Pharmacological treatment of osteoporosis in the oldest old

Figures & data

Table 1 Relative risk (95% CI) of new vertebral, hip, and nonvertebral fractures compared with placebo in postmenopausal and very elderly women receiving the currently available osteoporosis treatments

	RCT	Included participants	n	Mean age (years)	Vertebral fractures	Hip fractures	Nonvertebral fractures
Alendronate
Postmenopausal women aged <80 years	FIT Vertebral Fracture Arm (3 years)^Citation43	Women aged 55–81 years with at least one vertebral fracture	2,027	70.8	RR =0.45; 95% CI =0.27–0.72; P<0.001	RR =0.49; 95% CI =0.23–0.99; P=0.047	RR =0.80; 95% CI =0.63–1.01; P=0.063
	FIT Clinical Fracture Arm (4 years)^Citation44	Women aged 54–81 years with T-score ≤−1.6 at FN, but without vertebral fractures	4,272	67.7	RR =0.56; 95% CI =0.39–0.80; P=0.002	RR =0.79; 95% CI =0.43–1.44; P=0.44	RR =0.88; 95% CI =0.74–1.04; P=0.13
	FIT Vertebral and Clinical Fracture Arm with low BMD (3–4 years)^Citation45	Women aged 55–80 years with at least one vertebral fracture or T-score ≤−2.5 at FN without vertebral fractures	3,658	69.9	RR =0.52; 95% CI =0.42–0.66; P<0.001	RR =0.47; 95% CI =0.26–0.79; P=0.005	RR =0.73; 95% CI =0.61–0.87; P<0.001
Very elderly women	Post hoc analysis FIT vertebral fracture arm (3 years)^Citation46	Women aged 75–82 years	539	Not specified	RR =0.62; 95% CI =0.41–0.94; P<0.05 Pinteract <75 and ≥75 years = NS	–	–
	Pooled analysis FIT vertebral and clinical fracture arm with low BMD (3–4 years)^Citation47	Women aged 55–80 years  55–<65 years  65–<70 years  70–<75 years  75–85 years	3,658		RR =0.55; 95% CI =0.37–0.83 (constant RR)	RR =0.47; 95% CI =0.27–0.81 (constant RR)	–
	Axelsson et al^Citation48 (5 years)	Women aged 71.1–92.3 years with a prior fracture	110.190	82.4	–	HR =0.72; 95% CI =0.61–0.85; P<0.001	–
Risedronate
Postmenopausal women aged <80 years	VERT-NA (3 years)^Citation49	Women aged <85 years with at least one vertebral fracture	2,458	68.7	RR =0.59; 95% CI =0.43–0.82; P=0.003	–	RR =0.60; 95% CI =0.39–0.94; P=0.02
	VERT-MN (3 years)^Citation50	Women aged <85 years with at least two vertebral fractures	1,226	71	RR =0.51; 95% CI =0.36–0.73; P<0.001	–	RR =0.67; 95% CI =0.44–1.04; P=0.063 (not powered)
	HIP – arm 1 (3 years)^Citation51	Women aged 70–79 years with T-score <−4 at FN or with T-score <−3 plus a nonskeletal risk factor for hip fracture	5,445	74	–	RR =0.6; 95% CI =0.4–0.9; P=0.009	RR =0.8; 95% CI =0.7–1.0; P=0.03
Very elderly women	HIP – arm 2 (3 years)^Citation51	Women aged ≥80 years with at least one nonskeletal risk factor for hip fracture or T-score at FN <−4 or <−3+ hip axis length of ≥11.1 cm	3,886	83	–	RR =0.8; 95% CI =0.6–1.2; P=0.35	10.8% (risedronate) versus 11.9% (placebo); P=0.43
	Post hoc pooled analysis VERT-NA, VERT-MN, and HIP (3 years)^Citation52	Women aged ≥80 years with T-score <−2.5 at FN or at least one prevalent vertebral fracture	1,392	83	HR =0.56; 95% CI =0.39–0.81; P=0.003; Pinteract <80 and ≥85 years = NS	–	14.0% (risedronate) versus 16.2% (placebo); P=0.66
Zoledronic acid
