Bone Metabolism and Metabolic Bone Disease

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					Chapter 16

Bone Metabolism and Metabolic
Bone Disease
 Mathias P. G. Bostrom, MD




 Introduction                                                 Table 1
The fundamental understanding of bone metabolism               Factors Associated With the Regulation of
has changed dramatically over the past 10 years. Al-           Osteoblastogenesis and Bone Formation
though the three critical basic functions of the skeleton:
(1) mechanical support and locomotion, (2) protection          Transcriptional regulators
of the internal organs, and (3) metabolic activities re-         Shock protein factors
lated to calcium homeostasis remain, the fundamental             Activating transcription factors
mechanism of how bone successfully achieves these                Runt homology domain
functions is gradually being understood at the molecu-         Growth factors
lar level.1 Traditionally the study of bone metabolism
                                                                 Insulin-like growth factor-1 and -2
and disease has focused on the role of osteoblasts, os-
teocytes, and osteoclasts; however, with modern molec-           Platelet-derived growth factor
ular biologic analysis methods, a very precise regula-           Epidermal growth factor
tion of bone metabolism can be determined, allowing a            Endothelin
better understanding of the pathophysiologic abnor-            Hormones
malities involved so that new targeted therapeutic ap-           Parathyroid hormone
proaches can be devised.                                         1,25-dihydroxyvitamin D
                                                                 Glucocorticoids
                                                                 Sex steroids
 Bone Formation                                                    Progesterone
Osteoblasts are primarily responsible for bone forma-              Estrogen
tion. These cuboid cells are aligned in layers along os-           Androgen
teoid and synthesize the organic bone matrix that is             Growth hormone
subsequently mineralized to form bone. A subpopula-              Thyroid stimulating hormone
tion of these cells becomes embedded in the matrix and         Signaling molecules
develops into osteocytes, whose function includes cal-           Prostaglandin E2




                                                                                                                                                    2: Systemic Disorders
cium homeostasis and serving as mechanoreceptors of              Oncostatin 2
the skeleton.                                                    Leptin
   Osteoblasts and osteocytes are derived from pluri-
                                                                 Sclerostin
potential mesenchymal stem cells, which are present in
                                                               Osteoprogenitor cell commitment and expansion
many adult tissues but primarily in bone marrow stroma.
Depending on the precise molecular signaling, these stem         Bone morphogenetic proteins 2 through 7
cells differentiate and proliferate into cells that form         Indian hedgehog
bone, cartilage, and adipose and fibrous tissue.                 Interleukin-18
   The regulation of osteoblastogenesis and bone for-            Pleiotropin
mation is quite complex, involving several transcrip-          (Data from Favus MJ (ed): Primer on the Metabolic Bone Diseases and Disorders of
tional regulators, growth factors, hormones, and other         Mineral Metabolism, ed 6. Washington, DC, ASBMR, 2006.)
signal molecules2-4 (Table 1). It is these factors that de-
termine the sequence of differentiation and prolifera-
tion from mesenchymal stem cell, osteoprogenitor cell,
preosteoblast, and finally to mature osteoblast. Each of      teoblasts begin to synthesize bone matrix, which is pri-
these stages has defined phenotypic cell markers, allow-      marily composed of primarily type I collagen along
ing for the ability to modulate the differentiation into      with other collagen proteins and critical noncollaginous
different cell lineages. Once differentiated, mature os-      proteins.


American Academy of Orthopaedic Surgeons                                                              Orthopaedic Knowledge Update 9              189
                              Section 2: Systemic Disorders



