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M I N I R E V I E W

Osteoporosis in chronic inflammatory disease: the roleof malnutrition

Tiziana Montalcini Stefano Romeo

Yvelise Ferro Valeria Migliaccio

Carmine Gazzaruso Arturo Pujia

Received: 12 September 2012 / Accepted: 1 October 2012/ Published online: 9 October 2012

Springer Science+Business Media New York 2012

Abstract Osteoporosis is a metabolic bone disorder

affecting million of people worldwide. Increased under-standing of bone disease has led to a greater recognition of

factors affecting bones, and consequently many secondary

causes of osteoporosis were demonstrated. In this study, we

aim to explore possible causes of bone loss and fractures in

subjects affected by chronic inflammatory disease and to

suggest new targets for intervention. In fact several studies,

evaluated to perform this study, suggest that the patients

with chronic inflammatory disease could be at high risk for

fractures due to bone loss as consequence of malnutrition,

caused by inflammation and hormonal change. Conse-

quently, some actions could derive from the considerations

of these mechanisms: a change in actual approach of

chronic patients, that may include the investigation on the

possible presence of osteoporosis, as well as further

research on this topic to find a better therapy to prevent

osteoporosis considering all the mechanisms described.

Keywords Osteoporosis Malnutrition Inflammation

Anorexia Cachexia

Introduction

Osteoporosis is a metabolic bone disorder affecting more

than 200 million people worldwide [1]. This disease is

characterized by low bone mass and microarchitectural

changes, which makes bones susceptible to fractures.

About 50 % of Caucasian women and 20 % of Caucasian

men suffer a fragility fracture [2].

Therefore, the prevention of osteoporosis as well as its

early identification and treatment are of great importance.

It is well known that post-menopausal osteoporosis is

the main form of this disease since estrogen deficiency

causes accelerated bone resorption [3, 4]. However, the

increased understanding of bone metabolism has led to a

greater recognition of the multiple factors affecting bones.

Consequently, in recent years, several secondary causes of

osteoporosis as rheumatoid arthritis (RA), inflammatory

bowel disease (IBD), chronic disease of gastrointestinal

tract, chronic obstructive pulmonary disease (COPD),

cardiovascular disease, and other conditions as cancer,

affecting also youth, were demonstrated [517].

All these disease, unless different in clinical picture,

probably share similar mechanisms leading to osteoporo-

sis. In the present review, we aim to explore why subjects

affected by chronic inflammatory disease are susceptible

to bone loss and fractures, as well as to suggest new

targets for intervention in this form of secondary

osteoporosis.

T. Montalcini (&) S. Romeo Y. Ferro V. Migliaccio

A. Pujia

Department of Medical and Surgical Science, University Magna

Grecia, Catanzaro, Italy

e-mail: [email protected]

S. RomeoSahlgrenska Center for Cardiovascolar and Metabolic Research,

Department of Molecular and Clinical Medicine, University of

Gothenburg, Vasastan, Sweden

C. Gazzaruso

Diabetes, Endocrine-Metabolic Diseases and Cardiovascular

Prevention Unit, Clinical Institute Beato Matteo, Vigevano,

Italy

C. Gazzaruso

Department of Internal Medicine, I.R.C.C.S. Policlinico San

Donato Milanese, Milan, Italy

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Chronic inflammatory disease and osteoporosis:

the possible common traits

Inflammation

It is well known that the increased inflammatory cytokines

are relevant characteristics of inflammatory chronic dis-

ease. The adverse effects on bone tissue could be explainedby the action of specific inflammatory factors, as IL-6, that

showed to increase osteoclast activation, as well as by

impairment of local and/or systemic GH/IGF-1 signaling,

also well described in previously [1822].

Indeed, it was showed that RANKL, as TNF, is released

by infiltrating T cells and synoviocytes in RA, promoting

osteoclast activation and survival through its receptor

RANK [23].

IL-17 has been also proven to be critical in the patho-

genesis of various inflammatory diseases [2427], as well

as in the mechanisms of bone loss. In fact, it was showed

that its increased production induces the release of proos-teoclastogenic cytokines, including TNF-a, IL-6, and

RANKL [28]. However, the balance between inflammatory

and anti-inflammatory cytokines (as IL-12, IL-18, IL-33,

and interferons), is decisive whether inflammation triggers

bone loss or not [29].

