The potential osteoporosis due to exposure to particulate matter in ambient air: Mechanisms and preventive methods

ABSTRACT

Air pollution and health consequences associated with exposure to air pollutants, such as particulate matter, are of serious concerns in societies. Over the recent years, numerous studies have investigated the relation of many diseases with air pollutants. This review used a search strategy to provide the comprehensive information on the relationship between particle matters and osteoporosis. To this end, three search databases were used to find the articles focused on particle matters and osteoporosis. After the screening process, 13 articles related to the purpose of the study were selected and the relevant data were extracted. The results indicated that osteoporosis is significantly associated with PM₁₀. However, this association with PM_2.5 remains unclear. In addition, particle materials indirectly lead to the osteoporosis and bone fractures as a consequence of reduced UV-B, reduced adsorption of vitamin D. Furthermore, they can lead to other diseases by use of drugs with adverse effects on bone health, and creating conditions that may increase the risk of falling in the elderly. This review shows that although more accurate research is needed to determine the mechanism and risk of exposure to particulate matter in the air on bone health, the negative effects of this pollutant on bone mineral density (BMD) are evident.

Implications: PM is usually classified by its size or aerodynamic diameter; PM10 denotes particles < 10 µm in diameter; PM2.5 particles are <2.5 µm in diameter. Many epidemiological studies have shown that short-term exposure to PM might reduce lung function. However, short-term effects might be reversible, and the main concern is attributed to long-term exposure. A major public health concern that may be affected by numerous metabolic and even environmental risk factors is osteoporosis. The purpose of this systematic review was to investigate the role of PM in the occurrence or exacerbation of osteoporosis in citizens.

Introduction

Over the past decades, the rapid urbanization and industrialization has led to environmental pollution all over the world (Kim, Cho, and Park 2016). Nowadays, scientific evidences indicate that environmental pollution is the largest cause of disease and premature death (Balakrishnan et al. 2019; Landrigan et al. 2018). According to the Global Burden of Disease (GBD), diseases associated with environmental pollution were responsible for an estimated 9 million deaths in 2015–16% of all deaths worldwide, which was 3 times as many deaths as AIDS, malaria, and tuberculosis combined and 15 times as many deaths as all wars and other forms of violence (Forouzanfar et al. 2016; Landrigan et al. 2018; Wang et al. 2016).

Among all environmental and occupational risks to human, air pollution is known as the greatest environmental risk in the world (with more than 4.9 million deaths in 2017) (Gakidou et al. 2017). One component of air pollution, i.e. particulate matter (PM) pollution, is one of the top-ranking risk factors for overall global burden of disease (Antonsen et al. 2020; Forouzanfar et al. 2016; Gakidou et al. 2017, Nabizadeh et al.18). The GBD study estimated that PM pollution caused 4.58 million deaths and 143 million disability-adjusted life years (DALYs) in 2017 (Gakidou et al. 2017). Therefore, PM is the most important air pollutant and is considered as the most common proxy indicator for ambient air pollution (Antonsen et al. 2020).

PM is usually classified by its size or average aerodynamic diameter; PM10 denotes particles <10 µm in diameter; PM2.5 particles are <2.5 µm in diameter (Schraufnagel et al. 2019a). Particulates between PM10 and PM2.5 in size are known as “coarse particles”, which may affect mucous membranes and the upper airways, causing cough and tearing. Fine particles (PM2.5) easily find their way into lung alveoli and pass through the alveolar capillary membrane, are readily picked up by cells, and carried via the bloodstream to expose virtually all cells in the body (Block and Calderón-Garcidueñas 2009; Schraufnagel et al. 2019a). Beyond its size, the harmful effects caused by PM relate to its composition; toxic components such as heavy metals and polyaromatic hydrocarbons (PAHs) may be carried deep into the lung on the surface of the ultrafine particles (Schraufnagel et al. 2019a). In addition, particles <1 µm in diameter are known as “ultrafine particles”.

