New insights into osteoporosis treatment strategy

Rezumat:

Osteoporoza, o patologie scheletala sistemica, ce afecteaza milioane de oameni din intreaga lume, este cea mai des intalnita patologie osoasa, caracterizata printr-o densitate scazuta a masei osoase (BMD), prin distrugerea micro-arhitecturii osoase si prin cresterea fragilitatii osoase. Interactiunea a numerosi factori precum cei genetici, medicali, antropometrici, farmacologici, cei legati de stilul de viata si nutritie, pot conduce la pierderea de masa osoasa si de a creste riscul de fracturi osteoporotice.

In ultimile doua decenii s-au efectuat numeroase studii asupra tratamentului efectiv al osteoporozei, care necesita nu numai inhibitori ai resorbtiei osoase, dar si stimulatori ai formarii osului, in special la pacientii care deja au suferit un grad ridicat de pierdere a masei osoase. Aceasta lucrare este o trecere in revista a datelor din literatura de specialitate, privind rolul agentilor anabolici pentru reversarea osteoporozei.
Cuvinte-cheie: osteoporoza, densitatea minerala osoasa (BMD), agenti anabolici

Abstract:

Osteoporosis, a systemic skeletal pathology that affects millions of people all around the world is the most common metabolic bone disease, characterized by low bone mass density (BMD),disrupted bone micro architecture and increased bone brittleness. Interaction of numerous factors, such as: genetic, medical, anthropometric, pharmacological, lifestyle and nutrition, lead to loss of bone mass and to increased risk for the osteoporotic fractures.

In the past two decades have been done a lot of studies on osteoporosis effective treatment which requires not only resorption inhibitors, but also stimulators of bone formation especially in patients who already have lost a significant degree of bone. This paper is a review of literature data on anabolic agents for reversing osteoporosis.
Keywords: osteoporosis, bone mass density (BMD), anabolic agents

Introduction

Osteoporosis is a systemic skeletal disease characterized by low bone mineral density (BMD), microarchitectural deterioration of bone tissue, and an increase in fracture risk [1].Several drugs have been developed to treat osteoporosis: most of these are inhibitors of bone resorption. Effective treatment of osteoporosis requires not only resorption inhibitors, but also stimulators of bone formation especially in patients who already have lost a significant degree of bone. Although therapeutic alternatives are available for inhibiting bone resorption, options of bone anabolic agents are much more limited with regard to the bone resorption inhibitors.

Although patients included in randomised controlled trials have osteoporosis defined according to the WHO criteria, i.e. a T score below -2.5 SD and/or prevalent fragility fractures,a large proportion of fractures occurs at T-scores above -2.5 SD and in patients without prior fractures [1]. Therefore, therapies with proven fracture risk reduction efficacy in patients with osteopenia and/or clinical risk factors may contribute to earlier and more effective intervention against fractures.

The past decade has witnessed major advances in the diagnosis and treatment of osteoporosis. It would appear that anabolic drugs challenge prevailing paradigm by stimulating bone formation, therefore enhancing bone turnover. There is a great need to anabolic agents for reverse of osteoporosis. This is a review of the recent literature data anabolic hormones used as anabolic agents to reverse osteoporosis.

Parathyroid hormon (PTH) or Parathormon is released from the parathyroid glands and is an important regulator in the bloodstream’s levels of calcium phosphorus. It stimulates both bone formation and resorption [2,3]. Its intermittent low-dose using increases bone formation more than bone resorption, leading to increased bone mass. Intermittent PTH administration increases the number and activity of osteoblasts, enhances the mean wall thickness and trabecular bone volume, and improves bone microarchitecture by establishing trabecular connectivity and increasing cortical thickness [2,4].

Continuous infusions, which result in a persistent elevation of the serum parathyroid hormone concentration, lead to greater bone resorption than do daily injections, which cause only transient increases in the serum parathyroid hormone concentration [5,6]. The anabolic effects of PTH on bone formation are through the medium of PTH receptor-dependent mechanisms. Teriparatide (PTH 1-34) is the biological active, a recombinant form of PTH [7].

Patients with fractures of postmenopausal osteoporosis administered teriparatide 20 and 40μg/d in FPT (Fracture Prevention Trial) [8]. After 18 months teriparatide 20 μg/d reduces the risk of spine fracture by 65% and non-spine fracture risk by 53%. Over a median of 18 months spine fracture risk reduced by 69% and non-spine fracture risk reduced by 54% with the 40 μg/d regimen [8].

Subbiah et al. reported the second patient to develop osteosarcoma [9]. Although teriparatide reduces osteoporosis related fractures in select patient populations, important contraindications,such as prior radiation exposure, Paget’s disease of bone, unexplained elevations of serum alkaline phosphate, open epiphysis should be considered before use.
It has been suggested teriparatide could be useful for treatment of severe and resistant forms of osteoporosis to other medications [10].

It is belived that the clinical benefits of parathyroid hormone reflect its ability to stimulate bone formation and thereby increase bone mass and strength. This hormone appears to be effective in preventing fractures in postmenopausal women. Hovewer, it should be used attention because of its important contraindications.

It is known that growth hormone (GH) is important in the regulation of longitudinal bone growth [11]. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption.

GH increases bone formation in two ways [12]:
1. via a direct interaction with GHRs on osteoblasts
2. via an induction of endocrine and autocrine/paracrine IGF-I (Insulin like Growth Factor-1).rhGH (recombinant human Growth Hormone) increases bone turnover in normal subjects and improves bone mineral metabolism in postmenopausal females [11]. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures [11, 12]. Possible modulations of the GH/IGF (Insulin like Growth Factor) axis by glucocorticoids and estrogens are also [11].

