Paget’s Disease and Other Dysplasias of Bone

PHP-IA AND PHP-IB     Individuals with PHP-I, the most common of the disorders, show a deficient urinary cAMP response to administration of exogenous PTH. Patients with PHP-I are divided into type Ia and type Ib. Patients with PHP-Ia show evidence for AHO and reduced amounts of G_sα protein/activity, as determined in readily accessible tissues such as erythrocytes, lymphocytes, and fibroblasts. Patients with PHP-Ib typically lack evidence for AHO and they have normal G_sα activity. PHP-Ic, sometimes listed as a third form of PHP-I, is really a variant of PHP-Ia, although the mutant G_sα shows normal activity in certain in vitro assays.

Most patients who have PHP-Ia reveal characteristic features of AHO, which consist of short stature, round face, obesity, skeletal anomalies (brachydactyly), intellectual impairment, and/or heterotopic calcifications. Patients have low calcium and high phosphate levels, as with true hypoparathyroidism. PTH levels, however, are elevated, reflecting resistance to hormone action.

Amorphous deposits of calcium and phosphate are found in the basal ganglia in about one-half of patients. The defects in metacarpal and metatarsal bones are sometimes accompanied by short phalanges as well, possibly reflecting premature closing of the epiphyses. The typical findings are short fourth and fifth metacarpals and metatarsals. The defects are usually bilateral. Exostoses and radius curvus are frequent.

Inheritance and Genetic Defects     Multiple defects at the GNAS locus have now been identified in PHP-Ia, PHP-Ib, and PPHP patients. This gene, which is located on chromosome 20q13.3, encodes the α-subunit of the stimulatory G protein (G_sα), among other products (see below). Mutations include abnormalities in splice junctions associated with deficient mRNA production, point mutations, insertions, and/or deletion that all result in a protein with defective function resulting in a 50% reduction of G_sα activity in erythrocytes or other cells.

Detailed analyses of disease transmission in affected kindreds have clarified many features of PHP-Ia, PPHP, and PHP-Ib (Fig. 424-7). The former two entities, often traced through multiple generations, have an inheritance pattern consistent with genetic imprinting. The phenomenon of gene imprinting, involving methylation of genetic loci, independent of any mutation, impairs transcription from either the maternal or the paternal allele (Chap. 82). The G_sα transcript is biallelically expressed in most tissues; expression from paternal allele is silenced through as-of-yet unknown mechanisms in some tissues including the proximal renal tubules and the thyroid; consequently, inheritance of a defective paternal allele has no implications with regard to hormonal function. Thus, females affected by either PHP-Ia or PPHP will have offspring with PHP-Ia, if these children inherit the allele carrying the GNAS mutation; in contrast, if the mutant allele is inherited from a male affected by either disorder, the offspring will exhibit PPHP. Consistent with these data in humans, gene-ablation studies in mice have shown that inheritance of the mutant G_sα allele from the female causes much reduced G_sα protein in renal cortex, hypocalcemia, and resistance to PTH. Offspring inheriting the mutant allele from the male showed no evidence of PTH resistance or hypocalcemia.

FIGURE 424-7   Paternal imprinting of renal parathyroid hormone (PTH) resistance. An impaired excretion of urinary cyclic AMP and phosphate is observed in patients with pseudohypoparathyroidism type Ia (PHP-Ia). In the renal cortex, there is selective silencing of paternal G_sα expression. The disease becomes manifest only in patients who inherit the defective gene from an obligate female carrier (left). If the genetic defect is inherited from an obligate male gene carrier, there is no biochemical abnormality; administration of PTH causes an appropriate increase in the urinary cyclic AMP and phosphate concentration (pseudo-PHP [PPHP]; right). Both patterns of inheritance lead to Albright’s hereditary osteodystrophy (AHO), perhaps because of haplotype insufficiency—i.e., both copies of G_sα must be active for normal bone development.

Imprinting is tissue selective. Paternal G_sα expression is not silenced in most tissues. It seems likely, therefore, that the AHO phenotype recognized in PPHP as well as PHP-Ia reflects G_sα haploinsufficiency during embryonic or postnatal development.

The complex mechanisms that control the GNAS gene contribute to challenges involved in unraveling the pathogenesis of these disorders, especially that of PHP-Ib. Much intensive work with families in which multiple members are affected by PHP-Ib, as well as studies of the complex regulation of the GNAS gene locus, have now shown that PHP-Ib is caused by microdeletions within or upstream of the GNAS locus, which are associated with a loss of DNA methylation at one or several loci of the maternal allele (Table 424-6). These abnormalities in methylation silence the expression of the gene. This leads in the proximal renal tubules—where G_sα appears to be expressed exclusively from the maternal allele—to PTH resistance.

PHP-Ib, lacking the AHO phenotype in most instances, shares with PHP-Ia the hypocalcemia and hyperphosphatemia caused by PTH resistance, and thus the blunted urinary cAMP response to administered PTH, a standard test to assess the presence or absence of hormone resistance (Table 424-6). Furthermore, these endocrine abnormalities become apparent only if the disease-causing mutation is inherited maternally. Bone responsiveness may be excessive rather than blunted in PHP-Ib (and in PHP-Ia) patients, based on case reports that have emphasized an osteitis fibrosa–like pattern in several PHP-Ib patients.

PHP-II refers to patients with hypocalcemia and hyperphosphatemia, who have a normal urinary cAMP but an impaired urinary phosphaturic response to PTH. In a PHP-II variant, referred to as acrodysostosis with hormonal resistance (ADOHR), patients have a defect in the regulatory subunit of PKA (PRKAR1A) that mediates the response to PTH distal to cAMP production. Acrodysostosis without hormonal resistance is caused by mutations in the cAMP-selective phosphodiesterase 4 (ADOP4). It remains unclear why the PTH-resistance in some patients, labeled as PHP-II without bony abnormalities, resolves upon treatment with vitamin D supplements.

The diagnosis of these hormone-resistant states can usually be made without difficulty when there is a positive family history for features of AHO, in association with the signs and symptoms of hypocalcemia. In both categories—PHP-Ia and PHP-Ib—serum PTH levels are elevated, particularly when patients are hypocalcemic. However, patients with PHP-Ib or PHP-II without acrodysostosis present only with hypocalcemia and high PTH levels, as evidence for hormone resistance. In PHP-Ia and PHP-Ib, the response of urinary cAMP to the administration of exogenous PTH is blunted. The diagnosis of PHP-II, in the absence of acrodysostosis, is more complex, and vitamin D deficiency must be excluded before such a diagnosis can be entertained.

