Causes of low peak bone mass in women

Accepted Manuscript Title: Causes of low peak bone mass in women Authors: Chee Kian Chew, Bart L. Clarke PII: DOI: Reference:

S0378-5122(17)30909-X https://doi.org/10.1016/j.maturitas.2017.12.010 MAT 6932

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Please cite this article as: Chew Chee Kian, Clarke Bart L.Causes of low peak bone mass in women.Maturitas https://doi.org/10.1016/j.maturitas.2017.12.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Causes of Low Peak Bone Mass in Women

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Chee Kian Chew, M.D. and Bart L. Clarke, M.D.

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Authors’ Addresses: Chee Kian Chew, M.D. Bart L. Clarke, M.D. (Corresponding Author) Mayo Clinic E18-A 200 1st Street SW Rochester, Minnesota, USA 55905

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Corresponding author: Bart L. Clarke, M.D. Mayo Clinic E18-A 200 1st Street SW Rochester, Minnesota, USA 55905

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Phone: +1-507-266-4322 Fax: +1-507-284-5745

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Phone: +1-507-266-4322 Fax: +1-507-284-5745 Email: [email protected]

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Highlights  Peak bone mass is the maximum bone mass accrued during growth and development, with consolidation during early adulthood.  Peak bone mass is typically achieved at different skeletal sites from age 25 to age 35 years.  Low peak bone mass results either from failure to achieve peak genetic potential, or from processes that cause bone loss at younger ages than typically seen.

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Any condition or disorder limiting bone growth, or acquisition of bone mineral, during childhood, puberty, or adolescence will lead to lower premenopausal peak bone mass than would otherwise have been achieved. The multiple causes of low peak bone mass in premenopausal women may be broadly categorized to include heritability/genetic causes, endocrine disorders, nutritional disorders, chronic diseases of childhood or adolescence, medications and idiopathic causes.

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Abstract

Peak bone mass is the maximum bone mass that accrues during growth and development.

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Consolidation of peak bone mass normally occurs during early adulthood. Low peak bone mass

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results from failure to achieve peak bone mass genetic potential, primarily due to bone loss

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caused by a variety of conditions or processes occurring at younger ages than usual. Recognized

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causes of low peak bone mass include genetic causes, endocrine disorders, nutritional

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disorders, chronic diseases of childhood or adolescence, medications, and idiopathic factors.

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Keywords: Osteoporosis; Osteopenia; Peak Bone Mass; Premenopausal Status; Fractures

1. Introduction

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Peak bone mass (PBM) is defined as the maximal bone mineral density (BMD) that is accrued

during growth and development, with subsequent consolidation that continues during early adulthood

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[1]. In healthy girls, the rate of bone mass accrual (Fig. 1) peaks during puberty between 11 and 14 years [2] and falls dramatically after 16 years of age [2], within about 2 years after menarche [3]. Although women gain most of their PBM during their adolescent years, bone density continues to increase after adolescence and peaks around the age of 25-35 years, depending on the site in the skeleton [4]. For each 0.5 standard deviation (SD) increase in PBM, lifetime fracture risk is estimated to 2

decrease by 40% [5]. Therefore, puberty and adolescence is a crucial period for PBM accrual and any interruption of normal physiology by illness or other factors may lead to reduction in eventual PBM, as shown in Fig. 2.

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Low PBM in women may be due to failure to achieve peak genetic potential by the mid-30s, primarily due to processes that cause bone loss to occur at younger ages than typically seen. Any condition or disorder limiting bone growth, or acquisition of bone mineral, during childhood, puberty, or adolescence will necessarily lead to lower PBM than would otherwise have been achieved in an individual. Many conditions or disorders may cause significant bone loss in young women, just as they

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do in older adults.

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The multitude of recognized causes of low PBM in women may be broadly categorized to

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include heritability/genetic causes, endocrine disorders, nutritional disorders, chronic diseases of

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childhood or adolescence, medications, or idiopathic (Table 1). This review discusses some of the more common and important causes of low PBM in women and supports the importance of identifying and

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correcting risk factors when present.

