Best Practice & Research Clinical Rheumatology

Vol. 19, No. 6, pp. 1021–1037, 2005

doi:10.1016/j.berh.2005.06.005
available online at http://www.sciencedirect.com

11

The management of secondary osteoporosis

Ariella Kelman MD
Fellow
Division of Immunology and Rheumatology, Department of Medicine, Stanford University Medical Center,
Stanford, CA 94304, USA

Nancy E. Lane* MD
Professor
Department of Medicine, University of California at Davis, School of Medicine, 4625, 2nd Avenue,
Suite 2000, Sacramento, CA 95817, USA

Secondary osteoporosis is common among patients being evaluated for osteoporosis. All men
and premenopausal women with unexplained bone loss or a history of a fragility fracture
should undergo a work-up for secondary osteoporosis. Also, postmenopausal women with
risk factors for secondary osteoporosis should be carefully evaluated. The evaluation should
include a thorough history, physical examination, bone mineral density testing, and laboratory
testing. While there is no consensus for a cost-effective laboratory evaluation, some
recommendations include: 25-hydroxyvitamin D, parathyroid hormone (PTH), serum and urine
calcium, phosphate, creatinine, liver function tests, a complete blood count, testosterone in
men, and thyroid-stimulating hormone. After a thorough review of the evaluation for
secondary osteoporosis, this chapter reviews the pathophysiology and treatment of secondary
osteoporotic disorders, including vitamin D insufficiency, osteomalacia, the osteoporosis of
erosive inflammatory arthritis, ankylosing spondylitis, systemic lupus erythematosus, and
osteoporosis related to anti-androgenic therapy for prostate cancer and aromatase inhibitor
therapy for breast cancer. Physicians have a significant responsibility to evaluate and treat the
underlying medical problem that is the cause of secondary osteoporosis and to optimize bone
health in the individual patient.

Key words: secondary osteoporosis; vitamin D deficiency; osteomalacia; osteonecrosis;

glucocorticoids; rheumatoid arthritis; ankylosing spondylitis; lupus; aromatase inhibitors;
androgen deprivation therapy.

* Corresponding author. Tel.: C1 916 734 4534; Fax: C1 916 734 4773.
E-mail address: nancy.lane@ucdmc.ucdavis.edu (N.E. Lane).

1521-6942/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
1022 A. Kelman and N. E. Lane

Secondary osteoporosis in adults is bone loss caused by a specific disease or by

medications. Individuals with secondary osteoporosis experience bone loss above that
which would be expected for age and natural menopause. The differential diagnosis
for conditions and medications that contribute to secondary osteoporosis is broad
(Tables 1 and 2).
Secondary osteoporosis is common in men and in premenopausal women with
osteoporosis. In addition, as many as one third of women with postmenopausal
osteoporosis have identifiable secondary causes that contribute to bone loss.1
Secondary causes of osteoporosis in men account for 50–80% of cases of bone loss
leading to fracture in this population.1

Table 1. Conditions that cause or are risk factors for secondary osteoporosis.

Genetic disorders:
Cystic fibrosis Hypophosphatasia Osteogenesis imperfecta
Idiopathic hypercalciuria Marfan syndrome Porphyria
Ehlers-Danlos Gaucher’s disease Riley-Day syndrome
Glycogen storage diseases Hemochromatosis Menkes steely hair syndrome
Homocystinuria
Hypogonadal states:
Androgen insensitivity Hyperprolactinemia Turner’s syndrome
Eating disorders Panhypopituitarism Klinefelter’s syndrome
Athletic amenorrhea and the Premature ovarian failure/ Breast cancer treated with
‘female athlete triad’: eating hysterectomy aromatase inhibitors
disorders, amenorrhea, and
osteoporosis
Prostate cancer treated with
anti-androgen therapy
Other endocrine disorders
Cushing’s syndrome Acromegaly Hyperparathyroidism
Adrenal insufficiency Type I diabetes mellitus Thyrotoxicosis
Rheumatologic disease
Ankylosing spondylitis Rheumatoid arthritis Glucocorticoid-induced
Lupus Sarcoidosis
Gastrointestinal disease
Gastrectomy Malabsorption/celiac Primary biliary cirrhosis
Inflammatory bowel disease disease
Hematologic disease
Multiple myeloma Thalassemia Leukemias
Sickle cell disease Hemophilia Lymphomas
Systemic mastocytosis
Other
Immobilization Chronic obstructive Amyloidosis
Alcoholism pulmonary disease Idiopathic scoliosis
Congestive heart failure End-tage renal disease Multiple sclerosis
Vitamin D deficiency Epilepsy Muscular dystrophy
Calcium deficiency Post-transplant
Magnesium deficiency

Adapted from Bone Health and Osteoporosis: A Report of the Surgeon General, 2004, Chapter 3, with
permission.
 The management of secondary osteoporosis 1023

Table 2. Common medications that cause or are risk factors for secondary osteoporosis.

Glucocorticoids
Anticonvulsants
Heparin
Cancer chemotherapy, including methotrexate
Cyclosporine A and tacrolimus
Anti-androgens
Gonadotropin-releasing hormone agonists
Aromatase inhibitors

This chapter will focus on a few of the causes of secondary osteoporosis that are
common in rheumatology practice, including the management of osteoporosis in
the setting of rheumatic disease, vitamin D deficiency, and the emerging problems of
bone loss in men with prostate cancer treated with androgen-deprivation therapy and
women with breast cancer treated with aromatase inhibitors.