Many epidemiological studies have shown that short-term exposure to PM might reduce lung function. However, short-term effects might be reversible, while the main concern is attributed to long-term exposure (Guo et al. 2018; Henschel, Chan, and Organization 2013). To date, numerous studies have demonstrated that ambient concentrations of PM have been associated with increased morbidity, hospitalization, and mortality from respiratory (Hopke et al. 2020; Xing et al. 2016), cardiovascular diseases (Guo et al. 2018; Peng et al. 2008; Wang et al. 2020), cancer (Di Lorenzo et al. 2015; Zhang et al. 2020), impaired cognition (Ailshire, Karraker, and Clarke 2017), diabetes (Lao et al. 2019; Liang et al. 2019), chronic kidney disease (Bowe et al. 2017), etc.

A major public health concern that may be affected by numerous metabolic and even environmental risk factors is Osteoporosis (Gakidou et al. 2017). It is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone susceptibility to fracture (Xu et al. 2019). Osteoporosis is a growing health problem worldwide; over 200 million people are at risk of osteoporotic fracture (Quach et al. 2019). The annual direct cost of osteoporotic fracture is estimated to be approximately US$20.3 billion only in the USA, with 2.1 million cases per year (Burge et al. 2007). On the other hand, the death risks for older individuals increase by 10–20% with only 40% regaining full pre-fracture independence during 1 year of a bone fracture (Burge et al. 2007; Leibson et al. 2002; Li et al. 2014). Therefore, identifying the novel and preventable risk factors of osteoporosis is an urgent global priority (Prada et al. 2017).

It is been well known that the rate of bone disorders in highly polluted urban areas is higher than those in rural areas (Meyer et al. 2004; Prada et al. 2017). Moreover, there is a hypothesis that systemic oxidative and inflammation effects of air pollutants, especially airborne PM, may accelerate bone loss and increase risk of bone fractures in older individuals (Bind et al. 2012; Møller and Loft 2010; Prada et al. 2017). Therefore, PM may be a risk factor for osteoporosis and osteoporotic fractures.

To date, some observational studies reported sparse and controversial findings about the relationship between air pollutants and the osteoporosis and bone fracture (Alvær et al. 2007; Alver et al. 2010; Prada et al. 2017). Therefore, it is essential to review and analyze the current observational studies to obtain a broader picture on the impact of PM pollution on incidence of osteoporosis. In this review, we provide the current evidence on the association between exposure to PM pollution and risk of incident osteoporosis. Therefore, the main aim of this study was to find a conclusive and comprehensive explanation for the explicit effects of PM pollution on the incidence or acceleration of osteoporosis in people all over the world. Furthermore, we tried to find the main routes, through which PM may affect the osteoporosis.

The purpose of this review was to investigate the role of PM in the occurrence or exacerbation of osteoporosis in citizens. In this review, according to open literature that have focused on the effect of PM on the occurrence or exacerbation of osteoporosis, we tried to study the factors affecting this phenomenon and provide a comprehensive view.

Method

Literature search

As shown in Table 1, we searched three databases (Scopus, PubMed, and Web of knowledge) for effect-based studies focused on the association between PM and osteoporosis using the following search strings: (air) and (“particular matter” OR “particulate matter” OR “PM” OR “TSP” OR “suspended solids” OR “atmospheric aerosol” OR “PM₁₀” OR “PM₅” OR “PM_2.5” OR “PM₁” OR “PM_0.1” OR “suspended particles”) AND (“osteoporosis” OR “osteoporotic” OR “broken bone” OR “bone density” OR “bone mineral density” OR “bone mineral content” OR “bone fractures”) (accessed March 01, 2020). A total of 58 relevant studies were included and the duplicates were removed in the next stage (Table 2).

Table 1. Search protocol and the number of articles found on the databases.

Search protocol	Source	Article
[I] Study on the osteoporosis and air pollution, [II] Time limit for search was not considered, [III] the keyword “air” had to appear in the title- abstract-keyword, [IV] “particular matter” OR “particulate matter” OR “PM” OR “TSP” OR “suspended solids” OR “atmospheric aerosol” OR “PM10” OR “PM5” OR “PM2.5” OR “PM1” OR “PM0.1” OR “suspended particles” had to appear in the title- abstract-keyword, [V] “osteoporosis” OR “osteoporotic” OR “broken bone” OR “bone density” OR “bone mineral density” OR “bone mineral content” OR “bone fractures” had to appear in the title- abstract-keyword.	Scopus	25
	PubMed	11
	Web of Science	22

Table 2. Screening steps for selecting articles related to the purpose of the study.

