Bisphosphonates

Author: David Abbasi

Topic updated on 03/09/13 8:53am

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
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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Qbank (15 Questions)

TAG

(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? Topic

Review Topic

1. Inhibition of farnesyl diphosphate synthase
2. Conversion of drug into a non-functioning ATP-analogue
3. Interference of isoprenylation of small GTPases
4. Inhibition of geranylgeranyl diphosphate synthase (GGPPS)
5. Downregulation of the undecaprenyl diphosphate synthase (UPPS) pathway

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates are a class of antiresorptive agents used to treat diseases characterized by osteoclast-mediated bone resorption. Non-nitrogen containing bisphosphonates (such as etidronate) are metabolized into non-functioning ATP analogues which cause eventual osteoclast apoptosis. Nitrogen containing bisphsphonates (alendrolate/Fosamax and Zoledronic acid/Zometa) act by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases.

Reszka et al reviewed nitrogen containing bisphosphonates. They outlined the mechanism of action on farnesyl diphosphate synthase in the cholesterol biosynthesis pathway.

Guo et al also reviewed the mechanism of nitrogen-containing bisphosphonates. In addition to showing the decrease in prenylation of GTPase, they were shown to inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS).

Morris et al reviewed the bisphosphonates currently approved by the FDA. They outlined their use in the treatment of Paget disease, metastatic bone disease and widening applications in OI and fibrous dysplasia.

Incorrect answers:
1,3,4,5: Mechanism of nitrogen-containing bisphosphonates.

REFERENCES:

1. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH. Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. PMID:17535895 (Link to Abstract)

2. Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem. 2004 Sep;4(7):711-9. PMID:15379639 (Link to Abstract)

3. Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. PMID:15995133 (Link to Abstract)

Question Authors:

Terrill Julien MD, Ben Taylor MD, Dave Marcu MD,

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TAG

(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? Topic

Review Topic

1. Jaw
2. Lumbar spine
3. Femoral neck
4. Subtrochanteric femur
5. Anterior cortex of tibia

PREFERRED RESPONSE ▶

DISCUSSION: Subtrochanteric stress reaction and fracture is a known complication of longterm bisphosphonate use. Imaging typically shows lateral cortical thickening in the subtrochanteric femur (Illustration A). Without discontinuation of bisphosphonate use and prophylactic fixation, this stress reaction can go on to a transverse fracture (Illustration B.)

Koh et al studied the complication of femoral cortical stress lesions in patients on longterm bisphosphonate treatment. In their findings, they note that these fractures occured in the subtrochanteric region, and were preceded by "a dreaded black line," and lateral femoral cortical thickening. All patients with these fractures also reported lateral thigh pain for over one month.

Capeci et al did a retrospective review on alendronate therapy and its association with unilateral low-energy subtrochanteric femur and diaphyseal femur fractures. Although a rare complication, they recommended consideration of discontinuing alendronate with the consultation of an endocrinologist if it occurs. They also recommend routine contralateral leg imaging after to rule out contralateral stress fracture. If contralateral stress fracture is found, it should be treated with prophylactic intramedullary fixation.

Illustrations: A

REFERENCES:

1. Koh JS, Goh SK, Png MA, Kwek EB, Howe TS. Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture? J Orthop Trauma. 2010 Feb;24(2):75-81. PMID:20101130 (Link to Abstract)

2. Capeci CM, Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am. 2009 Nov;91(11):2556-61. PMID:19884427 (Link to Abstract)

Question Authors:

David Abbasi MD, John Badylak MD, Patrick McCulloch MD,

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TAG

(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? Topic

Review Topic

FIGURES: A

1. No change in bone pain
2. No change in future fracture incidence
3. An increase in osteoblast density
4. An increased risk of secondary osteosarcoma
5. An increase in bone density

PREFERRED RESPONSE ▶

DISCUSSION: The history and images are consistent with osteogenesis imperfecta (OI). Olecranon avulsion fractures are often seen in patients with OI and children presenting with these should be evaluated for OI. The clinical image of blue sclera can also be a characteristic finding in patients with OI. The Bisphosphonates have been shown to decrease fracture incidence and bone pain while improving bone density and overall function in OI patients.

