Author: Elena Lerro
Date: 10/07/2007



Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone
microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporotic bones are more at risk of fracture.

Osteoporosis represents a major and increasing public health problem with the aging of population :
the incidence of osteoporotic fractures is higher in whites or Asiatic ethnicity than in blacks , and higher in women than in men .



  • Idiopathic : children and adolescents with normal function of gonads
  • Type I : postmenopausal women with excess loss of cancellous bone and relative sparing of cortical bone .
  • Type II : men and women > 75 years with loss of both cortical and cancellous bone .



Osteoporosis is called "the silent disease" beacuse it's asymptomatic until the onset of
fractures ; its clinical manifestation are due to wrist , hip , humerus and tibia fractures but vertebral ones are
the most important . They cause an intense pain , limitation of motion , deformity with loss of
stature : in the thoracic spine this is associated with a progressive increase in the degree of
kyphosis and in the lumbar spine this is associated with progressive flattening of the lordotic
curve . The course of disease could not have been foreseen .


  • Clinic : loss of stature , local pain ( non specific )
  • Laboratory
    • bone-metabolism markes
    • genetic test
  • Rx : fracture evidence
    • QCT , scintigraphy
  • Ultrasound


    • Race
    • Sex
    • Familial prevalence
    • Cigarette use
    • Low physical activity
    • Excessive proteinic diet ( increase of acids)
    • Heparin-use as anti-coagulant


  • Hormones
    • Parathyroid Hormone = stimulates bone resorption indirectly because the osteoclasts does not have PTH receptos ; it can stimulate and inhibit bone collagen or matrix syntesis .
    • Calcitonin = inhibits bone resorption but is does not modify bone formation .
    • Insulin = causes a marked stimulation of bone matrix syntesis and cartilage formation ; necessary for bone mineralization .
    • Growth Hormone
    • Vitamin D = similar functions to PTH ; direct effects on the osteoblasts enhancing the synthesis of osteocalcin ( bone Gla protein ) .
    • Vitamin K = enhaces the synthesis of osteocalcin ; inhibits trasformation cells in osteoclasts and promotes osteoblasts differentiation .
    • Glucocorticoids = their long-term effect on bone collagen synthesis is inhibitory probably due to a marked decrease is preosteoblastis cell replication .
    • Sex steroids = estrogens decrease bone resorption ; decrease the synthesis of IL-6 which is present in the bone microenvironment and plays a role in the stimulation of bone resorption .
    • Thyroid Hormones = in contrast to their important role on cartilage and linear growth , they stimulate bone resorption .
  • Local Factors
    • Insulin-Like Growth Factors = enhance bone collagen and matrix synthesis ; stimulate the replication of cells of the osteoblast lineage ; they are regulated by PTH , Prostaglandin E2 and inhibit by Glucorticoids .
    • TGF-beta = beta 1 , 2 , 3 stimulate the replication of precursor cell of the osteoblast lineage and it also has a direct stimulatory effect on bone collagen synthesis ; decrease bone resorption .
    • FGF = stimulate bone cell replication capable of synthesizing bone collagen ; they are important in the process of healing and bone repair .
    • PDGF = stimulates bone resorption and bone cell replication .
    • Cytokines = IL-1 , IL-6 , macrophages , TNF , stimulate bone resorption either directly or by enhancing the recruitment of osteoclasts .


Scheme showing possible interactions between estrogen, statins, EFAs, NO, HMG-CoA reductase activity, BMPs, and osteoporosis. - indicates inhibition of activity.

Nitric Oxide as the Mediator of the Antiosteoporotic Actions of Estrogen, Statins, and Essential Fatty Acids 2002

Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. 2009


Papers microRNA ostoporosis

Polymorphisms in predicted miRNA binding sites and osteoporosis. 2010
J Bone Miner Res. 2010 Jul 16.
Lei SF, Papasian CJ, Deng HW.