Search results	Paper filtered (number)
	By title study	By abstract study	By content study
58 paper	18	15	13

Eligibility criteria

The final articles were selected based on the eligibility criteria; we exclusively focused on the studies that investigated osteoporosis. Accordingly, we excluded all studies that refer osteoporosis due to other pollutant or did not investigate the mechanisms and factors affecting PM on osteoporosis.

Selection of studies

All authors conducted an independent and blinded screening of the literature according to the criteria provided above. After the initial screening of titles, we selected 13 studies (Table 2). In case of conflicting decisions during initial screening, the respective study was included in the next stage of screening. Afterward, the articles that referred to any types of PM in the air and investigated its effects on health in the abstract were extracted (15 studies). Finally, in the third stage, the contents of the articles were studied and 13 articles that had data about relationship or non-relationship between PM and osteoporosis were selected.

Data extraction

Data from fully eligible studies were extracted into a predefined data extraction file. We extracted the following data on the content of the eligible articles: (1) type of PM, (2) influencing factors on observed osteoporosis, (3) mechanisms and the occurrence of bone diseases as a consequence of PM exposure.

Results and discussion

Throughout, the studies focused on the relationship between PM and osteoporosis, researchers considered some criteria to select the susceptible cases in order to enter the study. Therefore, it can be found that these parameters are important in the severity of bone as following exposure to PM; some cases have synergistic properties. The most common parameters mentioned in the researches are age (Alver et al. 2010; Calderón-Garcidueñas et al. 2013; Mazzucchelli et al. 2018; Ranzani et al. 2020); smoking (Alvær et al. 2007; Alver et al. 2010; Calderón-Garcidueñas et al. 2013; Prada et al. 2017; Ranzani et al. 2020; Saha et al. 2016); physical characteristics such as height, weight, and skin color (Calderón-Garcidueñas et al. 2013; Liu et al. 2015); and health status such as the background of fractures or systemic diseases (Calderón-Garcidueñas et al. 2013; Mazzucchelli et al. 2018); nutritional conditions such as medication and supplements and vitamins (Calderón-Garcidueñas et al. 2013; Chen et al. 2015; Feizabad et al. 2017); environmental conditions such as outdoor time during the day (Alver et al. 2010; Calderón-Garcidueñas et al. 2013), physical activity (Alvær et al. 2007; Alver et al. 2010; Chen et al. 2015; Liu et al. 2015; Prada et al. 2017), and distance from the main roads (Liu et al. 2015). The studies on the effects of PM on bone health in view of various aspects were investigated, and the corresponding findings are summarized in Table 3.

Table 3. The effect of PM on bone health in some literature.

