Clinical role of bisphosphonate therapy

Figures & data

Figure 1 Hydroxyapatite (HAP) adsorption affinity constants vary between the different bisphosphonates. The hydroxyl position at R1 as well as the R2 side-chain of BPs contribute to bone affinity.

©2006 Elsevier. Reproduced with permission from Nancollas GH, Tang R, Phipps RJ et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38(5):617–627.⁸⁶

Abbreviations: ALN, alendronate; CLO, clodronate; ETD, etidronate; IBN, ibandronate; RIS, risedronate; ZOL, zoledronate.

Figure 2 Effects of bisphosphonates on osteoclast morphology.

©1991 American Society for Clinical Investigation. Adapted with permission from Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991;88(6):2095–2105.⁸⁷

Table 1 Randomized placebo-controlled trials of bisphosphonates in postmenopausal osteoporosis summarizing their effect on fracture risk

Bisphosphonate	Average relative risk (95% confidence interval)
	Vertebral fracture	Nonvertebral fractures	Hip fracture
Alendronate
FIT-1^Citation12	0.53 (0.41–0.68)	0.8 (0.63–1.01)	0.49 (0.23–0.99)
FIT-2^Citation14	0.56 (0.39–0.8)	0.88 (0.74–1.04)	0.79 (0.43–1.44)
FLEX^Citation6	0.86 (0.6–1.22)	1.00 (0.76–1.32)	1.02 (0.51–2.10)
Risedronate
V ERT-NA^Citation13	0.59 (0.43–0.82)	0.6 (0.39–0.94)	Not available
V ERT-MN^Citation17	0.51 (0.36–0.73)	0.67 (0.44–1.04)	Not available
HIP^Citation18	Not available	0.8 (0.7–1.0)	0.7 (0.6–0.9)
Ibandronate
BONE^Citation15	0.5 (0.26–0.66)	Not available	Not available
Intermittent dosing
Zoledronate
HORIZON-PFT^Citation16	0.3 (0.24–0.38)	0.75 (0.64–0.87)	0.59 (0.42–0.83)
HORIZON-RFT^Citation19	0.54 (0.32–0.92)	0.73 (0.55–0.98)	0.7 (0.41–1.19)

Abbreviations: BONE, oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe; FIT, Fracture Intervention Trial; FLEX, Fracture intervention trial Long-term EXtension; HIP, Hip Intervention Program; HORIZON-PFT; HORIZON-RFT; VERT-MN, Vertebral Efficacy with Risedronate Therapy-MultiNational; VERTNA, Vertebral Efficacy with Risedronate Therapy-North America.

Figure 3 Changes in (A) bone mineral density and (B) markers of bone resorption expressed as percentage change from baseline during weekly (OW) alendronate (70 mg) and risedronate (35 mg).

©2005 John Wiley and Sons. Reproduced with permission from Rosen CJ, Hochberg MC, Bonnick SL, et al; Fosamax Actonel Comparison Trial Investigators. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res. 2005;20(1):141–151.²⁰

Abbreviations: CTx, C-terminal telopeptide; NTx, N-terminal telopeptide.

Figure 4 Changes in bone turnover markers following a single 5 mg infusion of zoledronic acid (ZOL) or risedronate (RIS; 30 mg orally for 60 days) for Paget’s disease of bone.

©2011 John Wiley and Sons. Reproduced with permission from Reid IR, Lyles K, Su G, et al. A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res. 2011;26(9):2261–2270. ⁵²

Notes: Bone turnover markers were lower in the zoledronic acid treatment arm throughout follow-up. Relapse rates were higher in the risedronate group (20%) compared to the zoledronic acid group (0.7%, P < 0.001).
Abbreviations: αCTX, alpha C-terminal telopeptide; ALP, alkaline phosphatase; βCTX, beta C-terminal telopeptide; Cr, creatinine; P1NP, serum procollagen type 1 amino-terminal propeptide.

