THIEME

122 Review Article

Osteoporosis: Current Concepts

Ibrahim Akkawi1 Hassan Zmerly1

1 Orthopaedics and Traumatology Unit, Villa Erbosa Hospital, Address for correspondence Ibrahim Akkawi, MD, Orthopaedics and
Bologna, Italy Traumatology Unit, Villa Erbosa Hospital, Bologna 40129, Italy
(e-mail: i.akkawi@libero.it).
Joints 2018;6:122–127.

Abstract Osteoporosis is a worldwide disease characterized by reduction of bone mass and alteration
of bone architecture resulting in increased bone fragility and increased fracture risk. Causes
of osteoporosis include increasing age, female sex, postmenopausal status, hypogonadism
or premature ovarian failure, low body mass index, ethnic background, rheumatoid
arthritis, low bone mineral density (BMD), vitamin D deficiency, low calcium intake,
hyperkyphosis, current smoking, alcohol abuse, immobilization, and long-term use of
certain medications. The diagnosis of osteoporosis is established by measurement of BMD
of the hip and spine using dual energy X-ray absorptiometry. According to the World Health
Organization criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviation or
Keywords more below the average value for young healthy women. Bone turnover biomarker
► osteoporosis detection may be useful in monitoring osteoporosis treatment and assessing fracture
► DEXA risk but not for diagnosis of osteoporosis. Management of osteoporosis consists of
► bone mineral density nonpharmacological interventions, which are recommended for all subjects, and pharma-
► anabolic agents cological therapy in all postmenopausal women who have had an osteoporotic fracture or
► antiresorptive agents have BMD values consistent with osteoporosis.

Introduction Definition

Osteoporosis is a worldwide disease characterized by reduc- According to the National Institutes of Health Consensus
tion of bone mass and alteration of bone architecture result- Development Panel on Osteoporosis,9 osteoporosis is defined
ing in increased bone fragility and increased fracture risk.1–4 as “a skeletal disorder characterized by compromised bone
The prevalence of osteoporosis is expected to increase sig- strength leading to an increased risk of fracture.” Moreover,
nificantly in the future because of aging of the population.5,6 according to the World Health Organization (WHO) criteria,
Osteoporosis mainly occurs in postmenopausal women and osteoporosis is defined as a bone mineral density (BMD) that
elderly men.7 lies 2.5 standard deviation (SD) or more below the average
Approximately 200 million people suffer from osteo- value for young healthy women (a T-score of < 2.5 SD).10
porosis and approximately 8.9 million fractures are Osteoporosis can be subdivided into primary osteoporo-
caused by osteoporotic fracture.6 These fractures occur sis, which includes postmenopausal osteoporosis (type I)
mainly at the hip, vertebrae, and distal forearm7 and are and senile osteoporosis (type II), and secondary osteoporo-
associated with significant morbidity, mortality, and sis, which has a clearly definable etiologic mechanism such
reduced quality of life, attributed not only to the fracture as malabsorption, medications such as glucocorticoids, and
itself but also to the high prevalence of comorbidities in some diseases such as hyperparathyroidism.11,12
this population of patients.6,7 Moreover, osteoporosis
represents a major concern of the health care systems
Risk Factors
because of its growing economic burden.5 In the United
States, costs related to osteoporosis fractures were esti- Causes of osteoporosis include increasing age, female sex,
mated at $13.8 billion.8 postmenopausal status, hypogonadism or premature

received DOI https://doi.org/ Copyright © 2018 Georg Thieme Verlag

September 3, 2017 10.1055/s-0038-1660790. KG Stuttgart · New York
accepted ISSN 2282-4324.
May 2, 2018
published online
June 14, 2018
 Osteoporosis Akkawi, Zmerly 123