  • MicroRNAs (miRNAs) regulate posttranscriptional gene expression usually by binding to 3'-untranslated regions (3'-UTRs) of target message RNAs (mRNAs). Hence, genetic polymorphisms on 3'-UTRs of mRNAs may alter the binding of miRNAs to target 3'-UTRs, thereby altering translational regulation of target mRNAs and/or degradation of mRNAs, leading to differential protein expression of target genes. Based on a database that catalogues predicted polymorphisms in miRNA target sites (PolymiRTS), we selected 568 polymorphisms within 3'-UTRs of target mRNAs, and performed association analyses between these selected PolymiRTSs and osteoporosis in 997 Caucasians that were genotyped by Affymetrix Human Mapping 500K arrays. Initial discovery (in the 997 subjects) and replication (in 1,728 Caucasian subjects) association analyses identified three PolymiRTSs (rs6854081, rs1048201, and rs7683093) in the FGF2 (Fibroblast Growth Factor 2) gene that were significantly associated with femoral neck bone mineral density (BMD). These three PolymiRTSs serve as potential binding sites for 9 miRNAs (e.g., miR-146a, miR-146b). Further gene expression analyses demonstrated that the FGF2 gene was differentially expressed between subjects with high vs. low BMD in three independent sample sets. Our initial and replicate association studies and subsequent gene expression analyses support the conclusion that these three polymorphisms of the FGF2 gene may contribute to susceptibility to osteoporosis, most likely through their effects on altered binding affinity for specific miRNAs. © 2010 American Society for Bone and Mineral Research.
  • Estrogens



The inflammatory cytokines of the immune system , specifically IL-1 and IL-6 , can cause calcium to be pulled from bone . When we are under stress , our stress hormone cortisol is secreted . Cortisol release signals the T-helper-2 cells to secrete IL-1 and IL-6 . As well , when cortisol levels go up , our anti-aging and immune regulating hormone DHEA decreases .
Osteoporosis can also be influenced by an overactive immune system . When macrophages eat invaders in the course of their daily surveillance , they release nitric oxide and IL-1 . Nitric oxide in small amounts protects against bone loss.But when the immune system is fighting infection (immune dysfunction) , macrophages release nitric oxide in large amounts , promoting the breackdown of bone . In this case there is an increase of others cytokines :

  • TNF-alfa : enhances bone resorption via stimulating osteoclasts development and activity as well as bone formation .
  • C-reactive protein
  • Fibrinogen

Among the factors released by osteoblast (IL-6,TNF-alfa,..) , M-CSF ( "Macrophage colony stimulating factors" ) has an important role : the CSF binds to its osteoclast receptor C-fms which associates with and activates phosphatidylinositol-3-kinases ( PI-3-KS ), important in osteoclast differentation and attachment . Na/P(i) cotransporters in the osteoclast plasma membrane provide P(i) for ATP synthesis and that the osteoclast may utilize part of the P(i) released from bone resorption for this purpose .

COMMON RISK FACTORS WITH CARDIOVASCULAR DISEASES : Age , Estrogen deficiency , Vit.D , Chronic Inflammation and oxidative stress .


COMMON THERAPY : statins , nitrogen-containg bisphosfonates, Denosumab

Italian Guide lines by SIOMMS

2012-02-21T21:13:54 - Stefania Rossatto


Osteoporosis is a major public health issue. Multiple studies report an association between depression and low bone mineral density, but a causal link between these two is discussed.
Here we resume the endocrine and immune alterations secondary to depression that might have effect on bone conditions. We also discuss the potential effect of antidepressants on bone loss.
We suppose that depression induces bone loss and osteoporotic fractures through specific immune and endocrine mechanisms, with poor lifestyle habits and use of specific antidepressants also potential contributory factors.

Unrecognized link between depression and osteoporosis

It is predicted that 14 million women and men will be affected by osteoporosis in the US with a projected 50% increase in fractures at a cost of 25 billion dollars per year.
Recognized risk factors for osteoporosis include menopause, Caucasian or Asian race, a thin frame, physical inactivity, smoking, alcohol use, inadequate calcium and vitamin D intake, corticosteroid use, and certain medical conditions. We suppose that also depression is a further risk factor for osteoporosis; even though a large body of evidence, this is not listed among the risk factors, but major depressive disorder (MDD) is an important cause of disability worlwide.

Relationship between depression, bone mass, and osteoporotic fractures

Schweiger et al. reported a 15% deficit in spine bone mass measured by computed tomography (CT) in patients with major depression, confirming the relationship with a large number of other reports. (ReviewDepression: a major, unrecognized risk factor for osteoporosis? [Trends Endocrinol Metab. 2001]).