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2. Heritability and Genetic Causes

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Heredity exerts powerful effects on PBM. Various studies in twins and families have shown that about three-fourths of the variance in PBM is determined by genetic factors. Harris et al. found a

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heritability of 77% for lumbar spine BMD and 72% for femoral neck BMD [6] and Moreira Kulak et al. reported that 71% of premenopausal women with low bone mass have a family history of osteoporosis

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[7]. Various genetic polymorphisms and syndromes have been identified to play an important role in the variance of PBM. 2.1. Vitamin D receptor gene polymorphisms The relationship between polymorphisms in the gene encoding the vitamin D receptor (VDR) and BMD has been extensively studied, with conflicting results. VDR polymorphisms account for more 3

than 1 SD difference in femoral and vertebral BMD between the homozygous recessive (aa, bb) and homozygous dominant (AA, BB) genotypes, with the homozygous dominant genotypes associated with higher bone mineral density [8]. In contrast, Ferrari et al. [9] found that VDR polymorphisms at the BsmI

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restriction site are associated with BMD in prepubertal and adolescent girls, but not in premenopausal adult women and Gunnes et al. [10] found no relationship between VDR genotypes at the BsmI restriction site and forearm BMD in healthy children, adolescents, or young adult women. Notwithstanding these varying results, two meta-analyses concluded that VDR polymorphisms account for about 0.3 SD difference between alternate homozygotes [11];[12].

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2.2. Estrogen receptor-alpha gene polymorphisms

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Differences in BMD associated with estrogen receptor-alpha (ERα) gene polymorphisms were

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first described in Japanese women in 1995 [13]. Thereafter, several other studies found similar

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associations in other populations [14];[15]. In premenopausal women, it was reported that the ERα gene XbaI polymorphism was associated with BMD [14]. However, a more recent study showed that

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this relationship only occurred in association with the ERα gene PvuII polymorphism and not with the

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ERα gene XbaI polymorphism, whereby women with dominant (PP) genotypes have higher average lumbar spine BMD values than those with recessive (pp) genotypes [16].

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2.3. Collagen 1 alpha 1 gene polymorphisms

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Extensive studies have evaluated correlations between collagen 1 alpha 1 (COL1A1) gene polymorphisms BMD and fracture risk, again with conflicting results. The Sp1 binding site of the COL1A1

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gene was found to be associated with nonvertebral [17] and vertebral fracture risk [18]. However, Erdogan et al. [16] found no relation between the COL1A1 gene at the Sp1 binding site and BMD. The meta-analysis by Mann et al. [19] concluded that COL1A1 gene polymorphisms are associated with a significant increase in risk of osteoporotic fracture, particularly vertebral fractures, with a modest reduction in BMD.

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2.4. Other gene polymorphisms Other gene polymorphisms have also been identified to be related to BMD and/or osteoporotic fracture risk, including those in the interleukin-6 gene, interleukin-1 receptor gene, transforming growth

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factor beta-1 (TGFβ1) gene, insulin-like growth factor-1 (IGF-1) gene, calcitonin receptor gene, parathyroid hormone receptor gene and apolipoprotein E gene [20]. Each of these polymorphisms is thought to contribute in a small way to PBM and fracture risk [20].

3. Endocrine Disorders

Optimal levels of thyroid hormone, growth hormone (GH), IGF-1 and gonadal sex steroids are

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crucial for completion of normal skeletal growth, puberty and bone mineral accrual. Longitudinal bone

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growth is largely GH-dependent before puberty, but estrogen is essential for epiphyseal fusion [21] and

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bone mineral acquisition during the adolescent years [22]. The importance of normal endocrine

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function for bone mineral acquisition is apparent from studies of several clinical hormonal disorders. 3.1. Growth hormone deficiency

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GH levels increase dramatically during normal puberty and its action on bone is mediated

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through hepatic production of IGF-1 that positively affects bone growth and bone turnover by

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stimulating osteoblasts, collagen synthesis and longitudinal bone growth [23];[24]. Therefore, reduced bone mineral density is commonly seen in children with GH deficiency (GHD) who fail to acquire bone

