Approach to the patient with secondary osteoporosis [631814]

REVIEW
Approach to the patient with secondary osteoporosis
Lorenz C Hofbauer1,3, Christine Hamann2and Peter R Ebeling4
1Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III and Center of Regenerative Therapies Dresden (CRTD) and
2Department of Orthopedics, Technical University Medical Center , Fetscherstrasse 74, D-01307 Dresden, Germany,3Center of Regenerative Therapies
Dresden, D-01307 Dresden, Germany and4Departments of Medicine (Royal Melbourne Hospital/W estern Hospital) and Endocrinology, W estern Hospital,
The University of Melbourne, Gordon Street, Footscray 3011, Victoria, Australia
(Correspondence should be addressed to L C Hofbauer at Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technica l
University Medical Center; Email: [anonimizat])
Abstract
Secondary osteoporosis is characterized by low bone mass with microarchitectural alterations in bone
leading to fragility fractures in the presence of an underlying disease or medication. Scenarios thatare highly suspicious for secondary osteoporosis include fragility fractures in younger men orpremenopausal women, very low bone mineral density (BMD) values, and fractures despite anti-osteoporotic therapy . An open-minded approach with a detailed history and physical examinationcombined with first-line laboratory tests are aimed at identifying clinical risk factors for fractures,osteoporosis-inducing drugs, and underlying endocrine, gastrointestinal, hematologic, or rheumatic
diseases, which then need to be confirmed by specific and/or more invasive tests. BMD should be
assessed with bone densitometry at the hip and spine. Lateral X-rays of the thoracic and lumbar spineshould be performed to identify or exclude prevalent vertebral fractures which may be clinically silent.Management of secondary osteoporosis includes treatment of the underlying disease, modification ofmedications known to affect the skeleton, and specific anti-osteoporotic therapy . Calcium and vitaminD supplementation should be initiated with doses that result in normocalcemia and serum25-hydroxyvitamin D concentrations of at least 30 ng/ml. Oral and i.v . bisphosphonates are effectiveand safe drugs for most forms of secondary osteoporosis. Severe osteoporosis may require the use
of teriparatide.
European Journal of Endocrinology 162 1009–1020
Background
Secondary osteoporosis is defined as bone loss, micro-
architecural alterations, and fragility fractures due toan underlying disease or concurrent medication (1).
Secondary osteoporosis remains a diagnostic and
therapeutic challenge as it frequently affects patientpopulations, e.g. premenopausal women or youngermen who are usually not target populations for routinescreening for osteoporosis. In addition, the underlying
conditions are diverse and rare, and require specific
diagnostic tests (1). Moreover, response to osteoporosis
therapy may be limited if the underlying disordergoes unrecognized and if other risk factors are present.
For example, alendronate displayed a reduced efficacy
in women with postmenopausal osteoporosis andTSH-suppressive
L-thyroxine ( L-T4)t h e r a p ya f t e r
treatment for differentiated thyroid cancer (2).A sa
caveat, the anti-fracture efficacy of many drugs has not
been clearly demonstrated, except for glucocorticoid-induced osteoporosis (GIO) and male hypogonadismin secondary osteoporosis, and the use of specificanti-osteoporosis drugs is based on bone mineral
density (BMD) as a surrogate.
Apart from the more well-known endocrine disorders,
including Cushing’s syndrome, hypogonadism, hyper-
thyroidism, and hyperparathyroidism, the adverse effects
of diabetes mellitus have just recently been acknowl-edged (3). In fact, patients with type 1 diabetes mellitus
have a 12-fold higher risk of sustaining osteoporotic
fractures, compared with non-diabetic controls (4).
In addition, chronic inflammation present in inflam-matory bowel disease and rheumatoid arthritis cause
osteoporosis, in part because of the pro-inflammatory
cytokine milieu and immunosuppressive regimens (5).
The emerging use of thiazolidinediones (TZDs) (6),
aromatase inhibitors (AIs) (7), androgen-deprivation
therapy in men with prostate cancer (8), and the growing
field of bariatric surgery (9)have emerged as novel
and important etiologies of secondary osteoporosis.
Here, we summarize the current state of knowledge
on the mechanisms of secondary osteoporosis, outline apractical diagnostic strategy, and provide management
recommendations.European Journal of Endocrinology (2010) 1621009–1020 ISSN 0804-4643
q2010 European Society of Endocrinology DOI: 10.1530/EJE-10-0015
Online version via www.eje-online.org

Mechanisms
Endocrine diseases
Glucocorticoid excess Endogenous overexpression or
systemic administration of glucocorticoids impairs
skeletal health through various cellular effects, ofwhich inhibition of bone formation due to induction of
osteoblast and osteocyte apoptosis is the most critical
(10). Predominant spinal bone loss and vertebral
fractures are characteristic features, as is an increased
risk of falls due to muscular atrophy and altered
neuromuscular function (11). Even low doses of
glucocorticoids (2.5–7.5 mg of prednisolone per day)
are associated with a 2.6-fold higher risk of vertebral
fractures, whereas doses higher than 7.5 mg ofprednisolone per day carry a fivefold higher risk (12).