Zeitlin et al performed a Level 5 review of OI. They state that Sillence Types I through IV are a mutation in the COL1A1 and COL1A2 genes that encode type I collagen. They report that cyclical intravenous pamidronate administration reduces bone pain and fracture incidence, and increases bone density and level of ambulation.

Burnei et al also performed a Level 5 review of OI. They report that the use of bone marrow transplantation to increase osteoblast density in OI patients is currently being researched as a potential treatment of OI.

REFERENCES:

1. Burnei G, Vlad C, Georgescu I, Gavriliu TS, Dan D. Osteogenesis imperfecta: diagnosis and treatment. J Am Acad Orthop Surg. 2008 Jun;16(6):356-66. Review. PMID:18524987 (Link to Abstract)

2. Zeitlin L, Fassier F, Glorieux FH. Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B. 2003 Mar;12(2):77-87. Review. PMID:12584489 (Link to Abstract)

Question Authors:

Michael Hughes MD, John Badylak MD, Ben Taylor MD,

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TAG

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

Review Topic

1. Selective Cox-2 inhibitors
2. Alendronate
3. Cholecalciferol
4. Etidronate
5. Indomethacin

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates are a class of antiresorptive bone agents. They are currently indicated to treat diseases that involve osteoclast-mediated bone resorption. Nitrogen containing bisphosphonates (alendronate, pamidronate, risedronate) exert their effects by inhibiting protein prenylation and GTPase formation. Non-nitrogen containing bisphosphonates (etidronate, clodronate, tiludronate) induce osteoclast apoptosis by forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. Common diseases currently treated with bisphosphonates include osteoporosis, Paget's disease, and metastatic bone disease. Research is underway for use in other conditions, such as AVN.

Morris et al review current treatment regimens for the most common treatment indications for this drug class and they note there is no long term data regarding current treatment.

Burnei et al discuss the treatment options for osteogenesis imperfecta which include both medical and surgical treatments. Bisphosphonates have been shown to reduce the fracture risk for this disease, but no long term data exists.

REFERENCES:

1. Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. Review. PMID:15995133 (Link to Abstract)

2. Burnei G, Vlad C, Georgescu I, Gavriliu TS, Dan D. Osteogenesis imperfecta: diagnosis and treatment. J Am Acad Orthop Surg. 2008 Jun;16(6):356-66. Review PMID:18524987 (Link to Abstract)

Question Authors:

Jan Szatkowski MD, Patrick McCulloch MD, Michael Hughes MD,

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2.0

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TAG

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

Review Topic

1. HMG-CoA reductase
2. farnesyl diphosphate synthase
3. tissue inhibitor of metalloprotease
4. alkaline phosphatase
5. calcitonin

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates can be divided according to their chemical structure into the earlier non-nitrogen (e.g. clodronate and etidronate) and the newer nitrogen containing (e.g alendronate) groups. The Nitrogen containing group is significantly more potent. Nitrogen containing bisphosphonates target farnesyl diphosphate synthase, a component of the mevalonate (cholesterol) pathway. Non-nitrogen containing bisphosphonates result in cytotoxic ATP to accumulate with an end result of apoptosis. The JBJS article by Morris is a good overview of bisphosphonate basic science, usages and adverse reactions.

