Bone Density Loss - 3
Internationally: Kidney transplant patients generally experience less transplant-related bone disease than cardiac (50% vertebral fracture prevalence), lung (Ferrari, 1996), or liver transplant patients. This may e due to the fact that renal transplant recipients are younger (on average) at the time of transplantation and may have better management and recognition of metabolic bone disease prior to transplantation; moreover, they may receive lower doses of immunosuppression overall. Kidney transplant patients with type 1 diabetes mellitus and SPKT recipients are probably an exception to this general statement because, for the reasons outlined above, they are predisposed by their type 1 diabetes to cortical osteopenia. Sex: Women are at greater risk for all forms of osteoporosis. Women with small frames and low body weight (ie, <70 kg) are particularly at risk; white or Asian women are at highest risk. Postmenopausal women (particularly women with early spontaneous or surgical menopause) are at increased risk because of estrogen deficiency. Women with a history of prolonged periods of amenorrhea and hypogonadism are also at increased risk.
History:
The pretransplant bone evaluation should include a careful history with particular attention to risk factors for osteoporosis. Any personal history of fracture is particularly relevant because prior fracture predicts future fracture (Ismail, 2001). Any family history of osteoporosis or fragility fractures is also relevant. A history of loss of height suggests established osteoporosis and occult thoracic compression fracture. The review of systems should include a review of gonadal function because a history of amenorrhea, decreased libido, or erectile or orgasmic
dysfunction could suggest underlying hypogonadism, predisposing to osteopenia. The review of systems should specifically inquire about bone pain, myalgias, or myopathic symptoms, which could suggest occult vitamin D deficiency or osteomalacia. Significant constitutional symptoms or symptomatic anemia could suggest occult multiple myeloma as a cause of osteopenia in the appropriate clinical context. Because immobility is known to promote negative bone balance, any history of periods of prolonged bed rest is also relevant. A careful drug history should be taken for past anticonvulsant use because these medications can derange vitamin D metabolism. Heparin, loop diuretics, and steroids (both oral and inhaled) are associa ed with negative calcium balance. Any history of tobacco or alcohol abuse is relevant because the use of these substances is an established risk factor for osteoporosis. A dietary history should be obtained. This should include an estimate of daily calcium intake. An overview of lifelong dairy intake or avoidance, lactose intolerance, malabsorption, or celiac disease (Scott, 2000), which predispose the patient to vitamin D deficiency, is also relevant. A history of sun avoidance is similarly important. Overall nutritional status, including any prior periods of malnutrition or energy (caloric) restriction, eg, anorexia nervosa, should be assessed. A history of dietary supplement intake is also relevant because recent observational data suggest that excess vitamin A intake (eg, as retinol) is associated with an increased hip fracture risk (Feskanich, 2002). Physical: Record height and weight, along with any loss of height or kyphosis, which could suggest occult compression fracture. The examiner should be alert for the presence of blue sclerae, whic suggest underlying osteogenesis imperfecta. Any areas of bone tenderness, which could suggest occult fracture or osteomalacia, should lead to further diagnostic evaluation. Any scoliosis or other regions of bony deformity should be noted. These deformities have the potential to render bone density determinations inaccurate in these regions, and the physician or technician performing bone densitometry should be made specifically aware of them.
