Osteoporosis - a current view of pharmacological prevention and treatment

Abstract

Postmenopausal osteoporosis is the most common bone disease, associated with low bone mineral density (BMD) and pathological fractures which lead to significant morbidity. It is defined clinically by a BMD of 2.5 standard deviations or more below the young female adult mean (T-score =-2.5). Osteoporosis was a huge global problem both socially and economically - in the UK alone, in 2011 £6 million per day was spent on treatment and social care of the 230,000 osteoporotic fracture patients - and therefore viable preventative and therapeutic approaches are key to managing this problem within the aging population of today. One of the main issues surrounding the potential of osteoporosis management is diagnosing patients at risk before they develop a fracture. We discuss the current and future possibilities for identifying susceptible patients, from fracture risk assessment to shape modeling and in relation to the high heritability of osteoporosis now that a plethora of genes have been associated with low BMD and osteoporotic fracture. This review highlights the current therapeutics in clinical use (including bisphosphonates, anti-RANKL [receptor activator of NF-κB ligand], intermittent low dose parathyroid hormone, and strontium ranelate) and some of those in development (anti-sclerostin antibodies and cathepsin K inhibitors). By highlighting the intimate relationship between the activities of bone forming (osteoblasts) and bone-resorbing (osteoclasts) cells, we include an overview and comparison of the molecular mechanisms exploited in each therapy.

Keywords: BMD; bisphosphonate; denosumab; fracture; raloxifene; strontium; teriparatide.

Figure 1

The cells responsible for bone remodeling, highlighting key signaling pathways that are targets for therapies recommended for the prevention of osteoporotic fracture. Notes: Osteocytes are embedded within mineralized bone and, in response to mechanical loading or microdamage, provide signals to osteoclasts to resorb. Osteoclast differentiation and function is dependent on the RANKL–RANK signaling pathway, which in vivo, is negatively regulated by OPG. Circulating PTH is a physiological regulator of plasma calcium and binds to PTHR on osteoblasts to indirectly stimulate osteoclast activity via upregulation of RANKL and downregulation of OPG expression. Calcitonin binds to the CTR expressed on mature osteoclasts to reversibly inhibit osteoclast function, although the exact physiological relevance for calcitonin is not fully understood. E₂ has a positive effect on bone, through effects on osteoblasts and osteoclasts via ERα. CatK is secreted by resorbing osteoclasts across the convoluted ruffled border membrane and is required to degrade collagen. Osteoclast activity releases factors from the bone, which attract osteoblasts to the site of resorption. Osteoblast differentiation and function is controlled by the Wnt signaling pathway via the LRP5/6 and Frizzled co-receptors, which is regulated by endogenous inhibitors such as sclerostin, expressed by osteocytes and upregulated in response to unloading. Abbreviations: CatK, cathepsin K; CTR, calcitonin receptor; E₂, estrogen; ERα, estrogen receptor; LRP5/6, lipoprotein-related protein 5/6; OPG, osteoprotegerin; PTH, parathyroid hormone; PTHR, PTH receptor; RANK, receptor activator of nuclear factor-κB; RANKL, RANK ligand.

Figure 2

Key milestones in the lifecourse of osteoporosis therapy. Strontium ranelate is not approved by the FDA but all other agents have been approved both by the FDA and EMA. Note: The dates shown represent the year that they were first approved by the FDA (or EMA for strontium ranelate) for use in the treatment of osteoporosis. Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration; IV, intravenous.

Figure 3

Sites of action of different classes of drugs that are either in clinical use (left hand side) or in development (right hand side). Notes: Drugs that inhibit resorption: BPs are internalized and inactivate resorbing osteoclasts, whilst calcitonin binds to a cell-surface receptor to inhibit osteoclast function. Denosumab prevents RANKL interacting with RANK, therefore potentially inhibiting both the differentiation of osteoclasts and the function of mature osteoclasts. Drugs that stimulate formation: Teriparatide, an analog of PTH, binds to the PTHR on osteoblasts and, following a transient increase in osteoclast activity, a coupled increase in osteoblast activity is observed. Anti-sclerostin antibodies prevent sclerostin binding to the LRP5/6 coreceptor, thereby allowing Wnt ligands to activate the canonical signaling pathway in osteoblasts. Drugs that uncouple bone formation from resorption: Raloxifene interacts with intracellular ERα in osteoblasts and, via upregulation of OPG and downregulation of RANKL, inhibits osteoclasts. Raloxifene also has positive effects on osteoblast proliferation. Strontium ranelate (Sr²⁺) substitutes for Ca²⁺ in the bone and interacts with the CaSR on osteoblasts, upregulating OPG expression and downregulating RANKL expression to indirectly inhibit osteoclasts, whilst acting directly on the CaSR on osteoclasts themselves to induce apoptosis. The anabolic effect of strontium ranelate on osteoblasts is also mediated via the CaSR as well as potentially other, unidentified receptors. Cathepsin K inhibitors uncouple resorption from formation since the cross-talk between inactive osteoclasts and osteoblasts is maintained. Abbreviations: BMD, bone mineral density; BP, bisphosphonate; CaSR, calcium-sensing receptor; CatK, cathepsin K; CTR, calcitonin receptor; ERα, estrogen receptor; LRP5/6, lipoprotein-related protein 5/6; OPG, osteoprotegerin; PTH, parathyroid hormone; PTHR, PTH receptor; RANK, receptor activator of nuclear factor-κB; RANKL, RANK ligand; OB, osteoblast; OC, osteoblast.

Figure 4

A summary of the National Institute for Clinical Excellence (NICE) guidelines (available at http://publications.nice.org.uk) for the therapeutic management of primary and secondary osteoporotic fractures in postmenopausal women. Notes: Alendronate is the treatment of choice in each case, but for those intolerant or contraindicated for alendronate, a hierarchy of treatment choices is recommended and patients are assigned to each treatment based on T-score, the magnitude of which depends on age and the number of independent clinical risk factors.