REFERENCES:

1. Einhorn TA, O’Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 315-330

2. Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. PMID:15995133 (Link to Abstract)

Question Authors:

Doug Nowak MD, Patrick McCulloch MD, Ben Taylor MD,

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TAG

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

Review Topic

1. Renal
2. Gastrointestinal
3. Liver
4. Skin
5. Pulmonary

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates are a broad class of medicines used to treat osteoporosis and Paget's disease. They work by inhibiting osteoclast-mediated resorption after being absorbed into the inorganic phase of bone and taken up by osteoclasts. The paper by Lin et al provides a nice review of bisphosphonates and describe their appropriate use in enhancing bone density in patients with structurally flawed bone. They describe the mechanism of action of bisphosphonates as pyrophosphate analogues and their renal mechanism of excretion, thus, prohibiting their use in patients with renal insufficiency. Rosier discusses the role of the orthopaedic surgeon in the diagnosis and treatment of patients with osteoporosis, now referred to as the "own the bone" initiative. Central to the treatment of osteoporosis are bisphosphonates and the anti-RANKL monoclonal antibody, Denosumab.

REFERENCES:

1. Lin JT, Lane JM. Bisphosphonates. J Am Acad Orthop Surg. 2003 Jan-Feb;11(1):1-4. PMID:12699366 (Link to Abstract)

2. Rosier RN. Expanding the role of the orthopaedic surgeon in the treatment of osteoporosis. Clin Orthop Relat Res. 2001 Apr;(385):57-67. PMID:11302327 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, Derek Moore, Patrick McCulloch MD,

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2.0

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TAG

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

Review Topic

1. Any effect can be counteracted by taking calcium supplements
2. No effect
3. Increased risk of wound infection
4. Smaller fusion mass
5. Decreased fusion rate

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates (e.g. alendronate) are used to treat osteoporosis. The mechanism of action is inhibiting the formation of the ruffled border of osteoclasts, resulting in decreasing bone turnover.

Huang et al performed a rat study comparing alendronate to placebo and found that fusion rates were lower in those treated with alendronate. However, the fusion masses were larger in the alendronate treated rats despite lower fusion rates (why #4 is incorrect).

Lehman et al in another placebo controlled rate study found that the fusion rates for placebo (76%) were greater than the alendronate group (45%). Alendronate works on osteoclasts and does not affect calcium directly. Taking calcium should have no effect on alendronate (why #1 is incorrect). At this time there are no formal recommendations of when to stop bisphononate medication prior to spinal fusion surgery.

REFERENCES:

1. Huang RC, Khan SN, Sandhu HS, Metzl JA, Cammisa FP Jr, Zheng F, Sama AA, Lane JM. Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005 Nov 15;30(22):2516-22 PMID:16284589 (Link to Abstract)

2. Lehman RA Jr, Kuklo TR, Freedman BA, Cowart JR, Mense MG, Riew KD. The effect of alendronate sodium on spinal fusion: a rabbit model. Spine J. 2004 Jan-Feb;4(1):36-43. PMID:14749192 (Link to Abstract)

Question Authors:

Doug Nowak MD, Patrick McCulloch MD, Ben Taylor MD,

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TAG

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

Review Topic

1. Warfarin
2. Low-molecular weight heparin
3. Diclofenac
4. Ketorolac
5. Alendronate

PREFERRED RESPONSE ▶

DISCUSSION: Migliorati et al review bisphosphonate-associated osteonecrosis. They state that it is characterized by the unexpected appearance of necrotic bone in the oral cavity.

Risk factors include intravenous therapy, duration of therapy >36mo, elderly patients with multiple myeloma, and those with a history of recent dental extraction. Incidence ranges from 4-17%.

Van den Wyngaert et al confirm the predisposition of multiple myeloma patients to develop osteonecrosis of the jaw, and conclude that although various treatment strategies have been reported, conservative management remains the mainstay of therapy.

Illustration A shows exposed bone in the mouth of a patient with osteonecrosis of the jaw who was on long term bisphosphonate therapy.

