Transient relief of metastatic cancer bone pain by oral administration of etidronate

 The aims of the present study were to determine whether patients with painful bone metastases from primary cancer sites showed a higher level of a bone resorption marker than those with no evidence of skeletal-related events, and to clarify the efficacy of oral administration of etidronate for pain due to bone metastases and bone resorption. Thirty outpatients with cancer were recruited: 10 with pain due to bone metastasis from the primary cancer site; lung (4), prostate (3), and breast (3) (M group), and 20 with primary cancer of the stomach (11), colon (4), breast (3), lung (1), and bladder (1) with no such evidence of skeletal-related events (non-M group). None of the patients in the M group either needed morphine for pain relief or had hypercalcemia, although all of them had been taking nonsteroidal anti-inflammatory drugs (NSAIDs). During the study, they continued taking NSAIDs, as they had before the study. The level of urinary cross-linked N-telopeptides of type I collagen (NTx) at baseline was significantly higher in the M group than in the non-M group (P < 0.01). Oral administration of etidronate (400 mg/day for 2 weeks) to patients in the M group significantly reduced bone pain 2 and 12 weeks after the start of treatment; however, the pain relief effect was diminished 12 weeks after the start of treatment, despite a significant decrease in urinary NTx level (P < 0.05 by one-way analysis of variance [ANOVA] with repeated measurements). The present study provides evidence suggesting that patients with painful bone metastases from primary cancer sites may have a higher level of urinary NTx than those with no evidence of skeletal-related events, and that oral administration of etidronate at the dose we used may have the potential to transiently relieve their bone pain by decreasing abnormally raised bone resorption. Although the present study had a small sample size, and had no placebo controls, the results may be useful, especially as they raise additional questions that could stimulate further research in Japan. Received: September 19, 2001 / Accepted: January 18, 2002     

Efficacy of oral etidronate for skeletal diseases in Japan

Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects.     

Pharmacotherapy of osteoporosis in men

Osteofragility fractures occur in men due to a compromise in bone strength, coupled with either trauma or a fall. In men ≥ 65years of age, osteoporosis can be defined as bone mineral density (at the proximal femur, spine or distal forearm) of 2.5 standard deviations or less below the mean for a normal young adult man, using a male reference database (i.e., T-score value of ≤-2.5) [1,2]. In men 50 – 65years of age, a similar definition is used if other risk factors for a fracture are present. Osteoporosis is increasingly recognised in men [3-11]. One in three men aged > 60years will suffer an osteoporotic fracture [3]. Spinal fractures occur in 5% of men (compared with 16% of women) and hip fractures in 6% of men (compared with 18% of women) > 50years of age [8]. The risk of hip fracture increases by ～ 2.6-fold for each standard deviation decrease in bone density measured at the hip [12,13]. At present, the life expectancy for men has increased to a mean age of 76.8years. With men now living longer, they can be expected to develop multiple coexisting illnesses contributing to bone loss and an increased likelihood of falling and fragility fractures [5,14,15]. It is estimated that 30 – 60% of men presenting with spinal fractures have another illness contributing to their bone disease [4,6-10,16-20]. The ideal therapy for men with osteoporosis should include an intervention which significantly increases bone strength and reduces fracture rates, is safe, easy to administer and economical. This review outlines the c-urrent treatment strategies available for men with osteoporosis.     

Bisphosphonates for osteoporosis prevention and treatment

As potent inhibitors of bone resorption, bisphosphonates (BPs) have been used to treat a variety of disorders of calcium and bone metabolism, including osteoporosis. Paget's disease, and metastatic bone disease. Numerous clinical studies have shown BPs to be useful and cost-effective options for the prevention and treatment of fractures and bone loss associated with postmenopausal osteoporosis, senile osteoporosis in men, and glucocorticoid-induced osteoporosis. With proper self-administration in patients without underlying gastrointestinal (GI) disorders, oral bisphosphonates are usually safe, however, they can cause upper GI irritation. The most common side effects are nausea, diarrhea, gastritis, and esophageal irritation Newer, longer-acting BPs and parenteral administration have lead to options for patients who cannot tolerate oral BPs.     

Effects of Etidronate Disodium on Crystallizations in Synthetic Urine and Calcium Oxalate Crystal Adhesion to Madin-Darby Canine Kidney (MDCK) Cells

Background : Several reports in the 1970s suggested that etidronate disodium might be clinically useful to prevent calcium stones, but the use of etidronate in the urolithiasis field was discontinued due to adverse effects of this drug on skeletal turnover and mineralization. Because the drug might affect not only crystallization, but also crystal-tubular interactions, we investigated the minimum dose of etidronate necessary to effectively prevent stone recurrence without adverse side effects.
Methods : We examined the effect of etidronate on the crystallization of calcium oxalate, calcium phosphate and magnesium ammonium phosphate using synthetic urine and measured by an aggregometer. We also studied its effect on the adhesion of calcium oxalate monohydrate crystals to Madin-Darby canine kidney (MDCK) cells in vitro.
Results : Etidronate affected the crystallization of not only calcium phosphate and calcium oxalate, but also magnesium ammonium phosphate in synthetic urine. The inhibitory activities on these crystallizations were detected at extremely low drug concentrations. Etidronate also had a strong inhibitory activity against the adhesion of calcium oxalate crystals to MDCK cells.
Conclusion : Although further studies are necessary regarding the effects of etidronate on crystallization and crystal adhesion both in vivo and in vitro, and the appropriate schedule of dosing to prevent side effects, it is possible that etidronate may be useful in the treatment of urinary stones.     

