t-score
Bone mass
0 to –1
Normal
–1 to –2.5
Low bone mass
<–2.5
Osteoporosis
Bone density measurements can be a powerful tool for determining who may be at risk for fracture. Since the evaluation is based on a population risk model in which the fracture and nonfracture groups overlap at certain levels of bone density, it is important to remember that large epidemiologic trials have determined that the overall risk increases exponentially for progressively lower BMD [15, 16]. Conversely, a minimally low bone mass (t-score between −1 and −2.5) does not absolve nor reduce the patient from fracture risk if certain clinical elements exist(ed) either in their bone formative years or in the pre-aging skeleton before age 50. To illustrate this point, the majority of osteoporotic fractures occur with a T score greater than −2.5 [17]. Clinicians should be aware that osteoporosis and fracture risks are multifactorial and any additive risks culminating in small changes in bone density may translate into much larger fracture risks. This fact is more evident at older ages where fracture risks rise significantly for small changes in BMD at any absolute density. Effective assessment can identify patients needing treatment and in whom the presence of osteoporosis and/or higher than age normal fracture risk may change the treatment recommendations during a PHPT evaluation.
Pathophysiology of Osteoporosis
Osteoporosis is a disease of structural fragility produced by functional differences in bone formation, resorption, and repair. Primary osteoporosis is a multifactorial and not well-understood multi-pathway process leading to low bone mass and increased fracture risks in the aging skeleton. Secondary osteoporosis occurs when clinical events or diseases lead to an increased fracture risk.
In general terms, the pathophysiology of osteoporosis is grouped into three functional categories:
- 1.
Failure to attain an optimized mean peak bone mass and quality,
- 2.
Accelerated bone loss from increases in resorption, and
- 3.
A decrease in bone formation during remodeling and repair.
Aging impacts all these mechanisms including an increase in falls and physical events that increase fracture risk.
Genetic determinants for skeletal strength, bone mass, bone maintenance, and fracture risk are known, but their overall respective contributions are still under active investigation [18]. In addition to genetic factors, the most common physiologic changes leading to increased fracture risk center on nutritional factors and sex steroids. A healthy skeleton is one that attains its genetically maximal peak bone mass and minimizes the effects of aging on bone loss. Maximizing peak bone mass is achieved through genetic determinants, nutritional access (including calcium, Vitamin D3, and good protein calorie nutrition), normal puberty and sex steroid maturation, normal thyroid and pituitary function, body habitus, and physical activity [19]. Preventing premature loss or accelerated age-related loss is achieved through avoiding severe illness, nutritional deficits, lifelong low Vitamin D3 and calcium intake, early changes in sex steroids (particularly estrogen for women), and certain medications, principally glucocorticoids. The interplay of these factors allows low bone mass, early osteoporosis, or accelerated bone loss to occur in any aging patient or in younger patients age less than 50 years.
Postmenopausal osteoporosis is defined as a state of increased bone turnover and lesser effective remodeling and bone deposition; however, a high turnover state is not the only pathophysiological risk for lower bone mass and / or fracture risk in all patients with low bone mass. For example, high bone turnover is present in adolescents and is not equated with elevated fracture risk; therefore, there must be other elements to consider in assessing for fracture risk and the structural changes that lead to a decrease in first microscopic bone stability and strength, followed by macroscopic structural failure and fracture. Various developmental influences, protracted clinical states (e.g., primary or secondary amenorrhea, anorexia) or repetitive use of glucocorticoids in the skeletal growth years may decrease the attainment of maximal peak bone mass. Later in life this may lead to an increased risk of fracture and higher rate of osteoporosis owing to a lower starting bone density from which age-related loss begins and an overall lessening of bone quality. Chronic diseases such as diabetes may also directly impact bone quality without an effect on bone density accounting for a higher fracture rate in diabetics [14]. Additionally, age itself independent of bone mass density is a fracture risk predictor. For example, at the same BMD (e.g., t-score −3 femoral neck), in someone at age 80 there is a sixfold higher risk of fracture as compared to age 50 [20]. These observations suggest that bone quality is important and understanding the effects of various positive and negative elements on bone will impact clinical decisions.
