Recommendation
Question 4: Does starting bisphosphonate therapy interfere with fracture healing?
Finding the evidence
• Cochrane Database with search terms: “osteoporosis and treatment and hip fracture”
• MEDLINE (1996 to August Week 1 2009) and Embase (1980 to 2009 Week 33) search strategy:
1 exp Bone Density Conservation Agents/tu [Therapeutic Use]
2 exp Hip Fractures/
3 1 and 2
4 limit 3 to (English language and humans)
• A review of reference lists of relevant articles for addi- tional published trials
Quality of the evidence
Level I• 8 systematic reviews or meta-analyses
• 18 randomized controlled trials
Findings
The majority of pharmacologic agents available for the treatment of osteoporosis are antiresorptive agents, which include bisphosphonates (oral or intravenous), hormone replacement therapy (HRT), raloxifene, denosumab, and calcitonin. Other available agents are parathyroid hormone (an anabolic agent) and strontium ranelate (a combination antiresorptive and anabolic agent).46 A summary of the effi- cacy of pharmacologic agents on the relative risk reduction of hip fractures is presented in Table 7.4. As the majority of pivotal clinical trials were in postmenopausal women, data in men is limited and will not be reviewed.
A recent review article47 summarized the efficacy results from pivotal clinical trials of four commonly prescribed bisphosphonates—alendronate, risedronate, ibandronate and zoledronic acid—for the treatment of postmenopausal osteoporosis. A total of 11 randomized placebo-controlled trials were identified (3 for alendronate,48–50 4 for risedro- nate,51–54 2 for ibandronate,55,56 and 2 for zoledronic acid57,58).
Compared with placebo controls, alendronate, risedronate, and zoledronic acid but not ibandronate (no available hip data) were found to reduce the relative risk of hip fractures in postmenopausal women with low BMD and/or prior vertebral fracture by 30% to 51%. Similarly, two rand- omized placebo-controlled trials looking at the fracture efficacy of HRT in postmenopausal women with59 and without60 hysterectomy demonstrated that HRT could reduce the relative risk of hip fracture by 39% and 30%
respectively. The clinical trial of denosumab reported a relative risk reduction of hip fracture with denosumab of 40%.61 In contrast, randomized placebo-controlled trials with raloxifene62 and calcitonin63 have failed to demon- strate successful relative risk reductions of hip fracture in postmenopausal women. Two pivotal trials64–71 have exam- ined the effects of hPTH(1–34) and hPTH(1–84) on fracture risk reduction in postmenopausal women. hPTH(1–34) was
shown to reduce the relative risk of nonvertebral frac- tures;71 however, the number of women with hip fractures was too small to estimate the incidence of hip fracture, and thus the specific relative risk reduction at the hip site.
Similarly, the hPTH(1–84) trial72 did not report on the spe- cific relative risk reduction of hip fractures, but the differ- ence in the number of reported nonvertebral fractures was not statistically significant between treated and untreated groups. Finally, four randomized placebo-controlled trials have evaluated the effects of strontium ranelate on fracture risk reduction in postmenopausal women.73–76 Only one of these trials specifically assessed the efficacy of the drug on the relative risk reduction of hip fractures,76 and failed to show a significant relative risk reduction.
C H A P T E R 7 Osteoporosis and Metabolic Disorders
Table 7.4 Efficacy of pharmacologic agents on the relative risk reduction of hip fractures in postmenopausal women
Drug Description of clinical trial % relative risk
reduction for hip fracture Oral bisphosphonates
Alendronate48–50 FIT-1; n = 2027; postmenopausal women with low femoral neck BMD and ≥1 vertebral fracture; alendronate 5 mg/d (then increased to 10 mg/d at 24 months) or placebo; 3 yrs
51%
FIT-2; n = 4432; postmenopausal women with low femoral neck BMD but no vertebral fracture; alendronate 5 mg/d (then increased to 10 mg/d at 24 months) or placebo; 4 yrs
NS
FLEX; n = 1099; postmenopausal women from FIT-1 and FIT-2 trials; alendronate 5 mg/d or alendronate 10 mg/d or placebo; 5 yrs
NR
Risedronate51–54 VERT-NA; n = 2458; postmenopausal women with ≥2 vertebral fractures or 1 vertebral fracture and low lumbar spine BMD; risedronate 2.5 mg/d (discontinued partway through trial) or risedronate 5 mg/d or placebo; 3 yrs