Treatment of PHP is similar to that of hypoparathyroidism, except that calcium and vitamin D doses are usually higher. Patients with PHP show no PTH-resistance in the distal tubules—hence, urinary calcium clearance is typically reduced, and they are not at risk of developing nephrocalcinosis as are patients with true hypoparathyroidism, unless overtreatment occurs, for example, after the completion of pubertal development and skeletal mutation, when calcium and 1,25(OH)₂D treatment should be reduced. Variability in response makes it necessary to establish the optimal regimen for each patient, based on maintaining appropriate blood calcium level and urinary calcium excretion and keeping the PTH level within or slightly above the normal range.

PTH OVERWHELMED

Occasionally, loss of calcium from the ECF is so severe that PTH cannot compensate. Such situations include acute pancreatitis and severe, acute hyperphosphatemia, often in association with renal failure, conditions in which there is rapid efflux of calcium from the ECF. Severe hypocalcemia can occur quickly; PTH rises in response to hypocalcemia but does not return blood calcium to normal.

Severe, Acute Hyperphosphatemia     Severe hyperphosphatemia is associated with extensive tissue damage or cell destruction (Chap. 423). The combination of increased release of phosphate from muscle and impaired ability to excrete phosphorus because of renal failure causes moderate to severe hyperphosphatemia, the latter causing calcium loss from the blood and mild to moderate hypocalcemia. Hypocalcemia is usually reversed with tissue repair and restoration of renal function as phosphorus and creatinine values return to normal. There may even be a mild hypercalcemic period in the oliguric phase of renal function recovery. This sequence, severe hypocalcemia followed by mild hypercalcemia, reflects widespread deposition of calcium in muscle and subsequent redistribution of some of the calcium to the ECF after phosphate levels return to normal.

Other causes of hyperphosphatemia include hypothermia, massive hepatic failure, and hematologic malignancies, either because of high cell turnover of malignancy or because of cell destruction by chemotherapy.

Treatment is directed toward lowering of blood phosphate by the administration of phosphate-binding antacids or dialysis, often needed for the management of CKD. Although calcium replacement may be necessary if hypocalcemia is severe and symptomatic, calcium administration during the hyperphosphatemic period tends to increase extraosseous calcium deposition and aggravate tissue damage. The levels of 1,25(OH)₂D may be low during the hyperphosphatemic phase and return to normal during the oliguric phase of recovery.

Osteitis Fibrosa after Parathyroidectomy     Severe hypocalcemia after parathyroid surgery is rare now that osteitis fibrosa cystica is an infrequent manifestation of hyperparathyroidism. When osteitis fibrosa cystica is severe, however, bone mineral deficits can be large. After parathyroidectomy, hypocalcemia can persist for days if calcium replacement is inadequate. Treatment may require parenteral administration of calcium; addition of calcitriol and oral calcium supplementation is sometimes needed for weeks to a month or two until bone defects are filled (which, of course, is of therapeutic benefit in the skeleton), making it possible to discontinue parenteral calcium and/or reduce the amount.

DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA

Care must be taken to ensure that true hypocalcemia is present; in addition, acute transient hypocalcemia can be a manifestation of a variety of severe, acute illnesses, as discussed above. Chronic hypocalcemia, however, can usually be ascribed to a few disorders associated with absent or ineffective PTH. Important clinical criteria include the duration of the illness, signs or symptoms of associated disorders, and the presence of features that suggest a hereditary abnormality. A nutritional history can be helpful in recognizing a low intake of vitamin D and calcium in the elderly, and a history of excessive alcohol intake may suggest magnesium deficiency.

Hypoparathyroidism and PHP are typically lifelong illnesses, usually (but not always) appearing by adolescence; hence, a recent onset of hypocalcemia in an adult is more likely due to nutritional deficiencies, renal failure, or intestinal disorders that result in deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathyroidism. A history of seizure disorder raises the issue of anticonvulsive medication. Developmental defects may point to the diagnosis of PHP. Rickets and a variety of neuromuscular syndromes and deformities may indicate ineffective vitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency.

A pattern of low calcium with high phosphorus in the absence of renal failure or massive tissue destruction almost invariably means hypoparathyroidism or PHP. A low calcium and low phosphorus pattern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clearance). The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders, and hereditary defects in vitamin D metabolism leads to secondary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia.

Exceptions to these patterns may occur. Most forms of hypomagnesemia are due to long-standing nutritional deficiency as seen in chronic alcoholics. Despite the fact that the hypocalcemia is principally due to an acute absence of PTH, phosphate levels are usually low, rather than elevated, as in hypoparathyroidism. Chronic renal failure is often associated with hypocalcemia and hyperphosphatemia, despite secondary hyperparathyroidism.

Diagnosis is usually established by application of the PTH immunoassay, tests for vitamin D metabolites, and measurements of the urinary cAMP response to exogenous PTH. In hereditary and acquired hypoparathyroidism and in severe hypomagnesemia, PTH is either undetectable or inappropriately in the normal range (Fig. 424-4). This finding in a hypocalcemic patient is supportive of hypoparathyroidism, as distinct from ineffective PTH action, in which even mild hypocalcemia is associated with elevated PTH levels. Hence a failure to detect elevated PTH levels establishes the diagnosis of hypoparathyroidism; elevated levels suggest the presence of secondary hyperparathyroidism, as found in many of the situations in which the hormone is ineffective due to associated abnormalities in vitamin D action. Assays for 25(OH)D can be helpful. Low or low-normal 25(OH)D indicates vitamin D deficiency due to lack of sunlight, inadequate vitamin D intake, or intestinal malabsorption. Recognition that mild hypocalcemia, rickets, and hypophosphatemia are due to anticonvulsant therapy is made by history.