A primary example of these differences exists in patients age <50 years who could have an equivalent fracture risk in the correct setting as compared to an older patient. For example, the addition of PHPT can be a singular tipping point in a younger patient that significantly raises their risk of fracture if they possess other low bone mass risk factors. Similarly, long standing mild PHPT in an older patient also may negate years of positive bone building effects and minimal age-related bone loss prior to PHPT onset. The FRAX algorithm [13] attempts to fuse these ideas towards a more inclusive risk assessment by using a complete clinical evaluation and BMD. FRAX uses a risk factor based algorithm, incorporating the risk of fracture and death from a number of prominent bone loss risks and conditions of secondary osteoporosis. The risk result is a 10-year probability of major osteoporotic fracture (spine, hip, humerus, wrist) or hip fracture alone. The National Osteoporosis Foundation (NOF) has recently adopted FRAX to their recommendations for treatment criteria with a fracture risk threshold of 3 % for hip fracture and 20 % risk for an osteoporotic fracture at any site [21]. Other countries and associations now include FRAX in their respective guidelines, although debate is ongoing at where a uniform intervention threshold will lie. Similar to BMD measurements alone, FRAX has limitations and cannot be used to judge response to therapy. One relevant limitation is that presence of concomitant PHPT is not included in the FRAX analysis since PHPT confers a variable risk for BMD reduction in individual patients. There is currently no predictive algorithm that accurately determines the bone loss rate or additive fracture risk in a PHPT patient. A bone quality assessment may be relevant in future work, since at a given BMD a PHPT patient with a low bone mass BMD may have more fracture risk than a BMD matched, non-PHPT patient. Using all of these tools, BMD, FRAX, and a comprehensive clinical assessment of risk factors for low bone mass and accelerated bone loss is the most complete way to determine fracture risk in an individual patient.
Therapy for Osteoporosis
Treating osteoporosis relies on identifying and modifying bone loss risk factors, supplying adequate material for new bone synthesis and using pharmacologic modifications of the bone remodeling cycle where indicated. Importantly, the risk and impact of falls must be addressed.
At any clinical assessment for osteoporosis and in particular for the aging patient, identifying daily risk factors for falls is critical. Modifying the home environment as well as strengthening, conditioning, agility, and muscle training are all factors that are often overlooked as elements that can prevent fragility fracture by averting the actual physical event that precipitates the fracture. Data from athletes, astronauts, and older adults in strengthening programs have all demonstrated there can be anatomic specific and global bone mass reductions from loss of use and gains from strengthening programs [22, 23].
Calcium and Vitamin D3
Metabolic and nutritional therapy is required for adequate bone formation during remodeling. Calcium and Vitamin D3 are necessary for this process and often inadequately acquired in the diet and poorly absorbed as people age. Calcium is absorbed minimally and passively in the small intestine (~20 % of a calcium load, limited efficiency past 500 mg) [24]. Active absorption up to ~80 % of a calcium load occurs in the presence of adequate activated Vitamin D3 [1,25(OH)2D3]. Calcium homeostasis is maintained through the activity of Parathyroid Hormone (PTH) and its actions on the kidney (active calcium reabsorption), skeleton, and the enzyme 1-alpha hydroxylase that synthesizes 1,25(OH)2D3 from its storage form, 25(OH)D3. Serum Vitamin D3 levels decline with aging, season, darker skin pigment and nutritional access. PTH and serum 25(OH)D3 are inversely proportionate in order to maintain serum calcium levels within a relatively narrow range. Inadequate intake of Vitamin D3 and or calcium leads to relative deficiencies and a decline in serum calcium with an appropriate, compensatory elevation in PTH. The PTH rise increases bone remodeling, calcium re-entry from the renal filtrate and synthesis of activated Vitamin D3 (1,25(OH)2D3) all to maintain serum calcium levels. Protracted deficiencies in calcium and Vitamin D3 produce chronic secondary HPT, a high bone turnover state that leads to accelerated bone loss, declining bone density, and bone quality thereby increasing the fracture risk. Access to adequate calcium intake of ~1000 mg elemental calcium per day can lower the remodeling rates ~20 % and increase BMD within 12–18 months [25]. Achieving Vitamin D3 sufficiency with adequate calcium intake will revert secondary HPT, lowering the PTH and decrease or revert the negative bone effects. Since calcium and Vitamin D3 insufficiency are very common in osteoporosis patients, these deficiencies must first be corrected before other therapies are used.