ovarian failure, low body mass index, ethnic background more specific for bone and, therefore, more sensitive in
(white persons are at higher risk than black persons), rheu- detecting the small changes in bone formation seen in
matoid arthritis (RA), low BMD, vitamin D deficiency, low osteoporosis.17,18 OC is considered a specific biomarker of
calcium intake, hyperkyphosis, current smoking, alcohol osteoblast function for the evaluation of bone formation rate
abuse, immobilization, and long-term use of certain medica- in osteoporosis.5,17 The concentration of P1NP and P1CP in
tions, such as glucocorticoids, anticoagulants, anticonvul- serum reflects bone formation rate,17 as they are produced
sants, aromatase inhibitors, cancer chemotherapeutic drugs, during conversion of procollagen type 1 to collagen type 1.19
and gonadotropin-releasing hormone agonists.2,4,13,14 Kučukalić-Selimović et al19 found that P1NP is significantly
higher in postmenopausal females with osteoporosis com-
pared with postmenopausal females with preserved bone
Diagnosis
mass, but its low specificity does not warrant its utility in
Osteoporosis is a silent disease without obvious symptoms diagnosing osteoporosis.
and evidence until a fracture occurs.5 Thus, screening by dual HYP is produced from the degradation of bone collagen
energy X-ray absorptiometry (DEXA) is important to obtain during bone resorption.17 Since HYP can be found in other
an early diagnosis and to avoid fractures.5 All women aged tissues such as skin and cartilage, it is considered a non-
65 years or older and men aged 70 years or older, postme- specific marker of bone resorption.5 Pyridinoline and DPD
nopausal women with medical causes of bone loss (e.g., are released during breakdown of bone and cartilage; their
steroid use) regardless of age, postmenopausal women concentration in urine are more sensitive and specific mar-
aged 50 years or older with additional risk factors for fracture kers of bone resorption than urinary HYP.17 TRAP 5b is
(e.g., current smoker, RA, history of hip fracture in a parent), normally secreted by osteoclasts and is considered a specific
and postmenopausal women with a fragility fracture should and high sensitive biomarker of bone resorption.20 CTX-1
be screened for osteoporosis by BMD measurement at the hip and NTX-1 are released during collagen degradation. CTX-1 is
and lumbar spine as recommended by the U.S. Preventive a specific and sensitive biomarker of bone resorption but is
Services Task Force (USPSTF), the National Osteoporosis influenced by food intake, thus blood withdrawal must take
Foundation, and by other guidelines.10–12,15 place in the fasting state in the morning.21 On the contrary,
BMD is mainly described as T-score, which represents the urinary NTX-1 is not affected by food intake.17
number of SD by which the BMD in an individual differs from According to the European guidance for the diagnosis and
the mean value expected in young healthy individuals.6 management of osteoporosis in postmenopausal women, the
Based on the report of the WHO, BMD with a T-score above most informative ones for the investigation of osteoporosis
1 SD is classified as normal BMD, a T-score between 1.0 and are OC and P1NP for assessing bone formation and CT1X to
2.5 SD is classified as osteopenia, and a T-score below 2.5 assess bone resorption.22
SD is defined as osteoporosis.10 According to Gourlay et al,16 According to the current guidelines on osteoporosis man-
rescreening intervals are 15 years for those with normal BMD agement, BTM cannot diagnose osteoporosis, but changes in
(T-score  1.0) or mild osteopenia (T-score < 1.0 and BTMs may be useful in monitoring osteoporosis treatment to
> 1.5), 5 years for those with moderate osteopenia (T- confirm the efficacy of treatment and treatment adher-
score < 1.5 and > 2.0), and 1 year for those with ence.11,21 Furthermore, the measurement of BTMs in women
advanced osteopenia (T-score < 2.0 and > 2.5). with a low BMD can improve the specificity of assessment of
fracture risk.21–24

