Keywords

Introduction

The shape and size of bones define our physical selves and provide protection for internal organs and leverage sites for muscles. These mechanical properties of the skeleton create a static image of bone health, with impaired microarchitecture of bone and consequent fracture hallmarks of tissue failure. Yet bone is constantly created, modeled, and remodeled throughout the course of a woman’s life, and its structure and health are intimately involved with calcium metabolism and sustenance of bone marrow cells. This chapter will discuss the systemic and local factors that affect bone health throughout the life of a woman, emphasizing the vulnerable, living quality of bone that is often lost in translation when tests are interpreted and treatments recommended. It is written with the intent to provide an overview of bone health in women, and to highlight current controversies.

Fetal Growth and Development

The fetal skeleton is formed predominantly by a process called endochondral bone formation, in which an anlage of the skeleton is laid down by chondrocytes, before osteoblasts are recruited to replace this with bone. Of the 206 bones formed by the skeleton, each bone is distinct, defined by its location and function and whether it informs the shape of the right or the left. Signaling in the growth plate, vascular invasion, and chondrocyte alignment all affect this process. Movement of the fetus is critical in defining bone shape and strength. By 9 weeks, the skeletal patterning has occurred [1]. Errors in the quality of collagen deposition (osteogenesis imperfecta), the timing and efficacy of mineralization (hypophosphatasia), and the definition of skeletal shape by chondrocytes (achondroplasia) result in impaired skeletal strength and function for the life of the individual. Many of these mutations are sporadic; some are inherited as autosomal dominant, some as recessive. Some of these mutations are associated with advanced paternal age.

During the 2nd and 3rd trimesters of pregnancy, adequate growth and mineralization of bone is required, and dramatic changes in 1,25-dihydroxyvitamin D (calcitriol) occur in the maternal circulation to effect this [2]. Maternal vitamin D insufficiency has been linked to increased risk for intrauterine growth retardation, preeclampsia, gestational diabetes, and higher rates of caesarian section [3]. How much vitamin D and in which populations were questions explored in a randomized clinical trial of supplementation in an endemically vitamin D-deficient Arab population. The findings from this study argue that vitamin D3 4,000 IU daily is safe and effective in ensuring adequate maternal vitamin D without adverse events [4]. While vitamin D sufficiency seems essential in fetal health, controversy exists whether maternal vitamin D insufficiency has long-lasting effects on skeletal health [5–8].

Screening by amniocentesis and imaging by ultrasound can begin to detect musculoskeletal abnormalities in utero. The ethical argument about how best to manage these findings is being raised by medical and laypersons across the country. Does early termination of pregnancies marked by Down’s, achondroplasia, or osteogenesis imperfecta deprive a population of diversity and the human obligation of kindness [9]? Many who inherit these diseases struggle for identity and accommodation.

Childhood and Adolescence

The median age of menarche in the USA is 12.5 years, with 90 % of adolescent girls beginning their menses by age 13 [10]. Why this is critical to bone health has to do with the determinants of peak bone mass, which include normal puberty, regular menses, normal weight, and adequate nutrition. Children grow comparably during early childhood, but with puberty, girls with robust bones will grow differently from those with slender bones. Girls with small build tend to have endocortical infilling by age 8, 3 years earlier than their large-boned counterparts, and tend to have more porous bones in which there is cellular suppression of remodeling [11]. Not only does structure of these bones convey different thresholds for enduring extreme stress, such as military training, but the bone composition seems to carry different cellular physiology as well.

As systems biology is sorting out the consequences of altered cellular physiology on the structural integrity of bone [12], there are some clarion issues during adolescence in terms of skeletal health. This is when most growth – hence bone modeling – occurs over the 3 years or so before epiphyseal closure. Normal menstruation, estrogen levels, and nutrition are critical at this time. The bone mass accrual that occurs after puberty reflects mostly cortical bone apposition. Once peak bone mass is achieved by the mid-20s to early 30s, this will define a set point in a woman’s life. Just as in fetal health, there is this window for skeletal patterning, so in adolescent health there is a window for bone growth and accrual of mass. Anorexia nervosa [13, 14], the female athlete triad [15], and drugs such as Depo-Provera [16] may result in lasting consequences to the skeleton, and teenagers should be screened for these issues. Adolescents should be counseled to receive adequate calcium, vitamin D, and caloric intake, avoid alcohol, and resist cigarette smoking.