Currently, there is debate about calcium and Vitamin D3 supplementation in the general population and these data are beyond the scope of this Chapter to review; however, it is important to recognize that in at risk populations there is good quality data showing bone mineral density gains [26] and vertebral but not nonvertebral fracture risk reduction [27] for calcium supplementation and both vertebral and nonvertebral fracture reduction with dose-dependent Vitamin D3 supplementation [28]. Recommendations for supplementation, daily intake, and therapeutic use vary significantly depending on the country and recommending group. In osteoporosis and older patients it is important to remember that adequacy is not often judged by the dose given based on generalized recommendations, but by effective absorption in each individual since these patients have an underlying disorder that by its nature requires adequate calcium and Vitamin D3 to revert increased bone loss. Nutritional adequacy for osteoporosis treatment with calcium and Vitamin D3 is often judged by measuring Vitamin D3 [25(OH)D3] levels and assessing calcium sufficiency by PTH and 24-h urine calcium measurements following normal Vitamin D3 levels (30 ng/mL; 75 nmol/L). Recommendations will vary, but on average osteoporotic patients require 800–1200 mg elemental calcium given in divided doses daily with a dose of Vitamin D3 necessary to achieve sufficiency.
Osteoporosis Pharmacotherapeutics
Pharmacologic therapy for osteoporosis centers on first establishing good calcium and Vitamin D3 use, correcting underlying deficiencies and secondary HPT and then using one of the available agents such as Bisphosphonates (e.g., Alendronate), estrogens, or Selective Receptor Estrogen Receptor Modulators (SERMs) (e.g., Raloxifene), inhibitors of the activator of nuclear factor kB ligand (RANKL) (Denosumab), recombinant PTH (Teriparatide), or calcitonin.
In aging women, as sex steroid levels decline in the peri-menopasuse into menopause for the first few years there is an accelerated rate of bone loss followed by a relatively constant, downward sloping loss. The use of postmenopausal estrogen, with the controversies surrounding its nonskeletal positive and negative effects is beyond the scope of this chapter. Historically, estrogen is known to improve bone density and reduce the risk of vertebral and nonvertebral fractures, but the effect lasts for only as long as estrogen is being used and BMD declines up to 5 % in the first year following cessation, mirroring the rate of early menopausal bone loss [29]. In general estrogen is not recommended as a primary therapy for prevention or treatment of osteoporosis, but will provide positive effects in those taking it for relief of postmenopausal symptoms.
Selective Receptor Estrogen Receptor Modulators such as Raloxifene have a significant reduction on vertebral but not nonvertebral fractures. Raloxifene decreased the risk of invasive breast cancer by 76 % [30], and in osteopenic patients Raloxifene can be used to prevent bone loss; however, the lack of efficacy at nonvertebral sites, other safety and long-term efficacy issues and failed clinical trials on newer molecules have reduced the use and recommendation for the use of SERMs.