Other Problems to be Considered:
Osteomalacia
Renal osteodystrophy
Vitamin D deficiency
Glucocorticoid-induced osteoporosis
Osteogenesis imperfecta Quick Find
Lab Studies:
The following laboratory studies are indicated in the pretransplant evaluation of all patients awaiting solid organs (Rodino, 1998;
Boncimino, 1999):
Serum calcium level
Phosphorus level
Bicarbonate level
Alkaline phosphatase level
BUN/creatinine levels
Intact PTH values
25-hydroxy vitamin D-3 value to assess total body vitamin D stores
Thyroid function tests (eg, thyroid-stimulating hormone, free levothyroxine)
Testosterone level (males)
Estradiol and FSH levels (in females with amenorrhea or irregular cycles)
Magnesium level
A 24-hour urine calcium study should also be considered in the absence of loop diuretic therapy because glucocorticoid administration can be associated with significant hypercalciuria, which is exacerbated by aggressive calcium and vitamin D therapy (Manelli, 2000). Moreover, a low 24-hour urine calcium value could suggest malabsorption or vitamin D deficiency, necessitating higher doses of vitamin D. Biochemical markers of bone remodeling are not uniformly indicated in the pretransplant evaluation because, although they may help to assess the rates of bone remodeling, changes in their concentration are quite variable and not uniformly predictive of fracture risk (Looker, 2000). Because aluminum use in the ESRD population has declined considerably in recent years, a serum aluminum level is optional in patients awaiting renal transplantation. Such testing should be reserved for dialysis patients in whom aluminum-related bone disease is a likely possibility, ie, patients with renal osteodystrophy and prior exposure to aluminum-containing binders or aluminum-containing dialysate (Hodsman, 1992). Recently, the predictive value of serum aluminum values for predicting aluminum-related bone disease has been questioned (Kausz, 1999), and aluminum staining at the mineralization front on bone biopsy specimens may more accurately reflect the histopathology found in patients on dialysis (Faugere, Kidney Int, 1986). In the appropriate clinical context of anemia or back pain or when a secondary cause of osteopenia is suggested, a serum protein electrophoresis study should be considered.
Imaging Studies:
Bone densitometry measurements by DEXA scanning of the LS spine and hips should be performed on all patients prior to transplantation. This should be performed not only to screen for preexisting bone loss in this medically ill population predisposed to osteoporosis, but also to establish a baseline in patients who will require long-term administration of glucocorticoids as part of an immunosuppressive posttransplantation regimen (Dodd, 1999). Guidelines established by the American College of Rheumatology and the UK Consensus Group recommend that patients receiving daily glucocorticoid at doses of 7.5 mg or more of prednisolone for 6 months or longer should have a BMD measurement (Eastell, 1998). Bone density of the distal radius should also be measured in patients with renal osteodystrophy and any evidence of hyperparathyroidism. Complete spine radiographs should be obtained because the prevalence of occult, asymptomatic fractures (in particular spinal compression
fractures) is considerable (Rodino, 1998). Further, radiographs of any painful bone sites should be obtained to help exclude the presence of Looser zones or Milkman fractures, which are pathognomonic for osteomalacia.
Medical Care: Because quality of life can be significantly diminished by the chronic pain of fractures, counsel patients with extremely low bone density or osteoporotic fractures documented prior to transplant about the increased fracture risk following transplantation (Dodd, 1999). The aim of medical therapy should be to prevent further bone loss and to restore (if possible) bone lost before transplantation. Guidelines established by the American College of Rheumatology and the UK Consensus Group (Eastell, 1998; Nishimura, 2000) recommend that patients who receive daily glucocorticoid at doses of 7.5 mg of prednisolone or more for 6 months or longer should begin preventive therapy. Transplant recipients clearly meet this criterion. Advise all patients to maintain an adequate total elemental calcium intake (ie, 1000-1500 mg) and to take supplements as necessary. The dose of supplemental calcium should be individualized based on the patient’s dietary intake, menopausal status, and underlying medical issues. For example, a pharmacologic dose of calcium administered to a renal transplant recipient with persistent secondary hyperparathyroidism could worsen hypercalciuria because of excess PTH action and could be contraindicated. Administer