Because of the changing size and shape of bones, bone mineral density examinations should be avoided in childhood and adolescence, as there is a tendency to compare them with normal young adult data, to misinterpret the Z scores, to report osteoporosis when none exists, and to overlook discrepancies in bone age. If needed, a bone mineral density in a child or adolescent should be done in a pediatric center familiar with these considerations. Fractures do occur at this age, and reflect rate of bone growth and vulnerable skeletal integrity. Some fractures occur simply due to excessive force or trauma. Studies have been published that address the question of whether childhood fracture predicts a fragility fracture later in life [17, 18]. The answer seems to be no.

Adolescence is a complicated time for all children but marked by significant illness in some. Depression, neuromuscular diseases (cerebral palsy), cancer, asthma, and juvenile inflammatory arthritis occur at this age; obesity is epidemic. These may result in inactivity, compromised height (steroids or chemotherapy), and complications of growth plates and modeling (micrognathia, leg length discrepancies, slipped capital femoral epiphysis, scoliosis, and spondylolisthesis). Endocrinopathies (delayed onset menses), inherited disorders of connective tissue (Marfan’s), and storage diseases (Gaucher’s) may all complicate skeletal growth and development.

As we do not know how to duplicate this phase of bone growth and bone mass accrual that occurs in early adolescence, these diseases may have devastating events in bone health. The safety of bisphosphonates has a mixed record in this population, diminishing fractures in some (osteogenesis imperfecta) [19, 20] and improving bone mineral density in others (anorexia nervosa) [13, 14]. Whether this will translate into significant gains in bone quality or in bone health in adults remains unclear [21]. It should be stressed that despite efficacy by the measurement of some parameters, e.g., bone mineral density or decreased fracture risk, there is no study on long-term safety in this vulnerable population [22, 23].

The importance in thinking of bone as vital tissue that is constantly remodeled is exemplified by this use of bisphosphonates in young women. These drugs have a long half-life in bone and are gradually released from the bone matrix over months to years. Their mechanism of action is usually one of inhibiting farnesyl synthase, an enzyme critical in the prenylation of small G proteins. This interferes with cytoskeletal rearrangement necessary for bone resorption. As we learn about bone turnover, we are beginning to understand that osteoclasts play an important role in balancing the skeletal needs for repair, the body’s needs for calcium, and the signals involved in bone formation [24]. Disturbing this interplay of bone cells with their environment should be done cautiously in the young and with specific endpoints of easing disease manifestations such as fragility fracture, rather than surrogate markers of bone turnover such as bone mineral density or bone turnover markers.

The creep of bisphosphonates into the premenopausal population where they are used for non-life-threatening diseases – such as accelerated bone loss in inflammatory rheumatic diseases and in patients with glucocorticoid-induced bone loss – has been largely unstudied in these terms. The bisphosphonates are classified as category C drugs by the FDA (alendronate (Fosamax), risedronate (Actonel), zoledronic acid 4 mg (Zometa)) and category D (pamidronate (Aredia), zoledronic acid 5 mg (Reclast)). As the FDA writes “There are no adequate and well-controlled studies in pregnant women.” Animal studies do show these drugs pass through the placenta and are adsorbed by fetal skeletons. Although the only data we have on pregnancy in humans are scattered case reports, there remains a serious risk of harm intuited from animal data. Women should be counseled not to become pregnant while taking these drugs [25–28]. There is a brief discussion of this by Dr. Susan Ott in the http://courses.washington.edu/bonephys web pages under Normal Pregnancy in which these case studies are cited.

