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Age and Ageing 2005 34(6):633-636; doi:10.1093/ageing/afi160
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© The Author 2005. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Research Letter

Intermittent intramuscular clodronate therapy: a valuable option for older osteoporotic women

SIR—Bisphosphonates are a heterogeneous group of molecules, stable in biological environments, that resemble pyrophosphates compounds used in technical chemistry for calcium binding. All bisphosphonates have high affinity to bone minerals and inhibit bone resorption by reducing osteoclast number and activity; therefore, they are used in disorders associated with excessive osteoclast-mediated bone resorption [1]. Clodronate, one of the bisphosphonate clinically available, has been proved useful in decreasing bone resorption in Paget’s disease, osteolytic bone metastasis and in patients with malignancy-associated hypercalcaemia [2–6].

Several studies have shown that clodronate decreases the number and rate of vertebral and non-vertebral fractures in patients with breast cancer- and myeloma-related osteolysis [6–9] and relieves metastatic bone pain caused by solid tumours with consequent improvement in quality of life [10, 11].

Clodronate, administered by the oral or parental route, has been used effectively in preventing and treating postmenopausal bone loss [12–18] and recently a 3-year multicentre, double-blind, placebo-controlled trial has demonstrated that oral administration of clodronate (800 mg/day) reduces fracture risk in osteoporotic postmenopausal women and in patients with secondary osteoporosis [18]. The 46% reduction of vertebral fracture incidence reported is comparable to that obtained with other anti-resorptive therapies [19–21] and already evident after 1 year of therapy [22]. No data are available concerning the use of clodronate and its effects on pain in older people with osteoporosis.

In Italy, clodronate is available for intramuscular (i.m.) administration, representing a useful alternative for osteoporotic patients who have contraindications or intolerance to bisphosphonate oral preparations, and may be particularly valuable in older patients who already receive several medicaments orally.

Therefore, the aim of the present study was to verify the efficacy of an intermittent i.m. administration of clodronate (100 mg every 1 or 2 weeks) on vertebral and femoral bone mineral density (BMD) and on subjective pain in a sample of older postmenopausal women.


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Two hundred and fifty women (mean age 70.8 ± 6.32 years) fulfilling the WHO criteria for osteoporosis (lumbar spine or hip T-score ≤2.5 SD and/or a prevalent vertebral or femoral fracture) were recruited; 67 patients had one or more vertebral fractures on lateral X-ray of the spine (anterior or medium height <20% of posterior height) and 12 had a history of femoral fracture at baseline evaluation. All patients received oral calcium (1000 mg/day) and vitamin D (880 IU/day). Participants were randomised to three, age-matched groups: (i) Group A received 100 mg i.m. clodronate every week (n = 85; 69.8 ± 4.33 years); (ii) Group B received 100 mg i.m. clodronate every 2 weeks (n = 90; 71.8 ± 5.50 years); (iii) Group C received only calcium and vitamin D (n = 75; 70.7 ± 4.24 years). Patients receiving oncologic treatments, with renal and hepatic disease or taking medications likely to influence skeletal metabolism (i.e. oestrogens, selective oestrogen receptor modulators, progestines, calcitonin, anabolic steroids, other bisphosphonates) were excluded from the study. Systolic and diastolic blood pressures, serum calcium, phosphorus and alkaline phosphatase were in the normal range and similar in the three groups of subjects. All the patients signed an informed consent and the research was conducted according to the principles of the Declaration of Helsinki.

BMD was measured at lumbar spine (L2–L4) and femoral sites (neck, Ward’s triangle and trochanter) at baseline and after 12 months follow-up, using dual energy X-ray absorptiometry (DEXA; DPX-100 Lunar, Madison, WI, USA). Chronic back pain was evaluated by means of a visual analogue scale (VAS) presented to the patients at the beginning and at the end of the trial.

Statistical analysis
Statistical differences were estimated by Student’s t-test for paired observations between two groups (baseline versus treatment) or by ANOVA with subsequent post-hoc test for groups comparisons. Statistical analyses were performed with CRUNCH software. Data are presented as means ± SD; a P value <0.05 was considered statistically significant.


   Results
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The changes in absolute BMD (g/cm2) in the lumbar spine and in femoral sites in the three groups of patients are shown in Table 1. In the groups given i.m. clodronate, a significant increase in BMD was obtained at the lumbar spine and at all femoral sites. No significant differences were detected in patients receiving only calcium and vitamin D (Table 1, Figure 1). There was a significant difference between the BMD increase at the lumbar spine (P = 0.02) and at the femoral neck (P = 0.05) when Groups A and B were compared without differences for BMD at Ward’s triangle (P = NS) and femoral trochanter (P = NS). With the exception of occasional complaint of local postinjection pain, i.m. clodronate was well tolerated and caused no side-effects directly attributable to the drug.


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  		Table 1.. Effects of intramuscular clodronate therapy on BMD (g/cm2)

 


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  		Figure 1.. Percent variations versus baseline in absolute BMD at different skeletal sites. Group A: patients were treated with 100 mg clodronate i.m. every week; Group B: patients were treated with 100 mg clodronate i.m. every 2 weeks; Group C: control patients. * indicates statistically significant difference (P<0.01) versus baseline. # indicates statistically significant differences (P<0.01) versus control.

 

An improvement of subjective back pain, assessed by VAS pain score, was reported by patients treated with clodronate (Group A: from 4.1 ± 4.6 to 2.8 ± 2.7; Group B: from 4.0 ± 3.7 to 2.9 ± 3.7; P < 0.01), while a non-significant reduction in subjective back pain was reported in Group C receiving only calcium and vitamin D (from 4.0 ± 0.4 to 3.7 ± 0.5; P = NS).