Illustrations: A

REFERENCES:

1. Van den Wyngaert T, Huizing MT, Vermorken JB: Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315-322 PMID:17545793 (Link to Abstract)

2. Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: A long-term complication of bisphosphonate treatment. Lancet Oncol 2006;7:508-514 PMID:16750501 (Link to Abstract)

Question Authors:

Greg Galano MD, Patrick McCulloch MD, John Badylak MD,

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TAG

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

Review Topic

1. TNF-alpha inhibitors
2. Bone morphogenic proteins
3. Bisphosphonates
4. Fluoroquinolones
5. RANKL antibiodies

PREFERRED RESPONSE ▶

DISCUSSION: Radiographic changes suggestive of osteopetrosis (marble bone disease) are a known complication of bisphosphonate usage. The common cellular pathway in this process is the osteoclast. Bisphosphonates target and inhibit the osteoclast, and these cells are not functioning in patients with osteopetrosis. Whyte et al describe a case report of a 12-year-old child with idiopathic hyperphosphatasia treated with bisphosphonates who developed osteopetrosis. Falk et al report on their small case series which showed the beneficial effects and known complications in the treatment of osteogenesis imperfecta with bisphosphonate therapy. Finally Marini presents a perspective article describing the off-label use of bisphosphonates in children.

REFERENCES:

1. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. PMID:12890844 (Link to Abstract)

2. Falk MJ, Heeger S, Lynch KA, DeCaro KR, Bohach D, Gibson KS, Warman ML. Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics. 2003 Mar;111(3):573-8. PMID:12612238 (Link to Abstract)

3. Marini JC. Do bisphosphonates make children's bones better or brittle? N Engl J Med. 2003 Jul 31;349(5):423-6. PMID:12890840 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, Patrick McCulloch MD,

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TAG

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

Review Topic

1. Inhibiting caspase
2. Inhibiting matrix metalloprotease
3. Inhibiting reverse transcriptase
4. Targeting of farnesyl diphosphate synthase
5. Creating toxic analog of adenosine triphosphate that targets mitochondria

PREFERRED RESPONSE ▶

DISCUSSION: Bisphosphonates work by one of two mechanisms. Non-nitrogren containing bisphosphonates (such as etidronate and clodronate) work by creating a toxic analog of ATP which inhibits ATP and leads to osteoclast apoptosis. Nitrogen containing bisphosphonates (such as alendronate, risedronate, and zoledronate) inhibit the enzyme farnesyl diphosphate synthase which prevents protein geranylgeranylation and prevents osteoclastic bone resorption.

Reska et. al. specifically discuss the difference between the two pathways. Non-nitrogen containing compounds inhibit ATP production and cause osteoclast apoptosis. Nitrogen containing bisphophonates inhibit protein synthesis by interrupting the cholesterol biosynthetic pathway, which prevents osteoclastic resorption.

REFERENCES:

1. Reska AA, Rodan GA: Mechanism of acition of bisphosphonates. Curr Osteoporos Rep 2003; 2: 45-52. PMID:16036064 (Link to Abstract)

Question Authors:

Anay Patel MD, Jan Szatkowski MD, John Badylak MD,

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TAG

(OBQ06.236) What is the mechanism of action of simple bisphosphonate (e.g. clodronate and etidronate) medications? Topic

Review Topic

1. Post-translational carboxylation of vitamin K dependent proteins
2. Decreased osteoblastic acivity
3. Inhibits farnesyl diphosphate synthase in osteoclasts
4. Increased osteoclast apoptosis
5. Increases bone turnover

PREFERRED RESPONSE ▶

DISCUSSION: The effect of bisphosphonates is focused directly on the osteoclast. Bisphosphonates preferentially bind to mineral exposed by bone-resorbing osteoclasts. The osteoclasts resorb the bone and take in the bisphosphonate. The net result of bisphosphonates is to decrease bone resorption and decrease bone turnover (why #5 is incorect).
There are two groups of bisphophonates: simple and nitrogen-containing. Simple bisphosphonates (e.g. clodronate and etidronate) induce osteoclast apoptosis. Clodronate creates a toxic analog of adenosine triphosphate, which targets the mitochondria. For nitrogen-containing bisphosphonates, farnesyl diphosphate synthase (important in the cholesterol biosynthetic pathway) is the direct intracellular target. Its inhibition suppresses protein geranylgeranylation, an essential step in the cellular processes required for osteoclastic bone resorption. Answer #3 would be the correct answer if the question asked about nitrogen-containing bisphosphonates.

