Management of osteoporosis in the aging male: Focus on zoledronic acid

Figures & data

Figure 1 Generic bisphosphonate structure.

Figure 2 Comparison of structures of different bisphosphonates.

Table 1 Relative potency of bisphosphonates³⁷

Drug	Relative potency
Pamidronate (Aredia)	1
Alendronate (Fosamax)	4
Ibandronate (Boniva)	10
Risedronate (Actonel)	20
Zoledronic acid (Zometa, Reclast)	67

Table 2 Studies of bisphosphonates for the treatment of osteoporosis in men

Citation	Drug	Study design	N	Follow-up (mo)	Men	Avg age	Fracture RRR			Δ % increase BMD
							Any	Vert	NV	H	FN	LS
Ryan et al^Citation43	pamidronate	RCT	122	24	9%	65.2						3.5%–5.0%
Brumsen et al^Citation44	pamidronate	RCT	101	36	23%	64.5		67%	67%		NS	5.3%
Boutsen et al^Citation45	pamidronate	RCT	27	12	44%	57				3.2%–4.8%	4.3%	6.3%–6.9%
Ho et al^Citation46	alendronate	PU	123	12	57%	64.2					NS	6.4%–7.0%
Orwoll et al^Citation47	alendronate	RCT	241	24	100%	63		86%	NS	2.6%	2.6%	5.3%
Ringe et al^Citation48	alendronate	RCT	134	36	100%	53		57%	NS		3.5%	8.0%
Ringe et al^Citation50	risedronate	RCT	316	12	100%	56.9		60%	NS	2.3%	1.6%	3.7%
Boonen et al^Citation51	risedronate	RCT	284	24	100%	60.7	NS					4.6%
Reid et al^Citation52	risedronate	RCT	184	12	100%	57.7		82%
Sato et al^Citation53	risedronate	RCT	280	18	100%	76.3			75%
Kanaji et al^Citation56	risedronate	RCT	23	12	100%	63–87		56%
Lamy et al^Citation55	ibandronate	PU	14	24	100%	57				0.9%	1.4%	6.7%
Ringe et al^Citation66	ibandronate	RCT	115	36	46%	64		62%	NS		3.3%	10.7%
HORIZON-RFT^Citation69	zoledronic acid	RCT	2127	36	24%	74.5	35%	46%	27%	6.4%	4.3%
Poole et al^Citation72	zoledronic acid	RCT	27	12	78%	69.8				5.5%	NS
Bolland et al^Citation75	zoledronic acid	RCT	43	24	100%	49.1				4.6%		6.3%
Brown et al^Citation79	zoledronic acid	PU	66	36	100%	42				4.3%		4.8%

Abbreviations: RCT, prospective, randomized controlled trial; PU, prospective, unrandomized trial; vert, vertebral; NV, nonvertebral; NS, not significant; H, total hip; FN, femoral neck; LS, lumbar spine. All comparisons are statistically significant with p< 0.05.

Table 3 Trials in prostate cancer with ADT

Citation	Drug	Study design	N	Duration (mo)	Avg age	Δ% increase BMD
						H	FN	LS
Smith et al^Citation84	pamidronate	RCT	47	48 wk	67	2.0%	NS	3.8%
Greenspan et al^Citation85	alendronate	RCT	112	12	71.4
Ryan et al^Citation86	zoledronic acid	RCT	120	12	72	3.8%	3.6%	6.7%
Smith et al^Citation87	zoledronic acid	RCT	106	12	70.7	3.9%	3.3%	7.8%
Michaelson et al^Citation88	zoledronic acid	RCT	40	12	65.5	2.6%	2.1%	7.1%
Ryan et al^Citation89	zoledronic acid	RCT	42	12	65		4.2%	7.1%

Table 4 Incidence of side effects in zoledronic acid trials reporting safety analyses

	HORIZON-RFT^Citation69		Poole et al^Citation72		Bolland et al^Citation75		Brown et al^Citation79	Ryan et al^Citation86		Smith et al^Citation87		Michaelson et al^Citation88		Ryan et al^Citation89		Composite
	ZA	p	ZA	p	ZA	p	ZA	ZA	p	ZA	p	ZA	p	ZA	p	ZA	p
	n =1054	n = 1057	n = 15	n = 16	n = 21	n = 22	n = 66	n = 61	n = 59	n = 55	n = 51	n = 22	n = 22	n = 22	n = 20	n = 1316	n = 1247
Any ADE	82%	81%
any serious	38%	41%					0%
ADE
death	10%	13%	7%	0%	5%	0%	0%	0%	0%	2%	0%	0%	0%	14%	0%	8%	11%
stop study due to ADE	2%	2%	0%	6%	10%	0%	0%	0%	0%	4%	6%	0%	0%	0%	0%	2%	2%
ARF	6%	6%	7%				0%
CrCl <30	7%	8%
mL/min
myalgias	3%	1%						5%	7%
flu-like	1%	0%					64%
symptoms
headache	2%	1%					<5%
arthralgia	3%	2%						13%	10%	22%	14%
fever	7%	1%	20%	6%				11%	3%					9%	10%
atrial fibrillation	3%	3%
CVA	4%	4%
MI	1%	2%
CV death	3%	5%
bone, joint, or	6%	3%						34%	27%	45%	27%			45%	30%
muscle pains

Abbreviations: ZA, zoledronic acid; p, placebo; ADE, adverse drug effect; ARF, acute renal failure; CrCl, creatinine clearance; CVA, cerebrovascular accident; MI, myocardial infarction; CV, cardiovascular.

