Updated: 8/11/2018

Bisphosphonates

Topic
Review Topic
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0
Questions
23
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0
Evidence
27
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0
Cases
1
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Introduction
  • Overview
    • class of drugs that prevent bone mass loss by inhibiting osteoclast resorption
      • prevent formation of osteoclast ruffled borders microtubules, causing apoptosis
      • inhibition of osteoclasts also infereres with normal bone healing and remodeling
    • there are two types of bisphosphonates  
      • non-nitrogen containing
        • tiludronate
        • clodronate
        • etidronate
      • nitrogen containing
        • alendronate
        • risedronate
        • pamidronate
        • zolendronate
          • zoledronic acid - relatively new and appealing to patients, due to IV adminstration every 12 months
  • Indications
    • osteoporosis
    • metastatic bone disease
    • multiple myeloma
    • paget's disease
    • polyostotic fibrous dysplasia
    • total joint arthroplasty to prevent osteolysis
    • early stage avascular necrosis
    • osteogenesis imperfecta
    • metastatic hypercalcemia
  • Contraindications
    • severe renal disease
      • primary mode of excretion is renal
    • following lumbar fusion
      • decreased spinal fusion rates in lab animal models (increased fusion mass size, but decreases the actual fusion rate)
Mechanism
  • Delivery
    • bisphophonates accumulate in high concentration in bone due to binding affinity to calcium
    • bisphosphonates are ingested by osteoclasts and work by two different methods depending on presence of nitrogen atom on the alkyl chain
  • Nitrogen containing bisphosphonates mechanism  
    • inhibits osteoclast farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol pathway)  
      • inhibits GTPase formation
  • Non-nitrogen containing bisphosphonates (simple) mechanism  
    • induce osteoclasts to undergo premature death and apoptosis
      • does so by forming a toxic adenosine triphosphate (ATP) analogue 
Treatment
  • Vertebral Compression Fractures 
    • indications
      • vertebral compression fracture in osteoporotic patient
        • bone mineral density 2.5 or more standard deviations below that of young healthy adults (T score < 2.5 SD)
    • outcomes
      • 1 year of treatment with a pharmacologic antiosteoporotic medication, the risk of vertebral fracture decreases by 50-60%
  • Non-vertebral Fragility fractures 
    • indications
      • fragility fracture in osteoporotic patient
    • outcomes
      • effective in reducing the risk of multiple fractures
  • Osteogenesis imperfecta 
    • cyclical IV pamidronate administration
      • reduces bone pain and fracture incidence
      • increases level of ambulation and bone density
  • Multiple myeloma 
    • indications
      • diagnosis of multiple myeloma
    • outcomes
      • reduced incidence of skeletal events in multiple myeloma
  • Avascular necrosis 
    • indications
      • early, precollapse AVN
    • outcomes
      • still considered investigational
      • randomized clinical trial showed that bisphosphonate treatment was more effective at preventing head collapse than placebo at 2 years (bisphosphonate collapse 6.9% vs placebo collapse 76%)
Side Effects & Complications
  • Jaw osteonecrosis
  • Atypical subtrochanteric and femoral stress fractures   
  • Radiographic changes consistent with osteopetrosis
 

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Questions (23)
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(OBQ07.134) What medication has been shown to decrease osteolysis after total joint replacement surgery? Review Topic

QID: 795
1

Bisphosphonates

68%

(1604/2350)

2

NSAIDs

4%

(101/2350)

3

TNF-alpha inhibitors

13%

(300/2350)

4

Calcium and vitamin D supplementation

12%

(292/2350)

5

BMP-7

2%

(41/2350)