                              Table 2                                                          Regulation of Cell Differentiation and
                                                                                               Calcium and Phosphorus Metabolism
                               Factors Influencing Renal Absorption                            Bone is a critical component of calcium homeostasis.
                               of Calcium                                                      Calcium is a critical regulator of muscle contraction,
                                                                                               coagulation, intracellular signal transaction, and con-
                               Decreased Renal Calcium         Increased Renal Calcium         trol of cell membrane potentials. Calcium levels are
                               Resorption                      Resorption                      tightly regulated by intestinal absorption of dietary in-
                               Increased calcium intake        Parathyroid hormone
                                                                                               take, excretion by the kidneys, and storage in the skel-
                                                                                               eton. Normal serum calcium levels range from 8.5 to
                               Increased sodium intake         Parathyroid hormone-related     10 mg/dL, and circulation calcium exists approximately
                                                                 protein
                                                                                               equally in free ionized form and protein-bound form,
                               Metabolic acidosis              1,25-dihydroxyvitamin D         with albumin as the major binding protein. A small
                               Phosphate depletion             Calcitonin                      portion of the body’s total calcium is bound to ions,
                               Glucocorticoids                 Increased phosphate intake      such as phosphate. The skeleton acts a reserve for cal-
                                                                                               cium that can be metabolized to maintain circulating
                               Furosemides                     Chronic thiazide diuretic use
                                                                                               concentrations. All calcium for the body is obtained
                                                                                               from the diet, and its absorption from the intestines is
                                                                                               regulated according to perceived body needs.
                               Bone Resorption                                                    Dietary calcium absorption in the intestine occurs
                                                                                               in the duodenum and the jejunum and is a function of
                              Whereas the osteoblasts are responsible for bone for-
                                                                                               active transport using a calcium-binding protein regu-
                              mation, the osteoclasts are responsible for bone resorp-
                              tion through enzymatic degradation. Osteoclasts are lo-          lated by vitamin D and passive gradient-dependent
                              cated on the calcified bone as multinucleated cells in           transport. Calcium absorption is regulated by 1,25-
                              resorption cavities known as Howship’s lacunae. The              dihydroxyvitamin D concentration and by calcium in-
                              characteristic feature of the osteoclast is its ruffled bor-     take. Increases in calcium intake and in 1,25-
                              der. This membrane secretes lysosomal enzymes, which             dihydroxyvitamin D serum concentration act to
                              degrade the organic matrix of bone, and a low pH                 increase intestinal calcium absorption.
                              causes dissolution of the calcium of the mineralized                Calcium is excreted in the kidneys at an approximate
                              bone.                                                            rate of 150 to 200 mg/day, an amount that balances the
                                 Osteoclasts are derived from hematopoietic mono-              calcium absorbed in the intestine. Most of the calcium is
                              cyte cell precursors, which are present in several tissues;      absorbed in the proximal tubule through solvent gradi-
                              osteoclast differentiation and proliferation are tightly         ent, although active transfer occurs in the distal por-
                              regulated by stromal and osteoblastic cells.5 Specifi-           tions by a sodium-calcium exchange pump. Some calci-
                              cally, the regulation of osteoclast differentiation and          um is also absorbed in the loop of Henle through an
                              maturation is dependent on the receptor activator of             electrochemical gradient. Factors that influence renal
                              nuclear factor-kappa B ligand (RANKL) pathway, with              resorption of calcium are outlined in Table 2.
                              the RANKL present on the osteoblasts stimulating                    Recommended dietary calcium intake varies by age
                              RANK on precursor osteoclasts to differentiate into ac-          (Table 3). Several calcium supplements are available;
                              tive osteoclasts. Thus, bone formation and resorption            although no single product is better than another, some
                              are tightly coupled. Both of these cell lineages are im-         are better tolerated than others. In general, calcium
                              portant because their regulation is critical in the main-        supplements should be taken several times a day with
                              tenance of normal calcium homeostasis as well as                 the maximum dose not exceeding 500 mg at any one
2: Systemic Disorders




                              maintenance of the structural integrity of the skeleton.         time so as to maximize absorption. Care should be ex-
                              The complex cell-to-cell interactions involve several            ercised when these supplements are taken with other
                              transcriptional factors. Several treatment modalities            medications, because certain antibiotics such as tetracy-
                              (antiresorptive agents such as the bisphosphonates and           cline interact with the calcium. In addition, iron supple-
                              anabolic agents such as parathyroid hormone [PTH])               ments should not be taken at the same time as a cal-
                              are now available for the treatment of osteoporosis and          cium supplement. Calcium carbonate is better absorbed
                              may have applicability in orthopaedics.6                         when taken with food, whereas calcium citrate can be
                                 In addition to the complex signaling involved in              taken on an empty stomach. Combination products are
                              bone homeostasis, the importance of a mechanical re-             not necessary as long as adequate intake of vitamin D is
                              sponse of the bone cell populations and maintaining              achieved through diet.
                              the biologic function of the skeleton has emerged.                  An increase in calcium is required during growth,
                              These pathways are critical in understanding bone heal-          pregnancy, and lactation, and calcium intake must be
                              ing and bone regeneration. Over the next decade, un-             increased in older individuals to counteract the effect of
                              derstanding these pathways will allow changes to the             calcium loss caused by increased bone resorption. Be-
                              local osseous environments through both local and sys-           cause dietary intake of calcium is usually not adequate
                              temic agents to enhance the bone repair process. This            in elderly people, supplementation is usually indicated.
                              should prove useful not only in the field of traumatol-             As with calcium, phosphorus is also critical for
                              ogy but arthroplasty and spine surgery as well.                  proper mineralization of bone, with 85% of all phos-