Pharmaceutical care and community pharmacists' understanding of bisphosphonate dosing information

OBJECTIVES: To evaluate pharmacists' knowledge of approved dosing information for cyclic etidronate, alendronate and risedronate in the treatment of postmenopausal osteoporosis; and to assess its relationship to demographic and pharmaceutical care factors. DESIGN: Fax-back questionnaire to evaluate pharmacists' knowledge of approved bisphosphonate dosing information and their involvement in pharmaceutical/patient care activities through independent indices. SETTING: Community pharmacies in both urban and rural settings in British Columbia. Participants: Pharmacies surveyed with 22% response rate (163 pharmacists), 47% male and 54% owners/managers. Most were independent (31%) or volunteer chain (28%) pharmacies. MEASUREMENTS AND MAIN RESULTS: Mean bisphosphonate dosing knowledge score was 76 +/- 11% (mean +/- SD). Mean scores (+/-SD) for questions pertaining to alendronate (92 +/- 13%) were higher than risedronate (81 +/- 26%) and etidronate (48 +/- 19). Pharmacists were least familiar with approved dosing instructions regarding the lack of need to remain upright after etidronate dosing, spacing out of etidronate from food/antacids/calcium/vitamins, and whether risedronate may be taken at bedtime. Factors found to affect pharmacists' bisphosphonate knowledge scores included employment in higher volume pharmacies and greater number of years in practice. Pharmacists in the upper tertile of pharmaceutical care index scores had similar bisphosphonate knowledge scores to those delivering less pharmaceutical care. Pharmacist gender, being owner/manager, and continuing education hours were not significantly associated with higher knowledge or pharmaceutical care scores. CONCLUSIONS: There is a wide range of knowledge of bisphosphonate dosing and delivery of pharmaceutical care amongst community pharmacists surveyed. Given the importance of proper bisphosphonate dosing to optimize drug absorption and to minimize toxicity, pharmacist education should be a priority.     

Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum

Background

In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease.

Effects of cyclical etidronate combined with calcitriol versus cyclical etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women

OBJECTIVES—Few data are available on the effects of combination therapy for the treatment of osteoporosis. The aim of this study was to compare the effects of intermittent cyclical etidronate (E) therapy alone with a combination of cyclical etidronate and calcitriol (E+C) on spine and femoral neck bone mineral density (BMD) at one year.
METHODS—Postmenopausal women with at least one non-traumatic vertebral fracture or z score < −1.5 were randomly allocated to an E group (each cycle = oral etidronate 400 mg daily for 14 days followed by calcium 500 mg daily for 76 days) or an E+C group (as for E plus oral calcitriol 0.5 µg daily). Lumbar spine and femoral neck BMDs were measured by dual energy x ray absorptiometry at baseline and at one year. The study design did not contain a placebo group.
RESULTS—The mean % increase in lumbar spine BMD was 5.2% (95%CI= 3.4 to 7.0) in the E+C group (n=24), which was significantly greater than the 2.7% (95%CI= 1.3 to 4.1) increase in the E group (n=23) (p<0.05). The femoral neck BMD in the E+C group increased by 2.0% (95%CI= 0.8 to 3.2), which was significantly different from the E group where there was a −0.4% (95%CI=−2.4 to 1.6) change (p=0.046).
CONCLUSIONS—These data show that a combination of cyclical etidronate and calcitriol is better than cyclical etidronate alone in terms of changes in BMD at both spine and femoral neck sites. Although further data are needed on fracture efficacy, this study suggests that combination therapies have additive therapeutic potential that may exceed that expected from their theoretical mode of action.

Keywords: bone density; calcitriol; etidronate; osteoporosis     

Understanding the Protective Effect of Phytate in Bone Decalcification Related-Diseases

Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals, legumes, and nuts, and it can bind to crystal surfaces and disturb crystal development, acting as crystallization inhibitor. The adsorption of such inhibitors to crystal faces can also inhibit crystal dissolution. The binding of phytate to metal cofactors suggests that it could be used for treatment of osteoporosis. Our in-vitro study showed that phytate inhibits dissolution of hydroxyapatite (HAP). The effect of phytate was similar to that of alendronate and greater than that of etidronate. This led us to perform a cross-sectional study to investigate the impact of consumption of IP6 on bone mineral density (BMD) in post-menopausal women. Our data indicate that BMD and t-score of lumbar spine increased with increasing phytate consumption, and a phytate consumption higher than 307 mg/day was associated with a normal BMD (t-score > −1). These data suggest that phytate may have a protective effect in bone decalcification by adsorbing on the surfaces of HAP, and a daily consumption of phytate-rich foods (at least one serving/day of legumes or nuts) may help to prevent or minimize bone-loss disorders, such as osteoporosis. However, further studies are needed to gain a better understanding about the mechanism of inhibition of phytate in bone-related diseases (see graphical abstract).