Bone is the second richest source of IGF-I in the body. Locally this peptide promotes osteoblast differentiation and growth [13]. Recently, studies show that low levels of IGF-I are associated with a greater risk of hip and spine fractures [14]. Hence, there is a strong opinion for considering human GH or IGF-I as potential anabolic agents for the treatment of osteoporosis. There are potential advantages for using rhIGF-I (recombinant human Insulin like Growth Factor-1) compared with rhGH in the treatment of osteoporosis.

These include 1. more direct stimulation of bone formation, 2. bypass of skeletal GH resistance that can be present, and 3. a reduction in GH-induced side-effects such as carpal tunnel and diabetes mellitus [15].

It was reported that low doses of rhIGF-I may directly increase osteoblastic function with only a minimal increase in bone resorption [16]. In 2008, it was suggested a potential role for IGF-1 in the early identification of women at risk for low bone mass and osteoporosis. They suggested measuring the serum level of IGF-1 in women around 40 years old. When its value is 1.5 SD below the peak, BMD measurement by DXA could be considered [17]. There are limited number studies using rhIGF-I than rhGH. Therefore, these advantages have not been validated yet.

Prostaglandins act as locally acting hormones, developed as new therapeutic approach. They show the effect and are metabolized in the tissue where they are synthesized.

Prostaglandins are synthesized from arachidonic acid, a polyunsaturated fatty acid with 20-carbon chain [18]. Prostaglandins are produced from bone cells by mediated cyclooxygenase. Prostaglandin production is regulated by mechanical stress, cytokines, growth factor and systemic hormones.

Furthermore, prostaglandins are able to regulate their own production [19]. Prostaglandins have both inhibitory and stimulatory effects on bone structuring. The most prominent effect of prostaglandin E2 (PGE2) is to stimulate bone resorption and formation [19]. PGE2 exerts its action through the cell surface receptors.

Four subtypes of prostaglandin E receptors (EP1, EP2, EP3 and EP4) [20] have been identified. PGE2 stimulates bone formation by EP4 receptor mediation [20]. The importance and impact of prostaglandins in bone metabolism is summarized in the mechanism of action and place of prostaglandins in bone metabolism [19].

It has been reported in certain studies that prostaglandins have anabolic effect on the bone formation, therefore can be used in osteoporosis treatment [21].

It has been demonstrated that systemic PGE2 administration stimulates proliferation of osteoblast precursors or differentiation of osteoprogenitor cells in bone marrow and 4.7% increase in bone mass eventually was found in the same study [21]. Increase of total bone surface by means of osteoblast stimulation with PGE2 administration to rats has been reported [22].
Misoprostol is a methylene analogue of prostaglandin E1 (PGE1) has been administered to oophorectomized rats.

Misoprostol is being used for treatment of gastric ulcer due to its cytoprotective effect by inhibiting gastric acid and pepcin secretion [18]. Rats receiving misoprostol had significantly reduced oophorectomy related bone loss at site of lumber spine.

Thus, it has been proposed that misoprostol is choice for treatment of post-menopausal osteoporosis prophylaxis [23]. Misoprostol 800 μg/d had been administered for 6 moths to post-menopausal osteoporotic patients. At the end of the treatment increase by 8.1% in femur bone mineral density, by 5% increase in lumber spine bone mineral density and by 3.6% increase in Ward’s triangle bone mineral density have been found. It has been reported that misoprostol can be an alternative on treatment of osteoporosis [24].

The authors think that misoprostol may be an alternative therapy for patients with osteopenia and osteoporosis who are not suitable for hormone replacement therapy.

Another approach is oxytocin (OT) that increases osteoblastic bone formation. It has been reported that OT may regulate maternal skeletal homeostasis during pregnancy and lactation. The fetal skeleton is unlikely to be mineralized effectively in the absence of calcium mobilized from the maternal skeleton [61].

It has been suggested that elevated OT levels during pregnancy and lactation not only enhance bone resorption by increasing the number of osteoclasts to make maternal calcium existing to the fetus, but also prevent unrestricted bone removal by inhibiting the activity of mature osteoclasts. Therefore, it was reported that recombinant OT or its analogs because of its skeletal anabolic action, might have potential utility in therapy for human osteoporosis [25].

Beta-blocker: Wiens et al found that beta-blocker use was associated with a significant decrease in fracture risk [26]. However, in 2008, Reid determinated that there was no any evidence to support the hypothesis that beta‚-blockers reduce fracture numbers [27]. In 2012,Yang et al reported that beta-blockers are associated with reduced risk of fracture in older adults, but the effect size is likely to be modes [28]. In summary, there was no an adequate evidence to support using beta-blockers in the treatment of osteoporosis.

Conclusion

Impaired bone formation which is a principal pathogenetic cause mediating bone fragility in osteoporosis is associated with aging. It is necessary that patients at high risk of fracture should be identified early and treated by a combination of lifestyle changes, correction of secondary causes of osteoporosis, and specific treatments to improve bone density and decrease fracture risk.

Since now, there were a limited number of therapeutic agents for activating bone formation and increasing bone mass and strength.
More effective and better tolerated therapies will become available soon.
The researchers conclusion is that new treatments will be able to contribute to increase the currently low treatment rate of even severe osteoporosis by allowing approaches aimed at minimising fracture risk at the individual patient level.

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