                        190   Orthopaedic Knowledge Update 9                                                      American Academy of Orthopaedic Surgeons
                                                                Chapter 16: Bone Metabolism and Metabolic Bone Disease



phorus present in the crystalline form in the skeleton         Table 3
and the remaining 15% largely present in either the ex-
tracellular fluid or as intracellular phosphorylated in-        Recommended Calcium Intake
termediates. Serum concentrations of phosphorus are
tightly regulated between 2.5 to 4.5 µg/dL in adults.           Age                               Amount (mg/d)
Passive transport is directly related to the intestinal
                                                                Birth to 6 months                       210
concentration of phosphate after eating.
                                                                6 months to 1 year                      270
Vitamin D                                                       1 to 3 years                            500
The principal regulators of calcium metabolism are vita-        4 to 8 years                            800
min D and PTH. Vitamin D is a fat-soluble steroid that
is derived from cholesterol and undergoes hydroxyla-            9 to 13 years                           1,300
tion in the liver and kidney to its biologically active form    14 to 18 years                          1,300
vitamin 1,25-dihydroxyvitamin D. Normal serum cal-              19 to 30 years                          1,000
cium levels are maintained by increasing intestinal absorp-
tion of calcium and maturation of osteoclasts to mobi-          31 to 50 years                          1,000
lize calcium from bone when needed. In addition,                51 to 70 years                          1,200
vitamin D affects cell differentiation and proliferation
                                                                71 or older                             1,200
and enhances insulin secretion that regulates the renin-
angiotensin system. Vitamin D is produced in the skin           Pregnant and lactating
during exposure to sunlight and is absorbed from dietary        14 to 18 years                          1,300
intake.
                                                                19 to 50 years                          1,000
   Sunscreen severely impairs the production of vitamin
D by sunlight. Dietary sources of vitamin D are limited
                                                               pause, during which bone loss accelerates to 2% to 3%
to oily fish (such as salmon, mackerel, or sardines);
                                                               per year for the first 6 to 8 years of the postmenopausal
however, many foods are fortified with vitamin D, such
                                                               period, returning to the normal age-related loss of 0.3%
as milk and orange juice. Multivitamins are also a
                                                               to 0.5% per year. Estrogen receptors are found on os-
source of vitamin D. In fair-skinned individuals, expo-
                                                               teoblasts and osteoclasts and may work through the
sure of the hands and face to bright sunlight for ap-
                                                               interleukin-6 as well as the RANKL pathway.
proximately 15 minutes is adequate for production of               The exact role of androgens in retaining skeletal mass
vitamin D; however, in darker-skinned individuals,             in men is not clear. Men with idiopathic hypogonadot-
more exposure is necessary. The recommended daily re-          ropic hypogonadism have reduced levels of cortical and
quirement is between 400 and 800 IU in individuals             trabecular bone loss, and delayed puberty is also asso-
who do not have adequate sunlight exposure. Vitamin            ciated with osteopenia in men. Androgens prevent bone
D levels decrease with age and impaired renal function,        resorption and may stimulate an increase in bone mass,
and these two factors can combine to affect vitamin D          but the mechanism is not known. Corticosteroids are
levels and calcium absorption in elderly people.               known to inhibit calcium absorption in the intestine by
                                                               decreasing the production of calcium-binding proteins,
Parathyroid Hormone                                            increasing calcium excretion in the kidneys, and inhib-
PTH is used to maintain serum calcium levels; its syn-         iting bone formation and resorption. In addition, corti-
thesis and release is stimulated by low extracellular ion-     costeroids may slow bone healing and can also indirectly
ized calcium levels. PTH binds to osteoblasts where it         stimulate secondary hyperparathyroidism.




                                                                                                                               2: Systemic Disorders
stimulates bone formation and the production of fac-
tors (such as interleukin-6) that stimulate osteoclasts to     Thyroid Hormone
resorb bone. PTH-stimulated osteoclasts secrete neutral        Hyperthyroidism is associated with osteoporosis. Thy-
proteases that degrade osteoid and initiate bone remod-        roid hormones T4 and T3 circulate bound to plasma
eling. Parathyroid hormone-related protein (PTHrP) in-         proteins. They interact with specific cell receptors and
creases osteoblast expression of RANKL and decreases           bind to nuclear DNA, increase thyroid hormone, and
production of osteoprogerin in the development and             stimulate bone resorption and formation; however, re-
progression of bone metastases in breast carcinoma.            sorption occurs at a slightly greater rate, eventually re-
   Intermittent PTH clearly seems to be anabolic in bone       sulting in bone loss. Thus, chronic hyperthyroidism
formation and, in preclinical animal studies, it stimulates    and thyroid supplementation can contribute to os-
increased bone formation and acceleration of healing.8         teoporosis.
Thus, PTH plays a central role in calcium regulation
and the coupling of bone resorption and formation.
                                                                Clinical Evaluation of Bone and
Sex Steroids and Estrogen                                       Mineral Disorders
There is a clear association between decreased estrogen
levels and increased rates of bone resorption, as indicated    Despite the plethora of sophisticated biochemical and
by the rapid acceleration of bone loss following meno-         diagnostic modalities, a through medical history and


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                              Section 2: Systemic Disorders