Bone mineral density (BMD) is considered a reliable predictor for fractures, accounting for approximately 70% of the risk, the remaining 30% might depend on factors such as biomechanical bone strength and anatomical properties. Because of the need for a large sample and long follow-up, few studies have examined osteoporotic fracture prevalence in subjects with depression.
(ReviewDiagnosis of osteoporosis and assessment of fracture risk. [Lancet. 2002]).

In the Multiple Outcomes of Raloxifene Evaluation Trial, postmenopausal women with vertebral fractures reported more depressive symptoms than women without vertebral fractures, but it remained unclear whether depression was reactive to fractures or causative. Many other studies reported as a greater risk for hip fracture the highest level of distress, defined as depression associated with life dissatisfaction, nervousness, loneliness, sleep disorders, and uneasy feelings. It was found that middle-aged women with depression had a 40% increase in risk for non-vertebral fractures compared to women without depression. Summarizing, a large body of evidence supports a causal link between MDD and osteoporosis and osteoporotic fractures.
(Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study. [J Rheumatol. 2007])

Possible causative factors of bone mass deficit in subjects with depression

Potential mechanisms of bone loss in depression

Hypercortisolemia is considered an important causative factor of bone deficit in depression. Depression causes a sustained and protracted activation of the stress system, activating the hypothalamic corticotropin-releasing hormone, thereby increasing cortisol. There is growing evidence that glucocorticoids (GC) alter vitamin D receptor (VDR) number.
Furthermore the sympathetic system modulates the production of pro-inflammatory cytokines, including interleukin (IL)-6, a potent bone resorption agent (Leptin causes bone loss in rodents by centrally inhibiting bone formation via activation of the sympathetic system). In a situation of chronic stress such as depression, the processes for reproduction and growth become inhibited, which results in decreased levels of estrogens and growth hormone (GH)/insulin-like growth factor (IGF)-1. Depression is associated with immune dysregulation characterized by increased cytokine activity, specifically that of interleukin-1, interleukin-6, and tumor necrosis factor-α (TNF-α).
The combination of increased cortisol, IL-6, decreased sex steroids and GH lead to reduced bone mass, as the net result of decreased bone formation and increased bone resorption.
(Relation of cortisol levels and bone mineral density among premenopausal women with major depression [Int J Clin Pract. 2007])

Gender effects

Bone mass is generally lower in men with depression compared to non-depressed men, especially at the total femur, men tend to have fractures at higher BMD values than women. Use of antidepressants such as fluoxetine has been associated with low testosterone levels in older men; conversely, testosterone supplementation in men seems to improve some of the symptoms of depression.

Effect of antidepressants on bone mass and osteoporotic fractures: in a large cohort, elderly women on selective serotonin reuptake inhibitors (SSRIs) experienced greater bone loss at the hip, serotonin transporter receptors have been identified on osteoblasts, making a direct effect on bone mass biologically plausible. Use of SSRIs and TCAs might induce fractures by increasing the risk of falls, especially in the elderly, possibly through cardiac arrhythmias or postural hypotension.
(ReviewDepression: a major, unrecognized risk factor for osteoporosis?[Trends Endocrinol Metab. 2001])


MDD is a risk factor for low BMD and fractures. This has been shown in middle-aged women, elderly subjects of both genders, White, African-Americans and Mexican-Americans, and for both vertebral and non-vertebral sites; lifestyle factors and the use of a particular class of anti-depressants appear to play contributory roles.
In this light subjects with depression should be considered for screening for osteoporosis and, vice versa, subjects with decreased BMD should be considered for screening for depression.