In most patients suffering from rheumatological
diseases as listed in Table 1 , in particular rheumatoid
arthritis, ankylosing spondylitis, and systemic lupuserythematosus, rapid bone loss and increased
fracture risk are caused by the pro-inflammatory
cytokine milieu or the immunosuppressive regimen,which initially includes glucocorticoids, or a balance
between both.Hyperthyroidism A history of overt hyperthyroidism
is an established risk factor for osteoporotic fractures
(13). A large study of 686 postmenopausal women
demonstrated that a serum TSH level !0.1 mU/l was
associated with a four- and fivefold risk of hip and
vertebral fractures respectively (14). A meta-analysis of
21 studies indicated that thyroid hormone therapy for
TSH suppression in differentiated thyroid cancer which
results in subclinical hyperthyroidism is associated withosteoporosis in postmenopausal women (15). Based on
animal models, thyroid hormone excess (16) as well as
suppressed thyrotropin levels (17) has been implicated.
Activation of thyroid hormone receptor aon osteoblasts
and osteoclasts results in enhanced bone resorption
and bone loss (16).
Primary hyperparathyroidism Women are three
times more often affected by primary hyperpara-
thyroidism than men, and its incidence is as high as1:500 in elderly women, a high-risk population for
osteoporosis (18). Chronic parathyroid hormone (PTH)
excess is catabolic to the skeleton, and preferentially
affects cortical rather than cancellous bone. Thus, bone
loss is most prominent at skeletal sites that consist ofcortical bone (middle third of the forearm and femoral
neck), while the spine, mainly composed of cancellous
bone, is less severely affected (18). Either osteoporotic
fractures or a Tscore of !K2.5 is an indication for
parathyroid surgery in otherwise asymptomatic
patients (18). A recent observational study over the
course of 15 years showed that parathyroidectomy
normalized biochemical indices of bone turnover and
preserved BMD, whereas cortical bone density decreasedin the majority of subjects without surgery during
long-term follow-up (19).
Male hypogonadism Androgens are crucial for the
accrual of peak bone mass in men and the maintenance
of bone strength thereafter (8, 20, 21) . The effects of
androgens on bone may be mediated by estrogens (22).
Hypogonadism is a major risk factor for low BMD and
osteoporotic fractures in men, and results in increased
bone remodeling with rapid bone loss (21) .A s
androgen-deprivation therapy using GnRH agonists
has become a mainstay in the multimodal management
of prostate cancer, treatment-related hypogonadism has
emerged as an important risk factor for osteoporotic
fractures in these men (8, 23) .
Pregnancy-associated osteoporosis The mechanisms
of this entity are poorly understood. Factors that have
been implicated include preexisting vitamin D defici-ency, low intake of calcium and protein, low bone mass,
increased PTH-related protein, and high bone turnover
(24, 25) . Multiple pregnancies or prolonged periods of
lactation per se are not associated with osteoporosis.
However, women are at risk of pregnancy-associatedTable 1 Common causes for secondary osteoporosis.
Endocrine diseases
Diabetes mellitusGH deficiency (rare)
Acromegaly (rare)
HypercortisolismHyperparathyroidismHyperthyroidismPremature menopauseMale hypogonadism
Gastrointestinal disorders
Gastrectomy
Celiac diseaseInflammatory bowel diseaseLiver cirrhosisChronic biliary tract obstructionChronic therapy with proton pump inhibitors
Hematologic diseases
Myeloma
Monoclonal gammopathy of undetermined significance
Lymphoma/leukemiaSystemic mastocytosis (rare)Disseminated carcinomaChemotherapy
Rheumatological diseases
Rheumatoid arthritis
Ankylosing spondylitis
Systemic lupus erythematosus
Connective tissue diseases
Osteogenesis imperfectaMarfan’s syndrome (rare)Ehlers–Danlos syndrome (rare)Pseudoxanthoma elasticum (rare)
Other
Anorexia nervosa1010 L C Hofbauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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osteoporosis, if they use unfractionated heparins for
thromboembolic disorders (26, 27) . The skeletal side
effects of low-molecular weight heparin are currentlyunknown (28).
Diabetes mellitus type 1 The risk of osteoporotic
fractures is increased by 12-fold in patients with type 1diabetes (4). Lack of the bone anabolic actions of insulin
and other b-cell-derived proteins such as amylin have
been postulated to contribute to low BMD and impaired
fracture risk (3). In long-standing disease, diabetic
complications, such as retinopathy, polyneuropathy,and nephropathy , are the major determinants of low
bone mass and increased fracture risk, in part due to the
enhanced propensity of falls (3). Data from the Women’s
Health Initiative Observational Study also indicate a20% higher risk for fractures after adjustment for
frequent falls and increased BMD (4–5% higher at the
hip) in women with type 2 diabetes mellitus (29).
An important additional risk factor for fractures inpostmenopausal women with type 2 diabetes mellitus is
the use of a TZD type insulin sensitizer, associated with
fractures of the hip, humerus, and small bones of thehands and feet (30).
GH deficiency Insulin-like growth factor 1 (IGF1) and
IGF-binding proteins, which are produced upon stimu-
lation of its hepatic receptor by human GH, represent apotent stimulator of osteoblastic functions and boneformation (31, 32) . Patients with untreated adult-onset
GH deficiency have a two- to threefold higher risk of
osteoporotic fractures (32), and the degree of osteopenia
is related to the extent of GH deficiency (33). Accurate
measurement of BMD in patients with pediatric-onsetGH deficiency is complicated because of short stature
and small bone size.