GENERAL APPROACH TO DIAGNOSIS AND MANAGEMENT OF

SECONDARY OSTEOPOROSIS

All men and premenopausal women with unexplained bone loss or a history of fragility
fractures should undergo a work-up for secondary causes of osteoporosis.
Postmenopausal women with risk factors for secondary osteoporosis should also be
evaluated in order to identify whether there is a treatable or preventable cause of bone
loss. The medical evaluation should include a history and physical examination to
identify risk factors for bone loss, bone mineral density testing with dual energy x-ray
absorptiometry (DXA), and laboratory testing.
Currently, there is no consensus for appropriate and cost-effective laboratory
testing for this evaluation. The American Association of Clinical Endocrinologists
recommends routine testing of serum calcium, phosphate, creatinine, liver function
tests, a complete blood count, testosterone (in men), 25-hydroxyvitamin D (25-OH D),
and thyroid-stimulating hormone (TSH).2 Additional testing should be guided by history
and physical examination and could include a 24-hour urinary calcium to evaluate for
hypercalciuria, a serum and urine protein electrophoresis, quantitative immuno-
globulins, parathyroid hormone (PTH), a 24-hour urinary cortisol to rule out Cushing’s
syndrome, and antigliadin and antiendomysial antibodies to evaluate malabsorption.
Other testing to consider includes serum tryptase, urine N-methylhistamine, or other
tests for mastocytosis, as well as bone-marrow biopsy when hematologic disease is
suspected. In cases where osteoporosis is diagnosed without any apparent cause or
response to therapy, or when osteomalacia or mastocytosis are suspected, bone biopsy
may be considered. This is best performed as an undecalcified iliac bone biopsy with
double tetracycline labeling prior to the biopsy to allow for the assessment of dynamic
bone turnover.2 A recent cross-sectional study by Tanenbaum et al confirmed the
importance of laboratory testing in the evaluation of secondary osteoporosis.3 The
investigators evaluated 664 women with postmenopausal osteoporosis in an urban
teaching hospital. History alone identified 173/664 (26%) with risk factors for
secondary osteoporosis. A laboratory work-up that included a serum complete blood
1024 A. Kelman and N. E. Lane

count (CBC), calcium, phosphate, liver function tests, creatinine, albumin/globulin,

PTH, 25-OH D, 24-hour urine calcium/creatinine ratio, and TSH found that 56/173
(32%) women had identifiable, treatable etiologies of secondary bone loss. The most
common of these were hypercalciuria (10% of cases), malabsorption (8% of cases),
hyperparathyroidism (7% of cases), vitamin D deficiency (4% of cases), and
hyperthyroidism (2% of cases).

VITAMIN D DEFICIENCY

Vitamin D deficiency is one of the most common causes of ‘low bone mass’ diagnosed
by DXA in adults. Vitamin D is essential for absorption of calcium from the
gastrointestinal tract; it is needed to maintain calcium homeostasis, skeletal integrity,
and muscle strength. It is synthesized in the skin upon exposure to sunlight, or is
ingested in foods such as egg yolks, fish liver, fortified milk, and supplements. Low
serum levels of vitamin D, or vitamin D ‘insufficiency’ (30–80 nmol/mL or 12–
32 ng/mL), can lead to secondary hyperparathyroidism and osteoporosis. Very low
serum levels of vitamin D, or vitamin D ‘deficiency’ (less than 25 nmol/mL or 10 ng/mL),
leads to rickets in children and osteomalacia in adults. Low levels of vitamin D are also
associated with proximal muscle weakness and increased fall propensity,4,5 thus further
increasing fracture risk.
Vitamin D deficiency is common among hospitalized patients, as well as in patients in
the community. A study by Thomas et al6 evaluated 290 consecutive patients admitted
to a medical service in an urban teaching hospital in September and March. The most
common reasons for admission in these patients were coronary artery disease,
hypertension, diabetes mellitus, and obstructive pulmonary disease. Serum 25-OH D
was measured in all patients, and 56% were found to have levels less than 15 ng/mL.
More patients deficient in vitamin D were observed in early spring, and 21% took a daily
multivitamin, leading to the conclusion that the levels of vitamin D in multivitamin
supplements may be insufficient. Vitamin D deficiency is common in sunny regions as
well. Adams et al evaluated 118 consecutive patients referred to a subspecialty clinic in
Southern California for osteoporosis or osteopenia and found that 18 (15%) had
vitamin D deficiency in the absence of other secondary etiologies.7 Repletion of vitamin
D in these patients resulted in improvement of secondary hyperparathyroidism and in
increases of BMD of about 4% at the spine and femoral neck after 10 months of follow-
up. A study in northern Italy evaluated bone metabolism in 104 people over the age of
98 who did not have acute illness.8 They found that 99 out of the 104 had undetectable
serum 25-OH D, 64% had elevated serum PTH, 90% had elevated levels of the marker
of bone resorption CTX-I and bone-specific alkaline phosphatase levels were at the
upper limits of normal, and 38% had suffered fractures.
Osteomalacia is a mineralization defect caused by disorders that prevent the calcium
x phosphate product at the mineralization front of bone. It is characterized by a delay in
mineralization, which results in an abnormally increased ratio of osteoid (poorly
mineralized bone) to mineralized bone on biopsy. This results in the classic rickets
phenotype in children, and in pathologic fractures (pseudofractures) and deep bone
pain in adults. The most common disorders that result in low levels of vitamin D include
hepatic and renal disease, lack of sunlight, malnutrition, gastrointestinal malabsorption,
and use of anticonvulsants. Most of these risk factors are commonly found in the
elderly, placing them at considerably high risk of osteomalacia. Osteomalacia can also
 The management of secondary osteoporosis 1025