Type of study	Remarks	References
Osteoporotic hip fracture	Exposure to particles in the air has a positive association between hip fracture risk in the elderly, although this effect was not as great as in other contaminants such as SO2 and NO2. In children and the elderly, the concentration of PM (PM2.5, PM10) is inversely related to BMD	Mazzucchelli et al. (2018)
Bone density and self-reported forearm fracture	No association was found between PM2.5 and PM10 and self-reported forearm fractures or BMD in both genders. In elderly men, an increment of 10 units in PM2.5 was associated with a reduction in distal forearm BMD of 64 mg/cm^2. In male smokers, there was an association between long-term exposure to PM2.5 and PM10 with higher prevalence of forearm fracture	Alver et al. (2010)
Bone mineral density	Higher exposure to PM2.5 was found to be associated with lower BMD in the pelvic bones However, the subjects who lived near the freeways had lower BMDs in the whole body and less pelvis independent of sex, age, weight, height, body fat percentage, physical activity, background variables, calcium and vitamin D. However, no link was found between BMD and ambient air pollutants, including PM2.5 NO2 and PM10 may have a synergistic effect on BMD The associations between exposure to air pollutants such as PM and low BMD by the activated immune system is a hypothesis that has not yet been tested	Chen et al. (2015)
Bone turnover markers	PM2.5–10 and PM10 mass exposure were positively and significantly associated with bone turnover markers The estimated coefficients were 3.0 for osteocalcin and 32.3 for C-terminal telopeptide of type I collagen (CTx)^a* with PM2.5–10; 3.2 for osteocalcin and 30.7 for CTx with PM10. Children living near a major road (≤350 m) had higher levels of both osteocalcin (1.4 ng/mL) and CTx (16.2 ng/L).	Liu et al. (2015)
	The estimated decrease in body BMD in older men (75 years) was about 12 mg/cm^2 in each increase in SD for PM2.5 and 11 mg/cm^2 in each increase in SD for PM10 The relationship between air pollution and body BMD was significant, while it was not significant for femur.	Alvær et al. (2007)
Indoor air pollution	Long-term exposure to PM in the indoor air can lead to alterations in receptor activator of nuclear factor-kappa ligand 1 (RANKL) and osteoprotegerin (OPG) levels which are a key molecular regulation system for bone remodeling.	Saha et al. (2016)
	Air pollution particles have high potential to cause systemic oxidative damage and inflammation, both of which are established mechanisms for bone demineralization and osteoporosis. Socio-economic factors, race, and obesity are associated with BMD. Association of PM2.5 exposure with bone fracture admission rates was higher among those communities in the lowest obesity rate quartile compared with those with the highest obesity rates, suggesting a protective influence of obesity rates. Particles emitted from traffic were identified as crucial contributors to decreased bone health.	Alvær et al. (2007)
Prevalence of osteoporosis in rural population	Around 14.9%, 14.6%, 7.3%, and 16.5% increases in the risk of osteoporosis were observed per 1 μg/m^3 increase in PM1, PM2.5, PM10 and NO2, respectively. The odd ratios (ORs) (95% confidence intervals) were 2.08 (1.72, 2.50) for PM1, 2.280 (1.90, 2.74) for PM2.5, and 1.93 (1.60, 2.32) for PM10. It was estimated that 20.29–24.36% of the osteoporosis cases could be prevented in rural areas of China, if air pollution could be reduced to below the corresponding P2.5 levels.	Qiao et al. (2020)

^aCTx is a marker of bone resorption and reflects the rate of bone loss (Liu et al. 2015).

A summary of studies focused on the association between PM and osteoporosis is given in Table 4. The effect of exposure to particles at different ages is influenced by the presence of different age groups in outdoor and exposure to pollution; older people and retirement spent more time outdoors, so they are exposed to more air pollution (Alver et al. 2010). In addition, older people are more affected by air pollution due to metabolic changes and physical characteristics in these age groups (Alver et al. 2010). Exposure to PM indirectly can also lead to a relative increase in bone fractures in the elderly; The effect of these pollutants on the body’s biological processes, which increases the risk of falling in the elderly can lead to bone fractures. Many studies reported that exposure to PM_2.5 particles can disrupt the heart rhythm and also can exacerbate the autonomic nervous system (ANS) stimulation and increases the risk of arrhythmia, orthostasis, and syncope in the elderly, which can be the cause of a fall and bone fracture (Mazzucchelli et al. 2018). In addition to people’s age, the type of bone has also important in the influence of air pollution particles on osteoporosis; young people are more resistant to these effects. However, significant negative relationship was reported between long-term black carbon exposure and BMD in femoral neck and ultradistal radius was not observed in single-third distal radius, total hip, and lumbar vertebral (Prada et al. 2017). One reason for the difference in the effect of PM on osteoporosis in different bones could be the difference in bone structure and the different resistance of these bones to oxidative stress generated by PM; the results of a study in India showed that the association between PM_2.5 and low bone mass was greater for the lumbar spine, which is mainly composed of trabecular bone, than for the hip, which has a higher proportion of cortical bone (Ranzani et al. 2020). However, the severity of the effects of exposure to PM in men and women is not the same. This difference can be influenced by physiological differences in men and women, especially in old age; the body’s hormones are also effective in bone density, which can be independent of the type and extent of exposure to air pollutants such as particles. For example, reduced estrogen production in postmenopausal women will reduce their bone density compared to men of the same age (Alver et al. 2010; Chen et al. 2015). In another example, the results of a study focused on estimating the Incidence Rate Ratios (IRRs) of PM changes on the hip fracture rate showed that women were more likely to hip fractures than men due to the presence of airborne particles. IRR was reported to be 0.92 and 1.03 for PM_2.5 for men and women, respectively, as well as 1.00 and 1.02 for PM₁₀ for men and women, respectively (Mazzucchelli et al. 2018). Another study on men and women over the age of 65 in Chile reported no significant relationship between PM_2.5 levels and bone fractures in men. However, a very weak direct association was observed between the incidence rate of osteoporotic hip fracture in men and the annual concentration of PM_2.5, which is not statistically significant (Ormeño Illanes and Quevedo Langenegger 2019). This is due to the fact that physical activity in all groups of ages and genders leads to a decrease in osteoporosis due to exposure to air pollutants including PM (Qiao et al. 2020).