Bone Turnover Biomarkers

Treatment
Bone turnover biomarkers (BTMs) are produced from the
bone remodeling process and can be measured in urine or The primary goal of osteoporosis therapy is to reduce the risk
serum. They are classified as markers of bone formation of fracture.25 Treatment and prevention strategies of osteo-
(total alkaline phosphatase [total ALP], bone-specific alkaline porosis and osteoporotic fractures include fall avoidance by
phosphatase [B-ALP], osteocalcin [OC], procollagen type 1 N- correcting decreased visual acuity, reducing consumption of
terminal propeptide [P1NP], and procollagen type 1 C-term- medication that alters alertness and balance, reducing fall
inal propeptide [P1CP]) and markers of bone resorption hazards in the home (slippery floors, obstacles, insufficient
(hydroxyproline [HYP], deoxypyridinoline [DPD], pyridino- light), practicing physical activity to improve muscle
line, tartrate-resistant acid phosphatase 5b [TRAP 5b], car- strength, balance, and maintaining bone mass, the avoidance
boxy-terminal cross-linked telopeptide of type 1 collagen of cigarette smoking and excessive alcohol intake, and ade-
[CTX-1], and amino-terminal cross-linked telopeptide of quate dietary intake of protein, calcium, and vitamin
type 1 collagen [NTX-1]).5,17 D.11,12,26 In women, the recommended daily allowance
The total ALP concentration represents the sum of ALP (RDA) for calcium is 1,000 mg/d for age range of 19 to 50 years
isoenzymes from bones, liver, and intestine. In adults with and increases to 1,200 mg/d for older than 50 years; in men,
normal liver function, almost 50% of ALP activity in serum is the RDA of calcium is 1,000 mg/d for age range of 19 to
derived from bone and is produced by osteoblasts during 70 years and increases to 1,200 mg/d for older than 70 years.
bone formation. Therefore, measurement of total ALP activity The RDA for vitamin D is 600 IU/d for men and women aged
lacks sensitivity and specificity in osteoporosis.17 B-ALP is 19 to 70 years and increases to 800 IU/d for those older than

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124 Osteoporosis Akkawi, Zmerly