develop as a result of disorders of hypocalcemia, and less commonly due to renal

tubular phosphate loss as a result of X-linked hypophosphatemia (familial vitamin
D-resistant rickets) and Fanconi’s syndrome.9
Several studies have evaluated the role of vitamin D in muscle strength and fall
propensity. Vitamin D-specific receptors have been identified in human muscle tissue.
One study observed that leg extension power is decreased in ambulatory elderly
men and women with very low levels of serum vitamin D (less than 12 ng/mL).5 In a
randomized placebo-controlled trial of 122 elderly women in assisted living, those who
received calcium 1200 mg and vitamin D 800 IU daily for 3 months had a 49% reduction
in falls versus those treated with calcium alone.4
A diagnosis of osteomalacia should be considered in any patient with unexplained
fractures, low BMD, and a history of chronic illness that puts them at risk for excessive
time indoors (lack of sunlight), anorexia, or malnutrition. Laboratory evaluation reveals
low 25-OH D, and may reveal high levels of serum bone-specific alkaline phosphatase
and low calcium. Alkaline phosphatase and calcium levels have been shown to be
unreliable predictors of vitamin D deficiency, and thus checking vitamin D levels directly
is important to improve diagnostic sensitivity.10 Radiographic evaluation may reveal
diffuse osteopenia and pseudofractures (also called ‘Looser’s zones’), which have the
appearance of thin, radiolucent bands perpendicular to the bone surface. Bowing of the
long bones is unusual in adults.
Vitamin D deficiency should be considered in the differential diagnosis of
musculoskeletal pain in patients with rheumatic disease. In a prospective study of
over 29 000 women aged 55–69, those with greater dietary vitamin D intake were 67%
less likely to develop rheumatoid arthritis over 11 years of follow-up.11 One study
observed that vitamin D levels were low in 7/12 adolescent women with systemic lupus
erythematosus (SLE) treated with glucocorticoids.12 Other small series have shown
similar findings.13,14 Several pathophysiologic mechanisms-including sun avoidance,
medication use (particularly glucocorticoid and hydroxychloroquine therapy), and the
presence of renal disease-have been postulated to be responsible for vitamin D
deficiency in patients with rheumatic diseases. Due to the photosensitive nature of the
disease, patients with SLE, for example, often avoid sunlight completely with clothing
and chronic use of sunblock. Patients with rheumatic disease are often treated with
hydroxychloroquine which has been shown to lower conversion of vitamin D2 to the
active vitamin D3 in vitro and in patients with sarcoidosis.15
Treatment and prevention of vitamin D insufficiency and deficiency is effective in
improving fall risk, fracture risk, and bone pain associated with osteomalacia. Treatment
consists of treating the underlying etiology and ensuring adequate calcium and vitamin
D supplementation. The effect of vitamin D supplementation on fracture risk was
evaluated in a large, placebo-controlled study of 2686 healthy volunteers aged 65–85
(mostly men) in the United Kingdom.16 In this study, 100 000 IU of vitamin D3
(cholecalciferol) administered orally every 4 months for 5 years (equivalent to 800 IU
daily) resulted in a 22% reduction in fracture risk with a 33% reduction in fragility
fractures, specifically. Subjects in the treatment group achieved mean serum vitamin D
levels of 74 nmol/mL.
Vitamin D supplementation should be guided by serum levels. The optimal serum
25-OH D level is the level associated with the maximal suppression of circulating PTH,
greatest intestinal calcium absorption, improved bone mineral density, decreased rates
of bone loss, decreased risk of falls, and ultimately decreased fracture risk.17 Studies
have consistently shown that serum levels O75–80 nmol/mL are protective against
fracture and falls,4,16 and that levels O80 nmol/L are associated with maximal fractional
1026 A. Kelman and N. E. Lane

intestinal absorption of calcium.17 In older individuals and in those with chronic disease,
supplementation of oral vitamin D3 at doses of 800–1000 IU/day is generally required to
achieve adequate serum levels. After initiation of therapy, levels of 25-OH D should be
maintained above 80 nmol/L (32 ng/mL) to ensure normal bone mineralization.18,19 In
the United States, vitamin D3 is not available in preparations over 2000 IU. More severe
cases of osteomalacia (serum 25-OH D !20 nmol/mL) that may be accompanied by
bone pain can be treated with ergocalciferol (vitamin D2) 50 000 IU twice a week for 6
weeks. This regimen has been shown to improve deep-seated bone pain. After
repletion of body stores, 800 IU per day or vitamin D2 50 000 IU once or twice a month
is usually adequate maintenance therapy.18 Treatment and prevention of vitamin D
deficiency in rheumatic disease is similar to that in other populations, with the caveat
that patients with rheumatic disease who avoid sunlight may require higher doses of
supplementation.20

