry results: lowest T-scores −2.8 at the upper four lumbar vertebrae.
- B.
Her fracture risk is elevated.
- C.
As she is essentially asymptomatic, there is no need for any medication for her bones.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
The densitometric diagnosis is osteoporosis and is discussed in other chapters. Osteoporosis is essentially an asymptomatic disease until a fracture occurs. The goal of treating asymptomatic patients with osteoporosis, i.e., before a fracture is sustained, is to avoid the increased mortality and morbidity associated with fractures. It must be emphasized that in older people, even under excellent circumstances, fractures, traumatic as well as fragility fractures, are associated with a poor long-term prognosis. Our present armamentarium includes effective medications with a good safely profile and a reasonable cost. Unfortunately, many patients with osteoporosis are still neither diagnosed nor treated for osteoporosis.
- A.
- 2.
At this stage, in BJ’s case, the following medications are recommended as a first choice for her osteoporosis:
- A.
Bisphosphonates, teriparatide, abaloparatide, denosumab, romosozumab, or raloxifene.
- B.
Bisphosphonates, teriparatide, abaloparatide, denosumab, or romosozumab.
- C.
Bisphosphonates, teriparatide, abaloparatide, or denosumab.
- D.
Bisphosphonates or denosumab.
- E.
Bisphosphonates.
Correct answer: D
Comments:
BJ’s lowest T-score is −2.8 in the upper four lumbar vertebrae. She therefore has densitometric evidence of osteoporosis and is at risk of sustaining fragility fractures, i.e., fractures resulting from trauma that ordinarily would not be expected to result in a fracture: low trauma or low impact fractures. Fragility fractures also can develop spontaneously in the absence of any trauma: atraumatic fractures.
In BJ’s case, medications that have been shown to effectively reduce the risk of fractures, especially hip fractures, should be the first choice. The long-term impact of a hip fracture is poor, even if the immediate outcome is excellent: most patients undergoing surgery are able to resume their daily activities, but, in time, the majority sustain more fractures.
A two-year retrospective study on 115,776 patients (72.3% women) showed that hip fractures were the most common second fracture (27.8%). Median time from index to second hip fracture was about 1.5 years. In addition, 71.9% of patients with an index hip fracture experienced postsurgery complications. In this group, one-year mortality from any cause after the index hip fracture was 26.2%. Therefore any fracture, especially hip fracture, should be a wake-up call to diagnose and treat osteoporosis. Raloxifene has not been shown to reduce the risk of hip fractures and therefore should not be considered as first-line therapy for BJ. Similarly, ibandronate has been shown to reduce the risk of hip and nonvertebral fractures only in patients with T-scores −3.0 and lower.
Given the patient’s age, and time since menopause, it is probable that her skeleton is going through the phase of increased bone resorption and therefore should benefit more from an antiresorptive medication than from an osteoanabolic medication. If there is any doubt, assaying the markers of bone formation and bone resorption should be helpful to confirm the patient’s bone status. This information can also be used to motivate the patient to comply with the intake of the orally administered bisphosphonate.
- A.
- 3.
In BJ’s case, the following bisphosphonate should be first choice:
- A.
Alendronate or risedronate.
- B.
Ibandronate.
- C.
Zoledronic acid.
- D.
Any of the above.
- E.
A or C.
Correct answer: E
Comment:
The major pivotal trials with fractures as end points have shown that whereas all bisphosphonates reduce the risk of vertebral fractures, not all reduce the risk of hip fracture. Placebo controlled, double-blind, randomized clinical trials have shown that alendronate, risedronate, and zoledronic acid significantly reduce the risk of hip and vertebral fractures. A major clinical trial on ibandronate did not show significant hip fracture risk reductions, although, a subsequent post hoc analysis showed a reduced hip fracture risk in patients with a T-score lower than −3.0.
- A.
- 4.
Bisphosphonates reduce bone resorption by:
- A.
Selective osteoclast intracellular enzyme inhibition.
- B.
Inducing osteoclast apoptosis.
- C.
Inhibiting osteoclast activation.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Bisphosphonates selectively inhibit the osteoclast intracellular farnesyl pyrophosphate synthase enzyme thus preventing downstream protein prenylation, inhibiting osteoclastic activity, and leading to osteoclast apoptosis.
- A.
- 5.
Bisphosphonates:
- A.
All have the same basic chemical structure.
- B.
Side chains determine their binding affinity and biological half-life.
- C.
Side chains determine their enzyme inhibitory activity and antiresorptive potency.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
All bisphosphonates have the same basic chemical structure: two phosphonic acid molecules joined to a carbon atom and two side chains. The side chains determine the degree of osteoclastic intracellular enzyme inhibition and affinity of the bisphosphonate to hydroxyapatite crystals. Differences in side chains are responsible for different pharmacologic profiles. Osteoclast enzymatic inhibition is highest with zoledronic acid followed by risedronate, ibandronate, and alendronate. Binding affinity is highest with zoledronic acid followed by alendronate, ibandronate, and risedronate.