Gastrointestinal diseases
Celiac disease Chronic diarrhea and malabsorption
due to villous atrophy are the hallmarks of celiacdisease. Intestinal absorption of calcium is impaired,and vitamin D deficiency is common ( Table 1 ), resulting
in osteomalacia and secondary hyperparathyroidism
(34). Associated autoimmune disorders such as type
A gastritis with achlorhydria, Graves’ disease withhyperthyroidism, or type 1 diabetes mellitus may
further impair skeletal health. A recent study demon-
strated a 17-fold higher prevalence of celiac diseaseamong osteoporotic individuals compared with non-osteoporotic individuals, supporting serologic screening
of all patients with osteoporosis for celiac disease (35).
Inflammatory bowel disease The pathogenesis of
osteoporosis in inflammatory bowel disease is complex,and patients with Crohn’s disease are more severely
affected compared with those with ulcerative colitis(36). Chronic inflammation, diarrhea and/or malab-
sorption, low body mass index (BMI), and intermittent
or chronic systemic glucocorticoid therapy for flares
are major causes of osteoporosis. In addition, vitamin D
deficiency in those with short bowel syndrome or
functional loss of terminal ileum integrity, repeatedhospitalizations, and prolonged immobility may
contribute to low bone mass. Short bowel syndrome is
a particular risk factor for bone loss (36).
Gastrectomy and chronic proton pump inhibitor
therapy After gastrectomy, osteoporosis develops in up
to one-third of patients postoperatively, and may
be related to decreased calcium absorption due to the
higher gastrointestinal pH value (37) . Similarly,
a prolonged high-dose use of proton pump inhibitorscarries a 3.5-fold increased risk of vertebral fractures in
postmenopausal women (38). Loss of gastric acidifica-
tion may impair the absorption of calcium carbonate
compared with calcium gluconate or calcium citrate,
which are absorbed in a pH-independent manner, but
are used less commonly .
Bariatric surgery Bone loss after bariatric surgery has
become a clinical challenge (39) . The various
procedures, including biliopancreatic diversion with
duodenal switch, gastric banding, and Roux-en-Y
gastric bypass, the last of which is the preferred method
in the US, are associated with variable degrees of
reduced fractional calcium absorption and vitamin D
malabsorption (9, 39) . Bone loss may be moderately
severe, and appears to be closely related to the degree of
weight loss (9). A preliminary study indicated a
doubling of fracture risk after bariatric surgery.
Myeloma bone disease and systemic
mastocytosis
Myeloma bone disease and monoclonal
gammopathy of undetermined significance Various
cellular and humoral communications between myel-
oma cells and bone cells contribute to osteoporosis,
and mainly affect the axial skeleton. Expression of
receptor activator of NF- kB ligand (RANKL) and other
pro-osteoclastogenic factors by myeloma cells results in
enhanced osteoclastogenesis and increased bone resorp-
tion (40). In addition, myeloma cells secrete dickkopf-1,
a soluble Wnt signaling inhibitor, which markedly supp-
resses osteoblastic differentiation (41). A population-
based retrospective cohort study that followed 165patients with myeloma for 537 person-years reported
that in the year before myeloma was diagnosed, 16 times
more fractures were observed than expected, of which
two-thirds were pathologic spinal or rib fractures (42).
The risk of subsequent osteoporotic fractures was
elevated two- to threefold. Up to 1 in 20 patients with
newly diagnosed osteoporosis have multiple myeloma or
monoclonal gammopathy of undetermined significanceSecondary osteoporosis 1011 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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(MGUS) (43). Of note, patients with MGUS, a disease
that can progress to multiple myeloma, also carry anincreased risk for osteoporotic fractures (44). A retro-
spective cohort study of 488 patients with MGUS found
a 2.7-fold increased risk of axial fractures, but noincrease in limb fractures (44).
Systemic mastocytosis Bone loss due to mastocytosis
may be rapid and severe, and affects both the long bonesand the spine. Osteoporosis results from excessive
degranulation of mast cell products, including inter-leukin (IL)-1, IL-3, IL-6, and histamine, which promoteosteoclast differentiation from precursor cells (45).A n
activating mutation of the tyrosine kinase c-kit (D816V
mutation), present in over 90% of adult patients withmastocytosis, contributes to elevated bone resorption.
HIV disease
Women and men with HIV disease are at increased riskof spinal, hip, distal radius, and other fractures due to
osteoporosis. In older individuals with HIV disease,
fracture risk is increased three- to fourfold comparedwith non-HIV-infected controls (46). The risk of having
osteoporotic bone density is also increased 3.7-fold forHIV-infected individuals compared with controls (47).
In addition to anti-retroviral drug use, the increase inosteoporosis risk is related to low BMI, hypogonadism,infection and inflammation, vitamin D deficiency, GH
deficiency, smoking, and alcohol abuse. An assessment
of bone health and vitamin D status is thereforeimportant in individuals with HIV disease.
Drug-induced osteoporosis
Numerous drugs affect bone metabolism ( Table 2 )
through interaction with the absorption of vitamin D,
calcium, and phosphate or vitamin D metabolism andaction, direct cellular effects on osteoblasts, osteoclasts,
and osteocytes, or interference with either the amount
or quality of bone matrix proteins. The adverse skeletal
effects of glucocorticoids (11) and calcineurin inhibitor-
type immunosuppressants such as cyclosporine A (48)
are well established in the management of inflam-
matory diseases and in transplantation medicine.
To minimize skeletal side effects, non-calcineurin
inhibitor immunosuppressants and glucocorticoid-
sparing regimens are increasingly employed.