NR
VERT-MN; n = 1226; postmenopausal women with ≥2 vertebral fractures; risedronate 2.5 mg/d (discontinued partway through trial) or risedronate 5 mg/d or placebo; 3 yrs
NR
VERT-MN Extension; n = 265; risedronate 5 mg/d or placebo; 2 yrs NR
HIP; n = 9331; postmenopausal women with osteoporosis at femoral neck and/or with ≥1 nonskeletal risk factor for hip fracture; risedronate 2 mg/d or risedronate 5 mg/d or placebo;
3 yrs
30%
Ibandronate55 BONE; n = 2946; postmenopausal women with 1 to 4 vertebral fractures and osteoporosis in
≥1 vertebra; ibandronate 2.5 mg/d or ibandronate 20 mg every other day for 12 doses every 3 months or placebo; 3 yrs
NR
Intravenous bisphosphonates
Ibandronate56 DIVA; n = 1395; postmenopausal women with osteoporosis; 2 mg ibandronate injections every 2 months plus oral placebo or 3 mg ibandronate injections every 3 months plus oral placebo or 1 of 2 groups receiving oral ibanronate 2.5 mg/day plus placebo injections every 2 or every 3 months; 1 yr
NR
Zoledronic acid57,58
HORIZON—Pivotal Fracture Trial; n = 7765; postmenopausal women with osteoporosis at femoral neck with or without vertebral fracture or osteopenia with radiologic evidence of ≥2 mild vertebral fractures or 1 moderate vertebral fracture; single 5 mg infusion of zoledronic acid every 12 months or placebo; 3 yrs
41%
HORIZON—Recurrent Fracture Trial; n = 2127 men and women ≥50 yrs who had undergone recent surgical repair of a low trauma hip fracture; single 5 mg infusion of zoledronic acid every year; 2 yrs
30%
Other
Raloxifene62 MORE; n = 7705; postmenopausal women with osteoporosis; raloxifene 60 mg/d or raloxifene 120 mg/d or placebo; 3 yrs
NS
Denosumab61 FREEDOM; n = 7868; postmenopausal women with osteoporosis; denosumab 60 mg subcutaneously every 6 months or placebo; 3 years
40%
Calcitonin63 PROOF; n = 1255; postmenopausal women with osteoporosis; calcitonin 100 IU/d or calcitonin 200 IU/d or calcitonin 400 IU/d or placebo; 5 yrs
NS
(Continued)
Table 7.4 (Continued)
Drug Description of clinical trial % relative risk
reduction for hip fracture
HRT59,60 WHI:
(a) n = 16608; postmenopausal women with intact uterus; conjugated equine estrogen 0.625 mg/d + medroxyprogesterone acetate 2.5 mg/d or placebo; 5.6 yrs
33%
(b) n = 10739;postmenopausal women who had undergone hysterectomy; conjugated equine estrogen 0.625 mg/d or placebo; 6.8 yrs
39%
Anabolic agents Teriparatide (parathyroid hormone 1–34)71
Neer et al. ; n = 1637; postmenopausal women with prior vertebral fractures; PTH(1–34) 20 µg/d or PTH(1–34) 40 µg/day of or placebo; 1.8 yrs
NR
Parathyroid hormone (1–84)72
TOP; n = 2679 ; postmenopausal women with low BMD at hip or spine; recombinant human PTH(1–84) 100 µg/d or placebo; 1.5 yrs
NR
Antiresorptive/anabolic agents Strontium
ranelate76
TROPOS; n = 5091; postmenopausal women with osteoporosis; strontium ranelate 2 g/d or placebo; 3 yrs
NS
BMD, bone mineral density; BONE, Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe; DIVA, Dosing Intravenous Administration Trial; FIT, Fracture Intervention Trial; FLEX, Fracture Intervention Trial Long-Term Extension; FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; HIP, Hip Intervention Program Trial; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly; HRT, hormone replacement therapy; IU, international units; MN, multinational; MORE, Multiple Outcomes of Raloxifene Evaluation;
n, total number of participants randomized; NA, North America; NR, (separate hip data) not reported; NS, not statistically significant; PROOF, Prevent Recurrence of Osteoporotic Fractures Study; PTH, parathyroid hormone; TOP, Treatment of Osteoporosis Study; TROPOS, Treatment of Peripheral Osteoporosis Study; VERT, Vertebral Efficacy with Risedronate Therapy; WHI, Women’s Health Initiative.
• A review of reference lists of relevant articles for addi- tional published trials
Quality of the evidence
Level I• 2 randomized controlled trials Level IV
• 1 case series No classification
• 14 trials in animals
Findings
The majority of studies examining the effects of bisphos- phonates on fracture healing have been in animal models.
Very few studies have examined this relationship in humans.
Animal studies Fourteen animal studies have documented the effects of bisphosphonate therapy on fracture healing78–91: 1 in sheep, 3 in dogs, 1 in rabbits and 9 in rats (Table 7.5).