                              Table 4                                                                             should also be measured along with magnesium levels.
                                                                                                                  Serum bone formation markers include bone-specific
                               Absolute Fracture Risk Versus Age                                                  alkaline phosphatase, osteocalcin, C-terminal propep-
                                                                                                                  tide of type I collagen, and N-terminal propeptide of
                               Age (Years)             T Score                    Absolute Risk                   type I collagen. Similarly, there are a number of bone
                                                                                                                  resorption markers including free and total pyridino-
                                    50                      0                            0.2%
                                                                                                                  lines, free and total deoxypyridinolines, N-telopeptide
                                                           −1                            0.4%                     of collagen at cross-links, and C-telopeptides at col-
                                                           −2                            1.1%                     lagen cross-links. In the serum, similar N- and
                                    60                      0                            0.4%                     C-telopeptides of collagen cross-links, tartrate-resistant
                                                                                                                  acid phosphatase, and cross-linked C-telopeptide of
                                                           −1                            1.0%                     type I collagen can be measured.9
                                                           −2                            2.7%                        Of these markers, urine and serum assays of
                                    70                      0                            0.7%                     N-telopeptides are commercially available and are im-
                                                                                                                  portant for establishing the nature of the metabolic bone
                                                           −1                            1.9%
                                                                                                                  disorder and also are of value in terms of monitoring ef-
                                                           −2                            5.3%                     fectiveness of any treatment, selection of patients for
                               (Reproduced with permission from Blake GM, Knapp KM, Fogelman I: Absolute          therapy, prediction of response to therapy, and predic-
                               fracture risk varies with bone densitometry technique used: A theoretical and in   tion of fracture risk, bone loss, and bone mass. Of these
                               vivo study of fracture cases. J Clin Densitom 2002;5:109-116.)
                                                                                                                  clinical uses, currently the most appropriate is monitor-
                                                                                                                  ing effectiveness of any treatment.
                              physical examination remain essential in evaluating any                                In terms of imaging studies for metabolic bone dis-
                              patient with metabolic bone disorders. The initial as-                              orders, standard radiographic techniques such as plain
                              sessment includes the patient’s age, sex, race, meno-                               skeletal radiography, CT, MRI, and nuclear medicine as
                              pausal status, and a complete medical, pharmacologic,                               well as ultrasound have value specifically in the diagno-
                              nutritional, and family history. Although the diagnosis                             sis of osteogenesis imperfecta, osteomalacia, and rick-
                              of postmenopausal osteoporosis or age-related os-                                   ets. They can also be of value in the diagnosis of pri-
                              teoporosis seems straightforward, other metabolic bone                              mary hyperparathyroidism, renal osteodystrophy,
                              disorders must be ruled out with the appropriate med-                               scurvy, hypothyroidism, hyperthyroidism, hypophos-
                              ical history, physical examination, and diagnostic tests.                           phatemia, hyperphosphatemia, osteopetrosis, Paget’s
                                 Of particular importance in the medical history are                              disease, and fibrous dysplasia.
                              questions regarding dietary and lifestyle issues, specifi-                             Although all of these modalities are important in the
                              cally whether or not adequate calcium, phosphorus,                                  diagnosis of unique metabolic bone disorders, the main-
                              and vitamin D are being consumed. The use of tobacco                                stay of diagnosis is the use of bone mass measurements
                              and caffeine as well as potential alcohol abuse needs to                            in the assessment and management of osteoporosis, pri-
                              be documented. Similarly, the patient’s medication his-                             marily the use of bone mineral density (BMD) for frac-
                              tory is of value, as many medications predispose pa-                                ture risk.10 The clinical indications for use of bone mass
                              tients to metabolic bone disorders. Questions regarding                             measurements include women age 65 years and older,
                              other endocrine, renal, or gastrointestinal diseases are                            postmenopausal women younger than 65 years with
                              important, and in women menstrual history is essential,                             risk factors, men age 70 years or older, adults with a
                              especially questions regarding amenorrhea, time of on-                              fragility fracture, adults with a disease or condition as-
                              set of menses, and menopause. Family history also re-                               sociated with low bone mass, adults taking medications
                              mains important as many metabolic bone disorders are                                associated with low bone mass or bone loss, anyone be-
2: Systemic Disorders




