Denosumab in Patients With Fibrous Dysplasia

In This Article

Abstract and Introduction

Abstract

Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete.

Objective: To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy.

Design: Case series.

Setting: Academic center of expertise for rare bone diseases.

Patients: Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months.

Main outcome(s): Sustained reduction of BTMs and bone pain.

Results: A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated.

Conclusion: Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

Introduction

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder characterized by replacement of bone by highly vascularized fibrous tissue in one (monostotic) or more skeletal sites (polyostotic) that may be associated with skeletal morbidity.^[1,2] The disorder is caused by postzygotic, somatic activating mutations of GNAS leading to overproduction of cAMP and abnormal cellular responses, such as increased production of the bone resorbing factors IL-6 and receptor activator of nuclear factor-κB ligand (RANKL).^[3–5] Extraskeletal distribution of the GNAS mutation may be associated with manifestations in other tissues, particularly endocrine glands, such as endocrinopathies and café-au-lait skin patches in MAS and therefore the disease is referred to as FD/MAS.^[6]

Although there is as yet no approved medical treatment of FD/MAS, several studies have reported clinical and biochemical improvement in patients treated with different bisphosphonate regimens.^[7–14] However, response to bisphosphonates may be inadequate in decreasing pain symptoms, particularly in patients with polyostotic disease and high skeletal burden.^[12,13] Recent case reports suggest successful response to treatment of patients with FD/MAS with the RANKL inhibitor, denosumab.^[15–18] In this case series we report the clinical and biochemical outcomes of treatment of 12 patients with bisphosphonate-refractory FD/MAS treated consecutively with denosumab.

Table 1. Characteristics of Patients With FD/MAS
Patient No.	Sex/Age	FD Type	SBS	FGF-23, pg/mL	ALP, IU/L	P1NP, ng/mL	CTX, pg/mL	Dmab Duration, mo	Duration BP Use, y	Months Between Stop BP and Start Dmab, mo
1	F/41	PFD	0.3	116	75	73	241	22	2.5	0.8
2	F/35	PFD	0.6	71	94	80	114	18	4.7	0.3
3	F/68	PFD	5.6	159	198	864	403	15	0.7	0
4	M/28	PFD	7.8	115	275	273	443	14	5.0	99.2
5	F/28	MFD	13.8	202	135	109	166	18	8.6	34.4
6	F/36	PFD	16.7	133	183	290	347	17	1.7	0.4
7	F/33	PFD	25.0	160	538	1235	600	30	11.8	6.4
8	M/52	PFD	25.0	133	330	354	548	15	9.5	4.2
9	M/33	MAS	31.3	173	144	124	604	16	11.8	103.5
10	F/46	MAS	38.7	162	203	208	148	13	18.5	4.2
11	F/41	MAS	44.0	161	161	198	333	15	22.1	4.1
12	F/50	MAS	64.7	273	503	812	999	23	8.9	8.8

Reference ranges: FGF-23 0–125 pg/mL, ALP 40–98 IU/L, P1NP <59 ng/mL, CTX <573 pg/mL.
Abbreviations: BP, bisphosphonate; Dmab, denosumab MFD, monostotic FD; PFD, polyostotic.

Table 2. Bisphosphonates Prior to Treatment With Denosumab
Patient No.	Duration BP Use, y	Time Between Stop BP and Start Denosumab, mo	Cumulative Dose of BP
1	2.5	0.8	Pamidronate 122 mg IV, olpadronate 80 mg IV and 255.00 mg oral
2	4.7	0.3	Zoledronate 4 mg IV and olpadronate 169.500 mg oral
3	0.7	0	Alendronate 3.600 mg oral and olpadronate 60 mg IV
4	5.0	99.2	Pamidronate 42 mg IV
5	8.6	34.4	Olpadronate 120 mg IV and 166.500 mg oral
6	1.7	0.4	Olpadronate 68 mg IV and 146.000 mg oral
7	11.8	6.4	Olpadronate 124 mg IV and 219.000 mg oral and zoledronate 10 mg IV
8	9.5	4.2	Alendronate 900 mg oral, risedronate 900 mg oral, zoledronate 28 mg IV, and olpadronate 24 mg IV
9	11.8	103.5	Olpadronate 20 mg IV and 328.500 mg oral
10	18.5	4.2	Alendronate 105.00 mg oral, risedronate 4.200 mg oral, zoledronate 4 mg IV, pamidronate 20 mg IV, olpadronate 116 mg IV and 629.750 mg oral
11	22.1	4.1	Olpadronate 764 mg IV and 144.000 mg oral
12	8.9	8.8	Olpadronate 720 mg IV and 365.000 mg oral

Data on treatment with bisphosphonates prior to start of denosuman injections.
Olpadronate was given orally (range, 50–200 mg daily) or IV (range, 4–8 mg for 3–5 consecutive d at 3-mo to 6-mo intervals). Risendronate was given orally (range, 10–30 mg daily), alendronate was given orally (70 mg weekly), pamidronate was given IV (30 mg for 3 consecutive d in 3-mo cycles), Zoledronate was given IV (6–12 mo cycles of single infusions with 4 mg).
Abbreviation: BP, bisphosphonate.

Table 3. Results From Linear Mixed Model Analysis After 9 Months of Treatment With Denosumab
BTM	Subtype	Time	Mean	95% CI	Significance
ALP	Polyostotic	T1	228.5	130–327	P = 0.083
		T2	172.6	73–272
		T3	138.0	40–236
	MAS	T1	252.8	113–392
		T2	95.7	−48–237
		T3	167.8	28 −307
P1NP	Polyostotic	T1	409.8	138–682	P = 0.110
		T2	380.0	103–657
		T3	230.6	−46–507
	MAS	T1	335.5	−50–721
		T2	42.0	−343− 427
		T3	223.0	−162 −608
CTX	Polyostotic	T1	357	143 −572	P = 0.010
		T2	511	287–736
		T3	292	67 −516
	MAS	T1	521	217 −825
		T2	129	−206 −464
		T3	603	300 −907

No statistically significant differences in serum ALP and P1NP values between patients with polyostotic FD and patients with MAS are shown. Serum CTX values differed significantly between patients with MAS and polyostotic FD, although these values should be interpreted with care, because blood samples for serum CTX levels was collected in the nonfasting state.

Table 4. Results From Linear Mixed Model: 3-Month vs 6-Month Doses
BTM	Doses	Time	Mean	95% CI	Significance
ALP	3-mo	T1	270.7	163 −378	0.007
		T2	173.5	66 −281
		T3	118.5	11 −226
	6–mo	T1	202.5	95 −310
		T2	116.7	6 −228
		T3	177.3	70–285
P1NP	3-mo	T1	450.3	144 −757	0.025
		T2	319.7	13 −626
		T3	91.4	−222–404
	6–mo	T1	319.7	13–626
		T2	175.1	−149 −499
		T3	342.7	36 −649
CTX	3-mo	T1	484	238 −731	0.162
		T2	555	308– 801
		T3	375	106 −643
	6-mo	T1	339	93– 586
		T2	129	−170 −428
		T3	431	185– 678

A statistically significant difference over time for ALP and P1NP between patients who received denosumab at 3-mo intervals compared with those with 6-mo intervals is shown.
Reference ranges: ALP 40–98 IU/L, P1NP <59 ng/mL, CTX <573 pg/mL.