Secondary Osteoporosis

Gregory R Emkey, Pennsylvania Regional Center for Arthritis & Osteoporosis Research, Wyomissing, PA, United States
© 2018 Elsevier Inc. All rights reserved.

Introduction 1
Endocrinology 2
Glucocorticoid Excess 2
Primary Hyperparathyroidism 2
Hyperthyroidism 3
Growth Hormone Deficiency 3
Acromegaly 3
Male Hypogonadism 3
Diabetes Mellitus 4
Vitamin D Deficiency 4
Rheumatologic and Inflammatory 4
Systemic Lupus Erythematosus 4
Rheumatoid Arthritis 5
Ankylosing Spondylitis 5
Neurologic 5
Spinal Cord Injury/Immobilization 5
Parkinson’s Disease 6
Multiple Sclerosis 6
Hematologic/Oncologic 6
Multiple Myeloma/Monoclonal Gammopathy of Undetermined Significance 6
Thalassemia Major 6
Systemic Mastocytosis 7
Infectious Disease 7
Human Immunodeficiency Virus (HIV) 7
Nephrology 8
Idiopathic Hypercalciuria 8
Psychiatry 8
Anorexia Nervosa 8
Gastrointestinal 8
Celiac Disease 8
Inflammatory Bowel Disease 9
Bariatric Surgery 9
Pulmonary 9
Chronic Obstructive Lung Disease (COPD) 9
Transplantation Medicine 10
Transplantation Osteoporosis 10
Drugs Associated With Bone Loss 10
Depot Medroxyprogesterone Acetate (DMPA) 10
Aromatase Inhibitors 10
Thiazolidinediones 10
Acid-Suppressive Medications 11
Antiepileptic Drugs 11
Selective Serotonin Reuptake Inhibitors 11
Heparin 12
Antihypertensives 12
Summary 12
References 12

Introduction

Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase
the susceptibility to fracture. It is estimated that 10 million Americans over the age of 50 have osteoporosis, and tens of millions
more are at risk. Bone mineral density testing has been the accepted standard for screening for this disease, and is routinely targeted
at postmenopausal females by general clinicians.

Encyclopedia of Endocrine Diseases, 2nd Edition https://doi.org/10.1016/B978-0-12-801238-3.65820-8 1

2 Secondary Osteoporosis

Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor
other than aging or postmenopausal status. A wide array of diseases, treatments, and medications can affect bone quality in men
and women of all ages, which is often not reflected in bone density testing. In light of the significant public health burden caused by
osteoporosis, a recognition and understanding of these factors is of utmost importance. The following is an organ-system based
review of the more common causes of secondary osteoporosis, with a focus on pathogenesis.

Endocrinology
Glucocorticoid Excess
Endogenous overproduction or systemic administration of glucocorticoids is a well-known cause of bone loss, and is the most
common iatrogenic cause of osteoporosis seen in clinical practice (Weinstein, 2011). The pathogenesis includes diverse effects on
three main cell types in bone biology, changes in calcium handling, as well as increased falls related to steroid-induced myopathy
(Natsui et al., 2006; Canalis et al., 2007). As many as 30%–50% of patients receiving chronic glucocorticoid therapy will experience
a fracture, making this a major contributor to the morbidity and mortality associated with steroid-responsive chronic diseases such
as lupus, rheumatoid arthritis, giant cell arteritis, transplant recipients, inflammatory bowel disease, and COPD (Steinbuch et al.,
2004; Angeli et al., 2006).
Glucocorticoids cause decreased production of osteoblast precursors and increased apoptosis of mature osteoblasts (Weinstein
et al., 1998; O’Brien et al., 2004). Histomorphometric studies have confirmed decreased numbers of osteoblasts on cancellous bone
in patients with glucocorticoid-induced osteoporosis (GIO) with associated thinning wall width. Decreased osteoblast differenti-
ation is in part mediated through inhibition of wingless (Wnt)/B-catenin signaling, as the expression of Dickkopf-1 and sclerostin,
both antagonists of Wnt signaling, can be enhanced by glucocorticoids (Ohnaka et al., 2005; Gifre et al., 2013). Enhanced apoptosis
of osteocytes is also seen, which are the main mechanosensing cells of bone that contribute to the ability to withstand significant
compressive forces.
While glucocorticoid therapy can decrease osteoclast production, the lifespan and activity of osteoclasts are increased, thereby
maintaining their effect relative to the decreased osteoblastic number and activity. Studies have shown increased production of
receptor activator of NF-kB ligand (RANKL) which promotes osteoclastic activity and survival, and suppression of osteoprotegerin
(OPG), a natural decoy receptor for RANKL (Hofbauer et al., 1999; Humphrey et al., 2006). Additionally, glucocorticoids have been
shown to confer a prosurvival effect directly to osteoclasts, independent of alterations in RANKL and OPG, in the early stages of
steroid exposure in mice (Jia et al., 2006). The bone abnormalities may also be enhanced by the decreased sex hormone secretion
because of suppressed hypothalamic-pituitary function.
Bone loss occurs quickly with glucocorticoid therapy and appears to be biphasic, with as much as a 6%–12% loss in BMD within
the first year, followed by a continued annual loss with ongoing therapy (LoCascio et al., 1990). Biochemical markers of bone
turnover are affected as early as 1–2 months following initiation of therapy, and the bulk of bone loss is seen within the first
6 months (Saag et al., 1998). Addressing the deleterious effects of steroid therapy on bone is imperative early on in the course,
particularly if long term use (i.e., 90 days or longer) or moderate to high dose (>7.5 mg/day) is planned. Risk factors associated with
GIO include advanced age, low BMI, dose and duration of glucocorticoid, as well as other traditional factors (Weinstein, 2012).
Bone density testing is recommended at the onset of therapy as a general screening, though changes in the mechanical qualities of
bone may occur prior to any changes reflected in BMD testing. Treatment recommendations are based on dose, additional risk
factors, prior fractures, and an updated guideline was recently published, and both anabolic and antiresorptive therapies may be
used in addition to calcium and vitamin D supplementation (Buckley et al., 2017; Saag et al., 2007).

Primary Hyperparathyroidism
Parathyroid hormone (PTH) is critically involved in calcium and phosphorus homeostasis, and continuous exposure to elevated
levels in primary hyperparathyroidism (PHPT) are known to be catabolic to the skeleton. The contribution to osteoporosis is so well
established that in patients with PHPT significant metabolic bone disease is generally considered an indication for parathyroidec-
tomy (Bilezikian et al., 2009). The majority of patients with PHPT are postmenopausal females, with an incidence as high as 1 in
500 reported in this population (Bilezikian et al., 2009). PHPT preferentially affects areas rich in cortical bone more so than
cancellous bone, therefore evaluating distal forearm and femoral neck BMD is recommended (Khan and Bilezikian, 2000).
Vertebral fracture prevalence is increased, both in symptomatic and asymptomatic patients (Cipriani et al., 2015).
The precise mechanism of bone loss in PHPT is not completely understood. Histomorphometrically, persistently elevated levels
of PTH induce a state of high bone turnover and have been associated not only with a low BMD but also with alterations in the
mineralization density distribution and collagen crosslinks affecting bone stiffness and quality (Roschger et al., 2007; Zoehrer et al.,
2008). At the cellular level, compared with healthy controls, patients with PHPT had a low OPG/RANKL ratio favoring a state of
bone resorption, which improves following parathyroid surgery (Szymczak and Bohdanowicz-Pawlak, 2013). The effects of PHPT
on Wnt pathway signaling is still being elucidated. Taken together, the finding of increased bone turnover, low BMD, and
reduced bone quality appear to confer an increased risk of fracture in PHPT, highlighting the need for proactive screening of
bone disease.
 Secondary Osteoporosis 3