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mineral at the expected rate [24], with consequential low PBM in adult life, if left untreated [25];[26]. Studies have demonstrated a significant increase of bone mineral content/density in children with GHD

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after one year of recombinant human GH (rhGH) therapy [27];[28]. 3.2. Hypogonadism Estrogen exerts various effects on skeletal cell activity via estrogen receptor-alpha and -beta (ERα and ERβ) [29] and is directly involved in skeletal growth and bone mineralization [30]. During puberty, estrogen stimulates GH secretion from the pituitary gland and GH exerts its effects on bone 5

growth as discussed above. Estrogen also increases the amplitude of pulsatile GH release, further potentiating its effect [31]. However, estrogen has also been shown to antagonize the effects of GH and IGF-1 by inducing mineralization and epiphyseal fusion with simultaneous inhibition of GH-dependent

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longitudinal growth of bones [32]. Estrogen is involved in the synthesis of various cytokines and growth factors by osteoblasts. Estradiol stimulates synthesis of TGF-β, IGF-1 and IGF-II and inhibits the synthesis of other cytokines (IL1, IL-6 and TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colonystimulating factor (M-CSF) and prostaglandin E2 (PGE-2), all of which are involved in the regulation of

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bone resorption [33]. TGF-β prevents bone resorption by inhibiting the recruitment of osteoclast

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precursors as well as the activity of existing osteoclasts, in addition to increasing alkaline phosphatase

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activity in osteoblasts [34]. IL-1, IL-6 and IL-11 are known to increase proliferation of osteoclast

osteoclast differentiation [35];[36].

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precursors and subsequently stimulate their differentiation [33], whereas TNF-α and M-CSF modulate

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The osteoprotegerin (OPG)/receptor activator of nuclear factor kB ligand (RANKL)/RANK system

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has been suggested to be the principal signaling pathway involved in bone remodeling [37]. Binding of RANKL to RANK receptor leads to osteoclast activation and differentiation and inhibition of osteoclast

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apoptosis, whereas OPG blocks binding of RANKL to RANK receptor, thus preventing activation of

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osteoclasts. Estrogen stimulates gene expression involved in osteoblast synthesis of OPG and its level is positively correlated with serum OPG [38]. Synthesis and activation of OPG leads to inhibition of the

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terminal phase of osteoclastogenesis, attenuation of the activation of mature osteoclasts and induction of osteoclast apoptosis [39]. Consequently, estrogen is considered to be a principal regulator of skeletal homeostasis in both men and women. Estrogen deficiency during puberty and adolescence has serious consequences for skeletal mineralization, which is reflected in high bone turnover, low PBM in adult life and increased risk

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for future fractures. There are multiple causes of estrogen deficiency in adolescent girls, some of which will be discussed in detail in the following sections of this review. Therefore, disorders resulting in estrogen deficiency during childhood or adolescence should be identified and estrogen therapy should

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be initiated at the appropriate developmental stage to prevent impairment of skeletal mineralization. 3.3. Turner’s syndrome

Women with Turner’s syndrome have increased fracture risk [40];[41].

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documented reduced BMD in this group of patients with variable estrogen deficiency [42];[43]. However, this bone defect may not be just due to estrogen deficiency. Failure to reach normal PBM

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despite adequate hormonal replacement therapy in young women with Turner’s syndrome who had

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normal BMD at the time of puberty [44] suggests that Turner’s syndrome causes an intrinsic bone defect

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that does not respond fully to estrogen therapy. Bakalov et al. [45] reported that women with Turner’s

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syndrome have lower BMD at cortical but not trabecular sites compared with age-matched women with primary ovarian failure and concluded that this selective deficiency in cortical bone is probably related

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to haploinsufficiency for bone-related X-chromosome genes.

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3.4 Hyperthyroidism

Reduced BMD is known to be a serious consequence of untreated hyperthyroidism in adults.

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However, there are limited data on the effects of hyperthyroidism on PBM in premenopausal women.

