Efficacy of Bisphosphonate for Urolithiasis Complicated by Osteogenesis Imperfecta

Abstract

A 44-year-old man with osteogenesis imperfecta presented with left renal colic. Non-contrast computed tomography revealed a stone (10×9 mm) in the left upper ureter. Ureteroscopic lithotripsy was performed twice and stone-free status was achieved. An analysis of the stone revealed a mixed composition including calcium oxalate and calcium phosphate. Postoperatively, we administered bisphosphonates to prevent recurrence of urolithiasis, as 24-hour urine collection revealed marked hypercalciuria. Eighteen months after surgery, the urinary calcium levels had normalized, and there was no recurrence of urolithiasis. Osteogenesis imperfecta can be complicated by urolithiasis, but bisphosphonates may be useful in preventing recurrence of this disease.

Introduction

Osteogenesis imperfecta (OI) is a congenitally-inherited disease caused by qualitative and quantitative abnormalities in the biosynthesis of type I collagen, a bone matrix (1). The Sillence classification is widely used as an indicator of the severity of OI and is classified into type I (mildest form), type II (lethal in perinatal period), type III (most severe survival form), and type IV (moderate severity) (2). Clinical manifestations include various extraskeletal symptoms, such as blue sclera, abnormal dentition, sensorineural deafness, and joint skin hyperextension, with the main symptom being decreased bone strength. More rarely, urolithiasis may be seen.

Surgical treatment for urolithiasis complicated by OI should be avoided when possible due to the high risk associated with general anesthesia (3) and surgical difficulty, so the thorough prevention of recurrence of urolithiasis is essential.

We herein report what is, to our knowledge, the first reported case in which bisphosphonates proved effective in preventing the recurrence of urolithiasis complicated by OI.

Case Report

A 44-year-old man with OI (Sillence classification type III) presented with left renal colic and a fever (37.5°C). Non-contrast computed tomography revealed a stone (10×9 mm, 1,067 Hounsfield units) in the left upper ureter (Fig. 1). Due to growth failure associated with OI, the patient was 96 cm tall, weighed 25 kg, and had prominent scoliosis and contractures of the lower limb (Fig. 2).

Figure 1.

Plain radiography of the kidneys, ureter, and bladder findings. A ureteral stone was found in the left upper ureter. This image also shows prominent scoliosis and contractures of the lower limbs.

Figure 2.

Non-contrast computed tomography. A stone (10×9 mm, 1,067 Hounsfield units) in the left upper ureter (arrow). (A) Axial image, (B) coronal image.

Dual-energy X-ray absorptiometry revealed a low bone mineral density (0.204 g/cm²), equivalent to 20% of young adult mean for the femur. He had undergone shock wave lithotripsy for ureteral stones twice within the last 3 years and been taking sodium potassium citrate (3 g/day) orally since then. Blood test results were as follows: serum creatinine 0.6 mg/dL, C-reactive protein 1.57 mg/dL, calcium 9.7 mg/dL, phosphorus 3.6 mg/dL, intact parathyroid hormone 18.1 pg/mL, and leukocyte count 10,960 /μl. Urinalysis results were as follows: urine pH 7.0, red blood cells >100 /high-power field, and white blood cells 10-20 /high-power field.

Obstructive pyelonephritis was diagnosed due to a left ureteral stone, and the patient was treated with a ureteral stent and antibacterial therapy (tazobactam piperacillin hydrate 4.5 g×3/day). Subsequently, ureteroscopic lithotripsy (URSL) was performed for a left ureteral stone under general anesthesia. There was difficulty in approaching the stone due to contractures of the lower limbs and tortuous ureter, but a stone-free status was achieved after two URSL procedures. An analysis of the stone revealed a mixed composition with calcium oxalate and calcium phosphate. Postoperatively, 24-hour urine revealed hypocitraturia and marked hypercalciuria, but other parameters were normal (Table). We therefore newly administered bisphosphonates (alendronate 35 mg/week) in addition to sodium potassium citrate to decrease the urinary calcium level and prevent the recurrence of urolithiasis.

Table.

Changes in the 24-hour Urine Collection Results after Administration of Bisphosphonates.

Parameter		Normal range (for men)		Before administration		3 months after administration		15 months after administration
Creatinine		20-25 mg/kg		16.1		18.8		15.5
Oxalate		<45 mg/day		15.3		19.4		17.0
Uric acid		<800 mg/day		306		416		283
Calcium		<4.0 mg/kg/day		7.2		8.6		3.7
Citrate		>320 mg/day		312		243		630
Sodium		170-340 mEq/day		123		144		132

Eighteen months after surgery, the urinary calcium and citrate levels had normalized (Table), and there was no recurrence of urolithiasis.