Hyperthyroidism
Thyrotoxicosis is an established cause of high-turnover osteoporosis, and many studies have shown a consistent decrease in BMD
and increase in fracture risk in patients with untreated hyperthyroidism (Vestergaard and Mosekilde, 2003; Ross, 1994). While bone
loss has been documented at all skeletal sites, there is preferential involvement of cortical bone, suggesting the need to screen distal
forearm BMD (Greenspan and Greenspan, 1999; Svare et al., 2009). While the cause of the hyperthyroidism may not matter, the
severity is an important factor, as a TSH of <0.1 mU/L was associated with a threefold increase risk of hip fracture and a fourfold
increase risk of vertebral fracture in a cohort of postmenopausal females, even in subclinical thyroid disease (Blum et al., 2015;
Bauer et al., 2001).
The effect of thyrotoxicosis on bone was felt to be mediated by the effects of T3 through its interaction with nuclear receptors
TR-a and TR-b, and excessive stimulation of these receptors leads to accelerated bone remodeling and ultimately osteoporosis.
Additionally, recent evidence has shown that thyroid stimulating hormone (TSH) may be a negative regulator of bone turnover, as
decreased expression of TSH-receptor leads to a high turnover state and low BMD (Abe et al., 2003). Bone-protective effects of TSH
include increased osteoblastic differentiation, and inhibited osteoclast formation (Baliram et al., 2017). This has important
implications for other situations with low TSH such as subclinical hyperthyroidism and use of thyroid replacement medications
in cancer, etc. In hypothyroidism the use of highly sensitive TSH measurements has allowed a more accurate control of patients on
replacement therapy and it is recommended that values be kept in mid normal range to avoid bone sequelae (Garber et al., 2012).

Growth Hormone Deficiency

Growth hormone (GH) is an important determinant of longitudinal bone growth and development of skeletal maturity, and
children with GH deficiency exhibit short stature and reduced peak bone mass (Giustina et al., 2008). The anabolic effect of GH on
osteoblasts appears to be dependent upon insulin-like growth factor 1 (IGF-1), whose production by the liver and osteoblasts is
stimulated by GH (Andreassen and Oxlund, 2001). The local interaction of IGF-1 and its binding proteins regulate GH receptor
(GHR) on osteoblasts, mediating some effects of GH on bone (De Jesus et al., 2009). A marked reduction in bone turnover is seen
histomorphometrically in adult-onset GH deficiency, primarily affecting cortical bone (Bravenboer et al., 1996). This is associated
with a lower BMD, and a fracture risk two to three times that of osteoporotic patients without GH deficiency (Wüster et al., 2001).
Treatment with GH replacement has been associated with a decrease in the fracture rate (Mazziotti et al., 2006).

Acromegaly
Acromegaly is associated with significant increase in markers of bone turnover due to the effect of excess GH and IGF-1 on
osteoblasts and osteoclasts (Ueland et al., 2006). Studies on the effect of acromegaly on BMD are nuanced due to the structural
changes in bone influencing the accuracy of testing, as well as the common finding of concurrent hypogonadism. Overall, the BMD
in acromegalics is generally preserved, with some showing a relative decrease in trabecular bone density (Kayath and Vieira, 1997;
Scillitani et al., 2003). Despite a preserved BMD, several studies document increased bone turnover and an increased incidence of
vertebral fractures compared with a control population, influenced by factors such as the duration of active acromegaly, serum
IGF-1 levels, and postmenopausal status (Mazziotti et al., 2013, 2015; Bonadonna et al., 2005).

Male Hypogonadism
Androgens are important for developing and maintaining skeletal health in men (Clarke and Khosla, 2009). Serum testosterone
levels decline with aging starting around the 5th decade of life in men, a time after which approximately 85% of cortical bone loss
occurs (Mohr et al., 2005; Ebeling, 1998). In addition to aging, medications such as androgen deprivation therapy (ADT) cause an
abrupt decline in androgen levels. In vitro studies have shown that androgens, via the androgen receptor, can stimulate osteoblastic
cell proliferation, upregulate TFG-b and IGF-1 (involved in bone formation), and downregulate IL-6 (involved in bone resorption)
(Kasperk et al., 1989, 1997). Testosterone also contributes to bone health indirectly in men via its conversion to estrogen by
aromatase in peripheral tissues (including osteoblasts and osteocytes), and men with low estrogen, or decreased aromatase activity,
can present with low BMD (Riggs et al., 2002; Leder et al., 2003; Miedlich et al., 2016). Estrogens play a role in both bone resorption
and bone formation in men. Several large studies have shown a relationship between low serum estradiol levels in men and low
BMD (Amin et al., 2000; Travison et al., 2009). In addition to these direct effects on bone, low testosterone may also be associated
with increased falls, a clear risk factor for fractures (Vandenput et al., 2017).
Measurement of sex hormone levels can be valuable in the workup and prognostication of bone health in men with
hypogonadism. While low testosterone levels are associated with decreased bone mass and muscle strength, a much stronger
correlation with fracture risk is seen with low bioavailable estradiol levels or high sex hormone binding globulin (SHBG) levels
(LeBlanc et al., 2009; Barrett-Connor et al., 2000; Vandenput et al., 2016). The highest correlation with fracture was when both the
bioavailable estradiol level was low and the SHBG level was high. Hypogonadism, whether from aging, surgery, or a medication, is a
major cause of osteoporosis in men, and the relative contributions of alterations in estradiol, testosterone, and SHBG need to be
better defined. In symptomatic patients, testosterone replacement therapy can also serve to improve the bone density at the spine
4 Secondary Osteoporosis

and later the hip, though concern of side effects and lack of antifracture efficacy affect its primary use to treat hypogonadal bone
disease (Seftel et al., 2015).