Bisphosphonates are a mainstay of osteoporosis therapy and can reduce vertebral fractures 35–65 % and nonvertebral fractures on average 20–25 % [31]. These reductions are seen after 2–3 years with correspondingly smaller gains in BMD, again highlighting the exponential effects of small bone density changes that correspond to large reductions in fracture risk. Different levels of effect have been seen in trials with the different drugs including the intravenous (Zoledronate) versus weekly (Alendronate) and monthly (Risedronate) oral preparations (Alendronate, Risedronate), but all significantly lower fracture risks. Length of therapy, combining different pharmacological agents with bisphosphonates, and protection from fracture after stopping therapy all have multifactorial confounders, but a starting BMD t-score <−2.5 in a higher risk, fracture naïve patient, appears to gain the most benefit from more prolonged therapy [32, 33].
Denosumab is a novel monoclonal antibody directed against RANKL. The balance between RANKL and osteoprotegrin as influenced by PTH, estrogens, and glucocorticoids can modify osteoclastic activation and therefore bone resorption. Various animal models and human genetic polymorphisms or deficiencies in parts of this system have shown inhibiting RANKL can lead to increases in bone formation and decreases in bone resorption [34]. In clinical trials Denosumab increases bone density on average at the spine 6.5 % and total hip 2.4 % over 2 years [35] while the largest trial to date powered for fracture shows relative risk reductions of 68 % spine, 20 % nonvertebral and 63 % hip [36]. Long-term use of Denosumab is still being evaluated, but cessation of therapy appears to return the bone turnover state to prior physiology, similar to stopping estrogen and different from bisphosphonates which have longer lasting effects on bone remodeling [37]. Unlike bisphosphonates, Denosumab can be used in patients with renal failure, and has proven to be particularly useful in treating osteoporosis in the elderly with impaired renal function.
Long-term safety, rare to very rare side effects including osteonecrosis of the jaw and atypical subtrochanteric fractures, use and monitoring concerns have received recent attention. The analysis of large-scale trials and epidemiology on these issues has shown these concerning side effects are very rare for bisphosphonates or Denosumab. A position statement and detailed analysis of the literature has been issued by the American Society for Bone and Mineral Research (ASBMR) and was recently updated [38]. Overall the use of these medications is an important part of overall osteoporosis therapy in reducing fracture risk and morbidity and mortality and the presence of these is exceedingly rare side effects does not compromise their known benefits.
Recombinant PTH (rPTH; Teriparatide) is an anabolic therapy providing larger incremental gains in bone density at the spine than other pharmacologic compounds. PTH may stimulate both bone formation initially and then resorption and formation simultaneously. The pharmacologic effect by pulsatile administration (daily injection) differs physiologically for its effect on bone than a continual elevation in PHPT or secondary HPT from Vitamin D3 deficiency, both of which lead to higher bone turnover and bone density reduction. Current therapeutic use is time limited because of an increase in osteosarcoma in rats during evaluation, but significant gains in vertebral (13.7 %) and femoral neck (6 %) BMD occurred with loss at the radius (2–4 %) over 18 months [39]. Vertebral fractures were reduced 69 % and nonvertebral fractures 54 %. Despite the decrease in BMD at the radius there was also a nonstatistical significant trend in fracture reduction at the wrist. Bone density gains are lost 12–18 months after cessation of rPTH but are maintained if treatment is followed with an anti-resorptive agent [40]. Use of Teriparatide in combination therapy and for other indications is under active consideration. Teriparatide is contraindicated in PHPT, Paget’s disease, disorders of high bone turnover or risk of osteosarcoma (prior radiation exposure) and unexplained alkaline phosphatase elevations.
Calcitonin has been examined for its use on osteoporosis but its efficacy on bone turnover, bone density gains, and fracture reduction has been mixed to minimal to none; therefore, Calcitonin is not usually considered amongst the typical therapeutic choices.