Discussion

In the present case, the recurrence of urolithiasis associated with OI was able to be prevented by administering a bisphosphonate. We highlight two clinical matters of note: OI can be complicated by urolithiasis, which is not infrequent, and bisphosphonates may be useful for preventing the recurrence of this disease.

One clinical matter is that OI can be complicated by urolithiasis. To our knowledge, only three cases, including ours, have been featured within case reports (4,5), but eight of 58 patients with OI (13%) were reported to have complications of urolithiasis, suggesting that it is not a very rare comorbidity (6). OI is known to present with hypercalciuria, which is a cause of urolithiasis (calcium-based kidney stones). Pathophysiologically, bone formation is reduced and bone resorption exceeds bone formation because of the impaired biosynthesis of type I collagen, the bone matrix. Calcium resorption from bone is then accelerated, leading to hypercalciuria. In addition, urinary excretion of calcium reportedly correlates with the clinical severity of the disorder, and hypercalciuria has been shown to be more frequent in patients with Sillence classification types II and III thanI (7). Most patients with OI with urolithiasis were classified as Sillence classification type III (4,5,7), supporting the notion that hypercalciuria is a contributing factor to urolithiasis. Given the above, we concluded that it is important to investigate the presence of hypercalciuria by 24-hour urine collection, and if hypercalciuria is found, attention should be paid to the complications of urolithiasis in patients with OI.

A second clinical matter is that bisphosphonates may be useful for preventing the recurrence of this disease. Bisphosphonate is a carbon-substituted pyrophosphate analog that inhibits bone resorption (8). It is used for patients with a low bone density to prevent fractures associated with osteopenia and osteoporosis. Osteoporosis is caused by bone resorption exceeds bone formation due to aging, menopause (estrogen depression), and lifestyle diseases, resulting in decreased bone mass and increased urinary excretion of calcium. Bisphosphonates inhibit bone resorption by blocking osteoclasts, thereby preventing decreased bone mass and increased urinary excretion of calcium. Osteoporosis has been previously reported to be associated with urolithiasis, and bisphosphonates may reduce the risk of urolithiasis in patients with osteoporosis by decreasing urinary excretion of calcium (8,9). Conversely, in OI, bone resorption relatively exceeds bone formation due to impaired biosynthesis of type I collagen, a bone matrix, resulting in decreased bone mass and increased urinary excretion of calcium. The etiology of hypercalciuria in these two diseases is similar in that bone resorption exceeds bone formation. There have been no previous reports on the usefulness of bisphosphonates in preventing the recurrence of urolithiasis complicated by OI, but we hypothesized that their effectiveness could be expected because of the similarity of the etiology of hypercalciuria to that of osteoporosis.

As a supplementary note, citrate has already been shown to be effective in preventing recurrence of calcium stones (10). Citric acid binds to calcium in urine and reduces the ion activity product of calcium oxalate and calcium phosphate, thereby inhibiting stone formation (11). However, in the present case, the patient had been taking sodium potassium citrate after the initial treatment, but the effect was poor, leading to recurrence. We believe that when a patient has underlying diseases with hypercalciuria, such as OI, citrate alone might not be effective in preventing recurrence, as it does not improve the actual disease that causes hypercalciuria.

Several limitations associated with the present study warrant mention. First, it focuses on a single case, so there is insufficient evidence to demonstrate the efficacy of bisphosphonates in preventing recurrent urolithiasis complicated by OI. Second, bone formation and resorption markers are important to consider in order to understand the bone metabolic status in patients with OI, but in the present case, these were not measured. Finally, there is no fixed opinion concerning the appropriate duration of administration of bisphosphonates to prevent urolithiasis complicated by OI. While long-term administration of bisphosphonates increases the risk of adverse events, such as osteonecrosis of the jaw, urinary calcium excretion may be increased if bisphosphonates are withdrawn. Since the optimal duration of administering bisphosphonates has not yet been established, a decision must be made on whether to withdraw or continue treatment while considering the risk-benefit of bisphosphonates.

In conclusion, OI can be complicated by urolithiasis, and bisphosphonates may be useful in preventing recurrence of this disease. To prevent recurrence of urolithiasis complicated by OI, it is very helpful to perform 24-hour urine collection. Further studies will be needed to confirm the efficacy of bisphosphonates in preventing recurrence.

notes

Written informed consent to publish this case report including the clinical details and clinical images was obtained from the patient himself. A copy of the written consent form is available for review upon reasonable request.

The authors state that they have no Conflict of Interest (COI).