The use of the insulin sensitizers TZDs (rosiglitazone
and pioglitazone) which act as agonists of theperoxisome proliferator-activated receptor- gis associ-
ated with a three- to five-fold higher risk of fractures of
the humerus, femur, and hip in postmenopausal women
(49). These alterations may result from shunting
pluripotent mesenchymal stem cells toward the adipo-
cyte phenotype at the cost of the osteoblastic lineage,
which resembles the bone changes that occur withaging (50). In particular, rosiglitazone decreases bone
formation in the face of on-going bone resorption,
leading to bone loss (51).
Ablation of androgen or estrogen production or action
has become a mainstay in modern therapy of prostate
and breast cancer respectively . Androgen-deprivation
therapy includes GnRH agonists (goserelin, buserelin,leuprolide, and triptorelin), which cause hypogonado-
tropic hypogonadism, or anti-androgens (bicalutamide
and cyproterone acetate) that block the peripheral
action of androgens. Similarly, the use of the AIs
anastrozole, letrozole, and exemestane reduces the
conversion from adrenal androgens into estrogens.
Thus, both strategies are aimed at reducing the amountof bioavailable androgens and estrogens, which act as
tumor-promoting hormones; however, they cause severe
and rapid high turnover bone loss and fractures (7, 52) .
Other drugs known to affect bone metabolism include
the injectable contraceptive depot-medroxyprogesterone
acetate (53), proton pump inhibitors (54), heparins
Table 2 Drugs known to cause osteoporosis and/or fragility fractures.
Drug classaExamples Indications
Glucocorticoidsa,bPrednisolone Autoimmune diseases
Calcineurin inhibitorsa,bCyclosporine A Allogeneic organ transplantation
Chemotherapeutic drugs Methotrexate, ifosfamide MiscellaneousTyrosine kinase inhibitors Imatinib Chronic myelogenous leukemiaThiazolidinediones
a,bRosiglitazone, pioglitazone Type 2 diabetes mellitus
GnRH agonistsa,bGoserelin, buserelin, flutamide Prostate cancer, endometriosis
Aromatase inhibitorsa,bAnastrozole, letrozole, exemestane ER-positive breast cancer
Progesterone Depot-medroxyprogesterone acetate ContraceptionProton pump inhibitora,bOmeprazole and pantoprazole Peptic ulcer and reflux diseases
Unfractionated heparinsa,bThromboembolic diseases
Lipase inhibitors Orlistat Morbid obesityThyroid hormonebL-thyroxine Replacement therapy for hypothyroidism, thyroid cancer
AnticonvulsantsaValproic acid Chronic seizure disorders
Antidepressantsa,bSelective serotonin re-uptake inhibitors Chronic depression
Anti-retroviral drugs Tenofovir HIV disease
aStrong evidence.
bDrug is associated with increased fractures.1012 L C Hofbauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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(26), antiepileptic drugs that induce hepatic enzymes
(phenytoin, phenobarbitone, primidone, and carbama-zepine) (55, 56) , antidepressants of the selective
serotonin re-uptake inhibitor class (57–59) ,a n d
anti-retroviral drugs used to treat HIV (47).
Diagnosis
The initial evaluation of secondary osteoporosis should
include a detailed history of clinical risk factors forfractures and the underlying medical conditions and
medications that cause bone loss, a thorough physical
examination and laboratory tests ( Table 3 ).
A comprehensive review of all used medications is
essential, as is an evaluation of the smoking and alcoholhabits, and the hereditary disposition of osteoporosis orfractures. Particular attention should be given to type 1diabetes mellitus, anorexia nervosa, and prolongedsex hormone deficiency as well as those endocrinedisorders that can in principle be cured ( Table 1 ). The
risk for falling should be assessed in patients withosteoporotic fractures who reported repeated falls (60).
A recommended clinical approach includes evaluation
of high-risk medications (sleeping medications,antidepressants, and anticonvulsants), vision, balanceand gait, and muscle strength. A reasonable screeningtest is the ‘Timed Up and Go’ tests which integratesmany of these functions.Based on these initial findings and the clinical index
of suspicion, further laboratory and imaging studies aswell as invasive tests are required.
BMD testing using dual-energy X-ray absorptiometry
is the method of choice for the diagnosis of secondaryosteoporosis and should be conducted at the lumbar
spine and hip (61). Aortic calcification and osteophytes,
which are particularly common in men, may interferewith spinal BMD measurement, allowing only hipmeasurement to be used. In the presence of anunderlying cause, fracture risk may be increasedindependently of BMD (57). For example, patients with
chronic renal failure may have increased skeletal
fragility despite normal BMD values. In addition, there
is a higher BMD fracture threshold in patients onsystemic glucocorticoids, so that most would supportintervention for patients with osteopenia. Spinal X-raysshould be performed in those with localized back pain,recent spinal deformities, or a loss of more than 3 cm inheight in order to detect prevalent vertebral fractures,osteolytic lesions, or tumors ( Table 3 ). Owing to their
low sensitivity, spinal X-rays should not be used to
screen for osteoporosis. A recent alternative has beenthe vertebral fracture assessment tool of the dual-energy X-ray absorptiometry which provides a lateralvertebral morphometry and is associated with lessradiation and, when available, is a useful screeningtest for vertebral fractures. The fracture risk can be
easily assessed with the FRAX tool ( http://www.shef.ac.
uk/FRAX/ ), a computer-based calculator that,
Table 3 Diagnostic tests in the work-up of secondary osteoporosis.