                              heritable, and many genetic disorders including osteo-                              ing considered for pharmacologic therapy, anyone be-
                              genesis imperfecta, Ehlers-Danlos syndrome, Marfan                                  ing treated to monitor treatment effect, and anyone not
                              syndrome, X-linked hypophosphatemic rickets, and vi-                                receiving therapy and in whom evidence of bone loss
                              tamin D-dependent rickets are associated with reduced                               would lead to treatment based on International Society
                              bone mass, fractures, or osteomalacia.                                              for Clinical Densitometry standards (www.iscd.org).
                                 During the physical examination, height and weight                                  The result of BMD measurements are given in terms
                              must be documented along with an evaluation for bony                                of a T score, which is a standard deviation below or
                              deformities and ligamentous laxity. In addition, exami-                             above a young adult mean value. For example, a pa-
                              nation for neuromuscular irritability associated with hy-                           tient with a T score of -2.5 has a BMD that is 2.5 times
                              pocalcemia may be done, and characteristic skeletal                                 below the mean of a young adult population. A patient
                              changes associated with Paget’s disease as well as the                              with a T score below -2.5 is considered to have os-
                              findings of established osteoporosis including dorsal ky-                           teoporosis by World Health Organization standards
                              phosis (or dowager’s hump) and loss of height should be                             and treatment is usually recommended. A patient with
                              noted. Secondary causes of osteoporosis such as Cush-                               a T score between -1.0 and 2.5 is considered to have
                              ing syndrome and hypogonadism should be noted.                                      osteopenia based on World Health Organization crite-
                                 Initial laboratory studies should include assessment                             ria. These relationships are important, as outlined in
                              of appropriate serum calcium levels as well as determi-                             Table 4, where the T scores clearly correlate with the
                              nation of total and free calcium. Phosphorus levels                                 absolute risk of fracture and age.


                        192   Orthopaedic Knowledge Update 9                                                                         American Academy of Orthopaedic Surgeons
                                                               Chapter 16: Bone Metabolism and Metabolic Bone Disease



   Although not used on a routine clinical basis, bone        Patients with significant pain after a fracture may ben-
biopsies and histomorphology remain important as re-          efit from either vertebroplasty or kyphoplasty.
search tools and in patients with metabolic bone disor-          The incidence of distal forearm fractures is higher in
ders with unclear diagnoses. If an iliac crest bone biopsy    women between the ages of 45 and 60 years than in the
is considered, then appropriate antibiotic labeling must      elderly population. This may be secondary to altered
be performed to maximize diagnostic information.              neuromuscular reflexes associated with aging. As aging
   The use of modern molecular biologic approaches            progresses, individuals tend to fall sideways or backward
such as polymerase chain reaction and direct DNA se-          and thus are not able to break the fall with an out-
quencing in combination with genetic information will         stretched upper extremity. Data from the United King-
be important in the future for the diagnosis and clinical     dom show that women have a 13% lifetime risk of wrist
management of patients with bone and mineral disor-           fracture, whereas the lifetime risk in men is 2%. Fortu-
ders.                                                         nately, these fractures rarely affect longevity and if
                                                              treated properly should not lead to significant disability.
                                                                 The most important determinants of postmenopausal
 Osteoporosis and Osteoporotic Fractures                      osteoporosis are those factors that determine peak bone
                                                              mass. Thus, postmenopausal osteoporosis can also often
The most prevalent metabolic bone disorder is os-             be viewed as the sequela of childhood and adolescence
teoporosis, specifically postmenopausal osteoporosis. It      factors because there is little increase in bone mass after
is estimated that 10 million Americans older than age         menarche. Resultant peak bone mass is achieved by age
50 years have osteoporosis; 1.5 million of these pa-          20 to 30 years and subsequently there is a steady decline
tients experience fragility fractures each year. Another      in bone mass, with an accelerated rate of bone loss in the
34 million Americans are at risk for osteoporosis.11          postmenopausal period.
    The cost of treatment of fragility fractures has in-         There are numerous genetic factors that determine
creased exponentially over the past several decades and       peak bone mass. Heritability seems to account for 50%
this increase is projected to continue. As the world pop-     to 80% of the variance in bone mass depending on skel-
ulation ages, the number of these fractures will con-         etal site. Several related genes seem to regulate bone
tinue to increase in parallel with the requirements of
                                                              mass, including genes for type I collagen, lipoprotein
health care systems for the treatment of these fractures.
                                                              receptor-related protein-5, and vitamin D receptors.
    Most fragility fractures are fractures of cancellous
                                                              Bone loss in the postmenopausal period is the result of
bone as opposed to diaphyseal cortical bone. They oc-
                                                              increased rate of bone remodeling and imbalance be-
cur either in metaphyseal regions of long bones such as
                                                              tween activity of osteoclasts and osteoblasts. One major
the proximal femur, distal forearm, proximal humerus,
and proximal tibia, or are vertebral fractures.               cause of bone loss and imbalance of this coupled mech-
    The overall fracture incidence in the developed           anism is estrogen deficiency associated with the post-
world is bimodal, with peaks in childhood and early           menopausal period. Aging has also been associated with
adulthood and in the elderly population. In young peo-        bone loss specifically related to such factors as increased
ple, fractures of long bones predominate, usually sec-        levels of PTH and to osteoblast senescence. Several dis-
ondary to significant trauma, and occur more fre-             eases and drugs are clearly important in the acceleration
quently in males than females. In women older than 35         of bone loss such as glucocorticoid therapy.
years, the fracture incidence increases steeply so that          Bone strength is not only related to BMD. The role
fracture rates become twice those of men, with frac-          of other factors, including bone geometry, fatigue dam-
tures of the distal forearm, hip, and vertebral body oc-      age, and loss of trabecular connectivity is currently be-
curring most often.12                                         ing studied. In addition to the risk factors noted above,