The management of hypoparathyroidism, PHP, chronic renal failure, and hereditary defects in vitamin D metabolism involves the use of vitamin D or vitamin D metabolites and calcium supplementation. Vitamin D itself is the least expensive form of vitamin D replacement and is frequently used in the management of uncomplicated hypoparathyroidism and some disorders associated with ineffective vitamin D action. When vitamin D is used prophylactically, as in the elderly or in those with chronic anticonvulsant therapy, there is a wider margin of safety than with the more potent metabolites. However, most of the conditions in which vitamin D is administered chronically for hypocalcemia require amounts 50–100 times the daily replacement dose because the formation of 1,25(OH)₂D is deficient. In such situations, vitamin D is no safer than the active metabolite because intoxication can occur with high-dose therapy (because of storage in fat). Calcitriol is more rapid in onset of action and also has a short biologic half-life.

Vitamin D (at least 1000 U/d [2–3 μg/d] [higher levels required in older persons]) or calcitriol (0.25–1 μg/d) is required to prevent rickets in normal individuals. In contrast, 40,000–120,000 U (1–3 mg) of vitamin D₂ or D₃ is typically required in hypoparathyroidism. The dose of calcitriol is unchanged in hypoparathyroidism, because the defect is in hydroxylation by the 25(OH)D-1α-hydroxylase. Calcitriol is also used in disorders of 25(OH)D-1α-hydroxylase; vitamin D receptor defects are much more difficult to treat.

Patients with hypoparathyroidism should be given 2–3 g of elemental calcium PO each day. The two agents, vitamin D or calcitriol and oral calcium, can be varied independently. Urinary calcium excretion needs to be monitored carefully. If hypocalcemia alternates with episodes of hypercalcemia in high-brittleness patients with hypoparathyroidism, administration of calcitriol and use of thiazides, as discussed above, may make management easier. Clinical trials with PTH(1–34) or PTH(1–84) are promising, but these alternative treatments have not yet been approved.

Osteoporosis, a condition characterized by decreased bone strength, is prevalent among postmenopausal women but also occurs in men and women with underlying conditions or major risk factors associated with bone demineralization. Its chief clinical manifestations are vertebral and hip fractures, although fractures can occur at almost any skeletal site. Osteoporosis affects almost 10 million individuals in the United States, but only a small proportion are diagnosed and treated.

DEFINITION

Osteoporosis is defined as a reduction in the strength of bone that leads to an increased risk of fractures. Loss of bone tissue is associated with deterioration in skeletal microarchitecture. The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same sex—also referred to as a T-score of –2.5. Postmenopausal women who fall at the lower end of the young normal range (a T-score <–1.0) are defined as having low bone density and are also at increased risk of osteoporosis. Although risk is lower in this group, more than 50% of fractures among postmenopausal women, including hip fractures, occur in this group with low bone density, because the number of individuals in this category is so much larger than that in the osteoporosis range. As a result, there are ongoing attempts to identify individuals within the low bone density range who are at high risk of fracture and might benefit from pharmacologic intervention. Furthermore, some have advocated using fracture risk as the “diagnostic” criterion for osteoporosis.

EPIDEMIOLOGY

In the United States, as many as 9 million adults have osteoporosis (T-score <–2.5 in either spine or hip), and an additional 48 million individuals have bone mass levels that put them at increased risk of developing osteoporosis (e.g., bone mass T-score <–1.0). Osteoporosis occurs more frequently with increasing age as bone tissue is lost progressively. In women, the loss of ovarian function at menopause (typically about age 50) precipitates rapid bone loss so that most women meet the diagnostic criterion for osteoporosis by age 70–80. As the population continues to age, the number of individuals with osteoporosis and fractures will also continue to increase, despite a recognized reduction in age-specific risk. It is estimated that about 2 million fractures occur each year in the United States as a consequence of osteoporosis, and that number is expected to increase as the population continues to age.

The epidemiology of fractures follows the trend for loss of bone density, with exponential increases in both hip and vertebral fractures with age. Fractures of the distal radius have a somewhat different epidemiology, increasing in frequency before age 50 and plateauing by age 60, with only a modest age-related increase thereafter. In contrast, incidence rates for hip fractures double every 5 years after age 70 (Fig. 425-1). This distinct epidemiology may be related to the way the elderly fall as they age, with fewer falls on an outstretched hand and more falls directly on the hip. About 300,000 hip fractures occur each year in the United States, most of which require hospital admission and surgical intervention. The probability that a 50-year-old white individual will have a hip fracture during his or her lifetime is 14% for women and 5% for men; the risk for African Americans is lower (about one-half those rates), and the risk for Asians is roughly equal to that for whites. Hip fractures are associated with a high incidence of deep vein thrombosis and pulmonary embolism (20–50%) and a mortality rate between 5 and 20% during the year after surgery. there is also significant morbidity, with about 20–40% of survivors requiring long-term care, and many who are unable to function as they did before the fracture.

FIGURE 425-1   Epidemiology of vertebral, hip, and Colles’ fractures with age. (Adapted from C Cooper, LJ Melton III: Trends Endocrinol Metab 3:224, 1992; with permission.)

There are about 550,000 vertebral crush fractures per year in the United States. Only a fraction (estimated to be one-third) of them are recognized clinically, because many are relatively asymptomatic and are identified incidentally during radiography for other purposes (Fig. 425-2). Vertebral fractures rarely require hospitalization but are associated with long-term morbidity and a slight increase in mortality rates, primarily related to pulmonary disease. Multiple vertebral fractures lead to height loss (often of several inches), kyphosis, and secondary pain and discomfort related to altered biomechanics of the back. Thoracic fractures can be associated with restrictive lung disease, whereas lumbar fractures are associated with abdominal symptoms that include distention, early satiety, and constipation.

FIGURE 425-2   Lateral spine x-ray showing severe osteopenia and a severe wedge-type deformity (severe anterior compression).

Approximately 400,000 wrist fractures and 135,000 pelvic fractures occur in the United States each year. Fractures of the humerus and other bones (estimated to be about 675,000 per year) also occur with osteoporosis; this is not surprising in light of the fact that bone loss is a systemic phenomenon. Although some fractures result from major trauma, the threshold for fracture is reduced for an osteoporotic bone (Fig. 425-3). In addition to bone density, there are a number of risk factors for fracture; the common ones are summarized in Table 425-1 Age, prior fractures (especially recent fractures), a family history of osteoporosis-related fractures, low body weight, smoking, and excessive alcohol use are all independent predictors of fracture. Chronic diseases with inflammatory components that increase skeletal remodeling such as rheumatoid arthritis, increase the risk of osteoporosis, as do diseases associated with malabsorption. Chronic diseases that increase the risk of falling or frailty, including dementia, Parkinson’s disease, and multiple sclerosis, also increase fracture risk.