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Mora et al. [46] demonstrated that serum thyroid hormone levels correlated inversely with lumbar spine and whole body BMD and positively with urinary N-terminal telopeptide of type I collagen (uNTX) levels

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in 13 girls aged 5.0-14.9 years who were diagnosed with hyperthyroidism. The untreated hyperthyroid girls had significantly lower lumbar spinal and whole body BMD and significantly higher uNTX levels compared with healthy controls. However, BMD and uNTX were no longer different after 12 and 24 months of anti-thyroid drug treatment in the hyperthyroid girls. In a group of young adults previously diagnosed with childhood/adolescent onset of Graves’ disease who had been treated, Radetti et al. [47]

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found normal lumbar spinal and femoral neck BMD and concluded that childhood/adolescent onset of Grave’s disease, when appropriately treated, does not limit attainment of PBM. 3.5. Type 1 diabetes mellitus

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Type 1 diabetes mellitus (T1DM) is one of the most common chronic pediatric diseases. Patients may fail to attain normal PBM due to multiple metabolic derangements associated with poorlycontrolled T1DM, with the consequence of developing osteoporosis and fractures later in life. Children with T1DM typically have hypersecretion of GH with low levels of IGF-1, which exerts negative effects on skeletal growth. During puberty, insulin requirements increase owing to the effects of physiological

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pubertal insulin resistance [48]. Low BMC has been found to correlate with low IGF-1 levels in children

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with diabetes (49). Low levels of IGF-1 are possibly due to portal insulinopenia [50], which in turn

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stimulates hypersecretion of GH [51], leading to hepatic GH resistance, that may further lower the levels

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of IGF-1.

Osteocalcin is an osteoblast-derived hormone that has been shown to regulate bone formation

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as well as beta-cell function, body adiposity and overall glucose metabolism [52];[53]. In T1DM, serum

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osteocalcin is negatively correlated with HbA1c levels and leptin, which correlate positively with body adiposity [54]. Low osteocalcin levels are associated with long duration of T1DM and correlate inversely

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with hemoglobin A1c (HbA1c) and body mass index (BMI) [55]. Reduced serum osteocalcin is thought to

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be due to reduced number or function of osteoblasts, contributing to reduced bone formation in T1DM. Hyperglycemia is known to generate advanced glycation end-products (AGEs) in patients with diabetes. Children and

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AGEs may promote osteoblast apoptosis [56] and induce bone resorption [57].

adolescents with T1DM have higher levels of serum RANKL and OPG and significantly lower BMD compared with controls [58] and plasma OPG levels significantly correlate with HbA1c in pre-pubertal children with T1DM [59]. Additionally, children with T1DM have higher levels of serum sclerostin and

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Dickkopf-1 compared to healthy controls. Sclerostin and Dickkopf-1 are endogenous inhibitors of the Wnt signaling pathway in osteoblasts [60] that lead to reduced bone formation.

4. Nutritional disorders

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Multiple nutrients are required for skeletal development, growth and maintenance. These include total protein intake, as well as vitamins C, D and K and the minerals calcium, phosphorus, copper, manganese and zinc [61]. Normal homeostasis of these nutrients is dependent on the daily balance between absorbed intake and excretory loss.

Disorders resulting in nutrient deficiency,

especially calcium and vitamin D deficiency during childhood, may affect attainment of normal PBM.

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4.1. Anorexia nervosa

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Anorexia nervosa (AN) is a condition associated with severe energy deprivation and low body

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weight, with peak age of onset during adolescence, when 40-60% of PBM is normally accrued. Young

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people with adolescent onset of AN have not yet attained their PBM. Patients with past history of AN have a two- to three-fold increased risk of fracture [62]. Studies have consistently shown a reduction in

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BMD, both in adult [63] and adolescent patients [64];[65], with lumbar spinal trabecular bone density

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most severely affected. Adult women with active AN lose bone mass at the rate of 2.5% per year [63].

