If you don’t take it – it can’t work: the consequences of not being treated or nonadherence to osteoporosis therapy

Figures & data

Table 1 Summary of patient populations and treatments examined in trials of antiresorptive osteoporosis treatments

Study	Patients	Number of patients	Treatments
			Active	Comparator
Postmenopausal Estrogen/Progestin Interventions (PEPI)^Citation18	Healthy PM women	875	Conjugated equine estrogen (CEE) 0.625 mg/day CEE 0.625 mg/day and medroxyprogesterone acetate (MPA) 10 mg/day (days 1–12) CEE 0.625 mg/day and MPA 2.5 mg/day CEE 0.625 mg/day and micronised progesterone 200 mg/day (days 1–12)	Placebo
Multiple Outcomes of Raloxifene Evaluation (MORE)^Citation9	PM women 31–80 years with lumbar spine or femoral neck BMD T score ≤–2.5 or low BMD and ≥1 moderate vertebral fracture or ≥2 mild vertebral fracture, or ≥2 moderate vertebral fracture regardless of BMD	7705	Raloxifene 60 mg/day Raloxifene 120 mg/day	Placebo
Fracture Intervention Trial (FIT)^Citation10	PM women 55–80 years	6459	Alendronate 5 mg/day (for 2 years) then	Placebo
Clinical fracture arm	Femoral neck BMD ≤0.68 g/cm^2	4438	10 mg/day (for 1 year)
Vertebral fracture arm	≥1 vertebral fracture	2027
Alendronate Phase III osteoporosis studies^Citation63	PM women 45–80 years with lumbar spine BMD T score ≤–2.5	804	Alendronate 5 mg/day Alendronate 10 mg/day Alendronate 20 mg/day (for 2 years then switched to 5 mg/day)	Placebo
Fosamax^® Interventional Trial Study (FOSIT)^Table Footnotea,Citation64	PM women ≤85 years with lumbar spine BMD T score ≤–2	1908	Alendronate 10 mg/day	Placebo
Vertebral Efficacy With Risedronate Therapy-National (VERT-NA) (USA based)^Citation13	PM women <85 years with ≥1 vertebral fracture	2458	Risedronate 2.5 mg* Risedronate 5 mg	Placebo
Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN) (Worldwide)^Citation65	PM women <85 years with ≥2 vertebral fractures	1226	Risedronate 2.5 mg^† Risedronate 5 mg	Placebo
Hip Intervention Program Study^Citation66	PM women 70–79 years with femoral neck BMD T score ≤–4 or femoral neck T score ≤–3 and one risk factor for hip fracture PM women ≥80 years with ≥1 risk factor for hip fracture and a femoral neck BMD T score ≤–4 or femoral neck BMD T score ≤–3 and hip axis length ≥11.1 cm or greater	5445	Risedronate 2.5 mg^‡	Placebo
		3886	Risedronate 5 mg^‡
Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE)^Citation12	PM women with lumbar spine BMD	2946	Ibandronate 2.5 mg/day	Placebo
	T score ≤–2.0 and 1–4 vertebral fractures		Ibandronate 20 mg every other day for 12 doses every 3 months
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial^Citation11	PM women with femoral neck BMD T score ≤–2.5 or T score ≤–1.5 and ≥2 mild vertebral fractures or 1 moderate vertebral fracture	7765	Zoledronic acid 5 mg once yearly	Placebo
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial^Citation59	Men and women with a surgically repaired hip fracture (within previous 90 days)	1065	Zoledronic acid 5 mg once yearly	Placebo
Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)^Citation17	PM women 60–90 years with lumbar spine or total hip BMD T score ≤–2.5	7868	Denosumab 60 mg/3 months	Placebo
Spinal Osteoporosis Therapeutic Intervention (SOTI)^Citation15	PM women ≥50 years with lumbar spine BMD ≤0.840 g/cm^2 and ≥1 vertebral fracture	1649	Strontium ranelate 2 g/day	Placebo
Treatment of Peripheral Osteoporosis (TROPOS)^Table Footnoteb,Citation16	PM women ≥74 years with femoral neck BMD T score ≤–2.5 or 70–74 years and one additional risk factor	5091	Strontium ranelate 2 g/day	Placebo