- A.
- 6.
Alendronate for the treatment of osteoporosis:
- A.
Orally administered, 70 mg, once a week.
- B.
The tablet should be taken with food to minimize GI adverse effects.
- C.
At least one hour must elapse between bisphosphonate intake and food intake.
- D.
All of the above.
- E.
A and B.
Correct answer: A
Comment:
As only 0.6%–3% of the orally administered bisphosphonate is absorbed through the gastrointestinal tract, any interference with absorption may impact the bioavailability of orally administered bisphosphonates. It is therefore important to ensure the patient takes the medication exactly as directed:
- •
While fasting and with no other medication, food, or beverage (except water) to prevent food particles or other medications from adhering to the bisphosphonate tablet and interfering with its already low gastrointestinal absorption. As often tap water, bottled water, and especially well water contain impurities or additives, it may be advantageous to take the bisphosphonate with distilled water to ensure least interference and maximal absorption.
- •
The oral bisphosphonate tablet should be taken with six ounces of water to avoid the tablet adhering to the mucosa in the esophagus and to ensure maximal dispersion and absorption of the bisphosphonate in the stomach.
- •
After taking the oral bisphosphonate tablet, the patient should refrain from eating or drinking any beverage apart from water for 30 min after taking alendronate or risedronate, or 60 min after ibandronate, to ensure maximal dispersion and absorption of the bisphosphonate. There is therefore no need to fast for longer periods of time.
- •
Having breakfast, preferably a high fiber breakfast, 30 min after taking alendronate or risedronate (60 min after ibandronate) ensures that whatever part of the tablet that has not been absorbed in the stomach is coated with the fiber-rich breakfast ingested and will not irritate the gastrointestinal mucosa. It also is likely to reduce the risk of abdominal pain occurring one to two hours after the ingestion of the bisphosphonate.
The maximal absorption of alendronate (and risedronate) occurs within the first half hour following its intake, there is therefore no need to fast for longer than 30 min after swallowing the bisphosphonate tablet. Fasting for more than 30 min may cause the unabsorbed bisphosphonate particles to reach the intestine without being coated by the high fiber breakfast and may irritate the mucosa and induce low abdominal pain.
- A.
- 7.
In patients with osteoporosis, alendronate:
- A.
Reduces the hip fracture risk.
- B.
Reduces the vertebral fracture risk.
- C.
Increases the BMD of the lumbar vertebrae and proximal femurs.
- D.
All of the above.
- E.
B and C.
Correct answer: D
Comment:
The Fracture Intervention Trial showed that over a 3-year period, compared to placebo, alendronate increases BMD at the lumbar vertebrae and proximal femurs and reduces hip fractures by 51%, single morphometric vertebral compression fractures by 47%, multiple vertebral compression fractures by 90%, and nonvertebral fractures by 55%.
The FOSIT ( FOS amax I nternational T rial) study concludes that, when compared to placebo, alendronate administered for 12 months to postmenopausal women (1908 subjects) with a lumbar vertebra T-score of −2.0 or less reduces the risk of nonvertebral fracture by 47%. Similarly, the BMD increased by 4.9%, 2.4%, 3.6%, and 3.0% in the lumbar vertebrae, femoral neck, trochanter, and total hip, respectively.
The administration of oral bisphosphonates for more than 10 years, however, is sometimes paradoxically associated with an increased risk of hip, wrist, and vertebral fractures. This is discussed further in the section on long-term antiresorptive therapy and atypical femoral shaft fractures.
- A.
- 8.
Risedronate for the treatment of osteoporosis:
- A.
Orally administered, once a week.
- B.
Can be taken with a hot drink.
- C.
Can be taken after breakfast.
- D.
A and B.
- E.
All of the above.
Correct answer: E
Comment:
There are, at present, two different formulations of risedronate: the conventional one (Actonel in the USA) and the delayed release formulation (Atelvia in the USA). Conventional risedronate should be taken with the same routine as alendronate. Delayed release risedronate, however, is as effective as conventional risedronate at increasing BMD but can be taken after breakfast.
Risedronate delayed release tablets are formulated in such a way that they can be taken after breakfast without interfering with its pharmacologic activity. This is achieved by the active ingredient being surrounded by a chelating agent and encapsulated in a pH-sensitive envelope that dissolves in an alkaline medium. The tablet therefore cruises unaffected through the stomach. In the alkaline medium of the small intestine, the outer layer is dissolved and releases the chelating agent which binds to cations present in the intestine, thus preventing them from interfering with the bioavailability of risedronate. Pharmacokinetic and pharmacodynamic studies have shown equivalence to the conventional preparation. The delayed release formulation simplifies dosing regimen and improves compliance. Many patients prefer it to the conventional formulation.