Diagnostic test Purpose
History and physical exam To identify risk factors for fractures, the underlying
disease, and potential drugs
Dual-energy X-ray absorptiometry (lumbar spine and hip) To quantify bone mineral densitySpinal X-rays To detect prevalent vertebral fractures
To exclude osteolytic lesions or tumors
Diagnostic test To detect or exclude
Complete blood count Anemia as in myeloma/celiac disease
Leukocytosis in leukemia
Renal and liver function test Renal or liver failure, alcohol abuseSerum calcium and phosphate levels Primary hyperparathyroidism, myelomaSerum C-reactive protein Chronic infection/inflammationSerum bone-specific or total AP activity Paget’s disease; osteomalaciaSerum 25-hydroxyvitamin D Vitamin D deficiency, osteomalacia
Serum levels of basal TSH Hyperthyroidism
Serum free testosterone levels (in men) Male hypogonadismFasting glucose levels Diabetes mellitusIntact parathyroid hormone Primary hyperparathyroidismSerum protein electrophoresis, immunofixation MGUS, myeloma24-h urinary calcium excretion (with creatinine and sodium control) Hypercalciuria
Anti-tissue transglutaminase antibodies Celiac disease
Anti-HIV antibodies HIV disease, AIDSMorning fasting serum cortisol after dexamethasone suppression Cushing’s syndromeSerum tryptase levels, urinary histamine excretion Systemic mastocytosisCOL1A genetic testing Osteogenesis imperfecta
Iliac crest bone biopsy Systemic mastocytosis, MGUS/myeloma,
osteomalacia, lymphoma/leukemia
AP, alkaline phosphatase.Secondary osteoporosis 1013 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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in addition to gender, age, BMD, and BMI, also includes
risk factors such as smoking, alcohol abuse, glucocorti-coid use, and the presence of rheumatoid arthritis and
secondary osteoporosis.
We recommend an initial laboratory evaluation with
standard renal and liver function tests, a complete blood
count, serum calcium and phosphate levels, C-reactive
protein, bone-specific (or total) alkaline phosphatase,serum 25-hydroxyvitamin D, serum levels of basal
thyrotropin, and serum testosterone levels in men
(Table 3 ). We also recommend free measurements of
serum levels of PTH, serum protein electrophoresis, and24-h urinary calcium excretion. The latter should be
performed including measurement of creatinine as inter-
nal quality control and sodium excretion to exclude saltrestriction with subsequent false-low calcium excretion.
To screen for celiac disease, anti-tissue transglutami-
nase antibodies should be measured, especially if iron-deficiency anemia and low 25-hydroxyvitamin D levels
are present, and if positive, a duodenal biopsy should be
performed to confirm the diagnosis. To rule outCushing’s syndrome, we measured morning fastingserum cortisol levels after administration of 1 mg
dexamethasone at midnight the previous day . If
systemic mastocytosis is suspected, we recommend themeasurement of mast cell-derived products, serum
tryptase levels, or 24-h urinary excretion of histamine,
although these may be normal, in part becausehistamine is thermolabile. Thus, if available, urinary
excretion of N-methylhistamine or 11- bprostaglandin
F
2amay be more robust and reliable than urinary
excretion of histamine. COL1A genetic testing is
required to confirm the diagnosis of osteogenesis
imperfecta. This is most commonly diagnosed basedon a positive family history, recurrent fragility fractures,blue sclerae, and hearing loss, and only rarely requires
genetic confirmation by COL1A1 genotyping.
We advocate iliac crest bone biopsy for those
individuals where the evaluation described above yields
unexplained laboratory findings or remains inconclusive,
in young adults with multiple fractures or fractures thatoccur during antiresorptive treatment. Typical scenarios
for a definitive role of bone biopsy are to distinguish
osteomalacia from osteoporosis, to establish a diagnosisof systemic mastocytosis, and to assist in diagnosinginfiltrating malignant diseases, including multiple myel-
oma, lymphoma, leukemia, or disseminated carcinoma.
Biochemical markers of bone turnover are of limited
use in establishing a secondary cause of osteoporosis;
however, they may be used to monitor therapeutic
efficacy or the patient’s adherence/compliance withtreatment.
Treatment
The management of secondary osteoporosis is aimedat i) treating the underlying disease, if known, and
ii) treating osteoporosis and preventing further fractures.A practical approach with patient-centered, individua-
lized therapy is warranted. Because of the variousetiologies of secondary osteoporosis and limited
randomized placebo-controlled trials in this area,
treatment guidelines are largely based on professional
opinion rather than the highest level clinical evidence.
Treatment of the underlying disease
Endocrine diseases Complete and sustained therapy of
the underlying endocrine disorder can be challenging.
Cushing’s syndrome and primary hyperparathyroidism
should be surgically treated if osteoporosis is present.Endogenous hyperthyroidism should be treated with
anti-thyroid drugs, radioiodine therapy, or surgery,
while exogenous hyperthyroidism requires adjustmentof the
L-T4dosage with a target serum thyrotropin level
within the normal range. If TSH-suppressive therapy for
differentiated thyroid carcinoma is required, the lowest
L-T4dose that suppresses TSH below the limit of
detection should be administered.
Sex hormone deficiency in premenopausal women
and men with osteoporosis should be replaced, if signs
and symptoms of hormone deficiency, such as decreasedlibido, sarcopenia, and visceral obesity, are present.