OSTEOPOROSIS IN RHEUMATOLOGIC PRACTICE

Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis (GiOP) is the most common form of

osteoporosis caused by a medication, and is also the most common form of
osteoporosis encountered in rheumatology practice. Management of GiOP is covered
extensively in another chapter of this publication.
Glucocorticoid (GC) treatment leads to rapid bone loss and worsening bone quality.
Glucocorticoids adversely affect bone remodeling by both reducing bone formation
and increasing resorption. Glucocorticoids have been shown to decrease osteo-
blastogenesis and osteoblast lifespan, and induce osteocyte apoptosis. Glucocorticoid
effects on bone resorption most likely result from accelerated osteoclast maturation
and activity induced by reductions in gonadal and adrenal hormones and a negative
calcium balance (reduced gastrointestinal absorption of calcium with an increase in
urinary excretion).21,22 The end result of these changes in bone metabolism induced by
GCs is an increased fracture risk in patients exposed to these agents. While the
estimates of fracture risk on GCs varies, van Staa and colleagues reported that
vertebral fracture rate increases upto fourfold after 3–6 months of therapy with low-
dose glucocorticoids (equivalent to prednisone R7.5 mg daily).23 Fortunately,
treatments directed at preventing the changes in bone metabolism induced by GCs
are effective, and some have been shown to reduce fracture risk. The critical therapies
include maintaining adequate calcium and vitamin D stores, prevention of falls by
strengthening muscles associated with balance and ambulation, and bisphosphonate
therapy, which has been shown to reduce fracture risk by 40–90%.24,25 Parathyroid
hormone fragments (hPTH 1–34) have been shown to significantly increase bone mass
and bone cross-sectional area in GC-treated subjects, but fracture data are not
currently available.26,27 Currently, large randomized studies are under way to assess
whether teriparatide does reduce fracture risk in GC-treated individuals.

Osteoporosis in erosive, inflammatory arthritis

Rheumatic disease patients have systemic and localized inflammation and inflammatory
disease by itself is associated with generalized osteoporosis.28,29 There are clearly
 The management of secondary osteoporosis 1027

associations between chronic inflammation and bone loss, and current understanding of
the role of inflammatory cytokines in bone loss is evolving. Inflammatory, erosive
arthritides, classically rheumatoid and psoriatic arthritis, are accompanied by focal bone
destruction and progressive generalized bone loss. Inflammation has been shown to
drive osteoclast differentiation and function by activating the RANK/RANKL (receptor
activator of nuclear factor-kB and RANK ligand) pathway, and inflammatory cytokines
and growth factors have been shown to promote osteoclastogenesis with subsequent
osteoclast-mediated bone loss. The interaction between RANK (expressed by
osteoclast precursors) and RANKL (expressed by bone-lining cells of osteoblast
lineage and activated T cells, macrophages and synovial fibroblasts) is necessary for
osteoclast differentiation. Osteoprotegerin (OPG, expressed by osteoblast lineage
cells) is an extracellular receptor to RANKL and prevents the RANK/RANKL
interaction, leading to suppression of osteoclast differentiation and function. Mouse
models of inflammatory arthritis that lack either RANKL or osteoclasts do not develop
erosions.30 Psoriatic arthritis patients have been shown to have increased osteoclast
precursor cells in peripheral blood that correlate with extent of bone destruction and
TNF-a levels.31 In the synovium of patients with erosive, inflammatory arthritis,
activated T-cell-mediated release of TNF-a results in induction of RANKL which
accelerates osteoclast-mediated bone resorption, and ultimately erosive disease.31,32
Furthermore, interleukin-1 (IL-1), a key cytokine in inflammatory arthritis, has been
shown to promote survival and function of mature osteoclasts and to promote
osteoclastogenesis in vitro.30,33 In a TNF-a transgenic mouse model of inflammatory
arthritis, the combination of a TNF-a inhibitor and IL-1Ra resulted in profound
suppression of inflammation, osteoclast numbers, and bone destruction.34 In the same
mouse model the addition of OPG reduced osteoclast numbers as well as focal bone
erosions and bone loss distal to the joint.35 The above findings all support the role of
RANKL and osteoclast-mediated bone loss in the setting of active inflammatory
arthritis. RANKL-mediated bone resorption in the setting of inflammatory disease may
play an important role in generalized osteoporosis as well as localized bone loss;
however, this has not been definitively proven.
The subject of osteoporosis in patients with ankylosing spondylitis (AS) deserves
special attention because it is common and diagnostically challenging. Abnormal bone
remodeling is present in AS with both excess bone formation at extra-osseous sites,
as well as osteoporosis at the spine. The prevalence of osteoporosis in AS is between
18.7 and 62%.36,37 A retrospective, population-based study in Rochester, Minnesota,
USA demonstrated increased fracture incidence of the spine, but not of the
appendicular skeleton.38 Annual loss of total body calcium has been observed as 4
times greater in men with AS compared with men over 50 years of age without AS.36,37
In early disease, inflammation seems to drive bone loss; in the chronic phase of the
disease, mechanical factors may play an important role in fracture risk, with decreased
mobility, stooped posture and impaired balance, as well as reduced capacity of shock
absorption in a bamboo spine, all contributing to fracture risk.39 Although fracture rate
at the spine increases with duration of disease, decreased BMD at the femoral neck is
seen even in early disease. The risk of fracture increases with time from diagnosis.
Interestingly, vertebral compression fractures in AS are more common in men than in
women, perhaps reflecting disease severity.36
Patients with AS experience chronic back pain, making diagnosis of vertebral
fracture somewhat more challenging than in other populations. It is therefore
important to perform imaging to rule out fragility fracture in any AS patient with
worsening of chronic back pain. Given that fracture incidence is increased, it is
1028 A. Kelman and N. E. Lane