- A.
- 9.
Ibandronate for the treatment of osteoporosis:
- A.
Orally administered, 150 mg, once a month.
- B.
The tablet must be taken while fasting, in the morning, with no other medication, no food and only water.
- C.
A full hour should elapse between the intake of the medication and subsequent food or beverage or medication intake.
- D.
All of the above.
- E.
None of the above.
Correct answer: D
Comment:
Orally administered ibandronate is available as 150-mg tablets to be taken once a month. Its bioavailability is reduced if the 60-min food/medication/drink (apart from water) abstention period is not observed. Oral ibandronate should be administered with the same caveats outlined before for the oral intake of alendronate. It is also available as an intravenous formulation administered every 3 months.
- A.
- 10.
Adverse effects of orally administered bisphosphonates include:
- A.
Dyspepsia.
- B.
Abdominal pain.
- C.
Musculoskeletal pain.
- D.
All of the above.
- E.
A and B.
Correct answer: D
Comment:
All listed adverse effects have been reported after the intake of oral bisphosphonates. Dyspepsia and abdominal pains are due to the irritating property of phosphonic acid molecules on the GI mucosa, hence the need to remain upright and avoid any activity that may increase the risk of gastroesophageal reflux, including jogging and “straightening” a room which involves a certain amount of bending to pick various objects that have been left on the floor.
The abdominal pain, diarrhea, sometimes tenesmus, and occasional fecal incontinence, experienced after the intake of oral bisphosphonates, can be partly relieved by consuming a high fiber meal after the prescribed fast period (30 min after the intake of the alendronate and risedronate tablets and 60 min after the intake of ibandronate): the fibers bind to the unabsorbed bisphosphonate particles and prevent them from getting in direct contact with, and irritating, the intestinal mucosa. Many patients who cannot tolerate one orally administered bisphosphonate are able to tolerate another one.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Postmenopause, no hormonal replacement therapy (HRT).
- •
Positive family history for osteoporosis, especially hip fracture in a biologic parent.
Factors reducing risk of bone demineralization/osteoporosis
- •
Physically active lifestyle.
- •
Good daily dietary calcium intake.
- •
No cigarette smoking.
- •
No excessive caffeine, sodium intake.
- •
No alcohol abuse.
Factors increasing risk of falls/fractures
- •
None: no factor that may increase the risk of falls, except the patient’s age.
Factors reducing risk of falls/fractures
- •
Physically active lifestyle.
- •
Normal serum vitamin D level.
Diagnosis
- •
Postmenopausal osteoporosis.
Management recommendations
Further diagnostic test(s)
- •
None at this stage. There is no biochemical evidence of impaired renal functions, and the serum vitamin D level is within the normal range.
- •
Serum bone markers levels can be used to ascertain the baseline rate of bone turnover and monitor the patient’s response to treatment.
Treatment(s)
- •
First-line pharmacologic therapy: antiresorptive, specifically:
- ○
Orally administered bisphosphonates (alendronate, risedronate, ibandronate).
- ○
Intravenously administered bisphosphonates such as zoledronic acid once a year or ibandronate every 3 months.
- ○
Subcutaneously administered denosumab at six-month intervals.
- ○
Important notice: if there is evidence of renal impairment, bisphosphonates should be avoided as they are excreted by the kidneys. Denosumab is the preferred medication for these patients. However, although denosumab is not nephrotoxic, its administration to patients with impaired renal functions should be monitored.
- ○
- •
Second-line pharmacologic therapy: Osteoanabolic therapy: teriparatide or abaloparatide. However, given the patient’s profile, there should be no need for such agents unless there is no response to antiresorptive medication as evidenced by the serum biomarker levels. Even in that case, before switching therapeutic lines, it is important to ascertain the patient is taking the medication exactly as directed and does not have secondary osteoporosis. Both are common causes of poor or nonresponse to antiresorptive therapy.
Follow-up
- •
Short term: depends on medication prescribed. A follow-up visit, or phone consultation, 4–6 weeks after initiation of treatment may identify noncompliers and emphasize the importance of adopting lifestyle changes, especially to ensure a good daily dietary intake of calcium and vitamin D.
- •
Two years: repeat DXA scan
- •
Given the long half-life of bisphosphonates, it is also sometimes recommended that antiresorptives be given initially for a period of 4–6 years and then the medication discontinued for 2–4 years, with DXA scans done at intervals of 2 years and the patient’s bone health reevaluated at yearly or every other year intervals.
- •
These periods of interrupted medication administration are sometimes referred to as “drug holidays.” The main objective is to avoid potentially serious long-term adverse effects such as osteonecrosis of the jaw and atypical femoral fracture. Unfortunately, however, in some instances, drug holidays are associated with an increased rate of bone resorption.
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