Table 2 Licensed indication for the commonly used bisphosphonates

Bisphosphonate	Indication	Method of administration	Standard dosage regimen (frequency and dose)	Relative potency
Etidronate	Treatment and prevention of osteoporosis Prevention and treatment of corticosteroidinduced osteoporosis Paget’s disease of bone	Oral	1 and 2. 400 mg/day for 2 weeks every 3 months 3. 1–9 200 mg tablets/day depending on weight and severity of disease but usually 2 tablets for between 3 and 6 months	1×
Clodronate	Management of osteolytic lesions Hypercalcemia and bone pain associated with skeletal metastases in patients with carcinoma of the breast or multiple myeloma Maintenance of clinically acceptable serum calcium levels in patients with hypercalcemia of malignancy initially treated with an IV infusion of disodium clodronate	Oral and IV	1 and 3. Oral 2 × 520 mg (1040 mg/day) or IV 6 mg every 3–4 weeks 2. 2 or 4 mg IV depending on calcium level	10×
Pamidronate	Treatment of tumor-induced hypercalcemia The prevention of skeletal-related events and bone pain in patients with breast cancer with bone metastases, or symptomatic multiple myeloma Paget’s disease of bone Used “off license” for osteoporosis	IV	15–30 mg up to 90 mg 90 mg every 4 weeks 180 mg course either 30 mg once/week for 6 weeks or 60 mg alternate weeks for 6 weeks 30 mg every 3 months	100×
Alendronate	Treatment of postmenopausal osteoporosis	Oral	70 mg once/week Also available as 10 mg daily	100× to 1000×
Ibandronate	Treatment of osteoporosis in postmenopausal women at increased risk of fracture Prevention of skeletal events in patients with breast cancer and bone metastases Treatment of tumor-induced hypercalcemia	Oral and IV	Oral 150 mg once/month. IV 3 mg every 3 months 6 mg IV every 3–4 weeks 2 or 4 mg depending on severity	1000× to <10,000×
Risedronate	Treatment of postmenopausal osteoporosis Treatment of osteoporosis in men Paget’s	Oral	1 and 2. 35 mg once/week; also available as 5 mg daily 3. 30 mg/day for 2 months	1000× to <10,000×
Zoledronate	Treatment of osteoporosis in postmenopausal women and men Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in postmenopausal women and men Paget’s disease Prevention of skeletal-related events in patients with advanced malignancies involving bone Treatment of tumor-induced hypercalcemia	IV	1 and 2. 5 mg IV once/year 3. 5 mg IV 4. 4. 4 mg IV (given usually every 3–4 weeks) 5. 4 mg IV	>10,000×

Abbreviation: IV, intravenous.

NancollasGHTangRPhippsRJNovel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatiteBone200638561762716046206

 PubMed Web of Science ®Google Scholar

SatoMGrasserWEndoNBisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructureJ Clin Invest1991886209521051661297

 PubMed Web of Science ®Google Scholar

BlackDMCummingsSRKarpfDBRandomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research GroupLancet19963489041153515418950879

 PubMed Web of Science ®Google Scholar

CummingsSRBlackDMThompsonDEFracture Intervention Trial Research GroupEffect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention TrialJAMA199828024207720829875874

 PubMed Web of Science ®Google Scholar

BlackDMSchwartzAVEnsrudKEEffects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trialJAMA2006296242927293817190893

 PubMed Web of Science ®Google Scholar

HarrisSTWattsNBGenantHKEffects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study GroupJAMA1999282141344135210527181

 PubMed Web of Science ®Google Scholar

ReginsterJMinneHWSorensenOHRandomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study GroupOsteoporos Int2000111839110663363

 PubMed Web of Science ®Google Scholar

McClungMRGeusensPMillerPDHip Intervention Program Study GroupEffect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study GroupN Engl J Med2001344533334011172164

 PubMed Web of Science ®Google Scholar

ChesnutICIIISkagAChristiansenCOral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE)Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosisJ Bone Miner Res20041981241124915231010

 PubMed Web of Science ®Google Scholar

BlackDMDelmasPDEastellRHORIZON Pivotal Fracture TrialOnce-yearly zoledronic acid for treatment of postmenopausal osteoporosisN Engl J Med2007356181809182217476007

 PubMed Web of Science ®Google Scholar

LylesKWColon-EmericCSMagazinerJSZoledronic acid and clinical fractures and mortality after hip fractureN Engl J Med2007357181799180917878149

 PubMed Web of Science ®Google Scholar

RosenCJHochbergMCBonnickSLFosamax Actonel Comparison Trial InvestigatorsTreatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind studyJ Bone Miner Res200520114115115619680

 PubMed Web of Science ®Google Scholar

ReidIRLylesKSuGA single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 yearsJ Bone Miner Res20112692261227021638319

 PubMed Web of Science ®Google Scholar