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Adolescent girls with AN have a lower number of lumbar spine trabeculae, decreased thickness of trabeculae, and a paradoxical increase in bone marrow adipose tissue compared to healthy controls

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[66];[67]. Adolescent girls with AN also have reduced bone strength as shown by lower failure load as estimated by finite element analysis [66]. Studies of bone turnover markers in adults and adolescents

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with AN have reported conflicting results. Adult patients have reduced bone formation markers and increased bone resorption markers [68], whereas adolescent patients have both deceased formation and resorption markers, suggestive of suppression of bone turnover [69]. Impaired bone health in AN may also be attributed to changes in body composition due to malnutrition and multiple endocrine disruptions. Patients with AN have both low BMI and lean body 9

mass that can lead to low BMD [70]. Additionally, the paradoxical increase in bone marrow adipose tissue has been found to be associated inversely with BMD in adults and adolescents with AN [71]. Following treatment of AN in adolescent girls, there is an increase in body weight and lean body mass

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associated with an increase in BMD [68]. Multiple changes and adaptations in multiple endocrine axes in patients with AN may have detrimental effects on bone health, leading to decreased bone formation and/or increased bone resorption [71]. These changes may include energy conservation by avoiding reproductive activity through suppression of the hypothalamic-pituitary-gonadal (HPG) axis, or mobilization of substrates to

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increase energy availability for vital functions through activation of the growth hormone axis and the

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hypothalamic-pituitary-adrenal (HPA) axis.

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Suppression of the HPG axis leads to hypogonadism with low levels of gonadal sex steroids,

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which have an important role in bone metabolism, with consequent low BMD, as discussed in the section on hypogonadism above. Patients with AN have increased levels of OPG [72], but a decreased

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ratio of OPG/RANKL which may lead to bone loss [72];[73]. Later age of onset of menarche and longer

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duration of amenorrhea have been found to be important determinants of low BMD in adolescent girls with AN [71];[74]. Activation of the growth hormone axis in AN increases GH secretion to increase

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lipolysis for substrate availability for body functions [75].

However, increased lipolysis results in

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increased growth hormone resistance with low levels of IGF-1, with consequential decreased bone formation.

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Similarly, increasing cortisol secretion through activation of the HPA axis in AN leads to

increased gluconeogenesis for substrate availability for body functions, which exerts deleterious effects on bone health [76]. Hypercortisolemia causes low BMD due to decreased bone formation and increased bone resorption. It also inhibits the HPG axis, impairs calcium metabolism by the gut and the kidney and inhibits OPG and increases RANKL secretion. Patients with AN also have low leptin [73],

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increased adiponectin [77] and peptide YY levels [78] and ghrelin resistance [79]. Leptin and ghrelin have been shown to stimulate osteoblast activity and increase bone formation whereas adiponectin and peptide YY are associated with low BMD in AN [77];[80].

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4.2. Inflammatory bowel disease The majority of children diagnosed with inflammatory bowel disease (IBD) are between the ages of 6 and 17 years [81], a period when most bone mass accrual occurs. IBD may interfere with attainment and maintenance of peak bone mass. Some studies suggest that patients with Crohn's disease are at greater risk of low BMD than those with ulcerative colitis [82];[83]. In a prospective study

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of 47 children and adolescents with IBD, Laakso et al. [84] found no improvement in bone mass accrual

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during puberty. Lumbar spine BMD and whole body bone mineral content (BMC) are significantly lower

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in patients who were pubertal at study onset and completed pubertal development during follow-up,

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indicating suboptimal PBM attainment during puberty. Mauro et al. [85] also found that premenopausal women have significantly lower BMD if they had Crohn's disease diagnosed before the age of 16 years

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compared to after age 16. Linear growth and lean body mass, which are positively related to bone mass

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accrual [86];[87], have been shown to be reduced in children or adolescents with IBD [88]. Children and adolescents with IBD are at risk of hypogonadism with delayed puberty and/or menstrual irregularity.