Moreover, in this contest the impairment in Wnt sig-

naling, that is a common trait in several inflammatory

disease [30] and bone loss [31], through the expression of

two well-known inhibitors, sclerostin and Dickkopf-1

(DKK1), could not be neglected.

But cytokines above mentioned seem to play also a key

role in the loss of protein and appetite [32]. It was sug-

gested that the increased release of cytokines could activate

POMC pathway in the hypothalamus, through a seroto-

ninergic activation [33] leading to anorexia. Moreover, the

patients with cachexia tend to have elevated inflammatory

markers, specifically IL-6, tumor necrosis factor alpha

(TNF-alpha), IL-1 beta, and interferon-gamma (IFGN-

gamma) [34, 35]. TNF-alpha stimulates the production of

catabolic cytokines and also induces anorexia and protein

loss [6, 8, 36, 37].

Moreover, it was showed that IL-17 can act on muscle

cells, together with proinflammatory cytokines, to amplify

the immune response leading to muscle damage [38], as

well as it was proved that Wnt signaling plays an essential

role in the maintenance of skeletal muscle homeostasis in

the adult, making some factors involved in Wnt pathway

promising candidates for treatment of muscular wasting

diseases, such as sarcopenia [39].

Therefore, the patients with chronic inflammation are

exposed to malnutrition, though all these mechanisms that,

in turn, causes osteoporosis.

Hormonal change

It has been shown that the different inflammatory stimuli,

including IL-1, IL-6, or lipopolysaccharide (LPS), regulate

leptin mRNA expression, as well as circulating leptin

levels [40]. Furthermore, leptin is released by inflamma-

tory-regulatory cells, suggesting that leptin expression

could take part in the inflammatory process through directpara- or autocrine actions [41]. Indeed, circulating leptin

levels result to be increased in experimental models of

acute inflammation [42]. Proinflammatory cytokines, such

as TNF-a and IL-1b, stimulate short-term release of stored

leptin.

The role of leptin on bone tissue could lie on the fact

that adipocytes, like osteoblasts, derive from mesenchymal

stem cells [4346]. In this regard, some experiments have

shown that very high leptin levels led to bone marrow

stromal cells apoptosis, and consequently to the block of

the differentiation into osteoblast cell lineage and to oste-

oporosis [47]. Moreover, long isoform of leptin receptor(Ob-R) is abundantly expressed not only in the hypothal-

amus, but also on osteoblasts, osteoclasts, and chondro-

cytes. Thus, it was suggested that leptin acts with a bimodal

effect, centrally as well as peripherally as a powerful

inhibitor of bone formation. However, studies in the liter-

ature report a positive correlation between leptin and bone

mineral density (BMD) [4850], while others reporting no

relation or negative correlation [5157].

Other effects of leptin are well known, such as the

influence on central nervous system to adjust both food

intake and energy expenditure. It was showed that when

administered in leptin-deficient mice, leptin can increase

the number of synapses on neurons that secrete the

anorexigenic neuropeptide Proopiomelanocortin (POMC)

and decrease the number of synapses on neurons that

secrete the orexigenic neuropeptide Y [58]. Consequently,

leptin may be considered a major factor influencing the

desire to eat and its release, inhibiting feeding for its effect

on the hypothalamus, can induce anorexia [33, 59].

However, it is well accepted that the adiponectin is the

most abundant adipokine circulating in the organism,

having different molecular forms. Unlike metabolic dis-

eases, systemic autoimmune and chronic inflammatory

diseases are characterized by increased production of

adiponectin [60]. High adiponectin levels are associated

with higher rates of bone loss [61, 62]. Adiponectin also

is relevant in the hypothalamic control of energy

homeostasis, thanks to its receptors located in this site

[63]. Thus, also this last hormonal factor, involved in

feeding as leptin, is a common tract influencing both

chronic inflammatory disease and the development of

osteoporosis.