Table 4. A summary of studies on association between PM and osteoporosis.

The studied group of ages	The characteristic of selected cases	Factors	Is PM proven to affect the osteoporosis?	References
Children and Parents (from 28 villages near Hyderabad, South India)	3717 participants were analyzed. mean [SD] age, 35.7 [14.0] years; 1711 [46.0%] women. The annual mean (SD) PM2.5 exposures was 32.8 (2.5) μg/m^3.	Bone mineral content (BMC) measured in grams, corrected by bone area at the lumbar spine and left hip	YES “exposure to PM2.5 was associated with lower bone mineral density in the spine (mean difference, −0.011 g/cm^2 per 3 μg/m^3 increase in PM2.5; 95% CI, −0.021 to 0 g/cm^2 per 3 μg/m^3 increase in PM2.5) and hip (mean difference, −0.004 g/cm^2 per 3 μg/m^3 increase in PM2.5; 95%CI, −0.008 to 0.001 g/cm^2 per 3 μg/m^3 increase in PM2.5)”	Ranzani et al. (2020)
Elderly men	590 participants were analyzed. 75–76 years old	Bone mineral density (BMD)	YES “There was a weak but statistically significant inverse association between PM and total body BMD”	Alvær et al. (2007)
Children	20 children from Mexico City (MC) (6.17 years ± 0.63 years) and 15 controls (6.27 years ± 0.76 years)	Bone mineral density (BMD)	YES “The impact of air pollution may have long-term bone detrimental outcomes, potentially increasing their risk of low bone mass and osteoporosis”.	Calderón-Garcidueñas et al. (2013)
Elderly people	Men and women 75/76 and 59/60 years (n = 5,976)	Forearm bone mineral density (BMD)	NO “no associations between air pollution and self-reported forearm fractures or BMD in men aged 59/60 years or in women. In men aged 75/76 years, an increment of 10 units in PM2.5 was associated with a reduction in distal forearm BMD of 64 mg/cm^2 (p < .05)”	Alver et al. (2010)
Elderly persons with asthma	76; mean age 64.6 years; 48 women with physician-diagnosed asthma	Adverse pulmonary health outcomes	YES “PM might increase use of asthma controller drugs containing corticosteroids with implication for elderly persons’ risk to develop osteoporosis and cardiovascular disease”	Arnetz et al. (2020)
Mexican American adults	n = 1,175; mean 34 years; 72% female	Bone mineral density (BMD)	MIGHT BE “Residential proximity to a freeway was associated with lower total body BMD (p-trend = 0.01) and pelvic BMD (p-trend = 0.03). Ambient air pollutants (NO2, O3, and PM2.5) were not significantly associated with BMD. Findings indicate that long-term exposures to traffic may contribute to the occurrence of osteoporosis and its consequences”	Chen et al. (2015)
Students	325 middle- and high school students (both girls and boys) in Tehran in the winter	Serum levels of calcium, vitamin D, osteocalcin, …	YES “Vitamin D deficiency was more prevalent in polluted areas than in non-polluted areas. atmospheric pollution may play a significant independent role in the development of vitamin D deficiency”	Feizabad et al. (2017)