Diabetes Mellitus
Both type 1 (T1DM) and 2 diabetes mellitus (T2DM) are increasingly associated with deleterious effects on the skeleton (Inzerillo
and Epstein, 2004; Epstein and Leroith, 2008). Compared with healthy controls, there was a 12-fold increased risk of hip fracture in
T1DM and a 1.7-fold increase in T2DM seen in the Iowa Women’s Health Study (Nicodemus et al., 2001). A similar increase in
fracture risk was seen in the Women’s Health Initiative in those with T2DM, even after adjusting for frequent falls and BMD changes
(Bonds et al., 2006). T1DM is associated with decreased BMD and failure to achieve peak bone mass (Pan et al., 2014). In T2DM,
however, there is often a normal or elevated BMD, implicating a decline in the quality of the bone as a contributor to fracture risk
(Ma et al., 2012). In T2DM, structural changes such as increased intracortical porosity, as well as decreased material strength seen in
micro-indentation testing, may explain fracture risk despite lack of BMD changes (Burghardt et al., 2010; Farr et al., 2014).
The osteoporosis associated with DM is one of low bone turnover, with decreased markers of osteoblastic activity (Bouillon
et al., 1995). Insulin and amylin have anabolic effects on bone, and their decrease in T1DM may lead to impaired bone formation
likely through decreased IGF-1 (Kemink et al., 2000; Fowlkes et al., 2011). Additionally, mouse models of insulin-dependent
diabetic osteopathy have shown an increased expression of Dkk1 and SOST, both antagonists of Wnt signaling and osteoblastogen-
esis (Hie et al., 2011). The accumulation of advanced glycation endproducts and lower enzymatic collagen crosslinks contribute to
altered biomechanical features of diabetic bone showing the importance of glycemic control over time (Khosravi et al., 2014).
In diabetes there is increased bone marrow adiposity which has been linked with osteoporosis (Rosen and Bouxsein, 2006).
Peroxisome proliferator activator receptors (PPARs), especially PPAR-gamma, are transcription factors and nuclear receptors
involved in glucose metabolism, and have been shown to be potent regulators of adipogenesis. The mesenchymal stem cells in
the bone marrow microenvironment can experience an adipogenic or osteogenic fate, and PPARs and their ligands rosiglitazone and
pioglitazone appear to drive the differentiation toward adipocytes and away from osteoblasts (Kawai and Rosen, 2010). This has
important implications as these agonists are commonly used in the treatment of T2DM (see below under drugs). In addition to the
above cellular mechanisms of bone compromise in DM, other factors such as retinopathy-induced visual impairment, neuropathy-
induced balance problems, renal osteodystrophy from dialysis, and renal transplantation all add to the fracture burden. In addition,
sarcopenia contributes to an increased risk for falls and fractures in this population (de Liefde et al., 2005). Close attention should
be given to bone health in diabetics of all ages, as fractures are an increasingly recognized complication.

Vitamin D Deficiency
Deficiency of vitamin D is leads to reduced intestinal absorption of calcium and phosphorus, resulting in secondary hyperpara-
thyroidism and demineralization of bone (Sai et al., 2011). The main sources of vitamin D are diet and sunlight exposure; lack of
fortification of foods and increased appreciation of the harmful skin effects of excessive sunlight exposure have contributed to the
amount of vitamin D deficiency seen in clinical practice. Serum 25(OH)D is best indicator for vitamin D status in clinical practice,
and while 20 ng/mL is generally considered the threshold for defining insufficiency with regards to bone health, optimal calcium
absorption and control of secondary hyperparathyroidism have been seen closer to 30 ng/mL (Sai et al., 2011; Heaney, 2004).
Extreme examples of the skeletal effects of vitamin D deficiency are seen in cases of osteomalacia, or rickets in children, where there
is a softening of the bones caused by an increase in the unmineralized osteoid component of the bone matrix.
Due to the difficulty involved in isolating the effect of vitamin D on clinical outcomes, and the heterogeneity of
the investigations, the magnitude of its effect on bone loss is debated, but most studies agree that levels of 25(OH)D below
20 ng/mL are associated lower BMD (Bischoff-Ferrari et al., 2004a; Lips et al., 2001). For similar reasons, the effect of vitamin
D deficiency on fracture risk is difficult to quantify, but large population studies of both men and women agree that hip fracture risk
is higher in those with a 25(OH)D level below 20–25 ng/mL (Cauley et al., 2008, 2010; Looker and Mussolino, 2008). The
contribution of vitamin D deficiency to muscle weakness and falls is debated, though recent review suggests supplementation can
reduce falls in adults (Bischoff-Ferrari et al., 2004b; Kalyani et al., 2010). While there is debate about the definition of optimal
vitamin D level for bone health, there is agreement that levels below 20 ng/mL are associated with lower BMD, increased fracture
risk, and decreased efficacy of pharmacologic and nonpharmacologic interventions for osteoporosis.

Rheumatologic and Inflammatory

Systemic Lupus Erythematosus
Low BMD is described in up to 50% of female patients with systemic lupus erythematosus (SLE) (Yee et al., 2005). In addition to
traditional risk factors, bones of SLE patients are affected by use of corticosteroids and other immunosuppressive drugs, physical
inactivity, and vitamin D deficiency on the basis of sun avoidance (Yee et al., 2005; Bultink, 2012; Lane, 2010). While HR-pQCT
studies have documented decreased bone strength in SLE patients on glucocorticoids, a recent study saw similar changes in SLE
patients without steroid exposure implicating effects of the disease rather than medications (Tang et al., 2013). Osteoclast-inducing
inflammatory cytokines are known to be elevated in SLE and contribute to bone loss (Walsh et al., 2005). An elevated risk of fracture
 Secondary Osteoporosis 5

is seen, some citing as high as 12.5% of patient experiencing fractures, with age at diagnosis, duration of disease, and glucocorticoid
use increasing that risk (Ramsey-Goldman et al., 1999; Lee et al., 2007). As SLE commonly affects premenopausal females,
heightened awareness of the deleterious skeletal effects and fracture risk is important to prompt early screening.

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory arthritis associated with several forms of skeletal remodeling including
marginal joint erosions, periarticular osteopenia, and systemic osteoporosis. Low BMD and an increased risk for fracture have
been seen in RA patients compared with control populations, though confounding variables make the underlying mechanism of
bone loss somewhat difficult to elucidate. These include age, female sex, physical inactivity, disease severity, and use of medications
such as glucocorticoids. An association between disease severity and bone loss has been observed, though there has been no
consistent correlation between joint erosions and low BMD (Lodder et al., 2004; Solomon et al., 2009). Many of the cytokines and
growth factors known to be involved in RA-associated inflammation, such as IL-1, IL-6, TNFa, can promote osteoclastic activity
themselves or modulate the expression of the osteoclastogenic factor RANKL and its inhibitor OPG (Goldring and
Gravallese, 2000).
Further insights into the control of bone turnover in RA have come from studies of RANKL and OPG. In early, active, untreated
RA patients, an increased RANKL:OPG ratio, as well as increased CTX levels, were predictors of rapid and persistent bone damage
over an 11 year follow up (Geusens et al., 2006; van Tuyl et al., 2010). Consistent with these findings, TNFa blockade, an effective
treatment of the inflammatory process, has been associated with decreased systemic bone loss, and these effects correlate with a fall
in serum RANKL levels (Vis et al., 2006). In addition to an increased RANKL:OPG ratio, increased levels of Dkk-1 and sclerostin,
inhibitors of bone formation, have been found in the serum of RA patients (Terpos et al., 2011). Treatment with inhibitors of IL-6,
was associated with a favorable decrease in the RANKL:OPG ratio as well as a drop in the Dkk-1 and sclerostin levels and less bone
mass loss (Terpos et al., 2011; Tanaka et al., 2014). Clearly, monitoring for bone loss and instituting timely therapy is of utmost
importance in RA.

Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a chronic arthritis characterized by inflammation in synovial joints as well as the entheses. In contrast
to RA, the inflammation can be accompanied by increased bone formation, particularly at areas of entheseal inflammation such as
at ligament insertion sites in the spine. Osteoporosis is a known complication of AS, which can often go undiagnosed because of the
young, mostly male population affected. Osteoporosis is seen in up to 25% of patients with AS, with osteopenia seen up to 50% of
the time, and is usually associated with disease activity and duration (Ghozlani et al., 2009). The fact that bone loss can be seen early
in the disease process argue that immobility is not the primary cause (van der Weijden et al., 2012). Vertebral and nonvertebral
fractures are seen with increased frequency in patients with AS contributing to the morbidity of the disease, and are associated with
advanced age, longer disease duration, and degree of structural changes (Ghozlani et al., 2009; Mitra et al., 2000; Muñoz-Ortego
et al., 2014). Chronic systemic inflammation is apparent, as is progressive immobility, which both are thought to contribute to the
bone loss. Recent data indicate that there are negative changes in the bone microarchitecture, bone strength, and vBMD in AS
patients, which will prompt further investigations into the pathogenesis of bone loss in this group, and treatment directions (Nigil
Haroon et al., 2015). Bone health, activity levels, and fracture prevention are a significant aspect of caring for this disease, and need
to be addressed early in disease course.