FIGURE 425-3   Factors leading to osteoporotic fractures.

In the United States and Europe, osteoporosis-related fractures are more common among women than men, presumably due to a lower peak bone mass as well as postmenopausal bone loss in women. However, this sex difference in bone density and age-related increase in hip fractures is not as apparent in some other cultures, possibly due to genetics, physical activity level, or diet.

Fractures are themselves risk factors for future fractures (Table 425-1). Vertebral fractures increase the risk of other vertebral fractures as well as fractures of the peripheral skeleton such as the hip and wrist. Wrist fractures also increase the risk of vertebral and hip fractures. The risk for subsequent fractures is particularly high in the first several years after the first fracture, and the risk wanes considerably thereafter. Consequently, among individuals over age 50, any fracture should be considered as potentially related to osteoporosis regardless of the circumstances of the fracture. Osteoporotic bone is more likely to fracture than normal bone at any level of trauma, and a fracture in a person over 50 should trigger evaluation for osteoporosis. This often does not occur because postfracture care is not always well coordinated.

PATHOPHYSIOLOGY

BONE REMODELING

Osteoporosis results from bone loss due to age-related changes in bone remodeling as well as extrinsic and intrinsic factors that exaggerate this process. These changes may be superimposed on a low peak bone mass. Consequently, understanding the bone remodeling process is fundamental to understanding the pathophysiology of osteoporosis (Chap. 423). During growth, the skeleton increases in size by linear growth and by apposition of new bone tissue on the outer surfaces of the cortex (Fig. 425-4). The latter process is called modeling, a process that also allows the long bones to adapt in shape to the stresses placed on them. Increased sex hormone production at puberty is required for skeletal maturation, which reaches maximum mass and density in early adulthood. It is around puberty that the sexual dimorphism in skeletal size becomes obvious, although true bone density remains similar between the sexes. Nutrition and lifestyle also play an important role in growth, although genetic factors primarily determine peak skeletal mass and density. Numerous genes control skeletal growth, peak bone mass, and body size, as well as skeletal structure and density. Heritability estimates of 50–80% for bone density and size have been derived on the basis of twin studies. Although peak bone mass is often lower among individuals with a family history of osteoporosis, association studies of candidate genes (vitamin D receptor; type I collagen, the estrogen receptor [ER], and interleukin 6 [IL-6]; and insulin-like growth factor I [IGF-I]) and bone mass, bone turnover, and fracture prevalence have been inconsistent. Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass. Families with high bone mass and without much apparent age-related bone loss have been shown to have a point mutation in LRP5, a low-density lipoprotein receptor–related protein. The role of this gene in the general population is not clear, although a nonfunctional mutation results in osteoporosis-pseudoglioma syndrome, and LRP5 signaling appears to be important in controlling bone formation. LRP5 acts through the Wnt signaling pathway. With LRP5 and Wnt activation, beta-catenin is translocated to the nucleus, allowing stimulation of osteoblast formation, activation, and life span as well as suppression of osteoclast activity, thereby increasing bone formation. The osteocyte product, sclerostin, is a negative inhibitor of Wnt signaling.

FIGURE 425-4   Mechanism of bone remodeling. The basic molecular unit (BMU) moves along the trabecular surface at a rate of about 10 μm/d. The figure depicts remodeling over ~120 days. A. Origination of BMU-lining cells contracts to expose collagen and attract preosteoclasts. B. Osteoclasts fuse into multinucleated cells that resorb a cavity. Mononuclear cells continue resorption, and preosteoblasts are stimulated to proliferate. C. Osteoblasts align at bottom of cavity and start forming osteoid (black). D. Osteoblasts continue formation and mineralization. Previous osteoid starts to mineralize (horizontal lines). E. Osteoblasts begin to flatten. F. Osteoblasts turn into lining cells; bone remodeling at initial surface (left of drawing) is now complete, but BMU is still advancing (to the right). (Adapted from SM Ott, in JP Bilezikian et al [eds]: Principles of Bone Biology, vol. 18. San Diego, Academic Press, 1996, pp 231–241.)

Genome-wide scans for low bone mass suggest multiple genes are involved, many of which are also implicated in control of body size.

In adults, bone remodeling, not modeling, is the principal metabolic skeletal process. Bone remodeling has two primary functions: (1) to repair microdamage within the skeleton to maintain skeletal strength and ensure the relative youth of the skeleton and (2) to supply calcium from the skeleton to maintain serum calcium. Remodeling may be activated by microdamage to bone as a result of excessive or accumulated stress. Acute demands for calcium involve osteoclast-mediated resorption as well as calcium transport by osteocytes. Chronic demands for calcium result in secondary hyperparathyroidism, increased bone remodeling, and overall loss of bone tissue.

Bone remodeling also is regulated by several circulating hormones, including estrogens, androgens, vitamin D, and parathyroid hormone (PTH), as well as locally produced growth factors such as IGF-I and immunoreactive growth hormone II (IGH-II), transforming growth factor β (TGF-β), parathyroid hormone–related peptide (PTHrP), interleukins (ILs), prostaglandins, and members of the tumor necrosis factor (TNF) superfamily. These factors primarily modulate the rate at which new remodeling sites are activated, a process that results initially in bone resorption by osteoclasts, followed by a period of repair during which new bone tissue is synthesized by osteoblasts. The cytokine responsible for communication between the osteoblasts, other marrow cells, and osteoclasts is RANK ligand (RANKL; receptor activator of nuclear factor-κB [NF-κB]). RANKL, a member of the TNF family, is secreted by osteoblasts and certain cells of the immune system (Chap. 423). The osteoclast receptor for this protein is referred to as RANK. Activation of RANK by RANKL is a final common path in osteoclast development, activation, and life span. A humoral decoy for RANKL, also secreted by osteoblasts, is osteoprotegerin (Fig. 425-5). Modulation of osteoclast recruitment and activity appears to be related to the interplay among these three factors. It appears that estrogens are pivotal in modulating secretion of osteoprotegerin (OPG) and perhaps also RANKL. Additional influences include nutrition (particularly calcium intake) and physical activity level.