Notes: All trials were 3-year, randomized, double-blind, placebo-controlled with the exception of:

a 1-year trial;

b 5-year trial;

* This dose was discontinued after 1 year;

† This dose was discontinued after 2 years;

‡ Doses were combined for analysis of efficacy.

Abbreviations: PM, postmenopausal; BMD, bone mineral density.

Table 2 Summary of results from trials of antiresorptive osteoporosis treatments

Study	Treatments	Fracture reduction versus placebo over 3 years (RR [95% CI])			Mean change from baseline over 3 years (percentage)
		Vertebral	Nonvertebral	Hip	Lumbar spine BMD	Femoral neck BMD	Serum CTX	Serum bone ALP
Postmenopausal Estrogen/Progestin Interventions (PEPI)^Citation18	Placebo				–2.8%	N/R	N/R	N/R
	Conjugated equine estrogen (CEE) 0.625 mg/day	N/R	N/R	N/R	All active treatments = 5.1%		N/R	N/R
	CEE 0.625 mg/day and medroxyprogesterone acetate (MPA) 10 mg/day (days 1–12)
	CEE 0.625 mg/day and MPA 2.5 mg/day
	CEE 0.625 mg/day and micronised progesterone 200 mg/day (days 1–12)
Multiple Outcomes of Raloxifene Evaluation (MORE)^Citation9	Placebo				N/R	N/R	Urinary CTX –8.1%	N/R
	Raloxifene 60 mg/day	0.7 (0.5–0.8)	Raloxifene combined group = 0.9 (0.8–1.1)	N/R	Change versus placebo 2.1%, P < 0.001	Change versus placebo 2.65, P < 0.001	Urinary CTX –34.0%, P < 0.001 versus placebo	N/R
	Raloxifene 120 mg/day	0.5 (0.4–0.7)	N/R	N/R	Change from placebo 2.7%, P < 0.001	Change from placebo 2.7%, P < 0.001	Urinary CTX –31.5%, P < 0.001 versus placebo	N/R
Fracture Intervention Trial (FIT)^Citation10	Placebo				N/R	N/R	N/R	N/R
Combined population	Alendronate 5 mg/day (for 2 years) then 10 mg/day (for 1 year)	0.52 (0.42–0.66), P < 0.001	0.73 (0.61–0.87), P < 0.001	0.47 (0.26–0.79), P = 0.005	N/R	N/R	N/R	N/R
Clinical fracture arm^Citation67	Placebo				1.5%	–0.8%	N/R	N/R
	Alendronate 5 mg/day (for 2 years) then 10 mg/day (for 2 years)^a	0.56 (0.39–0.80)	0.88 (0.74–1.04)	0.79 (0.43–1.44)	8.3%, P < 0.001 versus placebo	3.8%, P < 0.001 versus placebo	N/R	N/R
Vertebral fracture arm^Citation68	Placebo						N/R	N/R
	Alendronate 5 mg/day (for 2 years) then 10 mg/day (for 1 year)	0.45 (0.27–0.72)	0.80 (0.63–1.01)	0.49 (0.23–0.99)	Change versus placebo 6.2%, P < 0.001 versus placebo	Change versus placebo 4.1%, P < 0.001 versus placebo	N/R	N/R
Alendronate Phase III Osteoporosis Studies^Citation63	Placebo				∼–0.8%^†	∼–1.2%^†	N/R	N/R
	Alendronate 5 mg/day	Pooled alendronate data = 0.52 (0.28–0.95)	P = NS	N/R	∼5.0, P = NS versus placebo^†	∼1.7, P = NS versus placebo^†	N/R	N/R
	Alendronate 10 mg/day	N/R	N/R	N/R	∼8.2%, P < 0.001 versus placebo^†	∼3.2%, P < 0.001 versus placebo^†	N/R	N/R
	Alendronate 20 mg/day (for 2 years then switched to 5 mg/day)	N/R	N/R	N/R	∼7.8%, P = NS versus placebo^†	∼4.7%, P = NS versus placebo^†	N/R	N/R
Fosamax^® Interventional Trial Study (FOSIT)b,^Citation64	Placebo				0.1%, P = NS versus baseline	–0.2, P = NS versus baseline	Urinary NTX –21%,	–11%