Children	A total of 5991 newborns were recruited in obstetric clinics in Munich and Wesel, Germany, between September 1995 and July 1998. Follow-up occurred at the age of 1, 2, 3, 4, 6 and 10 years of age.	Serum bone turnover markers	MIGHT BE “The estimated coefficients were3.0 (95% CI: 0.1, 5.8) for osteocalcin and 32.3 (95% CI: 6.1, 58.5) for CTx with PM2.5–10; 3.2 (95% CI: 0.0,6.4) for osteocalcin and 30.7 (95% CI: 1.7, 59.7) for CTx with PM10. Children living close to a major road (≤ 350 m) had higher levels of both osteocalcin (1.4 [−1.2, 4.0] ng/ml) and CTx (16.2 [−7.4, 39.8] ng/L). Exposure to ambient air pollution, especially NO2, PM2.5–10 and PM10, may be associated with increased bone turnover rate in children.”	Liu et al. (2015)
Inhabitants of Alcorcon, Spain	–	Osteoporotic hip fracture	YES “A short-term association was observed with several indicators of air pollution on hip fracture incidence. Hip fracture incidence showed association with PM2.5 (IRR 1.02 (95% CI 0.94–1.11)), and PM10 (IRR 1.02 (95% CI 0.99–1.04))”	Mazzucchelli et al. (2018)
Elderly people	9.2 million Medicare enrollees (aged ≥65 years) of the northeast-mid-Atlantic USA between January 2003, and December 2010.	Osteoporosis-related fracture	YES “In the Medicare analysis, risk of bone fracture admissions at osteoporosis-related sites was greater in areas with higher PM2.5 concentrations (risk ratio [RR] 1.041, 95% CI 1.030 to 1.051). This risk was particularly high among low-income communities (RR 1.076, 95% CI 1.052 to 1.100). PM2.5 is a modifiable risk factor for bone fractures and osteoporosis, especially in low-income communities.”	Prada et al. (2017)
Women	Seventy-four pre-menopausal women from eastern India using biomass and 65 control women who cooked with cleaner liquefied petroleum gas were enrolled	Serum markers	YES “PM10 and PM2.5 levels were found to be positively associated with leukocyte and serum RANKL and CD14+ CD16+ monocyte levels, but negatively with serum OPG. So an increased risk of bone resorption and consequent osteoporosis.”	Saha et al. (2016)
Rural population	8,033 participants (18–79 years) derived from the Henan Rural Cohort Study (n = 39,259)	bone mineral density (BMD)	YES “per 1 μg/m^3 increase in PM1, PM2.5, PM10 and NO2 were associated with a 14.9%, 14.6%, 7.3%, and 16.5% elevated risk of osteoporosis. It was estimated that 20.29%-24.36% of osteoporosis cases could be attributable to air pollution in the rural population from China.”	Qiao et al. (2020)
Elderly people	Adults 65 years of age or older	Osteoporotic hip fracture	NO “In 2017 there were 8,322 hip fractures in adults 65 years of age or older, with a rate per 100,000 inhabitants of 216 and 567 for men and women, respectively. No statistically significant association was found between PM2.5 and the incidence rate of hospital discharges due to osteoporotic hip fractures in Chile.”	Ormeño Illanes and Quevedo Langenegger (2019)