FIGURE 425-5   Hormonal control of bone resorption. A. Proresorptive and calciotropic factors. B. Anabolic and antiosteoclastic factors. RANK ligand (RANKL) expression is induced in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation, activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. CFU-GM, colony-forming units, granulocyte macrophage; IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; OPG-L, osteoprotegerin-ligand; PDGF, platelet-derived growth factor; PGE₂, prostaglandin E₂; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor nuclear factor-κB; TGF-β, transforming growth factor β; TNF, tumor necrosis factor; TPO, thrombospondin. (From WJ Boyle et al: Nature 423: 337, 2003.)

In young adults, resorbed bone is replaced by an equal amount of new bone tissue. Thus, the mass of the skeleton remains constant after peak bone mass is achieved in adulthood. After age 30–45, however, the resorption and formation processes become imbalanced, and resorption exceeds formation. This imbalance may begin at different ages and varies at different skeletal sites; it becomes exaggerated in women after menopause. Excessive bone loss can be due to an increase in osteoclastic activity and/or a decrease in osteoblastic activity. In addition, an increase in remodeling activation frequency, and thus the number of remodeling sites, can magnify the small imbalance seen at each remodeling unit. Increased recruitment of bone remodeling sites produces a reversible reduction in bone tissue but also can result in permanent loss of tissue and disrupted skeletal architecture. In trabecular bone, if the osteoclasts penetrate trabeculae, they leave no template for new bone formation to occur, and, consequently, rapid bone loss ensues and cancellous connectivity becomes impaired. A higher number of remodeling sites increases the likelihood of this event. In cortical bone, increased activation of remodeling creates more porous bone. The effect of this increased porosity on cortical bone strength may be modest if the overall diameter of the bone is not changed. However, decreased apposition of new bone on the periosteal surface coupled with increased endocortical resorption of bone decreases the biomechanical strength of long bones. Even a slight exaggeration in normal bone loss increases the risk of osteoporosis-related fractures because of the architectural changes that occur, and osteoporosis is primarily a disease of disordered skeletal architecture. The main clinically available tool (dual-energy x-ray absorptiometry) measures mass not architecture. Emerging data from high-resolution peripheral quantitative computed tomography (CT) scans suggest that aging is associated with changes in microstructure of bone tissue, including increased cortical porosity and reduced cortical thickness.

CALCIUM NUTRITION

Peak bone mass may be impaired by inadequate calcium intake during growth among other nutritional factors (calories, protein, and other minerals), leading to increased risk of osteoporosis later in life. During the adult phase of life, insufficient calcium intake contributes to relative secondary hyperparathyroidism and an increase in the rate of bone remodeling to maintain normal serum calcium levels. PTH stimulates the hydroxylation of vitamin D in the kidney, leading to increased levels of 1,25-dihydroxyvitamin D [1,25(OH)₂D] and enhanced gastrointestinal calcium absorption. PTH also reduces renal calcium loss. Although these are all appropriate compensatory homeostatic responses for adjusting calcium economy, the long-term effects are detrimental to the skeleton because the increased remodeling rates and the ongoing imbalance between resorption and formation at remodeling sites combine to accelerate loss of bone tissue.

Total daily calcium intakes <400 mg are detrimental to the skeleton, and intakes in the range of 600–800 mg, which is about the average intake among adults in the United States, are also probably suboptimal. The recommended daily required intake of 1000–1200 mg for adults accommodates population heterogeneity in controlling calcium balance (Chap. 95e). Such intakes should preferentially come from dietary sources, and supplements should be used only when dietary intakes fall short. The supplement should contain enough calcium to bring total intake to about 1200 mg/d.

VITAMIN D

(See also Chap. 423) Severe vitamin D deficiency causes rickets in children and osteomalacia in adults. However, there is accumulating evidence that vitamin D insufficiency may be more prevalent than previously thought, particularly among individuals at increased risk such as the elderly; those living in northern latitudes; and individuals with poor nutrition, malabsorption, or chronic liver or renal disease. Dark-skinned individuals are also at high risk of vitamin D deficiency. There is controversy regarding optimal levels of serum 25-hydroxy-vitamin D [25(OH)D], with some advocating levels >20 ng/mL and others advocating optimal targets >75 nmol/L (30 ng/mL). To achieve this level for most adults requires an intake of 800–1000 units/d, particularly in individuals who avoid sunlight or routinely use ultra-violet-blocking lotions. Vitamin D insufficiency leads to compensatory secondary hyperparathyroidism and is an important risk factor for osteoporosis and fractures. Some studies have shown that >50% of inpatients on a general medical service exhibit biochemical features of vitamin D deficiency, including increased levels of PTH and alkaline phosphatase and lower levels of ionized calcium. In women living in northern latitudes, vitamin D levels decline during the winter months. This is associated with seasonal bone loss, reflecting increased bone turnover. Even among healthy ambulatory individuals, mild vitamin D deficiency is increasing in prevalence, in part due to decreased exposure to sunlight coupled with increased use of potent sunscreens. Treatment with vitamin D can return levels to normal and prevent the associated increase in bone remodeling, bone loss, and fractures. Improved muscle function and gait associated with reduced falls and fracture rates also have been documented among individuals in northern latitudes who have greater vitamin D intake and higher 25(OH)D levels (see below). Vitamin D adequacy also may affect risk and/or severity of other diseases, including cancers (colorectal, prostate, and breast), autoimmune diseases, and diabetes; however, many observational studies suggesting these potential extraskeletal benefits have not been confirmed with randomized controlled trials.

ESTROGEN STATUS

Estrogen deficiency probably causes bone loss by two distinct but interrelated mechanisms: (1) activation of new bone remodeling sites and (2) exaggeration of the imbalance between bone formation and resorption. The change in activation frequency causes a transient bone loss until a new steady state between resorption and formation is achieved. The remodeling imbalance, however, results in a permanent decrement in mass. In addition, the very presence of more remodeling sites in the skeleton increases the probability that trabeculae will be penetrated, eliminating the template on which new bone can be formed and accelerating the loss of bony tissue.