Neurologic
Spinal Cord Injury/Immobilization
Spinal cord injury (SCI), or any situation that results in prolonged immobilization and skeletal unloading, is associated with bone
loss and an increased risk of fracture (Szollar et al., 1998; Zehnder et al., 2004). While DEXA is an important tool for screening for
low BMD, the most affected areas of the skeleton in SCI patients appear to be the distal femur and proximal tibia, areas not routinely
accessible, limiting the value of the test. Initially following SCI there is massive mobilization of calcium from the mineral phase of
bone, which can lead to complications such as hypercalcemia and hypercalciuria. Animal studies have shown an increase in
osteoclasts and bone resorption surfaces after only 72 h of rat leg immobilization, and decreased trabecular bone volume at 10 days
(Weinreb et al., 1989). In human SCI patients, there is a minor initial increase in markers of bone formation with a profound and
sustained increase in bone resorption markers that peaks at 10–16 weeks after immobilization (Chantraine et al., 1986; Roberts
et al., 1998). Following a stroke and immobilization, sclerostin levels are elevated, implicating a role for antagonizing the Wnt
pathway in the skeletal response to mechanical unloading (Gaudio et al., 2010). Any situation where there will be prolonged
offloading of the skeleton, such as with injuries or as extreme as with space travel, can cause profound bone density loss and needs
to be addressed proactively (Vico et al., 2000).
6 Secondary Osteoporosis

Parkinson’s Disease
Parkinson’s disease (PD) is a progressive neurologic disorder associated with reduced mobility and an increased risk of falling
(Pickering et al., 2007). Compared to age and sex-matched controls, there is a decrease in femoral neck and lumbar spine BMD,
25-OH vitamin D levels, and an increase in bone turnover markers in patients with PD (Abou-Raya et al., 2009; Ozturk et al., 2016).
There is a significantly increased risk of bone fracture in PD, particularly at the proximal femur, which is likely affected by disease
duration and severity and propensity for falls (Johnell et al., 1992; Invernizzi et al., 2009). In addition to traditional risk factors
affecting this population, such as advanced age and female gender, contribution to bone loss by reduced mobility, low BMI, poor
nutrition, and vitamin D deficiency appear to increase the risk of osteoporosis (Vaserman, 2005). Screening BMD and vitamin
D levels are recommended at the onset of disease as appropriate therapy may prevent progression of bone loss and risk of fracture
(Cummings and Eastell, 2016).

Multiple Sclerosis
Multiple sclerosis (MS) is a chronic demyelinating neurologic condition often leading to profound disability and functional
limitation. Low BMD, particularly at the hip, has been consistently shown in MS compared to a control population in both male
and female patients (Ozgocmen et al., 2005; Weinstock-Guttman et al., 2004). While factors such as vitamin D deficiency, frequent
courses of glucocorticoid therapy, and female gender are considered risk factors, the most important determinants of bone loss are
degree of functional impairment, advanced age, and duration of disease (Ayatollahi et al., 2013). In a large multinational
longitudinal cohort of women (GLOW), MS was one of the comorbidities that appeared to contribute significantly to fracture
risk, though quantifying the specific contribution of MS to fracture risk has yet to be done (Dennison et al., 2012). Vitamin
D deficiency is very prevalent in MS, though the extent of its role in the pathogenesis of bone loss in MS is unclear (Nieves
et al., 1994).

Hematologic/Oncologic
Multiple Myeloma/Monoclonal Gammopathy of Undetermined Significance
Hematologic malignancies can directly and indirectly affect bone contributing to generalized osteoporosis and pathologic fractures,
bone pain, and hypercalcemia. Multiple myeloma (MM) has the highest incidence of bone involvement of all malignant diseases. It
is estimated that 70% of patients present with bone pain in MM, and up to 60% of patients will develop a pathologic fracture during
their course (Kyle et al., 2003). The skeletal involvement of MM is a major contributor to the morbidity and mortality associated
with MM, and up to 90% of patients will develop generalized osteoporosis or lytic bone lesions (Roodman, 2004).
The bone loss in MM is driven by the uncoupling of bone turnover, with marked increase in osteoclastic bone resorption and a
decrease in the rate of bone formation, leading to generalized osteolysis. In the bone marrow microenvironment, MM cells produce
multiple factors that increase osteoclast production, activity, and survival. By binding to bone marrow stromal cells, MM cells
stimulate production of osteoclastogenic cytokines such as RANKL, M-CSF, and IL-6 by the stromal cells and production of
osteoclastogenic factors IL-3 and macrophage inflammatory protein 1a (MIP-1a) by the MM cells (Gunn et al., 2006; Giuliani
et al., 2004; Choi et al., 2000). The RANKL:OPG axis is altered in MM, with an increase in the ratio observed favoring production
and survival of osteoclasts (Giuliani et al., 2001). Osteoblasts are involved in MM-related bone disease with normal or low levels of
bone formation markers seen despite increased resorption, as well as decreased osteoid formation and osteoblastic activity observed
histologically (Zangari et al., 2011). Recent work has focused on over-expression of DKK-1, a Wnt signaling inhibitor, by plasma
cells in MM patients with bone lesions, as well as increased levels of DKK-1 in MM cells and circulating in the plasma (Tian et al.,
2003). Consistent with this finding, anti DKK-1 treatment in a murine model of MM resulted in prevention of the suppression of
osteoblast number and surface seen in MM, and an increase in the bone formation rate (Heath et al., 2009).
Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder with a prevalence of
nearly 7% in the population age 80 or older (Bida et al., 2009). MGUS is a premalignant condition, with roughly a 1% risk per year
of progression to MM. Despite the lack of osteolytic lesions seen in MGUS, there is an increased risk of fracture particularly at axial
sites, and the level of the paraprotein in the blood does not seem to correlate with this increased risk (Melton et al., 2004). RANKL
levels are elevated in MGUS, and recent studies suggest that there could be bone architectural changes in MGUS, as well as a rise in
serum DKK-1 and MIP-1a before progression to MM (Ng et al., 2011; Politou et al., 2004). Measurement of serum protein
electrophoresis and immunofixation are important in the evaluation of elderly patients with osteoporosis, particularly those with
unexplained fragility fractures, as that may be the first clue to an underlying plasma cell disorder that requires monitoring and
potential treatment.