The presence of other pollutants in the air that have been proven to influence the tissue should be considered in studies and evaluation the effects of particles on bone density and fracture. For example, lead, cadmium (Alver et al. 2010), and PAHs (Chen et al. 2015; Liu et al. 2015) have shown an association with osteoporosis and this point can be considered in the study of different people, especially those who are smokers due to the presence of these pollutants in cigarette smoke. For this reason, due to the presence of several pollutants in cigarette smoke, several studies have identified an inverse relationship between smoking and BMD (Chen et al. 2015; Mazzucchelli et al. 2018). Another parameter that is important for bone health and should be considered is the use of some dietary supplements and medications that can have side effects on the bone. For this reason, researchers have identified cases that use such medications and excluded them from the study to investigate the effect of particles on human bones (Calderón-Garcidueñas et al. 2013; Chen et al. 2015; Feizabad et al. 2017). On the other hand, one of the indirect effects of PM2.5 on osteoporosis, especially in the elderly, is exacerbation of shortness of breath and worsening of asthma in people, resulting in the use of anti-asthma drugs, which may increase the risk of osteoporosis (Arnetz et al. 2020).

Although most studies focused on outdoor air pollution as an important part of people’s exposure to air pollution However, as long as the exposure to particles in the indoor environment neglected, it does not indicate the real exposure. This condition can cause a misunderstanding for the relationship between the BMD and the concentration of air pollutants, including PM. According to the findings of Saha et al., this is especially important. This study focused on two groups of housewives in India. They found that women who were more exposed to PM_2.5 and PM₁₀ at home due to the use of biomass fuel for cooking experienced an increased risk of bone resorption. Also, the researchers identified this condition as a threat to other groups of ages, such as children and the elderly, who are mostly at home (Saha et al. 2016).

It seems that the size of the PM in the air is effective in causing bone effects in people; PM₁₀ has a more noticeable effect on BMD than PM_2.5. The results of studies on children in Munich showed that there is a significant and positive relationship between coarse particles and the increase in bone turnover markers (osteocalcin and CTx) present in the blood, while no relationship was observed for fine particles (Liu et al. 2015). This different effects due to different particle sizes can explain the result of another study that reported no significant association between PM_2.5 and bone density in 6-year-old children (Calderón-Garcidueñas et al. 2013). Also, a study on adolescents in Tehran, Iran, illustrated that the studied cases in polluted areas and non-polluted areas (by PM_2.5) did not show a significant difference in osteocalcin, CTX or other serum biochemical components (Feizabad et al. 2017). In addition, it was observed a significant relationship between PM_2.5 concentrations and body BMD in smokers or previous smokers and the lack of this relationship for nonsmokers in the study of older men (Alvær et al. 2007). Overall, it was illustrated that PM_2.5 has less effect on BMD compared to PM₁₀, and other factors such as lead, cadmium, and PAHs in cigarette smoke can affect these relationships (Alver et al. 2010; Chen et al. 2015; Liu et al. 2015). However, a study on 9 million people in the United States found that osteoporotic bone fractures were statistically more common in areas with higher PM_2.5 concentrations (Schraufnagel et al. 2019b). One reason for this difference in research results could be associated with the study time; results of a long-term study in the United States showed that an increase of 4.18 µg/m³ of PM_2.5, the hospital admissions increased by 4.1% due to bone fractures in the elderly (Prada et al. 2017). This evidence was confirmed with the study on the effects of long-term exposure to a variety of particles in increasing the risk of osteoporosis in rural areas of China. In this study, it was reported that increased 1 µg/m³ of PM_2.5 increases the risk of osteoporosis by twice as much as PM₁₀ as the same concentration (Qiao et al. 2020). However, the same study found that at the beginning of the study, there was no significant relationship between black carbon concentration and PM_2.5 with BMD; a future 8-year study in the following years showed that living in locations with higher concentrations of particles, especially the higher concentration of black carbon led to lower BMD in patients (Prada et al. 2017).

Although, in some cases, researchers have not established significant relationships between various types of PM and osteoporosis or bone fractures (Alver et al. 2010; Feizabad et al. 2017; Liu et al. 2015; Ormeño Illanes and Quevedo Langenegger 2019), many studies have found that living in areas with high levels of air pollutants, especially PM, causes a relative increase in osteoporosis and bone fractures. For instance, the results of a study showed that the effects of air pollutants, including particles, can be proven in the presence of lower BMD symptoms in residents living close to the main streets compared to residents in areas farther from the main streets (Liu et al. 2015). According to the results of researches, the mechanisms of PM in the occurrence of bone diseases, including osteoporosis, can be expressed in two groups, direct and indirect.