The most common estrogen-deficient state is the cessation of ovarian function at the time of menopause, which occurs on average at age 51 (Chap. 413). Thus, with current life expectancy, an average woman will spend about 30 years without an ovarian supply of estrogen. The mechanism by which estrogen deficiency causes bone loss is summarized in Fig. 425-5. Marrow cells (macrophages, monocytes, osteoclast precursors, mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express ERs α and β. Loss of estrogen increases production of RANKL and may reduce production of OPG, increasing osteoclast recruitment. Estrogen also may play an important role in determining the life span of bone cells by controlling the rate of apoptosis. Thus, in situations of estrogen deprivation, the life span of osteoblasts may be decreased, whereas the longevity and activity of osteoclasts are increased. The rate and duration of bone loss after menopause are heterogeneous and unpredictable. Once surfaces are lost in cancellous bone, the rate of bone loss must decline. In cortical bone, loss is slower but continues for a longer time period.

Because remodeling is initiated at the surface of bone, it follows that trabecular bone—which has a considerably larger surface area (80% of the total) than cortical bone—will be affected preferentially by estrogen deficiency. Fractures occur earliest at sites where trabecular bone contributes most to bone strength; consequently, vertebral fractures are the most common early consequence of estrogen deficiency.

PHYSICAL ACTIVITY

Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss. Concordantly, athletes have higher bone mass than does the general population. These changes in skeletal mass are most marked when the stimulus begins during growth and before the age of puberty. Adults are less capable than children of increasing bone mass after restoration of physical activity. Epidemiologic data support the beneficial effects on the skeleton of chronic high levels of physical activity. Fracture risk is lower in rural communities and in countries where physical activity is maintained into old age. However, when exercise is initiated during adult life, the effects of moderate exercise on the skeleton are modest, with a bone mass increase of 1–2% in short-term studies of <2 years in duration. It is argued that more active individuals are less likely to fall and are more capable of protecting themselves upon falling, thereby reducing fracture risk.

CHRONIC DISEASE

Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis (Table 425-1). Mechanisms that contribute to bone loss are unique for each disease and typically result from multiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodeling. In most, but not all, circumstances the primary diagnosis is made before osteoporosis presents clinically.

MEDICATIONS

A large number of medications used in clinical practice have potentially detrimental effects on the skeleton (Table 425-1). Glucocorticoids are the most common cause of medication-induced osteoporosis. It is often not possible to determine the extent to which osteoporosis is related to glucocorticoids or to other factors, because treatment is superimposed on the effects of the primary disease, which in itself may be associated with bone loss (e.g., rheumatoid arthritis). Excessive doses of thyroid hormone can accelerate bone remodeling and result in bone loss.

Other medications have less detrimental effects on the skeleton than pharmacologic doses of glucocorticoids. Anticonvulsants are thought to increase the risk of osteoporosis, although many affected individuals have concomitant insufficiency of 1,25(OH)₂D, as some anticonvulsants induce the cytochrome P450 system and vitamin D metabolism. Patients undergoing transplantation are at high risk for rapid bone loss and fracture not only from glucocorticoids but also from treatment with other immunosuppressants such as cyclosporine and tacrolimus (FK506). In addition, these patients often have underlying metabolic abnormalities, such as hepatic or renal failure, that predispose to bone loss.

Aromatase inhibitors, which potently block the aromatase enzyme that converts androgens and other adrenal precursors to estrogen, reduce circulating postmenopausal estrogen levels dramatically. These agents, which are used in various stages for breast cancer treatment, also have been shown to have a detrimental effect on bone density and risk of fracture. More recently a variety of agents have been implicated in increased bone loss and fractures. These include selective serotonin reuptake inhibitors, proton pump inhibitors, and thiazolidinediones. It is difficult in some cases to separate the risk accrued by the underlying disease from that attributable to the medication. For example, both depression and diabetes are risk factors for fracture by themselves.

CIGARETTE CONSUMPTION

The use of cigarettes over a long period has detrimental effects on bone mass. These effects may be mediated directly by toxic effects on osteoblasts or indirectly by modifying estrogen metabolism. On average, cigarette smokers reach menopause 1–2 years earlier than the general population. Cigarette smoking also produces secondary effects that can modulate skeletal status, including intercurrent respiratory and other illnesses, frailty, decreased exercise, poor nutrition, and the need for additional medications (e.g., glucocorticoids for lung disease).

MEASUREMENT OF BONE MASS

Several noninvasive techniques are available for estimating skeletal mass or density. They include dual-energy x-ray absorptiometry (DXA), single-energy x-ray absorptiometry (SXA), quantitative CT, and ultrasound (US). DXA is a highly accurate x-ray technique that has become the standard for measuring bone density. Although it can be used for measurement in any skeletal site, clinical determinations usually are made of the lumbar spine and hip. DXA also can be used to measure body composition. In the DXA technique, two x-ray energies are used to estimate the area of mineralized tissue, and the mineral content is divided by the area, which partially corrects for body size. However, this correction is only partial because DXA is a two-dimensional scanning technique and cannot estimate the depth or posteroanterior length of the bone. Thus, small slim people tend to have lower than average bone mineral density (BMD), a feature that is important in interpreting BMD measurements when performed in young adults, and something that must be taken into account at any age. Bone spurs, which are common in osteoarthritis, tend to falsely increase bone density of the spine and are a particular problem in measuring the spine in older individuals. Because DXA instrumentation is provided by several different manufacturers, the output varies in absolute terms. Consequently, it has become standard practice to relate the results to “normal” values by using T-scores (a T-score of 1 equals 1 SD), which compare individual results to those in a young population that is matched for race and sex. Z-scores (also measured in SD) compare individual results to those of an age-matched population that also is matched for race and sex. Thus, a 60-year-old woman with a Z-score of –1 (1 SD below mean for age) has a T-score of –2.5 (2.5 SD below mean for a young control group) (Fig. 425-6). A T-score below –2.5 in the lumbar spine, femoral neck, or total hip has been defined as a diagnosis of osteoporosis. As noted above, because more than 50% of fractures occur in individuals with low bone mass rather than BMD osteoporosis, attempts are ongoing to redefine the disease as a fracture risk rather than a specific BMD. Consistent with this concept, fractures of the spine and hip that occur in the absence of major trauma would be considered to be sufficient to diagnose osteoporosis, regardless of BMD. Fractures of other sites, such as pelvis, proximal humerus, and wrist, would be tantamount to an osteoporosis diagnosis in the presence of low BMD. CT can also be used to measure the spine and the hip, but is rarely used clinically, in part because of higher radiation exposure and cost, in addition to a lesser body of data confirming its ability to predict fracture risk, compared with BMD by DXA. High-resolution peripheral CT is used to measure bone in the forearm or tibia as a research tool to noninvasively provide some measure of skeletal architecture. Magnetic resonance imaging (MRI) can also be used in research settings to obtain some architectural information on the forearm and perhaps the hip.