Several studies in both rat and dog models demonstrate
that long-term continuous administration of bisphospho- nates can delay hard callus remodeling.81,82,85,86,89,90 However, the mechanical integrity of the callus is generally not com- promised.85,86,90 In fact, further studies of continuous bisphosphonate administration in rat and sheep models suggest that treatment can improve the bone mineral content of the callus.81,82,87,91 The most promising results, however, have been seen with single-dosing regimens of bisphosphonates. When bisphosphonates such as zoledro- nate are given in a single dose, the delays in hard callus remodeling appear to be reduced89 and improvements are seen in both tissue volume and strength,78,79,88,89 suggesting that bisphosphonates may even assist the healing process.92 Human studies Despite the large number of patients treated annually with bisphosphonates, only two studies have examined the effects of these drugs on fracture healing in human models.93–95 One randomized placebo-controlled prospective trial examined BMD in the fracture callus of 32 postmenopausal women with a distal radial fracture treated with cast immobilization.93 At 2 months postfrac- ture, women treated with clodronate had a 20% increase in
C H A P T E R 7 Osteoporosis and Metabolic Disorders
Table 7.5 Summary of animal studies examining the effects of bisphosphonates on fracture healing
Reference Model Agent and mode of
administration
Effects on fracture healing
Goodship et al. 199482 Sheep Pamidronate; A More prolific callus formation with an associated rise in the rate of BMC as well as improved torsional strength; Callus remodeling was reduced but not arrested
Bauss et al. 200480 Dog Ibandronate; B and A No impairment in BMD, bone structure, bone repair, coupling nor serum parameters for bone formation and turnover after long-term administration
Peter et al. 199690 Dog Alendronate; B and A Treatment before or during fracture healing or both increased fracture callus size and delayed callus remodeling but had no adverse effects on the union, strength or mineralization of bone Lenehan et al. 198584 Dog EHDP; A Dose-dependent and reversible inhibitory effects on fracture healing Matos et al. 200788 Rabbit Zoledronate; A Improved bone formation resulting in larger trabecular bone volume
and little fibrosis volume
McDonald et al. 200889 Rat Zoledronate; A Weekly dosing delayed hard callus remodeling Yang et al. 200791 Rat Pamidronate; B and A Callus ultimate load to failure was decreased (NS) Amanat et al. 200779 Rat Zoledronate; A Greater callus BMD, volume and strength; Delayed drug
administration produced a larger and stronger callus Amanat et al. 200578 Rat Pamidronate; A Greater callus BMC, volume and strength
Koivukangas et al. 200383 Rat Clodronate; B and A Increased size of the fracture callus but fracture healing process not prolonged even with administration of the drug on a long-term basis before fracture
Cao et al. 200281 Rat Alendronate; B and A Suppressed remodeling of the callus leading to higher woven bone content, lower lamellar bone content and persistent visibility of the original fracture line
Li et al. 200185 Rat Incadronate; B and A Long-term continuous treatment delayed fracture healing particularly with high-dose treatment, but without impairing the mechanical integrity of the callus
Li et al. 199986 Rat Incadronate; B and A Pretreatment did not affect fracture healing; Continuous treatment led to a larger callus and delayed bone remodeling especially with high-dose treatment
Madsen et al. 199887 Rat Clodronate; B and A Increased BMC and BMD when drug given before and after fracture, but no adverse effects on fracture healing
A, after fracture; B, before fracture; BMC, bone mineral content; BMD, bone mineral density; NS, not statistically significant.
BMD at the fracture site compared with the placebo group;
however, the difference between groups diminished over time. A double-blind randomized placebo-controlled trial in a comparable population also showed similar effects on BMD postfracture after the administration of alendronate.95 Greater BMD was observed in the treated group compared with the placebo group up to 1 year postfracture. Finally, it is also noteworthy to mention that data from the pivotal clinical trials of bisphosphonates in patients with oste- oporosis (see Question 3) have not indicated that fracture healing is impaired, nor has return of fractures been reported with long-term bisphosphonate therapy.96
Recommendations
On the basis of evidence available from preclinical investi- gations, it is evident that:
• Continuous administration of a bisphosphonate in the presence of a fracture may modestly delay hard callus remodeling, but generally does not compromise the mechan- ical integrity of the fracture callus [overall quality: very low]
• Single-dosing of bisphosphonates in the presence of a fracture can reduce delays in hard callus remodeling and improve bone strength [overall quality: very low]
On the basis of evidence from clinical investigations, it is evident that:
• Administration of a bisphosphonate in the presence of a fracture can improve BMD in the short-term at the site of fracture [overall quality: moderate]
Question 5: What are the side effects