Fracture risk reduction has not been shown for
testosterone replacement therapy, but increases inBMD are seen in hypogonadal men treated with
testosterone (8). Specific contraindications, such as
breast cancer and thromboembolic diseases in women,and benign prostatic hypertrophy and prostate cancer
in men, need to be carefully considered.
While GH replacement therapy in adult GH deficiency
increases BMD in men (62, 63) , no data on fracture
reduction are available, and the cost–effectiveness ofthis therapy remains unclear. Patients with type 1
diabetes mellitus and low bone mass benefit from
intensive insulin therapy (64) and aggressive preven-
tion of diabetic vascular complications, including
retinopathy, nephropathy, and polyneuropathy (3).I n
addition, patients with both type 1 and type 2 diabetesmellitus require assessment of falls risk.
A systematic review on bone health in anorexia
nervosa (65) suggests that estrogen replacement
therapy resulted in variable increase in BMD, which
did not reach that of age-matched controls, whereasbisphosphonates were largely ineffective. As expected,
the most consistent finding was that enhanced caloric
intake that led to weight gain and ovulations resulted ina substantial gain of BMD.
Gastrointestinal diseases Restoration or maintenance
of normal body weight and gastrointestinal absorptionare pivotal for patients with osteoporosis due to
gastrointestinal diseases ( Table 1 ). Patients with celiac
disease require nutritiona l counseling emphasizing
adherence to a gluten-free diet, which may require1014
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close monitoring. Exocrine pancreatic enzymes should
be replaced in states of malabsorption due to pancreatic
insufficiency . For patients with inflammatory bowel
disease, in particular those with Crohn’s disease, an
attempt should be made to modify the immunosuppres-sive regimen to control inflammatory activity and to
reduce the glucocorticoid dose. The latter strategy
should also be applied in other inflammatory disorders
complicated by osteoporosis. Two small studies indicate
that suppression of the inflammation by tumour necrosis
factor- ablockade with infliximab increases BMD in
patients with Crohn’s disease (66) and rheumatoid
arthritis (67). The use of biologicals may also help to
reduce the glucocorticoid dose. Small bowel surgery in
Crohn’s disease should be used sparingly to avoid short
bowel syndrome and to thus preserve the terminal ileum.
The endocrine and skeletal status of patients who
underwent gastrointestinal surgery, particularly those
after bariatric surgery, should be monitored for life,as no long-term safety data are available.
Malignant diseases Patients with osteoporosis in the
setting of a malignant disease should be referred to a
comprehensive cancer center. Patients with breast or
prostate cancer and low bone density due to hormone-ablative therapy will be discussed below.
Drug-induced osteoporosis If drugs suspected to
promote osteoporosis are being taken ( Table 2 ), their
continued use needs to be evaluated and alternatives
should be sought. This holds particularly true for
alternative routes of administration, especially the use
of topical drugs (glucocorticoid aerosol for inflam-matory airway disease or enema for inflammatory
bowel diseases with rectal involvement). In allogeneic
organ transplantation and inflammatory disorders,
novel regimens without calcineurin inhibitors and
glucocorticoids may be feasible.
For patients with seizure disorders requiring pro-
longed anticonvulsive therapy, a variety of novel drugsare available that do not interfere with vitamin D and
mineral metabolism. In patients with diabetes, TZDs
should be discontinued and replaced by other insulin
sensitizers, if possible. Patients with heparin-induced
osteoporosis who require anticoagulation should be
switched to oral vitamin K antagonists. The adverse
effects of the injectable contraceptive depot-medroxypro-gesterone acetate on BMD need to be balanced against
the benefits of preventing unintended pregnancy (53).
Particular attention should be paid to anti-hyperten-
sive, sedative, psychotropic, and antidepressant drugs
alone or in combination, as they may indirectly cause
osteoporotic fractures by enhancing the propensity of
falls. We recommend all patients with secondaryosteoporosis to limit alcohol consumption to no more
than two standard drinks per day and to stop smoking.
Patients with hypercalciuria may benefit from a thiazide
(12.5–25 mg hydrochlorothiazide per day).Specific osteoporosis treatment
Vitamin D and calcium An adequate intake of
calcium (800–1200 mg/day) via dietary intake or
supplements is recommended. Vitamin D supple-mentation (at least 800 IU/day) is recommended asvitamin D deficiency has a high prevalence and, inaddition to various adverse extraskeletal effects, may
contribute to low bone mass and increase the propensity
to falls (68). In addition, the efficacy of anti-osteoporotic
drugs has only been demonstrated in the presence ofvitamin D and calcium supplementation. Therapyshould be titrated with doses that result in normocalce-
mia and serum 25-hydroxyvitamin D concentrations of
at least 30 ng/ml. In patients with normal renalfunction, a decrease in serum PTH levels from elevatedto normal levels indicates that 25-hydroxyvitamin Ddeficiency has been corrected. Some anti-epileptic
drugs, e.g. phenytoin, phenobarbitone, primidone, and
carbamazepine, increase hepatic metabolism of vitaminD, requiring higher vitamin D doses (56).
Intestinal calcium and vitamin D absorption may be
severely impaired in widespread Crohn’s disease, after
gastrectomy or with chronic use of proton pump
inhibitors, and after bariatric surgery. In these circum-stances, vitamin D should be administered parenterally(100 000–200 000 IU every 3 months) with titration of
doses to achieve serum 25-hydroxyvitamin D concen-
trations of at least 30 ng/ml. An alternative is oralvitamin D preparations administered at 50 000–100 000 IU once or twice a week, or daily , if needed.
