Pathogenesis of Osteoporosis and current pharmacological treatments

By Dr. Maria Benito

 

Pathogenesis

 

Osteoporosis is a systemic multifactorial bone disease characterized by progressive loss of bone mass accompanied by deterioration of bone tissue, bone fragility and susceptibility to fractures, commonly related to aging. A frequently silent disease, does not show symptoms until a broken bone is presented, usually when a hip fractures or a vertebra collapses.

 

According to the World Health Organization (WHO) criteria, ostreoporosis –both, primary and secondary types– is associated with the reduction in bone mineral density (BMD) –bone mass and microarchitecture–, which is influenced by age and gender –more prevalent in women than men at 34% versus 17%, with special incidence in postmenopausal women– and result in a significant increase in disability, morbidity, and fracture risk. Prevalence of osteoporosis is increasing worldwide with a subsequent increasing cost. Currently, the main goal of treatments is focused on increasing BMD and reducting fractures.

 

Bone comprises osteoblasts, osteoclasts, osteocytes, and bone matrix. It is constaqntly being remodeled by the coordinated action of these cells. Bone remodeling is an important process for maintaining blood calcium homeostasis, repairing micro cracks and fractures, and modifying bone structure. The reduction of BMD is caused by an imbalance between bone resorption mediated by osteoclast and bone formation mediated by osteoblast. Thus, depending on the balance between bone resorption and deposition, bone is finally generated or destroyed. On osteoporosis, the balance is leaning towards excessive resorption.

 

Genetic inheritance, endocrine disorders, nutritional and hormonal factors –including parathyroid hormone (PTH), calcitonin, estrogen and vitamin D (1, 25-dihydroxyvitamin D or Calcidiol) activated by PTH, estrogen deficiency, especially in postmenopausal women–, and aging are key elements in osteoporosis. People over 50 –particularly women–, those with a low weight, smokers, excessive alcohol drinkers, people with a history of fractures, and some medical conditions –including rheumatoid arthritis, hyperthyroidism and parathyroid disease– are mostly at risk of developing osteoporosis. The presence of other chronic diseases such as diabetes melitus –bone loss is one of the classical complications of type-1 diabetes mellitus but not type-2–, HIV (AIDS), organ transplant and respiratory diseases conditions, and some treatments –prolonged treatments with corticosteroids, anti-epileptic drugs and breast and prostate cancer drugs– also increases the risk of osteoporosis. The association between osteoporosis and obesity, as well as the implication of oxidative stress –presented as reduction in bone mass, bone formation, osteoblast numbers and dysfunction of osteoblasts– and epigenetic –including DNA methylation, posttranslational histone modification, and miRNA influenced by regulation of gene expression in bone cells– has also been reported.

 

Vitamin D and PTH are effective in bone development and calcium absorption; however, while PTH can also stimulate osteoclasts activity, calcitonin can reversibly blocks the function of osteoclasts. Estrogen has a critical role in osteoporosis as reduces bone remodeling and increases osteoclast apoptosis through the estrogen receptors α (ERα) and β (ERβ). PTH, PTH-related protein (PTHrP), cytokines, and prostaglandins increase osteoclastogenesis up-regulating RANKL –receptor activator of nuclear factor kB (NF-kB)–, and down-regulating osteoprotegerin (OPG). Local and systemic growth factors deficiencies –such as Insulin-like growth factor 1 (IGF-1) and tumour growth factor b (TGF- β)– and leptin deficiency or resistance associated with age-related reduction in the capacity of osteoblasts to replicate and differentiate, and impaire bone formation.

 

Autophagy –an essential cell survival pathway when osteoblasts are incorporated into the bone matrix and become osteocytes– plays an important role in the maintenance of bone homeostasis. Studies suggest that dysregulation of this process may also be associated with bone loss and subsequent osteoporosis. Studies in postmenopausal women have shown that increased oxidative stress in bone tissue is one of the major contributing factors to bone loss caused by aging. The mechanism by which autophagy reduces the bone loss caused by aging seems to be related to the antioxidant effect of autophagy on bone cells, although there is still a limited evidence of the relationship between autophagic dysfunction and osteoporosis in humans.

 

Osteoporosis Therapies.

 

Antiresorptive –which reducts bone resorption through the inhibition of osteoclasts activity– and anabolic agents –that induce new bone formation through stimulating the function of osteoblasts– are the two main groups of pharmacological agents used in osteoporosis.

 

Biphosphonates (BPs) –including alendronate (Fosamax®), risendronate (Actonel®), ibandronate (Boniva®), zoledronic acid (Reclast®), clodronate (Bonefos®, Clasteon®), minodronate (Onobis®), pamidronate (Aredia®), etidronate (Didronel®), and tiludronate (Skelid®)– are the first-line therapy for osteoporosis. They act through inactivation of osteoclastic bone resorption and acceleration of apoptosis of osteoclasts, can increase BMD and decrease fracture risk, and have a different affinity to bone.