reasonable to screen for low BMD with DXA in all patients with AS, keeping in mind
that the measurement site is especially important in this disease. Patients with AS
experience more fractures of the axial skeleton, specifically, and BMD at peripheral
sites-such as the calcaneus or distal radius-may not be useful for predicting fracture in
AS patients.36 Also, BMD by DXA may be falsely elevated at the spine due to the
presence of extra-osseous calcification, including syndesmophyte formation. Mitra
et al40 observed a lack of correlation between BMD at the spine and vertebral fracture
in 66 men with mild AS. More recently, Franck et al41 observed significantly lower total
hip and femoral neck but not spine BMD in 264 patients with AS, as compared with age-
matched controls. In these patients, lower BMD at the hip, but not the spine, correlated
with high biochemical markers of bone resorption (urinary pyridinium cross-links of
collagen), and low levels of osteoprotegerin. Thus, to improve diagnostic sensitivity,
BMD measurements should be performed at both the spine and the femoral neck and
total hip. In addition, a significant proportion (17%) of men with AS who are diagnosed
with osteoporosis have additional secondary etiologies for bone loss.42 Thus it is
important to screen for treatable abnormalities leading to bone loss, including
hypogonadism, vitamin D deficiency, and others as dictated by individual clinical
scenario.
Because there is evidence that inflammation contributes to osteoporosis,
management of bone loss in rheumatoid arthritis, spondyloarthropathies, and other
erosive, inflammatory arthritides at this time should focus around reduction in
inflammation, that is, treating the underlying disease. Treatment with TNF-a agents has
been shown to reduce progression of juxta-articular bone loss in both rheumatoid
arthritis and ankylosing spondylitis, and treatment with the recombinant Il-1 receptor
antagonist anakinra reduced erosions in rheumatoid arthritis.43,44 Longer-term studies
are needed to determine whether these therapies will have a significant effect on
generalized osteoporosis. Conversely, in view of the local and generalized bone loss
seen in inflammatory arthritis, bisphosphonates have been studied as potential disease-
modifying agents for both RA and AS. Small studies demonstrated improvements in
serologic markers of inflammation, but did not show clinically meaningful improvements
in disease activity.45,46 Primary prevention with calcium, vitamin D, and exercise should
be advised in all patients with inflammatory arthritis. In addition to patients with
ankylosing spondylitis, all patients treated with glucocorticoids and postmenopausal
women should be evaluated early with DXA. Confirmed osteopenia or osteoporosis
should be treated with antiresorptive or anabolic therapies, as in primary osteoporosis.
Clinical research evaluating a RANKL inhibitor is now ongoing for the treatment of
generalized and localized osteoporosis, and results are forthcoming. This type of
therapy might improve bone health in patients with inflammatory arthritis.

Osteoporosis in systemic lupus erythematosus

Patients with systemic lupus erythematosus are at increased risk for osteoporosis,
probably due to systemic inflammation as well as corticosteroid use and periods of
immobilization during disease flares. Yee and colleagues performed a cross-sectional
study of 242 patients with lupus with median disease duration of 7 years and a median
age of 40 years.47 In this cohort, 9% had sustained fragility fractures, and of those only
32% had BMD in the osteoporotic range. Fracture prevalence was 3.1% in the women
who were premenopausal. Reduced BMD and older age were both found to be risk
factors for fracture, but corticosteroid use was not an independent risk factor for
 The management of secondary osteoporosis 1029

fracture. Nevertheless, it is known that patients treated with glucocorticoids have

a high prevalence of fracture with BMDs that are not in the WHO osteoporotic range,
implicating significant changes in bone quality at higher BMD than would be expected.48
All lupus patients should receive adequate vitamin D and calcium supplementation,
and exercise encouraged. Given their augmented fracture risk, we advocate that all
postmenopausal women with lupus undergo BMD evaluations and all postmenopausal
women on glucocorticoids be treated with antiresorptive agents, e.g. bisphosphonates,
calcitonin, or an anabolic agent (e.g. teriparatide), as dictated by clinical history. Most
patients with lupus are women of child-bearing age, and management of osteoporosis in
these patients is more challenging. Premenopausal women with lupus who are treated
with glucocorticoids or have a history of fracture should undergo BMD evaluation and
be treated if BMD is low. It is unclear whether other young women with lupus benefit
from BMD screening. Also, bisphosphonates have a long skeletal half-life, and are
teratogenic in animal studies. Teratogenicity has not been adequately studied in humans,
but animal data imply that this group of drugs should be used with caution in women
who intend to become pregnant.