In the direct mechanism, PM may lead to biochemical processes in the body, which accordingly result in osteoporosis. Although, the biological mechanisms of the association of airborne particles with bone mineral metabolism are not well understood, inflammatory responses and pro-inflammatory cytokines on osteoclastogenesis are some of the cases that mentioned for this association (Qiao et al. 2020). Researchers have tried to find the true mechanism for the effect of airborne particles on osteoporosis. For example, the results of research by Liu et al. showed that exposure to air pollutants, including PM, can increase the concentration of elements in the body, which has a negative effect on bone density and may decrease BMD in people. A cohort study of 10-year-old children in Germany showed a significant association between increasing PM₁₀ and PM_2.5–10 levels in the air and increasing serum osteocalcin and C-terminal telopeptide type I collagen (CTx) concentrations in blood that has a negative effect on BMD (Liu et al. 2015). On the other hand, atmospheric pollution-induced cellular oxidative stress has been described as an effective pathogenic mechanism in osteoporosis caused through exposure to PM (Qiao et al. 2020). In addition, the increased bone mineral loss through systemic oxidative stress or inflammation due to exposure to PM was reported (Ranzani et al. 2020). Bones are targets of inflammation, as systemic bone loss may be occurred due to bone resorption. A probable bone detrimental effect of inflammation related to environmental pollution is taken place through osteoclastic synergistic action. Such action was observed for the children exposed to significant concentrations of lipopolysaccharides associated with PM in Mexico City. By the way, researchers emphasized on defining up-regulated critical mediators of bone loss and associated bone responses during children growing up in polluted environment (Calderón-Garcidueñas et al. 2013). However, mediators between PM and osteoporosis can be considered to find the mechanism of action in research, the most important of which are pro-inflammatory markers including interleukin, tumor necrosis factor alpha, and C-reactive protein, chronic inflammation (Qiao et al. 2020).

In the indirect mechanism, the PM reduce BMD and ultimately osteoporosis in two ways: (1) reducing UV-B flux, which may decrease calcium absorption and bone density, resulting in a decrease in vitamin D3 (Calderón-Garcidueñas et al. 2013; Chen et al. 2015) and a decrease in concentration of bone hormonal homeostasis, such as via parathyroid hormone (Prada et al. 2017; Ranzani et al. 2020), (2) development of other diseases requiring the use of drugs with adverse side effects in the bones (Arnetz et al. 2020). Feizabad et al. in a study in Tehran stated that there was no significant difference in bone turnover markers (osteocalcin and CTx) in school students of polluted and non-polluted areas of Tehran. It was revealed that the vitamin D levels in students living in areas with high levels of air pollution were less than those living in non-polluted areas probably due to the reduced solar UV-B caused by air pollutants, especially PM, with respect of its haze effect (Feizabad et al. 2017). Garciduenas et al. also reported that in Mexico City, the airborne PM_2.5 with concentrations of 8.04 ± 16.84, 8.34 ± 17.96, and 8.69 ± 18.39 µg/m³ during years 2007–2009 reduced the flux of UV-B radiation on the ground compared to the surrounding rural areas (Calderón-Garcidueñas et al. 2013).

Conclusion

The association between exposure to PM and bone health, and especially osteoporosis was reviewed. The results showed that variables such as age, sex, tobacco use, physical activity, nutrition, drug use, heredity, outdoor activities and physical characteristics such as skin color are influencing factors in the observed effects. The elderly, women, thinner people, and people who live in the vicinity of high traffic area including roads and highways, are more likely to be affected by PM-induced osteoporosis. Studies have shown that larger particles have a more significant relationship with osteoporosis, while the severity of BMD reduction is not the same in all bones. Although there are at least three mechanisms for the osteoporosis due to exposure to airborne PM, however, due to various interfering factors in the development of osteoporosis, determining the contribution of PM in reducing BMD in different individuals and in different bone types requires further research.

Acknowledgment

The authors gratefully acknowledge the financial support given by the Research Center for Environmental Health Technology, Iran University of Medical Sciences, Tehran, Iran (Grant number: 16815).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Iran University of Medical Sciences [Grant Number: 1401-2-61-23884].

Notes on contributors

Javad Torkashvand

Javad Torkashvand is Ph.D. in Environmental Health Engineering.

Ahmad Jonidi Jafari

Ahmad Jonidi Jafari is Ph.D. in Environmental Health Engineering.

Hasan Pasalari

Hasan Pasalari is Ph.D. in Environmental Health Engineering.

Abbas Shahsavani

Abbas Shahsavani is Ph.D. in Environmental Health Engineering.

Yasaman Oshidari

Yasaman Oshidari is MSc in Environmental Health Engineering.

Vida Amoohadi

Vida Amoohadi is MSc in Environmental Health Engineering.

Majid Kermani

Majid Kermani is Ph.D. in Environmental Health Engineering.