Thalassemia Major
Metabolic bone disease is a known complication of thalassemia major (TM), with the incidence of osteoporosis reported as high as
50%, and an additional 45% of patients have osteopenia (De Sanctis et al., 2013). The precise pathogenesis of bone disease in TM is
incompletely understood. Contributing factors include delay in sexual maturation, hypogonadism, decreased growth hormone and
 Secondary Osteoporosis 7

IGF-1 levels, diabetes, hypothyroidism, and vitamin D deficiency (De Sanctis et al., 2013). There is a decrease in the activity of
osteoblasts and an increase in bone resorption, leading to a decrease in BMD (Perisano et al., 2012). Bone histomorphometry
studies in adolescents with TM showed increased osteoid thickness, osteoid maturation time, and mineralization lag time, all of
which indicate impaired bone maturation and mineralization (Mahachoklertwattana et al., 2003). Voskaridou et al. showed
elevated serum levels of Dkk-1 and sclerostin in thalassemic patients compared with healthy controls, as well as increased bone
turnover markers, all of which correlated with low BMD (Voskaridou et al., 2012). This may give clues to the pathogenesis of
thalassemic bone disease, and sclerostin may make a reasonable therapeutic target. In terms of osteoclastic activity in TM, recent
studies have shown elevated circulating levels of RANKL, a relatively preserved levels of OPG, yielding a shift in the RANKL:OPG
ratio favoring bone resorption (Morabito et al., 2007). Bone marrow expansion, another feature of TM, can have effects on cortical
thickness of bone and increased fragility (Perisano et al., 2012). Delays in recognition of TM-associated bone disease can lead to
serious consequences of fractures and skeletal deformities as survival improves, making screening BMD and controlling associated
risk factors very important early in the disease. Bisphosphonates are a reasonable starting place for treatment when warranted
(Giusti et al., 2016).

Systemic Mastocytosis
In systemic mastocytosis, there is diffuse infiltration of mast cells and their products such as histamine, prostaglandins, leukotrienes,
and cytokines (IL-1, IL-3, IL-6) into various tissues of the body. Diagnosis is based on mast cells infiltration on a bone marrow
biopsy as well as the finding of a c-kit point mutation or elevated serum tryptase levels. Osteoporosis at the spine, as well as vertebral
compression fractures, is a common finding in both men and women with mastocytosis (Rossini et al., 2011). Given the often mild
or nonspecific symptoms in indolent mastocytosis, the true incidence of this disease and the magnitude of its contribution to
idiopathic osteoporosis is unknown. One series of asymptomatic men with idiopathic osteoporosis showed bone marrow
infiltration with mast cells in 9% of cases (Brumsen et al., 2002). The role of mast cells in bone turnover is still being elucidated,
but a deficiency appears to induce a low remodeling state, whereas an abundance is associated with accelerated bone loss
(Chiappetta and Gruber, 2006). Older age, lower DKK-1 levels, and alcohol use have also been shown to be associated with
increased fracture risk (Greene et al., 2016). Serum IL-6 levels are elevated in patients with aggressive mastocytosis, as well as in
those with bone pain and osteoporosis, implicating a role for this osteoclastogenic cytokine in the pathogenesis of the bone loss
(Theoharides et al., 2002). All patients with systemic mastocytosis warrant BMD testing and evaluation for vertebral fractures, and
clinicians need to consider this disease in working up patients with idiopathic osteoporosis, and consider treatment when
appropriate with bisphosphonates.

Infectious Disease
Human Immunodeficiency Virus (HIV)
Osteoporosis is common in HIV infection, and has become a more important issue as treatment advances have allowed the HIV-
infected population to enjoy longer life expectancy. Up to 70% of patients with HIV have evidence of low bone density, and the risk
appears to increase with exposure to antiretroviral therapy (Brown and Qaqish, 2006). Multiple factors contribute to the patho-
genesis of bone loss in HIV infection, including smoking and alcohol use, low BMI, chronic inflammatory response, hypogonadism,
decreased physical activity, and growth hormone deficiency. There is a significantly increased risk of fracture, with a more than
fivefold higher risk of hip fracture compared with a healthy population (Güerri-Fernandez et al., 2013). While bone loss is described
independent of medications, use of highly active antiretroviral therapy (HAART) has been associated with higher incidence of
osteopenia possibly driven by increased osteoclastic activity and bone resorption and vitamin D deficiency (Marques de Menezes
et al., 2016; Nylén et al., 2016; Mastaglia et al., 2017). Within as little as 2 years after initiating HAART, a 2%–6% loss in BMD is
seen, as well as an increased risk of fracture, and this effect may stabilize over time (Yin et al., 2012).
Recent attention has focused on the effect of the viral infection itself on pathogenesis of bone loss. Analysis of expression levels
of miRNAs in HIV patients showed changes in genes involved in the TGFb and Wnt signaling pathways, implicating potentially
altered osteoblastogenesis and osteoclastogenesis, which requires further study (Del Carpio-Cano et al., 2013). With regards to the
effect of the infection, HIV viral protein R and HIV glycoprotein, gp120 can both upregulate RANKL (Fakruddin and Laurence, 2003,
2005). The proinflammatory cytokines induced by HIV infection include TNFa, and OPG, both of which can affect osteoclast
development and function (Amorosa and Tebas, 2006). The infection itself can also increase TNF-related apoptosis-inducing ligand
(TRAIL) which binds OPG, limiting the capacity of OPG to regulate RANKL-associated osteoclastogenesis (Herbeuval et al., 2005).
Combining this with experience of decreased BMD and increased fracture incidence, attention to bone health is of paramount
importance in those infected with HIV.
8 Secondary Osteoporosis

Nephrology
Idiopathic Hypercalciuria
Idiopathic hypercalciuria (IH) is defined as urinary excretion of calcium >4 mg/kg/day in women and >4.5 mg/kg/day in men
without any underlying metabolic cause. There is an association between hypercalciuria and low BMD, and the prevalence is
increased among Ca-containing stone-formers (Sakhaee et al., 2011; García-Nieto et al., 2003). This is consistent with studies that
report a fourfold increased risk of vertebral fracture observed among urolithiasis patients compared with healthy controls (Melton
et al., 1998). The deleterious skeletal effects of hypercalciuria in the absence of stone formation is not as well established as in stone
formers, and consideration should be given to a radiographic evaluation for asymptomatic stones in osteopenic patients, as this
could alter management decisions (Miller, 2012). Clearly bone loss needs to be aggressively addressed in stone forming IH, and the
significance of increased urinary Ca in the absence of stone formation needs to be determined by the clinician on a case-by-case
basis. Decreased BMD is even seen in children with IH, and is associated with decreased 25-OHD3 levels (Artemiuk et al., 2015).
The precise mechanism of bone loss in IH remains incompletely understood despite recent advances. Bone histomorphometry
studies have consistently documented decreased osteoblastic activity, mineralization rates, and osteoid surfaces (Sakhaee et al.,
2011; Malluche et al., 1980). IH is characterized by increased intestinal calcium absorption, increased bone resorption, and
decreased renal tubular calcium reabsorption (Heilberg and Weisinger, 2006; Pak et al., 2005). In 40%–60% of hypercalciuric
stone formers elevated circulating 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) levels are found, as well as increased monocyte
expression of vitamin D receptor (VDR) (Coe et al., 1982; Favus et al., 2004). Animal studies have confirmed role of 1,25(OH)2D3
in urinary calcium concentration and decreased BMD (Frick et al., 2013; Ng et al., 2014). The significance of these findings needs to
be determined in humans, but they begin to provide insights into potential pathogenic mechanisms of IH-related bone disease.