ML 2

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PREFERRED RESPONSE 1
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(OBQ11.227) A 67-year-old female presented 2 months ago to her primary care physician with left sided thigh pain. A radiograph was taken at that time and is shown in Figure A. She was diagnosed at that time with a quadriceps strain and given a prescription for ibuprofen and physical therapy. She is now in the emergency room with severe left thigh pain and inability to bear weight on the left lower extremity after bending down to tie her shoes. She denies any constitutional symptoms. A current radiograph from the emergency room is shown in Figure B. Which of the following most likely explains this patient's fracture? Review Topic

QID: 3650
FIGURES:
1

Long-term corticosteroid use

2%

(35/1882)

2

Secondary malignancy arising from Paget disease

1%

(27/1882)

3

Long-term alendronate use

95%

(1795/1882)

4

Long-term ergocalciferol use

1%

(10/1882)

5

Short-term teraparatide use

0%

(5/1882)

ML 1

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

(OBQ13.147) It is recommended that invasive dental work be completed prior to the initiation of which of the following medications? Review Topic

QID: 4782
1

Glucosamine

0%

(12/3007)

2

Cholecalciferol

1%

(34/3007)

3

Levothyroxine

1%

(17/3007)

4

Teriparatide

17%

(503/3007)

5

Bisphosphonates

80%

(2416/3007)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(OBQ04.247) Which of the following molecules binds to the surface of hydroxyapatite crystals and prevents protein prenylation? Review Topic

QID: 1352
1

Calcitonin

14%

(64/451)

2

Parathyroid Hormone

6%

(29/451)

3

Raloxifene

15%

(69/451)

4

Calcium

13%

(58/451)

5

Alendronate

51%

(231/451)

ML 3

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PREFERRED RESPONSE 5

(OBQ06.72) Radiographic changes suggestive of osteopetrosis in children are a known complication of which of the following types of medications? Review Topic

QID: 183
1

TNF-alpha inhibitors

3%

(34/1036)

2

Bone morphogenic proteins

3%

(35/1036)

3

Bisphosphonates

72%

(746/1036)

4

Fluoroquinolones

11%

(111/1036)

5

RANKL antibiodies

11%

(109/1036)

ML 2

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PREFERRED RESPONSE 3

(OBQ06.86) What is the cellular mechanism of action for non-nitrogen containing bisphosphonates (such as clodronate and etidronate) to induce osteoclast apoptosis? Review Topic

QID: 197
1

Inhibiting caspase

2%

(26/1107)

2

Inhibiting matrix metalloprotease

8%

(88/1107)

3

Inhibiting reverse transcriptase

4%

(48/1107)

4

Targeting of farnesyl diphosphate synthase

31%

(348/1107)

5

Creating toxic analog of adenosine triphosphate that targets mitochondria

53%

(592/1107)

ML 3

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PREFERRED RESPONSE 5

(OBQ08.59) What effect do bisphosphonate medications have on spinal fusion surgery when taken in the postoperative period? Review Topic

QID: 445
1

Any effect can be counteracted by taking calcium supplements

0%

(3/1095)

2

No effect

19%

(212/1095)

3

Increased risk of wound infection

2%

(24/1095)

4

Smaller fusion mass

13%

(144/1095)

5

Decreased fusion rate

65%

(709/1095)

ML 3

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PREFERRED RESPONSE 5

(OBQ10.173) Which of the following agents has been shown to exert its effect by inhibiting protein prenylation and GTPase formation? Review Topic

QID: 3266
1

Selective Cox-2 inhibitors

6%

(126/2184)

2

Alendronate

64%

(1389/2184)

3

Cholecalciferol

7%

(144/2184)

4

Etidronate

19%

(425/2184)

5

Indomethacin

4%

(91/2184)

ML 3

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PREFERRED RESPONSE 2

(OBQ11.20) A 62-year-old woman with Paget’s disease is started on a non-nitrogen containing bisphosphonate for treatment of her condition. What is the mechanism of action of this drug? Review Topic

QID: 3443
1

Inhibition of farnesyl diphosphate synthase

29%

(783/2731)

2

Conversion of drug into a non-functioning ATP-analogue

53%

(1456/2731)