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Leptin is known to play an important role in regulation of the human reproductive system and its level is

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highly dependent on nutritional status and body fat [89], which are commonly low in patients with IBD. Additionally, nutritional factors such as use of hyperalimentation, vitamin D deficiency, or calcium

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malabsorption are associated with low BMD in adolescents with IBD [90] and accelerated bone loss may occur due to the use of glucocorticoid therapy [91];[92]. IBD is an inflammatory disease associated with production of inflammatory cytokines such as IL-1, IL-6 and TNF-α, which have deleterious effects on bone health as discussed above in the section on hypogonadism. 4.3. Celiac disease

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Celiac disease (CD) is an autoimmune disorder with malabsorption in individuals who are exposed to gluten. It may be associated with low BMD due to malabsorption, hypogonadism, or inflammation, with an abnormal RANKL/OPG ratio that favors bone resorption [93];[94].

Tissue

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transglutaminase antibody levels correlate inversely with BMD [95]. Trovato et al. [93] reported that 22% of children with CD had BMD Z-scores between −2.0 and −1.0 and 13% had BMD Z-scores less than −2.0, whereas Jatla et al. [96] found lower BMC for both lumbar spine and whole body in children at time of CD diagnosis compared with healthy controls, with a persistently significant difference in whole body BMC between groups, after adjusting for height.

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5. Chronic diseases of childhood and adolescence

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Multiple chronic diseases of childhood and adolescence resulting in decreased bone formation

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and/or increased bone resorption may affect attainment of normal PBM.

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5.1. Chronic kidney disease

Chronic acidosis, vitamin D deficiency and phosphate-induced secondary hyperparathyroidism in

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patients with chronic kidney disease (CKD) are known to have deleterious effects on bone health. In

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children with CKD, malnutrition, abnormal GH/IGF-1 axis and delayed puberty can aggravate these

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effects, leading to failure of normal PBM accrual. These patients have increased levels of GH with GH resistance and low IGF-1 levels. They also have increased levels of IGF binding proteins, resulting in

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decreased bioactivity of IGF-1 [97];[98]. Increases in unmineralized bone (osteoid) with delayed rates of mineral deposition are common in children with CKD [99]. In a cohort study, Groothoff et al. [100]

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reported that patients with juvenile onset of CKD had a mean BMD Z-score of -2.12 at the lumbar spine and -1.77 at the femoral neck. Low lean body mass was found to be associated with low lumbar spine BMD and low femoral neck BMD. The 2009 KDIGO guideline suggested that routine BMD testing should not be performed due to lack of evidence that BMD predicted fracture risk in patients with chronic kidney disease-mineral bone disease (CKD-MBD), as compared with the general population [101]. With 12

the demonstration that measurement of BMD by DXA predicted fractures in adults with CKD stages 3 to 5 in subsequent prospective cohort studies, the 2017 KDIGO guideline suggests that BMD testing be done to assess fracture risk if results will impact treatment decisions in patients with CKD with evidence

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of CKD-MBD and/or risk factors for osteoporosis [102]. However, to date, there are no data regarding use of DXA BMD for fracture risk prediction in children with CKD, although one prospective study found that lower cortical volumetric BMD based on tibial peripheral quantitative computed tomography predicted incident fractures [103]. 5.2. Chronic liver disease

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Bone disease is very common in patients with chronic liver disease (CLD). Patients with CLD

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have decreased bone formation due to decreased osteoblast proliferation and activity. Unconjugated

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bilirubin has been shown to impair osteoblast proliferation in a dose-dependent fashion [104]. Diamond

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et al. [105] found that cirrhotic patients had reduced osteoblast surface, bone formation rates and serum osteocalcin levels, consistent with reduced osteoblast function. In addition, the proinflammatory

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cytokines IL-1, IL-6 and TNF-α are increased with hepatic inflammation and fibrosis [106], leading to

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increased bone resorption and bone loss.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in

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children. Pardee et al. [107] found that obese children with NAFLD had significantly lower BMD Z-scores

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(−1.98) than obese children without NAFLD (0.48), and that among those children with NAFLD, children with nonalcoholic steatohepatitis (NASH) had a significantly lower BMD Z-score (−2.37) than children

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with NAFLD who did not have NASH (−1.58).