A small randomized study comparing alphacalcidol
and etidronate in cardiac transplant recipients indicated
that alphacalcidol was superior with respect to thepreservation of BMD and fracture reduction (69).
A larger study that compared alphacalcidol withthe more potent aminobisphosphonate alendronate in
patients with GIO indicated that alendronate, but
not alphacalcidiol, resulted in an increase in BMD andreduced vertebral fractures (70). A meta-analysis
suggests that alphacalcidol as well as calcitriol increasesBMD and may reduce fractures, in particular in patients
not taking systemic glucocorticoids (71). Based on these
studies, active vitamin D metabolites may play a role inthe management of secondary osteoporosis (other thanGIO), if bisphosphonates cannot be used.
Bisphosphonates Both oral and i.v . bisphosphonates
have been used in the treatment of secondary
osteoporosis. In general, alendronate (70 mg/week)and risedronate (35 mg/week) are reasonable anti-osteoporotic drugs for secondary osteoporosis.However, many patients with osteoporosis secondary
to gastrointestinal diseases or concurrent medications
not tolerating, or adhering to, oral bisphosphonatesand those in whom oral bisphosphonates arecontraindicated may benefit from treatment with i.v .ibandronate or zoledronic acid. I.v . bisphosphonatesSecondary osteoporosis 1015 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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are also favorable to oral bisphosphonates which are
poorly absorbed in malabsorption. Because of itspotency and convenient admi nistration, zoledronic
acid (4 or 5 mg/year) has recently been evaluated in
various forms of secondary osteoporosis. It is importantto note that the evidence for an anti-fracture effect ofbisphosphonates is limited for most forms of secondaryosteoporosis, except for women and men with GIO, menwith hypogonadism, and men after cardiac trans-plantation. In addition, most studies were not poweredto assess fracture risk reduction.
The use of bisphosphonates in patients with renal
insufficiency has been a concern. However, a post-hoc
analysis of the fracture intervention trial (FIT) demon-strated that alendronate reduced fractures in postme-nopausal women with osteoporosis and impaired renalfunction (glomerular filtration rate, GFR !45 ml/min)
(72) . A small study conducted in patients with
osteopenia on regular hemodialysis demonstrated anincrease in the spinal BMD with ibandronate (2 mg
every 4 weeks over 48 weeks) by 5.1%, although no
fracture risk reduction was assessed (73).
Glucocorticoid-induced osteoporosis . Oral alendronate
(10 mg/day) and risedronate (5 mg/day) increased BMDand reduced vertebral fractures in women and men withGIO(74, 75) . In a 12-month study , zoledronic acid was
more effective than risedronate in preventing bone loss in
men and women with GIO (76). In a randomized head-
to-head study , the BMD increase after 12 months washigher in patients with GIO treated with zoledronic acid(5 mg/year) ( C4.1%) compared to risedronate (5 mg/day)
(2.7%) (76). However, the study had insufficient power
to assess differences in fracture reduction.
The use of bisphosphonates in women of childbearing
age still represents a therapeutic dilemma, and the
decision on its use needs to be made on an individualbasis under effective contraception. A systematic reviewidentified 51 cases of bisphosphonate exposure before orduring pregnancy, none of which revealed skeletalabnormalities in the offspring (77).
Osteoporosis in men . Studies of treatment in men with
osteoporosis have been smaller and fewer in numberthan those in women. Treatment efficacy in men ismostly based on positive effects on BMD and boneturnover. In hypogonadal and eugonadal men, alen-dronate (10 mg/day) increased spinal and femoral neckBMD and reduced the incidence of vertebral fracturesby 80% over 2 years (78). Risedronate (5 mg/day)
increased spinal and femoral neck BMD, and reduced
spinal fractures by 60% over 1 year in an uncontrolledstudy, although it included men with primary andsecondary osteoporosis (79). Both studies had insuffi-
cient statistical power to measure differences in fracturerates at non-vertebral sites. Zoledronic acid (5 mgannually) given to elderly men (and women) after hipfractures increased femoral neck BMD, reduced risk ofall clinical fractures by 35%, and lowered all-causemortality by 28% over 3 years (80). This study included
patients with primary and secondary osteoporosis, butdid not assess those both separately .
Bone loss associated with androgen-deprivation therapy for
prostate cancer . Bisphosphonates have been shown to
prevent bone loss in men with non-metastatic prostatecancer receiving androgen-deprivation therapy . Oralalendronate (70 mg/week) (81) and i.v . pamidronate
(90 mg every 3 months) (82) have prevented bone loss
and, in fact, increased BMD at the lumbar spine and thehip, and decreased bone turnover. More recently, i.v .zoledronic acid (5 mg/year) was shown to prevent boneloss associated with androgen-deprivation therapy inmen with prostate cancer (83). However, none of these
studies were powered to demonstrate anti-fractureefficacy.
Bone loss associated with AI therapy for breast cancer .T w o
small trials of postmenopausal women with breastcancer taking AI reported that oral risedronate(35 mg/week) (84) and ibandronate (150 mg/month)
(85) reduced bone loss. Semi-annual therapy with 4 mg
of zoledronic acid for 3 years (Z- and ZO-FAST trials)prevented bone loss in women receiving AI therapy forbreast cancer to a greater extent compared with oralbisphosphonates (86, 87) . Taken together, both oral
and i.v . bisphosphonates reduce bone loss during AItherapy; however, none of the studies had sufficientpower to assess anti-fracture efficacy.