Osteonecrosis in patients with SLE

Osteonecrosis is a disease of bone metabolism frequently encountered in lupus
patients, and defined as death of bone marrow and trabecular bone as a result of
disruption of blood supply to the bone.49,50 Osteonecrosis may present with deep joint
pain or may be asymptomatic, but it should be considered in the differential diagnosis of
new or worsening arthralgia in a patient with lupus. Advanced osteonecrosis leads to
significant degenerative joint disease. Investigators recently performed musculoskeletal
magnetic resonance imaging (MRI) in 415 patients with lupus in South Korea and found
that 37 had findings consistent with osteonecrosis.51 These patients often had bilateral
and polyarticular involvement. The presence of osteonecrosis is associated with worse
health-related quality of life and disability in lupus patients. Osteonecrosis is associated
with higher total HAQ (Health Assessment Questionnaire) and physical function
domain of the SF-20 scores in lupus patients, as compared to age-matched lupus
patients without osteonecrosis.52 Sites most commonly involved include the femoral
head and the knees, but it can also be seen in the shoulders, elbows, ankles, wrists, and
rarely the distal tibia, bones of the feet, and vertebral bodies. The incidence of
osteonecrosis is associated with glucocorticoid use and with the presence of anti-
phospholipid syndrome (APS), and is seen in patients with primary APS as well.50
Diagnosis relies on imaging, either by plain radiograph or MRI. The radiographic
staging system by Marcus and Enneking includes six progressive stages of osteonecrosis
involving the hip: stage I is normal, and stage VI is advanced degenerative disease.53 The
‘crescent sign’ is diagnostic of subchondral fracture in osteonecrosis. Plain radiographs
may be normal in early stages; thus MRI should be performed if clinical suspicion is high
with a normal plain radiograph. Treatment is mostly surgical, either by core
decompression or total joint arthroplasty, and treatment performed at an earlier,
pre-collapse stage predicts a favorable outcome. Decompression is effective in the pre-
collapse stage, but patients with collapse of the femoral head generally require total hip
arthroplasty (THA). Investigators at a large tertiary surgical center reported a 95%
survival probability of 33 THAs at 5 years of follow-up in 25 lupus patients.54 In another
study of total knee arthroplasty in 25 knees for post-collapse osteonecrosis in 17 lupus
patients, 47% of procedures were associated with complications, including aseptic
loosening and infection.50,55
1030 A. Kelman and N. E. Lane

OSTEOPOROSIS IN THE SETTING OF PROSTATE CANCER TREATED

WITH ANTI-ANDROGENIC THERAPY

Prostate CA is the most common solid-organ malignancy in the US, affecting 1.6 million
men.56 Two million men in the United States are affected by osteoporosis. The subject
of osteoporosis in men with prostate cancer treated with androgen deprivation
deserves special attention since a high percentage of men now have osteoporosis, and
this type of secondary osteoporosis is on the rise.
Inducing hypogonadism in men with prostate cancer with androgen deprivation
therapy (ADT) places them at increased risk of osteoporosis. In addition, many
patients with prostate cancer are elderly and are therefore at increased risk of
bone loss independent of their disease. In men with prostate cancer, ADT-either
alone as depot gonadotropin-releasing hormone agonist (GnRH) or in combination
with anti-androgens (e.g. flutamide, cyproterone acetate) has been shown to
improve morbidity and survival in locally advanced and metastatic disease.57,58
Although survival benefit has not been demonstrated in these settings, GnRH
agonists are also often used to treat men with cancer confined to the prostate
and in men with rising serum prostate-specific antigen (PSA) tests after
prostatectomy.59,60
Hypogonadism in men results in increased bone resorption, decreased BMD, and
ultimately increased fracture. Although both estrogen and testosterone are important
for bone formation in men, estrogen appears to play a greater role in regulating and
protecting from bone resorption. In normal male aging, sex steroid binding globulin
levels decrease and this leads to reduced levels of bioavailable estrogens. Total
testosterone levels also decrease and are therefore unavailable for conversion to
estradiol by aromatization. ADT augments this process, thereby reducing the
protective effects of estrogen on bone.
Recent studies have shown an increase in bone resorption, a decrease in BMD and
an increase in fracture risk in men with prostate cancer treated with ADT shortly
after beginning therapy, as compared to those not treated with ADT. Small studies
have observed a rapid fall in BMD of 3–7% in the first 6–12 months after initiation of
ADT in elderly men with non-metastatic prostate cancer.61,62 Mittan and colleagues
found a 3.3% decrease in BMD at the hip and 5.3% decrease in BMD at the distal
radius after 12 months of ADT treatment.61 This was associated with increased levels
of urinary cross-linked N-telopeptide of type 1 collagen (NTX) at both 6 and 12
months after initiation of ADT in men with prostate cancer versus age-matched
controls. In a natural history study evaluating 4494 men with prostate cancer who
received ADT and were followed for up to 7 years, those treated with ADT for at
least 2 years were more likely to sustain a fracture than those treated for a shorter
duration.63
Shahinian et al recently evaluated the relationship of ADT with GnRH agonists or
orchiectomy in 50 613 men over the age of 66 years with prostate cancer who survived
at least 5 years after diagnosis.59 They found that men who were treated with ADT
sustained more overall fractures than those who were not (19.6% versus 12.6%, P!
0.001). They also observed that fracture risk correlates with duration of therapy, and
that men treated with at least 9 doses of ADTwithin the first year were 62% more likely
to suffer a fragility fracture (involving the hip, spine, or forearm) than those who were
not. Fracture risk for men who underwent orchiectomy was similar to that in those
treated with ADT.
 The management of secondary osteoporosis 1031