FIGURE 425-6   Relationship between Z-scores and T-scores in a 60-year-old woman. BMD, bone mineral density; SD, standard deviation.

DXA equipment can also be used to obtain lateral images of the spine, from T4 through L4, a technique called vertebral fracture assessment (VFA). Although not as definitive as radiography, it is a useful screening tool when height loss, back pain, or postural change suggests the presence of an undiagnosed vertebral fracture. Furthermore, because vertebral fractures are so prevalent with advancing age, screening vertebral imaging is recommended in women and men with low bone mass (T-score <1) by age 70 and 80, respectively.

US is used to measure bone mass by calculating the attenuation of the signal as it passes through bone or the speed with which it traverses the bone. It is unclear whether US assesses properties of bone other than mass (e.g., quality), but this is a potential advantage of the technique. Because of its relatively low cost and mobility, US is amenable for use as a screening procedure in stores or at health fairs.

All of these techniques for measuring BMD have been approved by the U.S. Food and Drug Administration (FDA) on the basis of their capacity to predict fracture risk. The hip is the preferred site of measurement in most individuals, because it predicts the risk of hip fracture, the most important consequence of osteoporosis, better than any other bone density measurement site. When hip measurements are performed by DXA, the spine can be measured at the same time. In younger individuals such as perimenopausal or early postmenopausal women, spine measurements may be the most sensitive indicator of bone loss. A risk assessment tool (FRAX) incorporates femoral neck BMD to assess 10-year fracture risk (see below).

WHEN TO MEASURE BONE MASS

Clinical guidelines have been developed for the use of bone densitometry in clinical practice. The original National Osteoporosis Foundation guidelines recommend bone mass measurements in postmenopausal women, assuming they have one or more risk factors for osteoporosis in addition to age, sex, and estrogen deficiency. The guidelines further recommend that bone mass measurement be considered in all women by age 65, a position ratified by the U.S. Preventive Health Services Task Force. Criteria approved for Medicare reimbursement of BMD are summarized in Table 425-2.

Source: From the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and Treatment of Osteoporosis. © National Osteoporosis Foundation.

WHEN TO TREAT BASED ON BONE MASS RESULTS

Most guidelines suggest that patients be considered for treatment when BMD is >2.5 SD below the mean value for young adults (T-score ≤–2.5), in either spine, total hip, or femoral neck. Treatment also should also be considered in postmenopausal women with fracture risk factors even if BMD is not in the osteoporosis range. Risk factors (age, prior fracture, family history of hip fracture, low body weight, cigarette consumption, excessive alcohol use, steroid use, and rheumatoid arthritis) can be combined with BMD to assess the likelihood of a fracture over a 5- or 10-year period. Treatment threshold depends on cost-effectiveness analyses but probably is ~1% per year of risk in the United States.

MANAGEMENT OF PATIENTS WITH FRACTURES

Treatment of a patient with osteoporosis frequently involves management of acute fractures as well as treatment of the underlying disease. Hip fractures almost always require surgical repair if the patient is to become ambulatory again. Depending on the location and severity of the fracture, condition of the neighboring joint, and general status of the patient, procedures may include open reduction and internal fixation with pins and plates, hemiarthroplasties, and total arthroplasties. These surgical procedures are followed by intense rehabilitation in an attempt to return patients to their prefracture functional level. Long bone fractures (e.g., wrist) often require either external or internal fixation. Other fractures (e.g., vertebral, rib, and pelvic fractures) usually are managed with supportive care, requiring no specific orthopedic treatment.

Only ~25–30% of vertebral compression fractures present with sudden-onset back pain. For acutely symptomatic fractures, treatment with analgesics is required, including nonsteroidal anti-inflammatory agents and/or acetaminophen, sometimes with the addition of a narcotic agent (codeine or oxycodone). A few small, randomized clinical trials suggest that calcitonin may reduce pain related to acute vertebral compression fracture. Percutaneous injection of artificial cement (polymethylmethacrylate) into the vertebral body (vertebroplasty or kyphoplasty) may offer significant immediate pain relief in patients with severe pain from acute or subacute vertebral fractures. Safety concerns include extravasation of cement with neurologic sequelae and increased risk of fracture in neighboring vertebrae due to mechanical rigidity of the treated bone. Exactly which patients are the optimal candidates for this procedure remains unknown. Short periods of bed rest may be helpful for pain management, but in general, early mobilization is recommended because it helps prevent further bone loss associated with immobilization. Occasionally, use of a soft elastic-style brace may facilitate earlier mobilization. Muscle spasms often occur with acute compression fractures and can be treated with muscle relaxants and heat treatments.

Severe pain usually resolves within 6–10 weeks. More chronic severe pain might suggest the possibility of multiple myeloma or underlying metastatic disease. Chronic pain following vertebral fracture is probably not bony in origin; instead, it is related to abnormal strain on muscles, ligaments, and tendons and to secondary facet-joint arthritis associated with alterations in thoracic and/or abdominal shape. Chronic pain is difficult to treat effectively and may require analgesics, sometimes including narcotic analgesics. Frequent intermittent rest in a supine or semireclining position is often required to allow the soft tissues, which are under tension, to relax. Back-strengthening exercises (paraspinal) may be beneficial. Heat treatments help relax muscles and reduce the muscular component of discomfort. Various physical modalities, such as US and transcutaneous nerve stimulation, may be beneficial in some patients. Pain also occurs in the neck region, not as a result of compression fractures (which almost never occur in the cervical spine as a result of osteoporosis) but because of chronic strain associated with trying to elevate the head in a person with a significant thoracic kyphosis.