	Alendronate 10 mg/day	N/R	After 1 year 0.53 (0.30–0.90)	N/R	5.0%, P < 0.001 versus baseline 1.1%, P < 0.05 versus baseline	2.3%, P < 0.001 versus baseline –1.2%, P < 0.05 versus baseline	Urinary NTX –74%, P < 0.001 versus placebo N/R	–52%, P < 0.001 versus placebo Median change –7%
Vertebral Efficacy With Risedronate Therapy-National (VERT-NA)^Citation13	Placebo
	Risedronate 5 mg	0.59 (0.43–0.82), P = 0.001	0.60 (0.39–0.94), P = 0.02	N/R	5.4%, P < 0.05 versus baseline	1.6%, P < 0.05 versus baseline	N/R	Median change –33%
Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN)^Citation69	Placebo				N/R	N/R	N/R	N/R
	Risedronate 5 mg	0.51 (0.36–0.73), P < 0.001	P = NS	N/R	Change versus placebo 5.9% (95% CI 4.5–7.3), P < 0.001	Change versus placebo 3.1% (95% CI 1.8–4.5), P < 0.001)	N/R	N/R
Hip Intervention Program Study^Citation66	Placebo				N/R	N/R	N/R	N/R
	Risedronate 5 mg*	N/R	N/R	All women = 0.7 (0.6–0.9), P = 0.02 Women aged 70–79 years = 0.6 (0.4–0.9), P = 0.009 Women aged ≥80 years = no significant reduction	N/R Change versus placebo 3.4%, P < 0.001 N/R	N/R	N/R	N/R
Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE)^Citation12,Citation70	Placebo				1.3%	–0.6%	N/R	N/R
	Ibandronate 2.5 mg/day	0.38 (41–75), P = 0.0001	P = NS	N/R	6.5%	2.8%	Urinary CTX –65.3%, P < 0.001 versus placebo	N/R
	Ibandronate 20 mg every other day for 12 doses every 3 months	0.50 (26–66), P = 0.0006	P = NS	N/R	5.7%	2.4%	Urinary CTX –52.7%, P < 0.001 versus placebo Mean value at 36 months 0.473 ng/mL	N/R Mean value at 36 months 53.43 ng/mL
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial^Citation11	Placebo
	Zoledronic acid 5 mg once yearly	0.30 (0.24–0.38), P < 0.001	0.75 (0.64–0.87), P < 0.001	0.59 (0.42–0.83), P = 0.002	Change versus placebo 6.71% (95% CI 5.69–7.74)	Change versus placebo 5.06% (95% CI 4.76–5.36)	Mean value at 36 months 0.205 ng/mL	Mean value at 36 months 10.61 ng/mL
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial^Citation59	Placebo				N/R	0.7%	N/R	N/R
	Zoledronic acid 5 mg once yearly	0.54 (0.32–0.92), P = 0.02	0.73 (0.55–0.98), P = 0.03	P = NS	N/R	3.6%, P < 0.001 versus placebo	N/R	N/R
Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)^Citation17	Placebo				N/R	N/R	N/R	N/R
	Denosumab 60 mg/3 months	0.32 (0.26–0.41), P < 0.001	0.80 (0.67–0.95), P = 0.01	0.60 (0.37–0.97), P = 0.04	Change versus placebo 9.2%, P < 0.001 versus placebo	N/R	Change versus placebo –72%	N/R
Spinal Osteoporosis Therapeutic Intervention (SOTI)^Citation15	Placebo				N/R	N/R	∼520 pmol/L^‡	∼1.4 ng/mL^‡
	Strontium ranelate 2 g/day	0.59 (0.48–0.73), P < 0.001	P = NS	N/R	Change versus placebo 14.4%, P < 0.001 versus placebo	Change versus placebo 8.3%, P < 0.001 versus placebo	∼290 pmol/L^‡	∼2.35 ng/mL^‡
Treatment of Peripheral Osteoporosis (TROPOS)c^Citation16	Placebo				N/R	N/R	N/R	N/R
	Strontium ranelate 2 g/day	0.61 (0.51–0.73), P < 0.001	0.84 (0.702–0.995), P = 0.04	P = NS	N/R	Change versus placebo 8.2%, P < 0.001 versus placebo	N/R	N/R