Psychiatry
Anorexia Nervosa
Anorexia nervosa (AN) is an eating disorder characterized by an obsessive fear of gaining weight and refusal to maintain an
adequate body weight, 10 times more common in females than in males. Significant caloric restriction and periods of amenorrhea
are the norm. Low BMD is a near universal finding in AN, often occurring in young adolescent females during a time of critical bone
mass accrual, with as many as 50% of young females with a z-score of less than
1 (Misra et al., 2004). Studies have documented the
detrimental effects of interruption of normal menstruation during adolescence on adult BMD (Wiksten-Almströmer et al., 2009).
The risk of fracture during childhood and early adult years is nearly 60% higher for AN females compared with healthy-weight
controls (Faje et al., 2014). Contributors to osteoporosis in this population include the low peak bone mass accrual, decreased
muscle mass, hypogonadism, decreased IGF-1 levels, and increased cortisol (Misra and Klibanski, 2011). Increased bone marrow
adiposity is seen in AN, despite decreased visceral adiposity, and this correlates inversely with BMD as it does in other disease states
(Bredella et al., 2009). During treatment of AN, bone density gains were more associated with increased fat mass, rather than
increased total body weight (Achamrah et al., 2017). Even in successfully treated AN, adults will have an increased risk of fracture
due to the low peak bone mass achieved, and screening for osteoporosis should be considered at a younger age.

Gastrointestinal
Celiac Disease
Celiac disease affects around 1% of the world’s population, and is characterized by inflammatory changes in the duodenum with
loss of normal small intestinal villi affecting dietary absorption. While classically thought to begin in childhood, it is now more
common to be diagnosed as an adult. The effect of celiac disease on bones has been established for a long time, with osteomalacia
historically complicating childhood disease, and low BMD affecting all ages. There is as much as a 17-fold higher prevalence of
celiac disease among patients with osteoporosis as compared to controls, suggesting the need for more intensive screening in this
population (Stenson et al., 2005). It is estimated that 40% of adults diagnosed with celiac disease will have osteoporosis, affecting
both women and men (Meyer et al., 2001). Low bone mass complicates all ends of the celiac spectrum, from severe to
asymptomatic disease (Mazure et al., 1994). A recent systematic review reported an increased risk of hip and nonhip fractures in
celiac patients compared with controls (Heikkilä et al., 2015).
The pathophysiology of bone loss in celiac disease is multifactorial, centered around inflammation, malabsorption, and
decreased intestinal absorption. Decreased absorption of calcium and vitamin D, as well as frequent avoidance of dietary calcium,
contribute to a net negative calcium balance and compensatory elevation in PTH (Keaveny et al., 1996; Chakravarthi et al., 2012).
The secondary hyperparathyroidism has been correlated with increased bone turnover and decreased BMD (Valdimarsson et al.,
2000). There has been a lot of attention recently on intestinal and systemic inflammation in celiac disease, with elevated levels of
inflammatory cytokines detected and correlate with bone loss (Fornari et al., 1998). The RANKL:OPG axis has been extensively
studied in celiac, and an increased ratio is seen favoring bone resorption (Taranta et al., 2004; Fiore et al., 2006). In addition to the
above factors, low BMI, hypogonadism, decreased physical activity often contribute to the bone loss associated with celiac disease.
Gluten free diet can improve the status of the bone disease, though the magnitude of the improvement is less in adult patients than
in children.
 Secondary Osteoporosis 9

Inflammatory Bowel Disease

Crohn’s disease and ulcerative colitis are two forms of chronic inflammatory bowel disease (IBD) and are associated with bone loss,
with as many as 40% having evidence of osteopenia (Frei et al., 2006). Risk of fracture appears to be elevated, though the magnitude
varies in different epidemiological studies (Vestergaard and Mosekilde, 2002; Loftus et al., 2002; Bernstein et al., 2000). The
pathophysiology is multifactorial, including the effect of osteoclastogenic inflammatory cytokines, intestinal malabsorption, low
BMI, malnutrition, decreased physical activity, and use of glucocorticoids (Rodriguez-Bores et al., 2007). Low bone mass has been
described in new-onset disease prior to any steroid therapy (Lamb et al., 2002). Lower BMD is associated with increased cumulative
dose of prednisolone and lower weight in young adults with IBD (Laakso et al., 2014).
Calcium intake and absorption is often poor in this population, and as many as 50% of patients with IBD are vitamin D deficient
(Ulitsky et al., 2011; Vernia et al., 2014). In Crohn’s disease, the primary tissue involved is at the terminal ileum, where the majority
of absorption of fat-soluble vitamins occurs, and resection of the terminal ileum has been described as one of the most important
determinants of developing osteoporosis (van Hogezand et al., 2006). The RANKL/OPG system has been implicated in the
metabolic bone effects of IBD, as elevated plasma levels of OPG are seen, as well as increased release of OPG from inflamed
colonic mucosa (Moschen et al., 2005). The elevated OPG levels correlate with lower BMD, and are felt to be a response to
osteopenia and RANKL driven osteoclastogenesis. There is little debate about the development of bone loss in IBD, though the
magnitude of the effect is still in question. Routine BMD testing, dietary questioning on calcium intake, and measuring of 25-OH
vitamin D levels are recommended for all patients at the onset of disease.

Bariatric Surgery
Obesity now affects nearly 30% of the US population, and using bariatric surgery to treat morbid obesity has become increasingly
popular (Ogden et al., 2014; Buchwald and Oien, 2009). Malabsorptive and restrictive bariatric procedures are successful for weight
loss and improvement in comorbid conditions such as diabetes and hypertension, but there has been growing recognition of the
negative skeletal effects that occur following the surgeries. Decrease in BMD has been consistently demonstrated in the 1 year
following bariatric surgery, as high as a 10% loss at the femoral neck and 3% loss at the lumbar spine (Vilarrasa et al., 2009). The
decrease in BMD is similar following Roux-en-Y gastric bypass and sleeve gastrectomy procedures (Vilarrasa et al., 2013). Decreased
calcium intake and absorption, low vitamin D, secondary hyperparathyroidism are common, though advanced age, menopausal
status, and greater lean mass loss seem to correlate more with degree of bone loss. Most studies to date use areal BMD (aBMD)
measurements to quantify bone density following surgery, a technique susceptible to artifactual changes in the setting of obesity and
profound weight loss, but a recent systematic review showed a significant decline in hip BMD and a trend toward decrease at the
spine at 1 year (Kalani et al., 2017).
Bone turnover markers are elevated as quickly as 3 months following bariatric surgery and persist through an 18-month follow-
up study (Sinha et al., 2011). This indicates a high turnover state consistent with the effect of elevated PTH. The same study also
showed that, even after a transient improvement in vitamin D and PTH levels following surgery (likely from aggressive repletion),
they both return to preoperative levels by 1 year. Another intriguing observation is that following gastric bypass surgery plasma
ghrelin levels fall, and the degree of this fall correlate with the degree of bone loss over 1 year (Carrasco et al., 2014). Ghrelin is a gut
derived peptide involved in energy homeostasis and growth hormone secretion, as well as a direct mitogenic and antiapoptotic
effect on osteoblasts (Fukushima et al., 2005). At this point, there are no consistent long-term data on fracture risk following
bariatric surgery. In addition to maintaining adequate calcium and vitamin D intake, all patients should have screening BMD done
at or before surgery, and have it closely monitored along with markers of bone turnover.