DunfordJEThompsonKCoxonFPStructure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonatesJ Pharmacol Exp Ther2001296223524211160603

 PubMed Web of Science ®Google Scholar

RyanPJBlakeGMDavieMHaddawayMGibsonTFogelmanIIntermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safetyOsteoporos Int200011217117610793877

 PubMed Web of Science ®Google Scholar

BrumsenCPapapoulosSELipsPDaily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extensionJ Bone Miner Res20021761057106412054161

 PubMed Web of Science ®Google Scholar

BoutsenYJamartJEsselinckxWDevogelaerJPPrimary prevention of glucocorticoid-induced osteoporosis with intravenous pamidronate and calcium: a prospective controlled 1-year study comparing a single infusion, an infusion given once every 3 months, and calcium aloneJ Bone Miner Res200116110411211149473

 PubMed Web of Science ®Google Scholar

HoYVFraumanAGThomsonWSeemanEEffects of alendronate on bone density in men with primary and secondary osteoporosisOsteoporos Int20001129810110793867

 PubMed Web of Science ®Google Scholar

OrwollEEttingerMWeissSAlendronate for the treatment of osteoporosis in menN Engl J Med200034360461010979796

 PubMed Web of Science ®Google Scholar

RingeJDDorstAFaberHIbachKAlendronate treatment of established primary osteoporosis in men: 2-year results of a prospective, comparative, two-arm studyRheumatol Int20042411011313680141

 PubMed Web of Science ®Google Scholar

RingeJDFaberHFarahmandPDorstAEfficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year studyRheumatol Int20062642743116001181

 PubMed Web of Science ®Google Scholar

BoonenSOrwollESWenderothDStonerKJEusebioRDelmasPDOnce-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter studyJ Bone Miner Res20092471972519049326

 PubMed Web of Science ®Google Scholar

ReidDMAdamiSDevogelaerJ-PChinesAARisedronate increases done density and reduces vertebral fracture risk within one year in men on corticosteroid therapyCalcif Tissue Int20016924224711730260

 PubMed Web of Science ®Google Scholar

SatoYIwamotoJKanokoTSatohKRisedronate sodium therapy for prevention of hip fracture in men 65 years or older after strokeArch Intern Med20051651743174816087822

 PubMed Web of Science ®Google Scholar

KanajiAHigashiMNamisatoMNishioMAndoKYamadaHEffects of risedronate on lumbar bone mineral density, bone resorption, and incidence of vertebral fracture in elderly male patients with leprosyLepr Rev20067714715316895071

 PubMed Web of Science ®Google Scholar

IshikawaSIshikawaAYohKTanakaHFujiwaraMOsteoporosis in male and female leprosy patientsCalcif Tissue Int1999641441479914322

 PubMed Web of Science ®Google Scholar

LamyOSandiniLPacheIFatioSBurnandJBurckhardtPIntravenous ibandronate in men with osteoporosis: an open pilot study over 2 yearsJ Endocrinol Invest200326872873214669826

 PubMed Web of Science ®Google Scholar

LylesKWColón-EmericCSMagazinerJSfor the HORI -ZON Recurrent Fracture TrialZoledronic acid and clinical fractures and mortality after hip fractureN Engl J Med20073571799180917878149

 PubMed Web of Science ®Google Scholar

PooleKELoveridgeNRoseCMWarburtonEAReeveJA single infusion of zoledronate prevents bone loss after strokeStroke2007381519152517395868

 PubMed Web of Science ®Google Scholar

BollandMJGreyABHorneAMAnnual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trialJ Clin Endocrinol Metab2007921283128817227801

 PubMed Web of Science ®Google Scholar

BrownJEEllisSPLesterJEProlonged efficacy of a single dose of the bisphosphonate zoledronic acidClin Cancer Res200713185406541017875770

 PubMed Web of Science ®Google Scholar

SmithMRMcGovernFJZietmanALPamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancerN Engl J Med200134594895511575286

 PubMed Web of Science ®Google Scholar

GreenspanSLNelsonJBTrumpDLSkeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapyJ Clin Oncol2008264426443418802155

 PubMed Web of Science ®Google Scholar

RyanCWHuoDDemersLMBeerTMLacernaLVfor the Zometa US05 InvestigatorsZoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancerJ Urol200617697297816890673

 PubMed Web of Science ®Google Scholar

SmithMREasthamJGleasonDMShashaDTchekmedyianSZinnerNRandomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancerJ Urol20031692008201212771706

 PubMed Web of Science ®Google Scholar

MichaelsonMDKaufmanDSLeeHRandomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist–induced bone loss in men with prostate cancerJ Clin Oncol2007251038104217369566

 PubMed Web of Science ®Google Scholar

RyanCWHuoDBylowKSuppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acidBJU Int2007100707517552955

 PubMed Web of Science ®Google Scholar