Treatment needs and current options for postmenopausal osteoporosis

ABSTRACT

Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased risk of fractures, affecting up to 50% of postmenopausal women worldwide. Over the past 2 decades there have been consistent developments in the pharmacotherapy of osteoporosis with the availability of potent inhibitors of bone resorption (bisphosphonates, and denosumab) or stimulators of bone formation (PTH analogs) with substantial improvements over calcitonin or estrogen replacement.

Areas covered: In this review we summarize the effects of existing treatment options for postmenopausal osteoporosis along with the unmet clinical needs and we discuss about the potential benefits of new compounds under development.

Expert opinion: Despite the recent progresses, there are still limitations and unmeet needs with all the available drugs, mainly concerning treatment adherence, efficacy on the prevention of nonvertebral fractures and the long-term adverse events of antiresorptive regimens. Moreover, PTH analogs are the only available compounds able to stimulate bone formation, but with a restricted anabolic window of no more than 2 years. Of interest, the more recent advances in bone biology identified new targets for the development of drugs with a more potent and selective activity on either osteoclasts or osteoblasts, thus making possible to uncouple bone formation from bone resorption.

KEYWORDS:

• Osteoporosis
• bisphosphonates
• denosumab
• cathepsin K
• teriparatide
• SERMS
• sclerostin
• odanacatib
• romosozumab
• abaloparatide

Article highlights

• Treatment of postmenopausal osteoporosis has advanced significantly beyond hormone replacement therapy and calcitonin (the only available options until 1980s), thanks to the availability of potent antiresorptive agents such as aminobisphosphonates or denosumab and the discovery of the osteoanabolic effects of PTH analogs like teriparatide.

• Because of the biological coupling between osteoclast and osteoblast activities, all the available antiresorptive agents also retain a suppressive effect on bone formation, while PTH analogs concomitantly increase bone resorption, with a restriction of use of no more than 2 years. Thus, the effects of these drugs on the prevention of fractures and particularly nonvertebral fractures remain somewhat limited and there are concerns about the long-term safety of antiresorptive compounds, underlining the need of new treatment options.

• Current recommendations suggest to consider a drug holyday of 2-3 years after long term treatment with antiresorptives (i.e. 5-7 years), particularly in women at low risk of fracture. However, major uncertainties remain to establish when treatment should be restarted and what alternative drug should be used. Moreover, there is no evidence concerning the recommended therapeutic approach beyond 10 years in high risk individuals.

• Novel drugs should include compounds selectively inhibiting osteoclasts bone-resorptive activity (without affecting the coupling pathways with osteoblasts and thus maintaining normal bone formation), new anabolic agents with a more specific activity on the osteoblast and hopefully dual acting agents with either antiresorptive and anabolic activity on bone.

• Thanks to the advances in bone biology of the past few years, novel therapeutic targets have been now detected and new promising antiresorptive agents with a lower inhibitory effect on bone formation such as odanacatib or true anabolic compounds such romosozumab are in the final stage of clinical development and could offer remarkable benefits beyond currently available drugs. Importantly, their cost-effectiveness and their long term safety profile are both key elements to be carefully addressed over the next few years.

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Declaration of interests

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.