Pulmonary
Chronic Obstructive Lung Disease (COPD)
COPD and osteoporosis share many common risk factors such as smoking use, advanced age, and reduced physical activity
(Xiaomei et al., 2014). The addition of chronic steroid use, systemic inflammation, reduced muscle mass, hypogonadism, and
vitamin D deficiency augment the risk of bone loss in COPD patients. In a large study of 2699 newly diagnosed COPD patients, the
prevalence of osteoporosis was elevated compared to a non-COPD population (RR 3.1) (Soriano et al., 2005). Radiographic
emphysema, regardless of other factors or airway obstruction, is a risk factor for bone loss, indicating a possible common pathway
between lung parenchymal damage and bone loss (Bon et al., 2011). There is significant body composition change in COPD
patients, and the loss of fat-free mass is associated with osteopenia (Bolton et al., 2004). The increased risk of osteoporosis seems to
be present in both steroid-users and nonusers, though the rate of fractures is likely higher among those that frequently use oral or
inhaled corticosteroids, have more severe COPD, and low muscle mass (de Vries et al., 2005; Loke et al., 2011; Gonçalves et al.,
2017). Systemic inflammation in a feature COPD, including elevated levels of osteoclastogenic cytokines such as TNFa and IL-6
(Gan et al., 2004). Vitamin D deficiency is reported in nearly half of patients with COPD, and the level is associated with both BMD
and severity of the lung disease (Romme et al., 2013). Adding to the importance of addressing bone health in COPD patients, is the
fact that vertebral fractures negatively affect pulmonary function in general, thereby increasing the morbidity of both disease
processes (Schlaich et al., 1998).
10 Secondary Osteoporosis

Transplantation Medicine
Transplantation Osteoporosis
Transplantation is an increasingly viable option for the treatment of end-stage diseases of the kidney, heart, endocrine pancreas,
liver, and lung as well as for many hematological disorders. Immunosuppressive medications have improved patient and graft
survival, while at the same time allowing for better recognition of long-term complications of transplantation, including osteopo-
rosis and fractures (Ebeling, 2009). Posttransplant bone loss is multifactorial. The primary contributors are the immunosuppressive
medications, namely glucocorticoids and calcineurin inhibitors (CIs), though factors such as decreased mobility, poor nutrition,
hypogonadism, and the underlying disease all play a role (Epstein et al., 2003). High doses of glucocorticoids are often used,
especially in the immediate posttransplant time period, causing significant deleterious effects to bone by mechanisms reviewed
above. Cyclosporine (CsA) and tacrolimus (FK506) are the principle CIs used following a transplant, and both have been shown to
cause acute, rapid, and severe bone loss (Movsowitz et al., 1988; Kirino et al., 2004). Histomorphometrically, a high-turnover state
of bone remodeling was seen, with the resorption far exceeding the bone formation (Movsowitz et al., 1989).
Clinically, the bulk of the bone loss is in the first 6–12 months following transplantation, a time when close monitoring of BMD
and other risk factors is of utmost importance. BMD at the spine tends to improve especially at 1 year but cortical bone loss at the
femur continues to decline. Fragility fracture rates are generally elevated, and vary depending upon the organ transplanted,
osteoporotic BMD, underlying condition, dosage and duration of immunosuppression, and preexisting bone disease. Fractures
add significantly to the morbidity associated with transplantation, and every effort should be made to address bone loss in a timely
manner in this population.

Drugs Associated With Bone Loss

Depot Medroxyprogesterone Acetate (DMPA)
The injectable contraceptive DMPA (Depo-Provera) has been associated with decreased BMD which has received tremendous
attention because of its popularity as an effective form of contraception. In 2004, the US Food and Drug Administration attached a
black-box warning to its label, suggesting it should only be used as a long-term form of contraception only of other methods are
inadequate despite lack of long term serious skeletal events (Cromer et al., 2006). As a progestin-only contraceptive, it induces a
state of estrogen deficiency, which is the primary mechanism of its effect on bones (Cundy et al., 1991). A decrease in BMD is often
seen in the first 2 years of therapy, though the loss has been shown to be mild and dose-dependent, worse with prolonged use, and
reversible upon discontinuation (Curtis and Martins, 2006; Clark et al., 2006; Kaunitz et al., 2008; Lange et al., 2017). While
anything that can negatively affect bone mass, particularly during development and adolescence warrants caution and discussion
with patients, the use of DMPA as an effective form of contraception should not be avoided solely on the basis of its mild skeletal
effects.

Aromatase Inhibitors
Adjuvant treatment of hormone receptor positive breast cancer with an aromatase inhibitor (AI) is highly effective at decreasing the
reoccurrence of the disease in postmenopausal women. By blocking the peripheral conversion of androgens to estrogen, they reduce
endogenous production of estrogen by nearly 90%. This reduction in circulating estrogen has a deleterious effect on the skeleton,
and induces a state of increased bone turnover (Eastell et al., 2006). For example, after 5 years of therapy in the Arimidex,
Tamoxifen, Alone, or in Combination (ATAC), anastrazole was associated with a decline in BMD at the spine and total hip of
6.08% and 7.24%, respectively (Eastell et al., 2008). A retrospective study of nonosteoporotic AI users over 3 years, not on
bisphosphonate therapy, showed a steady decline in BMD as well as trabecular bone score, and altered hip geometry, indicating
bone structural changes occur early on in therapy (Hong et al., 2017). There is an increase in the fracture occurrence during AI
therapy, that seems to decrease upon cessation of therapy (Forbes et al., 2008). The presence of low BMD prior to treatment seems to
affect the fracture incidence, as 9.8% of women with baseline osteoporosis had a fracture during 3 years of AI therapy, compared
with 5.6% of those without baseline osteoporosis (Bouvard et al., 2014). Denosumab is proving to be an effective alternative to
bisphosphonate therapy for these patients (Nakatsukasa et al., 2017).

Thiazolidinediones
Thiazolidinediones (TZDs) are ligands for PPARg, and are commonly used in DM2 for improved glycemic control and insulin
sensitization. Evidence for the effects of TZDs on bone come from several mouse models, where PPARg deficiency is associated with
increased bone mass, and activation of PPARg with rosiglitazone resulted in increased marrow adipocytes, reduced bone formation,
and decreased expression of osteoblastogenic transcription factors (Ali et al., 2005). In the bone environment, PPARg controls
differentiation of cells of mesenchymal and hematopoietic lineages, and its activation can shift away from bone formation and
 Secondary Osteoporosis 11

osteoblastogenesis and increase adipogenesis (Beck et al., 2013). The increase in bone marrow fat is similar to that which is seen
with the aging process. Additionally, PPARg activation can inhibit the Wnt/B-catenin pathway and decrease IGF-1 production, both
of which have negative effects on bone formation (Moldes et al., 2003; Lecka-Czernik et al., 2007).
There is accumulating evidence that TZD use is associated with bone loss in humans, particularly in women. In the ADOPT study
(A Diabetes Outcome Progression Trial), a randomized controlled trial of 4360 patients with DM2 comparing treatment with
rosiglitazone, metformin, and glibenclamide, there was an increased incidence of fractures among women taking rosiglitazone
(9.3%) compared with metformin and glibenclamide (5.1% and 3.5%, respectively) (Kahn et al., 2008). In a subset of this study, a
significant increase in a serum marker of bone resorption (C-telopeptide) was seen in women taking rosiglitazone, not with the
other agents; there was no increase in markers of bone formation (Zinman et al., 2010). A meta-analysis confirmed the increased
risk of fracture among female long-term users of TZDs, along with decline of BMD at the total hip and spine of 1%–2% (Loke et al.,
2009). Evaluation of bone health should happen before prescribing TZDs for DM, and if fracture risk is elevated, other hypogly-
cemic medications are preferable.