Pregnancy itself does not confer a risk for lifelong osteoporosis in most women. Calcium recruited from the maternal skeleton for fetal and then newborn health seems rapidly restored as breast-feeding ends. Rarely, regional or systemic osteoporosis complicates pregnancy in a woman.

Premenopause

It is clear that bone loss is occurring in some women before menopause. Premenopausal fractures may indicate risk or predict subsequent fracture in this still young population [29, 30]. Estrogen deficiency might be treated with hormone replacement therapy until the normal age of menopause (about 52 years) if there is no contraindication. Drugs enhancing bone loss should be identified – aromatase inhibitors, proton pump inhibitors, steroids, and thiazolidiones – and discontinued when possible. Calcium must be sufficient in the diet and supplemented when not. Calcium is best taken with food. Malabsorption should be sought as one factor that may contribute to impaired nutrition and mineralization. Exercise, reasonable sunlight, and vitamin D 800–1,000 IU daily should be ensured. A dogmatic approach to low bone mineral density reports should be avoided. Fracture is less common in younger women, and evaluation for secondary causes of osteoporosis should be aggressive (Table 3.1).

Table 3.1 Some determinants of bone loss and fracture risk
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Postmenopause

The issue that brought bone health to the forefront of medicine was the emergence of drugs effective in the treatment of osteoporosis. According to the World Health Organization, there are an estimated 8.9 million fractures annually in the world. As America ages, this risk of fracture and the attendant morbidity and mortality it incurs are the subject of the rest of this chapter. The premise in this discussion is an understanding that postmenopausal bone is not the same as young bone and that in menopause with the loss of estrogen, there is enhanced remodeling with imperfect bone formation in response to bone resorption. Adipocytes become more prevalent in bone marrow and seem to play a role in driving some aspects of bone loss with aging [31]. Genetics play a significant role in the development of osteoporosis, and the concomitants of aging – osteoarthritis, gait instability, muscle weakness, and medications resulting in altered mental status or blood pressure changes – contribute to falls. In this population, intervention is safe and effective and should be undertaken.

Osteoporosis is defined as a skeletal disorder in which impaired microarchitecture of bone leads to a higher risk of fracture. Perhaps a natural process of aging, this has become a significant health problem as women live longer. Nearly 40% of Caucasian women will suffer an osteoporotic fracture in her lifetime; The ability to diagnose osteoporosis by bone mineral density has given physicians a chance to alter the consequences of this by improving bone strength with medication, diminishing bone loss, and thus decreasing the risk of fracture. Bone mineral density has proven an excellent correlate for fracture when interpreted in light of the patient’s age and risk factors for fracture (Fig. 3.1) [32, 33].

Fig. 3.1
figure 1

Age as a determinant of fracture risk plotted against bone mineral density (Used with permission from Heaney [76])

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Bone mineral density (BMD) interpretation depends on accurate positioning and appropriate interval testing to ensure a meaningful interpretation of the test. This is because bone loss is subtle in osteoporosis, and intervals of testing <2 years in untreated women will tend to result in variation rather than true difference. Interpreting bone mineral density changes from readings done on different BMD machines is difficult. A recent study on the indication for repeat testing by BMD argued that for those women with early osteopenia or normal BMD, the study might be repeated every 15 years rather than every 2 years [34]. This might be a bit dogmatic, as some women may be edging towards an indication for treatment based upon fracture risk assessment (see below), and it may be prudent to repeat BMD more frequently. While rates of fracture increase with age, the number of women with extant fractures are those with osteopenia. A good discussion on the evaluation and treatment of osteopenia may be found in a clinical case study written to address this in the New England Journal of Medicine 2007 (Fig. 3.2) [35, 36].

