Table 1:

Hypotheses for cellular causes of developing DS skeletal deficits

Hypothesis	Cellular or molecular mechanism	References
Early developmental aberrations	Low percent bone volume in E17.5 Ts65Dn mice.	Blazek et al 2015
	Lower mineralizing surface in 6-week-old male Ts65Dn mice.	Blazek et al 2011
	Lower osteoclast number in 6-week-old Ts65Dn mice.	Blazek et al 2015
Low bone turnover	Low osteoblast and osteoclast numbers in 12-week-old male Ts65Dn mice.	Fowler et al 2012
	Low P1NP and TRAP quantification in 2-year-old male Ts65Dn mice.	Williams et al 2017
Altered bone homeostasis	Low osteoblast and high osteoclast activity in 6-week-old male Ts65Dn mice. 16-week- old male mice continue with altered trabecular and cortical bone.	Blazek et al 2011
		Blazek et al 2015
Sex and age specific changes	Increased osteoblast activity and reduced osteoclast activity in trabecular bone of 16- week-old male Dp1Tyb mice.	Thomas et al 2020
	Decrease in osteoblast activity in trabecular bone of 16-week-old male Dp1Tyb mice.
Low bone formation	Low serum P1NP and normal CTx in adult males and females (combined) with DS as compared to controls	McKelvey et al 2017
Increased osteoblastogenesis	Higher P1NP and ALP levels in adult males and females (combined) with DS as compared to controls	Garcia Hoyos et al 2017
Adynamic bone	Reduced osteoblasts and no observed osteoclasts in 49-year-old man with DS.	Grimwood et al 2000
Mechanostat	Reduced physical activity correlates with low bone mass. Increasing activity improves bone mass.	Garcia Hoyos et al 2017
		Matute-Llorente 2013
		Matute-Llorente 2017
		Matute-Llorente 2015