Practical Considerations of Osteoporosis in Primary Hyperparathyroidism Patients
Primary Hyperparathyroidism produces a generally asymptomatic hypercalcemia, predominately from a single gland adenoma. There is a wide range of clinical presentation, but in general a less severe pathologic presentation exists than in the past, likely due to shortened time of disease before discovery. PHPT in past years and currently in certain patient populations still can present with pathologic fractures and severe skeletal changes such as osteitis fibrosa cystica. Other chapters in this book have extensively assessed the specific evaluation, treatment and long, and short-term sequelae of PHPT. How PHPT patients should be assessed and treated for osteoporosis is an important part of their comprehensive care.
The decline of severe PHPT in North America and Europe does not mean the skeletal risk is lessened for patients with long-present disease or additive bone mass loss risks. Undiagnosed low bone mass or osteoporosis in the PHPT patient factors into both surgical decision making and medical management pre and post-parathyroidectomy. The impact on bone health varies, depending on whether the patient is to be treated surgically and potentially cured or followed medically. In medical observation, patients have the potential for further bone loss and an increased fracture risk from both the PHPT and any additional osteoporosis risk factors. Some studies suggest that all cause mortality in PHPT is increased during long-term observation past a certain threshold of years; however, these studies are not powered to look at an increase in fracture [41, 42]. Determining skeletal risk should occur at the initial evaluation and raises two important clinical questions.
- 1.
What is the patient’s underlying skeletal health status and do they have low bone mass or osteoporosis?
- 2.
How does a patient’s BMD and fracture risks affect the recommendation for surgical correction or medical management?
What Is the Patient’s Underlying Skeletal Health Status and Do They Have Low Bone Mass or Osteoporosis?
The aging patient of both genders (age >50 years) is at risk for osteoporosis and fracture. Patients at any age may also be at risk for secondary osteoporosis if certain medical conditions and/or therapies have occurred. Coincident clinical conditions may also lead to a blunting of osteoporosis therapy and exacerbate underlying bone loss. PHPT is a high bone turnover state and therefore increases the risk of fracture by decreasing the micro-architecture stability and bone quality [43]. Cortical bone loss occurs predominately at the distal 1/3 radius, although recent evidence suggests previously unrecognized trabecular bone loss and qualitative changes at the spine and hip also increase fracture risk at these sites. Since osteoporosis is common in older patients, coincident presentation is likely and therefore a complete bone loss risk evaluation should be completed on each PHPT patient age > 50 and on appropriate younger patients in whom there may be a risk for reduction in bone quality and therefore a lower than expected age-related BMD.
Secondary osteoporosis is present in 30–50 % of pre and postmenopausal women and 50–80 % of men with factors that are detrimental to skeletal health [44]. Common risk factors leading to either accelerated bone loss or decreased bone formation with a decrease in skeletal strength are shown in Table 29.2. Among these are conditions that may affect adequate nutrition (celiac disease), changes in bone turnover (hyperparathyroidism), disorders of mineral homeostasis (primary hypercalciuria), medications that affect bone either directly or indirectly (glucocorticoids, anti-convulsants), and disorders of bone marrow (multiple myeloma). Some of these events may have influenced a patient’s maximal bone mass attainment in their formative years resulting in a lower peak bone mass. These patients have less tolerable cumulative loss before reaching a point of increased fracture risk and/or osteoporosis much earlier than their peers, even in their early 40’s. Many of these risks are indications for a BMD at an early age, but often those are not completed except in specific situations where governing bodies have recommended the test as standard of care (e.g., transplant patients, severe asthma using glucocorticoids). Additionally, younger PHPT patients (< age 40) can have the disorder for many years before it is identified with the potential for early bone loss. All of these populations warrant an increased attention to their skeletal loss and fracture risks at the initial evaluation for PHPT and prior to surgical correction.