70 years.2,12 All postmenopausal women, regardless of their Denosumab

bone density or clinical risk factors for osteoporosis should Receptor activator of nuclear factor-kappa B ligand (RANKL)
observe these recommendations.12 is expressed on the membrane of osteoblastic cells and binds
The North American Menopause Society12 recommends to its receptor, RANK, on the surface of osteoclasts, which is
adding osteoporosis drug therapy in all postmenopausal essential for osteoclast formation, activity, and survival.
women who have had an osteoporotic vertebral or hip Denosumab is a human monoclonal antibody that binds
fracture, all those who have BMD values consistent with RANKL and prevents it from combining with RANK on the
osteoporosis at the lumbar spine, femoral neck, or total hip osteoclast membrane, thus inhibiting its action, favoring
region and all those who have T-scores from 1.0 to 2.5 and bone formation over bone resorption, and increasing bone
a 10-year risk of major osteoporotic fracture of at least 20% or mass and strength in both trabecular and cortical bone,
a risk of hip fracture of at least 3%. thereby reducing radiographic vertebral, nonvertebral, and
Pharmacological agents are classified into two groups: hip fractures in postmenopausal osteoporotic women.4,31,32
those that decrease bone resorption (antiresorptive agents) Similarly to BP, denosumab therapy is associated with
and those that increase skeletal formation (anabolic agents).7 mild upper gastrointestinal symptoms, AFF and ONJ; more-
Antiresorptive drugs (bisphosphonates [BPs], denosumab, over, it is associated with increased risk for infection, rash,
strontium ranelate, estrogen replacement therapy [ERT], and and/or eczema.4 Therefore, in patients considered at low risk
selective estrogen receptor modulator [SERM]) reduce the of fracture after 5 years of treatment, discontinuation of
rate of bone resorption and the rate of bone formation. The denosumab is recommended, whereas in patients with a low
overall changes are associated with increases of BMD, but up BMD or multiple vertebral fractures or a high fracture risk
to a certain point due to the coupling between bone resorp- score, it is advisable to continue treatment with denosumab
tion and formation.7 Anabolic drugs (teriparatide, romoso- for up to 10 years and consolidate with a single infusion of
zumab) stimulate bone formation and partially bone zoledronic acid.32
resorption.
Strontium Ranelate
Bisphosphonates Strontium ranelate (Sr RAN) increases the osteoblast differ-
BPs are the first option for the treatment of osteoporosis. entiation while osteoclast formation is inhibited simulta-
These drugs, such as alendronate, risedronate, ibandronate, neously, thus Sr RAN significantly improves bone mass and
etidronate, clodronate, and zoledronic acid, are potent inhi- quality, and increases bone strength; therefore, it remark-
bitors of bone resorption and mainly increase the BMD of ably reduces the risk of vertebral, nonvertebral, and hip
trabecular bones.3,26 It has been showed that BPs reduce fractures in a wide range of postmenopausal women with
vertebral, nonvertebral, and hip fractures compared with documented osteoporosis.33
placebo in postmenopausal osteoporotic women.4 The most common reported adverse effects of Sr RAN are
Oral BPs are associated with mild upper gastrointestinal cardiovascular events, venous thromboembolism, myocar-
symptoms such as dysphagia and esophagitis.4,12,26 More- dial infarction, gastrointestinal discomfort, and signs and
over, BPs are associated with atypical femoral fractures (AFF), symptoms of nervous system such as headache, seizure, and
and osteonecrosis of the jaw (ONJ), albeit these events are memory loss.34 Sr RAN is not recommended for patients
rare (5.9/100,000 person-years and 2/100,000 patient-years, with severe renal impairment (creatinine clearance below
respectively).11,27,28 Park-Wyllie et al29 found that among 30 mL/min), patients with a previous history of throm-
older women, treatment with a BP for more than 5 years was bophlebitis, and patients with established current or pre-
associated with an increased risk of AFF. Galis et al30 vious history of ischemic heart disease, peripheral arterial
observed that the risk of ONJ development is increased by disease and/or cerebrovascular disease, and uncontrolled
several factors, such as duration of BP therapy, administra- hypertension.11,26
tion route of BP, type of BP, invasive dental procedures or The Italian guidelines for the diagnosis, prevention, and
dental prostheses, oncological disease, Caucasian origin, and management of osteoporosis stated that the use of Sr RAN
multiple myeloma. Other adverse effects include hypocalce- must be restricted to the treatment of severe osteoporosis
mia, influenza-like symptoms, uveitis, and episcleritis.4 BPs in postmenopausal women or in adult men with high risk
are contraindicated in patients with low serum calcium and of fracture for whom treatment with other medicinal
severe renal impairment (creatinine clearance below 30–35 products approved for the treatment of osteoporosis is
mL).12 not possible.11
After 3 years of treatment with intravenous zoledronic
acid or 5 years with oral BP, a treatment break should be Estrogen Replacement Therapy
considered as suggested by the American Society for Bone Since menopause is characterized by estrogen deficiency
and Mineral Research, USPSTF, and the American College of that results in bone loss, it has been suggested that the use
Physicians (ACP), whereas if there are characteristics indi- of ERT is effective for prevention of osteoporosis in post-
cative of high fracture risk, such as old age, low hip T-score or menopausal women, but it is not recommended as the first-
high fracture risk score, previous major osteoporotic frac- line preventive treatment of osteoporosis.13 ERT is associated
tures, or fractures on therapy, it is recommended to continue with an increased risk of coronary heart disease, breast
the treatment with BPs up to 10 years.4,11 cancer, stroke, and dementia.11,26

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 Osteoporosis Akkawi, Zmerly 125

