Russell, R.G.G.

Abstract Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ∼400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro . Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from “bench to bedside and back again”. Several of the leading BPs achieved “blockbuster” status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.

1. To investigate whether there is a nyctohemeral rhythm in bone turnover, we measured serum bone Gla-protein (osteocalcin, an index of osteoblast activity) concentration every 2 h and urinary deoxypyridinoline (a marker of bone collagen resorption) excretion for 8 h periods in 10 pubertal girls (aged 10–14 years), 15 premenopausal women (aged 20–49 years) and 17 postmenopausal women (aged 50–75 years). 2. The serum concentration of bone Gla-protein and the urinary excretion of deoxypyridinoline were five times higher in the pubertal girls than in the premenopausal women. The urinary excretion of deoxypyridinoline in the postmenopausal women was twice that in the premenopausal women. 3. There was a nyctohemeral pattern in all age groups with mean night-time increases of 28% (P<0.001) in the urinary excretion of deoxypyridinoline and of 5% (P<0.001) in the serum bone Gla-protein concentration. 4. There also were nyctohemeral patterns in the urinary excretion of calcium (P<0.02), sodium (P<0.001) and potassium (P<0.001), with decreases at night. There was a negative correlation between the night-time changes in the urinary excretion of deoxypyridinoline and calcium, especially in adult women (P<0.01). 5. The serum level of parathyroid hormone increased with age, but this effect was only observed at night (01.00 to 07.00 hours). There was a nyctohemeral rhythm of the serum intact parathyroid hormone level at all ages, with a peak in the afternoon and night. 6. Thus, at night, there is a large increase in bone resorption and a small increase in osteoblastic activity, representing a nyctohemeral rhythm of bone turnover. Although the amplitudes of bone formation and bone resorption are greater during growth, the pattern of nyctohemeral changes present during growth continues up to the age of 75 years.