The reference by Reszka et al reviews the above information about the mechanism of action of bisphosphonates as well as reviews their indications.

The reference by Rodan et al is a 2003 review of bisphosphonate use in osteoporosis and reviews the use of this class of medications at that time.

REFERENCES:

1. Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep. 2003 Sep;1(2):45-52. PMID:16036064 (Link to Abstract)

2. Rodan GA Reszka AA: Osteoporosis and bisphosphonates. J Bone Joint Surg Am 2003; 85 S3:8-12. PMID:12925603 (Link to Abstract)

Question Authors:

Ben Taylor MD, Ben Taylor MD, John Badylak MD,

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TAG

(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? Topic

Review Topic

1. remain the same
2. decrease by 20%
3. decrease by 40%
4. decrease by 60%
5. increase by 10%

PREFERRED RESPONSE ▶

DISCUSSION: The answer for this question specifically targets the work done by Harris et. al in the JAMA article. When patients were treated with bisphosphonates (risendronate, 5mg/day), the incidence of new vertebral fractures was reduced by 65% following one year of treatment and by 41% following 3 years of treatement. In addition to these findings, the authors noted a 39% decrease in incidence of non-vertebral fractures and a significant increase in bone mineral density.

REFERENCES:

1. Rao RD, Singrakhia MD. Painful osteoporotic vertebral fracture. Pathogenesis, evaluation, and roles of vertebroplasty and kyphoplasty in its management. J Bone Joint Surg Am. 2003 Oct;85-A(10):2010-22. PMID:14563813 (Link to Abstract)

2. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13;282(14):1344-52. PMID:10527181 (Link to Abstract)

Question Authors:

Greg Galano MD, Derek Moore, Guillem Lomas MD,

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TAG

(OBQ04.247) Which of the following molecules binds to the surface of hydroxyapatite crystals and inhibits osteoclast-mediated bone resorption? Topic

Review Topic

1. Calcitonin
2. Parathyroid Hormone
3. Raloxifene
4. Calcium
5. Alendronate

PREFERRED RESPONSE ▶

DISCUSSION: Bisphophonates accumulate in high concentration in bones due to their binding affinity to hydroxyapatite crystals. There are two types of bisphosphonates with different mechanisms, although both classes ultimately inhibit osteoclast resorption of bone. Nitrogen containing bisphosphonates (alendronate/Fosamax, pamidronate/Aredia, risedronate/Actonel) prevent protein prenylation by inhibiting farnesyl diphosphate synthase, an enzyme in the mevalonate (cholesterol) pathway. The non-nitrogenous bisphosphonates (etidronate/Didronel, clodronate, tiludronate) are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. Due to this disruption in metabolism, the osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.

REFERENCES:

1. Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal system, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 217-237

Question Authors:

Khalid Yousuf MD, Patrick McCulloch MD,

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Evidence & References Show References

Level of Evidence 4 (Case Series)

Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma. 2008 May-Jun;22(5):346-50. PMID:18448990 (Link to Abstract)
Capeci CM, Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am. 2009 Nov;91(11):2556-61. PMID:19884427 (Link to Abstract)
Falk MJ, Heeger S, Lynch KA, DeCaro KR, Bohach D, Gibson KS, Warman ML. Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics. 2003 Mar;111(3):573-8. PMID:12612238 (Link to Abstract)

