Osteoporosis treatment: recent developments and ongoing challenges

Abstract

Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing.

The underlying pathophysiology and therapeutic approaches for osteoporosis

“…The common side effects associated with strontium ranelate treatment are cardiovascular events, venous thromboembolism, gastro‐intestinal discomfort, headache, seizure, memory loss and is contraindicated in hypertensive patients . Due to these potential adverse effects strontium production has been permanently discontinued …”

Effects of strontium ranelate on ligature‐induced periodontitis in estrogen‐deficient and estrogen‐sufficient rats

“…Currently, bisphosphonates are the most commonly used anti‐resorptive agents for the treatment of osteoporosis; however, the initiation or continuation of bisphosphonate therapies has declined due to the risk of adverse effects including osteonecrosis of the jaw and atypical fractures . Hence, there is an unceasing search for medications that can effectively treat osteopenia/osteoporosis, reducing the fracture risk at all skeletal sites, with minimal contraindications, maximum tolerability, and the best risk‐benefit balance . During the last decade, several reports have investigated strontium ranelate as an antiosteoporosis drug due to its promising physicochemical and pharmacokinetic features .…”

Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice

“…The clinically available therapies for osteoporosis can be classified as either antiresorptive (bisphosphonates, denosu- mab, estrogen, and raloxifene; for a review, see Khosla and Hofbauer (3) ), which target the bone resorbing osteoclasts, or anabolic, which increase bone formation. Currently, the only US Food and Drug Administration (FDA)-approved anabolic therapies are teriparatide (PTH 1-34) and the PTHrP analog, abaloparatide.…”