Treatment and prevention of osteoporosis in the setting of ADT-treated prostate

cancer with antiresorptive agents-including bisphosphonates, transdermal estrogen,
and selective estrogen receptor modulators (SERMS)-has been recently evaluated.
Smith et al64 performed a placebo-controlled RCT evaluating intravenous zolendronic
acid at a dose of 4 mg every 3 months in 106 elderly men with non-metastatic prostate
cancer starting ADT. Patients in the control group decreased BMD by about 2% at the
spine and hip, whereas patients in the active group had increases in BMD of 5.6% at the
spine and 1% at the hip. The study was not large enough to evaluate fracture prevention.
Similar findings were observed in a smaller study evaluating intravenous neridronate.65
Clinical trials evaluating zolendronate and risedronate for bone loss in men with
prostate cancer on ADT are under way.
Estrogen and the SERM raloxifene have been observed to prevent bone loss in
men with prostate cancer in small open-label studies. Oral estrogens were the
treatment of choice for inducing androgen suppression in men with prostate cancer
in the past; however, their use in this setting has been largely abandoned due to
cardiovascular morbidity. The use of transdermal, as opposed to oral, estradiol may
reduce cardiovascular risk in these patients, as may a lower dose of oral
estrogen.66 In a study of 20 patients with locally advanced or metastatic cancer,
transdermal estradiol was administered in a dose sufficient to induce androgen
suppression. At 1-year follow-up, patients had an increase in BMD of 3% at the hip
and spine.66 Further studies of safety and efficacy are under way to determine
whether transdermal or low-dose oral estrogen is a viable option for men with
prostate cancer at high risk for osteoporosis. Raloxifene was evaluated in an open-
label study of 48 patients with non-metastatic prostate cancer treated with a
GnRH agonist. The treatment group had slightly improved BMD at the hip by
DXA, as compared to a loss of 1% in the control group. Anabolic therapies for
osteoporosis in the setting of prostate cancer have not been thoroughly evaluated.
Subcutaneous PTH is considered contraindicated in this setting due to the potential
for stimulating osteoblastic metastatic lesions.67
Diamond and colleagues have proposed recommendations for management of
osteoporosis in men with prostate cancer treated with ADT.67 Recommendations
include ensuring adequate vitamin D status and calcium intake and evaluating BMD in all
patients with prostate cancer treated with ADT. They recommend bisphosphonate
treatment in patients with WHO criteria for osteoporosis or known osteoporotic
fracture. It is essential to work up all suspected fractures with imaging studies to rule
out metastatic disease. There are currently no routine recommendations for
prophylactic treatment of osteoporosis with antiresorptive medication in these
patients; however, given that the risk of fracture increases within the first year of
treatment with ADT, this may be prudent.

OSTEOPOROSIS IN PATIENTS WITH BREAST CANCER TREATED

WITH AROMATASE INHIBITORS

The increased use of aromatase inhibitors as adjuvant therapy in breast cancer raises
concerns about long-term skeletal health in breast cancer survivors. Breast cancer is
the most common malignancy in women in Western countries, and most cases occur in
postmenopausal women.68 About two thirds of postmenopausal women with breast
cancers have hormone-receptor-positive disease, and may therefore potentially benefit
1032 A. Kelman and N. E. Lane