2010-09-01T23:01:06 - Gianpiero Pescarmona

Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. 2011


Osteoporosis and ferritin

Osteoporosi e BPCO

Keywords: osteoporosi, bronchite cronica

La Bronco-pneumopatia cronica ostruttiva (BPCO) rappresenta un problema sanitario emergente nel mondo occidentale con morbilità e disabilità in continua progressione al punto che nelle previsioni per il 2020 si stima che possa diventare la terza causa di morte. La BPCO è una malattia complessa con esordio insidioso caratterizzato da tosse produttiva a cui possono associarsi altri sintomi durante la sua progressione. Pazienti in uno stadio di grado moderato o severo hanno spesso una malattia sistemica che interessa vari organi, con insufficienza respiratoria, limitazione nell'attività fisica, scompenso ventricolare destro e ridotta qualità di vita. Se la malattia progredisce, l'osteoporosi può rappresentare un aspetto prevalente nella popolazione di pazienti BPCO, determinando un rischio di frattura elevato.
Alcuni fattori di rischio come il fumo di sigaretta, l'età avanzata, l'inattività, la malnutrizione e il basso Indice di massa corporea (BMI) possono essere implicati primariamente; tuttavia sembrano giocare un ruolo prevalente alcuni aspetti fisiopatologici come la presenza di uno stato infiammatorio cronico con aumento dei livelli di citochine pro-infiammatorie e di enzimi del catabolismo proteico in grado di promuovere il riassorbimento osseo. L'uso di steroidi nella terapia della BPCO rappresenta un altro fattore di rischio aggiuntivo. Tutti questi aspetti rendono necessario aumentare la consapevolezza rispetto all'aumentato rischio di osteoporosi nella BPCO, per garantire una diagnosi precoce di osteoporosi in questa popolazione di pazienti.

Una recente review pubblicata su Current Opinion in Pulmonary Medicine (1) ha esaminato lo stato delle conoscenze e gli aspetti di pratica clinica relativi a Osteoporosi BPCO e incidenza di fratture. L'osteoporosi è caratterizzata da una riduzione di massa ossea con alterazioni microstrutturali che determinano un'aumento della suscettibilità fratturativa dell'osso. Le sedi preferenziali di frattura sono a livello di anca, torace, polso e rachide lombare. La densitometria ossea (DXA) rappresenta il gold standard per la determinazione quantitativa della massa ossea (BMD, i.e. Bone Mineral Density). Le sedi preferenziali di misurazione sono il rachide e il femore; la BMD misurata in queste sedi è maggiormente predittiva di frattura rispetto alle altre. Operativamente l'Organizzazione Mondiale della Sanità definisce l'osteoporosi utilizzando come riferimento un valore di BMD <2,5 DS (Deviazione Standard) rispetto al valore medio normale corretto per l'età di individui dello stesso sesso. Per una riduzione di BMD tra 1 e 2,5 DS si parla di osteopenia e ogni punto di DS sotto la norma corrisponde ad un aumento del rischio di frattura da 1,5 a 3 volte.

Perché i pazienti con BPCO sviluppino osteoporosi non è chiaro. Sono stati chiamati in causa sia il fumo che l'inattività; tuttavia, in questi pazienti l'osteoporosi può non essere diagnosticata per una maggiore attenzione dei medici sulla funzionalità respiratoria, piuttosto che sulla perdita di massa ossea. In ogni caso, l'osteoporosi, causando compressione vertebrale e riduzione di altezza, è responsabile della disabilità con conseguente peggioramento della funzionalità respiratoria. Una delle sue cause più ovvie è la terapia con steroidi per via inalatoria e sistemica. Due revisioni sistematiche del Cochrane Database (2,3) hanno ottenuto rispettivamente nessuno dato o risultati conflittuali relativamente all'aumento del rischio di fratture. Uno studio che ha esaminato la correlazione tra grado di severità della BPCO e osteoporosi ha evidenziano un aumento dell'incidenza di osteopenia e osteoporosi negli stadi di gravità più avanzati (4) così come altri studi hanno documentato osteopenia o osteoporosi nel 68% dei pazienti con BPCO in stadio III o IV GOLD. Pertanto, sembra ragionevolmente indicato lo screening per osteoporosi per i gradi più avanzati di severità della malattia.
Inoltre, nei soggetti con BPCO è presente uno stato infiammatorio cronico associato alla produzione di markers di flogosi, in particolare interleuchina (IL)-6 e livelli elevati di Tumor Necrosis Factor (TNF)-α, fattori condizionanti un turnover osseo accelerato (5) e conseguente perdita di massa ossea.

Le linee guida più recenti non danno specifiche raccomandazioni sul management dell'osteoporosi nella BPCO; tuttavia, forniscono un'indicazione a focalizzare e gestire le comorbilità presenti nei singoli soggetti. I fattori più critici concorrenti a definire l'alto rischio di fratture nella BPCO insieme ai valori di BMD sono: il basso peso (BMI<19), l'immobilizzazione, l'insufficiente apporto di vitamina D e calcio, l'età avanzata, la terapia sistemica con steroidi e il fumo. Questo rappresenta un pattern utile per classificare i soggetti con BPCO ad alto rischio di fratture, identificandoli precocemente e per indirizzarli ad una eventuale valutazione quantitativa con DXA, necessaria a decidere se iniziare un' appropriata terapia.