3

Interference of isoprenylation of small GTPases

9%

(253/2731)

4

Inhibition of geranylgeranyl diphosphate synthase (GGPPS)

5%

(140/2731)

5

Downregulation of the undecaprenyl diphosphate synthase (UPPS) pathway

3%

(81/2731)

ML 3

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PREFERRED RESPONSE 2

(OBQ11.223) A 10-year-old child falls from a standing height and sustains the injury shown in Figure A. Her medical history includes hearing defects and the facial appearance shown in Figure B. In addition to operative fixation of her fracture she is scheduled to receive cyclical intravenous pamidronate administration as a treatment after the fracture is healed. Which of the following is associated with this form of treatment? Review Topic

QID: 3646
FIGURES:
1

No change in bone pain

4%

(20/559)

2

No change in future fracture incidence

5%

(27/559)

3

An increase in osteoblast density

10%

(56/559)

4

An increased risk of secondary osteosarcoma

8%

(43/559)

5

An increase in bone density

73%

(410/559)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(OBQ06.236) What is the mechanism of action of non-nitrogen containing bisphosphonate (e.g. clodronate and etidronate) medications? Review Topic

QID: 247
1

Post-translational carboxylation of vitamin K dependent proteins

0%

(4/918)

2

Decreased osteoblastic acivity

3%

(30/918)

3

Inhibits farnesyl diphosphate synthase in osteoclasts

45%

(412/918)

4

Increased osteoclast apoptosis

50%

(457/918)

5

Increases bone turnover

1%

(10/918)

ML 3

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PREFERRED RESPONSE 4

(OBQ11.39) Longterm bisphosphonate usage has been shown to cause an increased risk of stress reaction leading to fracture at which of the following areas? Review Topic

QID: 3462
1

Jaw

4%

(116/3299)

2

Lumbar spine

1%

(27/3299)

3

Femoral neck

2%

(73/3299)

4

Subtrochanteric femur

93%

(3058/3299)

5

Anterior cortex of tibia

0%

(15/3299)

ML 1

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PREFERRED RESPONSE 4

(OBQ09.262) What is the primary mode of bisphosphonate excretion? Review Topic

QID: 3075
1

Renal

88%

(1305/1483)

2

Gastrointestinal

4%

(60/1483)

3

Liver

7%

(100/1483)

4

Skin

0%

(5/1483)

5

Pulmonary

1%

(10/1483)

ML 1

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PREFERRED RESPONSE 1

(OBQ08.223) Osteonecrosis of the jaw has been recognized as a possible complication of chronic therapy with which of the following medications? Review Topic

QID: 609
1

Warfarin

2%

(11/634)

2

Low-molecular weight heparin

0%

(3/634)

3

Diclofenac

2%

(14/634)

4

Ketorolac

1%

(6/634)

5

Alendronate

94%

(597/634)

ML 1

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PREFERRED RESPONSE 5

(OBQ09.63) Nitrogen containing bisphosphonates inhibit osteoclasts by targeting what enzyme or hormone? Review Topic

QID: 2876
1

HMG-CoA reductase

7%

(63/927)

2

farnesyl diphosphate synthase

82%

(759/927)

3

tissue inhibitor of metalloprotease

2%

(23/927)

4

alkaline phosphatase

6%

(57/927)

5

calcitonin

2%

(23/927)

ML 2

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

(OBQ05.30) An 85-year-old patient diagnosed with osteoporosis is begun on a bisphosphonate. What can you tell her about her risk of vertebral fracture after 3 years of treatment? Review Topic

QID: 67
1

remain the same

8%

(41/506)

2

decrease by 20%

21%

(104/506)

3

decrease by 40%

49%

(249/506)

4

decrease by 60%

20%

(100/506)

5

increase by 10%

2%

(9/506)

ML 4

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PREFERRED RESPONSE 3
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