Postmenopausal women aged <80 years	HORIZON-PFT (3 years)^Citation57	Women aged 65–89 years with T-score ≤−2.5 at FN or T-score ≤−1.5 plus at least two mild or one moderate vertebral fracture	7,765	73	RR =0.30; 95% CI =0.24–0.38; P<0.001	RR =0.59; 95% CI =0.42–0.83; P=0.002	RR =0.75; 95% CI =0.64–0.87; P<0.001
	HORIZON-RFT (1.9 years)^Citation58	Women aged ≥50 years with hip fracture	2,127	74.4	RR =0.54; 95% CI =0.32–0.92; P=0.02	RR =0.70; 95% CI =0.41–1.19; P=0.18	RR =0.73; 95% CI =0.55–0.98; P=0.03
Very elderly women	Post hoc analysis HORIZON-PFT and RFT (3 years)^Citation56	Women aged ≥75 years with T-score ≤−2.5 at FN or ≥1 vertebral or hip fracture	3,888	79.4	HR =0.34; 95% CI =0.21–0.55; P<0.001; Pinteract <75 and ≥75 years = NS	HR =0.82; 95% CI =0.56–1.2; P=0.297; Pinteract <70 and ≥75 years = SS	HR =0.73; 95% CI =0.60–0.90;P=0.002;Pinteract <70 and ≥75 years = NS
Denosumab
Postmenopausal women aged <80 years	FREEDOM (3 years)^Citation59	Women aged 60–90 years with T-score <−2.5, but not <−4 at LS or total hip	7,808	72.3	RR =0.32; 95% CI =0.26–0.41; P<0.001	RR =0.60; 95% CI =0.37–0.97; P=0.04	RR =0.80; 95% CI =0.67–0.95; P=0.01
Very elderly women	Post hoc analysis FREEDOM (3 years)^Citation60	Women aged ≥75 years	2,471	78.2	–	0.9% (denosumab) versus 2.3% (placebo); P<0.01; ARR =1.4%; Pinteract <75 and ≥75 years = NS	–
	Preplanned analysis FREEDOM (3 years)^Citation61	Women aged ≥75 years	2,471	78.2	RR =0.36; 95% CI =0.25–0.53; Pinteract <75 and ≥75 years = NS	–	RR =0.84; 95% CI =0.63–1.12; Pinteract <75 and ≥75 years = NS
Strontium ranelate
Postmenopausal women aged <80 years	SOTI (3 years)^Citation63	Women aged ≥50 years with low BMD and at least one vertebral fracture	1,442 (ITT)	69.3	RR =0.59; 95% CI 0.48–0.73; P<0.001		RR = 0.90; 95% CI 0.69–1.17 (not powered)
	TROPOS (3 years)^Citation64	Women aged ≥74 years with T-score <−2.5 Women aged 70–74 years with one additional fracture risk factor	4,932 (ITT)	76.7	RR =0.61; 95% CI =0.51–0.73; P<0.001	RR =0.85 (NS); (not powered)	RR =0.84; 95% CI =0.702–0.995; P=0.04
		Post hoc subgroup: women aged ≥74 years and FN T-score ≤−3	1,997	79.5		RR =0.64; 95% CI =0.412–0.997; P=0.046
Very elderly women	Preplanned pooled analysis SOTI and TROPOS (3 years)^Citation65	Women aged 80–100 years	1,488	83.5	RR =0.68; 95% CI =0.50–0.92; P=0.013	RR =0.68; 95% CI =0.42–1.10; P=0.112; (not powered)	RR =0.69; 95% CI =0.52–0.92; P=0.011
	Preplanned pooled analysis SOTI and TROPOS (5 years)^Citation5	Women aged 80–100 years	1,489	83.5	RR =0.69; 95% CI =0.52–0.92	RR =0.76; 95% CI =0.50–1.15; (not powered)	RR =0.73; 95% CI =0.57–0.95
Teriparatide
Postmenopausal women aged <80 years	FPT (21 months)^Citation66	Postmenopausal women with 1 moderate or 2 mild vertebral fractures	1,637	69.5	RR =0.35; 95% CI =0.22–0.55	1 (PTH) versus 4 (placebo); (not powered)	RR =0.47; 95% CI =0.25–0.88
Very elderly women	Prespecified subgroup analysis FPT (19 months)^Citation67	Women aged ≥75 years	244	78.3	RR =0.35; P<0.05; Pinteract <75 and ≥75 years = NS	–	RR =0.75; P=0.661; (not powered); Pinteract <75 and ≥75 years = NS

