The prevalence of obesity over the past 100 years has dramatically increased, with obesity identified as the most common metabolic disorder. Globally, an estimated 600 million adults were obese (body mass index ≥ 30 kg/m²), and 1.9 billion adults were overweight in 2015 (body mass index 25–30 kg/m²) (1). The prevalence of obesity is expected to reach 1.12 billion individuals by 2030 (2). Obese individuals have an increased risk of morbidity from type 2 diabetes mellitus (T2DM), cardiovascular disease, specific cancers, and osteoarthritis (3).

The incidence of obesity in women of reproductive age has also increased. Maternal obesity is a significant risk factor for maternal, fetal, and neonatal morbidities, including miscarriage, preterm delivery, hypertension, pre-eclampsia, and gestational diabetes (4–6). Research in the field of developmental origins of health and disease (DOHaD) has highlighted that maternal obesity during pregnancy predisposes offspring to develop obesity and other non-communicable diseases, including T2DM, hypertension, and cardiovascular disease, later in adulthood (7). Paternal obesity also increases the risk of developing non-communicable diseases in offspring (8–10), and both maternal and paternal obesity have transgenerational effects on subsequent generations via epigenetic effects on the germline (10–12). Thus, obesity and its related comorbidities represent an increasing burden on healthcare systems.

Although not fully understood, the effect of maternal obesity on the development of various organs and tissues such as the brain, liver, kidney, endocrine pancreas, and skeletal muscle and their structure and function have been well-researched with the aid of animal models. In these models, maternal obesity is induced via a high-fat diet (HFD) (13, 14). Recently the effects of maternal HFD on bone mass and strength in offspring and the risk of developing osteoporosis later in life have been researched. This mini-review will discuss evidence that maternal HFD-induced obesity affects bone development and microarchitecture, focusing on recent advancements using rodent models, and will discuss the potential mechanisms involved.

The skeleton develops in utero from mesenchymal condensations. Most of the skeleton forms via a process known as endochondral ossification: initially, a cartilaginous template forms, which is later progressively replaced by mineralized bone matrix. Cartilaginous growth plates continue to control the longitudinal growth of bones throughout neonatal and childhood growth, while the overall bone shape, mineralization, and microarchitecture are determined by the balance of bone formation by osteoblasts and bone resorption by osteoclasts in different locations. Longitudinal skeletal growth continues until the late teens in humans, ending when the growth plates fuse. However, bone mineral density (BMD) continues to increase slowly until peak bone mass is reached in the mid-20s to early-30s. Rodents continue to grow slowly for a longer portion of their life, but mice reach peak bone mass at ~12-weeks of age. Bone mass begins to decline as bone resorption outpaces bone formation as we age. In women, there is a dramatic period of bone loss following menopause when reductions in sex hormone levels affect homeostasis. Skeletal size, BMD, and bone microarchitecture are largely determined by genetics, with up to 85% of the variation in BMD explained by genetic factors (15). However, various non-genetic factors also influence both bone accrual during growth and bone loss in later life. Nutrition is a major factor influencing both growth and bone mass and can have effects at all life stages. Exercise, or the effect of loading on the skeleton, plays a major role in bone accrual and retention.

Osteoporosis is characterized by low BMD and a high risk of fracture, and affects one-half of elderly women and about one-fifth of elderly men. While osteoporosis is considered a disease of aging, early life events and a failure to achieve maximal peak bone mass determined by an individual's genetics can significantly impact future osteoporosis risk. One line of evidence for long-term impacts of events earlier in life comes from studies in athletes. Baseball pitchers who develop larger, stronger bones in their throwing arm during early adulthood can retain better bone structure in this arm for 50 years following retirement from the game (16). Various drugs are available that effectively reduce fracture risk in people with osteoporosis; however, the majority are antiresorptive therapies that prevent further bone loss but do not enable the replacement of bone already lost (17). Anabolic treatments restore bone microarchitecture to some degree, but are expensive biologics so not available to everyone. Understanding risk factors for low bone mass and identifying people at high risk of fracture are important for preventing fracture-related morbidity and mortality in aging populations.

Thirteen rodent studies considered the effects of maternal HFD on offspring bone development (Table 1). The majority of studies implemented the maternal HFD regime before mating (4–15 weeks before conception) and continued through pregnancy and lactation. However, in three studies, the maternal HFD-feeding window was exclusively during pregnancy and lactation and exclusively during lactation in one study.