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH. Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. PMID:17535895 (Link to Abstract)
Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem. 2004 Sep;4(7):711-9. PMID:15379639 (Link to Abstract)
Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. PMID:15995133 (Link to Abstract)
Burnei G, Vlad C, Georgescu I, Gavriliu TS, Dan D. Osteogenesis imperfecta: diagnosis and treatment. J Am Acad Orthop Surg. 2008 Jun;16(6):356-66. Review. PMID:18524987 (Link to Abstract)
Zeitlin L, Fassier F, Glorieux FH. Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B. 2003 Mar;12(2):77-87. Review. PMID:12584489 (Link to Abstract)
Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. Review. PMID:15995133 (Link to Abstract)
Lin JT, Lane JM. Bisphosphonates. J Am Acad Orthop Surg. 2003 Jan-Feb;11(1):1-4. PMID:12699366 (Link to Abstract)
Rosier RN. Expanding the role of the orthopaedic surgeon in the treatment of osteoporosis. Clin Orthop Relat Res. 2001 Apr;(385):57-67. PMID:11302327 (Link to Abstract)
Van den Wyngaert T, Huizing MT, Vermorken JB: Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315-322 PMID:17545793 (Link to Abstract)
Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: A long-term complication of bisphosphonate treatment. Lancet Oncol 2006;7:508-514 PMID:16750501 (Link to Abstract)
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. PMID:12890844 (Link to Abstract)
Marini JC. Do bisphosphonates make children's bones better or brittle? N Engl J Med. 2003 Jul 31;349(5):423-6. PMID:12890840 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012

Undefined

Koh JS, Goh SK, Png MA, Kwek EB, Howe TS. Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture? J Orthop Trauma. 2010 Feb;24(2):75-81. PMID:20101130 (Link to Abstract)
Capeci CM, Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am. 2009 Nov;91(11):2556-61. PMID:19884427 (Link to Abstract)
Burnei G, Vlad C, Georgescu I, Gavriliu TS, Dan D. Osteogenesis imperfecta: diagnosis and treatment. J Am Acad Orthop Surg. 2008 Jun;16(6):356-66. Review PMID:18524987 (Link to Abstract)
Einhorn TA, O’Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 315-330
Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18. PMID:15995133 (Link to Abstract)
Huang RC, Khan SN, Sandhu HS, Metzl JA, Cammisa FP Jr, Zheng F, Sama AA, Lane JM. Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005 Nov 15;30(22):2516-22 PMID:16284589 (Link to Abstract)
Lehman RA Jr, Kuklo TR, Freedman BA, Cowart JR, Mense MG, Riew KD. The effect of alendronate sodium on spinal fusion: a rabbit model. Spine J. 2004 Jan-Feb;4(1):36-43. PMID:14749192 (Link to Abstract)
Shanabhag AS J Am Acad Ortho Srg 2006, 14(4):215-25. PMID:16585363 (Link to Abstract)
Arabmotlagh M, Pilz M, Warzecha J, Rauschmann M. J Orthop Res 2009; 27(2):183-8. PMID:18752281 (Link to Abstract)
Reska AA, Rodan GA: Mechanism of acition of bisphosphonates. Curr Osteoporos Rep 2003; 2: 45-52. PMID:16036064 (Link to Abstract)
Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep. 2003 Sep;1(2):45-52. PMID:16036064 (Link to Abstract)
Rodan GA Reszka AA: Osteoporosis and bisphosphonates. J Bone Joint Surg Am 2003; 85 S3:8-12. PMID:12925603 (Link to Abstract)
Rao RD, Singrakhia MD. Painful osteoporotic vertebral fracture. Pathogenesis, evaluation, and roles of vertebroplasty and kyphoplasty in its management. J Bone Joint Surg Am. 2003 Oct;85-A(10):2010-22. PMID:14563813 (Link to Abstract)
Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13;282(14):1344-52. PMID:10527181 (Link to Abstract)
Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal system, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 217-237

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Bisphosphonates

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