Notes: All trials were 3-year, randomized, double-blind, placebo-controlled with the exception of:

a Mean treatment duration was 4.2 years;

b 1-year trial;

c 5-year trial;

* Risedronate 2.5 mg and 5 mg doses were combined for analysis of efficacy;

† Estimated from Figure 1 from Liberman UA, et al. (1995) N Engl J Med. 333:1437–1443;

‡ Estimated from Figure 4 from Meunier PJ, et al (2004). N Engl J Med. 350:459–468.

Abbreviations: CI, confidence interval; N/R, not reported; RR, risk reduction; NS, not significant; BMD, bone mineral density; CTX, serum C-telopeptide of type I collagen; ALP, alkaline phosphatase.

Table 3 Summary of patient populations and treatments examined in trials of anabolic osteoporosis treatments

Study	Patients	Number of patients	Treatments
			Active	Comparative
Fracture Prevention Trial (FPT)^Citation14	PM women with ≥1 moderate or ≥2 mild vertebral fractures	1637	Teriparatide 20 μg Teriparatide 40 μg	Placebo
Treatment of Osteoporosis with Parathyroid Hormone Study (TOPS)^Citation71	PM women 45–54 years with lumbar spine, femoral neck or total hip BMD T score ≤–3.0 or BMD T score = −2.5 and 1–4 vertebral fractures PM women aged ≥55 years with BMD T score ≤–2.5 or BMD T score ≤–2.0 and 1–4 vertebral fractures	2532	PTH (1–84) 100 μg/day	Placebo

Note: All trials were 18-month, randomized, double-blind, placebo-controlled.

Abbreviations: PM, postmenopausal; BMD, bone mineral density; PTH, parathyroid hormone.

Table 4 Summary of results from trials of anabolic osteoporosis treatments

Study	Treatments	Fracture reduction versus placebo over 18 months (RR [95% CI])			Change from baseline over 18 months (percentage)
		Vertebral	Nonvertebral	Hip	Lumbar spine BMD	Femoral neck BMD	Serum CTX	Serum P1NP
Fracture Prevention Trial (FPT)^Citation14	Placebo				1.1%	–0.7%	N/R	N/R
	Teriparatide 20 μg	0.35 (0.22–0.55), P ≤ 0.001	0.47 (0.25–0.88)	N/R	9.7%, P < 0.001 versus placebo	2.8%, P < 0.001 versus placebo	N/R	N/R
	Teriparatide 40 μg	0.31 (0.19–0.50), P ≤ 0.001	0.46 (0.25–0.86)	N/R	13.7%, P < 0.001 versus placebo	5.1%, P < 0.001 versus placebo	N/R	N/R
Treatment of Osteoporosis with Parathyroid Hormone Study (TOPS)^Citation71	Placebo				–0.323%	–0.69	N/R	N/R
	PTH (1–84) 100 μg/day	0.42 (0.24–0.72), P = 0.001	P = NS	N/R	6.53%, P < 0.001 versus placebo	1.78, P < 0.001 versus placebo	Urinary NTX 85%	80%

Note: All trials were 18-month, randomized, double-blind, placebo-controlled.