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Malnutrition

Malnutrition is the most common condition in elderly people

with chronic diseases, with a prevalence, in medical patients,

suggested to be 1744 % [6467]. It was showed that

undernourished elderly have an increased mortality, as well

as are at increased risk of impaired immune function,

infections, impaired muscle function, falls, and global dete-riorationof functionalstatus[6873]. Malnutrition causedby

anorexia and cachexia (often defined as anorexia-cachexia

syndrome), dueto inflammation andto the hormonal changes

characterizes also young with chronic disease or cancer, and

could be the main determinant of osteoporosis [6, 8, 36, 37].

In fact,it is well acceptedthe positiveroleof some nutrition

factors not only to the attainment but also to the maintenance

of peak bone mass, as well as the detrimental effects of con-

ditions like anorexia nervosa on the fracture risk [74].

The main nutrients involved are, as known, calcium,

vitamin D, fluoride, magnesium, and other trace elements.

Calcium is fundamental for bone mineralization, confershardness and strength to bones [75].

Calcium homeostasis is regulated by vitamin D and

parathyroid hormone. Vitamin D regulate calcium

absorption from the gut. Consequently, vitamin D defi-

ciency can affect calcium availability and may lead to a

condition with severe alteration of the bone mineralization

namely osteomalacia [76]. Several scientific evidences

demonstrate a high prevalence of hypovitaminosis D and

the role of calcium and vitamin D supplements in reducing

osteoporotic fracture risk [77, 78].

Magnesium is another nutrient that could be relevant for

bone since 5060 % of it is stored in bone. Its deficiency

was suspected to be important for the onset of osteoporosis

[79, 80], but data are yet insufficient on this issue. Fluoride

accumulates in bone leading to a net gain in bone mass, but

may be associated with a tissue of poor quality [80].

However, the involvements of the trace elements in oste-

oporosis have not yet been fully clarified.

In conclusion, we hypothesized that the osteoporosis

should be integrated in the clinical picture of the chronic

inflammatory disease as confirmed by the observation of

patients with high prevalence of chronic disease and

comorbidity [81], in whom malnutrition, sarcopenia, and

cachexia are concomitant conditions and expose them to

the highest incidence of hip fractures [82]. Therefore, in

these condition osteoporosis may be not an independent

disease, but an obvious and expected consequence.

Perspective

The novelty that we would like to propose in this study is

the concept for which patients with chronic inflammatory

disease, independently of age, could be at high risk forfractures due to bone loss as consequence of malnutrition,

caused by inflammation and hormonal change (Fig. 1).

Thus, two actions could derive from these consider-

ations: first, a change in actual diagnostic approach of these

patients that now should include the investigation on pos-

sible presence of osteoporosis, by using Dexa, instrument

also useful for the follow-up of nutritional status. [83]

Second, a call for research aimed to find a better therapy to

prevent osteoporosis in these conditions, which could contrast

bone loss with one or more approach considering the mech-

anisms above described. Of course a classical nutritional

approach could be based on administration of calcium and

vitamin D supplements, but innovative approaches could

provide alternative osteoporosis management strategies

including, for example, the development of agents that

modulate the actions of IL-6 since it seems to increase

osteoclast activity. In addition, a therapy acting on pathways

involving TNF could be of interest [84, 85] since it was

showed that ovariectomy does not induce bone loss in

TNF-/-mice and mice lacking the TNF receptorp55 [86] or

mice treated with the TNF inhibitor and TNF binding protein

[87]. Thereis a new agent, Denosumab, that bind RANKL,the

well-known ligand for RANK, a receptor belonging to the

TNF family, showed to be effective in increasing BMD and

reducing the fractures risk in patients with osteoporosis [84,

85, 88]. Denosumab is a monoclonal antibody, which is able

to inhibit osteoclast activity. The use of TNF-alpha inhibitors

do not seem a good strategy since their neutral effects on

BMD, while in the past it was showed even their negative

effects on BMD in pre-clinical model [89].

Finally, since IL-1 directly promotes osteoclast differ-

entiation [90] it could be also a new target for develop new

pharmacological interventions.

Fig. 1 Mechanisms of bone loss in chronic inflammatory disease

Endocrine (2013) 43:5964 61

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These mechanisms are not completely explored and to

find the best therapy among the nutritional or anti-inflam-

matory ones will offer a more efficacious strategy for

fractures preventions in this kind of secondary osteoporosis.

Conflict of interest All authors state that they have no conflicts of

interest.

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