 

Denosumab (Prolia®) –a human monoclonal RANKL antibody that results in osteoclast inactivation, apoptosis, and decreased differentiation of osteoclasts– also reduces bone resorption. It can be used as a first-line choice for certain patients who are intolerant to BPs or have renal failure, and it has shown efficacy among osteoporotic women and older men under androgen-deprivation therapy for prostate cancer.

 

Estrogen replacement therapy (ERT) or estrogen-progestin (hormone) replacement therapy (HRT) alone –reduce bone resorption– is effective for prevention of osteoporosis in postmenopausal women. Tibolone (Boltin®, Tibocina® or Xyvion®) is an estrogen-progestin combination used for prevention of osteoporosis in post-menopausal women. However, HRT and ERT can increase the risk of venous thromboembolic disorders, breast and endometrial cancer, andstroke. HRT or ERT are not recommended as the first-line preventive treatment of osteoporosis.

 

Selective estrogen receptor modulators (SERMs) –raloxifene (Evsita®), tamoxifene (Soltamox®), lasofoxifene (Fablyn®), and bazedoxifene (Viviant®, Conbriza®)– display similar effects of estrogen on bone enhancing bone turnover or increasing bone density without adverse effects on breast and endometrium, but stopping treatment may accelerate BMD loss. They are not used as a first-line treatment.

 

Calcitonin (Fortical®, Miacalcin®, Calcimar®) is considered as a second-line therapy when first-line drugs have failed or patients are intolerant to first-line treatments. Calcitonin inhibits bone resorption through increasing osteoblast activity, with beneficial effects in both sexes. It is recommended as a second-line treatment for women 5 years after menopause. It is used to relief acute pain secondary to osteoporotic fracture, but not for chronic pain.

 

PTH peptides –Teriparatide (recombinant human parathyroid 1-34) (Forteo®)– and abaloparatide (BA058®) –a synthetic peptide analog of PTHrP– have anabolic effects on bone by promoting bone formation increasing BMD and reducing fracture risk. They are not recommended as first-line drug mainly for the elevated cost.

 

Studies have shown than combinations of agents with different mechanism of action –possibly with the exception of the combination of anti-inflammatory agents such as anti-tumor necrosis factor (anti-TNF) with anti-sclerostin antibodies tried in animal models– do not add additional advantage, and can on the contrary, reduce the potential benefits of the individual drugs.

 

In men, the most common cause of osteoporosis is hypogonadism, and testosterone replacement therapy can increase BMD in spine. Alendronate or risendronate are the first line therapy BPs recommended for osteoporosis in men. Other options for men include zoledronic acid, denosumab, and PTH therapy.

 

New potential treatments –such as cathepsin k inhibitor and strontium ranelate–, are generally restricted to patients who are at high risk of fracture or failed to respond to first line treatments options due to their high cost. Growth hormones and the role of genes are also being studied.

 

Cathepsin k –a cysteine protease expressed by osteoclasts–, can degrade matrix proteins and type I collagen that results in bone resorption. Cathepsin k inhibitors –odanacatib balicatib, ONO-5334– can reduce bone resorption and/or bone formation, although the beneficial effects are reversible after stopping treatment.

 

Strontium ranelate (Protelos®) is an antiresorptive agent recommended for treatment of severe osteoporosis in postmenopausal women and men at high risk of fractures who cannot tolerate other pharmacological agents. The mechanism of action is based in the inhibition of osteoclasts and promotion of the activity of osteoblasts through calcium sensing receptor (CaSR) by strontium, which results in a slight increase of BMD and decrease of fracture risk.

 

Sclerostin –a glycoprotein specifically expressed in osteocytes– is a potent inhibitor of bone formation and a key negative regulator of bone metabolism, which may have a catabolic action through promoting osteoclast formation and activity by osteocytes. Anti-sclerostin monoclonal antibodies include romosozumb, blosozumab, and BPS804.

 

Additional therapies for postmenopausal osteoporotic women include vitamin K, folic acid, vitamin B12 supplementations, androgens, and fluoride. RGD –sequence and human ß3 integrin–, osteoprotegerin (OPG) –known as osteoclastogenesis inhibitory factor (OCIF) –, bone morphogenetic proteins (BMPs) –a group of growth factors known as cytokines and as metabologens–, and PTH have been reported as the most promising molecules for osteoporosis treatment, but not many new molecules have been studied as possible targets. Matrix metalloproteinases (MMPs), selective androgen receptor modulators (SARMs), cell adhesion molecules (CAMs), L-carnitine and insulin like growth factor-1 (IGF-1) are potential new drugs.

 

More studies to signalling pathways involved in bone loss, and new drug –to treat osteoporosis and to enhance safety– are still necessary to improve outcomes for patients with this disease. Early diagnose and personalized medicine should be considered for future evaluation of genetic risk score and also for environmental exposure assessment. It has also been pointed out the need for more well-designed clinical trials.

 

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