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A recent study by Rodriguez et al. [1] investigated the relationship between bisphosphonate use and cardiovascular (CV) events. In this cohort, over 2000 Danish bisphosphonate users undergoing bone mineral density (BMD) assessment were matched to controls. Oral bisphosphonate use was associated with an approximate 33% reduced risk in CV events. Adjustment for BMD did not alter outcomes. The study design resembles real-world clinical practice.


The relationship between anti-osteoporosis drugs and CV events is relevant. The availability of strontium ranelate was stopped following an apparent increase in CV events from several smaller studies combined [2]. The development of odanacatib (cathepsin K inhibitor) was terminated because of a trend towards CV events [3]. Recently romosozumab showed no increase in CV events when compared to placebo, but development was nearly derailed when an increase in CV events was evidenced in comparison to alendronate-treated patients [4]. The results of the present study strongly suggest that this was because of the favourable effect of alendronate on CV events. The exact mechanism by which bisphosphonates (BPs) influence CV events is unknown

The use of BPs as an anti-resorptive agent was based on chance discovery. Pyrophosphate-containing formulations were used commercially as decalcifying agents. It was only later established that the mode of action of the BPs on bone is by partial inhibition of the mevalonic acid pathway. The fracture intervention trials were landmark studies proving the fracture risk reduction ability of alendronate [5]. BPs still dominate the market for osteoporosis treatment, but the utility has been limited by a small association with osteonecrosis of the jaw as well as atypical femur fractures [6]. This has led to a decrease in the use of these drugs and to the occurrence of many preventable hip fractures.

Several studies have shown that bisphosphonates have an anti-tumour effect through direct and indirect effects [7]. BPs are being used in the prevention and treatment of bony metastases. BPs may also reduce tumour load by interrupting the vicious cycle in the bone microenvironment between tumour cells and osteoclasts.

The continued use of BPs after five years is under review. It is suggested that it only be used if fracture risk remains high, and no other suitable drug is available. CV risk reduction and anti-tumour action should be introduced as benefits in the benefit/risk calculation of the individual. Based on price, efficacy and safety, BPs can prevent many fractures for many more years.

Tobie De Villiers
Stellenbosch University, Cape Town, South Africa


  1. Rodríguez AJ, Ernst MT, Nybo M, et al. Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density. J Clin Endocrinol Metab. 2020;105(10):dgaa481.
  2. Reginster JY. Cardiac concerns associated with strontium ranelate. Expert Opin Drug Saf. 2014;13(9):1209-1213.
  3. McClung MR, O’Donoghue ML, Papapoulos SE, et al. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study. Lancet Diabetes Endocrinol. 2019;7(12):899-911.
  4. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016;375(16):1532-1543.
  5. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082.
  6. Abrahamsen B. Adverse effects of bisphosphonates. Calcif Tissue Int. 2010;86(6):421-435.
  7. Berenson JR. Anti-tumor effects of bisphosphonates: from the laboratory to the clinic. Curr Opin Support Palliat Care. 2011;5(3):233-240.
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