Selective Estrogen Receptor Modulator pathway, a well-known metabolic route to drive osteoblast
Raloxifene is the only SERM widely available for the preven- proliferation. Thus, it increases bone formation, bone mass,
tion and treatment of postmenopausal osteoporosis.26 It and strength at various skeletal sites.7 Romosozumab has
reduces the risk of vertebral fractures in postmenopausal been evaluated in a double-blind study at a monthly dose of
women with osteoporosis but has no effect on the risk for 210 mg versus placebo in 7,180 postmenopausal women
nonvertebral fractures. Therefore, it is not a first-line agent who had a T-score of 2.5 to 3.5 at the total hip or femoral
for postmenopausal osteoporosis. Moreover, the long-term neck. At 12 months, new vertebral fractures had occurred in
use of raloxifene increases the risk of venous thromboem- 16 of 3,321 patients (0.5%) in the romosozumab group, as
bolic events.2 compared with 59 of 3,322 (1.8%) in the placebo group
ACP recommends against using menopausal estrogen (representing a 73% lower risk with romosozumab). Clinical
therapy or menopausal estrogen plus progestogen therapy fractures had occurred in 58 of 3,589 patients (1.6%) in the
or raloxifene for the treatment of osteoporosis in women.4 romosozumab group, as compared with 90 of 3,591 (2.5%) in
the placebo group (a 36% lower risk with romosozumab).
Calcitonin Nonvertebral fractures had occurred in 56 of 3,589 patients
Calcitonin inhibits osteoclastic bone resorption.26 The use of (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in
a nasal spray formulation of salmon calcitonin to treat the placebo group.37
osteoporosis is associated with an increased risk of cancer.
Hence, salmon calcitonin has been withdrawn from the Combined Treatments
market in Europe and Canada. Although it is available in Osteoporosis treatments are currently limited to the use of a
the United States for treating osteoporosis (but not for single drug at a fixed dose,38 while combination pharma-
prevention), the Food and Drug Administration Advisory cotherapy is not recommended.2 Combination of more than
Committee has not recommended it.12,35 Drug-related two antiresorptive agents have demonstrated very limited
adverse effects include nausea, local inflammation, and additive effects on bone mass.39 Similarly, combination of
flushing of the face or hands when calcitonin is given as an PTH and teriparatide with BPs or SERM does not have an
injection, and local nasal irritation with the nasal spray overall superior effect on BMD compared with monother-
formulation.12 apy.40,41 On the contrary, it has been shown that combined
therapy of teriparatide with denosumab or zoledronate may
Teriparatide be an effective treatment option for patients who do not
Teriparatide is a peptide corresponding to the 34 N-terminal respond to teriparatide monotherapy.25 A study found that
amino acids of parathyroid hormone (PTH). Candidates for the addition of alendronate to teriparatide after the first
teriparatide treatment include patients with contraindica- 9 months of teriparatide treatment contributed to a reopen-
tions to oral and intravenous BPs, those who have had a ing of the anabolic window and led to a return of bone
major osteoporotic fracture while receiving oral BPs, and resorption to levels comparable at the initiation of teripara-
treatment-naive persons with very low BMD T-scores tide therapy, whereas bone formation was less suppressed
( 3.5).2 It is contraindicated in conditions characterized and remained elevated.36 Furthermore, the recent denosu-
by abnormally increased bone turnover (e.g., preexisting mab and teriparatide administration study indicated that the
hypercalcemia, metabolic bone diseases other than primary combination of denosumab and teriparatide produced a
osteoporosis, unexplained elevation of ALP, severe renal more prominent effect on increasing BMD and decreasing
impairment, prior skeletal irradiation, or patients with ske- fracture risk than each drug did alone.38 It also indicated that
letal malignancies or bone metastasis).12,26 teriparatide treatment after denosumab was associated with
Teriparatide treatment reduces vertebral and nonverteb- transient bone loss in lumbar spine and proximal femur and
ral fractures among women with postmenopausal osteo- with prolonged BMD decrease in distal radius, while teri-
porosis.4 Treatment with teriparatide is characterized by an paratide followed by denosumab continuously increased the
early period dominated by bone formation that lasts for 6 to BMD of lumbar spine and proximal femur. The authors
9 months and is referred to as the anabolic window. Then, concluded that it is necessary to consider the timing of
bone resorption increases and mitigates the overall bone teriparatide use, as well as the order of sequential use of
anabolic effect.36 teriparatide, in the long-term management of patients with
Teriparatide treatment is associated with mild upper osteoporosis.38 Finally, since discontinuation of estrogens,
gastrointestinal symptoms, nausea, pain in the limbs, dizzi- SERMs, denosumab, or teriparatide therapy is associated
ness, headache, hypercalcemia, hypercalciuria, hyperurice- with a rapid loss of their effects on BMD and BTMs over 1
mia, and hypotension.4,26 Moreover, the use of teriparatide is to 2 years, a follow-up treatment with BP should be con-
limited to 2 years in any life span, and this is because of the sidered to reduce or prevent the rebound increase in bone
development of osteosarcoma in preclinical animal studies.3 turnover.38