Fig. 3.2
figure 2

Fracture rates in women and women with fracture as plotted against BMD (Used with permission from Siris et al. [35])

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Wrist fractures occur early in postmenopausal women, followed by rising rates of spinal compression fractures by age 65 and hip fractures by 70. The epidemiology of fracture accounts for the recommendations by the National Osteoporosis Foundation that a woman be screened for osteoporosis at age 65 by BMD, earlier if she has identifiable risk factors for fracture. Prior fracture, increasing age and maternal history of hip fracture are some of these indications for early screening. In an effort to calculate the absolute risk of hip and other fractures in women, the FRAX was developed, which is an online fracture risk assessment tool that uses the BMD at the hip, the patient’s age, and corresponding risk factors to develop a 10-year risk of fracture [77]. While FRAX is an imperfect tool, since it fails to assess bone loss in the spine and fails to account for prior treatment, it is useful for creating a threshold for treatment. FRAX also helps women put into real terms their own personal fracture risk.

It is easy to treat a postmenopausal woman for osteoporosis, and yet our inclination to do so seems marginal [37, 38]. Even if we do write out a prescription for a bisphosphonate, compliance with the medication is poor without good communication about goals and length of treatment with the patient. In the USA, bisphosphonates, raloxifene, estrogen, denosumab, and teriparatide are available for the treatment of osteoporosis. Their indications, complications, and controversies are reviewed in Table 3.2, where references are provided for each of these issues.

Table 3.2 Overview of medications in postmenopausal women with osteoporosis
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Vitamin D and calcium are essential to ensure the proper mineralization of bone, but by themselves will not mitigate the risk of bone loss in the early postmenopausal years. There may be some efficacy in fracture reduction in their use in the elderly [67]. This is an active area of research [68].

There has been considerable controversy in the literature about the role vitamin D and calcium play in preventing osteoporotic fractures and the risk of supplemental calcium in the epidemiology of renal stones and cardiovascular disease [69–72]. Despite these arguments in the literature, all women deserve adequate nutrition for bone mineralization. If they are unable to achieve this through dietary calcium, then supplements are needed to achieve a calcium balance near 1,200 mg daily for older adult women. Generally, vitamin D3 800–1,000 IU daily reflects adequate intake. This information is readily available to the public on the National Osteoporosis Foundation website (www.nof.org) and the National Institutes of Health, Osteoporosis and Related Bone Diseases (www.niams.nih.gov).

Many patients with end-stage renal disease have poor bone quality, and some have adynamic bone disease. Antiresorptive drugs – bisphosphonates and denosumab – are probably poor choices in the setting of low bone turnover. Concurrent metabolic problems such as hyperparathyroidism and elevated FGF23 indicate other insults to bone. Teriparatide is not an option in this setting. While renal transplant patients are routinely given intravenous bisphosphonates prior to transplantation in an effort to mitigate the high risk of posttransplant fracture, there is no clear physiologic basis for this [73, 74].

In postmenopausal women, glucocorticoid therapy is associated with a high risk of fracture, particularly vertebral compression fracture, even in those with normal bone mineral density. Bisphosphonates and teriparatide [66] have demonstrated efficacy in mitigating this fracture risk and should be instituted within weeks to months of initiating therapy. Controversy exists around the wisdom of using antiresorptive agents such as the bisphosphonates in such settings [75], but these theoretical concerns have not yet been translated into clinical practice guidelines or current recommendations.

As “women hold up half the sky,” they have been a vulnerable target for drug companies. There is direct marketing to the consumer. Estrogen, once on the cover of Time magazine as “every woman’s dilemma” June 1995, was transformed from a positive intervention to one filled with more risk than benefit. In addition, the rapid newspaper coverage of toxicities and the changing impressions of the academic community on the wisdom of estrogen, calcium, and vitamin D use have left both patients and practitioners bewildered. Understandably, women have become more skeptical of these medications due to post-marketing reports of complications (atypical femoral fractures, osteonecrosis of jaw). Still, in the postmenopausal population, there is much good to be gained from prudent use of these drugs.

By thinking about bone as a living tissue and by understanding the impact of drugs on bone and the controversies that surround bone health, it is possible to weigh the benefits and risks of each of these medications in a woman’s life. My own recommendation is to limit skeletal exposure to these long-acting bisphosphonates, consider drug holidays after 3–5 years in the postmenopausal woman with osteoporosis, and reassess the need for these drugs at all in women of childbearing years. The references are meant as an updated guide to these issues.