What is the role of antiresorptive therapy in the treatment of organ transplantation-related osteoporosis?

Updated: Jul 02, 2020
  • Author: Carmel M Fratianni, MD, FACE; Chief Editor: George T Griffing, MD  more...
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Unfortunately, the literature regarding medical therapy to prevent or treat transplant-associated bone loss is plagued by relatively small numbers of patients with insufficient power to detect significant differences in BMD, differing immunosuppressant regimens, no randomization, or randomization at varying intervals following transplantation. This is particularly important because it is not appropriate to compare interventions in the early posttransplant period (within 6 mo of transplant) when bone loss is greatest, with later interventions. Moreover, the vast majority of studies are not powered to detect fracture outcomes. [69]

In humans, a pilot study in heart transplant recipients demonstrated a benefit of bisphosphonates (both PO and IV) plus oral calcitriol versus 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%. [105]

Valero et al demonstrated a benefit of both etidronate and calcitonin in 120 patients after liver transplantation. At 1-year posttransplant, 35% had documented osteoporosis. Patients received calcium at 1000 mg/d and cyclical etidronate 400 mg orally for 15 days every 3 months or calcitonin, 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). [106]

In a controlled, nonrandomized, nonblinded study from the University of North Carolina in 34 cystic fibrosis patients after lung transplantation, patients receiving intravenous pamidronate gained approximately 8.8% BMD at the LS spine and 8.2% at the femur over 2 years. [107] Pamidronate at 30 mg intravenously was administered every 3 months together with vitamin D at 800 IU/d and calcium at 1000 mg/d. 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.

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 posttransplant, spine and femur-neck BMD were preserved in the pamidronate group, whereas in the control group, spine and femur-neck BMD fell 6.4% and 9%, respectively. In this small study, transient hypocalcemia was the only noted adverse effect, seen in 2 patients. [108]

Haas et al demonstrated the ability of a third-generation bisphosphonate, zoledronic acid, to prevent bone loss in the first 6 months after renal transplant. [109] In a randomized, placebo-controlled study, 20 renal transplant recipients received either 4 mg of zoledronic acid or placebo twice within 3 months posttransplant.

In addition to BMD by DEXA, mean trabecular calcium and trabecular morphometry were assessed by bone biopsy. Renal function did not change after zoledronic acid infusion. Two IV infusions of zoledronic acid prevented bone loss and increased average trabecular calcium concentration significantly over the first 6 months after transplant, compared with placebo group in which no change was seen.

BMD at the femoral neck showed no change in the zoledronic acid group but fell in the placebo group. BMD at the lumbar spine increased in the zoledronic acid group and was unchanged in the placebo group. Improved trabecular mineralization and architecture despite ongoing use of high-dose steroids was notable. Cancellous bone was stabilized. An increase in osteoid surface was seen and osteomalacia excluded based on bone turnover markers, although tetracycline labeling was not performed.

The increase in bone mineralization density distribution with zoledronic acid suggested increased trabecular mineralization and argued against osteomalacia. Adynamic bone disease was excluded on the basis of increased osteoid in the zoledronic acid group.

Disappointingly, the early bone-sparing effects of short- term zoledronic acid conferred no sustained benefit compared with placebo at 3 years after transplantation.

Giannini et al reported on the ability of alendronate to prevent further bone loss in renal transplant recipients. [100] The patients’ initial BMD scores were depressed, suggesting at least osteopenia at all measured sites (ie, lumbar spine, total femur, and femoral neck). During a 12-month period of observation, while subjects received 980 mg of dietary calcium, BMD fell further. Bone density decreased at the spine, total femur, and femoral neck.

Subjects were then randomized to alendronate plus calcitriol and calcium versus calcium and calcitriol alone. After 12 months of calcium 500 mg/d with calcitriol at 0.5 mcg/d, no trend toward further bone loss was noted. However, after 12 months of alendronate therapy at 10 mg/d plus calcitriol at 0.5 mcg and calcium at 500 mg, bone density increased 5% at the LS spine and 4% at the femur.

Another study demonstrated that the rapid, severe bone loss associated with heart transplantation could be attenuated by either of two preventive regimens. Both nasal salmon calcitonin at 200 U/d with continuous calcitriol at 0.5 mcg/d or intermittent pamidronate at 0.5 mg/kg intravenously every third month were equally effective by 18 months, although initially, pamidronate slowed bone loss more. [110]

A randomized, controlled clinical trial comparing oral clodronate with intranasal calcitonin for the treatment of low bone mass in 46 patients with osteopenia or osteoporosis after kidney transplantation found that both treatments improved BMD at the LS spine. No adverse effect on graft function was noted, although biochemical exacerbation of secondary hyperparathyroidism was documented. [67]

To date, limited data suggest that pretransplant treatment with bisphosphonates decreases posttransplant fracture risk. If administered prior to liver transplant, intravenous pamidronate prevents osteoporotic vertebral collapse. [111] Similarly, a prospective, uncontrolled pilot study using intravenous pamidronate in lung transplant recipients decreased the fracture rate and preserved bone mass at 1-year posttransplantation. The authors urged that bisphosphonate therapy be started before transplant surgery is contemplated. [112]

A study of bisphosphonate therapy administered to kidney transplant patients after the first posttransplant year found significant bone preservation in the femoral neck in the bisphosphonate group but nonetheless saw no correlation between bone loss at the femoral neck and fracture rates in the study's patients, whether or not they had undergone bisphosphonate therapy. [113] The study's patients, who were retrospectively assessed, underwent BMD measurements approximately 1 year after transplantation and again about 2.5 years after that, with 315 patients receiving bisphosphonate during that interval and 239 receiving no bisphosphonate.

A meta-analysis by Zhao et al found that vertebral BMD in post-cardiac transplant patients treated with bisphosphonates was approximately 0.06 g/cm2 higher than in the control group. [114]

Transdermal estrogen therapy provides protection against osteoporosis in postmenopausal women with liver transplants, as it does in healthy postmenopausal women. [115] Estrogen is also known to improve BMD in women receiving glucocorticoids and to prevent CsA-mediated bone loss in animals.

If estrogen is prescribed together with progesterone, fixed daily doses are preferred over cyclic regimens because estrogen can enhance the hepatic metabolism of cyclosporine, resulting in erratic blood levels. Estrogen alone is probably insufficient to prevent transplant-induced bone loss, particularly in the first year following transplantation. [116]

The National Kidney Foundation (K/DOQI) recommends that if a patient has a BMD t-score of –2 or lower at the time of transplantation or at subsequent evaluations, therapy with a parenteral amino-bisphosphonate should be considered. [85] There remain significant concerns for the use of bisphosphonates in renal patients with preexisting low bone turnover disease, wherein bisphosphonates could further slow bone turnover and potentially increase fracture rate. [98]

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