Acid-Suppressive Medications
Acid-suppressive medications, proton-pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs), are some of the most
commonly prescribed medications worldwide. Studies have recently been reporting increased adverse consequences of chronic
acid suppression, one of which has been an increased risk of fracture. In a 1997 study of male hip fractures, Grisso et al. found an
increased risk in those that used cimetidine, an H2RA (Grisso et al., 1997). Several case–control studies have been done since that
time and have shown an increased risk of osteoporotic fractures among PPI users (Yang et al., 2006; Vestergaard et al., 2006; Gray
et al., 2010). The fracture data on H2RAs have been a bit more inconsistent, with some showing a slight increased risk, and others
actually showing a slightly decreased risk. The length of time and dose used appear to increase the adverse skeletal events (Grisso
et al., 1997). The effect of chronic acid suppression on BMD is unknown, with stable or mild decreases seen over short-term follow
up (Gray et al., 2010; Yu et al., 2008). In that study, females had a higher risk of nonspine fractures, and the increased risk in men
was only seen in those with poor calcium intake.
The leading hypothesis for the mechanism of adverse skeletal events in the setting of acid suppression was that it induces a state
of hypochlorhydria and affects calcium absorption leading to a negative calcium balance (Graziani et al., 1995). Recent studies have
refuted that finding that calcium absorption is the cause (Hansen et al., 2010). The difficulty in controlling for multiple confound-
ing factors has limited our understanding of the full scope of the effect of acid suppressive medications on bone health, and while
the overall fracture risk may be small, the large number of people potentially affected make this a serious issue. There is a possible
increased risk of fracture in patients cotreated with bisphosphonates and PPIs, and careful consideration of the need for PPIs should
be given to these patients (Yang et al., 2015). At this point, it is advisable to recommend optimal calcium intake in people that need
PPIs, address other contributors to fracture risk, and limit the use to the lowest dose and shortest time possible. The calcium
supplement which may be the most suitable is calcium citrate because of its better absorption profile (Heller et al., 2000).

Antiepileptic Drugs
The association between antiepileptic drugs (AEDs) and metabolic bone abnormalities has been observed since the 1960s, when
anticonvulsants and osteomalacia were linked together. Since that time there have been several cohort and prospective studies that
have shown an association of AEDs with low BMD and increased fracture risk (Farhat et al., 2002; Vestergaard et al., 2004; Lee et al.,
2010). The pathophysiology was felt to be primarily through induction of the cytochrome P450 enzyme system in the liver, which
would convert 25(OH)D to an inactive metabolite, leading to less active vitamin D, less calcium absorption, and increase in PTH
levels (Meier and Kraenzlin, 2011). In fact, in a randomized trial, Mikati et al. showed that using high dose vitamin
D supplementation in patients on AEDs could help stabilize the BMD at the spine and total hip compared with low dose vitamin
D supplementation (Mikati et al., 2006). Some studies have found an association of lower BMD even with AEDs that do not induce
the cytochrome P450 system, suggesting an alternative mechanism. A recent retrospective study of some of the newer anticonvul-
sants (gabapentin, topiramate, levetiracetam) did not show any adverse effects on BMD (Lee et al., 2012). A meta-analysis of
22 studies showed a significant increase in both enzyme-inducing and nonenzyme-inducing AEDs, particularly with phenytoin,
phenobarbital, and topiramate (Shen et al., 2014). Clearly more studies need to be done to definitively link AEDs with bone loss
and fractures, and it is recommended to screen for vitamin D deficiency, particularly in those on enzyme-inducing AEDs, and
address other aspects of bone health on an individual basis.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressant medications that have recently received a lot of
attention for negative effects on bone and fracture risk. They act by potently blocking the serotonin transporters (5-HTT) which are
located in the CNS as well as in the periphery, such as bone (Bliziotes et al., 2001). While depression itself has been linked with
bone loss, cross-sectional studies have supported an association between decreased BMD and SSRI use in both men and women
(Diem et al., 2007; Haney et al., 2007; Richards et al., 2007). Longitudinal studies have documented a 1.6-fold greater decline in
12 Secondary Osteoporosis

BMD in those using SSRIs compared with nonuser (Diem et al., 2013). These studies, however, have been contrasted by
investigations of several large databases (The National Health and Nutrition Examination Survey III, Women’s Health Initiative,
and Study of Women’s Health Across the Nation) that did not reveal an association of BMD decrease with SSRI use (Spangler et al.,
2008; Kinjo et al., 2005). Even though there is discrepancy on the effect of SSRI on BMD, most agree that there is an increased risk of
fragility fractures among depressed individuals on SSRIs (Richards et al., 2007; Spangler et al., 2008; Moura et al., 2014).
The exact mechanism of bone loss among users of SSRI is unknown, and recent focus has been on the effect of serotonin on
osteoblasts. Circulating serotonin of gut origin was shown to reduce osteoblast proliferation, an effect modulated by LDL-receptor
related protein 5 (LRP5) (Yadav et al., 2008). The interaction of LRP5, serotonin, and the Wnt pathway is being elucidated, and will
guide our understanding of SSRI use and bone effects (Warden et al., 2010). While not always possible, use of SSRIs should be
avoided in those at high risk of fracture.

Heparin
The long-term use of unfractionated heparin has been associated with reduced BMD, increased rates of bone loss, and an increased
risk of fracture (de Swiet et al., 1983; Barbour et al., 1994). Using rat histomorphometry and bone turnover markers, it has been
shown that extended us of heparin reduces bone formation and increases bone resorption; low molecular weight heparin (LMWH)
only seems to reduce bone formation markers, possibly contributing to its lessened effects on bone (Muir et al., 1997). However
there has been a recent report of postpartum osteoporosis with fractures in women treated with LMWH during pregnancy (Ozdemir
et al., 2015). Recently, long-term use of heparin is mostly limited to treatment of thromboembolism during pregnancy, and as such
bone loss should be a consideration in these women.

Antihypertensives
The frequency of use of antihypertensives increases with advanced age, as does the incidence of falling, which has led to numerous
studies of the effects of these medications on BMD and fracture risk (Wiens et al., 2006). There is an increased risk of falls when
initiating any antihypertensive medication in an elderly patient, particularly within the first few weeks, which has obvious
implications on fracture risk (Butt et al., 2013). Diuretics appear to have differential effects on bone based on their mechanism
of action, as loop diuretics increase urinary calcium excretion and are associated with elevated markers of bone turnover and lower
BMD, while thiazide diuretics decrease urinary loss of calcium and may have protective effects on bone and the risk of fracture
(Wiens et al., 2006; Rejnmark et al., 2006). Despite this, a recent prospective study identified increased fracture risk with both
thiazide and loop diuretics (Paik et al., 2016). Baseline osteoporosis status and fracture risk should be considered when placing a
patient on an antihypertensive medication, especially with the elderly.

Summary

As outlined in this article, there are many disease states and medications that can affect the metabolic activity of bone and its relative
strength and risk of fracture. It is important for the clinician to consider the scope of these conditions when evaluating a patient with
osteoporosis, as well as keeping bone health in mind when treating patients with these diseases and medications, even if they fall
out of the normal scope of the elderly and postmenopausal women. This approach can help to limit the added morbidity and
mortality an osteoporotic fracture to their other comorbid conditions.

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