1. Jorgensen N R, Schwarz P Osteoporosis in chronic obstructive pulmonary disease patients. Curr Opin Pulm Med. 2008;1:122-127
2. Yang IA, Fong KM, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007; (2):CD002991.
3. Jones A, Fay JK, Burr M, et al. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; (1):CD003537
4. Kjensli A, Mowinckel P, Ryg MS, Falch JA. Low bone mineral density is related to severity of chronic obstructive pulmonary disease. Bone 2007; 40:493-497.
5. Forli L, Mellbye OJ, Halse J, et al. Cytokines, bone turnover markers and weight change in candidates for lung transplantation. Pulm Pharmacol Ther 2007; 24 February [Epub ahead of print].

2008-02-06T05:39:42 - Gianpiero Pescarmona

Therapy side effects

Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications 2012

Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection.
The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound.
The present document is the result of a national consensus, based on a systematic and critical review of the literature.
Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed.
Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.

Fratture vertebrali: trattamento inadeguato
Nelle donne con fratture vertebrali indotte dall'osteoporosi, rilevate mediante radiografia di routine, l'assenza di sostanziali differenze nel rischio di nuove fratture tra pazienti trattate e non trattate può essere spiegata con l'inadeguatezza del trattamento. Questa la conclusione della valutazione prospettica effettuata su 4.045 donne che sono state sottoposte a radiografia del torace per qualsiasi indicazione presso il dipartimento di Radiologia della Università Campus Bio-Medico di Roma. Lo studio, svolto da Bruno Beomonte Zobel e collaboratori, ha identificato 166 donne portatrici di almeno una frattura vertebrale (età 73 /- 10,5 anni). Di queste, 101 hanno risposto a un questionario per raccogliere informazioni su diagnosi di osteoporosi, storia di malattie tumorali e sistemiche, impiego di farmaci a rischio osteoporosi e trattamenti ricevuti farmacologici, radiologici o chirurgici. Il 97,1% delle pazienti era in menopausa, esordita a un'età media di 48,2 anni. Tra le pazienti in menopausa, il 15,8% era stato sottoposto a isterectomia. A tutte le pazienti è stata posta una diagnosi di osteoporosi, conseguente nel 23,7% dei casi al referto radiografico. Una nuova frattura scheletrica è occorsa nel 20,5% delle pazienti in trattamento per l'osteoporosi contro una frequenza del 20,8% registrata nelle donne non trattate: non si è riscontrata una differenza statistica tra i gruppi.

Radiol Med, 2010 Jun 24. [Epub ahead of print]

C'erano già vecchi lavori di prima del 2000

Osteoporosi comune dopo gastrectomia
E' stata confermata l'elevata prevalenza dell'osteoporosi e della deformità delle ossa vertebrali a seguito di una gastrectomia, a prescindere dal tipo di procedura di ricostruzione seguito e dal tempo trascorso dall'intervento. Probabilmente dunque è la gastrectomia in sé ad influenzare la BMD piuttosto che il tipo di ricostruzione effettuato, e quest'ultimo non è in grado di predire il tasso di osteoporosi in questi pazienti. Considerato il fatto che i pazienti affetti da tumori gastrici dopo la gastrectomia sono portatori di molti fattori di rischio di fratture osteoporotiche, è necessario che diagnosi e trattamento siano precoci. Benchè alcuni dati preliminari suggeriscano che l'osteoporosi post-gastrectomia sia resistente al trattamento, sono stati riportati anche risultati positivi con lo sviluppo di molti nuovi farmaci antiosteoporotici. (World J Gastroenterol 2007; 13: 6492-7)

Arteriosclerosi e perdita d'osso
Sussistono associazioni indipendenti fra BMD volumetrica trabecolare del rachide lombare ed arteriosclerosi calcificata delle coronarie e dell'aorta addominale. Tali correlazioni sono state dimostrate nell'arco di studi durati 50 anni, che complessivamente investigano l'associazione fra arteriosclerosi ed integrità ossea. Le correlazioni finora dimostrate sono comunque di modesta entità, ed è al momento prematuro speculare sulle loro possibili implicazioni a livello clinico: esse potrebbero tuttavia costituire la base per ulteriori approfondimenti all'interno dell'area del legame fra osso ed arterie. (Am J Epidemiol 2009; 169: 186-94)

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