Miscellaneous . Oral alendronate (70 mg/week or
10 mg/day) has been shown to increase BMD inpatients with primary hyperparathyroidism (88, 89)
as well as women with type 2 diabetes mellitus (90) and
with pregnancy- and lactation-associated osteoporosisafter delivery and lactation (91), although none of these
studies were powered to assess fractures. Semi-annualtherapy with 4 mg of zoledronic acid prevented boneloss in patients with MGUS (92). Zoledronic acid (4 mg
given five times per year) also prevented bone loss afterliver transplantation (93) and after allogeneic bone
marrow transplantation (94, 95) . Similarly, i.v . iban-
dronate (2 mg given four times per year) prevented boneloss and reduced fractures in men after cardiactransplantation (96). I.v . neridronate increased BMD
at the spine and hip and reduced fractures in childrenwith osteogenesis imperfecta (97). Oral alendronate or
i.v . pamidronate may work equally well if neridronate isnot available (98). A large meta-analysis that included
eight studies with 403 participants indicated that oraland i.v . bisphosphonates improved BMD also in adultswith OI, although no data were available for fracturereduction (99).
Teriparatide Bone formation is severely impaired in
GIO and in many men with osteoporosis, thus providinga rationale to use the bone anabolic teriparatide.1016
L C Hofbauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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Glucocorticoid-induced osteoporosis . In an 18-month
controlled trial that directly compared teriparatide(20mg/day s.c.) with alendronate (10 mg/day orally)
in patients with GIO, teriparatide increased spinal BMD
by 7.2% compared with 3.4% in the alendronate group.A superior effect of teriparatide on BMD at the lumbar
spine was observed as early as 6 months after the start
of the study . While 25–30% of the patients hadestablished vertebral fractures, the incidence of new
vertebral fractures was 0.6% in the teriparatide and
6.1% in the alendronate group (100) .
Osteoporosis in men . In hypogonadal and eugonadal
men with osteoporosis, teriparatide (20 mg/day s.c.)
increased spinal and proximal femur BMD (101) , and in
follow-up studies, it reduced the risk of spinal fractures.
The concurrent use of alendronate and teriparatideblunted the bone anabolic effect of teriparatide in men
(102) . Thus, oral bisphosphonates should be used only
after teriparatide has been discontinued. This strategymay preserve the BMD gain. Owing to the high costand need for daily injection, teriparatide is generally
recommended for severe osteoporosis or individuals
who do not respond adequately to bisphosphonates.
Denosumab Denosumab is a human MAB directed
against RANKL, an essential cytokine for osteoclasto-
genesis (103) . In men receiving androgen-deprivation
therapy for prostate cancer, denosumab (60 mg s.c.
every 6 months for 2 years) increased spinal BMD by 7%
and reduced vertebral fractures by 62% (104) . Similarly,
in women on AI therapy for breast cancer, denosumab
increased BMD at the spine and the femoral neck (105) ,
although this study was not powered to assess fractures.Denosumab has not been approved for primary or
secondary osteoporosis, but may expand our armamen-
tarium to treat bone loss conditions.
Conclusion
Fragility fractures in men or premenopausal women,very low values of BMD, and fractures that occur whileon anti-osteoporotic therapy should prompt a work-up
for secondary osteoporosis. BMD should be assessed
with bone densitometry at the hip and spine, and thepresence of prevalent vertebral fractures with lateral
X-rays of the thoracic and lumbar spine. A detailed
history and physical examination combined with first-line laboratory tests may reveal an underlying diseasethat needs to be confirmed by definitive diagnostic tests.
Treatment of the underlying disease is pivotal, if
possible, using a regimen that does not harm theskeleton further. All patients with secondary osteoporo-
sis should receive adequate calcium and vitamin D
supplementation, ensuring normal calcium and PTHserum levels and 25-hydroxyvitamin D
3serum concen-
trations of at least 30 ng/ml. Oral bisphosphonates(alendronate and risedronate) given once per week are
antiresorptive and prevent bone loss. Poor compliance,malabsorption, or impaired gastrointestinal tolerance oforal bisphosphonates may favor the use of parenteralbisphosphonates (ibandronate and zoledronic acid). Inthis regard, zoledronic acid infused intravenously onceor twice per year, depending on the indication for
treatment, is potent in preventing bone loss. However,
an acute phase reaction is a frequent side effect,particularly after the first infusion. Teriparatide maybe used in patients with severe GIO or men withvertebral fractures of very low BMD when anabolictherapy is warranted. New therapies are currentlyunder investigation, including denosumab, a humanantibody against RANKL, odanacatib, a specific cath-epsin K inhibitor, and third-generation selective estro-gen receptor modulators.
Declaration of interest
L C Hofbauer has received honoraria from Amgen, Merck, Novartis,
and Nycomed. C Hamann has nothing to declare. P R Ebeling hasreceived honoraria from Amgen, Merck, Novartis, and Sanofi-Aventis,and has been a speaker for Eli-Lilly .
Funding
Dr Hofbauer’s research program is supported by DFG/SFB Transregio67, HO 1875/8-1, and RA 1923/1-1.
Acknowledgements
The authors thank Theresa Reiche for secretarial assistance.
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Received 26 February 2010
Accepted 15 March 20101020 L C Hofbauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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