Multiple vertebral fractures often are associated with psychological symptoms; this is not always appreciated. The changes in body configuration and back pain can lead to marked loss of self-image and a secondary depression. Altered balance, precipitated by the kyphosis and the anterior movement of the body’s center of gravity, leads to a fear of falling, a consequent tendency to remain indoors, and the onset of social isolation. These symptoms sometimes can be alleviated by family support and/or psychotherapy. Medication may be necessary when depressive features are present. Multiple thoracic vertebral fractures may be associated with restrictive lung disease symptoms and increased pulmonary infections. Multiple lumbar vertebral fractures are often associated with abdominal pain, constipation, protuberance, and early satiety. Multiple vertebral fractures are associated with greater age-specific mortality.

Multiple studies show that the majority of patients presenting in adulthood with fractures are not evaluated or treated for osteoporosis. Estimates suggest only about 20% of fracture patients receive follow-up care. Patients who sustain acute fractures are at dramatically elevated risk for more fractures, particularly within the first several years, and pharmacologic intervention can reduce that risk substantially. Recently, several studies have demonstrated the effectiveness of a relatively simple and inexpensive program that reduces the risk of subsequent fractures. In the Kaiser system, it is estimated that a 20% decline in hip fracture occurrence was seen with the introduction of what is called a fracture liaison service. This typically involves a health care professional (usually a nurse) whose job is to coordinate follow-up care and education of fracture patients. If the Kaiser experience can be repeated, there would be significant savings of health care dollars, as well as a dramatic drop in hip fracture incidence and a marked improvement in morbidity and mortality among the aging population.

MANAGEMENT OF THE UNDERLYING DISEASE

Patients presenting with typical osteoporosis-related fractures (certainly hip and spine) can be assumed to have osteoporosis and can be treated appropriately. Patients with osteoporosis by BMD are handled in a similar fashion. Other fracture patients and those with reduced bone mass can be classified according to their future risk of fracture and treated if that risk is sufficiently high. It must be emphasized, however, that risk assessment is an inexact science when applied to individual patients. Fractures are chance occurrences that can happen to anyone. Patients often do not understand the relative benefits of medications, compared to the perceived risks of the medications themselves.

Risk Factor Reduction     Several tools exist for risk assessment. The most commonly available is the FRAX tool, developed by a working party for the WHO, and available as part of the report from many DXA machines. It is also available online (http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) (Fig. 425-7). In the United States, it has been estimated that it is cost-effective to treat a patient if the 10-year major fracture risk (including hip, clinical spine, proximal humerus, and tibia) from FRAX is ≥20% and/or the 10-year risk of hip fracture is ≥3%. FRAX is an imperfect tool because it does not include any assessment of fall risk and secondary causes are excluded when BMD is entered. Moreover, it does not include any term for multiple fractures or recent versus remote fracture. Nonetheless, it is useful as an educational tool for patients.

FIGURE 425-7   FRAX calculation tool. When the answers to the indicated questions are filled in, the calculator can be used to assess the 10-year probability of fracture. The calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk adjust for various ethnic groups.

After risk assessment, patients should be thoroughly educated to reduce the impact of modifiable risk factors associated with bone loss and falling. All medications that increase risk of falls, bone loss, or fractures should be reviewed to ensure that they are necessary and being used at the lowest required dose. For those on thyroid hormone replacement, TSH testing should be performed to confirm that an excessive dose is not being used, because biochemical and symptomatic thyrotoxicosis can be associated with increased bone loss. In patients who smoke, efforts should be made to facilitate smoking cessation. Reducing risk factors for falling also include alcohol abuse treatment and a review of the medical regimen for any drugs that might be associated with orthostatic hypotension and/or sedation, including hypnotics and anxiolytics. If nocturia occurs, the frequency should be reduced, if possible (e.g., by decreasing or modifying diuretic use), because arising in the middle of sleep is a common precipitant of a fall. Patients should be instructed about environmental safety with regard to eliminating exposed wires, curtain strings, slippery rugs, and mobile tables. Avoiding stocking feet on wood floors, checking carpet condition (particularly on stairs), and providing good light in paths to bathrooms and outside the home are important preventive measures. Treatment for impaired vision is recommended, particularly a problem with depth perception, which is specifically associated with increased falling risk. Elderly patients with neurologic impairment (e.g., stroke, Parkinson’s disease, Alzheimer’s disease) are particularly at risk of falling and require specialized supervision and care.

Nutritional Recommendations • CALCIUM A large body of data indicates that optimal calcium intake reduces bone loss and suppresses bone turnover. Recommended intakes from an Institute of Medicine report are shown in Table 425-5.

The National Health and Nutrition Examination Surveys (NHANES) have consistently documented that average calcium intakes fall considerably short of these recommendations. Food sources of calcium are dairy products (milk, yogurt, and cheese) and fortified foods such as certain cereals, waffles, snacks, juices, and crackers. Some of these fortified foods contain as much calcium per serving as milk. Green leafy vegetables and nuts, particularly almonds, are also sources of calcium, although their bioavailability may be lower than with dairy products. Calcium intake from the diet can also be assessed (Table 425-6) and calculators are available at NOF.org or NYSOPEP.org.

If a calcium supplement is required, it should be taken in doses sufficient to supplement dietary intake to bring total intake to the required level (1000–1200 mg/d). Doses of supplements should be ≤600 mg at a time, because the calcium absorption fraction decreases at higher doses. Calcium supplements should be calculated on the basis of the elemental calcium content of the supplement, not the weight of the calcium salt. Calcium supplements containing carbonate are best taken with food because they require acid for solubility. Calcium citrate supplements can be taken at any time. To confirm bioavailability, calcium supplements can be placed in distilled vinegar. They should dissolve within 30 min.

Several controlled clinical trials of calcium, mostly plus vitamin D, have confirmed reductions in clinical fractures, including fractures of the hip (~20–30% risk reduction). All recent studies of pharmacologic agents have been conducted in the context of calcium replacement (± vitamin D). Thus, it is standard practice to ensure an adequate calcium and vitamin D intake in patients with osteoporosis whether they are receiving additional pharmacologic therapy or not. A systematic review confirmed a greater BMD response to antiresorptive therapy when calcium intake was adequate.

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