Table 29.2
Common clinical conditions assocaited with either accelerated bone loss or decreased bone mass attainment leading to Secondary Osteoporosis
Factors Associated with Secondary Osteoporosis |
|---|
Endocrine Disorders |
Hypogonadism |
Hyperthyroidism |
Primary Hyperparathyroidism |
Vitamin D insufficiency/deficiency (secondary HPT) |
Cushing’s Disease |
Phosphate or Calcium wasting |
Gastrointestinal disorders |
Malabsorption (celiac disease, IBD) |
Cirrhosis, poor nutrition |
Eating disorders in younger patients |
Bone marrow disorders |
Leukemia and lymphoma |
Multiple myeloma |
Connective tissue disorders |
Rheumatoid arthritis |
Renal disorders |
Hypercalciuria |
Medications associated with low bone mass |
Anti-epileptics (many) |
Aromatase inhibitors (breast cancer) |
Chemotherapy/immunosuppressive agents |
Corticosteroids |
Excess thyroid hormone |
Gonadotropin-releasing hormone agonists |
Heparin |
A BMD measurement is recommended for the initial evaluation in all PHPT patients [45–47]; however, some studies show these are not routinely performed in preoperative assessments [48]. In some patients, a disparately low radial BMD compared to the hip and spine may be an indicator that the disease has been present longer than suspected. One might see this in pre-menopausal women where estrogen is more protective at the hip and spine. Finding a t-score <−2.5 at any site in a patient age >50 years is an indication for surgery. If the patient is <50 years old, then a Z-score determination should be made and if <−2.5 this is also an indication for surgery. Using Z-scores in the age <50 years population of PHPT patients is indicated and consistent with the positions of governing bodies on interpretation of BMD in younger patients [49].
The complete medical evaluation of skeletal health as part of the recommended workup for PHPT is covered extensively in other Chapters. The skeletal portion of those recommendations includes the following:
- 1.
A full medical history looking for reasons for early bone loss, early formative years bone qualitative changes or reasons for poor bone formation prior to age 50.
- 2.
Additional risk factor analysis including family history of osteoporosis, hypercalcemia, PHPT, nephrolithiasis, or other metabolic bone disorders.
- 3.
Biochemical workup including serum total and ionized calcium, albumin, phosphorous, magnesium, PTH, 25(OH)D3, alkaline phosphatase, creatinine, urine calcium, and creatinine with calculated Ca/Cr.
- 4.
A 3 site BMD (spine, hip, and distal 1/3 radius) by DXA.
- 5.
Vertebral fracture assessment by X-ray.
How Does a Patient’s BMD and Fracture Risks Affect the Recommendation for Surgical Correction or Medical Management?
Increased bone turnover in PHPT does not have a direct, clear association with increased fracture rates because of confounding and coexisting bone loss, low bone mass, and osteoporosis. In classical, severe PHPT the fracture rates are elevated [50, 51]. Some cohorts show differences in both increased vertebral and nonvertebral fractures [52], despite lesser degrees of bone loss at the trabecular sites. Some studies have shown a very high prevalence (~44 %) of vertebral fractures that were both silent and asymptomatic, even in mild PHPT [53]. A recent single center analysis of consecutive patients showed a 34 % prevalence of vertebral fractures, ~10 % nonvertebral fractures with a 60 % prevalence of osteoporosis [54]. If any PHPT patient has additional osteoporosis risk factors, or if significantly low spine or hip BMD is found in a newly diagnosed PHPT patient, then there may be a previously unrecognized, considerably increased fracture risk. Recent guidelines revisited this issue and recommend routine screening for fractures in addition to BMD [45]. If the prevalence of silent fracture data [54] are widely applicable in other centers, then this observation lends power to the recommendation in those patients who might be considered nonsurgical that screening for occult fracture by X-ray may essentially “re-stage” the patients’ long-term fracture risk and change the recommendations for surgical correction and medical management. Since a known fracture is part of the surgical criteria and if the prevalence is truly higher than previously suspected, a screening lumbar spine X-ray becomes as important as the BMD since these data suggest routine screening would both increase the number of patients identified as surgical candidates and accelerate the medical management of an otherwise unknown fragility fracture.
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