vitamin D at 400-800 IU/d to all patients. However, patients with malabsorption, cystic fibrosis, or PBC have higher vitamin D requirements (Donovan, 1998; Lark, 2001), and 25-hydroxy vitamin D levels should be followed to assess the adequacy of replacement. Kidney transplant and SPKT patients may continue to require posttransplant calcitriol for a brief period at doses lower than used during dialysis (Giannini, 2001). However, therapy must be individualizedbecause a significant proportion of patients have persistent hyperparathyroidism, and calcitriol could worsen hypercalciuria and hypercalcemia. Vitamin D and calcium alone are clearly insufficient to prevent transplant-related bone loss (Spira, 2000). Bisphosphonates are clearly the drugs of choice for steroid-induced osteoporosis (Nishimura, 2000). Although the sun is the major source of vitamin D, unnecessary exposure to ultraviolet light cannot be recommended because of the increased incidence of skin cancers in transplant recipients. Hypogonadism is common and frequently untreated in this medically complex population (Cahill, 2001). Consider hormonal replacement (estrogen or androgen) if evidence of hypogonadism exists, if not medically contraindicated. Review of antiresorptive strategies in transplantation A pilot study in heart transplant recipients compared bisphosphonates administered (both PO and IV) with oral calcitriol against calcium and oral vitamin D. The antiresorptive group of 18 patients received 1 dose of intravenous pamidronate at 60 mg within 2 weeks of transplant and calcitriol at 0.25 mcg/d. This was followed by cyclical etidronate at 400 mg/d for 14 days every 3 months. A second group received similar calcium and vitamin D but no antiresorptives. After 12 months, spinal BMD was maintained in the group receiving bisphosphonates and calcitriol, whereas the comparator group lost 6-7%. Over this same period, femur-neck BMD fell 2.7% in the antiresorptive group, while the comparator group lost 10.6% (Shane, 1998).Valero et al (1995) studied 120 patients after liver transplantation. At 1-year posttransplantation, 35% had documented osteoporosis. Patients received calcium at 1000 mg/d and cyclical etidronate at 400 mg orally for 15 days every 3 months or calcitonin at 40 IU intramuscularly daily. After 1 year, this uncontrolled study showed significant improvements in vertebral BMD in both groups (6.4% and 8.2%, respectively). A controlled, nonrandomized, nonblinded study from the University of North Carolina examined the efficacy of intravenous pamidronate in 34 cystic fibrosis patients after lung transplantation. Pamidronate at 30 mg intravenously was administered every 3 months together with vitamin D at 800 IU/d and calcium at 1000 mg/d for 2 years. The pamidronate group was compared with a similar group receiving vitamin D and calcium alone. Although the study was not powered to detect differences in fracture prevalence, intravenous pamidronate was significantly more effective than placebo in improving BMD. Over the 2 years, patients gained BMD on the order of 8.8% at the LS spine and 8.2% at the femur (Aris, 2000). The rapid early bone loss during the first 12 months following renal transplant can be prevented by intravenous pamidronate. In a prospective, randomized, controlled study, 26 male renal transplant patients received either placebo or intravenous pamidronate at 0.5 mg/kg at the time of transplant and 1 month later. All patients received prednisolone, cyclosporine, and azathioprine. Patient profiles were similar, as were PTH levels. With transplantation, similar decreases in serum creatinine levels were observed in both groups. At 12 months osttransplant, spine and femur-neck BMD were maintained unchanged in the pamidronate group. However, in the control group, spine and femur-neck BMD fell 6.4% and 9%, respectively. In this small study, the only noted adverse effect was transient hypocalcemia in 2 patients (Fan, 2000). Alendronate prevents CsA-induced osteopenia in rats, maintaining trabecular bone volume at the tibia (Sass, 1997). A recent study of 40 patients examined the effects of alendronate, calcitriol, and calcium on bone loss at least 6 months following renal transplantation (Giannini, 2001). The t scores were depressed, suggesting at least osteopenia at all sights measured (ie, lumbar spine, -2.4 ±1; total femur, -2 ±0.7; femoral neck, -2.2 ±0.6). During a 12-month period of observation, while receiving 980 mg of dietary calcium, BMD fell further. Bone density decreased at the spine (-2.6 ±5.7%, P <.01), total femur (-1.4 ±4.2%, P <.05), and femoral neck (-2 ±3%, P <.001). Subjects were then randomized to alendronate plus calcitriol and calcium versus calcium and calcitriol alone.