Romosozumab
Conclusion
Romosozumab is another anabolic drug, which is still under
clinical development. It is an antibody of sclerostin that Osteoporosis is a skeletal disorder characterized by compro-
represent an important component of the Wnt signaling mised bone strength leading to an increased risk of fracture.

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126 Osteoporosis Akkawi, Zmerly

It is defined as a BMD that lies 2.5 SD or more below the meta-analysis. Semin Arthritis Rheum 2017;pii:S0049-0172(17)
average value for young healthy women, as measured with 30649-2
DEXA. According to the current guidelines on osteoporosis 14 Tawaratsumida H, Setoguchi T, Arishima Y, et al. Risk factors for
bone loss in patients with rheumatoid arthritis treated with
management, BTMs cannot diagnose osteoporosis, but
biologic disease-modifying anti-rheumatic drugs. BMC Res Notes
changes in BTMs may be useful in monitoring osteoporosis 2017;10(01):765
treatment to confirm the efficacy of treatment and treat- 15 U.S. Preventive Services Task Force. Screening for osteoporosis: U.-
ment adherence and can improve the specificity of assess- S. Preventive Services Task Force recommendation statement.
ment of fracture risk. All postmenopausal women should be Ann Intern Med 2011;154(05):356–364
16 Gourlay ML, Fine JP, Preisser JS, et al; Study of Osteoporotic
encouraged to maintain a healthy weight; to obtain adequate
Fractures Research Group. Bone-density testing interval and
calcium, vitamin D, and protein intake; to participate in
transition to osteoporosis in older women. N Engl J Med 2012;
appropriate exercise; to avoid excessive alcohol consump- 366(03):225–233
tion and smoking; and to utilize measures that prevent falls. 17 Vasikaran SD. Utility of biochemical markers of bone turnover and
Finally, drug therapy is recommended in all postmenopausal bone mineral density in management of osteoporosis. Crit Rev
women who have a history of osteoporotic vertebral or hip Clin Lab Sci 2008;45(02):221–258
18 Kyd PA, Vooght KD, Kerkhoff F, Thomas E, Fairney A. Clinical
fracture, in those who have BMD values consistent with
usefulness of bone alkaline phosphatase in osteoporosis. Ann Clin
osteoporosis, and in those who have T-scores from 1.0 to Biochem 1998;35(Pt 6):717–725
2.5 and a 10-year risk of major osteoporotic fracture. 19 Kučukalić-Selimović E, Valjevac A, Hadžović-Džuvo A. The utility
of procollagen type 1 N-terminal propeptide for the bone status
Conflict of Interest assessment in postmenopausal women. Bosn J Basic Med Sci
2013;13(04):259–265
None.
20 Nenonen A, Cheng S, Ivaska KK, et al. Serum TRACP 5b is a useful
marker for monitoring alendronate treatment: comparison with
other markers of bone turnover. J Bone Miner Res 2005;20(10):
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