Note: Results in bold indicate statistical significance.

Abbreviations: ARR, absolute risk reduction; BMD, bone mineral density; CI, confidence interval; FIT, Fracture Intervention Trial; FN, femoral neck; FPT, Fracture Prevention Trial; HIP, Hip Intervention Program; HORIZON-PFT, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly – Pivotal Fracture Trial; HORIZON-RFT, HORIZON-Recurrent Fracture Trial; HR, hazard ratio; ITT, intention to treat; LS, lumbar spine; NS, not significant; PTH, parathyroid hormone; RCT, randomized controlled trial; RR, relative risk; SOTI, Spinal Osteoporosis Therapeutic Intervention; SS, statistically significant; TROPOS, the Treatment of Peripheral Osteoporosis; VERT-MN, Vertebral Efficacy with Risedronate Therapy – Multinational; VERT-NA, VERT – North America.

Table 2 Summary of most relevant adverse events from the currently available osteoporosis treatments in very elderly women

AE	Risedronate^Citation52			Zoledronic acid^Citation56			Denosumab^Citation60			Strontium ranelate 3 years^Citation65–5 years^Citation5				Teriparatide^Citation67
	Placebo	Risedronate	P-value	Placebo	Zoledronic acid	P-value	Placebo	Denosumab	P-value	Reference	Placebo	SR	P-value	Placebo	Teriparatide	P-value
≥1 adverse event	89.7%	90.9%	NS	91.8%	92.6%	0.34	93.0%	93.4%	0.86	Seeman et al^Citation65 Seeman et al^Citation5	89.2% 90%	86.8% 88%	NS NS	91%	83%	NS
Nausea	8.3%	9.4%	NS	5.9%	7.5%	0.05				Seeman et al^Citation65 Seeman et al^Citation5	4.4% 4.8%	6.7% 7.1%	NS NS	9%	8%	NS
Dyspepsia	6.8%	6.8%	NS											5%	4%	NS
Abdominal pain	7.7%	8.2%	NS											13%	6%	NS
Diarrhea				5.6%	6.8%	0.11				Seeman et al^Citation65 Seeman et al^Citation5	5.8% 6.2%	7.3% 8.1%	NS NS	3%	10%	NS
Constipation				9.1%	8.2%	0.46				Seeman et al^Citation65	8.9%	7.9%	NS
Oesophagitis	1.3%	1.7%	NS
Stomach ulcer	1.0%	1.4%	NS
AEs within 3 days				25.7%	41.5%	<0.001
Pyrexia				4.0%	12.1%	<0.001
Myalgia				3.1%	8.6%	<0.001
Influenza-like illness				2.1%	5.2%	<0.001
Bone pain				1.5%	4.3%	<0.001
Chills				0.6%	3.5%	<0.001
Arthralgia				19.7%	20.3%	0.63				Seeman et al^Citation65	6.6%	5.3%	NS	10%	8%	NS
Back pain				21.4%	21.6%	0.94				Seeman et al^Citation65	10.2%	8.2%	NS	25%	15%	SS
Leg cramps														2%	2%	NS
Headache				6.1%	7.7%	0.07				Seeman et al^Citation65 Seeman et al^Citation5	1.6% 1.7%	2.9% 3.3%	NS SS	5%	6%	NS
Dizziness				7.1%	7.2%	>0.99								8%	9%	NS
Hypertension				12.4%	12.8%	0.70				Seeman et al^Citation65	10.2%	12.6%	NS	11%	9%	NS
Cataract				5.7%	6.8%	0.16								10%	2%	SS
Deafness														3%	1%	NS
Pruritus														5%	0%	SS
Weight loss														5%	2%	NS
Increased creatinine >0.5 mg/dL				3.5%	4.7%	0.08
Atrial fibrillation				3.3%	3.5%	0.72
Any serious AE				37.9%	37.5%	0.82	30.2%	30.0%	0.76	Seeman et al^Citation65 Seeman et al^Citation5	29.8% 35%	30.0% 35%	NS NS
Death	7.1%	5.7%	0.276	7.5%	7.0%	0.58	4.1%	3.2%	0.18	Seeman et al^Citation65	12.3%	11.1%	NS
Withdrawals due to AEs	20.3%	20.6%	0.947							Seeman et al^Citation65	23.5%	23.7%	NS
Dermatitis and eczema										Seeman et al^Citation5	5.1%	4.8%	NS
DVT										Seeman et al^Citation5	2.5%	4.5%	SS
Seizures disorders										Seeman et al^Citation5	0%	0.7%	SS

Note: Results in bold indicate statistical significance.

Abbreviations: AE, adverse event; DVT, deep venous thromboembolic events; NS, not significant; SR, strontium ranelate; SS, statistically significant.

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