Table 1.

Potential pathophysiological mechanisms by which smoking damages bone health.

INDIRECT EFFECTS	Pathophysiological Mechanism	Methods	Bone Effects	References
	Nicotine causes an alteration in body weight, suppressing appetite and increasing dopamine and serotonin levels	Height, weight, and waist circumference measurement Percent total body weight measurement via electrical bioimpedance	Weight loss causes a decrease in the mechanical load on the skeletal system, leading to a decrease in BMD	[23]
		Quantity of cigarettes smoked BMI measurement Waist circumference measurement		[24]
		Quantity of cigarettes smoked Appendicular skeletal muscle mass evaluation Percent of fat mass		[28]
		BMI measurement Body weight, waist and hip circumferences measurement Adipose cell metabolism and resting metabolic rate evaluation		[26]
	Tobacco suppresses PTH, cholecalciferol, and calcitriol production Nicotine increases skin aging, causing it to lose its capacity to synthesize cholecalciferol	25(OH)D levels measurement BMD at L2-L4 and proximal femur measurement Smoking habits, daily dietary calcium intake, and alcohol consumption evaluation	The reduction in serum levels of PTH and consequent vitamin D activation causes a decrease in BMD	[33]
		Gene expression analysis of MMP-1 with qRT-PCR		[34]
		Smoking status evaluation Measurement of serum PTH levels Evaluation of intakes of calcium and vitamin D with a food-frequency questionnaire		[30]
	Smoking causes a decrease in testosterone levels Some alkaloids derived from tobacco inhibit the activity of the aromatic enzyme, exerting an antiestrogenic effects	Steroid hormone levels measurement	The decrease in gonadal hormone levels causes a reduction in the activity and proliferation of osteoblasts and an increase in the resorption activity of osteoclasts	[35]
		Radiometric assay of estradiol 2-hydroxlation		[36]
	Smoking causes an increase in levels of adrenocorticotrophin, causing a consequent increase in circulating cortisol levels	Evaluation of the number of cigarettes smoked Saliva sample collection for the assessment of cortisol	Cortisol causes a reduction in collagen and bone matrix synthesis	[41]
DIRECT EFFECTS	Smoking causes an increase in the RANKL/OPG ratio	Smoking status and physical activity assessment Blood specimen collection to determine serum levels of bone turnover markers	Increase in osteoclastogenesis and bone resorption	[45]
		Gene expression analysis of RANK/RANKL/OPG with qRT-PCR in rat model		[46]
	Smoking causes an increase in DKK1 (bone formation inhibitor) levels and a decrease in P1NP (bone formation marker) levels	BMD measurement Serum analyses of CTX-1, P1NP, OPG, RANKL, DKK1, Sclerostin, TNF-α, and Leptin	Alteration of bone formation	[30]

BMI: bone mass index; BMD: bone mineral density; PTH: parathyroid hormone; MMP-1: metalloproteinase 1; qRT-PCR: quantitative real-time polymerase chain reaction; RANK: receptor activator of nuclear factor kappa-B; RANKL: receptor activator of nuclear factor kappa-B ligand; OPG: osteoprotegerin; DKK1: dickkopf-1; CTX-1: C-terminal telopeptide of collagen type 1; P1NP: N-terminal propeptide of procollagen; TNF-α: tumor necrosis factor-alpha.