   Discussion
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Our results demonstrate that intermittent i.m. administration of clodronate effectively increases BMD at vertebral and femoral sites in older women with osteoporosis, and reduces subjective back pain.

Bisphosphonates reduce bone resorption by inhibiting osteoclastic recruitment and activity, and by shortening osteoclastic lifespan [1]. Clodronate increases macrophage apoptosis and possesses anti-inflammatory properties, not shared with amino-bisphosphonates [23]. Generally bisphosphonates are poorly absorbed from the gastrointestinal tract because they are poorly lipophilic, disappear rapidly from plasma (approximately half taken up by bone and half excreted unmodified by the kidney), and are not metabolised by the liver [1, 24]. Therefore, oral bisphosphonates need to be consumed in strictly fasting conditions, which is not always well received by the patients and may contribute to lessening long-term compliance. On the other hand, a number of osteoporotic patients, in particular older subjects, have contraindications (gastrointestinal disease) or intolerance to oral preparations and some may present adverse gastrointestinal effects [25].

Several double-blind placebo-controlled studies have shown that clodronate significantly decreases the incidence of vertebral and non-vertebral fractures in patients with breast cancer- and myeloma-related osteolysis [6–9]. Bisphosphonates prevent tumour deposits into bone and may reduce pain arising from bone metastasis [10, 11]. The pain-relieving actions of clodronate have been as well reported in arthritis and corticosteroid-induced osteoporosis [26], reflex sympathetic dystrophy syndrome [27] and vertebral fractures [28]. Our observation of a significant reduction in VAS pain score in our patients confirms the analgesic properties of the drug which, especially in older subjects, may help to improve overall functionality and quality of life.

Clodronate has been shown to reduce or prevent oophorectomy- and immobilisation-associated bone loss in experimental animal models [29, 30]. In humans, several open studies have demonstrated beneficial effects of clodronate (doses from 400 mg daily p.o. to 200 mg intravenously every 3 weeks) [12–18, 22]. In short-term studies, women with postmenopausal osteoporosis obtained a significant increase in lumbar and femoral BMD [15, 16] after intermittent therapy (400 mg/day, 1 of every 3 months). Similar results were reported in a double-blind study with intermittent intravenous clodronate (150–600 mg three times with 1 week intervals) or placebo [14]. Rossini et al. [17] showed that parenteral clodronate therapy was well tolerated in a group of postmenopausal women with significant increases in vertebral BMD and prevention of bone loss at femoral sites. Our results suggest a dose-dependent effect of i.m. clodronate since 100 mg every week induced a higher increase in BMD than every 2-week administration. Data are also available, although limited, on the efficacy of clodronate on fracture reduction. Filipponi et al. [12], in an open, controlled study, reported a significant decrease in vertebral fracture frequency over a 6-year exposure to treatment in women with postmenopausal osteoporosis, and McCloskey et al. [18, 22] have recently published the results of a multicentre 3-year study with significant reduction of vertebral fracture incidence in men and women with osteoporosis.

Some caveats to the interpretation of our data may be considered. We did not measure markers of bone remodelling in our study patients. However, previous studies have consistently shown a steady and significant decrease in bone turnover parameters with both oral and i.m. clodronate administration [12–17]. The slightly higher increase in BMD obtained in our study compared to that observed by Rossini et al. [17] may have been the result of differences in calcium/vitamin D supplementation, since all our patients were supplemented while an adjusted diet was used in the previous study. This is a relatively small study and we were not able to obtain data on fracture incidence changes with clodronate therapy, since this endpoint overwhelmed the possibility of the population size studied here; future larger size studies are needed for analyses of i.m. clodronate effects on fracture incidence in older persons.

We conclude that intermittent i.m. clodronate administration is effective in increasing BMD at vertebral and femoral sites, and may reduce pain in older women with osteoporosis. Although these BMD increases may be lower compared to those reported with other bisphosphonates, it emerges as a useful alternative in patients who do not tolerate oral therapy, or in older subjects already taking multiple medications by mouth, and also because of its lower cost. Nevertheless, larger, controlled, long-term prospective studies on the effects of i.m. clodronate on fracture incidence and on osteoporotic pain are needed.


   Key points
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 Subjects and methods
 Results
 Discussion
 Key points
Funding
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 References
 

  • Osteoporosis is one of the major world health concerns especially relevant for older populations.
  • Parenteral administration of bisphosphonates represents a useful alternative for older osteoporotic patients who already receive several medications per os.
  • Intermittent intramuscular clodronate administration increases bone mineral density at vertebral and femoral sites in older women with osteoporosis.
  • There was a reduction in subjective back pain after this therapy.


   Funding
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 Results
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 Key points
 Funding
Conflict of interest
 References
 
There was no external funding for the study.


   Conflict of interest
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 Subjects and methods
 Results
 Discussion
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 Funding
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There were no conflicts of interest.

Ligia J. Dominguez1, Antonio Galioto1, Anna Ferlisi1, Maria Adele Alessi1, Mario Belvedere1, Ernesto Putignano1, Giuseppe Costanza1, Maurizio Bevilacqua2 and Mario Barbagallo1,*

1 Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Viale F. Scaduto 6/c, 90144 Palermo, Italy Fax: (+39) 091 6552952 Email: mabar{at}unipa.it
2 Endocrine and Diabetes Unit, Department of Internal Medicine, L. Sacco Hospital (Vialba)-University of Milan, Via GB Grassi 74, 20157 Milan, Italy

* To whom correspondence should be addressed


   References
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 Funding
 Conflict of interest
 References
 

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