                                                                                                                              2: Systemic Disorders
    It has been estimated that in the United Kingdom the      there are several other clinical risk factors for fractures
lifetime risk of a hip fracture for a 50-year-old is ap-      (Table 5).
proximately 14% for women and 3% for men, with                   Patients recommended for osteoporosis screening
these fractures requiring hospitalization. These frac-        with bone densitometry include patients who have ex-
tures have a significant degree of morbidity and mortal-      perienced low trauma fractures, men with significant
ity. Universally these patients lose one level of function    risk factors, and women older than 65 years or those
after any hip fracture.                                       who are postmenopausal or have other fracture risks
    Although most if not all hip fractures require some       such as maternal/paternal history of fracture, substan-
medical intervention, vertebral body fractures may be         tial weight loss, and long-term use of benzodiazepines
asymptomatic and initially remain undiagnosed. If ver-        and anticonvulsants. At minimum, any patient treated
tebral fractures are correctly diagnosed, the incidence is    for a fragility fracture should be referred for evaluation
probably much higher than previously suspected, with          and secondary prevention therapy.
a 28% lifetime risk in women and a 12% lifetime risk
in men. Most of these fractures occur as a result of nor-     Treatment
mal activities such as lifting rather than a fall, which is   The mainstay of treatment of osteoporosis in addition
the mechanism most often associated with hip frac-            to calcium and vitamin D supplementation is antire-
tures. Few of these fractures require hospitalization but     sorptive agents. These agents include calcitonin and the
they are associated with significant pain and disability.     bisphosphonates. Although the number of currently


American Academy of Orthopaedic Surgeons                                                   Orthopaedic Knowledge Update 9   193
                              Section 2: Systemic Disorders



                              Table 5                                                     Table 6

                               Clinical Risk Factors for Fracture                          Causes of Drug-Induced Rickets/Osteomalacia
                               Female sex                                                  Drugs resulting in hypocalcemia
                               Advanced age                                                  Inhibitors of vitamin D formation or intestinal absorption
                               Caucasian                                                        Suncreens
                               Prior fragility fracture                                         Cholestyramine
                               Medications                                                   Increased catabolism of vitamin D or its metabolites
                                Glucocorticoids                                                 Anticonvulsants
                                Anticonvulsants                                            Drugs resulting in hypophosphatemia
                                 Benzodiazepines                                             Inhibitors of intestinal phosphate reabsorption
                                 Antidepressants                                                Aluminum containing antacids
                               Medical conditions
                                                                                             Impaired renal phosphate reabsorption
                                Diabetes
                                                                                                Cadmium
                                 Hyperparathyroidism
                                                                                                Ifosfamide
                                 Hyperthyroidism
                                                                                                Saccharated ferric oxide
                                 Inflammatory arthritis
                                                                                             Direct impairment of mineralization
                                 Hypercortisolism
                                                                                                Parental aluminum
                                 Neuromuscular conditions
                                                                                                Fluoride
                               Eating disorders
                                                                                                Etidronate
                               Family history
                                                                                           (Reproduced from Pettifor JM: 2003 Nutritional and Drug-Induced Rickets and
                               Low body mass index                                         Osteomalacia, in Favus MJ (ed): The Primer on the Metabolic Bone Diseases and
                               Smoking                                                     Disorders of Mineral Metabolism, ed 5. American Society for Bone and Mineral
                                                                                           Research, Washington, DC, pp 399-407 with permission of the American Society for
                                                                                           Bone and Mineral Research.)


                              available bisphosphonates has increased, overall the
                              treatment approach has not changed. The oral bisphos-           A combination of environmental and genetic factors
                              phonates in the United States for which the most clini-     is required for the disease to develop. Multiple studies
                              cal data has been compiled are alendronate, risedro-        have demonstrated a genetic predisposition for Paget’s
                              nate, and ibandronate. Newer, more potent intravenous       disease, and recently gene mutations in specific genes
                              forms of bisphosphonates such as zoledronic acid are        involved in bone remodeling have been mapped in
                              appealing because the dosing can be as infrequent as        these familial cases. Specifically, mutations of the p62/
                              every 12 months. Whether these newer agents pose a          ZIP gene have been documented but genetic predispo-
                              higher risk for the development of osteonecrosis of the     sition is not enough to cause the disease. Many believe
                              jaw remains to be determined.                               that paramyxoviral infection may also be required.
                                 In addition to the antiresorptive agents, the use of     Why paramyxoviral infections, such as measles, which
                              intermittent PTH (teriparatide) has been shown to be        occur worldwide, only affect individuals in certain geo-
2: Systemic Disorders