6. Medications Multiple medications have been identified to cause increased bone resorption and/or decreased bone formation, leading to bone loss or low PBM if they are used during the crucial period for PBM

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accrual (Table 1). Some of the medications commonly used by premenopausal women that exert deleterious effects to bone health are discussed here. 6.1. Glucocorticoids

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Glucocorticoids are widely used in treatment of patients with chronic noninfectious inflammatory diseases, such as chronic lung diseases, connective tissue diseases, and inflammatory bowel disease and in organ transplantation.

Low BMD and growth retardation are common

complications in children or adolescents on long-term glucocorticoid therapy. Low BMD and failure to attain normal PBM due to glucocorticoid therapy are thought to result from multiple factors, including

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direct suppressive effects of glucocorticoids on bone formation [108] and resorption [109], changes in

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intestinal [110] and renal [111] calcium handling, as well as impairment of the HPG [112] and GH/IGF-1

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[113] axes. Glucocorticoids directly affect osteoblasts, osteocytes and osteoclasts. Histomorphometric

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studies in patients on glucocorticoid therapy show fewer osteoblasts with a decreased lifespan, increased osteocyte apoptosis and decreased osteoclast production but with prolonged lifespan

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[108];[109]. With long-term therapy, the number of osteoclasts is usually unchanged, but the number Glucocorticoids reduce

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of osteoblasts and bone formation are substantially reduced [108];[109].

intestinal calcium absorption [110] and inhibit renal reabsorption of calcium [111], leading to a net

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negative calcium balance that can adversely affect bone mineralization. Additionally, glucocorticoids

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can also cause hypogonadism via direct suppression of pituitary luteinizing hormone (LH) secretion [112] and attenuation of GH secretion [113], resulting in bone loss.

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6.2. Drugs that decrease sex steroid levels Drugs that reduce sex steroids in premenopausal women include contraceptives, aromatase

inhibitors and gonadotropin releasing hormone (GnRH) analogues. Depot medroxyprogesterone, a widely used injectable contraceptive, is known to cause loss of BMD in premenopausal women due to induction of low estrogen levels [114]. This bone loss is partially reversible when treatment is stopped

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[115].

Aromatase inhibitors, which reduce endogenous estrogen levels by blocking peripheral

conversion of androgen to estrogen, are used to treat early-stage estrogen receptor-positive breast cancers in women. Aromatase inhibitors are known to increase rates of bone loss [116] and fracture risk

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[117]. In premenopausal women, GnRH analogues may be used for in vitro fertilization, gonadal preservation with chemotherapy and treatment of precocious puberty, endometriosis, or uterine fibroids. GnRH analogues suppress production of LH and follicle stimulating hormone from the pituitary gland, leading to substantial reductions in sex hormone production [118], with consequent bone loss and low BMD.

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6.3. Oral contraceptives

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Extensive studies done to evaluate the effects of oral contraceptives on bone mass in

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adolescents and young adult women have shown no effect of oral contraceptives on bone mass in the

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majority of the studies [119];[120]. However, a recent study by Gersten et al. [121] showed significantly lower bone mass accrual in adolescent girls aged 12-18 years while taking 20 µg estradiol compared with

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7. Idiopathic

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a reference group not taking estradiol.

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Women may be diagnosed with idiopathic low PBM if they have low BMD without an identifiable cause. These women tend to have smaller stature, lower body mass index and a family

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history of osteoporosis [122];[123]. In various studies they have been found to have higher bone resorption markers, but normal bone formation markers compared with controls, suggestive of

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increased bone resorption without changes in bone formation, as an underlying mechanism for bone loss and failure to attain normal PBM.