Abbreviations: CI, confidence interval; N/R, not reported; RR, risk reduction; BMD, bone mineral density.

Figure 1 Changes in lumbar spine BMD: A) during, and after treatment with raloxifene (mean ± SEM [g/cm²]);⁴³ B) during alendronate treatment in the FIT trial and alendronate or placebo treatment in the FLEX trial (mean percent change from baseline);⁴⁴ C) during 3 years of blinded treatment with placebo or risedronate 5 mg daily, followed by 1 year of open label treatment with calcium (and vitamin D, if needed) [mean percent change from baseline];⁴⁶ D) during and after treatment with teriparatide in women who did not use any osteoporosis drugs during the 18 month follow-up period (mean percent change from baseline).⁵¹

Notes: A) *P < 0.05 for within-group analysis (baseline versus. treatment); ^†P < 0.05 for within-group analysis (treatment versus. post-treatment); B) BMD = bone mineral density, FIT = Fracture Intervention Trial, FLEX = Fracture Intervention Trial Long-term Extension. Error bars indicate 95% confidence intervals. Data are shown for the period spanning the beginning of FIT through the completion of FLEX, a total of 10 years; C) *P < 0.05 from baseline based upon a paired t-test; ^#P < 0.05 from placebo; D) EP = end point of the Fracture prevention Trial (end of teriparatide treatment), *P < 0.001.

Figure 2 Changes in femoral neck BMD: A) during and after treatment with raloxifene (mean ± SEM [g/cm²]);⁴³ B) during alendronate treatment in the FIT trial and alendronate or placebo treatment in the FLEX trial (mean percent change from baseline);⁴⁴ C) during 3 years of blinded treatment with placebo or risedronate 5 mg daily, followed by 1 year of open label treatment with calcium (and vitamin D, if needed) [mean percent change from baseline].⁴⁶

Notes: A) *P < 0.05 for within-group analysis (baseline versus treatment); ^†P < 0.05 for within-group analysis (treatment versus post-treatment); B) BMD = bone mineral density, FIT = Fracture Intervention Trial, FLEX = Fracture Intervention Trial Long-term Extension. Error bars indicate 95% confidence intervals. Data are shown for the period spanning the beginning of FIT through the completion of FLEX, a total of 10 years; C) *P < 0.05 from baseline based upon a paired t-test’ ^#P < 0.05 from placebo.

Figure 3 Changes in bone resorption markers: A) serum β-CTX during alendronate treatment in the FIT trial and alendronate or placebo treatment in the FLEX trial (mean);⁴⁴ B) urinary NTX during 3 years of blinded treatment with placebo or risedronate 5 mg daily, followed by 1 year of open label treatment with calcium (and vitamin D, if needed) [median percent change from baseline];⁴⁶ C) serum β-CTX during and after treatment with denosumab (median value, ng/mL).⁴⁹

Notes: A) FIT = Fracture Intervention Trial, FLEX = Fracture Intervention Trial Long-term Extension. Error bars indicate 95% confidence intervals. Data are shown for the period spanning the beginning of FIT through the completion of FLEX, a total of 10 years; B) *P < 0.05 from baseline based upon a Signed Rank t-test, ^#P < 0.05 from placebo; C) Group receiving 30 mg Q3M discontinued denosumab treatment at Month 24 and were retreated with 60 mg Q6M denosumab at Month 36. Groups receiving 210 mg Q6M or alendronate discontinued treatment for the last 24 months. The dashed line at Month 24 indicates the time at which dosing was reallocated.

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