                              effective in the treatment of osteoporosis. This anabolic   graphic distributions and why these viruses, which gen-
                              agent alone has been shown to stimulate significant in-     erally affect children, lead to a disease that is primarily
                              creases in cancellous BMD and decrease fracture risk.       diagnosed in patients older than age 55 years are ques-
                              The combination of PTH with antiresorptive agents has       tions about the viral etiology of Paget’s disease that re-
                              solid theoretic justification but has not yet been demon-   main unanswered.
                              strated clinically.                                             Treatment for Paget’s disease has evolved from the
                                                                                          1970s, when bisphosphonates were first introduced, to
                                                                                          newer bisphosphonates such as pamidronate, alendro-
                                                                                          nate, and zoledronic acid. The rationale behind treat-
                               Other Metabolic Bone Diseases                              ment is to avoid complications. Calcitonin is also used
                                                                                          in the treatment of Paget’s disease. Other agents such
                              Paget’s Disease of Bone                                     as nonsteroidal anti-inflammatory drugs have a role in
                              Paget’s disease is a localized disorder of bone remodel-    relieving pain related to Paget’s disease but do not mod-
                              ing that initially involves an increase in osteoclast-      ify the underlying disease process.
                              mediated bone resorption followed by compensatory               Surgery on pagetoid bone may be necessary for an
                              increase in bone formation. The result is that of a dis-    established or impending fracture and occasionally to-
                              organized mosaic of woven and lamellar bone at the af-      tal joint arthroplasties are necessary when associated
                              fected sites.                                               with osteoarthritis. It is strongly suggested that a po-


                        194   Orthopaedic Knowledge Update 9                                                         American Academy of Orthopaedic Surgeons
                                                               Chapter 16: Bone Metabolism and Metabolic Bone Disease



tent bisphosphonate be used before elective surgery on        also further understanding of bone healing and repair.
pagetoid bone with the goal being to reduce the hyper-        The future of enhanced bone healing and repair and
vascularity associated with the moderate active disease,      other orthopaedic applications therefore lies within the
thus diminishing the amount of blood loss during sur-         arena of bone metabolism and understanding these
gery.                                                         processes.

Osteomalacia and Rickets
Osteomalacia results from failure of mineralization at         Annotated References
newly formed osteoid sites either periosteal or en-
dosteal, whereas rickets is failure of or delay in the
mineralization of new bone formation at growth plates.         1.   Favus MJ (ed): Primer on the Metabolic Bone Diseases
Rickets is a disease of childhood whereas osteomalacia              and Disorders of Mineral Metabolism, ed 6. Washing-
tends to occur in adults, although children also may                ton, DC, American Society of Bone and Mineral Re-
have areas of osteomalacic bone.                                    search, 2006.
   Although vitamin D supplementation and fortifica-                An overview of metabolic bone diseases and bone me-
tion of foods have dramatically decreased the world-                tabolism is presented, written by experts in the field.
wide incidence of osteomalacia and rickets, some pa-
tients are still affected by these metabolic bone              2.   Bennett CN, Longo KA, Wright WS, et al: Regulation of
disorders; vitamin D dietary deficiencies in combina-               osteoblastogenesis and bone mass by Wnt 10b. Proc
tion with calcium deficiencies often is the causative fac-          Natl Acad Sci USA 2005;102:3324-3329.
tor. There are several drug-induced causes of rickets               In this comprehensive study, the importance of wnt as
and osteomalacia (Table 6). Several medications that                an endogenous regulator of bone formation is demon-
result in hypophosphatemia such as inhibitors of intes-             strated. The authors present convincing evidence that
tinal phosphate absorption and those that impair renal              wnt10b stimulates osteoblastogenesis and inhibits adi-
phosphate reabsorption also lead to osteomalacia.                   pogenesis in mesenchymal stem cells.
   Rickets and osteomalacia may also be caused by im-
paired vitamin D activation and hormone resistance.            3.   Canalis E, Economdies AN, Gazzerro E: Bone morpho-
Pseudovitamin D-deficient rickets and hereditary vita-              genetic proteins, their antagonists and the skeleton.
min D-resistant rickets both have specific gene muta-               Endocr Rev 2003;24:218-235.
tions, with pseudovitamin D-deficient rickets having a
mutation in one α hydroxylase, and hereditary vitamin          4.   Janssens K, Ten DP, Janssens S, Van HW: Transforming
                                                                    growth factor beta 1 to the bone. Endocr Rev 2005;26:
D-resistant deficiencies having a gene mutation of the
                                                                    743-774.
vitamin D receptor gene. Another form of osteomalacia
is hypophosphatemic vitamin D-resistant rickets, which              Transforming growth factor-beta is a ubiquitous protein
is caused by a mutation in the phosphate regulating                 involved in embryogenesis, angiogenesis, inflammation,
gene with homologies to endopeptidase on the X chro-                and wound healing. It also plays a critical role in bone
                                                                    development, homeostasis, and repair; this article de-
mosome (Phex). Rarer forms of osteomalacia occur
                                                                    scribes its role as it pertains to bone.
such as tumor-induced osteomalacia and high turnover
renal osteodystrophy have not been completely elimi-
                                                               5.   Xing L, Boyce BF: Regulation of apoptosis in osteo-
nated.                                                              clasts and osteoblastic cells 2005. Biochem Biophys Res
                                                                    Commun 2005;328:709-720.