8. Management All women are advised to follow healthy diet and lifestyle recommendations to maintain bone health. Recommendations include adequate calcium and vitamin D intake, adequate weight bearing 15

exercise, smoking cessation and avoidance of excessive alcohol intake. Pharmacological therapy is rarely needed for premenopausal women with isolated low BMD without history of fracture. Low BMD may be due to genetically determined low PBM, but treatment for low BMD in premenopausal women

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with known secondary causes should be directed to the underlying cause. Data on the effect of antiresorptive or anabolic therapy in premenopausal women are scarce, making it difficult to recommend optimal pharmacological management in this group of patients. Bisphosphonate therapy is recommended for the treatment of glucocorticoid-induced osteoporosis in premenopausal women [124]. However, bisphosphonates should be used with caution in women of

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childbearing potential due to their ability to accumulate in the maternal skeleton, cross the placenta

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during subsequent pregnancy and accumulate in the fetal skeleton, as has been shown in mice [125].

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Denosumab and teriparatide are FDA-approved treatments for postmenopausal osteoporosis, but safety

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and long term effects in young women are not known. Therefore, these agents should be used with caution and reserved for premenopausal women with low BMD and high risk of fracture or recurrent

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fractures. Premenopausal women with osteoporosis who have fractures may be treated with oral

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contraceptive therapy, if not contraindicated, or teriparatide if necessary. Teriparatide wears off quickly when it is stopped, which may minimize the risk of adverse effects in an early pregnancy.

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9. Conclusion

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Normal PBM accrual during childhood, adolescence, and young adulthood is a complex process involving genetic determinants and effects of gonadal sex steroids and GH/IGF-1. Nutritional and other

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environmental factors, including chronic diseases during childhood or adolescence, may affect the attainment of PBM due to various mechanisms, leading to decreased PBM and increased risk of osteoporosis and higher fracture risk later in life. This review supports the importance of identifying risk factors for low PBM in premenopausal women. The presence of underlying disorders likely to cause reduced PBM should be addressed as early as possible to prevent low PBM. 16

Contributors

Conflict of interest The authors declare that they have no conflict of interest.

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Funding

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The two authors contributed equally to the preparation of this review.

Provenance and peer review

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No specific funding was received for the preparation of this review.

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References

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This article has undergone peer review.

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Fig. 1. Bone mass gain during adolescence. Yearly increase in bone mineral density (BMD) at lumbar spine (L2-L4) and femoral neck. Reproduced with permission from Theintz G., Buchs B., Rizzoli R., et al: Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J. Clin. Endocrinol. Metab. 75 (1992) 1060-1065.

A

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EP

TE

D

Fig. 2. Diagrammatic representation of the bone mass life-line in individuals who achieve their full genetic potential for skeletal mass and in those who do not. (The magnitude of the difference between the curves is not intended to be to scale.) Reproduced with permission from R.P. Heaney, S. Abrams, B. Dawson-Hughes, et al. Peak Bone Mass. Osteoporos. Int. 11 (2000) 985-1009.

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SC RI PT U N A M D TE EP CC A TABLE 1. Causes of low peak bone mass in premenopausal women

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A

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EP

TE

D

M

A

N

U

SC RI PT

Heritability/Genetic syndrome Genetic polymorphisms Turner syndrome Hypogonadism during adolescence Hypogonadotropic hypogonadism Permanent, e.g. Kallman’s syndrome, idiopathic Delayed, e.g., constitutional delay, anorexia nervosa Hypergonadotropic hypogonadism Gonadal dysgenesis Gonadal failure, e.g., autoimmunity, chemotherapy, radiation exposure Estrogen receptor defect Other endocrine disorders Growth hormone deficiency Hyperthyroidism Cushing’s disease Diabetes mellitus Rickets/osteomalacia Nutritional Chronic dietary calcium/vitamin D deficiency Malnutrition Nutritional disorders Anorexia nervosa Inflammatory bowel disease Celiac disease Cystic fibrosis Chronic diseases of childhood and adolescence Chronic kidney disease Chronic liver disease Cancer Rheumatologic disorders Connective tissue diseases Osteogenesis imperfecta Marfan syndrome Ehlers-Danlos syndrome Medications Glucocorticoids Depot medroxyprogesterone Aromatase inhibitors GnRH analogues Immunosuppressants (e.g. Cyclosporine) Antiepileptic drugs (particularly cytochrome P450 inducers, such as phenytoin and carbamazepine) Chemotherapeutic drugs Idiopathic

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