from estrogen deprivation therapy.69,70 Adjuvant hormone therapy for breast cancer
most often includes the SERM tamoxifen or the aromatase inhibitors (anastrozole,
letrozole, and exemestane). The anti-estrogenic effects of these therapies pose
potential risks to bone health in both pre-and postmenopausal women.
Tamoxifen is effective for the treatment of hormone-receptor-positive breast cancer
and for breast cancer risk reduction.69,71 Tamoxifen competes for estrogen receptor
binding with estrogen and has both agonist and antagonist effects on estrogen. Two
large breast cancer prevention randomized clinical trials evaluating the use of tamoxifen
versus placebo failed to show a statistically significant difference in fracture risk in
tamoxifen-treated patients. There was a trend toward reduced fracture risk in
women over 50 years old.71,72
The aromatase inhibitors (AIs) prevent androgen aromatization, thereby reducing
total estrogen levels. The aromatase inhibitors almost completely suppress production
of estradiol, estrone, and estrone sulfate. In the ATAC trial (Arimidexe, tamoxifen,
alone, or in combination), anastrazole was shown to have improved disease-free
survival, decreased time to recurrence, and reduced distant metastases, as compared
with tamoxifen in 6186 postmenopausal women with localized breast cancer over 5
years of follow-up.73 Patients in the tamoxifen group experienced more venous
thromboembolic events, hot flushes, and vaginal bleeding and discharge. The
anastrazole-treated patients, however, experienced more fractures (340 [11.0%]
versus 237 [7.7%], OR 1.49 [95% CI:1.25–1.77], P!0.0001) and arthralgias (1100
[35.6%] versus 911 [29.4%], OR 1.32 [95% CI:1.19–1.47], P!0.0001).73 It is not known,
however, whether postmenopausal women with breast cancer treated with anastrazole
in fact have an increased fracture risk compared to postmenopausal women in the
general population, or whether the effect seen in the study is a consequence of a bone-
sparing effect of tamoxifen.69 Several studies have observed an increase in markers of
bone resorption after treatment with anastrazole, letrozole, and exemestane.69,73,74 In
contrast with the non-steroidal aromatase inhibitors anastrazole and letrozole,
treatment with exemestane, a steroid aromatase inhibitor, was associated with both
increased markers of bone resorption coupled with markers of bone formation.74 It has
been postulated that this may be related to an androgenic effect of 17–
hydroxyexemestane, a metabolite of exemestane.69 A randomized clinical trial
comparing exemestane versus tamoxifen in 4742 postmenopausal women with early
breast cancer following 2–3 years of tamoxifen therapy observed an increased
incidence of osteoporosis by WHO criteria in the exemestane-treated patients (7.4%
versus 5.7%, PZ0.05) and a trend toward increased fracture (3.1% versus 2.3%, PZ
0.08).75
Given the increased risk of fracture in these patients, all postmenopausal women
treated with aromatase inhibitors should be screened for osteoporosis with history,
physical exam, and BMD, as postmenopausal women in general practice. The risk of
fracture in premenopausal women treated with aromatase inhibitors has not been
adequately assessed. Adequate calcium and vitamin D should be ensured in all patients
treated with aromatase inhibitors regardless of menopausal status. Estrogen therapy is
contraindicated in patients with a history of breast cancer. The SERM raloxifene is also
contraindicated in this setting as it has potential adverse effects on micrometastatic
disease and interacts with aromatase inhibitors. Bisphosphonates have been used
extensively for the treatment of metastatic bone disease in breast cancer patients, and
are generally considered safe in this population. The bisphosphonates clodronate and
zolendronic acid have been shown to preserve BMD in women with breast cancer
undergoing chemotherapy or treated with aromatase inhibitors, respectively.76–78
 The management of secondary osteoporosis 1033

These studies were not large enough to evaluate effect on fracture risk. Additional
clinical trials evaluating risedronate and zolendronate for bone loss in women with
breast cancer treated with aromatase inhibitors are ongoing.

SUMMARY

Secondary osteoporosis, vitamin D deficiency, and osteonecrosis are commonly

encountered in rheumatology practice. Patients with chronic disease, particularly
inflammatory autoimmune disease, have an increased risk of fracture due to
medication, inflammation, sedentary lifestyle, and vitamin D deficiency. The focus in
rheumatology practice is prevention and treatment of glucocorticoid-induced
osteoporosis and adequate control of inflammatory disease. Treatments for erosive
arthritis that target proinflammatory cytokines may prove beneficial for preserving
generalized skeletal integrity. Fracture related to anti-androgenic and anti-estrogenic
therapies for prostate and breast cancer is increasingly being recognized as common
and amenable to prevention and treatment.

Practice points

† hypovitaminosis D is common cause of low bone mass, as measured by DXA,

and is especially common in the chronically ill, the elderly, and in patients with
photosensitive autoimmune diseases who avoid sunlight
† vitamin D3 at doses of 800–1000 IU/day are required in order to maintain
serum vitamin D levels at O80 nmol/L to promote normal bone mineralization
† treatment with glucocorticoids induces changes in bone metabolism and
increases fracture risk even at low doses, and treatments including nutritional
supplementation and bisphosphonate therapy are effective in preventing
fracture in patients treated with glucocorticoids
† patients treated with glucocorticoids have increased risk for fracture at BMDs
higher than would be expected
† patients with erosive, inflammatory arthritis are at increased risk of generalized
osteoporosis, even in the absence of glucocorticoid therapy
† patients with ankylosing spondylitis (AS) should be screened for osteoporosis,
and imaging should be considered to rule out vertebral osteoporotic fracture
in patients with worsening of chronic back pain
† patients with AS may have falsely elevated BMD by DXA due to extra-osseus
calcification; BMD evaluation should therefore include the spine and total hip
† osteonecrosis should be considered in the differential diagnosis of worsening
arthralgias in patients with SLE
† survivors of prostate cancer treated with androgen deprivation therapy are at
increased risk for fracture; bisphosphonates have been shown to improve bone
health in these patients
† women with breast cancer treated with aromatase inhibitors seem to be at
increased risk for osteoporosis. Estrogen therapy and the addition of a SERM
are contraindicated in these patients. Bisphosphonates have been shown to
improve BMD in these patients
1034 A. Kelman and N. E. Lane

Research agenda

† the inflammation of erosive arthritis-such as that of rheumatoid arthritis,

ankylosing spondylitis, and psoriatic arthritis-drives osteoclast differentiation
and function by activating the RANK/RANKL pathway, and inflammatory
cytokines-including TNF-a( and Il-1 have been shown to promote osteoclas-
togenesis and osteoclast-mediated bone loss
† longitudinal studies are needed to determine whether treatments that target
inflammatory cytokines and RANKL prevent generalized osteoporosis and
fracture in patients with inflammatory arthritis
† studies are under way to determine whether low-dose transdermal estrogen is
safe and effective for the prevention of osteoporosis in men with prostate
cancer who are at increased risk for fracture

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