Several studies have specifically addressed whether maternal obesity or maternal HFD during pregnancy affects bone development in offspring, both in utero and post-partum (33). Longitudinal studies show that obese mothers have babies with increased body length, whole-body bone area, and mineral content (34–36), but maternal diet was not reported. Two studies demonstrated that mothers consuming a high-fat “Western diet” during pregnancy, defined as a diet high in meat, processed food, and saturated fat, have children with lower whole-body bone area, bone mineral content, and BMD, compared with children of mothers on low-fat “prudent diets” during pregnancy, defined as a diet high in fruits, vegetables, grains and low-fat dairy products (37, 38). Interestingly, offspring of mothers in the Danish National Birth Cohort who consumed a Western diet had a significantly increased risk of fracture between birth and 16-years of age (39). None of these studies reported maternal BMI related to study groups. Due to the paucity of human data (33), it is unclear whether maternal obesity in the absence of HFD, maternal HFD in the absence of obesity, or any other dietary conditions of over-nutrition with or without maternal obesity affects the skeletal phenotype in human offspring.

Research into the mechanisms involved in linking maternal HFD with a bone phenotype in rodents remains in its infancy, and to our knowledge, no studies in humans have explored any mechanisms of action. The following section discusses some key mechanisms demonstrated in rodent maternal HFD studies, linking the early life environment and the observed bone phenotype in these offspring (Figure 1).

Many unanswered questions surrounding how HFD-induced maternal obesity affects bone development and microarchitecture in offspring remain.

One outstanding question is whether the detrimental effects on offspring skeleton are driven by maternal obesity, maternal HFD, or both. In humans, most studies explore the effects of obesity during pregnancy, commonly assessed by measuring body mass index rather than dietary patterns (46). In rodents, the majority of studies implemented a maternal HFD regime at least 4 weeks before mating. This would have induced an obesity phenotype in these dams, as well as ongoing exposure to HFD. However, it is unlikely that maternal obesity would have been induced in studies where HFD-feeding was restricted to pregnancy and lactation, or lactation alone. Therefore, these offspring likely experienced exposure to HFD in the absence of maternal obesity. It is challenging to tease out whether HFD-induced obesity before pregnancy or ongoing maternal HFD affects the skeleton in offspring using a rodent model. Unlike in humans, changing the diet of a rodent from HFD to CD induces rapid weight loss (47). This could be overcome using embryo transfer following pre-conception maternal HFD, placing embryos into CD-fed recipients (46).

Another gap in our understanding is deciphering the effects of maternal HFD on other tissues in offspring and how these effects, in turn, modulate the skeleton. For instance, there is cross-talk between the skeleton and skeletal muscle, adipose tissue, and the endocrine pancreas (48–52). The structure and function of these tissues are affected by the early life environment (7). Therefore, it would be interesting to determine whether this cross-talk is affected by maternal HFD and the downstream effects on the skeleton.

In this mini-review, we exclusively discussed the effect of maternal HFD on the skeleton in offspring; however, other paradigms of early life exposure to nutritional excess are also worthy of exploration. For instance, a maternal high-protein diet (53) and a combination of high-fat and high-sugar diet (54) also negatively impact the skeleton in offspring. Additionally, pre-conception paternal nutrition also has long-term effects on the metabolic health of offspring (55). We are unaware of any studies that have addressed the paternal influence of skeletal development in offspring. Thus, understanding the impact of paternal health will also be necessary for understanding the mechanisms that link the early life environment with skeletal health in offspring.

Critically, we are unaware of any studies investigating the effect of nutritional, pharmacological, or behavioral interventions on skeletal outcomes in the offspring. Whilst we do not yet fully understand the mechanisms that impact the developing skeleton in response to maternal HFD, a significant gap lies in the lack of intervention studies.

There is growing evidence that exposure to maternal HFD during pregnancy has long-lasting adverse effects on the skeleton of offspring. However, many details surrounding these changes and the mechanisms of action that drive these effects remain unclear, and further basic studies are required. Given the consequences of low bone mass and deranged bone microarchitecture for offspring, advances in our understanding of the developmental origins of bone health is critical in our battle against diseases like osteoporosis.

EB designed the review. EB, SB, and MT collected relevant articles. All authors have contributed to writing and revision of the manuscript, read, and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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