                                                                                                                                   2: Systemic Disorders
                                                                    The regulation of osteoblasts and osteoclasts is becom-
 Summary                                                            ing increasingly clear. This article describes the role of
                                                                    apoptosis in the regulation of these two cell lineages and
The bone healing and repair process involves not                    how this affects bone homeostasis.
merely recruiting stem cells and allowing them to pro-
liferate and differentiate, but also allows the skeleton to
                                                               6.   Rogers MJ: From molds and macrophages to mevalo-
repair itself to achieve its normal architecture and ma-            nate: A decade of progress in understanding the molec-
terial properties. The process of fracture healing in-              ular action of bisphosphonates. Calcif Tissue Int 2004;
volves a complex cascade of growth factors, cytokines,              75:451-461.
and signaling molecules with many of the same regula-
                                                                    Bisphosphonates are a class of one of the most com-
tory mechanisms for bone turnover, formation, and re-               monly used pharmacologic agents currently available
sorption that are also involved in the regulation of                for the treatment of osteoporosis. The molecular action
bone homeostasis.13 Similarly, hematopoietic and in-                of this class of molecules is described, along with the
flammatory mediators are involved in fracture healing               difficulties associated with determining the pathway of
as is the process of angiogenesis.7 These same media-               action of these agents.
tors and processes also play a role in the development
of osteoporosis and other bone disorders. An under-            7.   Simon AM, Manigrasso MB, O’Connor JP: Cyclo-
standing of how these morphogenetic factors play a                  oxygenase 2 function is essential for bone fracture heal-
role in skeletal development and bone metabolism may                ing. J Bone Miner Res 2002;17:963-976.


American Academy of Orthopaedic Surgeons                                                      Orthopaedic Knowledge Update 9     195
                              Section 2: Systemic Disorders



                               8.   Rubin MR, Bilezikian JP: The anabolic effects of par-       11.   Melton JL III, Chrisschilles EA, Cooper C, Lane AW,
                                    athyroid hormone therapy. Clin Geriatr Med 2003;19:               Riggs BL: How many women have osteoporosis? J Bone
                                    415-432.                                                          Miner Res 2005;20:886-892.
                                                                                                      This article is an update of the classic article describing
                               9.   Sarkar S, Reinster JY, Frans GG, Diez-Perez A, Pinette            the prevalence of osteoporosis in women.
                                    KV, Delmas PD: Relationship between changes in bio-
                                    chemical markers of bone turnover and BMD to predict        12.   Johnell O, Kanis JA: Epidemiology of osteoporotic frac-
                                    vertebral fracture risk. J Bone Miner Res 2004;19:394-
                                                                                                      tures. Osteoporos Int 2005;16(suppl2):S3-S7.
                                    401.
                                                                                                      This article reviews the most current epidemiology of
                                    Changes in osteocalcin, a marker of bone turnover, was
                                                                                                      osteoporotic fractures worldwide and provides accurate
                                    found to be a better predictor of vertebral fracture risk
                                    than lumbar BMD in a large multicenter trial of an oral           data on this growing public health issue.
                                    selective estrogen receptor modulator that is used in the
                                    prevention of osteoporosis in postmenopausal women.         13.   Lehmann W, Edgar CM, Wang K, et al: Tumor necrosis
                                                                                                      factor alpha coordinately regulates the expression of
                              10.   Kanis JA, Borgstrom F, DeLaet C, et al: Assessment of             specific matrix metalloproteinases and angiogenetic fac-
                                    fracture risk. Osteoporos Int 2005;16:581-589.                    tors during fracture healing. Bone 2005;36:300-310.
                                    Risk factors other than BMD such as age, prior fragility          Tumor necrosis factor alpha is an important regulator of
                                    fracture, parental history of hip fracture, smoking, use          a variety of immune functions. It also plays a role in
                                    of systemic corticosteroids, excess alcohol intake, and           bone homeostasis, specifically in osteoclastogenesis as
                                    rheumatoid arthritis are important in the determination           well as bone healing and repair through both matrix
                                    of fracture risk. Once the probability of fracture has            metalloproteinases and angiogenetic pathways.
                                    been determined, proper treatment can be instituted.
2: Systemic Disorders




                        196   Orthopaedic Knowledge Update 9                                                          American Academy of Orthopaedic Surgeons

				
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